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University of Massachusetts Medical School

2019

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Articles 1 - 30 of 297

Full-Text Articles in Life Sciences

The Structure Of The Endogenous Esx-3 Secretion System, Nicole Poweleit, Nadine Czudnochowski, Rachel Nakagawa, Donovan Trinidad, Kenan C. Murphy, Christopher M. Sassetti, Oren S. Rosenberg Dec 2019

The Structure Of The Endogenous Esx-3 Secretion System, Nicole Poweleit, Nadine Czudnochowski, Rachel Nakagawa, Donovan Trinidad, Kenan C. Murphy, Christopher M. Sassetti, Oren S. Rosenberg

Open Access Articles

The ESX (or Type VII) secretion systems are protein export systems in mycobacteria and many Gram-positive bacteria that mediate a broad range of functions including virulence, conjugation, and metabolic regulation. These systems translocate folded dimers of WXG100-superfamily protein substrates across the cytoplasmic membrane. We report the cryo-electron microscopy structure of an ESX-3 system, purified using an epitope tag inserted with recombineering into the chromosome of the model organism Mycobacterium smegmatis. The structure reveals a stacked architecture that extends above and below the inner membrane of the bacterium. The ESX-3 protomer complex is assembled from a single copy of the EccB3 ...


Sensitive Detection Of Ebv Micrornas Across Cancer Spectrum Reveals Association With Decreased Survival In Adult Acute Myelocytic Leukemia, Mercedeh J. Movassagh, Cliff Oduor, Catherine Forconi, Ann M. Moormann, Jeffrey A. Bailey Dec 2019

Sensitive Detection Of Ebv Micrornas Across Cancer Spectrum Reveals Association With Decreased Survival In Adult Acute Myelocytic Leukemia, Mercedeh J. Movassagh, Cliff Oduor, Catherine Forconi, Ann M. Moormann, Jeffrey A. Bailey

Open Access Articles

Epstein Barr virus (EBV) is the etiologic agent involved in numerous human cancers. After infecting the host, EBV establishes a latent infection, with low levels of messenger RNA (mRNA) and protein expression, evolved to evade immune recognition. Conversely, EBV microRNAs (miRNA) are expressed ubiquitously and abundantly within infected cells. Their role in tumor biology and clinical outcomes across the spectrum of cancer is not fully explained. Here, we applied our bioinformatics pipeline for quantitative EBV miRNA detection to examine sequencing data of 8,955 individual tumor samples across 27 tumor types representing the breadth of cancer. We uncover an association ...


Comparing Sensitivity To Change Using The 6-Item Versus The 17-Item Hamilton Depression Rating Scale In The Guided Randomized Controlled Trial, Boadie W. Dunlop, Sagar V. Parikh, Anthony J. Rothschild, Michael E. Thase, Charles Debattista, Charles R. Conway, Brent P. Forester, Francis M. Mondimore, Richard C. Shelton, Matthew Macaluso, Jennifer Logan, Paul Traxler, James Li, Holly Johnson, John F. Greden Dec 2019

Comparing Sensitivity To Change Using The 6-Item Versus The 17-Item Hamilton Depression Rating Scale In The Guided Randomized Controlled Trial, Boadie W. Dunlop, Sagar V. Parikh, Anthony J. Rothschild, Michael E. Thase, Charles Debattista, Charles R. Conway, Brent P. Forester, Francis M. Mondimore, Richard C. Shelton, Matthew Macaluso, Jennifer Logan, Paul Traxler, James Li, Holly Johnson, John F. Greden

Open Access Articles

BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.

METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent ...


Data Infrastructure And Local Stakeholder Engagement With Biodiversity Conservation Research, Ali Krzton Dec 2019

Data Infrastructure And Local Stakeholder Engagement With Biodiversity Conservation Research, Ali Krzton

Journal of eScience Librarianship

Biodiversity research that informs conservation action is increasingly data intensive. Cutting-edge projects at large institutions use massive aggregated datasets to build dynamic models and conduct novel analyses of natural systems. Most of these research institutions are geographically distant from the highest-priority conservation areas, which are found in South America, Africa, and Southeast Asia. There, data is typically collected by or with the help of local residents hired as field assistants. These field assistants have few meaningful opportunities to participate in biodiversity research and conservation beyond data logging. The literature indicates the data revolution has increased demand for impersonal and integrated ...


Regulation Of Zebrafish Melanocyte Development By Ligand-Dependent Bmp Signaling, Alec Gramann, Arvind M. Venkatesan, Melissa Guerin, Craig J. Ceol Dec 2019

Regulation Of Zebrafish Melanocyte Development By Ligand-Dependent Bmp Signaling, Alec Gramann, Arvind M. Venkatesan, Melissa Guerin, Craig J. Ceol

Open Access Articles

Preventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligand GDF6 as a novel melanoma oncogene showed GDF6-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles for GDF6 orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligand gdf6a, a zebrafish ortholog of human GDF6, during the development of melanocytes from the neural crest. We establish that the loss of gdf6a or inhibition of BMP signaling during neural crest development ...


Intestinal Neurod1 Expression Impairs Paneth Cell Differentiation And Promotes Enteroendocrine Lineage Specification, Joyce H. Li, Subir Ray, Ning Pan, Jody Haigh, Bernd Fritzsch, Andrew B. Leiter Dec 2019

Intestinal Neurod1 Expression Impairs Paneth Cell Differentiation And Promotes Enteroendocrine Lineage Specification, Joyce H. Li, Subir Ray, Ning Pan, Jody Haigh, Bernd Fritzsch, Andrew B. Leiter

Open Access Articles

Transcription factor Neurod1 is required for enteroendocrine progenitor differentiation and maturation. Several earlier studies indicated that ectopic expression of Neurod1 converted non- neuronal cells into neurons. However, the functional consequence of ectopic Neurod1 expression has not been examined in the GI tract, and it is not known whether Neurod1 can similarly switch cell fates in the intestine. We generated a mouse line that would enable us to conditionally express Neurod1 in intestinal epithelial cells at different stages of differentiation. Forced expression of Neurod1 throughout intestinal epithelium increased the number of EECs as well as the expression of EE specific transcription ...


Agi-134: A Fully Synthetic Alpha-Gal Glycolipid That Converts Tumors Into In Situ Autologous Vaccines, Induces Anti-Tumor Immunity And Is Synergistic With An Anti-Pd-1 Antibody In Mouse Melanoma Models, Stephen M. Shaw, Kim Wigglesworth, Giles F. Whalen, Arik A. Zur Dec 2019

Agi-134: A Fully Synthetic Alpha-Gal Glycolipid That Converts Tumors Into In Situ Autologous Vaccines, Induces Anti-Tumor Immunity And Is Synergistic With An Anti-Pd-1 Antibody In Mouse Melanoma Models, Stephen M. Shaw, Kim Wigglesworth, Giles F. Whalen, Arik A. Zur

Open Access Articles

Background: Treatments that generate T cell-mediated immunity to a patient's unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galalpha1-3Galbeta1-4GlcNAc (alpha-Gal) in situ leading to opsonization with pre-existing natural anti-alpha-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity.

Methods: Various immunological effects of coating tumor cells with alpha-Gal via AGI-134 in vitro ...


Identification Of The Hyaluronic Acid Pathway As A Therapeutic Target For Facioscapulohumeral Muscular Dystrophy, Alec M. Desimone, John D. Leszyk, Kathryn Wagner, Charles P. Emerson, Jr. Dec 2019

Identification Of The Hyaluronic Acid Pathway As A Therapeutic Target For Facioscapulohumeral Muscular Dystrophy, Alec M. Desimone, John D. Leszyk, Kathryn Wagner, Charles P. Emerson, Jr.

Open Access Articles

Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic derepression of the germline/embryonic transcription factor DUX4 in skeletal muscle. However, the etiology of muscle pathology is not fully understood, as DUX4 misexpression is not tightly correlated with disease severity. Using a DUX4-inducible cell model, we show that multiple DUX4-induced molecular pathologies that have been observed in patient-derived disease models are mediated by the signaling molecule hyaluronic acid (HA), which accumulates following DUX4 induction. These pathologies include formation of RNA granules, FUS aggregation, DNA damage, caspase activation, and cell death. We also observe previously unidentified pathologies including mislocalization of mitochondria and ...


Comparative Pangenomics Of The Mammalian Gut Commensal Bifidobacterium Longum, Korin Albert, Asha Rani, David Sela Dec 2019

Comparative Pangenomics Of The Mammalian Gut Commensal Bifidobacterium Longum, Korin Albert, Asha Rani, David Sela

Open Access Articles

Bifidobacterium longum colonizes mammalian gastrointestinal tracts where it could metabolize host-indigestible oligosaccharides. Although B. longum strains are currently segregated into three subspecies that reflect common metabolic capacities and genetic similarity, heterogeneity within subspecies suggests that these taxonomic boundaries may not be completely resolved. To address this, the B. longum pangenome was analyzed from representative strains isolated from a diverse set of sources. As a result, the B. longum pangenome is open and contains almost 17,000 genes, with over 85% of genes found in < /=28 of 191 strains. B. longum genomes share a small core gene set of only ~500 genes, or ~3% of the total pangenome. Although the individual B. longum subspecies pangenomes share similar relative abundances of clusters of orthologous groups, strains show inter- and intrasubspecies differences with respect to carbohydrate utilization gene content and growth phenotypes.


Functional Analysis Of Dnmt3a Dna Methyltransferase Mutations Reported In Patients With Acute Myeloid Leukemia, Daria A. Khrabrova, Andrei G. Loiko, Anastasia A. Tolkacheva, Natalia A. Cherepanova, Maria I. Zvereva, Olga V. Kirsanova, Elizaveta S. Gromova Dec 2019

Functional Analysis Of Dnmt3a Dna Methyltransferase Mutations Reported In Patients With Acute Myeloid Leukemia, Daria A. Khrabrova, Andrei G. Loiko, Anastasia A. Tolkacheva, Natalia A. Cherepanova, Maria I. Zvereva, Olga V. Kirsanova, Elizaveta S. Gromova

Open Access Articles

In mammals, DNA methylation is necessary for the maintenance of genomic stability, gene expression regulation, and other processes. During malignant diseases progression, changes in both DNA methylation patterns and DNA methyltransferase (MTase) genes are observed. Human de novo MTase DNMT3A is most frequently mutated in acute myeloid leukemia (AML) with a striking prevalence of R882H mutation, which has been extensively studied. Here, we investigate the functional role of the missense mutations (S714C, R635W, R736H, R771L, P777R, and F752V) found in the catalytic domain of DNMT3A in AML patients. These were accordingly mutated in the murine Dnmt3a catalytic domain (S124C, R45W ...


Combining Multi-Omics And Drug Perturbation Profiles To Identify Novel Treatments That Improve Disease Phenotypes In Spinal Muscular Atrophy, Katharina Meijboom, Viola Volpato, Jimena Monzón-Sandoval, Joseph M. Hoolachan, Suzan M. Hammond, Frank Abendroth, Olivier Gerrit De Jong, Gareth Hazell, Nina Ahlskog, Matthew J.A. Wood, Caleb Webber, Melissa Bowerman Dec 2019

Combining Multi-Omics And Drug Perturbation Profiles To Identify Novel Treatments That Improve Disease Phenotypes In Spinal Muscular Atrophy, Katharina Meijboom, Viola Volpato, Jimena Monzón-Sandoval, Joseph M. Hoolachan, Suzan M. Hammond, Frank Abendroth, Olivier Gerrit De Jong, Gareth Hazell, Nina Ahlskog, Matthew J.A. Wood, Caleb Webber, Melissa Bowerman

University of Massachusetts Medical School Faculty Publications

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies.


The Aminoalkylindole Bml-190 Negatively Regulates Chitosan Synthesis Via The Cyclic Amp/Protein Kinase A1 Pathway In Cryptococcus Neoformans, Brian T. Maybruck, Woei C. Lam, Charles A. Specht, Xenia G. Ilagan, Maureen J. Donlin, Jennifer K. Lodge Dec 2019

The Aminoalkylindole Bml-190 Negatively Regulates Chitosan Synthesis Via The Cyclic Amp/Protein Kinase A1 Pathway In Cryptococcus Neoformans, Brian T. Maybruck, Woei C. Lam, Charles A. Specht, Xenia G. Ilagan, Maureen J. Donlin, Jennifer K. Lodge

Open Access Articles

Cryptococcus neoformans can cause fatal meningoencephalitis in patients with AIDS or other immunocompromising conditions. Current antifungals are suboptimal to treat this disease; therefore, novel targets and new therapies are needed. Previously, we have shown that chitosan is a critical component of the cryptococcal cell wall and is required for survival in the mammalian host and that chitosan deficiency results in rapid clearance from the mammalian host. We had also identified several specific proteins that were required for chitosan biosynthesis, and we hypothesize that screening for compounds that inhibit chitosan biosynthesis would identify additional genes/proteins that influence chitosan biosynthesis. To ...


Solenodon Genome Reveals Convergent Evolution Of Venom In Eulipotyphlan Mammals, Nicholas R. Casewell, Elinor K. Karlsson, Daniel Petras, Daren C. Card, Vivek Suranse, Alexis M. Mychajliw, David Richards, Ivan Koludarov, Laura-Oana Albulescu, Julien Slagboom, Benjamin-Florian Hempel, Neville M. Ngum, Rosalind J. Kennerley, Jorge L. Brocca, Gareth Whiteley Dec 2019

Solenodon Genome Reveals Convergent Evolution Of Venom In Eulipotyphlan Mammals, Nicholas R. Casewell, Elinor K. Karlsson, Daniel Petras, Daren C. Card, Vivek Suranse, Alexis M. Mychajliw, David Richards, Ivan Koludarov, Laura-Oana Albulescu, Julien Slagboom, Benjamin-Florian Hempel, Neville M. Ngum, Rosalind J. Kennerley, Jorge L. Brocca, Gareth Whiteley

Program in Bioinformatics and Integrative Biology Publications

Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan ...


Modulating Mcm Levels Causes Differential Loading At Origins Of Replication And Changes Replication Timing, Livio Dukaj Dec 2019

Modulating Mcm Levels Causes Differential Loading At Origins Of Replication And Changes Replication Timing, Livio Dukaj

GSBS Dissertations and Theses

DNA replication is a highly complex part of cell metabolism that ensures safe propagation of the genome through tight regulation of the expression, localization, and activity of a large number of factors. Replication starts from distinct sites in the genome and initiation events are temporally ordered in a manner that is, on average, highly reproducible across cell populations. The specific order with which different parts of the genome are replicated has been proposed to be important to processes such as gene expression, cell differentiation, development, and genome evolution. Nevertheless, the fundamental mechanisms that are responsible for establishing these timing programs ...


Curing Hemophilia A By Nhej-Mediated Ectopic F8 Insertion In The Mouse, Jian-Ping Zhang, Xin-Xin Cheng, Mei Zhao, Guo-Hua Li, Jing Xu, Feng Zhang, Meng-Di Yin, Fei-Ying Meng, Xin-Yue Dai, Ya-Wen Fu, Zhi-Xue Yang, Cameron Arakaki, Ruijun Jeanna. Su, Wei Wen, Wen-Tian Wang, Wanqiu Chen, Hannah Choi, Charles Wang, Guangping Gao, Lei Zhang, Tao Cheng, Xiao-Bing Zhang Dec 2019

Curing Hemophilia A By Nhej-Mediated Ectopic F8 Insertion In The Mouse, Jian-Ping Zhang, Xin-Xin Cheng, Mei Zhao, Guo-Hua Li, Jing Xu, Feng Zhang, Meng-Di Yin, Fei-Ying Meng, Xin-Yue Dai, Ya-Wen Fu, Zhi-Xue Yang, Cameron Arakaki, Ruijun Jeanna. Su, Wei Wen, Wen-Tian Wang, Wanqiu Chen, Hannah Choi, Charles Wang, Guangping Gao, Lei Zhang, Tao Cheng, Xiao-Bing Zhang

Open Access Articles

BACKGROUND: Hemophilia A, a bleeding disorder resulting from F8 mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of F8 in hepatocytes at highly expressed gene loci, such as albumin (Alb). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%).

RESULTS: We report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We ...


Robustness Mechanisms Of Temporal Cell-Fate Progression In C. Elegans, Orkan Ilbay Dec 2019

Robustness Mechanisms Of Temporal Cell-Fate Progression In C. Elegans, Orkan Ilbay

GSBS Dissertations and Theses

Robustness is a ubiquitous property of biological systems, however, underlying mechanisms that help reinforce the optimal phenotypes despite environmental or physiological perturbations are poorly understood.

C. elegans development consists of four larval stages (L1-L4) and well-characterized invariant cell lineages, within which the heterochronic pathway controls the order and timing of cell-fates. Environmental or physiological stress signals can slow or temporarily halt larval stage progression; remarkably, however, temporal cell-fate progression remains unaffected.

We show that two widely conserved signaling pathways, insulin and TGF- β, that regulate C. elegans larval stage progression in response to starvation and crowding, respectively, also regulate a ...


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 ...


Selection Of An Efficient Aav Vector For Robust Cns Transgene Expression, Killian S. Hanlon, Miguel Sena-Esteves, Eloise Hudry, Casey A. Maguire Dec 2019

Selection Of An Efficient Aav Vector For Robust Cns Transgene Expression, Killian S. Hanlon, Miguel Sena-Esteves, Eloise Hudry, Casey A. Maguire

Open Access Articles

Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection rounds of the library delivered intravenously in transgenic mice carrying a Cre-inducible fluorescent protein, we flow sorted fluorescent cells from brain, and DNA sequencing revealed two dominant capsids. One of the capsids, termed AAV-F, mediated transgene expression in the brain cortex more than 65-fold (astrocytes) and 171-fold (neurons) higher than the parental AAV9. High transduction efficiency was sex-independent ...


Impact Of Th1 Cd4 Tfh Skewing On Antibody Responses To An Hiv-1 Vaccine In Rhesus Macaques, Anil Verma, Keith A. Reimann, David H. Foehl, Smita S. Iyer Dec 2019

Impact Of Th1 Cd4 Tfh Skewing On Antibody Responses To An Hiv-1 Vaccine In Rhesus Macaques, Anil Verma, Keith A. Reimann, David H. Foehl, Smita S. Iyer

Open Access Articles

Generating durable humoral immunity through vaccination depends upon effective interaction of follicular helper T cells (Tfh) with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing co-stimulatory and cytokine-dependent Tfh help to B cells. However, the question remains whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced anti-Envelope (Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein (IP)-10-adjuvanted HIV-1 DNA prime ...


Hox Paralogs Selectively Convert Binding Of Ubiquitous Transcription Factors Into Tissue-Specific Patterns Of Enhancer Activation, Laure Bridoux, Peyman Zarrineh, Joshua Mallen, Mike Phuycharoen, Victor Latorre, Frank Ladam, Marta Losa, Charles G. Sagerstrom, Kimberley A. Mace, Magnus Rattray, Nicoletta Bobola Dec 2019

Hox Paralogs Selectively Convert Binding Of Ubiquitous Transcription Factors Into Tissue-Specific Patterns Of Enhancer Activation, Laure Bridoux, Peyman Zarrineh, Joshua Mallen, Mike Phuycharoen, Victor Latorre, Frank Ladam, Marta Losa, Charles G. Sagerstrom, Kimberley A. Mace, Magnus Rattray, Nicoletta Bobola

University of Massachusetts Medical School Faculty Publications

Gene expression programs determine cell fate in embryonic development and their dysregulation results in disease. Transcription factors (TFs) control gene expression by binding to enhancers, but how TFs select and activate their target enhancers is still unclear. HOX TFs share conserved homeodomains with highly similar sequence recognition properties, yet they impart the identity of different animal body parts. To understand how HOX TFs control their specific transcriptional programs in vivo, we compared HOXA2 and HOXA3 binding profiles in the mouse embryo. HOXA2 and HOXA3 directly cooperate with TALE TFs and selectively target different subsets of a broad TALE chromatin platform ...


The Pseudomonas Aeruginosa Accessory Genome Elements Influence Virulence Towards Caenorhabditis Elegans, Alejandro Vasquez-Rifo, Isana Veksler-Lublinsky, Zhenyu Cheng, Frederick M. Ausubel, Victor R. Ambros Dec 2019

The Pseudomonas Aeruginosa Accessory Genome Elements Influence Virulence Towards Caenorhabditis Elegans, Alejandro Vasquez-Rifo, Isana Veksler-Lublinsky, Zhenyu Cheng, Frederick M. Ausubel, Victor R. Ambros

Open Access Articles

BACKGROUND: Multicellular animals and bacteria frequently engage in predator-prey and host-pathogen interactions, such as the well-studied relationship between Pseudomonas aeruginosa and the nematode Caenorhabditis elegans. This study investigates the genomic and genetic basis of bacterial-driven variability in P. aeruginosa virulence towards C. elegans to provide evolutionary insights into host-pathogen relationships.

RESULTS: Natural isolates of P. aeruginosa that exhibit diverse genomes display a broad range of virulence towards C. elegans. Using gene association and genetic analysis, we identify accessory genome elements that correlate with virulence, including both known and novel virulence determinants. Among the novel genes, we find a viral-like mobile ...


Systemic Rage Ligands Are Upregulated In Tuberculosis Individuals With Diabetes Co-Morbidity And Modulated By Anti-Tuberculosis Treatment And Metformin Therapy, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Shanmugam Sivakumar, Syed Hissar, Hardy Kornfeld, Subash Babu Dec 2019

Systemic Rage Ligands Are Upregulated In Tuberculosis Individuals With Diabetes Co-Morbidity And Modulated By Anti-Tuberculosis Treatment And Metformin Therapy, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Shanmugam Sivakumar, Syed Hissar, Hardy Kornfeld, Subash Babu

Open Access Articles

BACKGROUND: Ligands of the receptor for advanced glycation end products (RAGE) are key signalling molecules in the innate immune system but their role in tuberculosis-diabetes comorbidity (TB-DM) has not been investigated.

METHODS: We examined the systemic levels of soluble RAGE (sRAGE), advanced glycation end products (AGE), S100A12 and high mobility group box 1 (HMGB1) in participants with either TB-DM, TB, DM or healthy controls (HC).

RESULTS: Systemic levels of AGE, sRAGE and S100A12 were significantly elevated in TB-DM and DM in comparison to TB and HC. During follow up, AGE, sRAGE and S100A12 remained significantly elevated in TB-DM compared to ...


A Dna-Guided Argonaute Protein Functions In Dna Replication In Thermus Thermophilus, Samson M. Jolly, Ildar Gainetdinov, Han Zhang, Lara Strittmatter, Gregory M. Hendricks, Avantika Dhabaria, Beatrix Ueberheide, Phillip D. Zamore Dec 2019

A Dna-Guided Argonaute Protein Functions In Dna Replication In Thermus Thermophilus, Samson M. Jolly, Ildar Gainetdinov, Han Zhang, Lara Strittmatter, Gregory M. Hendricks, Avantika Dhabaria, Beatrix Ueberheide, Phillip D. Zamore

University of Massachusetts Medical School Faculty Publications

Argonaute proteins use nucleic acid guides to protect organisms against transposons and viruses. In the eubacterium Thermus thermophilus, the DNA-guided Argonaute TtAgo defends against transformation by DNA plasmids. Here, we report that TtAgo also participates in DNA replication. TtAgo binds small DNA guides derived from the chromosomal region where replication terminates and associates with proteins known to act in DNA replication. T. thermophilus deploys a single type II topoisomerase, gyrase. When gyrase is inhibited, T. thermophilus relies on TtAgo to complete replication of its circular genome; loss of both gyrase and TtAgo activity produces long filaments that fail to separate ...


Investigating The Influence Of Environment On The Evolution Of Hsp90 Using Comprehensive Fitness Maps, Julia M. Flynn, Ammeret Rossouw, Pamela A. Cote-Hammarlof, Ines Fragata, David Mavor, Carl Hollins Iii, Claudia Bank, Daniel N. Bolon Dec 2019

Investigating The Influence Of Environment On The Evolution Of Hsp90 Using Comprehensive Fitness Maps, Julia M. Flynn, Ammeret Rossouw, Pamela A. Cote-Hammarlof, Ines Fragata, David Mavor, Carl Hollins Iii, Claudia Bank, Daniel N. Bolon

University of Massachusetts Medical School Faculty Publications

Gene-environment interactions have long been theorized to influence molecular evolution. However, the environmental dependence of most mutations remains unknown. Using deep mutational scanning, we engineered budding yeast with all 44,604 single codon changes encoding 14,160 amino acid variants in Hsp90 and quantified growth effects under standard laboratory conditions and under five stress conditions (elevated temperature, nitrogen starvation, elevated salinity, high ethanol concentration, and oxidative stress caused by diamide). To our knowledge these are the largest comprehensive fitness maps of point mutant growth effects that have been determined. The growth effects of many variants differed between each of the ...


Regulatory Asymmetry In The Negative Single-Input Module Network Motif: Role Of Network Size, Growth Rate And Binding Affinity, Zulfikar Ali, Vinuselvi Parisutham, Sandeep Choubey, Robert C. Brewster Dec 2019

Regulatory Asymmetry In The Negative Single-Input Module Network Motif: Role Of Network Size, Growth Rate And Binding Affinity, Zulfikar Ali, Vinuselvi Parisutham, Sandeep Choubey, Robert C. Brewster

University of Massachusetts Medical School Faculty Publications

The single-input module (SIM) is a regulatory motif capable of coordinating gene expression across functionally related genes. We explore the relationship between regulation of the central autoregulated TF in a negatively regulated SIM and the target genes using a synthetic biology approach paired with stochastic simulations. Surprisingly, we find a fundamental asymmetry in the level of regulation experienced by the TF gene and its targets, even if they have identical regulatory DNA; the TF gene experiences stronger repression than its targets. This asymmetry is not predicted from deterministic modeling of the system but is revealed from corresponding stochastic simulations. The ...


Yap/Taz Activation Drives Uveal Melanoma Initiation And Progression, Huapeng Li, Qi Li, Kyvan Dang, Shan Ma, Jennifer L. Cotton, Sun Yang, Lihua Julie Zhu, April C. Deng, Y. Tony Ip, Randy L. Johnson, Xu Wu, Claudio Punzo, Junhao Mao Dec 2019

Yap/Taz Activation Drives Uveal Melanoma Initiation And Progression, Huapeng Li, Qi Li, Kyvan Dang, Shan Ma, Jennifer L. Cotton, Sun Yang, Lihua Julie Zhu, April C. Deng, Y. Tony Ip, Randy L. Johnson, Xu Wu, Claudio Punzo, Junhao Mao

Open Access Articles

Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GalphaQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is ...


Structural Organization And Dynamics Of Homodimeric Cytohesin Family Arf Gtpase Exchange Factors In Solution And On Membranes, Sanchaita Das, Andrew W. Malaby, Agata Nawrotek, Wenhua Zhang, Mahel Zeghouf, Sarah Maslen, Mark Skehel, Srinivas Chakravarthy, Thomas C. Irving, Osman Bilsel, Jacqueline Cherfils, David G. Lambright Dec 2019

Structural Organization And Dynamics Of Homodimeric Cytohesin Family Arf Gtpase Exchange Factors In Solution And On Membranes, Sanchaita Das, Andrew W. Malaby, Agata Nawrotek, Wenhua Zhang, Mahel Zeghouf, Sarah Maslen, Mark Skehel, Srinivas Chakravarthy, Thomas C. Irving, Osman Bilsel, Jacqueline Cherfils, David G. Lambright

Open Access Articles

Membrane dynamic processes require Arf GTPase activation by guanine nucleotide exchange factors (GEFs) with a Sec7 domain. Cytohesin family Arf GEFs function in signaling and cell migration through Arf GTPase activation on the plasma membrane and endosomes. In this study, the structural organization of two cytohesins (Grp1 and ARNO) was investigated in solution by size exclusion-small angle X-ray scattering and negative stain-electron microscopy and on membranes by dynamic light scattering, hydrogen-deuterium exchange-mass spectrometry and guanosine diphosphate (GDP)/guanosine triphosphate (GTP) exchange assays. The results suggest that cytohesins form elongated dimers with a central coiled coil and membrane-binding pleckstrin-homology (PH) domains ...


A Minimal Crispr-Cas3 System For Genome Engineering, Bálint Csörgő, Lina M. León, Ilea J. Chau-Ly, Alejandro Vasquez-Rifo, Joel D. Berry, Caroline Mahendra, Emily D. Crawford, Jennifer D. Lewis, Joseph Bondy-Denomy Dec 2019

A Minimal Crispr-Cas3 System For Genome Engineering, Bálint Csörgő, Lina M. León, Ilea J. Chau-Ly, Alejandro Vasquez-Rifo, Joel D. Berry, Caroline Mahendra, Emily D. Crawford, Jennifer D. Lewis, Joseph Bondy-Denomy

University of Massachusetts Medical School Faculty Publications

CRISPR-Cas technologies have provided programmable gene editing tools that have revolutionized research. The leading CRISPR-Cas9 and Cas12a enzymes are ideal for programmed genetic manipulation, however, they are limited for genome-scale interventions. Here, we utilized a Cas3-based system featuring a processive nuclease, expressed endogenously or heterologously, for genome engineering purposes. Using an optimized and minimal CRISPR-Cas3 system (Type I-C) programmed with a single crRNA, large deletions ranging from 7 - 424 kb were generated in Pseudomonas aeruginosa with high efficiency and speed. By comparison, Cas9 yielded small deletions and point mutations. Cas3-generated deletion boundaries were variable in the absence of a homology-directed ...


The History Of Farm Foxes Undermines The Animal Domestication Syndrome, Kathryn A. Lord, Greger Larson, Raymond P. Coppinger, Elinor K. Karlsson Dec 2019

The History Of Farm Foxes Undermines The Animal Domestication Syndrome, Kathryn A. Lord, Greger Larson, Raymond P. Coppinger, Elinor K. Karlsson

Program in Bioinformatics and Integrative Biology Publications

The Russian Farm-Fox Experiment is the best known experimental study in animal domestication. By subjecting a population of foxes to selection for tameness alone, Dimitry Belyaev generated foxes that possessed a suite of characteristics that mimicked those found across domesticated species. This 'domestication syndrome' has been a central focus of research into the biological pathways modified during domestication. Here, we chart the origins of Belyaev's foxes in eastern Canada and critically assess the appearance of domestication syndrome traits across animal domesticates. Our results suggest that both the conclusions of the Farm-Fox Experiment and the ubiquity of domestication syndrome have ...


Lattice Arrangement Of Myosin Filaments Correlates With Fiber Type In Rat Skeletal Muscle, Weikang Ma, Kyounghwan Lee, Shixin Yang, Thomas C. Irving, Roger Craig Dec 2019

Lattice Arrangement Of Myosin Filaments Correlates With Fiber Type In Rat Skeletal Muscle, Weikang Ma, Kyounghwan Lee, Shixin Yang, Thomas C. Irving, Roger Craig

Radiology Publications

The thick (myosin-containing) filaments of vertebrate skeletal muscle are arranged in a hexagonal lattice, interleaved with an array of thin (actin-containing) filaments with which they interact to produce contraction. X-ray diffraction and EM have shown that there are two types of thick filament lattice. In the simple lattice, all filaments have the same orientation about their long axis, while in the superlattice, nearest neighbors have rotations differing by 0 degrees or 60 degrees . Tetrapods (amphibians, reptiles, birds, and mammals) typically have only a superlattice, while the simple lattice is confined to fish. We have performed x-ray diffraction and electron microscopy ...