Our Collaboratory Fellows have published papers on a variety of research topics, stemming from Collaboratory-supported collaborations across campus.
Find us on Google Scholar: https://scholar.google.com/citations?user=XN6DdggAAAAJ&hl=en
1.
Valentina Poli Francesco Borriello, Ellen Shrock
An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity Bachelor Thesis
2022, ISBN: 0092-8674.
@bachelorthesis{Borriello2022Modulation,
title = {An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity},
author = {Francesco Borriello, Valentina Poli, Ellen Shrock, Roberto Spreafico, Xin Liu, Novalia Pishesha, Claire Carpenet, Janet Chou, Marco Di Gioia, Marisa E. McGrath, Carly A. Dillen, Nora A. Barrett, Lucrezia Lacanfora, Marcella E. Franco, Laura Marongiu, Yoichiro Iwakura, Ferdinando Pucci, Michael D. Kruppa, Zuchao Ma, Douglas W. Lowman, Harry E. Ensley, Etsuro Nanishi, Yoshine Saito, Timothy R. O’Meara, Hyuk-Soo Seo, Sirano Dhe-Paganon, David J. Dowling, Matthew Frieman, Stephen J. Elledge, Ofer Levy, Darrell J. Irvine, Hidde L. Ploegh, David L. Williams, Ivan Zanoni,},
doi = {https://doi.org/10.1016/j.cell.2022.01.009},
isbn = {0092-8674},
year = {2022},
date = {2022-02-17},
journal = {Cell},
volume = {185},
number = {4},
pages = {614-629},
abstract = {Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.
2.
Eric Y. Lin Paul C Adamson, Sung-Min Ha
Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance Journal Article
In: Journal of Antimicrobial Chemotherapy, (dkab262), 2021.
@article{Adamson2021Neisseria,
title = {Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance },
author = { Paul C Adamson, Eric Y. Lin, Sung-Min Ha, Jeffrey D. Klausner,},
doi = {https://doi.org/10.1093/jac/dkab262},
year = {2021},
date = {2021-07-29},
journal = {Journal of Antimicrobial Chemotherapy},
number = {dkab262},
abstract = {Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.
3.
Eric Y Lin Paul C Adamson, Sung-Min Ha
Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance Bachelor Thesis
2021.
@bachelorthesis{nokey,
title = {Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance },
author = {Paul C Adamson, Eric Y Lin, Sung-Min Ha, Jeffrey D Klausner},
doi = {https://doi.org/10.1093/jac/dkab262},
year = {2021},
date = {2021-07-29},
journal = {Journal of Antimicrobial Chemotherapy},
volume = {76},
number = {11},
pages = {2847-2849},
abstract = {Background
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.
Objectives
To determine the prevalence of three amino acid mutations associated with zoliflodacin resistance within a large, public database of nearly 13 000 N. gonorrhoeae genomes.
Methods
PathogenWatch is an online genomic epidemiology platform with a public database of N. gonorrhoeae genomes. That database was used to extract gyrB sequence data and a Basic Local Alignment Search Tool (BLAST) search was performed to identify any of the three amino acid mutations in GyrB that are associated with increased zoliflodacin MICs: D429N, K450N or K450T. As a control for the search methodology, all GyrA sequences were also extracted and S91F mutations were identified and compared with the PathogenWatch database.
Results
In total, 12 493 N. gonorrhoeae genomes from the PathogenWatch database were included. Among those genomes, none was identified that harboured any of the three mutations associated with increased zoliflodacin MICs. One genome was identified to have a mutation at position 429 in GyrB (D429V).
Conclusions
The findings suggest that the prevalence of the three mutations associated with zoliflodacin resistance in N. gonorrhoeae is very low. However, further research into the mechanisms of zoliflodacin resistance in N. gonorrhoeae is needed. Genomic epidemiology platforms like PathogenWatch can be used to enhance the global surveillance of AMR.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Background
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.
Objectives
To determine the prevalence of three amino acid mutations associated with zoliflodacin resistance within a large, public database of nearly 13 000 N. gonorrhoeae genomes.
Methods
PathogenWatch is an online genomic epidemiology platform with a public database of N. gonorrhoeae genomes. That database was used to extract gyrB sequence data and a Basic Local Alignment Search Tool (BLAST) search was performed to identify any of the three amino acid mutations in GyrB that are associated with increased zoliflodacin MICs: D429N, K450N or K450T. As a control for the search methodology, all GyrA sequences were also extracted and S91F mutations were identified and compared with the PathogenWatch database.
Results
In total, 12 493 N. gonorrhoeae genomes from the PathogenWatch database were included. Among those genomes, none was identified that harboured any of the three mutations associated with increased zoliflodacin MICs. One genome was identified to have a mutation at position 429 in GyrB (D429V).
Conclusions
The findings suggest that the prevalence of the three mutations associated with zoliflodacin resistance in N. gonorrhoeae is very low. However, further research into the mechanisms of zoliflodacin resistance in N. gonorrhoeae is needed. Genomic epidemiology platforms like PathogenWatch can be used to enhance the global surveillance of AMR.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.
Objectives
To determine the prevalence of three amino acid mutations associated with zoliflodacin resistance within a large, public database of nearly 13 000 N. gonorrhoeae genomes.
Methods
PathogenWatch is an online genomic epidemiology platform with a public database of N. gonorrhoeae genomes. That database was used to extract gyrB sequence data and a Basic Local Alignment Search Tool (BLAST) search was performed to identify any of the three amino acid mutations in GyrB that are associated with increased zoliflodacin MICs: D429N, K450N or K450T. As a control for the search methodology, all GyrA sequences were also extracted and S91F mutations were identified and compared with the PathogenWatch database.
Results
In total, 12 493 N. gonorrhoeae genomes from the PathogenWatch database were included. Among those genomes, none was identified that harboured any of the three mutations associated with increased zoliflodacin MICs. One genome was identified to have a mutation at position 429 in GyrB (D429V).
Conclusions
The findings suggest that the prevalence of the three mutations associated with zoliflodacin resistance in N. gonorrhoeae is very low. However, further research into the mechanisms of zoliflodacin resistance in N. gonorrhoeae is needed. Genomic epidemiology platforms like PathogenWatch can be used to enhance the global surveillance of AMR.
4.
D. A. Vaughn, Maggiora
Modulation of attention and stress with arousal: The mental and physical effects of riding a motorcycle Journal Article
In: Brain Research, 1752 (147203), 2021.
@article{Vaugh2001Modulation,
title = {Modulation of attention and stress with arousal: The mental and physical effects of riding a motorcycle},
author = {Vaughn, D. A., Maggiora, M. B., Vaughn, K. J., Maggiora, C. J., Tavakoli, A.-V., Liang, W., Zava, D., Cohen, M. S., & Lenartowicz, A. },
doi = {https://doi.org/10.1016/j.brainres.2020.147203},
year = {2021},
date = {2021-02-01},
journal = {Brain Research},
volume = {1752},
number = {147203},
abstract = {Existing theories suggest that moderate arousal improves selective attention, as would be expected in the context of competitive sports or sensation-seeking activities. Here we investigated how riding a motorcycle, an attention-demanding physical activity, affects sensory processing. To do so, we implemented the passive auditory oddball paradigm and measured the EEG response of participants as they rode a motorcycle, drove a car, and sat at rest. Specifically, we measured the N1 and mismatch negativity to auditory tones, as well as alpha power during periods of no tones. We investigated whether riding and driving modulated non-CNS metrics including heart rate and concentrations of the hormones epinephrine, cortisol, DHEA-S, and testosterone. While participants were riding, we found a decrease in N1 amplitude, increase in mismatch negativity, and decrease in relative alpha power, together suggesting enhancement of sensory processing and visual attention. Riding increased epinephrine levels, increased heart rate, and decreased the ratio of cortisol to DHEA-S. Together, these results suggest that riding increases focus, heightens the brain’s passive monitoring of changes in the sensory environment, and alters HPA axis response. More generally, our findings suggest that selective attention and sensory monitoring seem to be separable neural processes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Existing theories suggest that moderate arousal improves selective attention, as would be expected in the context of competitive sports or sensation-seeking activities. Here we investigated how riding a motorcycle, an attention-demanding physical activity, affects sensory processing. To do so, we implemented the passive auditory oddball paradigm and measured the EEG response of participants as they rode a motorcycle, drove a car, and sat at rest. Specifically, we measured the N1 and mismatch negativity to auditory tones, as well as alpha power during periods of no tones. We investigated whether riding and driving modulated non-CNS metrics including heart rate and concentrations of the hormones epinephrine, cortisol, DHEA-S, and testosterone. While participants were riding, we found a decrease in N1 amplitude, increase in mismatch negativity, and decrease in relative alpha power, together suggesting enhancement of sensory processing and visual attention. Riding increased epinephrine levels, increased heart rate, and decreased the ratio of cortisol to DHEA-S. Together, these results suggest that riding increases focus, heightens the brain’s passive monitoring of changes in the sensory environment, and alters HPA axis response. More generally, our findings suggest that selective attention and sensory monitoring seem to be separable neural processes.
5.
Perri, Angela R; Mitchell, Kieren J.; Mouton, Alice and
Dire wolves were the last of an ancient New World canid lineage Journal Article
In: Nature, 2021.
@article{Perri2021Wolves,
title = {Dire wolves were the last of an ancient New World canid lineage},
author = {Perri, Angela R and Mitchell, Kieren J. and Mouton, Alice and et al. },
doi = {https://doi.org/10.1038/s41586-020-03082-x},
year = {2021},
date = {2021-01-13},
journal = {Nature},
abstract = {Dire wolves are considered to be one of the most common and widespread large carnivores in Pleistocene America1, yet relatively little is known about their evolution or extinction. Here, to reconstruct the evolutionary history of dire wolves, we sequenced five genomes from sub-fossil remains dating from 13,000 to more than 50,000 years ago. Our results indicate that although they were similar morphologically to the extant grey wolf, dire wolves were a highly divergent lineage that split from living canids around 5.7 million years ago. In contrast to numerous examples of hybridization across Canidae2,3, there is no evidence for gene flow between dire wolves and either North American grey wolves or coyotes. This suggests that dire wolves evolved in isolation from the Pleistocene ancestors of these species. Our results also support an early New World origin of dire wolves, while the ancestors of grey wolves, coyotes and dholes evolved in Eurasia and colonized North America only relatively recently.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dire wolves are considered to be one of the most common and widespread large carnivores in Pleistocene America1, yet relatively little is known about their evolution or extinction. Here, to reconstruct the evolutionary history of dire wolves, we sequenced five genomes from sub-fossil remains dating from 13,000 to more than 50,000 years ago. Our results indicate that although they were similar morphologically to the extant grey wolf, dire wolves were a highly divergent lineage that split from living canids around 5.7 million years ago. In contrast to numerous examples of hybridization across Canidae2,3, there is no evidence for gene flow between dire wolves and either North American grey wolves or coyotes. This suggests that dire wolves evolved in isolation from the Pleistocene ancestors of these species. Our results also support an early New World origin of dire wolves, while the ancestors of grey wolves, coyotes and dholes evolved in Eurasia and colonized North America only relatively recently.
6.
Miikeda A Zhang W, Zuckerman J
Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice. Bachelor Thesis
2021.
@bachelorthesis{Zhang2001Inhibition,
title = {Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice. },
author = {Zhang W, Miikeda A, Zuckerman J, Jia X, Charugundla S, Zhou Z, Kaczor-Urbanowicz KE, Magyar C, Guo F, Wang Z, Pellegrini M, Hazen SL, Nicholas SB, Lusis AJ, Shih DM},
doi = {doi: 10.1038/s41598-020-80063-0.},
year = {2021},
date = {2021-01-12},
urldate = {2021-01-12},
journal = {Scientific Reports},
volume = {11},
number = {518},
abstract = {Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.
7.
K. E. Kaczor-Urbanowicz, Cheng
Reviews on Current Liquid Biopsy for Detection and Management of Pancreatic Cancers Bachelor Thesis
2020.
@bachelorthesis{Kaczor-Urbanowicz2020Liquid,
title = {Reviews on Current Liquid Biopsy for Detection and Management of Pancreatic Cancers},
author = {Kaczor-Urbanowicz, K. E., Cheng, J., King, J. C., Sedarat, A., Pandol, S. J., Farrell, J. J., Wong, D., & Kim, Y. },
doi = {DOI: 10.1097/MPA.0000000000001662},
year = {2020},
date = {2020-10-01},
journal = {Pancreas},
volume = {49},
number = {9},
pages = {1141-1152},
abstract = {Pancreatic cancer is the fourth leading cause of cancer death in the United States. Pancreatic cancer presents dismal clinical outcomes in patients, and the incidence of pancreatic cancer has continuously increased to likely become the second most common cause of cancer-related deaths by as early as 2030. One of main reasons for the high mortality rate of pancreatic cancer is the lack of tools for early-stage detection. Current practice in detecting and monitoring therapeutic response in pancreatic cancer relies on imaging analysis and invasive endoscopic examination. Liquid biopsy-based analysis of genetic alterations in biofluids has become a fundamental component in the diagnosis and management of cancers. There is an urgent need for scientific and technological advancement to detect pancreatic cancer early and to develop effective therapies. The development of a highly sensitive and specific liquid biopsy tool will require extensive understanding on the characteristics of circulating tumor DNA in biofluids. Here, we have reviewed the current status of liquid biopsy in detecting and monitoring pancreatic cancers and our understanding of circulating tumor DNA that should be considered for the development of a liquid biopsy tool, which will greatly aid in the diagnosis and healthcare of people at risk.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Pancreatic cancer is the fourth leading cause of cancer death in the United States. Pancreatic cancer presents dismal clinical outcomes in patients, and the incidence of pancreatic cancer has continuously increased to likely become the second most common cause of cancer-related deaths by as early as 2030. One of main reasons for the high mortality rate of pancreatic cancer is the lack of tools for early-stage detection. Current practice in detecting and monitoring therapeutic response in pancreatic cancer relies on imaging analysis and invasive endoscopic examination. Liquid biopsy-based analysis of genetic alterations in biofluids has become a fundamental component in the diagnosis and management of cancers. There is an urgent need for scientific and technological advancement to detect pancreatic cancer early and to develop effective therapies. The development of a highly sensitive and specific liquid biopsy tool will require extensive understanding on the characteristics of circulating tumor DNA in biofluids. Here, we have reviewed the current status of liquid biopsy in detecting and monitoring pancreatic cancers and our understanding of circulating tumor DNA that should be considered for the development of a liquid biopsy tool, which will greatly aid in the diagnosis and healthcare of people at risk.
8.
D. A. Covino, Kaczor-Urbanowicz
2020.
@bachelorthesis{Covino2020Transcriptome,
title = {Transcriptome Profiling of Human Monocyte-Derived Macrophages Upon CCL2 Neutralization Reveals an Association Between Activation of Innate Immune Pathways and Restriction of HIV-1 Gene Expression},
author = {Covino, D. A., Kaczor-Urbanowicz, K. E., Lu, J., Chiantore, M. V., Fiorucci, G., Vescio, M. F., Catapano, L., Purificato, C., Galluzzo, C. M., Amici, R., Andreotti, M., Gauzzi, M. C., Pellegrini, M., & Fantuzzi, L.},
doi = { DOI: 10.3389/fimmu.2020.02129},
year = {2020},
date = {2020-09-18},
journal = {Frontiers in immunology},
volume = {11},
pages = {2129},
abstract = {Macrophages are key targets of human immunodeficiency virus type 1 (HIV-1) infection and main producers of the proinflammatory chemokine CC chemokine ligand 2 (CCL2), whose expression is induced by HIV-1 both in vitro and in vivo. We previously found that CCL2 neutralization in monocyte-derived macrophages (MDMs) strongly inhibited HIV-1 replication affecting post-entry steps of the viral life cycle. Here, we used RNA-sequencing to deeply characterize the cellular factors and pathways modulated by CCL2 blocking in MDMs and involved in HIV-1 replication restriction. We report that exposure to CCL2 neutralizing antibody profoundly affected the MDM transcriptome. Functional annotation clustering of up-regulated genes identified two clusters enriched for antiviral defense and immune response pathways, comprising several interferon-stimulated, and restriction factor coding genes. Transcripts in the clusters were enriched for RELA and NFKB1 targets, suggesting the activation of the canonical nuclear factor κB pathway as part of a regulatory network involving miR-155 up-regulation. Furthermore, while HIV-1 infection caused small changes to the MDM transcriptome, with no evidence of host defense gene expression and type I interferon signature, CCL2 blocking enabled the activation of a strong host innate response in infected macrophage cultures, and potently inhibited viral genes expression. Notably, an inverse correlation was found between levels of viral transcripts and of the restriction factors APOBEC3A (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 A), ISG15, and MX1. These findings highlight an association between activation of innate immune pathways and HIV-1 restriction upon CCL2 blocking and identify this chemokine as an endogenous factor contributing to the defective macrophage response to HIV-1. Therapeutic targeting of CCL2 may thus strengthen host innate immunity and restrict HIV-1 replication.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Macrophages are key targets of human immunodeficiency virus type 1 (HIV-1) infection and main producers of the proinflammatory chemokine CC chemokine ligand 2 (CCL2), whose expression is induced by HIV-1 both in vitro and in vivo. We previously found that CCL2 neutralization in monocyte-derived macrophages (MDMs) strongly inhibited HIV-1 replication affecting post-entry steps of the viral life cycle. Here, we used RNA-sequencing to deeply characterize the cellular factors and pathways modulated by CCL2 blocking in MDMs and involved in HIV-1 replication restriction. We report that exposure to CCL2 neutralizing antibody profoundly affected the MDM transcriptome. Functional annotation clustering of up-regulated genes identified two clusters enriched for antiviral defense and immune response pathways, comprising several interferon-stimulated, and restriction factor coding genes. Transcripts in the clusters were enriched for RELA and NFKB1 targets, suggesting the activation of the canonical nuclear factor κB pathway as part of a regulatory network involving miR-155 up-regulation. Furthermore, while HIV-1 infection caused small changes to the MDM transcriptome, with no evidence of host defense gene expression and type I interferon signature, CCL2 blocking enabled the activation of a strong host innate response in infected macrophage cultures, and potently inhibited viral genes expression. Notably, an inverse correlation was found between levels of viral transcripts and of the restriction factors APOBEC3A (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 A), ISG15, and MX1. These findings highlight an association between activation of innate immune pathways and HIV-1 restriction upon CCL2 blocking and identify this chemokine as an endogenous factor contributing to the defective macrophage response to HIV-1. Therapeutic targeting of CCL2 may thus strengthen host innate immunity and restrict HIV-1 replication.
9.
M. Mediouni, Madiouni
COVID-19: How the quarantine could lead to the depreobesity Bachelor Thesis
2020.
@bachelorthesis{covid-19MediouniQuarantine,
title = {COVID-19: How the quarantine could lead to the depreobesity},
author = {Mediouni, M., Madiouni, R., & Kaczor-Urbanowicz, K. E.},
doi = { DOI: 10.1016/j.obmed.2020.100255},
year = {2020},
date = {2020-09-01},
journal = {Obesity medicine},
volume = {19},
number = {100255},
abstract = {In this paper, we will introduce coronavirus (COVID-19) and how it spreads around the globe. We will also present the term of quarantine and associated with it requirement of locking down at home in some countries. We will study how frustration related to quarantine relates to several psychological problems including depression. This environment pushes people to consume high sugar foods that increase obesity. In conclusion, countries should be prepared for the upcoming epidemic (depreobesity).},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
In this paper, we will introduce coronavirus (COVID-19) and how it spreads around the globe. We will also present the term of quarantine and associated with it requirement of locking down at home in some countries. We will study how frustration related to quarantine relates to several psychological problems including depression. This environment pushes people to consume high sugar foods that increase obesity. In conclusion, countries should be prepared for the upcoming epidemic (depreobesity).
10.
Karolina Elżbieta Kaczor-Urbanowicz Mohamed Mediouni, Riadh Madiouni
Future epidemic: Depreobesity Bachelor Thesis
2020.
@bachelorthesis{Future2020Mediouni,
title = {Future epidemic: Depreobesity},
author = {Mohamed Mediouni, Karolina Elżbieta Kaczor-Urbanowicz, Riadh Madiouni,},
doi = {https://doi.org/10.1016/j.obmed.2020.100240},
year = {2020},
date = {2020-09-01},
journal = {Obesity Medicine},
volume = {19},
number = {100240},
abstract = {Obesity and depression are both global health problems that have a major impact on human life and are costly to health services. Both of them have a substantial health impact including long-term complications, reduction in health-related functioning, reduction of quality of life and reduced overall life expectancy. In this article, we propose ‘‘depreobesity’’ as a modern epidemic, which indicates the coexistence of both depression and obesity. It is thus urgent to understand and manage this concept to optimize public health and medical intervention planning.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Obesity and depression are both global health problems that have a major impact on human life and are costly to health services. Both of them have a substantial health impact including long-term complications, reduction in health-related functioning, reduction of quality of life and reduced overall life expectancy. In this article, we propose ‘‘depreobesity’’ as a modern epidemic, which indicates the coexistence of both depression and obesity. It is thus urgent to understand and manage this concept to optimize public health and medical intervention planning.
11.
Leandro Bueno Bergantin Mohamed Mediouni, Riadh Madiouni
Can we represent the depreobesity genetically? Bachelor Thesis
2020, ISBN: 2451-8476.
@bachelorthesis{Mediouni2020Depreobesity,
title = {Can we represent the depreobesity genetically?},
author = {Mohamed Mediouni, Leandro Bueno Bergantin, Riadh Madiouni, Karolina Elżbieta Kaczor-Urbanowicz, Andrzej Urbanowicz,},
doi = {https://doi.org/10.1016/j.obmed.2020.100273.},
isbn = {2451-8476},
year = {2020},
date = {2020-09-01},
journal = {Obesity Medicine},
volume = {19},
number = {100273},
abstract = {Obesity and depression are serious public health problems and cause death in the world. In this article, we will study the concept of depreobesity that explains the depression in the context of obesity and vice versa. We will review whether animals can be used to understand the interrelationship between obesity and depression. We will propose saliva as a translational paradigm to predict the depreobesity. Policymakers need to identify new strategies for depreobesity by understanding the complexity of shared biology (depression-obesity). Perspectives for the future are promising.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Obesity and depression are serious public health problems and cause death in the world. In this article, we will study the concept of depreobesity that explains the depression in the context of obesity and vice versa. We will review whether animals can be used to understand the interrelationship between obesity and depression. We will propose saliva as a translational paradigm to predict the depreobesity. Policymakers need to identify new strategies for depreobesity by understanding the complexity of shared biology (depression-obesity). Perspectives for the future are promising.
12.
Eagleman, David M.; Vaughn, Don A.
The Defensive Activation theory: dreaming as a mechanism to prevent takeover of the visual cortex Journal Article
In: bioRxiv , 2020.
@article{Eagleman2020Defensiveb,
title = {The Defensive Activation theory: dreaming as a mechanism to prevent takeover of the visual cortex},
author = {David M. Eagleman and Don A. Vaughn},
doi = {doi.org/10.1101/2020.07.24.219089 },
year = {2020},
date = {2020-07-24},
journal = {bioRxiv },
abstract = {Regions of the brain maintain their territory with continuous activity: if activity slows or stops (e.g., because of blindness), the territory tends to be taken over by its neighbors. A surprise in recent years has been the speed of takeover, which is measurable within an hour. These findings lead us to a new hypothesis on the origin of dream sleep. We hypothesize that the circuitry underlying dreaming serves to amplify the visual system’s activity periodically throughout the night, allowing it to defend its territory against takeover from other senses. We find that measures of plasticity across 25 species of primates correlate positively with the proportion of rapid eye movement (REM) sleep. We further find that plasticity and REM sleep increase in lockstep with evolutionary recency to humans. Finally, our hypothesis is consistent with the decrease in REM sleep and parallel decrease in neuroplasticity with aging.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Regions of the brain maintain their territory with continuous activity: if activity slows or stops (e.g., because of blindness), the territory tends to be taken over by its neighbors. A surprise in recent years has been the speed of takeover, which is measurable within an hour. These findings lead us to a new hypothesis on the origin of dream sleep. We hypothesize that the circuitry underlying dreaming serves to amplify the visual system’s activity periodically throughout the night, allowing it to defend its territory against takeover from other senses. We find that measures of plasticity across 25 species of primates correlate positively with the proportion of rapid eye movement (REM) sleep. We further find that plasticity and REM sleep increase in lockstep with evolutionary recency to humans. Finally, our hypothesis is consistent with the decrease in REM sleep and parallel decrease in neuroplasticity with aging.
13.
Y. Lau, Ding
Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients Bachelor Thesis
2020.
@bachelorthesis{Lau2020Omega,
title = {Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients},
author = {Lau, Y., Ding, J. A., Simental, A., Mirzoyan, H., Lee, W., Diamante, G., Cely, I., Tran, M., Morselli, M., Dang, J., Kaczor-Urbanowicz, K. E., Sayre, J., Stiles, L., Yang, X., Pellegrini, M., & Fiala, M. },
doi = {DOI: 10.1096/fj.202000669RR},
year = {2020},
date = {2020-07-02},
urldate = {2020-07-02},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {34},
number = {8},
pages = {9982-9994},
abstract = {Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients’ macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients’ macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.
14.
Bhat, Kruttika; Saki, Mohammad; Vlashi, Erina; Cheng, Fei; Duhachek-Muggy, Sara; Alli, Claudia; Yu, Garrett; Medina, Paul; He, Ling; Damoiseaux, Robert; Pellegrini, Matteo; Zemke, Nathan R.; Nghiemphu, Phioanh Leia; Cloughesy, Timothy F.; Liau, Linda M.; Kornblum, Harley I.; Pajonk, Frank
The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma Journal Article
In: Proceedings of the National Academy of Sciences , 32358191 , 2020.
@article{Bhat2020Dopamine,
title = {The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma},
author = {Kruttika Bhat and Mohammad Saki and Erina Vlashi and Fei Cheng and Sara Duhachek-Muggy and Claudia Alli and Garrett Yu and Paul Medina and Ling He and Robert Damoiseaux and Matteo Pellegrini and Nathan R. Zemke and Phioanh Leia Nghiemphu and Timothy F. Cloughesy and Linda M. Liau and Harley I. Kornblum and Frank Pajonk },
doi = {https://doi.org/10.1073/pnas.1920154117},
year = {2020},
date = {2020-05-01},
journal = {Proceedings of the National Academy of Sciences },
volume = {32358191},
abstract = {Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs). },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).
15.
Lau YCC Fiala M, Aghajani A
2020.
@bachelorthesis{nokey,
title = {Omega-3 Fatty Acids Increase Amyloid-β Immunity, Energy, and Circadian Rhythm for Cognitive Protection of Alzheimer's Disease Patients Beyond Cholinesterase Inhibitors},
author = {Fiala M, Lau YCC, Aghajani A, Bhargava S, Aminpour E, Kaczor-Urbanowicz KE, Mirzoyan H, Nichols I, Ko MW, Morselli M, Santana J, Dang J, Sayre J, Paul K, Pellegrini M. },
doi = {DOI: 10.3233/JAD-200252},
year = {2020},
date = {2020-03-24},
journal = {Journal of Alzheimer's disease},
volume = {75},
number = {3},
pages = {993-1002},
abstract = {Background: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer's disease (AD) are palliative for a limited time.
Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish.
Methods: We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients.
Results: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2.
Conclusion: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Background: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer's disease (AD) are palliative for a limited time.
Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish.
Methods: We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients.
Results: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2.
Conclusion: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.
Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish.
Methods: We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients.
Results: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2.
Conclusion: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.
16.
Neal, Adam S.; Nunez, Miguel; Lai, Tiffany; Tosevska, Anela; Morselli, Marco; Amneus, Malaika; Zakhour, Mae; Moatamed, Neda A.; Pellegrini, Matteo; Memarzadeh, Sanaz
In: Reproductive Sciences, 2020.
@article{Neal2020Expression,
title = {Expression of Stromal Progesterone Receptor and Differential Methylation Patterns in the Endometrium May Correlate with Response to Progesterone Therapy in Endometrial Complex Atypical Hyperplasia.},
author = {Adam S. Neal and Miguel Nunez and Tiffany Lai and Anela Tosevska and Marco Morselli and Malaika Amneus and Mae Zakhour and Neda A. Moatamed and Matteo Pellegrini and Sanaz Memarzadeh},
doi = {https://doi.org/10.1007/s43032-020-00175-w},
year = {2020},
date = {2020-03-02},
journal = {Reproductive Sciences},
abstract = {Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.
17.
Brito, Jaqueline J; Mosqueiro, Thiago; Rotman, Jeremy; Xue, Victor; Chapski, Douglas J; la Hoz, Juan De; Matias, Paulo; Martin, Lana S; Zelikovsky, Alex; Pellegrini, Matteo; Mangul, Serghei
Telescope: an interactive tool for managing large-scale analysis from mobile devices Journal Article
In: GigaScience, 9 (1), 2020.
@article{Brito2020Telescope,
title = {Telescope: an interactive tool for managing large-scale analysis from mobile devices},
author = {Jaqueline J Brito and Thiago Mosqueiro and Jeremy Rotman and Victor Xue and Douglas J Chapski and Juan De la Hoz and Paulo Matias and Lana S Martin and Alex Zelikovsky and Matteo Pellegrini and Serghei Mangul },
url = {https://doi.org/10.1093/gigascience/giz163},
year = {2020},
date = {2020-01-23},
journal = {GigaScience},
volume = {9},
number = {1},
abstract = {In today's world of big data, computational analysis has become a key driver of biomedical research. High-performance computational facilities are capable of processing considerable volumes of data, yet often lack an easy-to-use interface to guide the user in supervising and adjusting bioinformatics analysis via a tablet or smartphone.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In today's world of big data, computational analysis has become a key driver of biomedical research. High-performance computational facilities are capable of processing considerable volumes of data, yet often lack an easy-to-use interface to guide the user in supervising and adjusting bioinformatics analysis via a tablet or smartphone.
18.
Lozano‐Huntelman, Natalie Ann; Singh, Nina; Valencia, Alondra; Mira, Portia; Sakayan, Maral; Boucher, Ian; Tang, Sharon; Brennan, Kelley; Gianvecchio, Crystal; Fitz‐Gibbon, Sorel; Yeh, Pamela
In: Evolutionary Applications, 2019.
@article{Lazano2019evolution,
title = {Evolution of Antibiotic Cross‐resistance and Collateral Sensitivity in Staphylococcus Epidermidis Using the Mutant Prevention Concentration and the Mutant Selection Window},
author = {Natalie Ann Lozano‐Huntelman and
Nina Singh and
Alondra Valencia and
Portia Mira and
Maral Sakayan and
Ian Boucher and
Sharon Tang and
Kelley Brennan and
Crystal Gianvecchio and
Sorel Fitz‐Gibbon and
Pamela Yeh},
doi = {https://doi.org/10.1111/eva.12903},
year = {2019},
date = {2019-12-12},
journal = {Evolutionary Applications},
abstract = {In bacteria, evolution of resistance to one antibiotic is frequently associated with increased resistance (cross‐resistance) or increased susceptibility (collateral sensitivity) to other antibiotics. Cross‐resistance and collateral sensitivity are typically evaluated at the minimum inhibitory concentration (MIC). However, these susceptibility changes are not well characterized with respect to the mutant prevention concentration (MPC), the antibiotic concentration that prevents a single‐step mutation from occurring. We measured the MIC and the MPC for Staphylococcus epidermidis and 14 single‐drug resistant strains against seven antibiotics. We found that the MIC and the MPC were positively correlated but that this correlation weakened if cross‐resistance did not evolve. If any type of resistance did evolve, the range of concentrations between the MIC and the MPC tended to shift right and widen. Similar patterns of cross‐resistance and collateral sensitivity were observed at the MIC and MPC levels, though more symmetry was observed at the MIC level. Whole‐genome sequencing revealed mutations in both known‐target and nontarget genes. Moving forward, examining both the MIC and the MPC may lead to better predictions of evolutionary trajectories in antibiotic‐resistant bacteria.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In bacteria, evolution of resistance to one antibiotic is frequently associated with increased resistance (cross‐resistance) or increased susceptibility (collateral sensitivity) to other antibiotics. Cross‐resistance and collateral sensitivity are typically evaluated at the minimum inhibitory concentration (MIC). However, these susceptibility changes are not well characterized with respect to the mutant prevention concentration (MPC), the antibiotic concentration that prevents a single‐step mutation from occurring. We measured the MIC and the MPC for Staphylococcus epidermidis and 14 single‐drug resistant strains against seven antibiotics. We found that the MIC and the MPC were positively correlated but that this correlation weakened if cross‐resistance did not evolve. If any type of resistance did evolve, the range of concentrations between the MIC and the MPC tended to shift right and widen. Similar patterns of cross‐resistance and collateral sensitivity were observed at the MIC and MPC levels, though more symmetry was observed at the MIC level. Whole‐genome sequencing revealed mutations in both known‐target and nontarget genes. Moving forward, examining both the MIC and the MPC may lead to better predictions of evolutionary trajectories in antibiotic‐resistant bacteria.
19.
Galmozzi, Andrea; Kok, Bernard P.; Kim, Arthur S.; Montenegro-Burke, J. Rafael; Lee, Jae Y.; Spreafico, Roberto; Mosure, Sarah; Albert, Verena; Cintron-Colon, Rigo; Godio, Cristina; Webb, William R.; Conti, Bruno; Solt, Laura A.; Kojetin, Douglas; Parker, Christopher G.; Peluso, John J.; Pru, James K.; Siuzdak, Gary; Cravatt, Benjamin F.; Saez, Enrique
PGRMC2 is an intracellular haem chaperone critical for adipocyte function Journal Article
In: 2019.
@article{Galmozzi2019PGRMC2,
title = {PGRMC2 is an intracellular haem chaperone critical for adipocyte function},
author = {Andrea Galmozzi and Bernard P. Kok and Arthur S. Kim and J. Rafael Montenegro-Burke and Jae Y. Lee and Roberto Spreafico and Sarah Mosure and Verena Albert and Rigo Cintron-Colon and Cristina Godio and William R. Webb and Bruno Conti and Laura A. Solt and Douglas Kojetin and Christopher G. Parker and John J. Peluso and James K. Pru and Gary Siuzdak and Benjamin F. Cravatt and Enrique Saez},
editor = {Nature},
doi = {doi:10.1038/s41586-019-1774-2},
year = {2019},
date = {2019-11-20},
abstract = {Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.
20.
Kurmangaliyev, Yerbol Z; Yoo, Juyoun; LoCascio, Samuel A; Zipursky, S Lawrence
Modular transcriptional programs separately define axon and dendrite connectivity. Journal Article
In: eLife, 2019.
@article{Kurmangaliyev2019Modular,
title = {Modular transcriptional programs separately define axon and dendrite connectivity.},
author = { Yerbol Z Kurmangaliyev and Juyoun Yoo and Samuel A LoCascio and S Lawrence Zipursky},
doi = {https://doi.org/10.7554/eLife.50822.001 },
year = {2019},
date = {2019-11-05},
journal = {eLife},
abstract = {Patterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless, a clear logic underlying the transcriptional control of neuronal connectivity has yet to emerge. Here, we focused on Drosophila T4/T5 neurons, a class of closely related neuronal subtypes with different wiring patterns. Eight subtypes of T4/T5 neurons are defined by combinations of two patterns of dendritic inputs and four patterns of axonal outputs. Single-cell profiling during development revealed distinct transcriptional programs defining each dendrite and axon wiring pattern. These programs were defined by the expression of a few transcription factors and different combinations of cell surface proteins. Gain and loss of function studies provide evidence for independent control of different wiring features. We propose that modular transcriptional programs for distinct wiring features are assembled in different combinations to generate diverse patterns of neuronal connectivity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Patterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless, a clear logic underlying the transcriptional control of neuronal connectivity has yet to emerge. Here, we focused on Drosophila T4/T5 neurons, a class of closely related neuronal subtypes with different wiring patterns. Eight subtypes of T4/T5 neurons are defined by combinations of two patterns of dendritic inputs and four patterns of axonal outputs. Single-cell profiling during development revealed distinct transcriptional programs defining each dendrite and axon wiring pattern. These programs were defined by the expression of a few transcription factors and different combinations of cell surface proteins. Gain and loss of function studies provide evidence for independent control of different wiring features. We propose that modular transcriptional programs for distinct wiring features are assembled in different combinations to generate diverse patterns of neuronal connectivity.
2022
Valentina Poli Francesco Borriello, Ellen Shrock
An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity Bachelor Thesis
2022, ISBN: 0092-8674.
Abstract | Links | BibTeX | Tags: coronavirus, Dectin, inflammation, influenza A virus, innate immunity, interferon, PAMP, pathogen-associated molecular pattern, pattern recognition receptor, PRR, SARS-CoV-2, viral glycoprotein
@bachelorthesis{Borriello2022Modulation,
title = {An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity},
author = {Francesco Borriello, Valentina Poli, Ellen Shrock, Roberto Spreafico, Xin Liu, Novalia Pishesha, Claire Carpenet, Janet Chou, Marco Di Gioia, Marisa E. McGrath, Carly A. Dillen, Nora A. Barrett, Lucrezia Lacanfora, Marcella E. Franco, Laura Marongiu, Yoichiro Iwakura, Ferdinando Pucci, Michael D. Kruppa, Zuchao Ma, Douglas W. Lowman, Harry E. Ensley, Etsuro Nanishi, Yoshine Saito, Timothy R. O’Meara, Hyuk-Soo Seo, Sirano Dhe-Paganon, David J. Dowling, Matthew Frieman, Stephen J. Elledge, Ofer Levy, Darrell J. Irvine, Hidde L. Ploegh, David L. Williams, Ivan Zanoni,},
doi = {https://doi.org/10.1016/j.cell.2022.01.009},
isbn = {0092-8674},
year = {2022},
date = {2022-02-17},
journal = {Cell},
volume = {185},
number = {4},
pages = {614-629},
abstract = {Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.},
keywords = {coronavirus, Dectin, inflammation, influenza A virus, innate immunity, interferon, PAMP, pathogen-associated molecular pattern, pattern recognition receptor, PRR, SARS-CoV-2, viral glycoprotein},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.
2021
Eric Y. Lin Paul C Adamson, Sung-Min Ha
Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance Journal Article
In: Journal of Antimicrobial Chemotherapy, (dkab262), 2021.
Abstract | Links | BibTeX | Tags: Antimicrobial resistance
@article{Adamson2021Neisseria,
title = {Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance },
author = { Paul C Adamson, Eric Y. Lin, Sung-Min Ha, Jeffrey D. Klausner,},
doi = {https://doi.org/10.1093/jac/dkab262},
year = {2021},
date = {2021-07-29},
journal = {Journal of Antimicrobial Chemotherapy},
number = {dkab262},
abstract = {Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.},
keywords = {Antimicrobial resistance},
pubstate = {published},
tppubtype = {article}
}
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.
Eric Y Lin Paul C Adamson, Sung-Min Ha
Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance Bachelor Thesis
2021.
Abstract | Links | BibTeX | Tags: amino acids, antibiotics, basic local alignment search tool, drug resistance, epidemiology, genome, gonococcal infection, malnutrition-inflammation-cachexia syndrome, medical, microbial, mutation, neisseria gonorrhoeae, surveillance, world health, zoliflodacin
@bachelorthesis{nokey,
title = {Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance },
author = {Paul C Adamson, Eric Y Lin, Sung-Min Ha, Jeffrey D Klausner},
doi = {https://doi.org/10.1093/jac/dkab262},
year = {2021},
date = {2021-07-29},
journal = {Journal of Antimicrobial Chemotherapy},
volume = {76},
number = {11},
pages = {2847-2849},
abstract = {Background
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.
Objectives
To determine the prevalence of three amino acid mutations associated with zoliflodacin resistance within a large, public database of nearly 13 000 N. gonorrhoeae genomes.
Methods
PathogenWatch is an online genomic epidemiology platform with a public database of N. gonorrhoeae genomes. That database was used to extract gyrB sequence data and a Basic Local Alignment Search Tool (BLAST) search was performed to identify any of the three amino acid mutations in GyrB that are associated with increased zoliflodacin MICs: D429N, K450N or K450T. As a control for the search methodology, all GyrA sequences were also extracted and S91F mutations were identified and compared with the PathogenWatch database.
Results
In total, 12 493 N. gonorrhoeae genomes from the PathogenWatch database were included. Among those genomes, none was identified that harboured any of the three mutations associated with increased zoliflodacin MICs. One genome was identified to have a mutation at position 429 in GyrB (D429V).
Conclusions
The findings suggest that the prevalence of the three mutations associated with zoliflodacin resistance in N. gonorrhoeae is very low. However, further research into the mechanisms of zoliflodacin resistance in N. gonorrhoeae is needed. Genomic epidemiology platforms like PathogenWatch can be used to enhance the global surveillance of AMR.},
keywords = {amino acids, antibiotics, basic local alignment search tool, drug resistance, epidemiology, genome, gonococcal infection, malnutrition-inflammation-cachexia syndrome, medical, microbial, mutation, neisseria gonorrhoeae, surveillance, world health, zoliflodacin},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Background
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.
Objectives
To determine the prevalence of three amino acid mutations associated with zoliflodacin resistance within a large, public database of nearly 13 000 N. gonorrhoeae genomes.
Methods
PathogenWatch is an online genomic epidemiology platform with a public database of N. gonorrhoeae genomes. That database was used to extract gyrB sequence data and a Basic Local Alignment Search Tool (BLAST) search was performed to identify any of the three amino acid mutations in GyrB that are associated with increased zoliflodacin MICs: D429N, K450N or K450T. As a control for the search methodology, all GyrA sequences were also extracted and S91F mutations were identified and compared with the PathogenWatch database.
Results
In total, 12 493 N. gonorrhoeae genomes from the PathogenWatch database were included. Among those genomes, none was identified that harboured any of the three mutations associated with increased zoliflodacin MICs. One genome was identified to have a mutation at position 429 in GyrB (D429V).
Conclusions
The findings suggest that the prevalence of the three mutations associated with zoliflodacin resistance in N. gonorrhoeae is very low. However, further research into the mechanisms of zoliflodacin resistance in N. gonorrhoeae is needed. Genomic epidemiology platforms like PathogenWatch can be used to enhance the global surveillance of AMR.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.
Objectives
To determine the prevalence of three amino acid mutations associated with zoliflodacin resistance within a large, public database of nearly 13 000 N. gonorrhoeae genomes.
Methods
PathogenWatch is an online genomic epidemiology platform with a public database of N. gonorrhoeae genomes. That database was used to extract gyrB sequence data and a Basic Local Alignment Search Tool (BLAST) search was performed to identify any of the three amino acid mutations in GyrB that are associated with increased zoliflodacin MICs: D429N, K450N or K450T. As a control for the search methodology, all GyrA sequences were also extracted and S91F mutations were identified and compared with the PathogenWatch database.
Results
In total, 12 493 N. gonorrhoeae genomes from the PathogenWatch database were included. Among those genomes, none was identified that harboured any of the three mutations associated with increased zoliflodacin MICs. One genome was identified to have a mutation at position 429 in GyrB (D429V).
Conclusions
The findings suggest that the prevalence of the three mutations associated with zoliflodacin resistance in N. gonorrhoeae is very low. However, further research into the mechanisms of zoliflodacin resistance in N. gonorrhoeae is needed. Genomic epidemiology platforms like PathogenWatch can be used to enhance the global surveillance of AMR.
D. A. Vaughn, Maggiora
Modulation of attention and stress with arousal: The mental and physical effects of riding a motorcycle Journal Article
In: Brain Research, 1752 (147203), 2021.
Abstract | Links | BibTeX | Tags: arousal., Modulation, stress
@article{Vaugh2001Modulation,
title = {Modulation of attention and stress with arousal: The mental and physical effects of riding a motorcycle},
author = {Vaughn, D. A., Maggiora, M. B., Vaughn, K. J., Maggiora, C. J., Tavakoli, A.-V., Liang, W., Zava, D., Cohen, M. S., & Lenartowicz, A. },
doi = {https://doi.org/10.1016/j.brainres.2020.147203},
year = {2021},
date = {2021-02-01},
journal = {Brain Research},
volume = {1752},
number = {147203},
abstract = {Existing theories suggest that moderate arousal improves selective attention, as would be expected in the context of competitive sports or sensation-seeking activities. Here we investigated how riding a motorcycle, an attention-demanding physical activity, affects sensory processing. To do so, we implemented the passive auditory oddball paradigm and measured the EEG response of participants as they rode a motorcycle, drove a car, and sat at rest. Specifically, we measured the N1 and mismatch negativity to auditory tones, as well as alpha power during periods of no tones. We investigated whether riding and driving modulated non-CNS metrics including heart rate and concentrations of the hormones epinephrine, cortisol, DHEA-S, and testosterone. While participants were riding, we found a decrease in N1 amplitude, increase in mismatch negativity, and decrease in relative alpha power, together suggesting enhancement of sensory processing and visual attention. Riding increased epinephrine levels, increased heart rate, and decreased the ratio of cortisol to DHEA-S. Together, these results suggest that riding increases focus, heightens the brain’s passive monitoring of changes in the sensory environment, and alters HPA axis response. More generally, our findings suggest that selective attention and sensory monitoring seem to be separable neural processes.},
keywords = {arousal., Modulation, stress},
pubstate = {published},
tppubtype = {article}
}
Existing theories suggest that moderate arousal improves selective attention, as would be expected in the context of competitive sports or sensation-seeking activities. Here we investigated how riding a motorcycle, an attention-demanding physical activity, affects sensory processing. To do so, we implemented the passive auditory oddball paradigm and measured the EEG response of participants as they rode a motorcycle, drove a car, and sat at rest. Specifically, we measured the N1 and mismatch negativity to auditory tones, as well as alpha power during periods of no tones. We investigated whether riding and driving modulated non-CNS metrics including heart rate and concentrations of the hormones epinephrine, cortisol, DHEA-S, and testosterone. While participants were riding, we found a decrease in N1 amplitude, increase in mismatch negativity, and decrease in relative alpha power, together suggesting enhancement of sensory processing and visual attention. Riding increased epinephrine levels, increased heart rate, and decreased the ratio of cortisol to DHEA-S. Together, these results suggest that riding increases focus, heightens the brain’s passive monitoring of changes in the sensory environment, and alters HPA axis response. More generally, our findings suggest that selective attention and sensory monitoring seem to be separable neural processes.
Perri, Angela R; Mitchell, Kieren J.; Mouton, Alice and
Dire wolves were the last of an ancient New World canid lineage Journal Article
In: Nature, 2021.
Abstract | Links | BibTeX | Tags: Evolutionary genetics, Palaeontology, Phylogenetics, Speciation
@article{Perri2021Wolves,
title = {Dire wolves were the last of an ancient New World canid lineage},
author = {Perri, Angela R and Mitchell, Kieren J. and Mouton, Alice and et al. },
doi = {https://doi.org/10.1038/s41586-020-03082-x},
year = {2021},
date = {2021-01-13},
journal = {Nature},
abstract = {Dire wolves are considered to be one of the most common and widespread large carnivores in Pleistocene America1, yet relatively little is known about their evolution or extinction. Here, to reconstruct the evolutionary history of dire wolves, we sequenced five genomes from sub-fossil remains dating from 13,000 to more than 50,000 years ago. Our results indicate that although they were similar morphologically to the extant grey wolf, dire wolves were a highly divergent lineage that split from living canids around 5.7 million years ago. In contrast to numerous examples of hybridization across Canidae2,3, there is no evidence for gene flow between dire wolves and either North American grey wolves or coyotes. This suggests that dire wolves evolved in isolation from the Pleistocene ancestors of these species. Our results also support an early New World origin of dire wolves, while the ancestors of grey wolves, coyotes and dholes evolved in Eurasia and colonized North America only relatively recently.},
keywords = {Evolutionary genetics, Palaeontology, Phylogenetics, Speciation},
pubstate = {published},
tppubtype = {article}
}
Dire wolves are considered to be one of the most common and widespread large carnivores in Pleistocene America1, yet relatively little is known about their evolution or extinction. Here, to reconstruct the evolutionary history of dire wolves, we sequenced five genomes from sub-fossil remains dating from 13,000 to more than 50,000 years ago. Our results indicate that although they were similar morphologically to the extant grey wolf, dire wolves were a highly divergent lineage that split from living canids around 5.7 million years ago. In contrast to numerous examples of hybridization across Canidae2,3, there is no evidence for gene flow between dire wolves and either North American grey wolves or coyotes. This suggests that dire wolves evolved in isolation from the Pleistocene ancestors of these species. Our results also support an early New World origin of dire wolves, while the ancestors of grey wolves, coyotes and dholes evolved in Eurasia and colonized North America only relatively recently.
Miikeda A Zhang W, Zuckerman J
Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice. Bachelor Thesis
2021.
Abstract | Links | BibTeX | Tags: Cardiology, Cell biology, Diseases, Molecular Biology, Nephrology
@bachelorthesis{Zhang2001Inhibition,
title = {Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice. },
author = {Zhang W, Miikeda A, Zuckerman J, Jia X, Charugundla S, Zhou Z, Kaczor-Urbanowicz KE, Magyar C, Guo F, Wang Z, Pellegrini M, Hazen SL, Nicholas SB, Lusis AJ, Shih DM},
doi = {doi: 10.1038/s41598-020-80063-0.},
year = {2021},
date = {2021-01-12},
urldate = {2021-01-12},
journal = {Scientific Reports},
volume = {11},
number = {518},
abstract = {Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.},
keywords = {Cardiology, Cell biology, Diseases, Molecular Biology, Nephrology},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.
2020
K. E. Kaczor-Urbanowicz, Cheng
Reviews on Current Liquid Biopsy for Detection and Management of Pancreatic Cancers Bachelor Thesis
2020.
Abstract | Links | BibTeX | Tags: ctDNA, early detection, liquid biopsy, oncogenic mutations, pancreatic cancer
@bachelorthesis{Kaczor-Urbanowicz2020Liquid,
title = {Reviews on Current Liquid Biopsy for Detection and Management of Pancreatic Cancers},
author = {Kaczor-Urbanowicz, K. E., Cheng, J., King, J. C., Sedarat, A., Pandol, S. J., Farrell, J. J., Wong, D., & Kim, Y. },
doi = {DOI: 10.1097/MPA.0000000000001662},
year = {2020},
date = {2020-10-01},
journal = {Pancreas},
volume = {49},
number = {9},
pages = {1141-1152},
abstract = {Pancreatic cancer is the fourth leading cause of cancer death in the United States. Pancreatic cancer presents dismal clinical outcomes in patients, and the incidence of pancreatic cancer has continuously increased to likely become the second most common cause of cancer-related deaths by as early as 2030. One of main reasons for the high mortality rate of pancreatic cancer is the lack of tools for early-stage detection. Current practice in detecting and monitoring therapeutic response in pancreatic cancer relies on imaging analysis and invasive endoscopic examination. Liquid biopsy-based analysis of genetic alterations in biofluids has become a fundamental component in the diagnosis and management of cancers. There is an urgent need for scientific and technological advancement to detect pancreatic cancer early and to develop effective therapies. The development of a highly sensitive and specific liquid biopsy tool will require extensive understanding on the characteristics of circulating tumor DNA in biofluids. Here, we have reviewed the current status of liquid biopsy in detecting and monitoring pancreatic cancers and our understanding of circulating tumor DNA that should be considered for the development of a liquid biopsy tool, which will greatly aid in the diagnosis and healthcare of people at risk.},
keywords = {ctDNA, early detection, liquid biopsy, oncogenic mutations, pancreatic cancer},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Pancreatic cancer is the fourth leading cause of cancer death in the United States. Pancreatic cancer presents dismal clinical outcomes in patients, and the incidence of pancreatic cancer has continuously increased to likely become the second most common cause of cancer-related deaths by as early as 2030. One of main reasons for the high mortality rate of pancreatic cancer is the lack of tools for early-stage detection. Current practice in detecting and monitoring therapeutic response in pancreatic cancer relies on imaging analysis and invasive endoscopic examination. Liquid biopsy-based analysis of genetic alterations in biofluids has become a fundamental component in the diagnosis and management of cancers. There is an urgent need for scientific and technological advancement to detect pancreatic cancer early and to develop effective therapies. The development of a highly sensitive and specific liquid biopsy tool will require extensive understanding on the characteristics of circulating tumor DNA in biofluids. Here, we have reviewed the current status of liquid biopsy in detecting and monitoring pancreatic cancers and our understanding of circulating tumor DNA that should be considered for the development of a liquid biopsy tool, which will greatly aid in the diagnosis and healthcare of people at risk.
D. A. Covino, Kaczor-Urbanowicz
2020.
Abstract | Links | BibTeX | Tags: CCL2 (MCP-1), HIV-1, innate response, macrophage, miR-155, NF-κB, RNA-sequencing, transcriptional profile
@bachelorthesis{Covino2020Transcriptome,
title = {Transcriptome Profiling of Human Monocyte-Derived Macrophages Upon CCL2 Neutralization Reveals an Association Between Activation of Innate Immune Pathways and Restriction of HIV-1 Gene Expression},
author = {Covino, D. A., Kaczor-Urbanowicz, K. E., Lu, J., Chiantore, M. V., Fiorucci, G., Vescio, M. F., Catapano, L., Purificato, C., Galluzzo, C. M., Amici, R., Andreotti, M., Gauzzi, M. C., Pellegrini, M., & Fantuzzi, L.},
doi = { DOI: 10.3389/fimmu.2020.02129},
year = {2020},
date = {2020-09-18},
journal = {Frontiers in immunology},
volume = {11},
pages = {2129},
abstract = {Macrophages are key targets of human immunodeficiency virus type 1 (HIV-1) infection and main producers of the proinflammatory chemokine CC chemokine ligand 2 (CCL2), whose expression is induced by HIV-1 both in vitro and in vivo. We previously found that CCL2 neutralization in monocyte-derived macrophages (MDMs) strongly inhibited HIV-1 replication affecting post-entry steps of the viral life cycle. Here, we used RNA-sequencing to deeply characterize the cellular factors and pathways modulated by CCL2 blocking in MDMs and involved in HIV-1 replication restriction. We report that exposure to CCL2 neutralizing antibody profoundly affected the MDM transcriptome. Functional annotation clustering of up-regulated genes identified two clusters enriched for antiviral defense and immune response pathways, comprising several interferon-stimulated, and restriction factor coding genes. Transcripts in the clusters were enriched for RELA and NFKB1 targets, suggesting the activation of the canonical nuclear factor κB pathway as part of a regulatory network involving miR-155 up-regulation. Furthermore, while HIV-1 infection caused small changes to the MDM transcriptome, with no evidence of host defense gene expression and type I interferon signature, CCL2 blocking enabled the activation of a strong host innate response in infected macrophage cultures, and potently inhibited viral genes expression. Notably, an inverse correlation was found between levels of viral transcripts and of the restriction factors APOBEC3A (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 A), ISG15, and MX1. These findings highlight an association between activation of innate immune pathways and HIV-1 restriction upon CCL2 blocking and identify this chemokine as an endogenous factor contributing to the defective macrophage response to HIV-1. Therapeutic targeting of CCL2 may thus strengthen host innate immunity and restrict HIV-1 replication.},
keywords = {CCL2 (MCP-1), HIV-1, innate response, macrophage, miR-155, NF-κB, RNA-sequencing, transcriptional profile},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Macrophages are key targets of human immunodeficiency virus type 1 (HIV-1) infection and main producers of the proinflammatory chemokine CC chemokine ligand 2 (CCL2), whose expression is induced by HIV-1 both in vitro and in vivo. We previously found that CCL2 neutralization in monocyte-derived macrophages (MDMs) strongly inhibited HIV-1 replication affecting post-entry steps of the viral life cycle. Here, we used RNA-sequencing to deeply characterize the cellular factors and pathways modulated by CCL2 blocking in MDMs and involved in HIV-1 replication restriction. We report that exposure to CCL2 neutralizing antibody profoundly affected the MDM transcriptome. Functional annotation clustering of up-regulated genes identified two clusters enriched for antiviral defense and immune response pathways, comprising several interferon-stimulated, and restriction factor coding genes. Transcripts in the clusters were enriched for RELA and NFKB1 targets, suggesting the activation of the canonical nuclear factor κB pathway as part of a regulatory network involving miR-155 up-regulation. Furthermore, while HIV-1 infection caused small changes to the MDM transcriptome, with no evidence of host defense gene expression and type I interferon signature, CCL2 blocking enabled the activation of a strong host innate response in infected macrophage cultures, and potently inhibited viral genes expression. Notably, an inverse correlation was found between levels of viral transcripts and of the restriction factors APOBEC3A (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 A), ISG15, and MX1. These findings highlight an association between activation of innate immune pathways and HIV-1 restriction upon CCL2 blocking and identify this chemokine as an endogenous factor contributing to the defective macrophage response to HIV-1. Therapeutic targeting of CCL2 may thus strengthen host innate immunity and restrict HIV-1 replication.
M. Mediouni, Madiouni
COVID-19: How the quarantine could lead to the depreobesity Bachelor Thesis
2020.
Abstract | Links | BibTeX | Tags: COVID‐19, Depreobesity, Depression, Obesity, Quarantine.
@bachelorthesis{covid-19MediouniQuarantine,
title = {COVID-19: How the quarantine could lead to the depreobesity},
author = {Mediouni, M., Madiouni, R., & Kaczor-Urbanowicz, K. E.},
doi = { DOI: 10.1016/j.obmed.2020.100255},
year = {2020},
date = {2020-09-01},
journal = {Obesity medicine},
volume = {19},
number = {100255},
abstract = {In this paper, we will introduce coronavirus (COVID-19) and how it spreads around the globe. We will also present the term of quarantine and associated with it requirement of locking down at home in some countries. We will study how frustration related to quarantine relates to several psychological problems including depression. This environment pushes people to consume high sugar foods that increase obesity. In conclusion, countries should be prepared for the upcoming epidemic (depreobesity).},
keywords = {COVID‐19, Depreobesity, Depression, Obesity, Quarantine.},
pubstate = {published},
tppubtype = {bachelorthesis}
}
In this paper, we will introduce coronavirus (COVID-19) and how it spreads around the globe. We will also present the term of quarantine and associated with it requirement of locking down at home in some countries. We will study how frustration related to quarantine relates to several psychological problems including depression. This environment pushes people to consume high sugar foods that increase obesity. In conclusion, countries should be prepared for the upcoming epidemic (depreobesity).
Karolina Elżbieta Kaczor-Urbanowicz Mohamed Mediouni, Riadh Madiouni
Future epidemic: Depreobesity Bachelor Thesis
2020.
Abstract | Links | BibTeX | Tags: Depreobesity, Depression, Epidemic, Obesity
@bachelorthesis{Future2020Mediouni,
title = {Future epidemic: Depreobesity},
author = {Mohamed Mediouni, Karolina Elżbieta Kaczor-Urbanowicz, Riadh Madiouni,},
doi = {https://doi.org/10.1016/j.obmed.2020.100240},
year = {2020},
date = {2020-09-01},
journal = {Obesity Medicine},
volume = {19},
number = {100240},
abstract = {Obesity and depression are both global health problems that have a major impact on human life and are costly to health services. Both of them have a substantial health impact including long-term complications, reduction in health-related functioning, reduction of quality of life and reduced overall life expectancy. In this article, we propose ‘‘depreobesity’’ as a modern epidemic, which indicates the coexistence of both depression and obesity. It is thus urgent to understand and manage this concept to optimize public health and medical intervention planning.},
keywords = {Depreobesity, Depression, Epidemic, Obesity},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Obesity and depression are both global health problems that have a major impact on human life and are costly to health services. Both of them have a substantial health impact including long-term complications, reduction in health-related functioning, reduction of quality of life and reduced overall life expectancy. In this article, we propose ‘‘depreobesity’’ as a modern epidemic, which indicates the coexistence of both depression and obesity. It is thus urgent to understand and manage this concept to optimize public health and medical intervention planning.
Leandro Bueno Bergantin Mohamed Mediouni, Riadh Madiouni
Can we represent the depreobesity genetically? Bachelor Thesis
2020, ISBN: 2451-8476.
Abstract | Links | BibTeX | Tags: Depreobesity, Depression, genes, Obesity, Saliva
@bachelorthesis{Mediouni2020Depreobesity,
title = {Can we represent the depreobesity genetically?},
author = {Mohamed Mediouni, Leandro Bueno Bergantin, Riadh Madiouni, Karolina Elżbieta Kaczor-Urbanowicz, Andrzej Urbanowicz,},
doi = {https://doi.org/10.1016/j.obmed.2020.100273.},
isbn = {2451-8476},
year = {2020},
date = {2020-09-01},
journal = {Obesity Medicine},
volume = {19},
number = {100273},
abstract = {Obesity and depression are serious public health problems and cause death in the world. In this article, we will study the concept of depreobesity that explains the depression in the context of obesity and vice versa. We will review whether animals can be used to understand the interrelationship between obesity and depression. We will propose saliva as a translational paradigm to predict the depreobesity. Policymakers need to identify new strategies for depreobesity by understanding the complexity of shared biology (depression-obesity). Perspectives for the future are promising.},
keywords = {Depreobesity, Depression, genes, Obesity, Saliva},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Obesity and depression are serious public health problems and cause death in the world. In this article, we will study the concept of depreobesity that explains the depression in the context of obesity and vice versa. We will review whether animals can be used to understand the interrelationship between obesity and depression. We will propose saliva as a translational paradigm to predict the depreobesity. Policymakers need to identify new strategies for depreobesity by understanding the complexity of shared biology (depression-obesity). Perspectives for the future are promising.
Eagleman, David M.; Vaughn, Don A.
The Defensive Activation theory: dreaming as a mechanism to prevent takeover of the visual cortex Journal Article
In: bioRxiv , 2020.
Abstract | Links | BibTeX | Tags: REM, visual cortex
@article{Eagleman2020Defensiveb,
title = {The Defensive Activation theory: dreaming as a mechanism to prevent takeover of the visual cortex},
author = {David M. Eagleman and Don A. Vaughn},
doi = {doi.org/10.1101/2020.07.24.219089 },
year = {2020},
date = {2020-07-24},
journal = {bioRxiv },
abstract = {Regions of the brain maintain their territory with continuous activity: if activity slows or stops (e.g., because of blindness), the territory tends to be taken over by its neighbors. A surprise in recent years has been the speed of takeover, which is measurable within an hour. These findings lead us to a new hypothesis on the origin of dream sleep. We hypothesize that the circuitry underlying dreaming serves to amplify the visual system’s activity periodically throughout the night, allowing it to defend its territory against takeover from other senses. We find that measures of plasticity across 25 species of primates correlate positively with the proportion of rapid eye movement (REM) sleep. We further find that plasticity and REM sleep increase in lockstep with evolutionary recency to humans. Finally, our hypothesis is consistent with the decrease in REM sleep and parallel decrease in neuroplasticity with aging.},
keywords = {REM, visual cortex},
pubstate = {published},
tppubtype = {article}
}
Regions of the brain maintain their territory with continuous activity: if activity slows or stops (e.g., because of blindness), the territory tends to be taken over by its neighbors. A surprise in recent years has been the speed of takeover, which is measurable within an hour. These findings lead us to a new hypothesis on the origin of dream sleep. We hypothesize that the circuitry underlying dreaming serves to amplify the visual system’s activity periodically throughout the night, allowing it to defend its territory against takeover from other senses. We find that measures of plasticity across 25 species of primates correlate positively with the proportion of rapid eye movement (REM) sleep. We further find that plasticity and REM sleep increase in lockstep with evolutionary recency to humans. Finally, our hypothesis is consistent with the decrease in REM sleep and parallel decrease in neuroplasticity with aging.
Y. Lau, Ding
Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients Bachelor Thesis
2020.
Abstract | Links | BibTeX | Tags: Amyloid-beta, citric acid cycle, glycolysis, mild cognitive impairment, omega-3 fatty acids, phagocytosis.
@bachelorthesis{Lau2020Omega,
title = {Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients},
author = {Lau, Y., Ding, J. A., Simental, A., Mirzoyan, H., Lee, W., Diamante, G., Cely, I., Tran, M., Morselli, M., Dang, J., Kaczor-Urbanowicz, K. E., Sayre, J., Stiles, L., Yang, X., Pellegrini, M., & Fiala, M. },
doi = {DOI: 10.1096/fj.202000669RR},
year = {2020},
date = {2020-07-02},
urldate = {2020-07-02},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {34},
number = {8},
pages = {9982-9994},
abstract = {Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients’ macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.},
keywords = {Amyloid-beta, citric acid cycle, glycolysis, mild cognitive impairment, omega-3 fatty acids, phagocytosis.},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients’ macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.
Bhat, Kruttika; Saki, Mohammad; Vlashi, Erina; Cheng, Fei; Duhachek-Muggy, Sara; Alli, Claudia; Yu, Garrett; Medina, Paul; He, Ling; Damoiseaux, Robert; Pellegrini, Matteo; Zemke, Nathan R.; Nghiemphu, Phioanh Leia; Cloughesy, Timothy F.; Liau, Linda M.; Kornblum, Harley I.; Pajonk, Frank
The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma Journal Article
In: Proceedings of the National Academy of Sciences , 32358191 , 2020.
Abstract | Links | BibTeX | Tags: dedifferentiation; dopamine receptor antagonist; glioblastoma; glioma-initiating cells; radiation
@article{Bhat2020Dopamine,
title = {The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma},
author = {Kruttika Bhat and Mohammad Saki and Erina Vlashi and Fei Cheng and Sara Duhachek-Muggy and Claudia Alli and Garrett Yu and Paul Medina and Ling He and Robert Damoiseaux and Matteo Pellegrini and Nathan R. Zemke and Phioanh Leia Nghiemphu and Timothy F. Cloughesy and Linda M. Liau and Harley I. Kornblum and Frank Pajonk },
doi = {https://doi.org/10.1073/pnas.1920154117},
year = {2020},
date = {2020-05-01},
journal = {Proceedings of the National Academy of Sciences },
volume = {32358191},
abstract = {Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs). },
keywords = {dedifferentiation; dopamine receptor antagonist; glioblastoma; glioma-initiating cells; radiation},
pubstate = {published},
tppubtype = {article}
}
Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).
Lau YCC Fiala M, Aghajani A
2020.
Abstract | Links | BibTeX | Tags: Amyloid-beta, bioenergy, cell signaling, cholinesterase inhibitor, glycolysis, phagocytosis, tricarboxylic cycle, ω-3 fatty acids.
@bachelorthesis{nokey,
title = {Omega-3 Fatty Acids Increase Amyloid-β Immunity, Energy, and Circadian Rhythm for Cognitive Protection of Alzheimer's Disease Patients Beyond Cholinesterase Inhibitors},
author = {Fiala M, Lau YCC, Aghajani A, Bhargava S, Aminpour E, Kaczor-Urbanowicz KE, Mirzoyan H, Nichols I, Ko MW, Morselli M, Santana J, Dang J, Sayre J, Paul K, Pellegrini M. },
doi = {DOI: 10.3233/JAD-200252},
year = {2020},
date = {2020-03-24},
journal = {Journal of Alzheimer's disease},
volume = {75},
number = {3},
pages = {993-1002},
abstract = {Background: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer's disease (AD) are palliative for a limited time.
Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish.
Methods: We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients.
Results: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2.
Conclusion: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.},
keywords = {Amyloid-beta, bioenergy, cell signaling, cholinesterase inhibitor, glycolysis, phagocytosis, tricarboxylic cycle, ω-3 fatty acids.},
pubstate = {published},
tppubtype = {bachelorthesis}
}
Background: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer's disease (AD) are palliative for a limited time.
Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish.
Methods: We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients.
Results: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2.
Conclusion: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.
Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish.
Methods: We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients.
Results: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2.
Conclusion: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.
Neal, Adam S.; Nunez, Miguel; Lai, Tiffany; Tosevska, Anela; Morselli, Marco; Amneus, Malaika; Zakhour, Mae; Moatamed, Neda A.; Pellegrini, Matteo; Memarzadeh, Sanaz
In: Reproductive Sciences, 2020.
Abstract | Links | BibTeX | Tags: Biomarker, Endometrial hyperplasia, Hormonal therapy, Progesterone receptor, Progesterone therapy
@article{Neal2020Expression,
title = {Expression of Stromal Progesterone Receptor and Differential Methylation Patterns in the Endometrium May Correlate with Response to Progesterone Therapy in Endometrial Complex Atypical Hyperplasia.},
author = {Adam S. Neal and Miguel Nunez and Tiffany Lai and Anela Tosevska and Marco Morselli and Malaika Amneus and Mae Zakhour and Neda A. Moatamed and Matteo Pellegrini and Sanaz Memarzadeh},
doi = {https://doi.org/10.1007/s43032-020-00175-w},
year = {2020},
date = {2020-03-02},
journal = {Reproductive Sciences},
abstract = {Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.},
keywords = {Biomarker, Endometrial hyperplasia, Hormonal therapy, Progesterone receptor, Progesterone therapy},
pubstate = {published},
tppubtype = {article}
}
Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.
Brito, Jaqueline J; Mosqueiro, Thiago; Rotman, Jeremy; Xue, Victor; Chapski, Douglas J; la Hoz, Juan De; Matias, Paulo; Martin, Lana S; Zelikovsky, Alex; Pellegrini, Matteo; Mangul, Serghei
Telescope: an interactive tool for managing large-scale analysis from mobile devices Journal Article
In: GigaScience, 9 (1), 2020.
Abstract | Links | BibTeX | Tags: DAG, directed acyclic graph, Graphical User Interface, GUI, Research Computing, Secure Shell, SGE, Sun Grid Engine, telescopes, VDI
@article{Brito2020Telescope,
title = {Telescope: an interactive tool for managing large-scale analysis from mobile devices},
author = {Jaqueline J Brito and Thiago Mosqueiro and Jeremy Rotman and Victor Xue and Douglas J Chapski and Juan De la Hoz and Paulo Matias and Lana S Martin and Alex Zelikovsky and Matteo Pellegrini and Serghei Mangul },
url = {https://doi.org/10.1093/gigascience/giz163},
year = {2020},
date = {2020-01-23},
journal = {GigaScience},
volume = {9},
number = {1},
abstract = {In today's world of big data, computational analysis has become a key driver of biomedical research. High-performance computational facilities are capable of processing considerable volumes of data, yet often lack an easy-to-use interface to guide the user in supervising and adjusting bioinformatics analysis via a tablet or smartphone.},
keywords = {DAG, directed acyclic graph, Graphical User Interface, GUI, Research Computing, Secure Shell, SGE, Sun Grid Engine, telescopes, VDI},
pubstate = {published},
tppubtype = {article}
}
In today's world of big data, computational analysis has become a key driver of biomedical research. High-performance computational facilities are capable of processing considerable volumes of data, yet often lack an easy-to-use interface to guide the user in supervising and adjusting bioinformatics analysis via a tablet or smartphone.
2019
Lozano‐Huntelman, Natalie Ann; Singh, Nina; Valencia, Alondra; Mira, Portia; Sakayan, Maral; Boucher, Ian; Tang, Sharon; Brennan, Kelley; Gianvecchio, Crystal; Fitz‐Gibbon, Sorel; Yeh, Pamela
In: Evolutionary Applications, 2019.
Abstract | Links | BibTeX | Tags: antibiotic resistance, antimicrobial, bacterial evolution, correlated traits, susceptible
@article{Lazano2019evolution,
title = {Evolution of Antibiotic Cross‐resistance and Collateral Sensitivity in Staphylococcus Epidermidis Using the Mutant Prevention Concentration and the Mutant Selection Window},
author = {Natalie Ann Lozano‐Huntelman and
Nina Singh and
Alondra Valencia and
Portia Mira and
Maral Sakayan and
Ian Boucher and
Sharon Tang and
Kelley Brennan and
Crystal Gianvecchio and
Sorel Fitz‐Gibbon and
Pamela Yeh},
doi = {https://doi.org/10.1111/eva.12903},
year = {2019},
date = {2019-12-12},
journal = {Evolutionary Applications},
abstract = {In bacteria, evolution of resistance to one antibiotic is frequently associated with increased resistance (cross‐resistance) or increased susceptibility (collateral sensitivity) to other antibiotics. Cross‐resistance and collateral sensitivity are typically evaluated at the minimum inhibitory concentration (MIC). However, these susceptibility changes are not well characterized with respect to the mutant prevention concentration (MPC), the antibiotic concentration that prevents a single‐step mutation from occurring. We measured the MIC and the MPC for Staphylococcus epidermidis and 14 single‐drug resistant strains against seven antibiotics. We found that the MIC and the MPC were positively correlated but that this correlation weakened if cross‐resistance did not evolve. If any type of resistance did evolve, the range of concentrations between the MIC and the MPC tended to shift right and widen. Similar patterns of cross‐resistance and collateral sensitivity were observed at the MIC and MPC levels, though more symmetry was observed at the MIC level. Whole‐genome sequencing revealed mutations in both known‐target and nontarget genes. Moving forward, examining both the MIC and the MPC may lead to better predictions of evolutionary trajectories in antibiotic‐resistant bacteria.},
keywords = {antibiotic resistance, antimicrobial, bacterial evolution, correlated traits, susceptible},
pubstate = {published},
tppubtype = {article}
}
In bacteria, evolution of resistance to one antibiotic is frequently associated with increased resistance (cross‐resistance) or increased susceptibility (collateral sensitivity) to other antibiotics. Cross‐resistance and collateral sensitivity are typically evaluated at the minimum inhibitory concentration (MIC). However, these susceptibility changes are not well characterized with respect to the mutant prevention concentration (MPC), the antibiotic concentration that prevents a single‐step mutation from occurring. We measured the MIC and the MPC for Staphylococcus epidermidis and 14 single‐drug resistant strains against seven antibiotics. We found that the MIC and the MPC were positively correlated but that this correlation weakened if cross‐resistance did not evolve. If any type of resistance did evolve, the range of concentrations between the MIC and the MPC tended to shift right and widen. Similar patterns of cross‐resistance and collateral sensitivity were observed at the MIC and MPC levels, though more symmetry was observed at the MIC level. Whole‐genome sequencing revealed mutations in both known‐target and nontarget genes. Moving forward, examining both the MIC and the MPC may lead to better predictions of evolutionary trajectories in antibiotic‐resistant bacteria.
Galmozzi, Andrea; Kok, Bernard P.; Kim, Arthur S.; Montenegro-Burke, J. Rafael; Lee, Jae Y.; Spreafico, Roberto; Mosure, Sarah; Albert, Verena; Cintron-Colon, Rigo; Godio, Cristina; Webb, William R.; Conti, Bruno; Solt, Laura A.; Kojetin, Douglas; Parker, Christopher G.; Peluso, John J.; Pru, James K.; Siuzdak, Gary; Cravatt, Benjamin F.; Saez, Enrique
PGRMC2 is an intracellular haem chaperone critical for adipocyte function Journal Article
In: 2019.
Abstract | Links | BibTeX | Tags: adipocytes, cytotoxic, gene, haem, haemoproteins, intracellular, molecules, proteins, signalling, thermogenesis
@article{Galmozzi2019PGRMC2,
title = {PGRMC2 is an intracellular haem chaperone critical for adipocyte function},
author = {Andrea Galmozzi and Bernard P. Kok and Arthur S. Kim and J. Rafael Montenegro-Burke and Jae Y. Lee and Roberto Spreafico and Sarah Mosure and Verena Albert and Rigo Cintron-Colon and Cristina Godio and William R. Webb and Bruno Conti and Laura A. Solt and Douglas Kojetin and Christopher G. Parker and John J. Peluso and James K. Pru and Gary Siuzdak and Benjamin F. Cravatt and Enrique Saez},
editor = {Nature},
doi = {doi:10.1038/s41586-019-1774-2},
year = {2019},
date = {2019-11-20},
abstract = {Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.},
keywords = {adipocytes, cytotoxic, gene, haem, haemoproteins, intracellular, molecules, proteins, signalling, thermogenesis},
pubstate = {published},
tppubtype = {article}
}
Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.
Kurmangaliyev, Yerbol Z; Yoo, Juyoun; LoCascio, Samuel A; Zipursky, S Lawrence
Modular transcriptional programs separately define axon and dendrite connectivity. Journal Article
In: eLife, 2019.
Abstract | Links | BibTeX | Tags: D. melanogaster; genetics; genomics; neuronal connectivity; neuroscience; single-cell sequencing; transcriptional programs
@article{Kurmangaliyev2019Modular,
title = {Modular transcriptional programs separately define axon and dendrite connectivity.},
author = { Yerbol Z Kurmangaliyev and Juyoun Yoo and Samuel A LoCascio and S Lawrence Zipursky},
doi = {https://doi.org/10.7554/eLife.50822.001 },
year = {2019},
date = {2019-11-05},
journal = {eLife},
abstract = {Patterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless, a clear logic underlying the transcriptional control of neuronal connectivity has yet to emerge. Here, we focused on Drosophila T4/T5 neurons, a class of closely related neuronal subtypes with different wiring patterns. Eight subtypes of T4/T5 neurons are defined by combinations of two patterns of dendritic inputs and four patterns of axonal outputs. Single-cell profiling during development revealed distinct transcriptional programs defining each dendrite and axon wiring pattern. These programs were defined by the expression of a few transcription factors and different combinations of cell surface proteins. Gain and loss of function studies provide evidence for independent control of different wiring features. We propose that modular transcriptional programs for distinct wiring features are assembled in different combinations to generate diverse patterns of neuronal connectivity.},
keywords = {D. melanogaster; genetics; genomics; neuronal connectivity; neuroscience; single-cell sequencing; transcriptional programs},
pubstate = {published},
tppubtype = {article}
}
Patterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless, a clear logic underlying the transcriptional control of neuronal connectivity has yet to emerge. Here, we focused on Drosophila T4/T5 neurons, a class of closely related neuronal subtypes with different wiring patterns. Eight subtypes of T4/T5 neurons are defined by combinations of two patterns of dendritic inputs and four patterns of axonal outputs. Single-cell profiling during development revealed distinct transcriptional programs defining each dendrite and axon wiring pattern. These programs were defined by the expression of a few transcription factors and different combinations of cell surface proteins. Gain and loss of function studies provide evidence for independent control of different wiring features. We propose that modular transcriptional programs for distinct wiring features are assembled in different combinations to generate diverse patterns of neuronal connectivity.
Bulterys, P. L.; Toesca, I. J.; Norris, M. H.; Maloy, J. P.; Fitz-Gibbon, S. T.; France, B.; Toffig, B.; Morselli, M.; Somprasong, N.; Pellegrini, M.; Schweizer, H. P.; Tuanyok, A; Damoiseaux, R; French, C. T.; Miller, J. F.
An in situ high-throughput screen identifies inhibitors of intracellular Burkholderia pseudomallei with therapeutic efficacy. Journal Article
In: Proc Natl Acad Sci U S A. , 2019.
Abstract | Links | BibTeX | Tags: Burkholderia pseudomallei; drug discovery; melioidosis; small molecule; type 6 secretion system
@article{Bulterys2019AnInSitu,
title = {An in situ high-throughput screen identifies inhibitors of intracellular Burkholderia pseudomallei with therapeutic efficacy.},
author = {Bulterys, P.L. and Toesca, I.J. and Norris, M.H. and Maloy, J.P. and Fitz-Gibbon, S.T. and France, B. and Toffig, B. and Morselli, M. and Somprasong, N. and Pellegrini, M. and Schweizer, H.P. and Tuanyok, A and Damoiseaux, R and French, C.T. and Miller, J.F.},
url = {https://doi.org/10.1073/pnas.1906388116},
doi = {10.1073/pnas.1906388116},
year = {2019},
date = {2019-09-10},
journal = {Proc Natl Acad Sci U S A. },
abstract = {urkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are Tier-1 Select Agents that cause melioidosis and glanders, respectively. These are highly lethal human infections with limited therapeutic options. Intercellular spread is a hallmark of Burkholderia pathogenesis, and its prominent ties to virulence make it an attractive therapeutic target. We developed a high-throughput cell-based phenotypic assay and screened ∼220,000 small molecules for their ability to disrupt intercellular spread by Burkholderia thailandensis, a closely related BSL-2 surrogate. We identified 268 hits, and cross-species validation found 32 hits that also disrupt intercellular spread by Bp and/or Bm Among these were a fluoroquinolone analog, which we named burkfloxacin (BFX), which potently inhibits growth of intracellular Burkholderia, and flucytosine (5-FC), an FDA-approved antifungal drug. We found that 5-FC blocks the intracellular life cycle at the point of type VI secretion system 5 (T6SS-5)-mediated cell-cell spread. Bacterial conversion of 5-FC to 5-fluorouracil and subsequently to fluorouridine monophosphate is required for potent and selective activity against intracellular Burkholderia In a murine model of fulminant respiratory melioidosis, treatment with BFX or 5-FC was significantly more effective than ceftazidime, the current antibiotic of choice, for improving survival and decreasing bacterial counts in major organs. Our results demonstrate the utility of cell-based phenotypic screening for Select Agent drug discovery and warrant the advancement of BFX and 5-FC as candidate therapeutics for melioidosis in humans.},
keywords = {Burkholderia pseudomallei; drug discovery; melioidosis; small molecule; type 6 secretion system},
pubstate = {published},
tppubtype = {article}
}
urkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are Tier-1 Select Agents that cause melioidosis and glanders, respectively. These are highly lethal human infections with limited therapeutic options. Intercellular spread is a hallmark of Burkholderia pathogenesis, and its prominent ties to virulence make it an attractive therapeutic target. We developed a high-throughput cell-based phenotypic assay and screened ∼220,000 small molecules for their ability to disrupt intercellular spread by Burkholderia thailandensis, a closely related BSL-2 surrogate. We identified 268 hits, and cross-species validation found 32 hits that also disrupt intercellular spread by Bp and/or Bm Among these were a fluoroquinolone analog, which we named burkfloxacin (BFX), which potently inhibits growth of intracellular Burkholderia, and flucytosine (5-FC), an FDA-approved antifungal drug. We found that 5-FC blocks the intracellular life cycle at the point of type VI secretion system 5 (T6SS-5)-mediated cell-cell spread. Bacterial conversion of 5-FC to 5-fluorouracil and subsequently to fluorouridine monophosphate is required for potent and selective activity against intracellular Burkholderia In a murine model of fulminant respiratory melioidosis, treatment with BFX or 5-FC was significantly more effective than ceftazidime, the current antibiotic of choice, for improving survival and decreasing bacterial counts in major organs. Our results demonstrate the utility of cell-based phenotypic screening for Select Agent drug discovery and warrant the advancement of BFX and 5-FC as candidate therapeutics for melioidosis in humans.
Romero, Zulema; Lomova, Anastasia; Said, Suzanne; Miggelbrink, Alexandra; Kuo, Caroline Y.; Campo-Fernandez, Beatriz; D.Hoban, Megan; E.Masiuk, Katelyn; N.Clark, Danielle; Long, Joseph; M.Sanchez, Julie; MiriamVelez,; Miyahira, Eric; Zhang, Ruixue; Brown, Devin; Wang, Xiaoyan; Z.Kurmangaliyev, Yerbol; P.Hollis, Roger; B.Kohn., Donald
Editing the Sickle Cell Disease Mutation in Human Hematopoietic Stem Cells: Comparison of Endonucleases and Homologous Donor Templates. Journal Article
In: Molecular Therapy, 27 (8), pp. 1389-1406, 2019.
Abstract | Links | BibTeX | Tags: CRISPR/Cas9; adeno-associated virus 6; gene editing; hematopoietic stem cells; homologous recombination; non-homologous end joining; sickle cell disease; zinc finger nuclease
@article{Romero2019Editing,
title = {Editing the Sickle Cell Disease Mutation in Human Hematopoietic Stem Cells: Comparison of Endonucleases and Homologous Donor Templates.},
author = {Zulema Romero and Anastasia Lomova and Suzanne Said and Alexandra Miggelbrink and Caroline Y. Kuo and Beatriz Campo-Fernandez and Megan D.Hoban and Katelyn E.Masiuk and Danielle N.Clark and Joseph Long and Julie M.Sanchez and MiriamVelez and Eric Miyahira and Ruixue Zhang and Devin Brown and Xiaoyan Wang and Yerbol Z.Kurmangaliyev and Roger P.Hollis and Donald B.Kohn. },
url = {https://doi.org/10.1016/j.ymthe.2019.05.014},
doi = {doi: 10.1016/j.ymthe.2019.05.014},
year = {2019},
date = {2019-08-07},
journal = {Molecular Therapy},
volume = {27},
number = {8},
pages = {1389-1406},
abstract = {Site-specific correction of a point mutation causing a monogenic disease in autologous hematopoietic stem and progenitor cells (HSPCs) can be used as a treatment of inherited disorders of the blood cells. Sickle cell disease (SCD) is an ideal model to investigate the potential use of gene editing to transvert a single point mutation at the β-globin locus (HBB). We compared the activity of zinc-finger nucleases (ZFNs) and CRISPR/Cas9 for editing, and homologous donor templates delivered as single-stranded oligodeoxynucleotides (ssODNs), adeno-associated virus serotype 6 (AAV6), integrase-deficient lentiviral vectors (IDLVs), and adenovirus 5/35 serotype (Ad5/35) to transvert the base pair responsible for SCD in HBB in primary human CD34+ HSPCs. We found that the ZFNs and Cas9 directed similar frequencies of nuclease activity. In vitro, AAV6 led to the highest frequencies of homology-directed repair (HDR), but levels of base pair transversions were significantly reduced when analyzing cells in vivo in immunodeficient mouse xenografts, with similar frequencies achieved with either AAV6 or ssODNs. AAV6 also caused significant impairment of colony-forming progenitors and human cell engraftment. Gene correction in engrafting hematopoietic stem cells may be limited by the capacity of the cells to mediate HDR, suggesting additional manipulations may be needed for high-efficiency gene correction in HSPCs.},
keywords = {CRISPR/Cas9; adeno-associated virus 6; gene editing; hematopoietic stem cells; homologous recombination; non-homologous end joining; sickle cell disease; zinc finger nuclease},
pubstate = {published},
tppubtype = {article}
}
Site-specific correction of a point mutation causing a monogenic disease in autologous hematopoietic stem and progenitor cells (HSPCs) can be used as a treatment of inherited disorders of the blood cells. Sickle cell disease (SCD) is an ideal model to investigate the potential use of gene editing to transvert a single point mutation at the β-globin locus (HBB). We compared the activity of zinc-finger nucleases (ZFNs) and CRISPR/Cas9 for editing, and homologous donor templates delivered as single-stranded oligodeoxynucleotides (ssODNs), adeno-associated virus serotype 6 (AAV6), integrase-deficient lentiviral vectors (IDLVs), and adenovirus 5/35 serotype (Ad5/35) to transvert the base pair responsible for SCD in HBB in primary human CD34+ HSPCs. We found that the ZFNs and Cas9 directed similar frequencies of nuclease activity. In vitro, AAV6 led to the highest frequencies of homology-directed repair (HDR), but levels of base pair transversions were significantly reduced when analyzing cells in vivo in immunodeficient mouse xenografts, with similar frequencies achieved with either AAV6 or ssODNs. AAV6 also caused significant impairment of colony-forming progenitors and human cell engraftment. Gene correction in engrafting hematopoietic stem cells may be limited by the capacity of the cells to mediate HDR, suggesting additional manipulations may be needed for high-efficiency gene correction in HSPCs.
Cantarella, S.; Carnevali, D.; Morselli, M.; Conti, A.; Pellegrini, M.; Montanini, B.; Dieci, G.
Alu RNA Modulates the Expression of Cell Cycle Genes in Human Fibroblasts. Journal Article
In: Int J Mol Sci. , 20 (13), 2019.
Abstract | Links | BibTeX | Tags: Alu retrotransposons; cell cycle; non-coding RNA
@article{Cantarella2019AluRNA,
title = {Alu RNA Modulates the Expression of Cell Cycle Genes in Human Fibroblasts.},
author = {Cantarella, S. and Carnevali, D. and Morselli, M. and Conti, A. and Pellegrini, M. and Montanini, B. and Dieci, G.},
url = {https://doi.org/10.3390/ijms20133315},
doi = {10.3390/ijms20133315},
year = {2019},
date = {2019-07-05},
journal = {Int J Mol Sci. },
volume = {20},
number = {13},
abstract = {Alu retroelements, whose retrotransposition requires prior transcription by RNA polymerase III to generate Alu RNAs, represent the most numerous non-coding RNA (ncRNA) gene family in the human genome. Alu transcription is generally kept to extremely low levels by tight epigenetic silencing, but it has been reported to increase under different types of cell perturbation, such as viral infection and cancer. Alu RNAs, being able to act as gene expression modulators, may be directly involved in the mechanisms determining cellular behavior in such perturbed states. To directly address the regulatory potential of Alu RNAs, we generated IMR90 fibroblasts and HeLa cell lines stably overexpressing two slightly different Alu RNAs, and analyzed genome-wide the expression changes of protein-coding genes through RNA-sequencing. Among the genes that were upregulated or downregulated in response to Alu overexpression in IMR90, but not in HeLa cells, we found a highly significant enrichment of pathways involved in cell cycle progression and mitotic entry. Accordingly, Alu overexpression was found to promote transition from G1 to S phase, as revealed by flow cytometry. Therefore, increased Alu RNA may contribute to sustained cell proliferation, which is an important factor of cancer development and progression.},
keywords = {Alu retrotransposons; cell cycle; non-coding RNA},
pubstate = {published},
tppubtype = {article}
}
Alu retroelements, whose retrotransposition requires prior transcription by RNA polymerase III to generate Alu RNAs, represent the most numerous non-coding RNA (ncRNA) gene family in the human genome. Alu transcription is generally kept to extremely low levels by tight epigenetic silencing, but it has been reported to increase under different types of cell perturbation, such as viral infection and cancer. Alu RNAs, being able to act as gene expression modulators, may be directly involved in the mechanisms determining cellular behavior in such perturbed states. To directly address the regulatory potential of Alu RNAs, we generated IMR90 fibroblasts and HeLa cell lines stably overexpressing two slightly different Alu RNAs, and analyzed genome-wide the expression changes of protein-coding genes through RNA-sequencing. Among the genes that were upregulated or downregulated in response to Alu overexpression in IMR90, but not in HeLa cells, we found a highly significant enrichment of pathways involved in cell cycle progression and mitotic entry. Accordingly, Alu overexpression was found to promote transition from G1 to S phase, as revealed by flow cytometry. Therefore, increased Alu RNA may contribute to sustained cell proliferation, which is an important factor of cancer development and progression.
Leung CS,; Douglass SM,; Morselli M,; Obusan MB,; Pavlyukov MS,; Pellegrini M,; TL., Johnson
H3K36 Methylation and the Chromodomain Protein Eaf3 Are Required for Proper Cotranscriptional Spliceosome Assembly. Journal Article
In: Cell Rep. , 27 (13), pp. 3760-3769, 2019.
Abstract | Links | BibTeX | Tags: Eaf3; H3K36; Set2; chromatin; cotranscriptional splicing; methylation
@article{Leung2019H3K36Methylation,
title = {H3K36 Methylation and the Chromodomain Protein Eaf3 Are Required for Proper Cotranscriptional Spliceosome Assembly.},
author = {Leung CS, and Douglass SM, and Morselli M, and Obusan MB, and Pavlyukov MS, and Pellegrini M, and Johnson TL.},
url = {https://doi.org/10.1016/j.celrep.2019.05.100},
doi = {10.1016/j.celrep.2019.05.100},
year = {2019},
date = {2019-06-25},
journal = {Cell Rep. },
volume = {27},
number = {13},
pages = {3760-3769},
abstract = {In the eukaryotic cell, spliceosomes assemble onto pre-mRNA cotranscriptionally. Spliceosome assembly takes place in the context of the chromatin environment, suggesting that the state of the chromatin may affect splicing. The molecular details and mechanisms through which chromatin affects splicing, however, are still unclear. Here, we show a role for the histone methyltransferase Set2 and its histone modification, H3K36 methylation, in pre-mRNA splicing through high-throughput sequencing. Moreover, the effect of H3K36 methylation on pre-mRNA splicing is mediated through the chromodomain protein Eaf3. We find that Eaf3 is recruited to intron-containing genes and that Eaf3 interacts with the splicing factor Prp45. Eaf3 acts with Prp45 and Prp19 after formation of the precatalytic B complex around the time of splicing activation, thus revealing the step in splicing that is regulated by H3K36 methylation. These studies support a model whereby H3K36 facilitates recruitment of an "adapter protein" to support efficient, constitutive splicing.},
keywords = {Eaf3; H3K36; Set2; chromatin; cotranscriptional splicing; methylation},
pubstate = {published},
tppubtype = {article}
}
In the eukaryotic cell, spliceosomes assemble onto pre-mRNA cotranscriptionally. Spliceosome assembly takes place in the context of the chromatin environment, suggesting that the state of the chromatin may affect splicing. The molecular details and mechanisms through which chromatin affects splicing, however, are still unclear. Here, we show a role for the histone methyltransferase Set2 and its histone modification, H3K36 methylation, in pre-mRNA splicing through high-throughput sequencing. Moreover, the effect of H3K36 methylation on pre-mRNA splicing is mediated through the chromodomain protein Eaf3. We find that Eaf3 is recruited to intron-containing genes and that Eaf3 interacts with the splicing factor Prp45. Eaf3 acts with Prp45 and Prp19 after formation of the precatalytic B complex around the time of splicing activation, thus revealing the step in splicing that is regulated by H3K36 methylation. These studies support a model whereby H3K36 facilitates recruitment of an "adapter protein" to support efficient, constitutive splicing.
2018
Sammy Pontrelli,; and Shao Thing Teoh Riley C. B. Fricke,; Walter A. Laviña,; Sastia Prama Putri,; Sorel Fitz-Gibbon,; Matthew Chung,; Matteo Pellegrini,; Eiichiro Fukusaki,; Liao, James C.
Metabolic repair through emergence of new pathways in Escherichia coli Journal Article
In: Nature Chemical Biology, 14 (11), pp. 1005–1009, 2018.
Abstract | Links | BibTeX | Tags: e.coli, metabolic repair
@article{Pontrelli2018Metabolic,
title = {Metabolic repair through emergence of new pathways in Escherichia coli},
author = {Pontrelli, Sammy, and Riley C. B. Fricke,and Shao Thing Teoh, and Walter A. Laviña, and Sastia Prama Putri, and Sorel Fitz-Gibbon, and Matthew Chung, and Matteo Pellegrini, and Eiichiro Fukusaki, and James C. Liao},
doi = {https://doi.org/10.1038/s41589-018-0149-6},
year = {2018},
date = {2018-10-16},
journal = {Nature Chemical Biology},
volume = {14},
number = {11},
pages = {1005–1009},
abstract = {Escherichia coli can derive all essential metabolites and cofactors through a highly evolved metabolic system. Damage of pathways may affect cell growth and physiology, but the strategies by which damaged metabolic pathways can be circumvented remain intriguing. Here, we use a ΔpanD (encoding for aspartate 1-decarboxylase) strain of E. coli that is unable to produce the β-alanine required for CoA biosynthesis to demonstrate that metabolic systems can overcome pathway damage by extensively rerouting metabolic pathways and modifying existing enzymes for unnatural functions. Using directed cell evolution, rewiring and repurposing of uracil metabolism allowed formation of an alternative β-alanine biosynthetic pathway. After this pathway was deleted, a second was evolved that used a gain-of-function mutation on ornithine decarboxylase (SpeC) to alter reaction and substrate specificity toward an oxidative decarboxylation–deamination reaction. After deletion of both pathways, yet another independent pathway emerged using polyamine biosynthesis, demonstrating the vast capacity of metabolic repair. },
keywords = {e.coli, metabolic repair},
pubstate = {published},
tppubtype = {article}
}
Escherichia coli can derive all essential metabolites and cofactors through a highly evolved metabolic system. Damage of pathways may affect cell growth and physiology, but the strategies by which damaged metabolic pathways can be circumvented remain intriguing. Here, we use a ΔpanD (encoding for aspartate 1-decarboxylase) strain of E. coli that is unable to produce the β-alanine required for CoA biosynthesis to demonstrate that metabolic systems can overcome pathway damage by extensively rerouting metabolic pathways and modifying existing enzymes for unnatural functions. Using directed cell evolution, rewiring and repurposing of uracil metabolism allowed formation of an alternative β-alanine biosynthetic pathway. After this pathway was deleted, a second was evolved that used a gain-of-function mutation on ornithine decarboxylase (SpeC) to alter reaction and substrate specificity toward an oxidative decarboxylation–deamination reaction. After deletion of both pathways, yet another independent pathway emerged using polyamine biosynthesis, demonstrating the vast capacity of metabolic repair.
Eagleman, Sarah L.; Vaughn, Don A.; Drover, David R.; Drover, Caitlin M.; Cohen, Mark S.; Ouellette, Nicholas T.; MacIver., M. Bruce
Do Complexity Measures of Frontal EEG Distinguish Loss of Consciousness in Geriatric Patients Under Anesthesia? Journal Article
In: Frontiers in neuroscience, 12 , pp. 645, 2018.
Abstract | Links | BibTeX | Tags: anesthesia, electroencephalogram, entropy, geriatric, multiscale
@article{Eagleman2018DoComplexity,
title = { Do Complexity Measures of Frontal EEG Distinguish Loss of Consciousness in Geriatric Patients Under Anesthesia?},
author = { Sarah L. Eagleman and Don A. Vaughn and David R. Drover and Caitlin M. Drover and Mark S. Cohen and Nicholas T. Ouellette and M. Bruce MacIver.},
url = {https://doi.org/10.3389/fnins.2018.00645},
doi = {10.3389/fnins.2018.00645},
year = {2018},
date = {2018-09-20},
journal = {Frontiers in neuroscience},
volume = {12},
pages = {645},
abstract = {While geriatric patients have a high likelihood of requiring anesthesia, they carry an increased risk for adverse cognitive outcomes from its use. Previous work suggests this could be mitigated by better intraoperative monitoring using indexes defined by several processed electroencephalogram (EEG) measures. Unfortunately, inconsistencies between patients and anesthetic agents in current analysis techniques have limited the adoption of EEG as standard of care. In attempts to identify new analyses that discriminate clinically-relevant anesthesia timepoints, we tested 1/f frequency scaling as well as measures of complexity from nonlinear dynamics. Specifically, we tested whether analyses that characterize time-delayed embeddings, correlation dimension (CD), phase-space geometric analysis, and multiscale entropy (MSE) capture loss-of-consciousness changes in EEG activity. We performed these analyses on EEG activity collected from a traditionally hard-to-monitor patient population: geriatric patients on beta-adrenergic blockade who were anesthetized using a combination of fentanyl and propofol. We compared these analyses to traditional frequency-derived measures to test how well they discriminated EEG states before and after loss of response to verbal stimuli. We found spectral changes similar to those reported previously during loss of response. We also found significant changes in 1/f frequency scaling. Additionally, we found that our phase-space geometric characterization of time-delayed embeddings showed significant differences before and after loss of response, as did measures of MSE. Our results suggest that our new spectral and complexity measures are capable of capturing subtle differences in EEG activity with anesthesia administration—differences which future work may reveal to improve geriatric patient monitoring.},
keywords = {anesthesia, electroencephalogram, entropy, geriatric, multiscale},
pubstate = {published},
tppubtype = {article}
}
While geriatric patients have a high likelihood of requiring anesthesia, they carry an increased risk for adverse cognitive outcomes from its use. Previous work suggests this could be mitigated by better intraoperative monitoring using indexes defined by several processed electroencephalogram (EEG) measures. Unfortunately, inconsistencies between patients and anesthetic agents in current analysis techniques have limited the adoption of EEG as standard of care. In attempts to identify new analyses that discriminate clinically-relevant anesthesia timepoints, we tested 1/f frequency scaling as well as measures of complexity from nonlinear dynamics. Specifically, we tested whether analyses that characterize time-delayed embeddings, correlation dimension (CD), phase-space geometric analysis, and multiscale entropy (MSE) capture loss-of-consciousness changes in EEG activity. We performed these analyses on EEG activity collected from a traditionally hard-to-monitor patient population: geriatric patients on beta-adrenergic blockade who were anesthetized using a combination of fentanyl and propofol. We compared these analyses to traditional frequency-derived measures to test how well they discriminated EEG states before and after loss of response to verbal stimuli. We found spectral changes similar to those reported previously during loss of response. We also found significant changes in 1/f frequency scaling. Additionally, we found that our phase-space geometric characterization of time-delayed embeddings showed significant differences before and after loss of response, as did measures of MSE. Our results suggest that our new spectral and complexity measures are capable of capturing subtle differences in EEG activity with anesthesia administration—differences which future work may reveal to improve geriatric patient monitoring.
Sammy Pontrelli,; Riley C. B. Fricke,; Memon, Sana Subhan; Sakurai, Sastia; Prama Putri,; Sorel Fitz-Gibbon,; Matthew Chung,; Hsin-Yi Wu,
Directed strain evolution restructures metabolism for 1-butanol production in minimal media Journal Article
In: Metabolic Engineering, 49 , pp. 153-163, 2018.
Abstract | Links | BibTeX | Tags: butanol, metabolomics, proteomics
@article{Pontrelli2018,
title = {Directed strain evolution restructures metabolism for 1-butanol production in minimal media},
author = {Pontrelli, Sammy, and Riley C. B. Fricke, and Sana Subhan Memon and Sakurai, Sastia and Prama Putri, and Sorel Fitz-Gibbon, and Matthew Chung, and Hsin-Yi Wu,},
doi = {https://doi.org/10.1016/j.ymben.2018.08.004},
year = {2018},
date = {2018-09-03},
journal = {Metabolic Engineering},
volume = {49},
pages = {153-163},
abstract = {Engineering a microbial strain for production sometimes entails metabolic modifications that impair essential physiological processes for growth or production. Restoring these functions may require amending a variety of non-obvious physiological networks, and thus, rational design strategies may not be practical. Here we demonstrate that growth and production may be restored by evolution that repairs impaired metabolic function. Furthermore, we use genomics, metabolomics and proteomics to identify several underlying mutations and metabolic perturbations that allow metabolism to repair. Previously, high titers of butanol production were achieved by Escherichia coli using a growth-coupled, modified Clostridial CoA-dependent pathway after all native fermentative pathways were deleted. However, production was only observed in rich media. Native metabolic function of the host was unable to support growth and production in minimal media. We use directed cell evolution to repair this phenotype and observed improved growth, titers and butanol yields. We found a mutation in pcnB which resulted in decreased plasmid copy numbers and pathway enzymes to balance resource utilization. Increased protein abundance was measured for biosynthetic pathways, glycolytic enzymes have increased activity, and adenosyl energy charge was increased. We also found mutations in the ArcAB two-component system and integration host factor (IHF) that tune redox metabolism to alter byproduct formation. These results demonstrate that directed strain evolution can enable systematic adaptations to repair metabolic function and enhance microbial production. Furthermore, these results demonstrate the versatile repair capabilities of cell metabolism and highlight important aspects of cell physiology that are required for production in minimal media.},
keywords = {butanol, metabolomics, proteomics},
pubstate = {published},
tppubtype = {article}
}
Engineering a microbial strain for production sometimes entails metabolic modifications that impair essential physiological processes for growth or production. Restoring these functions may require amending a variety of non-obvious physiological networks, and thus, rational design strategies may not be practical. Here we demonstrate that growth and production may be restored by evolution that repairs impaired metabolic function. Furthermore, we use genomics, metabolomics and proteomics to identify several underlying mutations and metabolic perturbations that allow metabolism to repair. Previously, high titers of butanol production were achieved by Escherichia coli using a growth-coupled, modified Clostridial CoA-dependent pathway after all native fermentative pathways were deleted. However, production was only observed in rich media. Native metabolic function of the host was unable to support growth and production in minimal media. We use directed cell evolution to repair this phenotype and observed improved growth, titers and butanol yields. We found a mutation in pcnB which resulted in decreased plasmid copy numbers and pathway enzymes to balance resource utilization. Increased protein abundance was measured for biosynthetic pathways, glycolytic enzymes have increased activity, and adenosyl energy charge was increased. We also found mutations in the ArcAB two-component system and integration host factor (IHF) that tune redox metabolism to alter byproduct formation. These results demonstrate that directed strain evolution can enable systematic adaptations to repair metabolic function and enhance microbial production. Furthermore, these results demonstrate the versatile repair capabilities of cell metabolism and highlight important aspects of cell physiology that are required for production in minimal media.
Camacho, J; Truong, L; Kurt, Z; Chen, YW; Morselli, M; Gutierrez, G; Pellegrini, M; Yang, X; Allard, P.
The Memory of Environmental Chemical Exposure in C. elegans Is Dependent on the Jumonji Demethylases jmjd-2 and jmjd-3/utx-1. Journal Article
In: Cell Rep., 23 (8), pp. 2392-2404, 2018.
Abstract | Links | BibTeX | Tags: Bisphenol A; C. elegans; epigenetic; histone demethylase; reproductive function; transgenerational inheritance
@article{Camacho2018Memoryb,
title = {The Memory of Environmental Chemical Exposure in C. elegans Is Dependent on the Jumonji Demethylases jmjd-2 and jmjd-3/utx-1.},
author = {Camacho, J and Truong, L and Kurt, Z and Chen, YW and Morselli, M and Gutierrez, G and Pellegrini, M and Yang, X and Allard, P. },
url = {https://doi.org/10.1016/j.celrep.2018.04.078},
doi = {10.1016/j.celrep.2018.04.078},
year = {2018},
date = {2018-05-22},
journal = {Cell Rep.},
volume = {23},
number = {8},
pages = {2392-2404},
abstract = {How artificial environmental cues are biologically integrated and transgenerationally inherited is still poorly understood. Here, we investigate the mechanisms of inheritance of reproductive outcomes elicited by the model environmental chemical Bisphenol A in C. elegans. We show that Bisphenol A (BPA) exposure causes the derepression of an epigenomically silenced transgene in the germline for 5 generations, regardless of ancestral response. Chromatin immunoprecipitation sequencing (ChIP-seq), histone modification quantitation, and immunofluorescence assays revealed that this effect is associated with a reduction of the repressive marks H3K9me3 and H3K27me3 in whole worms and in germline nuclei in the F3, as well as with reproductive dysfunctions, including germline apoptosis and embryonic lethality. Furthermore, targeting of the Jumonji demethylases JMJD-2 and JMJD-3/UTX-1 restores H3K9me3 and H3K27me3 levels, respectively, and it fully alleviates the BPA-induced transgenerational effects. Together, our results demonstrate the central role of repressive histone modifications in the inheritance of reproductive defects elicited by a common environmental chemical exposure.},
keywords = {Bisphenol A; C. elegans; epigenetic; histone demethylase; reproductive function; transgenerational inheritance},
pubstate = {published},
tppubtype = {article}
}
How artificial environmental cues are biologically integrated and transgenerationally inherited is still poorly understood. Here, we investigate the mechanisms of inheritance of reproductive outcomes elicited by the model environmental chemical Bisphenol A in C. elegans. We show that Bisphenol A (BPA) exposure causes the derepression of an epigenomically silenced transgene in the germline for 5 generations, regardless of ancestral response. Chromatin immunoprecipitation sequencing (ChIP-seq), histone modification quantitation, and immunofluorescence assays revealed that this effect is associated with a reduction of the repressive marks H3K9me3 and H3K27me3 in whole worms and in germline nuclei in the F3, as well as with reproductive dysfunctions, including germline apoptosis and embryonic lethality. Furthermore, targeting of the Jumonji demethylases JMJD-2 and JMJD-3/UTX-1 restores H3K9me3 and H3K27me3 levels, respectively, and it fully alleviates the BPA-induced transgenerational effects. Together, our results demonstrate the central role of repressive histone modifications in the inheritance of reproductive defects elicited by a common environmental chemical exposure.
Sarin, Sumeet; Zuniga-Sanchez, Elizabeth; Z.Kurmangaliyev, Yerbol; Cousins, Henry; Patel, Mili; Hernandez, Jeanette; X.Zhang, Kelvin; A.Samuel, Melanie; Morey, Marta; R.Sanes, Joshua; Zipursky, Lawrence
Role for Wnt Signaling in Retinal Neuropil Development: Analysis via RNA-Seq and In Vivo Somatic CRISPR Mutagenesis Journal Article
In: Neuron, 98 (1), pp. 109-126, 2018.
Abstract | Links | BibTeX | Tags: Fzd4; Fzd5; OPL; Ryk; Wnt5; bipolars; neuron; photoreceptors; retina; synapse
@article{Sarin2018Role,
title = {Role for Wnt Signaling in Retinal Neuropil Development: Analysis via RNA-Seq and In Vivo Somatic CRISPR Mutagenesis},
author = {Sumeet Sarin and Elizabeth Zuniga-Sanchez and Yerbol Z.Kurmangaliyev and Henry Cousins and Mili Patel and Jeanette Hernandez and Kelvin X.Zhang and Melanie A.Samuel and Marta Morey and Joshua R.Sanes and Lawrence Zipursky},
doi = {https://doi.org/10.1016/j.neuron.2018.03.004 },
year = {2018},
date = {2018-04-04},
journal = {Neuron},
volume = {98},
number = {1},
pages = {109-126},
abstract = {Screens for genes that orchestrate neural circuit formation in mammals have been hindered by practical constraints of germline mutagenesis. To overcome these limitations, we combined RNA-seq with somatic CRISPR mutagenesis to study synapse development in the mouse retina. Here synapses occur between cellular layers, forming two multilayered neuropils. The outer neuropil, the outer plexiform layer (OPL), contains synapses made by rod and cone photoreceptor axons on rod and cone bipolar dendrites, respectively. We used RNA-seq to identify selectively expressed genes encoding cell surface and secreted proteins and CRISPR-Cas9 electroporation with cell-specific promoters to assess their roles in OPL development. Among the genes identified in this way are Wnt5a and Wnt5b. They are produced by rod bipolars and activate a non-canonical signaling pathway in rods to regulate early OPL patterning. The approach we use here can be applied to other parts of the brain.},
keywords = {Fzd4; Fzd5; OPL; Ryk; Wnt5; bipolars; neuron; photoreceptors; retina; synapse},
pubstate = {published},
tppubtype = {article}
}
Screens for genes that orchestrate neural circuit formation in mammals have been hindered by practical constraints of germline mutagenesis. To overcome these limitations, we combined RNA-seq with somatic CRISPR mutagenesis to study synapse development in the mouse retina. Here synapses occur between cellular layers, forming two multilayered neuropils. The outer neuropil, the outer plexiform layer (OPL), contains synapses made by rod and cone photoreceptor axons on rod and cone bipolar dendrites, respectively. We used RNA-seq to identify selectively expressed genes encoding cell surface and secreted proteins and CRISPR-Cas9 electroporation with cell-specific promoters to assess their roles in OPL development. Among the genes identified in this way are Wnt5a and Wnt5b. They are produced by rod bipolars and activate a non-canonical signaling pathway in rods to regulate early OPL patterning. The approach we use here can be applied to other parts of the brain.
S, Ziyad; JD, Riordan; AM, Cavanaugh; T, Su; GE, Hernandez; G, Hilfenhaus; M, Morselli; K, Huynh; K, Wang; JN, Chen; AJ, Dupuy; ML., Iruela-Arispe
A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis. Journal Article
In: Cell Rep. , 22 (5), pp. 1211-1224, 2018.
Abstract | Links | BibTeX | Tags: Akt; Erk; PI4KAP2; Pi4ka; erythropoiesis; hematopoiesis; hemogenic endothelium; leukemia; lipid kinase; myelopoiesis
@article{Ziyad2018Forwardb,
title = {A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis.},
author = {Ziyad S and Riordan JD and Cavanaugh AM and Su T and Hernandez GE and Hilfenhaus G and Morselli M and Huynh K and Wang K and Chen JN and Dupuy AJ and Iruela-Arispe ML.},
url = {https://doi.org/10.1016/j.celrep.2018.01.017},
doi = {10.1016/j.celrep.2018.01.017},
year = {2018},
date = {2018-01-30},
journal = {Cell Rep. },
volume = {22},
number = {5},
pages = {1211-1224},
abstract = {Given its role as the source of definitive hematopoietic cells, we sought to determine whether mutations initiated in the hemogenic endothelium would yield hematopoietic abnormalities or malignancies. Here, we find that endothelium-specific transposon mutagenesis in mice promotes hematopoietic pathologies that are both myeloid and lymphoid in nature. Frequently mutated genes included previously recognized cancer drivers and additional candidates, such as Pi4ka, a lipid kinase whose mutation was found to promote myeloid and erythroid dysfunction. Subsequent validation experiments showed that targeted inactivation of the Pi4ka catalytic domain or reduction in mRNA expression inhibited myeloid and erythroid cell differentiation in vitro and promoted anemia in vivo through a mechanism involving deregulation of AKT, MAPK, SRC, and JAK-STAT signaling. Finally, we provide evidence linking PI4KAP2, previously considered a pseudogene, to human myeloid and erythroid leukemia.},
keywords = {Akt; Erk; PI4KAP2; Pi4ka; erythropoiesis; hematopoiesis; hemogenic endothelium; leukemia; lipid kinase; myelopoiesis},
pubstate = {published},
tppubtype = {article}
}
Given its role as the source of definitive hematopoietic cells, we sought to determine whether mutations initiated in the hemogenic endothelium would yield hematopoietic abnormalities or malignancies. Here, we find that endothelium-specific transposon mutagenesis in mice promotes hematopoietic pathologies that are both myeloid and lymphoid in nature. Frequently mutated genes included previously recognized cancer drivers and additional candidates, such as Pi4ka, a lipid kinase whose mutation was found to promote myeloid and erythroid dysfunction. Subsequent validation experiments showed that targeted inactivation of the Pi4ka catalytic domain or reduction in mRNA expression inhibited myeloid and erythroid cell differentiation in vitro and promoted anemia in vivo through a mechanism involving deregulation of AKT, MAPK, SRC, and JAK-STAT signaling. Finally, we provide evidence linking PI4KAP2, previously considered a pseudogene, to human myeloid and erythroid leukemia.
Thorsson, Vésteinn; Gibbs, David L; Brown, Scott D; Wolf, Denise; Bortone, Dante S; Yang, Tai-Hsien Ou; Porta-Pardo, Eduard; Gao, Galen F; Plaisier, Christopher L; Eddy, James A; others,
The immune landscape of cancer Journal Article
In: Immunity, 48 (4), pp. 812–830, 2018.
@article{thorsson2018immune,
title = {The immune landscape of cancer},
author = {Vésteinn Thorsson and David L Gibbs and Scott D Brown and Denise Wolf and Dante S Bortone and Tai-Hsien Ou Yang and Eduard Porta-Pardo and Galen F Gao and Christopher L Plaisier and James A Eddy and others},
url = {https://doi.org/10.1016/j.immuni.2018.03.023},
doi = {10.1016/j.immuni.2018.03.023},
year = {2018},
date = {2018-01-01},
journal = {Immunity},
volume = {48},
number = {4},
pages = {812--830},
publisher = {Elsevier},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Ricketts, Christopher J; Cubas, Aguirre A De; Fan, Huihui; Smith, Christof C; Lang, Martin; Reznik, Ed; Bowlby, Reanne; Gibb, Ewan A; Akbani, Rehan; Beroukhim, Rameen; others,
The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma Journal Article
In: Cell reports, 23 (1), pp. 313–326, 2018.
@article{ricketts2018cancer,
title = {The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma},
author = {Christopher J Ricketts and Aguirre A De Cubas and Huihui Fan and Christof C Smith and Martin Lang and Ed Reznik and Reanne Bowlby and Ewan A Gibb and Rehan Akbani and Rameen Beroukhim and others},
url = {https://doi.org/10.1016/j.celrep.2018.03.075},
doi = {10.1016/j.celrep.2018.03.075},
year = {2018},
date = {2018-01-01},
journal = {Cell reports},
volume = {23},
number = {1},
pages = {313--326},
publisher = {Elsevier},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Listgarten, Jennifer; Weinstein, Michael M; Kleinstiver, Benjamin P; Sousa, Alexander A; Joung, Keith J; Crawford, Jake; Gao, Kevin; Hoang, Luong; Elibol, Melih; Doench, John G; others,
Prediction of off-target activities for the end-to-end design of CRISPR guide RNAs Journal Article
In: Nature Biomedical Engineering, 2 (1), pp. 38, 2018.
@article{listgarten2018prediction,
title = {Prediction of off-target activities for the end-to-end design of CRISPR guide RNAs},
author = {Jennifer Listgarten and Michael M Weinstein and Benjamin P Kleinstiver and Alexander A Sousa and Keith J Joung and Jake Crawford and Kevin Gao and Luong Hoang and Melih Elibol and John G Doench and others},
url = {https://doi.org/10.1038/s41551-017-0178-6},
doi = {10.1038/s41551-017-0178-6},
year = {2018},
date = {2018-01-01},
journal = {Nature Biomedical Engineering},
volume = {2},
number = {1},
pages = {38},
publisher = {Nature Publishing Group},
keywords = {CRISPR},
pubstate = {published},
tppubtype = {article}
}
Shi, Baochen; Leung, Donald YM; Taylor, Patricia A; Li, Huiying
Methicillin-Resistant Staphylococcus aureus Colonization Is Associated with Decreased Skin Commensal Bacteria in Atopic Dermatitis. Journal Article
In: The Journal of investigative dermatology, 2018.
Links | BibTeX | Tags: bacteria
@article{shi2018methicillin,
title = {Methicillin-Resistant Staphylococcus aureus Colonization Is Associated with Decreased Skin Commensal Bacteria in Atopic Dermatitis.},
author = {Baochen Shi and Donald YM Leung and Patricia A Taylor and Huiying Li},
url = {https://doi.org/10.1016/j.jid.2018.01.022},
doi = {10.1016/j.jid.2018.01.022},
year = {2018},
date = {2018-01-01},
journal = {The Journal of investigative dermatology},
keywords = {bacteria},
pubstate = {published},
tppubtype = {article}
}
Fraser, Devaughn; Mouton, Alice; Serieys, Laurel EK; Cole, Steve; Carver, Scott; Vandewoude, Sue; Lappin, Michael; Riley, Seth PD; Wayne, Robert
Genome-wide expression reveals multiple systemic effects associated with detection of anticoagulant poisons in bobcats (Lynx rufus) Journal Article
In: Molecular ecology, 27 (5), pp. 1170–1187, 2018.
@article{fraser2018genome,
title = {Genome-wide expression reveals multiple systemic effects associated with detection of anticoagulant poisons in bobcats (Lynx rufus)},
author = {Devaughn Fraser and Alice Mouton and Laurel EK Serieys and Steve Cole and Scott Carver and Sue Vandewoude and Michael Lappin and Seth PD Riley and Robert Wayne},
url = {https://doi.org/10.1111/mec.14531},
doi = {10.1111/mec.14531},
year = {2018},
date = {2018-01-01},
journal = {Molecular ecology},
volume = {27},
number = {5},
pages = {1170--1187},
publisher = {Wiley Online Library},
keywords = {GWAS},
pubstate = {published},
tppubtype = {article}
}
Ziyad, Safiyyah; Riordan, Jesse D; Cavanaugh, Ann M; Su, Trent; Hernandez, Gloria E; Hilfenhaus, Georg; Morselli, Marco; Huynh, Kristine; Wang, Kevin; Chen, Jau-Nian; others,
A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo-and Erythropoiesis Journal Article
In: Cell reports, 22 (5), pp. 1211–1224, 2018.
Links | BibTeX | Tags: cancer, gene mutation, leukemia, RNA-seq
@article{ziyad2018forward,
title = {A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo-and Erythropoiesis},
author = {Safiyyah Ziyad and Jesse D Riordan and Ann M Cavanaugh and Trent Su and Gloria E Hernandez and Georg Hilfenhaus and Marco Morselli and Kristine Huynh and Kevin Wang and Jau-Nian Chen and others},
url = {https://doi.org/10.1016/j.celrep.2018.01.017},
doi = {10.1016/j.celrep.2018.01.017},
year = {2018},
date = {2018-01-01},
journal = {Cell reports},
volume = {22},
number = {5},
pages = {1211--1224},
publisher = {Elsevier},
keywords = {cancer, gene mutation, leukemia, RNA-seq},
pubstate = {published},
tppubtype = {article}
}
Ko, Albert; Venkatesan, Natarajan; Chatoff, Jenna; Morselli, Marco; Fishbein, Gregory; Bomont, Pascale; Pellegrini, Matteo; Wang, Marilene; Srivatsan, Eri
GAN gene exon 8 SNP is related to gigaxonin expression and increased expression of e-cadherin in head and neck cancer Miscellaneous
2018.
@misc{ko2018gan,
title = {GAN gene exon 8 SNP is related to gigaxonin expression and increased expression of e-cadherin in head and neck cancer},
author = {Albert Ko and Natarajan Venkatesan and Jenna Chatoff and Marco Morselli and Gregory Fishbein and Pascale Bomont and Matteo Pellegrini and Marilene Wang and Eri Srivatsan},
url = {https://doi.org/10.1158/1538-7445.AM2018-5505},
doi = {10.1158/1538-7445.AM2018-5505},
year = {2018},
date = {2018-01-01},
publisher = {AACR},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Khalid, Aysha B; Slayden, Alexandria V; Kumpati, Jerusha; Perry, Chanel D; Berryhill, Stuart B; Crawford, Julie A; Fatima, Iram; Morselli, Marco; Pellegrini, Matteo; Miranda-Carboni, Gustavo A; others,
GATA4 represses RANKL via multiple long-range enhancers to regulate osteoclast differentiation Journal Article
In: Bone, 2018.
@article{khalid2018gata4,
title = {GATA4 represses RANKL via multiple long-range enhancers to regulate osteoclast differentiation},
author = {Aysha B Khalid and Alexandria V Slayden and Jerusha Kumpati and Chanel D Perry and Stuart B Berryhill and Julie A Crawford and Iram Fatima and Marco Morselli and Matteo Pellegrini and Gustavo A Miranda-Carboni and others},
url = {https://doi.org/10.1016/j.bone.2018.07.014},
doi = {10.1016/j.bone.2018.07.014},
year = {2018},
date = {2018-01-01},
journal = {Bone},
publisher = {Elsevier},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Borgognone, Alessandra; Castanera, Raul; Morselli, Marco; López-Varas, Leticia; Rubbi, Liudmilla; Pisabarro, Antonio G; Pellegrini, Matteo; Ramirez, Lucia
Transposon-associated epigenetic silencing during Pleurotus ostreatus life cycle Journal Article
In: DNA Research, 2018.
@article{borgognone2018transposon,
title = {Transposon-associated epigenetic silencing during Pleurotus ostreatus life cycle},
author = {Alessandra Borgognone and Raul Castanera and Marco Morselli and Leticia López-Varas and Liudmilla Rubbi and Antonio G Pisabarro and Matteo Pellegrini and Lucia Ramirez},
url = {https://doi.org/10.1093/dnares/dsy016},
doi = {10.1093/dnares/dsy016},
year = {2018},
date = {2018-01-01},
journal = {DNA Research},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mitchell, Simon; Roy, Koushik; Zangle, Thomas A; Hoffmann, Alexander
Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation Journal Article
In: Proceedings of the National Academy of Sciences, 115 (12), pp. E2888–E2897, 2018.
@article{mitchell2018nongenetic,
title = {Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation},
author = {Simon Mitchell and Koushik Roy and Thomas A Zangle and Alexander Hoffmann},
url = {https://doi.org/10.1073/pnas.1715639115},
doi = {10.1073/pnas.1715639115},
year = {2018},
date = {2018-01-01},
journal = {Proceedings of the National Academy of Sciences},
volume = {115},
number = {12},
pages = {E2888--E2897},
publisher = {National Acad Sciences},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Roy, Koushik; Shokhirev, Maxim Nikolaievich; Mitchell, Simon; Hoffmann, Alexander
Deriving Quantitative Cell Biological Information from Dye-Dilution Lymphocyte Proliferation Experiments Incollection
In: B Cell Receptor Signaling, pp. 81–94, Springer, 2018.
@incollection{roy2018deriving,
title = {Deriving Quantitative Cell Biological Information from Dye-Dilution Lymphocyte Proliferation Experiments},
author = {Koushik Roy and Maxim Nikolaievich Shokhirev and Simon Mitchell and Alexander Hoffmann},
url = {https://doi.org/10.1007/978-1-4939-7474-0_6},
doi = {10.1007/978-1-4939-7474-0_6},
year = {2018},
date = {2018-01-01},
booktitle = {B Cell Receptor Signaling},
pages = {81--94},
publisher = {Springer},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
Gangalum, Rajendra K; Kim, Dongjae; Kashyap, Raj K; Mangul, Serghei; Zhou, Xinkai; Elashoff, David; Bhat, Suraj
Spatial Analysis of Single Fiber Cells of the Developing Ocular Lens Reveals Regulated Heterogeneity of Gene Expression Journal Article
In: Available at SSRN 3205412, 2018.
@article{gangalum2018spatial,
title = {Spatial Analysis of Single Fiber Cells of the Developing Ocular Lens Reveals Regulated Heterogeneity of Gene Expression},
author = {Rajendra K Gangalum and Dongjae Kim and Raj K Kashyap and Serghei Mangul and Xinkai Zhou and David Elashoff and Suraj Bhat},
url = {http://dx.doi.org/10.2139/ssrn.3205412},
doi = {10.2139/ssrn.3205412},
year = {2018},
date = {2018-01-01},
journal = {Available at SSRN 3205412},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mangul, Serghei; Martin, Lana S; Eskin, Eleazar
Involving undergraduates in genomics research to narrow the education--research gap Journal Article
In: Nature biotechnology, 36 (4), pp. 369, 2018.
Links | BibTeX | Tags: education, training
@article{mangul2018involving,
title = {Involving undergraduates in genomics research to narrow the education--research gap},
author = {Serghei Mangul and Lana S Martin and Eleazar Eskin},
url = {https://doi.org/10.1038/nbt.4113},
doi = {10.1038/nbt.4113},
year = {2018},
date = {2018-01-01},
journal = {Nature biotechnology},
volume = {36},
number = {4},
pages = {369},
publisher = {Nature Publishing Group},
keywords = {education, training},
pubstate = {published},
tppubtype = {article}
}
Lay, Fides D; Kelly, Theresa K; Jones, Peter A
Nucleosome Occupancy and Methylome Sequencing (NOMe-seq) Incollection
In: DNA Methylation Protocols, pp. 267–284, Springer, 2018.
@incollection{lay2018nucleosome,
title = {Nucleosome Occupancy and Methylome Sequencing (NOMe-seq)},
author = {Fides D Lay and Theresa K Kelly and Peter A Jones},
url = {10.1007/978-1-4939-7481-8_14},
doi = {https://doi.org/10.1007/978-1-4939-7481-8_14},
year = {2018},
date = {2018-01-01},
booktitle = {DNA Methylation Protocols},
pages = {267--284},
publisher = {Springer},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
Miao, Jianwei; Pryor, Alan; Yang, Yongsoo; Rana, Arjun; Gallagher-Jones, Marcus; Zhou, Jihan; Lo, Yuan Hung; Rodriguez, Jose A; Chiu, Wah
GENFIRE: from Precisely Localizing Single Atoms in Materials to High Resolution 3D Imaging of Cellular Structures Journal Article
In: Microscopy and Microanalysis, 24 (S1), pp. 1446–1447, 2018.
@article{miao2018genfire,
title = {GENFIRE: from Precisely Localizing Single Atoms in Materials to High Resolution 3D Imaging of Cellular Structures},
author = {Jianwei Miao and Alan Pryor and Yongsoo Yang and Arjun Rana and Marcus Gallagher-Jones and Jihan Zhou and Yuan Hung Lo and Jose A Rodriguez and Wah Chiu},
url = {https://doi.org/10.1017/S1431927618007717},
doi = {10.1017/S1431927618007717},
year = {2018},
date = {2018-01-01},
journal = {Microscopy and Microanalysis},
volume = {24},
number = {S1},
pages = {1446--1447},
publisher = {Cambridge University Press},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pryor, Alan; Rana, Arjun; Xu, Rui; Rodriguez, Jose A; Yang, Yongsoo; Gallagher-Jones, Marcus; Jiang, Huaidong; Kanhaiya, Krishan; Nathanson, Michael; Park, Jae Hyun; others,
Single-shot 3D coherent diffractive imaging of core-shell nanoparticles with elemental specificity Journal Article
In: Scientific reports, 8 (1), pp. 8284, 2018.
@article{pryor2018single,
title = {Single-shot 3D coherent diffractive imaging of core-shell nanoparticles with elemental specificity},
author = {Alan Pryor and Arjun Rana and Rui Xu and Jose A Rodriguez and Yongsoo Yang and Marcus Gallagher-Jones and Huaidong Jiang and Krishan Kanhaiya and Michael Nathanson and Jae Hyun Park and others},
url = {https://doi.org/10.1038/s41598-018-26182-1},
doi = {10.1038/s41598-018-26182-1},
year = {2018},
date = {2018-01-01},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {8284},
publisher = {Nature Publishing Group},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lo, Yuan Hung; Zhao, Lingrong; Gallagher-Jones, Marcus; Rana, Arjun; Lodico, Jared; Xiao, Weikun; Regan, BC; Miao, Jianwei
In situ coherent diffractive imaging Journal Article
In: Nature communications, 9 (1), pp. 1826, 2018.
@article{lo2018situ,
title = {In situ coherent diffractive imaging},
author = {Yuan Hung Lo and Lingrong Zhao and Marcus Gallagher-Jones and Arjun Rana and Jared Lodico and Weikun Xiao and BC Regan and Jianwei Miao},
url = {https://doi.org/10.1038/s41467-018-04259-9s},
doi = {10.1038/s41467-018-04259-9},
year = {2018},
date = {2018-01-01},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {1826},
publisher = {Nature Publishing Group},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Park, Shuin; Ranjbarvazirj, Sara; Lay, Fides D; Zhao, Peng; Miller, Mark J; Dhaliwal, Jasmeet S; Huertas-Vazquez, Adriana; Wu, Xiuju; Qiao, Rong; Soffer, Justin M; others,
Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis Journal Article
In: Circulation, pp. CIRCULATIONAHA–118, 2018.
@article{park2018genetic,
title = {Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis},
author = {Shuin Park and Sara Ranjbarvazirj and Fides D Lay and Peng Zhao and Mark J Miller and Jasmeet S Dhaliwal and Adriana Huertas-Vazquez and Xiuju Wu and Rong Qiao and Justin M Soffer and others},
url = {https://doi.org/10.1161/CIRCULATIONAHA.118.035420},
doi = {10.1161/CIRCULATIONAHA.118.035420},
year = {2018},
date = {2018-01-01},
journal = {Circulation},
pages = {CIRCULATIONAHA--118},
publisher = {Am Heart Assoc},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cheng, Lucy; Marinelli, Laura J; Grosset, Noel; Fitz-Gibbon, Sorel T; Bowman, Charles A; Dang, Brian Q; Russell, Daniel A; Jacobs-Sera, Deborah; Shi, Baochen; Pellegrini, Matteo; others,
In: BMC microbiology, 18 (1), pp. 19, 2018.
Links | BibTeX | Tags: bacteria
@article{cheng2018complete,
title = {Complete genomic sequences of Propionibacterium freudenreichii phages from Swiss cheese reveal greater diversity than Cutibacterium (formerly Propionibacterium) acnes phages},
author = {Lucy Cheng and Laura J Marinelli and Noel Grosset and Sorel T Fitz-Gibbon and Charles A Bowman and Brian Q Dang and Daniel A Russell and Deborah Jacobs-Sera and Baochen Shi and Matteo Pellegrini and others},
url = {https://doi.org/10.1186/s12866-018-1159-y},
doi = {10.1186/s12866-018-1159-y},
year = {2018},
date = {2018-01-01},
journal = {BMC microbiology},
volume = {18},
number = {1},
pages = {19},
publisher = {BioMed Central},
keywords = {bacteria},
pubstate = {published},
tppubtype = {article}
}
Vaughn, Don A; van Deen, Welmoed K; Kerr, Wesley T; Meyer, Travis R; Bertozzi, Andrea L; Hommes, Daniel W; Cohen, Mark Steven
Using insurance claims to predict and improve hospitalizations and biologics use in members with inflammatory bowel diseases Journal Article
In: Journal of biomedical informatics, 81 , pp. 93–101, 2018.
@article{vaughn2018using,
title = {Using insurance claims to predict and improve hospitalizations and biologics use in members with inflammatory bowel diseases},
author = {Don A Vaughn and Welmoed K van Deen and Wesley T Kerr and Travis R Meyer and Andrea L Bertozzi and Daniel W Hommes and Mark Steven Cohen},
url = {https://doi.org/10.1016/j.jbi.2018.03.015},
doi = {10.1016/j.jbi.2018.03.015},
year = {2018},
date = {2018-01-01},
journal = {Journal of biomedical informatics},
volume = {81},
pages = {93--101},
publisher = {Elsevier},
keywords = {},
pubstate = {published},
tppubtype = {article}
}