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. | Perri, Angela R; Mitchell, Kieren J; Mouton, Alice ; et al.,: Dire wolves were the last of an ancient New World canid lineage. In: Nature, 2021. (Type: Journal Article | Abstract | Links | BibTeX) @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. |
| 2. | Eagleman, David M; Vaughn, Don A: The Defensive Activation theory: dreaming as a mechanism to prevent takeover of the visual cortex. In: bioRxiv , 2020. (Type: Journal Article | Abstract | Links | BibTeX) @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. |
| 3. | 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. In: Proceedings of the National Academy of Sciences , 32358191 , 2020. (Type: Journal Article | Abstract | Links | BibTeX) @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). |
| 4. | Neal, Adam S; Nunez, Miguel; Lai, Tiffany; Tosevska, Anela; Morselli, Marco; Amneus, Malaika; Zakhour, Mae; Moatamed, Neda A; Pellegrini, Matteo; Memarzadeh, Sanaz: Expression of Stromal Progesterone Receptor and Differential Methylation Patterns in the Endometrium May Correlate with Response to Progesterone Therapy in Endometrial Complex Atypical Hyperplasia.. In: Reproductive Sciences, 2020. (Type: Journal Article | Abstract | Links | BibTeX) @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. |
| 5. | 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. In: GigaScience, 9 (1), 2020. (Type: Journal Article | Abstract | Links | BibTeX) @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. |
| 6. | 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: Evolution of Antibiotic Cross‐resistance and Collateral Sensitivity in Staphylococcus Epidermidis Using the Mutant Prevention Concentration and the Mutant Selection Window. In: Evolutionary Applications, 2019. (Type: Journal Article | Abstract | Links | BibTeX) @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. |
| 7. | Galmozzi, Andrea; Kok, Bernard P; Kim, Arthur S; Montenegro-Burke, Rafael J; 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. In: 2019. (Type: Journal Article | Abstract | Links | BibTeX) @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. |
| 8. | Kurmangaliyev, Yerbol Z; Yoo, Juyoun; LoCascio, Samuel A; Zipursky, Lawrence S: Modular transcriptional programs separately define axon and dendrite connectivity.. In: eLife, 2019. (Type: Journal Article | Abstract | Links | BibTeX) @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. |
| 9. | 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.. In: Proc Natl Acad Sci U S A. , 2019. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 10. | 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.. In: Molecular Therapy, 27 (8), pp. 1389-1406, 2019. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 11. | 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.. In: Int J Mol Sci. , 20 (13), 2019. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 12. | 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.. In: Cell Rep. , 27 (13), pp. 3760-3769, 2019. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 13. | Pontrelli Sammy, ; Riley C. B. Fricke and Shao Thing Teoh, ; 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. In: Nature Chemical Biology, 14 (11), pp. 1005–1009, 2018. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 14. | Eagleman, Sarah L; Vaughn, Don A; Drover, David R; Drover, Caitlin M; Cohen, Mark S; Ouellette, Nicholas T; MacIver., Bruce M: Do Complexity Measures of Frontal EEG Distinguish Loss of Consciousness in Geriatric Patients Under Anesthesia?. In: Frontiers in neuroscience, 12 , pp. 645, 2018. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 15. | Pontrelli Sammy, ; 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. In: Metabolic Engineering, 49 , pp. 153-163, 2018. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 16. | 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.. In: Cell Rep., 23 (8), pp. 2392-2404, 2018. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 17. | 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. In: Neuron, 98 (1), pp. 109-126, 2018. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 18. | 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.. In: Cell Rep. , 22 (5), pp. 1211-1224, 2018. (Type: Journal Article | Abstract | Links | BibTeX) @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 = {}, 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. |
| 19. | 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. In: Immunity, 48 (4), pp. 812–830, 2018. (Type: Journal Article | Links | BibTeX) @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} } |
| 20. | Ricketts, Christopher J; Cubas, Aguirre De A; 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. In: Cell reports, 23 (1), pp. 313–326, 2018. (Type: Journal Article | Links | BibTeX) @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} } |
2021 |
Perri, Angela R; Mitchell, Kieren J; Mouton, Alice ; et al., Dire wolves were the last of an ancient New World canid lineage Journal Article 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. |
2020 |
Eagleman, David M; Vaughn, Don A The Defensive Activation theory: dreaming as a mechanism to prevent takeover of the visual cortex Journal Article 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. |
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 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). |
Neal, Adam S; Nunez, Miguel; Lai, Tiffany; Tosevska, Anela; Morselli, Marco; Amneus, Malaika; Zakhour, Mae; Moatamed, Neda A; Pellegrini, Matteo; Memarzadeh, Sanaz 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 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 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, Rafael J; 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 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, Lawrence S Modular transcriptional programs separately define axon and dendrite connectivity. Journal Article 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 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 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 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 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 |
Pontrelli Sammy, ; Riley C. B. Fricke and Shao Thing Teoh, ; 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 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., Bruce M Do Complexity Measures of Frontal EEG Distinguish Loss of Consciousness in Geriatric Patients Under Anesthesia? Journal Article 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. |
Pontrelli Sammy, ; 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 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 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 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 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 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 De A; 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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, 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 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} } |
Loohuis, Loes Olde M; Mangul, Serghei; Ori, Anil PS; Jospin, Guillaume; Koslicki, David; Yang, Harry Taegyun; Wu, Timothy; Boks, Marco P; Lomen-Hoerth, Catherine; Wiedau-Pazos, Martina; others, Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia Journal Article Translational psychiatry, 8 (1), pp. 96, 2018. @article{loohuis2018transcriptome, title = {Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia}, author = {Loes Olde M Loohuis and Serghei Mangul and Anil PS Ori and Guillaume Jospin and David Koslicki and Harry Taegyun Yang and Timothy Wu and Marco P Boks and Catherine Lomen-Hoerth and Martina Wiedau-Pazos and others}, url = {https://doi.org/10.1038/s41398-018-0107-9}, doi = {10.1038/s41398-018-0107-9}, year = {2018}, date = {2018-01-01}, journal = {Translational psychiatry}, volume = {8}, number = {1}, pages = {96}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Mangul, Serghei; Yang, Harry Taegyun; Strauli, Nicolas; Gruhl, Franziska; Porath, Hagit T; Hsieh, Kevin; Chen, Linus; Daley, Timothy; Christenson, Stephanie; Wesolowska-Andersen, Agata; others, ROP: Dumpster Diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues Journal Article Genome biology, 19 (1), pp. 36, 2018. @article{mangul2018rop, title = {ROP: Dumpster Diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues}, author = {Serghei Mangul and Harry Taegyun Yang and Nicolas Strauli and Franziska Gruhl and Hagit T Porath and Kevin Hsieh and Linus Chen and Timothy Daley and Stephanie Christenson and Agata Wesolowska-Andersen and others}, url = {https://doi.org/10.1186/s13059-018-1403-7}, doi = {10.1186/s13059-018-1403-7}, year = {2018}, date = {2018-01-01}, journal = {Genome biology}, volume = {19}, number = {1}, pages = {36}, publisher = {BioMed Central}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Vaughn, Don A; Savjani, Ricky R; Cohen, Mark Steven; Eagleman, David M Empathic neural responses predict group allegiance Journal Article Frontiers in Human Neuroscience, 12 , pp. 302, 2018. @article{vaughn2018empathic, title = {Empathic neural responses predict group allegiance}, author = {Don A Vaughn and Ricky R Savjani and Mark Steven Cohen and David M Eagleman}, url = {https://doi.org/10.3389/fnhum.2018.00302}, doi = {10.3389/fnhum.2018.00302}, year = {2018}, date = {2018-01-01}, journal = {Frontiers in Human Neuroscience}, volume = {12}, pages = {302}, publisher = {Frontiers}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Shirali, Aditya S; Romay, Milagros C; McDonald, Austin I; Su, Trent; Steel, Michelle E; Iruela-Arispe, Luisa M A multi-step transcriptional cascade underlies vascular regeneration in vivo Journal Article Scientific reports, 8 (1), pp. 5430, 2018. Links | BibTeX | Tags: endothelial growth, Galaxy, gene expression, RNA-seq, wound repair @article{shirali2018multi, title = {A multi-step transcriptional cascade underlies vascular regeneration in vivo}, author = {Aditya S Shirali and Milagros C Romay and Austin I McDonald and Trent Su and Michelle E Steel and Luisa M Iruela-Arispe}, url = {https://doi.org/10.1038/s41598-018-23653-3}, doi = {10.1038/s41598-018-23653-3}, year = {2018}, date = {2018-01-01}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {5430}, publisher = {Nature Publishing Group}, keywords = {endothelial growth, Galaxy, gene expression, RNA-seq, wound repair}, pubstate = {published}, tppubtype = {article} } |
Gallagher-Jones, Marcus; Glynn, Calina; Boyer, David R; Martynowycz, Michael W; Hernandez, Evelyn; Miao, Jennifer; Zee, Chih-Te; Novikova, Irina V; Goldschmidt, Lukasz; McFarlane, Heather T; others, Sub-ångström cryo-EM structure of a prion protofibril reveals a polar clasp Journal Article Nature structural & molecular biology, 25 (2), pp. 131, 2018. @article{gallagher2018sub, title = {Sub-ångström cryo-EM structure of a prion protofibril reveals a polar clasp}, author = {Marcus Gallagher-Jones and Calina Glynn and David R Boyer and Michael W Martynowycz and Evelyn Hernandez and Jennifer Miao and Chih-Te Zee and Irina V Novikova and Lukasz Goldschmidt and Heather T McFarlane and others}, url = {https://doi.org/10.1038/s41594-017-0018-0}, doi = {10.1038/s41594-017-0018-0}, year = {2018}, date = {2018-01-01}, journal = {Nature structural & molecular biology}, volume = {25}, number = {2}, pages = {131}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Buckner, Janet C; Ellingson, Ryan; Gold, David A; Jones, Terry L; Jacobs, David K Molecular phylogenetics and evolution, 122 , pp. 102–109, 2018. @article{buckner2018mitogenomics, title = {Mitogenomics supports an unexpected taxonomic relationship for the extinct diving duck Chendytes lawi and definitively places the extinct Labrador Duck}, author = {Janet C Buckner and Ryan Ellingson and David A Gold and Terry L Jones and David K Jacobs}, url = {https://doi.org/10.1016/j.ympev.2017.12.008}, doi = {10.1016/j.ympev.2017.12.008}, year = {2018}, date = {2018-01-01}, journal = {Molecular phylogenetics and evolution}, volume = {122}, pages = {102--109}, publisher = {Elsevier}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Hattne, Johan; Shi, Dan; Glynn, Calina; Zee, Chih-Te; Gallagher-Jones, Marcus; Martynowycz, Michael W; Rodriguez, Jose A; Gonen, Tamir Analysis of global and site-specific radiation damage in cryo-EM Journal Article Structure, 26 (5), pp. 759–766, 2018. @article{hattne2018analysis, title = {Analysis of global and site-specific radiation damage in cryo-EM}, author = {Johan Hattne and Dan Shi and Calina Glynn and Chih-Te Zee and Marcus Gallagher-Jones and Michael W Martynowycz and Jose A Rodriguez and Tamir Gonen}, url = {https://doi.org/10.1016/j.str.2018.03.021}, doi = {10.1016/j.str.2018.03.021}, year = {2018}, date = {2018-01-01}, journal = {Structure}, volume = {26}, number = {5}, pages = {759--766}, publisher = {Elsevier}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
McDonald, Austin I; Shirali, Aditya S; Aragón, Raquel L; Ma, Feiyang; Hernandez, Gloria E; Vaughn, Don A; Mack, Julia J; Lim, Tiffany Y; Sunshine, Hannah; Zhao, Peng; others, Endothelial regeneration of large vessels is a biphasic process driven by local cells with distinct proliferative capacities Journal Article Cell stem cell, 23 (2), pp. 210–225, 2018. @article{mcdonald2018endothelial, title = {Endothelial regeneration of large vessels is a biphasic process driven by local cells with distinct proliferative capacities}, author = {Austin I McDonald and Aditya S Shirali and Raquel L Aragón and Feiyang Ma and Gloria E Hernandez and Don A Vaughn and Julia J Mack and Tiffany Y Lim and Hannah Sunshine and Peng Zhao and others}, url = {https://doi.org/10.1016/j.stem.2018.07.011}, doi = {10.1016/j.stem.2018.07.011}, year = {2018}, date = {2018-01-01}, journal = {Cell stem cell}, volume = {23}, number = {2}, pages = {210--225}, publisher = {Elsevier}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Merkurjev, Daria; Hong, Wan-Ting; Iida, Kei; Oomoto, Ikumi; Goldie, Belinda J; Yamaguti, Hitoshi; Ohara, Takayuki; Kawaguchi, Shin-ya; Hirano, Tomoo; Martin, Kelsey C; others, Synaptic N 6-methyladenosine (m 6 A) epitranscriptome reveals functional partitioning of localized transcripts Journal Article Nature neuroscience, pp. 1, 2018. @article{merkurjev2018synaptic, title = {Synaptic N 6-methyladenosine (m 6 A) epitranscriptome reveals functional partitioning of localized transcripts}, author = {Daria Merkurjev and Wan-Ting Hong and Kei Iida and Ikumi Oomoto and Belinda J Goldie and Hitoshi Yamaguti and Takayuki Ohara and Shin-ya Kawaguchi and Tomoo Hirano and Kelsey C Martin and others}, url = {https://doi.org/10.1038/s41593-018-0173-6}, doi = {10.1038/s41593-018-0173-6}, year = {2018}, date = {2018-01-01}, journal = {Nature neuroscience}, pages = {1}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Gallaher, Sean D; Fitz-Gibbon, Sorel T; Strenkert, Daniela; Purvine, Samuel O; Pellegrini, Matteo; Merchant, Sabeeha S The Plant Journal, 93 (3), pp. 545–565, 2018. @article{gallaher2018high, title = {High-throughput sequencing of the chloroplast and mitochondrion of Chlamydomonas reinhardtii to generate improved de novo assemblies, analyze expression patterns and transcript speciation, and evaluate diversity among laboratory strains and wild isolates}, author = {Sean D Gallaher and Sorel T Fitz-Gibbon and Daniela Strenkert and Samuel O Purvine and Matteo Pellegrini and Sabeeha S Merchant}, url = {https://doi.org/10.1111/tpj.13788}, doi = {10.1111/tpj.13788}, year = {2018}, date = {2018-01-01}, journal = {The Plant Journal}, volume = {93}, number = {3}, pages = {545--565}, publisher = {Wiley Online Library}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Kuo, Caroline Y; Long, Joseph D; Campo-Fernandez, Beatriz; de Oliveira, Satiro; Cooper, Aaron R; Romero, Zulema; Hoban, Megan D; Joglekar, Alok V; Lill, Georgia R; Kaufman, Michael L; others, Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome Journal Article Cell reports, 23 (9), pp. 2606–2616, 2018. @article{kuo2018site, title = {Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome}, author = {Caroline Y Kuo and Joseph D Long and Beatriz Campo-Fernandez and Satiro de Oliveira and Aaron R Cooper and Zulema Romero and Megan D Hoban and Alok V Joglekar and Georgia R Lill and Michael L Kaufman and others}, url = {https://doi.org/10.1016/j.celrep.2018.04.103}, doi = {10.1016/j.celrep.2018.04.103}, year = {2018}, date = {2018-01-01}, journal = {Cell reports}, volume = {23}, number = {9}, pages = {2606--2616}, publisher = {Elsevier}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Gusev, Alexander; Mancuso, Nicholas; Won, Hyejung; Kousi, Maria; Finucane, Hilary K; Reshef, Yakir; Song, Lingyun; Safi, Alexias; McCarroll, Steven; Neale, Benjamin M; others, Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights Journal Article Nature genetics, 50 (4), pp. 538, 2018. @article{gusev2018transcriptome, title = {Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights}, author = {Alexander Gusev and Nicholas Mancuso and Hyejung Won and Maria Kousi and Hilary K Finucane and Yakir Reshef and Lingyun Song and Alexias Safi and Steven McCarroll and Benjamin M Neale and others}, url = {https://doi.org/10.1038/s41588-018-0092-1}, doi = {10.1038/s41588-018-0092-1}, year = {2018}, date = {2018-01-01}, journal = {Nature genetics}, volume = {50}, number = {4}, pages = {538}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |