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Full-Text Articles in Life Sciences

Long-Term Therapeutic Efficacy Of Intravenous Aav-Mediated Hamartin Replacement In Mouse Model Of Tuberous Sclerosis Type 1, Shilpa Prabhakar, Pike See Cheah, Xuan Zhang, Max Zinter, Maria Gianatasio, Eloise Hudry, Roderick T. Bronson, David J. Kwiatkowski, Anat Stemmer-Rachamimov, Casey A. Maguire, Miguel Sena-Esteves, Bakhos A. Tannous, Xandra O. Breakefield Dec 2019

Long-Term Therapeutic Efficacy Of Intravenous Aav-Mediated Hamartin Replacement In Mouse Model Of Tuberous Sclerosis Type 1, Shilpa Prabhakar, Pike See Cheah, Xuan Zhang, Max Zinter, Maria Gianatasio, Eloise Hudry, Roderick T. Bronson, David J. Kwiatkowski, Anat Stemmer-Rachamimov, Casey A. Maguire, Miguel Sena-Esteves, Bakhos A. Tannous, Xandra O. Breakefield

Open Access Articles

Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome caused by mutations in TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins act as a complex that inhibits mammalian target of rapamycin (mTOR)-mediated cell growth and proliferation. Loss of either protein leads to overgrowth in many organs, including subependymal nodules, subependymal giant cell astrocytomas, and cortical tubers in the human brain. Neurological manifestations in TSC include intellectual disability, autism, hydrocephalus, and epilepsy. In a stochastic mouse model of TSC1 brain lesions, complete loss of Tsc1 is achieved in homozygous Tsc1-floxed mice in a subpopulation of neural cells in ...


Bta-Mir-24-3p Controls The Myogenic Differentiation And Proliferation Of Fetal, Bovine, Skeletal Muscle-Derived Progenitor Cells By Targeting Acvr1b, Xin Hu, Yishen Xing, Ling Ren, Yahui Wang, Qian Li, Xing Fu, Qiyuan Yang, Lingyang Xu, Luc Willems, Junya Li, Lupei Zhang Oct 2019

Bta-Mir-24-3p Controls The Myogenic Differentiation And Proliferation Of Fetal, Bovine, Skeletal Muscle-Derived Progenitor Cells By Targeting Acvr1b, Xin Hu, Yishen Xing, Ling Ren, Yahui Wang, Qian Li, Xing Fu, Qiyuan Yang, Lingyang Xu, Luc Willems, Junya Li, Lupei Zhang

Open Access Articles

MicroRNAs modulate a variety of cellular events, including skeletal muscle development, but the molecular basis of their functions in fetal bovine skeletal muscle development is poorly understood. In this study, we report that bta-miR-24-3p promotes the myogenic differentiation of fetal bovine PDGFRalpha(-) progenitor cells. The expression of bta-miR-24-3p increased during myogenic differentiation. Overexpression of bta-miR-24-3p significantly promoted myogenic differentiation, but inhibited proliferation. A dual-luciferase assay identified ACVR1B as a direct target of bta-miR-24-3p. Similarly, knocking down ACVR1B by RNA interference also significantly inhibited proliferation and promoted the differentiation of bovine PDGFRalpha(-) progenitor cells. Thus, our study provides a mechanism in ...


Research Data Management Among Life Sciences Faculty: Implications For Library Service, Kelly A. Johnson, Vicky Steeves Oct 2019

Research Data Management Among Life Sciences Faculty: Implications For Library Service, Kelly A. Johnson, Vicky Steeves

Journal of eScience Librarianship

Objective: This paper aims to inform on opportunities for librarians to assist faculty with research data management by examining practices and attitudes among life sciences faculty at a tier one research university.

Methods: The authors issued a survey to estimate actual and perceived research data management needs of New York University (NYU) life sciences faculty in order to understand how the library could best contribute to the research life cycle.

Results: Survey responses indicate that over half of the respondents were aware of publisher and funder mandates, and most are willing to share their data, but many indicated they do ...


Coronary Disease Is Not Associated With Robust Alterations In Inflammatory Gene Expression In Human Epicardial Fat, Timothy P. Fitzgibbons, Nancy Lee, Khanh-Van T. Tran, Sarah M. Nicoloro, Mark Kelly, Stanley Kc Tam, Michael P. Czech Oct 2019

Coronary Disease Is Not Associated With Robust Alterations In Inflammatory Gene Expression In Human Epicardial Fat, Timothy P. Fitzgibbons, Nancy Lee, Khanh-Van T. Tran, Sarah M. Nicoloro, Mark Kelly, Stanley Kc Tam, Michael P. Czech

Open Access Articles

Epicardial adipose tissue (EAT) is the visceral fat depot of the heart. Inflammation of EAT is thought to contribute to coronary artery disease (CAD). Therefore, we hypothesized that the EAT of patients with CAD would have increased inflammatory gene expression compared with controls without CAD. Cardiac surgery patients with (n = 13) or without CAD (n = 13) were consented, and samples of EAT and subcutaneous adipose tissue (SAT) were obtained. Transcriptomic analysis was performed using Affymetrix Human Gene 1.0 ST arrays. Differential expression was defined as a 1.5-fold change (ANOVA P < 0.05). Six hundred ninety-three genes were differentially expressed between SAT and EAT in controls and 805 in cases. Expression of 326 genes was different between EAT of cases and controls; expression of 14 genes was increased in cases, while 312 were increased in controls. Quantitative reverse transcription PCR confirmed that there was no difference in expression of CCL2, CCR2, TNF-alpha, IL-6, IL-8, and PAI1 between groups. Immunohistochemistry showed more macrophages in EAT than SAT, but there was no difference in their number or activation state between groups. In contrast to prior studies, we did not find increased inflammatory gene expression in the EAT of patients with CAD. We conclude that the specific adipose tissue depot, rather than CAD status, is responsible for the majority of differential gene expression.


Genetic Rescue Of Fragile X Syndrome Links Fmrp Deficiency To Codon Optimality-Dependent Rna Destabilization, Huan Shu, Elisa Donnard, Botao Liu, Joel D. Richter Oct 2019

Genetic Rescue Of Fragile X Syndrome Links Fmrp Deficiency To Codon Optimality-Dependent Rna Destabilization, Huan Shu, Elisa Donnard, Botao Liu, Joel D. Richter

University of Massachusetts Medical School Faculty Publications

Fragile X syndrome (FXS) is caused by inactivation of FMR1 gene and loss of its encoded product the RNA binding protein FMRP, which generally represses translation of its target transcripts in the brain. In mouse models of FXS (i.e., Fmr1 knockout animals; Fmr1 KO), deletion of Cpeb1, which encodes a translational activator, mitigates nearly all pathophysiologies associated with the disorder. Here we reveal unexpected wide-spread dys-regulation of RNA abundance in Fmr1 KO brain cortex and its rescue to normal levels in Fmr1/Cpeb1 double KO mice. Alteration and restoration of RNA levels are the dominant molecular events that drive ...


Fmrp Control Of Ribosome Translocation Promotes Chromatin Modifications And Alternative Splicing Of Neuronal Genes Linked To Autism, Sneha Shah, Gemma Molinaro, Botao Liu, Ruijia Wang, Kimberly M. Huber, Joel D. Richter Oct 2019

Fmrp Control Of Ribosome Translocation Promotes Chromatin Modifications And Alternative Splicing Of Neuronal Genes Linked To Autism, Sneha Shah, Gemma Molinaro, Botao Liu, Ruijia Wang, Kimberly M. Huber, Joel D. Richter

University of Massachusetts Medical School Faculty Publications

Silencing of FMR1 and loss of its gene product FMRP results in Fragile X Syndrome. FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wildtype tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes; and its loss results in decline of ribosome stalling on specific mRNAs. One ...


Ripk1 Mediates Tnf-Induced Intestinal Crypt Apoptosis During Chronic Nf-Kappab Activation, Jerry Wong, Matija Zelic, John Bertin, Michelle A. Kelliher, Monica Guma Oct 2019

Ripk1 Mediates Tnf-Induced Intestinal Crypt Apoptosis During Chronic Nf-Kappab Activation, Jerry Wong, Matija Zelic, John Bertin, Michelle A. Kelliher, Monica Guma

Open Access Articles

BACKGROUND AND AIMS: Tumor necrosis factor (TNF) is a major pathogenic effector and a therapeutic target in inflammatory bowel disease (IBD), yet the basis for TNF-induced intestinal epithelial cell (IEC) death is unknown, because TNF does not kill normal IECs. Here, we investigated how chronic nuclear factor (NF)- kappaB activation, which occurs in human IBD, promotes TNF-dependent IEC death in mice.

METHODS: Human IBD specimens were stained for p65 and cleaved caspase-3. C57BL/6 mice with constitutively active IKKbeta in IEC (Ikkbeta(EE)(IEC)), Ripk1(D138N/D138N) knockin mice, and Ripk3(-/-) mice were injected with TNF or lipopolysaccharide. Enteroids were ...


Inhibiting Pad2 Enhances The Anti-Tumor Effect Of Docetaxel In Tamoxifen-Resistant Breast Cancer Cells, Fujun Li, Lixia Miao, Teng Xue, Hao Qin, Santanu Mondal, Paul R. Thompson, Scott A. Coonrod, Xiaoqiu Liu, Xuesen Zhang Oct 2019

Inhibiting Pad2 Enhances The Anti-Tumor Effect Of Docetaxel In Tamoxifen-Resistant Breast Cancer Cells, Fujun Li, Lixia Miao, Teng Xue, Hao Qin, Santanu Mondal, Paul R. Thompson, Scott A. Coonrod, Xiaoqiu Liu, Xuesen Zhang

Open Access Articles

BACKGROUND: Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance.

METHODS: We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen ...


Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C. Lam, Rajendra Upadhya, Charles A. Specht, Abigail E. Ragsdale, Camaron R. Hole, Stuart M. Levitz, Jennifer K. Lodge Oct 2019

Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C. Lam, Rajendra Upadhya, Charles A. Specht, Abigail E. Ragsdale, Camaron R. Hole, Stuart M. Levitz, Jennifer K. Lodge

Open Access Articles

Cryptococcus gattii R265 is a hypervirulent fungal strain responsible for the recent outbreak of cryptococcosis in Vancouver Island of British Columbia in Canada. It differs significantly from Cryptococcus neoformans in its natural environment, its preferred site in the mammalian host, and its pathogenesis. Our previous studies of C. neoformans have shown that the presence of chitosan, the deacetylated form of chitin, in the cell wall attenuates inflammatory responses in the host, while its absence induces robust immune responses, which in turn facilitate clearance of the fungus and induces a protective response. The results of the present investigation reveal that the ...


Control Of Cellular Responses To Mechanical Cues Through Yap/Taz Regulation, Ishani Dasgupta, Dannel Mccollum Oct 2019

Control Of Cellular Responses To Mechanical Cues Through Yap/Taz Regulation, Ishani Dasgupta, Dannel Mccollum

Open Access Articles

To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, differentiation as well as the processes of tissue regeneration and wound repair (1). Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states such as fibrosis, muscle diseases ...


Reduced Brain Activity In The Right Putamen As An Early Predictor For Treatment Response In Drug-Naive, First-Episode Schizophrenia, Renrong Wu, Yangpan Ou, Feng Liu, Jindong Chen, Huabing Li, Jingping Zhao, Wenbin Guo, Xiaoduo Fan Oct 2019

Reduced Brain Activity In The Right Putamen As An Early Predictor For Treatment Response In Drug-Naive, First-Episode Schizophrenia, Renrong Wu, Yangpan Ou, Feng Liu, Jindong Chen, Huabing Li, Jingping Zhao, Wenbin Guo, Xiaoduo Fan

Open Access Articles

Antipsychotic medications can have a significant effect on brain function after only several days of treatment. It is unclear whether such an acute effect can serve as an early predictor for treatment response in schizophrenia. Thirty-two patients with drug-naive, first-episode schizophrenia and 32 healthy controls underwent resting-state functional magnetic resonance imaging. Patients were treated with olanzapine and were scanned at baseline and 1 week of treatment. Healthy controls were scanned once at baseline. Symptom severity was assessed within the patient group using the Positive and Negative Syndrome Scale (PANSS) at three time points (baseline, 1 week of treatment, and 8 ...


Common Nodes Of Virus-Host Interaction Revealed Through An Integrated Network Analysis, Korbinian Bosl, Richard K. Kandasamy Oct 2019

Common Nodes Of Virus-Host Interaction Revealed Through An Integrated Network Analysis, Korbinian Bosl, Richard K. Kandasamy

Open Access Articles

Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve ...


The Genome-Wide Multi-Layered Architecture Of Chromosome Pairing In Early Drosophila Embryos, Jelena Erceg, Jumana Alhaj Abed, Anton Goloborodko, Bryan R. Lajoie, Geoffrey Fudenberg, Nezar Abdennur, Maxim Imakaev, Ruth B. Mccole, Son C. Nguyen, Wren Saylor, Eric F. Joyce, T. Niroshini Senaratne, Mohammed A. Hannan, Guy Nir, Job Dekker, Leonid A. Mirny, C-Ting Wu Oct 2019

The Genome-Wide Multi-Layered Architecture Of Chromosome Pairing In Early Drosophila Embryos, Jelena Erceg, Jumana Alhaj Abed, Anton Goloborodko, Bryan R. Lajoie, Geoffrey Fudenberg, Nezar Abdennur, Maxim Imakaev, Ruth B. Mccole, Son C. Nguyen, Wren Saylor, Eric F. Joyce, T. Niroshini Senaratne, Mohammed A. Hannan, Guy Nir, Job Dekker, Leonid A. Mirny, C-Ting Wu

Program in Systems Biology Publications and Presentations

Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. Here, we focus on trans interactions in Drosophila, where homologous chromosomes are paired in somatic cells from embryogenesis through adulthood. We first address long-standing questions regarding the structure of embryonic homolog pairing and, to this end, develop a haplotype-resolved Hi-C approach to minimize homolog misassignment and thus robustly distinguish trans-homolog from cis contacts. This computational approach, which we call Ohm, reveals pairing to be surprisingly structured genome-wide, with trans-homolog domains, compartments, and interaction peaks, many coinciding with analogous cis features. We also find a ...


Highly Structured Homolog Pairing Reflects Functional Organization Of The Drosophila Genome, Jumana Alhaj Abed, Jelena Erceg, Anton Goloborodko, Son C. Nguyen, Ruth B. Mccole, Wren Saylor, Geoffrey Fudenberg, Bryan R. Lajoie, Job Dekker, Leonid A. Mirny, C-Ting Wu Oct 2019

Highly Structured Homolog Pairing Reflects Functional Organization Of The Drosophila Genome, Jumana Alhaj Abed, Jelena Erceg, Anton Goloborodko, Son C. Nguyen, Ruth B. Mccole, Wren Saylor, Geoffrey Fudenberg, Bryan R. Lajoie, Job Dekker, Leonid A. Mirny, C-Ting Wu

Program in Systems Biology Publications and Presentations

Trans-homolog interactions have been studied extensively in Drosophila, where homologs are paired in somatic cells and transvection is prevalent. Nevertheless, the detailed structure of pairing and its functional impact have not been thoroughly investigated. Accordingly, we generated a diploid cell line from divergent parents and applied haplotype-resolved Hi-C, showing that homologs pair with varying precision genome-wide, in addition to establishing trans-homolog domains and compartments. We also elucidate the structure of pairing with unprecedented detail, observing significant variation across the genome and revealing at least two forms of pairing: tight pairing, spanning contiguous small domains, and loose pairing, consisting of single ...


Evaluation Of Il-1 Blockade As A Host-Directed Therapy For Tuberculosis In Mice And Macaques, Caylin G. Winchell, Bibhuti B. Mishra, University Of Massachusetts Medical School, Samantha J. Nelson, Christopher M. Sassetti, Joanne L. Flynn Oct 2019

Evaluation Of Il-1 Blockade As A Host-Directed Therapy For Tuberculosis In Mice And Macaques, Caylin G. Winchell, Bibhuti B. Mishra, University Of Massachusetts Medical School, Samantha J. Nelson, Christopher M. Sassetti, Joanne L. Flynn

University of Massachusetts Medical School Faculty Publications

In 2017, there were over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB), emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for antibiotic-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, a pathway important for early immunity during M. tuberculosis infection that later contributes to pathology. We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce BM toxicity and TB associated-inflammation. We used two ...


Principles For Enhancing Virus Capsid Capacity And Stability From A Thermophilic Virus Capsid Structure, Nicholas P. Stone, Gabriel Demo, Emily Agnello, Brian A. Kelch Oct 2019

Principles For Enhancing Virus Capsid Capacity And Stability From A Thermophilic Virus Capsid Structure, Nicholas P. Stone, Gabriel Demo, Emily Agnello, Brian A. Kelch

Open Access Articles

The capsids of double-stranded DNA viruses protect the viral genome from the harsh extracellular environment, while maintaining stability against the high internal pressure of packaged DNA. To elucidate how capsids maintain stability in an extreme environment, we use cryoelectron microscopy to determine the capsid structure of thermostable phage P74-26 to 2.8-A resolution. We find P74-26 capsids exhibit an overall architecture very similar to those of other tailed bacteriophages, allowing us to directly compare structures to derive the structural basis for enhanced stability. Our structure reveals lasso-like interactions that appear to function like catch bonds. This architecture allows the capsid ...


Leptin Induces Cell Migration And Invasion In A Fak-Src- Dependent Manner In Breast Cancer Cells, Juan Carlos Juarez-Cruz, Miriam Daniela. Zuniga-Eulogio, Monserrat Olea-Flores, Eduardo Castaneda-Saucedo, Miguel Angel. Mendoza-Catalan, Carlos Ortuno-Pineda, Ma Elena. Moreno-Godinez, Socrates Villegas-Comonfort, Teresita Padilla-Benavides, Napoleon Navarro-Tito Oct 2019

Leptin Induces Cell Migration And Invasion In A Fak-Src- Dependent Manner In Breast Cancer Cells, Juan Carlos Juarez-Cruz, Miriam Daniela. Zuniga-Eulogio, Monserrat Olea-Flores, Eduardo Castaneda-Saucedo, Miguel Angel. Mendoza-Catalan, Carlos Ortuno-Pineda, Ma Elena. Moreno-Godinez, Socrates Villegas-Comonfort, Teresita Padilla-Benavides, Napoleon Navarro-Tito

Open Access Articles

Breast cancer is the most common invasive neoplasia, and the second leading cause of the cancer deaths in women worldwide. Mammary tumorigenesis is severely linked to obesity, one potential connection is leptin. Leptin is a hormone secreted by adipocytes, which contributes to the progression of breast cancer. Cell migration, metalloproteases secretion, and invasion are cellular processes associated with various stages of metastasis. These processes are regulated by the kinases FAK and Src. In this study, we utilized the breast cancer cell lines MCF7 and MDA-MB-231 to determine the effect of leptin on FAK and Src kinases activation, cell migration, metalloprotease ...


Plasma Eicosanoid Levels In Tuberculosis And Tuberculosis-Diabetes Co-Morbidity Are Associated With Lung Pathology And Bacterial Burden, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Sivakumar Shanmugam, Syed Hissar, Hardy Kornfeld, Subash Babu Oct 2019

Plasma Eicosanoid Levels In Tuberculosis And Tuberculosis-Diabetes Co-Morbidity Are Associated With Lung Pathology And Bacterial Burden, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Sivakumar Shanmugam, Syed Hissar, Hardy Kornfeld, Subash Babu

Open Access Articles

Host eicosanoids are lipid mediators of inflammation that are commonly accepted as important modulators of the host immune response in Mycobacterium tuberculosis infection. During active tuberculosis (TB), eicosanoids may play an important role in the regulation of inflammatory responses. However, a detailed investigation of the relationship of eicosanoids in TB and TB-diabetes comorbidity (TB-DM) and association to disease pathology or bacterial burdens has not been studied. To study this, we examined the plasma levels of Lipoxin A4 (LXA4), 15-epi-LXA4, Leukotriene B4 (LTB4), and Prostaglandin E2 (PGE2) in individuals with either TB-DM, TB, diabetes mellitus (DM) or healthy controls (HC). Plasma ...


A Small Peptide Antagonist Of The Fas Receptor Inhibits Neuroinflammation And Prevents Axon Degeneration And Retinal Ganglion Cell Death In An Inducible Mouse Model Of Glaucoma, Anitha Krishnan, Andrew J. Kocab, David N. Zacks, Ann Marshak-Rothstein, Meredith Gregory-Ksander Sep 2019

A Small Peptide Antagonist Of The Fas Receptor Inhibits Neuroinflammation And Prevents Axon Degeneration And Retinal Ganglion Cell Death In An Inducible Mouse Model Of Glaucoma, Anitha Krishnan, Andrew J. Kocab, David N. Zacks, Ann Marshak-Rothstein, Meredith Gregory-Ksander

Open Access Articles

BACKGROUND: Glaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and inducible mouse models of glaucoma and that Fas activation triggered RGC apoptosis, glial activation, and inflammation. Here, we investigated whether targeting the Fas receptor with a small peptide antagonist, ONL1204, has anti-inflammatory and neuroprotective effects in a microbead-induced mouse model of glaucoma.

METHODS: Intracameral injection of microbeads was used to elevate intraocular pressure (IOP) in ...


Pollen-Derived Rnas Are Found In The Human Circulation, Milka Koupenova-Zamor, Eric O. Mick, Heather A. Corkrey, Anupama Singh, Selim E. Tanriverdi, Olga Vitseva, Daniel Levy, Allison M. Keeler, Marzieh Ezzaty Mirhashemi, Mai K. Elmallah, Mark Gerstein, Joel Rozowsky, Kahraman Tanriverdi, Jane E. Freedman Sep 2019

Pollen-Derived Rnas Are Found In The Human Circulation, Milka Koupenova-Zamor, Eric O. Mick, Heather A. Corkrey, Anupama Singh, Selim E. Tanriverdi, Olga Vitseva, Daniel Levy, Allison M. Keeler, Marzieh Ezzaty Mirhashemi, Mai K. Elmallah, Mark Gerstein, Joel Rozowsky, Kahraman Tanriverdi, Jane E. Freedman

Open Access Articles

The presence of nonhuman RNAs in man has been questioned and it is unclear if food-derived miRNAs cross into the circulation. In a large population study, we found nonhuman miRNAs in plasma by RNA sequencing and validated a small number of pine-pollen miRNAs by RT-qPCR in 2,776 people. The presence of these pine-pollen miRNAs associated with hay fever and not with overt cardiovascular or pulmonary disease. Using in vivo and in vitro models, we found that transmission of pollen-miRNAs into the circulation occurs via pulmonary transfer and this transfer was mediated by platelet-pulmonary vascular cell interactions and platelet pollen-DNA ...


Distinct Transcriptional Roles For Histone H3-K56 Acetylation During The Cell Cycle In Yeast, Salih Topal, Pauline Vasseur, Marta Radman-Livaja, Craig L. Peterson Sep 2019

Distinct Transcriptional Roles For Histone H3-K56 Acetylation During The Cell Cycle In Yeast, Salih Topal, Pauline Vasseur, Marta Radman-Livaja, Craig L. Peterson

Open Access Articles

Dynamic disruption and reassembly of promoter-proximal nucleosomes is a conserved hallmark of transcriptionally active chromatin. Histone H3-K56 acetylation (H3K56Ac) enhances these turnover events and promotes nucleosome assembly during S phase. Here we sequence nascent transcripts to investigate the impact of H3K56Ac on transcription throughout the yeast cell cycle. We find that H3K56Ac is a genome-wide activator of transcription. While H3K56Ac has a major impact on transcription initiation, it also appears to promote elongation and/or termination. In contrast, H3K56Ac represses promiscuous transcription that occurs immediately following replication fork passage, in this case by promoting efficient nucleosome assembly. We also detect ...


Oligogenic Effects Of 16p11.2 Copy-Number Variation On Craniofacial Development, Yuqi Qiu, Curtis K. Deutsch, Jonathan Sebat Sep 2019

Oligogenic Effects Of 16p11.2 Copy-Number Variation On Craniofacial Development, Yuqi Qiu, Curtis K. Deutsch, Jonathan Sebat

Open Access Articles

A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have "mirror" effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify ...


Leptin Promotes Expression Of Emt-Related Transcription Factors And Invasion In A Src And Fak-Dependent Pathway In Mcf10a Mammary Epithelial Cells, Monserrat Olea-Flores, Miriam Zuniga-Eulogio, Arvey Tacuba-Saavedra, Magdalena Bueno-Salgado, Andrea Sanchez-Carvajal, Yovani Vargas-Santiago, Miguel A. Mendoza-Catalan, Eduardo Perez Salazar, Alejandra Garcia-Hernandez, Teresita Padilla-Benavides, Napoleon Navarro-Tito Sep 2019

Leptin Promotes Expression Of Emt-Related Transcription Factors And Invasion In A Src And Fak-Dependent Pathway In Mcf10a Mammary Epithelial Cells, Monserrat Olea-Flores, Miriam Zuniga-Eulogio, Arvey Tacuba-Saavedra, Magdalena Bueno-Salgado, Andrea Sanchez-Carvajal, Yovani Vargas-Santiago, Miguel A. Mendoza-Catalan, Eduardo Perez Salazar, Alejandra Garcia-Hernandez, Teresita Padilla-Benavides, Napoleon Navarro-Tito

Open Access Articles

Leptin is one of the main adipokines secreted in breast tissue. Leptin promotes epithelial-mesenchymal transition (EMT), cell migration and invasion in epithelial breast cells, leading to tumor progression. Although, the molecular mechanisms that underlie these events are not fully understood, the activation of different signaling pathways appears to be essential. In this sense, the effects of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, are not completely described. Therefore, we investigated the involvement of these kinases using an in vitro model for leptin-induced EMT process in the non-tumorigenic MCF10A ...


Plasmodium Vivax Chloroquine Resistance Links To Pvcrt Transcription In A Genetic Cross, Juliana M. Sa, Derrick K. Deconti, Jeffrey A. Bailey, Thomas E. Wellems Sep 2019

Plasmodium Vivax Chloroquine Resistance Links To Pvcrt Transcription In A Genetic Cross, Juliana M. Sa, Derrick K. Deconti, Jeffrey A. Bailey, Thomas E. Wellems

Open Access Articles

Mainstay treatment for Plasmodium vivax malaria has long relied on chloroquine (CQ) against blood-stage parasites plus primaquine against dormant liver-stage forms (hypnozoites), however drug resistance confronts this regimen and threatens malaria control programs. Understanding the basis of P. vivax chloroquine resistance (CQR) will inform drug discovery and malaria control. Here we investigate the genetics of P. vivax CQR by a cross of parasites differing in drug response. Gametocytogenesis, mosquito infection, and progeny production are performed with mixed parasite populations in nonhuman primates, as methods for P. vivax cloning and in vitro cultivation remain unavailable. Linkage mapping of progeny surviving > 15 ...


Mutations In The Sptlc1 Gene Are A Cause Of Amyotrophic Lateral Sclerosis That May Be Amenable To Serine Supplementation, Janel O. Johnson, Ruth Chia, Robert H. Brown Jr., John E. Landers Sep 2019

Mutations In The Sptlc1 Gene Are A Cause Of Amyotrophic Lateral Sclerosis That May Be Amenable To Serine Supplementation, Janel O. Johnson, Ruth Chia, Robert H. Brown Jr., John E. Landers

University of Massachusetts Medical School Faculty Publications

SPTLC1 encodes a critical subunit of serine palmitoyltransferase, the enzyme catalyzing the first and rate-limiting step in de novo sphingolipid biosynthesis, and mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A. Using exome sequencing, we identified a de novo variant in SPTLC1 resulting in a p.Ala20Ser amino acid change in an individual diagnosed with juvenile-onset amyotrophic lateral sclerosis (ALS) and confirmed its pathogenicity by showing elevated plasma levels of neurotoxic deoxymethyl-sphinganine. A second case of juvenile-onset ALS arising again from a p.Ala20Ser mutation was later identified, confirming the association of SPTLC1 with this ...


Neural Jnk3 Regulates Blood Flow Recovery After Hindlimb Ischemia In Mice Via An Egr1/Creb1 Axis, Shashi Kant, Siobhan M. Craige, Kai Chen, Michaella M. Reif, Heather Learnard, Mark Kelly, Amada D. Caliz, Khanh-Van T. Tran, Kasmir Ramo, Owen M. Peters, Marc R. Freeman, Roger J. Davis, John F. Keaney Jr. Sep 2019

Neural Jnk3 Regulates Blood Flow Recovery After Hindlimb Ischemia In Mice Via An Egr1/Creb1 Axis, Shashi Kant, Siobhan M. Craige, Kai Chen, Michaella M. Reif, Heather Learnard, Mark Kelly, Amada D. Caliz, Khanh-Van T. Tran, Kasmir Ramo, Owen M. Peters, Marc R. Freeman, Roger J. Davis, John F. Keaney Jr.

University of Massachusetts Medical School Faculty Publications

Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1 ...


A Critical Role Of Vmp1 In Lipoprotein Secretion, Hideaki Morishita, Yan G. Zhao, Norito Tamura, Taki Nishimura, Yuki Kanda, Yuriko Sakamaki, Mitsuyo Okazaki, Dongfang Li, Noboru Mizushima Sep 2019

A Critical Role Of Vmp1 In Lipoprotein Secretion, Hideaki Morishita, Yan G. Zhao, Norito Tamura, Taki Nishimura, Yuki Kanda, Yuriko Sakamaki, Mitsuyo Okazaki, Dongfang Li, Noboru Mizushima

Open Access Articles

Lipoproteins are lipid-protein complexes that are primarily generated and secreted from the intestine, liver, and visceral endoderm and delivered to peripheral tissues. Lipoproteins, which are assembled in the endoplasmic reticulum (ER) membrane, are released into the ER lumen for secretion, but its mechanism remains largely unknown. Here, we show that the release of lipoproteins from the ER membrane requires VMP1, an ER transmembrane protein essential for autophagy and certain types of secretion. Loss of vmp1, but not other autophagy-related genes, in zebrafish causes lipoprotein accumulation in the intestine and liver. Vmp1 deficiency in mice also leads to lipid accumulation in ...


Signaling To Trp53 And Tap63 From Chk1/Chk2 Is Responsible For Elimination Of Most Oocytes Defective For Either Chromosome Synapsis Or Recombination, Vera D. Rinaldi, Jordana C. Bloom, John C. Schimenti Sep 2019

Signaling To Trp53 And Tap63 From Chk1/Chk2 Is Responsible For Elimination Of Most Oocytes Defective For Either Chromosome Synapsis Or Recombination, Vera D. Rinaldi, Jordana C. Bloom, John C. Schimenti

University of Massachusetts Medical School Faculty Publications

Eukaryotic organisms have evolved mechanisms to prevent the accumulation of cells bearing genetic aberrations. This is especially crucial for the germline, because fecundity, and fitness of progeny would be adversely affected by an excessively high mutational incidence. The process of meiosis poses unique problems for mutation avoidance, due to the requirement for SPO11-induced programmed double strand breaks (DSBs) in recombination-driven pairing and segregation of homologous chromosomes. Mouse meiocytes bearing unrepaired meiotic DSBs or unsynapsed chromosomes are eliminated before completing meiotic prophase I. In previous work, we showed that checkpoint kinase 2 (CHK2; CHEK2), a canonical DNA damage response protein, is ...


Extensive Ribosome And Rf2 Rearrangements During Translation Termination, Egor Svidritskiy, Gabriel Demo, Anna B. Loveland, Chen Xu, Andrei A. Korostelev Sep 2019

Extensive Ribosome And Rf2 Rearrangements During Translation Termination, Egor Svidritskiy, Gabriel Demo, Anna B. Loveland, Chen Xu, Andrei A. Korostelev

Open Access Articles

Protein synthesis ends when a ribosome reaches an mRNA stop codon. Release factors (RFs) decode the stop codon, hydrolyze peptidyl-tRNA to release the nascent protein, and then dissociate to allow ribosome recycling. To visualize termination by RF2, we resolved a cryo-EM ensemble of E. coli 70S*RF2 structures at up to 3.3 A in a single sample. Five structures suggest a highly dynamic termination pathway. Upon peptidyl-tRNA hydrolysis, the CCA end of deacyl-tRNA departs from the peptidyl transferase center. The catalytic GGQ loop of RF2 is rearranged into a long beta-hairpin that plugs the peptide tunnel, biasing a nascent ...


Co-Option Of The Gibbon-Specific Lava Retrotransposon In Dna Repair Pathways, Mariam Okhovat, Kimberly A. Nevonen, Brett Davis, Pryce S. Michener, Samantha Ward, Mark Milhaven, Lana Harshman, Ajuni Sohota, Rachel J. O’Neill, Nadav Ahituv, Krishna R. Veeramah, Lucia Carbone Sep 2019

Co-Option Of The Gibbon-Specific Lava Retrotransposon In Dna Repair Pathways, Mariam Okhovat, Kimberly A. Nevonen, Brett Davis, Pryce S. Michener, Samantha Ward, Mark Milhaven, Lana Harshman, Ajuni Sohota, Rachel J. O’Neill, Nadav Ahituv, Krishna R. Veeramah, Lucia Carbone

University of Massachusetts Medical School Faculty Publications

Transposable elements (TEs) can shape gene regulation networks by being co-opted as enhancers. However, the contribution of lineage-specific TE insertions to recent adaptations remains poorly understood. Gibbons present a suitable model to study these contributions, as they have evolved many distinct traits, including heavily rearranged genomes and a novel TE called LAVA. The LAVA retrotransposon is still active in the gibbon genome and is thought to have contributed to evolution of gibbon-specific traits. In this study, we characterized fixed and polymorphic LAVA insertions across multiple gibbon genomes and found that 10% of all LAVA elements overlap chromatin states associated with ...