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Full-Text Articles in Life Sciences

The Clinical Review Committee: Impact Of The Development Of In Vitro Diagnostic Tests For Sars-Cov-2 Within Radx Tech, Matthew L. Robinson, Laura L. Gibson, David D. Mcmanus Apr 2021

The Clinical Review Committee: Impact Of The Development Of In Vitro Diagnostic Tests For Sars-Cov-2 Within Radx Tech, Matthew L. Robinson, Laura L. Gibson, David D. Mcmanus

Open Access Publications by UMMS Authors

The NIH Rapid Acceleration of Diagnostics (RADx SM ) Tech Program was created to speed the development, validation, and commercialization of innovative point-of-care (POC) and home-based tests, and to improve clinical laboratory tests, that can directly detect SARS-CoV-2. Leveraging the experience of the Point-of-Care Technologies Research Network, a Clinical Review Committee (CRC) composed of clinicians, bioengineers, regulatory experts, and laboratorians was created to provide structured feedback to SARS-CoV-2 diagnostic innovators. The CRC convened 53 meetings with 49 companies offering SARS-CoV-2 tests in POC and reference laboratory formats as well as collection materials. The CRC identified common barriers to device design finalization ...


A Multi-Institutional Partnership Catalyzing The Commercialization Of Medical Devices And Biotechnology Products., Nathaniel Hafer, Bryan Buchholz, Denise Dunlap, Brennan Fournier, Scott Latham, Mary Ann Picard, Steven Tello, Laura L. Gibson, Craig M. Lilly, David D. Mcmanus Apr 2021

A Multi-Institutional Partnership Catalyzing The Commercialization Of Medical Devices And Biotechnology Products., Nathaniel Hafer, Bryan Buchholz, Denise Dunlap, Brennan Fournier, Scott Latham, Mary Ann Picard, Steven Tello, Laura L. Gibson, Craig M. Lilly, David D. Mcmanus

COVID-19 Publications by UMMS Authors

The commercialization of medical devices and biotechnology products is characterized by high failure rates and long development lead times particularly among start-up enterprises. To increase the success rate of these high-risk ventures, the University of Massachusetts Lowell (UML) and University of Massachusetts Medical School (UMMS) partnered to create key academic support centers with programs to accelerate entrepreneurship and innovation in this industry. In 2008, UML and UMMS founded the Massachusetts Medical Device Development Center (M2D2), which is a business and technology incubator that provides business planning, product prototyping, laboratory services, access to clinical testing, and ecosystem networking to medical device ...


The Ssdna Theory Of Brcaness And Genotoxic Agents, Nicholas J. Panzarino Apr 2021

The Ssdna Theory Of Brcaness And Genotoxic Agents, Nicholas J. Panzarino

GSBS Dissertations and Theses

Cancers that are deficient in BRCA1 or BRCA2 are thought to be hypersensitive to genotoxic agents because they cannot prevent or repair DNA double strand breaks, but observations in patients suggest this dogma may no longer agree with experiment. Here, we propose that single stranded DNA underlies the hypersensitivity of BRCA deficient cancers, and that defects in double strand break repair and prevention do not. Specifically, in BRCA deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. In addition, we observed gaps could be suppressed by either restored fork restraint or by gap filling ...


Predictors Of Irritability Symptoms In Mildly Depressed Perimenopausal Women, Anouk E. De Wit, Erik J. Giltay, Marrit K. De Boer, Margo Nathan, Aleta Wiley, Sybil L. Crawford, Hadine Joffe Apr 2021

Predictors Of Irritability Symptoms In Mildly Depressed Perimenopausal Women, Anouk E. De Wit, Erik J. Giltay, Marrit K. De Boer, Margo Nathan, Aleta Wiley, Sybil L. Crawford, Hadine Joffe

Graduate School of Nursing Publications

OBJECTIVE: Irritability is a highly burdensome complaint, commonly, but not universally, linked with depressive symptoms. While increased variability in estradiol has been associated with depressive symptoms during perimenopause, more insight is needed into reproductive hormone dynamics and other factors that predispose perimenopausal women to irritable mood.

METHODS: Among 50 mildly depressed perimenopausal women (mean (SD) age 48.4 (3.9) years), severity of irritability symptoms (on Symptom Questionnaire Hostility subscale, range 0-23) was assessed weekly for eight weeks, concurrent with potential predictors. Associations between these were examined using generalized estimating equating models.

RESULTS: Most women (82.0%) reported having moderate ...


Challenges In Defining Long Covid: Striking Differences Across Literature, Electronic Health Records, And Patient-Reported Information, Halie M. Rando, Feifan Liu, Melissa A. Haendel Mar 2021

Challenges In Defining Long Covid: Striking Differences Across Literature, Electronic Health Records, And Patient-Reported Information, Halie M. Rando, Feifan Liu, Melissa A. Haendel

UMass Center for Clinical and Translational Science Supported Publications

Since late 2019, the novel coronavirus SARS-CoV-2 has introduced a wide array of health challenges globally. In addition to a complex acute presentation that can affect multiple organ systems, increasing evidence points to long-term sequelae being common and impactful. The worldwide scientific community is forging ahead to characterize a wide range of outcomes associated with SARS-CoV-2 infection; however the underlying assumptions in these studies have varied so widely that the resulting data are difficult to compare. Formal definitions are needed in order to design robust and consistent studies of Long COVID that consistently capture variation in long-term outcomes. Even the ...


The High Prevalence Of Clostridioides Difficile Among Nursing Home Elders Associates With A Dysbiotic Microbiome, John P. Haran, Doyle V. Ward, Shakti K. Bhattarai, Ethan Loew, Protiva Dutta, Amanda Higgins, Beth A. Mccormick, Vanni Bucci Mar 2021

The High Prevalence Of Clostridioides Difficile Among Nursing Home Elders Associates With A Dysbiotic Microbiome, John P. Haran, Doyle V. Ward, Shakti K. Bhattarai, Ethan Loew, Protiva Dutta, Amanda Higgins, Beth A. Mccormick, Vanni Bucci

University of Massachusetts Medical School Faculty Publications

Clostridioides difficile disproportionally affects the elderly living in nursing homes (NHs). Our objective was to explore the prevalence of C. difficile in NH elders, over time and to determine whether the microbiome or other clinical factors are associated with C. difficile colonization. We collected serial stool samples from NH residents. C. difficile prevalence was determined by quantitative polymerase-chain reaction detection of Toxin genes tcdA and tcdB; microbiome composition was determined by shotgun metagenomic sequencing. We used mixed-effect random forest modeling machine to determine bacterial taxa whose abundance is associated with C. difficile prevalence while controlling for clinical covariates including demographics ...


Lung Epithelial Cell Transcriptional Regulation As A Factor In Covid-19 Associated Coagulopathies, Ethan S. Fitzgerald, Yongzhi Chen, Katherine A. Fitzgerald, Amanda M. Jamieson Mar 2021

Lung Epithelial Cell Transcriptional Regulation As A Factor In Covid-19 Associated Coagulopathies, Ethan S. Fitzgerald, Yongzhi Chen, Katherine A. Fitzgerald, Amanda M. Jamieson

COVID-19 Publications by UMMS Authors

SARS-CoV-2 has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of COVID-19 (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19 associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short and long term thrombotic risks of sick and recovered COVID-19 patients. We aimed to perform coagulation focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient derived bronchial alveolar lavage (BALF) cells, and circulating immune cells during SARS-CoV-2 infection. Our ...


Gwas-Associated Variants, Non-Genetic Factors, And Transient Transcriptome In Multiple Sclerosis Etiopathogenesis: A Colocalization Analysis [Preprint], Renato Umeton, Gianmarco Bellucci, Rachele Bigi, Silvia Romano, Maria Chiara Buscarinu, Roberta Reniè, Virginia Rinaldi, Raffaella Pizzolato Umeton, Emanuele Morena, Carmela Romano, Rosella Mechelli, Marco Salvetti, Giovanni Ristori Mar 2021

Gwas-Associated Variants, Non-Genetic Factors, And Transient Transcriptome In Multiple Sclerosis Etiopathogenesis: A Colocalization Analysis [Preprint], Renato Umeton, Gianmarco Bellucci, Rachele Bigi, Silvia Romano, Maria Chiara Buscarinu, Roberta Reniè, Virginia Rinaldi, Raffaella Pizzolato Umeton, Emanuele Morena, Carmela Romano, Rosella Mechelli, Marco Salvetti, Giovanni Ristori

University of Massachusetts Medical School Faculty Publications

A clinically actionable understanding of multiple sclerosis (MS) etiology goes through GWAS interpretation, prompting research on new gene regulatory models. Our previous works on these topics suggested a stochastic etiologic model where small-scale random perturbations could eventually reach a threshold for MS onset and progression. A new sequencing technology has mapped the transient transcriptome (TT), including intergenic RNAs, and antisense intronic RNAs. Through a rigorous colocalization analysis, here we show that genomic regions coding for the TT were significantly enriched for both MS-associated GWAS variants, and DNA binding sites for molecular transducers mediating putative, non-genetic, etiopathogenetic factors for MS (e ...


Development Of Potency, Breadth And Resilience To Viral Escape Mutations In Sars-Cov-2 Neutralizing Antibodies [Preprint], Frauke Muecksch, Shurong Hou, Celia A. Schiffer, Michel Nussenzweig, Pamela J. Bjorkman, Theodora Hatziioannou, Paul Bieniasz Mar 2021

Development Of Potency, Breadth And Resilience To Viral Escape Mutations In Sars-Cov-2 Neutralizing Antibodies [Preprint], Frauke Muecksch, Shurong Hou, Celia A. Schiffer, Michel Nussenzweig, Pamela J. Bjorkman, Theodora Hatziioannou, Paul Bieniasz

University of Massachusetts Medical School Faculty Publications

Antibodies elicited in response to infection undergo somatic mutation in germinal centers that can result in higher affinity for the cognate antigen. To determine the effects of somatic mutation on the properties of SARS-CoV-2 spike receptor-binding domain (RBD)-specific antibodies, we analyzed six independent antibody lineages. As well as increased neutralization potency, antibody evolution changed pathways for acquisition of resistance and, in some cases, restricted the range of neutralization escape options. For some antibodies, maturation apparently imposed a requirement for multiple spike mutations to enable escape. For certain antibody lineages, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and ...


The Mycobacterium Tuberculosis Transposon Sequencing Database (Mtbtndb): A Large-Scale Guide To Genetic Conditional Essentiality [Preprint], Adrian Jinich, Anisha Zaveri, Michael A. Dejesus, Emanuel Flores-Bautista, Clare M. Smith, Christopher M. Sassetti, Jeremy M. Rock, Sabine Ehrt, Dirk Schnappinger, Thomas R. Ioerger, Kyu Rhee Mar 2021

The Mycobacterium Tuberculosis Transposon Sequencing Database (Mtbtndb): A Large-Scale Guide To Genetic Conditional Essentiality [Preprint], Adrian Jinich, Anisha Zaveri, Michael A. Dejesus, Emanuel Flores-Bautista, Clare M. Smith, Christopher M. Sassetti, Jeremy M. Rock, Sabine Ehrt, Dirk Schnappinger, Thomas R. Ioerger, Kyu Rhee

University of Massachusetts Medical School Faculty Publications

Characterization of gene essentiality across different conditions is a useful approach for predicting gene function. Transposon sequencing (TnSeq) is a powerful means of generating genome-wide profiles of essentiality and has been used extensively in Mycobacterium tuberculosis (Mtb) genetic research. Over the past two decades, dozens of TnSeq screens have been published, yielding valuable insights into the biology of Mtb in vitro, inside macrophages, and in model host organisms. However, these Mtb TnSeq profiles are distributed across dozens of research papers within supplementary materials, which makes querying them cumbersome and assembling a complete and consistent synthesis of existing data challenging. Here ...


Cnbp, Rel, And Bhlhe40 Variants Are Associated With Il-12 And Il-10 Responses And Tuberculosis Risk [Preprint], Javeed A. Shah, Christopher M. Sassetti, Katherine A. Fitzgerald Mar 2021

Cnbp, Rel, And Bhlhe40 Variants Are Associated With Il-12 And Il-10 Responses And Tuberculosis Risk [Preprint], Javeed A. Shah, Christopher M. Sassetti, Katherine A. Fitzgerald

University of Massachusetts Medical School Faculty Publications

Rationale: The major human genes regulating M. tuberculosis (Mtb)-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling.

Objectives: To determine whether common human genetic variation in CNBP, REL and BHLHE40 is associated with IL-12 and IL-10 expression, adaptive immune responses to mycobacteria, and susceptibility to TB.

Methods and Main Measurements: We characterized the association between common variants in CNBP, REL, and BHLHE40 and innate immune responses in dendritic ...


Virtualized Clinical Studies To Assess The Natural History And Impact Of Gut Microbiome Modulation In Non-Hospitalized Patients With Mild To Moderate Covid-19 A Randomized, Open-Label, Prospective Study With A Parallel Group Study Evaluating The Physiologic Effects Of Kb109 On Gut Microbiota Structure And Function: A Structured Summary Of A Study Protocol For A Randomized Controlled Study [Preprint], John P. Haran, Jose C. Pinero, Yan Zheng, Norma Alonzo Palma, Mark Wingertzahn Mar 2021

Virtualized Clinical Studies To Assess The Natural History And Impact Of Gut Microbiome Modulation In Non-Hospitalized Patients With Mild To Moderate Covid-19 A Randomized, Open-Label, Prospective Study With A Parallel Group Study Evaluating The Physiologic Effects Of Kb109 On Gut Microbiota Structure And Function: A Structured Summary Of A Study Protocol For A Randomized Controlled Study [Preprint], John P. Haran, Jose C. Pinero, Yan Zheng, Norma Alonzo Palma, Mark Wingertzahn

COVID-19 Publications by UMMS Authors

These 2 parallel studies (K031 and K032) aim to evaluate the safety of KB109 in addition to supportive self-care (SSC) compared with SSC alone in outpatients with mild to moderate coronavirus disease 2019 (COVID-19). KB109 is a novel synthetic glycan that was formulated to modulate the gut microbiome composition and metabolic output in order to increase beneficial short-chain fatty acid (SCFA) production in the gut. The K031 study is designed to evaluate the safety of KB109 and characterize its impact on the natural progression of COVID-19 in patients with mild to moderate disease. The K032 study is evaluating the effect ...


Swi/Snf Senses Carbon Starvation With A Ph-Sensitive Low Complexity Sequence [Preprint], J. Ignacio Gutiérrez, Gregory P. Brittingham, Yonca Karadeniz, Kathleen D. Tran, Arnob Dutta, Alex S. Holehouse, Craig L. Peterson, Liam J. Holt Mar 2021

Swi/Snf Senses Carbon Starvation With A Ph-Sensitive Low Complexity Sequence [Preprint], J. Ignacio Gutiérrez, Gregory P. Brittingham, Yonca Karadeniz, Kathleen D. Tran, Arnob Dutta, Alex S. Holehouse, Craig L. Peterson, Liam J. Holt

University of Massachusetts Medical School Faculty Publications

It is increasingly appreciated that intracellular pH changes are important biological signals. This motivates the elucidation of molecular mechanisms of pH-sensing. We determined that a nucleocytoplasmic pH oscillation was required for the transcriptional response to carbon starvation in S. cerevisiae. The SWI/SNF chromatin remodeling complex is a key mediator of this transcriptional response. We found that a glutamine-rich low complexity sequence (QLC) in the SNF5 subunit of this complex, and histidines within this sequence, were required for efficient transcriptional reprogramming during carbon starvation. Furthermore, the SNF5 QLC mediated pH-dependent recruitment of SWI/SNF to a model promoter in vitro ...


Somatic Pirnas And Transposons Are Differentially Regulated During Skeletal Muscle Atrophy And Programmed Cell Death [Preprint], Junko Tsuji, Travis Thomson, Christine Brown, Subhanita Ghosh, William E. Theurkauf, Zhiping Weng, Lawrence M. Schwartz Mar 2021

Somatic Pirnas And Transposons Are Differentially Regulated During Skeletal Muscle Atrophy And Programmed Cell Death [Preprint], Junko Tsuji, Travis Thomson, Christine Brown, Subhanita Ghosh, William E. Theurkauf, Zhiping Weng, Lawrence M. Schwartz

University of Massachusetts Medical School Faculty Publications

PiWi-interacting RNAs (piRNAs) are small single-stranded RNAs that can repress transposon expression via epigenetic silencing and transcript degradation. They have been identified predominantly in the ovary and testis, where they serve essential roles in transposon silencing in order to protect the integrity of the genome in the germline. The potential expression of piRNAs in somatic cells has been controversial. In the present study we demonstrate the expression of piRNAs derived from both genic and transposon RNAs in the intersegmental muscles (ISMs) from the tobacco hawkmoth Manduca sexta. These piRNAs are abundantly expressed, are ~27 nt long, map antisense to transposons ...


Nox4 Mediates Skeletal Muscle Metabolic Responses To Exercise, Kalyn S. Specht, Shashi Kant, Heather Learnard, Maura Campbell, Amada D. Caliz, Yongmei Pei, Michaella M. Reif, John F. Keaney Jr., Siobhan M. Craige Mar 2021

Nox4 Mediates Skeletal Muscle Metabolic Responses To Exercise, Kalyn S. Specht, Shashi Kant, Heather Learnard, Maura Campbell, Amada D. Caliz, Yongmei Pei, Michaella M. Reif, John F. Keaney Jr., Siobhan M. Craige

Open Access Publications by UMMS Authors

OBJECTIVE: The immediate signals that couple exercise to metabolic adaptations are incompletely understood. Nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) produces reactive oxygen species (ROS) and plays a significant role in metabolic and vascular adaptation during stress conditions. Our objective was to determine the role of Nox4 in exercise-induced skeletal muscle metabolism.

METHODS: Mice were subjected to acute exercise to assess their immediate responses. mRNA and protein expression responses to Nox4 and hydrogen peroxide (H2O2) were measured by qPCR and immunoblotting. Functional metabolic flux was measured via ex vivo fatty acid and glucose oxidation assays using (14)C-labeled palmitate and ...


Relaxed Tarantula Skeletal Muscle Has Two Atp Energy-Saving Mechanisms, Weikang Ma, Sebastian Duno-Miranda, Thomas Irving, Roger W. Craig, Raul A. Padron Mar 2021

Relaxed Tarantula Skeletal Muscle Has Two Atp Energy-Saving Mechanisms, Weikang Ma, Sebastian Duno-Miranda, Thomas Irving, Roger W. Craig, Raul A. Padron

Radiology Publications

Myosin molecules in the relaxed thick filaments of striated muscle have a helical arrangement in which the heads of each molecule interact with each other, forming the interacting-heads motif (IHM). In relaxed mammalian skeletal muscle, this helical ordering occurs only at temperatures > 20 degrees C and is disrupted when temperature is decreased. Recent x-ray diffraction studies of live tarantula skeletal muscle have suggested that the two myosin heads of the IHM (blocked heads [BHs] and free heads [FHs]) have very different roles and dynamics during contraction. Here, we explore temperature-induced changes in the BHs and FHs in relaxed tarantula skeletal ...


Ifnγ And Inos-Mediated Alterations In The Bone Marrow And Thymus And Its Impact On Mycobacterium Avium-Induced Thymic Atrophy [Preprint], Palmira Barreira-Silva, Rita Melo-Miranda, Claudia Nobrega, Susana Roque, Cláudia Serre-Miranda, Margarida Borges, Daniela De Sá Calçada, Samuel M. Behar, Rui Appelberg, Margarida Correia-Neves Feb 2021

Ifnγ And Inos-Mediated Alterations In The Bone Marrow And Thymus And Its Impact On Mycobacterium Avium-Induced Thymic Atrophy [Preprint], Palmira Barreira-Silva, Rita Melo-Miranda, Claudia Nobrega, Susana Roque, Cláudia Serre-Miranda, Margarida Borges, Daniela De Sá Calçada, Samuel M. Behar, Rui Appelberg, Margarida Correia-Neves

University of Massachusetts Medical School Faculty Publications

Disseminated infection with the high virulence strain of Mycobacterium avium 25291 lead to progressive thymic atrophy. We previously uncovered that M. avium-induced thymic atrophy is due to increased levels of glucocorticoids synergizing with nitric oxide (NO) produced by interferon gamma (IFNγ) activated macrophages. Where and how these mediators are playing, was yet to be understood. We hypothesized that IFNγ and NO might be affecting bone marrow (BM) T cell precursors and/or T cell differentiation in the thymus. We show that M. avium infection causes a reduction on the percentage of lymphoid-primed multipotent progenitors (LMPP) and common lymphoid progenitors ...


Cd4 T Cell Help Prevents Cd8 T Cell Exhaustion And Promotes Control Of Mycobacterium Tuberculosis Infection [Preprint], Yu-Jung Lu, Palmira Barreira-Silva, Shayla Boyce, Jennifer Powers, Kelly Cavallo, Samuel M. Behar Feb 2021

Cd4 T Cell Help Prevents Cd8 T Cell Exhaustion And Promotes Control Of Mycobacterium Tuberculosis Infection [Preprint], Yu-Jung Lu, Palmira Barreira-Silva, Shayla Boyce, Jennifer Powers, Kelly Cavallo, Samuel M. Behar

University of Massachusetts Medical School Faculty Publications

CD4 T cells are essential for immunity to tuberculosis because they produce cytokines including interferon-γ. Whether CD4 T cells act as “helper” cells to promote optimal CD8 T cell responses during Mycobacterium tuberculosis is unknown. Using two independent models, we show that CD4 T cell help enhances CD8 effector functions and prevents CD8 T cell exhaustion. We demonstrate synergy between CD4 and CD8 T cells in promoting the survival of infected mice. Purified helped, but not helpless, CD8 T cells efficiently restrict intracellular bacterial growth in vitro. Thus, CD4 T cell help plays an essential role in generating protective CD8 ...


Physiology, Rem Sleep, Joshua Feriante, John F. Araujo Feb 2021

Physiology, Rem Sleep, Joshua Feriante, John F. Araujo

Open Access Publications by UMMS Authors

Sleep is a reversible state of disconnection from the environment, including reduced consciousness, skeletal muscle mobility, and metabolism. All forms of sensory responses are markedly decreased to varying degrees depending on the sleep cycle stage. Although this phenomenon is observed in all species that have been studied and occupies a significant fraction of the human lifespan, the purpose and function of sleep remain poorly understood.

Sleep is measured primarily by polysomnography (PSG) which is considered the gold standard for diagnosing sleep disorders.. PSG reveals that sleep architecture has several distinct stages that vacillate between the non-rapid eye movement (NREM) stages ...


Deficient Spermiogenesis In Mice Lacking Rlim, Feng Wang, Maria Gracia Gervasi, Ana Boskovic, Fengyun Sun, Vera D. Rinaldi, Jun Yu, Mary C. Wallingford, Darya A. Tourzani, Jesse Mager, Lihua Julie Zhu, Oliver J. Rando, Pablo E. Visconti, Lara Strittmatter, Ingolf Bach Feb 2021

Deficient Spermiogenesis In Mice Lacking Rlim, Feng Wang, Maria Gracia Gervasi, Ana Boskovic, Fengyun Sun, Vera D. Rinaldi, Jun Yu, Mary C. Wallingford, Darya A. Tourzani, Jesse Mager, Lihua Julie Zhu, Oliver J. Rando, Pablo E. Visconti, Lara Strittmatter, Ingolf Bach

Radiology Publications

The X-linked gene Rlim plays major roles in female mouse development and reproduction, where it is crucial for the maintenance of imprinted X chromosome inactivation in extraembryonic tissues of embryos. However, while females carrying a systemic Rlim knockout (KO) die around implantation, male Rlim KO mice appear healthy and are fertile. Here, we report an important role for Rlim in testis where it is highly expressed in post-meiotic round spermatids as well as in Sertoli cells. Systemic deletion of the Rlim gene results in lower numbers of mature sperm that contains excess cytoplasm, leading to decreased sperm motility and in ...


Differential Role Of Mlkl In Alcohol-Associated And Non-Alcohol-Associated Fatty Liver Diseases In Mice And Humans, Tatsunori Miyata, Bruce A. Barton, Laura E. Nagy Feb 2021

Differential Role Of Mlkl In Alcohol-Associated And Non-Alcohol-Associated Fatty Liver Diseases In Mice And Humans, Tatsunori Miyata, Bruce A. Barton, Laura E. Nagy

University of Massachusetts Medical School Faculty Publications

Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and ...


Annotation Of Chromatin States In 66 Complete Mouse Epigenomes During Development, Arjan Van Der Velde, Kaili Fan, Junko Tsuji, Jill E. Moore, Michael J. Purcaro, Henry E. Pratt, Zhiping Weng Feb 2021

Annotation Of Chromatin States In 66 Complete Mouse Epigenomes During Development, Arjan Van Der Velde, Kaili Fan, Junko Tsuji, Jill E. Moore, Michael J. Purcaro, Henry E. Pratt, Zhiping Weng

Open Access Publications by UMMS Authors

The morphologically and functionally distinct cell types of a multicellular organism are maintained by their unique epigenomes and gene expression programs. Phase III of the ENCODE Project profiled 66 mouse epigenomes across twelve tissues at daily intervals from embryonic day 11.5 to birth. Applying the ChromHMM algorithm to these epigenomes, we annotated eighteen chromatin states with characteristics of promoters, enhancers, transcribed regions, repressed regions, and quiescent regions. Our integrative analyses delineate the tissue specificity and developmental trajectory of the loci in these chromatin states. Approximately 0.3% of each epigenome is assigned to a bivalent chromatin state, which harbors ...


Xct-Driven Expression Of Gpx4 Determines Sensitivity Of Breast Cancer Cells To Ferroptosis Inducers, Namgyu Lee, Anne E. Carlisle, Austin Peppers, Sung Jin Park, Mihir B. Doshi, Meghan E. Spears, Dohoon Kim Feb 2021

Xct-Driven Expression Of Gpx4 Determines Sensitivity Of Breast Cancer Cells To Ferroptosis Inducers, Namgyu Lee, Anne E. Carlisle, Austin Peppers, Sung Jin Park, Mihir B. Doshi, Meghan E. Spears, Dohoon Kim

Open Access Publications by UMMS Authors

Inducers of ferroptosis such as the glutathione depleting agent Erastin and the GPX4 inhibitor Rsl-3 are being actively explored as potential therapeutics in various cancers, but the factors that determine their sensitivity are poorly understood. Here, we show that expression levels of both subunits of the cystine/glutamate antiporter xCT determine the expression of GPX4 in breast cancer, and that upregulation of the xCT/selenocysteine biosynthesis/GPX4 production axis paradoxically renders the cancer cells more sensitive to certain types of ferroptotic stimuli. We find that GPX4 is strongly upregulated in a subset of breast cancer tissues compared to matched normal ...


Cryo-Tem Simulations Of Amorphous Radiation-Sensitive Samples Using Multislice Wave Propagation [Preprint], Benjamin A. Himes, Nikolaus Grigorieff Feb 2021

Cryo-Tem Simulations Of Amorphous Radiation-Sensitive Samples Using Multislice Wave Propagation [Preprint], Benjamin A. Himes, Nikolaus Grigorieff

University of Massachusetts Medical School Faculty Publications

Image simulation plays a central role in the development and practice of high-resolution electron microscopy, including transmission electron microscopy of frozen-hydrated specimens (cryo-EM). Simulating images with contrast that matches the contrast observed in experimental images remains challenging, especially for amorphous samples. Current state-of-the-art simulators apply post hoc scaling to approximate empirical solvent contrast, attenuated image intensity due to specimen thickness, and amplitude contrast. This practice fails for images that require spatially variable scaling, e.g., simulations of a crowded or cellular environment. Modeling both the signal and the noise accurately is necessary to simulate images of biological specimens with contrast ...


Yap And Taz Are Transcriptional Co-Activators Of Ap-1 Proteins And Stat3 During Breast Cellular Transformation [Preprint], Lizhi He, Henry E. Pratt, Fengxiang Wei, Mingshi Gao, Zhiping Weng, Kevin Struhl Feb 2021

Yap And Taz Are Transcriptional Co-Activators Of Ap-1 Proteins And Stat3 During Breast Cellular Transformation [Preprint], Lizhi He, Henry E. Pratt, Fengxiang Wei, Mingshi Gao, Zhiping Weng, Kevin Struhl

University of Massachusetts Medical School Faculty Publications

The YAP and TAZ paralogues are transcriptional co-activators recruited to target sites, primarily by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB and STAT3, key factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, co-occupy many target sites in vivo via AP-1 and (to a lesser extent) STAT3 sequence motifs, and stimulate transcriptional activation by AP-1 proteins. A few target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes ...


Recombinant Paraprobiotics As A New Paradigm For Treating Gastrointestinal Nematode Parasites Of Humans, Hanchen Li, Gary R. Ostroff, Raffi V. Aroian Feb 2021

Recombinant Paraprobiotics As A New Paradigm For Treating Gastrointestinal Nematode Parasites Of Humans, Hanchen Li, Gary R. Ostroff, Raffi V. Aroian

Open Access Publications by UMMS Authors

Gastrointestinal nematodes (GINs) of humans, e.g., hookworms, negatively impact childhood growth, cognition, nutrition, educational attainment, income, productivity, and pregnancy. Hundreds of millions of people are targeted with mass drug administration (MDA) of donated benzimidazole anthelmintics. However, benzimidazole efficacy against GINs is suboptimal, and reduced/low efficacy has been seen. Developing an anthelmintic for human MDA is daunting: it must be safe, effective, inexpensive, stable without a cold chain, and massively scalable. Bacillus thuringiensis crystal protein 5B (Cry5B) has anthelmintic properties that could fill this void. Here, we developed an active pharmaceutical ingredient (API) containing B. thuringiensis Cry5B compatible with ...


Quantifying And Mitigating Motor Phenotypes Induced By Antisense Oligonucleotides In The Central Nervous System [Preprint], Michael P. Moazami, Julia M. Rembetsy-Brown, Feng Wang, Pranathi Meda Krishnamurthy, Alexandra Weiss, Miklos G. Marosfoi, Robert M. King, Mona Motwani, Heather L. Gray-Edwards, Katherine A. Fitzgerald, Robert H. Brown Jr., Jonathan K. Watts Feb 2021

Quantifying And Mitigating Motor Phenotypes Induced By Antisense Oligonucleotides In The Central Nervous System [Preprint], Michael P. Moazami, Julia M. Rembetsy-Brown, Feng Wang, Pranathi Meda Krishnamurthy, Alexandra Weiss, Miklos G. Marosfoi, Robert M. King, Mona Motwani, Heather L. Gray-Edwards, Katherine A. Fitzgerald, Robert H. Brown Jr., Jonathan K. Watts

University of Massachusetts Medical School Faculty Publications

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into the cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. The effect of sugar and phosphate modifications on these phenotypes has not previously been systematically studied. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence ...


Vaccines, Troy Moon Feb 2021

Vaccines, Troy Moon

PEER Liberia Project

This is a lecture in the PEER Liberia Infectious Disease Lecture Series. This presentation provides an overview of: prevention and control of vaccine preventable diseases; global impact of vaccines - successes and challenges; and vaccine fundamentals - basic immunology, introduction to vaccinology.


Host Tropism Determination By Convergent Evolution Of Immunological Evasion In The Lyme Disease System [Preprint], Thomas M. Hart, Alan P. Dupuis, Ii, Danielle M. Tufts, Anna M. Blom, Simon Starkey, Ryan O. M. Rego, Sanjay Ram, Peter Kraiczy, Laura D. Kramer, Maria A. Diuk-Wasser, Sergios-Orestis Kolokotronis, Yi-Pin Lin Feb 2021

Host Tropism Determination By Convergent Evolution Of Immunological Evasion In The Lyme Disease System [Preprint], Thomas M. Hart, Alan P. Dupuis, Ii, Danielle M. Tufts, Anna M. Blom, Simon Starkey, Ryan O. M. Rego, Sanjay Ram, Peter Kraiczy, Laura D. Kramer, Maria A. Diuk-Wasser, Sergios-Orestis Kolokotronis, Yi-Pin Lin

University of Massachusetts Medical School Faculty Publications

Microparasites selectively adapt in some hosts, known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, the Lyme disease (LD) bacterium is a well-suited model to study such tropism. LD bacteria species vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different LD bacteria species, utilizing feeding chambers and live mice and quail, we found species-level differences of bacterial transmission. These differences localize on the tick blood meal, and complement, a defense in vertebrate blood, and a bacterial polymorphic protein, CspA, which inactivates complement by binding to a host complement inhibitor, FH ...


Cohesin Mutations Alter Dna Damage Repair And Chromatin Structure And Create Therapeutic Vulnerabilities In Mds/Aml, Zuzana Tothova, Anne-Laure Valton, Sergey V. Venev, Job Dekker, Benjamin L. Ebert Feb 2021

Cohesin Mutations Alter Dna Damage Repair And Chromatin Structure And Create Therapeutic Vulnerabilities In Mds/Aml, Zuzana Tothova, Anne-Laure Valton, Sergey V. Venev, Job Dekker, Benjamin L. Ebert

Open Access Publications by UMMS Authors

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven ...