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2019

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Articles 1 - 30 of 338

Full-Text Articles in Life Sciences

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 ...


Cognitively Normal Women With Alzheimer’S Disease Proteinopathy Show Relative Preservation Of Memory But Not Of Hippocampal Volume, Jessica Z.K. Caldwell, Jeffrey L. Cummings, Sarah J. Banks, Sebastian Palmqvist, Oskar Hansson Dec 2019

Cognitively Normal Women With Alzheimer’S Disease Proteinopathy Show Relative Preservation Of Memory But Not Of Hippocampal Volume, Jessica Z.K. Caldwell, Jeffrey L. Cummings, Sarah J. Banks, Sebastian Palmqvist, Oskar Hansson

School of Medicine Faculty Publications

Background: We examined interactive effects of sex, diagnosis, and cerebrospinal fluid (CSF) amyloid beta/phosphorylated tau ratio (Aβ/P-tau) on verbal memory and hippocampal volumes. Methods: We assessed 682 participants (350 women) from BioFINDER (250 cognitively normal [CN]; and 432 symptomatic: 186 subjective cognitive decline [SCD], 246 mild cognitive impairment [MCI]). General linear models evaluated effects of Alzheimer’s disease (AD) proteinopathy (CSF Aß/p-tau ratio), diagnosis, and sex on verbal memory (ADAS-cog 10-word recall), semantic fluency (animal naming fluency), visuospatial skills (cube copy), processing speed/attention functions (Symbol Digit Modalities Test and Trail Making Part A), and hippocampal volumes ...


Intralingual And Intrapleural Aav Gene Therapy Prolongs Survival In A Sod1 Als Mouse Model, Allison M. Keeler, Marina Zieger, Carson Semple, Logan Pucci, Alessandra Veinbachs, Robert H. Brown Jr., Christian Mueller, Mai K. Elmallah Dec 2019

Intralingual And Intrapleural Aav Gene Therapy Prolongs Survival In A Sod1 Als Mouse Model, Allison M. Keeler, Marina Zieger, Carson Semple, Logan Pucci, Alessandra Veinbachs, Robert H. Brown Jr., Christian Mueller, Mai K. Elmallah

Pediatric Publications

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in death from respiratory failure. No cure exists for this devastating disease, but therapy that directly targets the respiratory system has the potential to prolong survival and improve quality of life in some cases of ALS. The objective of this study was to enhance breathing and prolong survival by suppressing superoxide dismutase 1 (SOD1) expression in respiratory motor neurons using adeno-associated virus (AAV) expressing an artificial microRNA targeting the SOD1 gene. AAV-miR(SOD1) was injected in the tongue and intrapleural space of SOD1(G93A) mice, and repetitive respiratory and ...


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 ...


Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann Dec 2019

Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann

Theses & Dissertations

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. Bringing ...


Characterizing The Combination Of Rpa Inhibitors With Parp Inhibitors In High-Grade Serous Ovarian Cancer, Yat Tang Dec 2019

Characterizing The Combination Of Rpa Inhibitors With Parp Inhibitors In High-Grade Serous Ovarian Cancer, Yat Tang

Theses & Dissertations

High-grade serous ovarian cancer (HGSC) is the most common and deadly gynecologic malignancy. HGSC patients with BRCA1/2 mutations have homologous recombination deficiency (HRD), requiring parallel pathways to maintain genome integrity (e.g., PARP1, PARP2). Approximately 50% of ovarian carcinomas are estimated to exhibit HRD. For the remaining 50% and the large percentage of HRD patients with acquired or innate resistance to single-agent PARP inhibitors, there is a need to develop alternative therapeutic strategies.

Replication Protein A (RPA) is a heterotrimeric protein crucial for genome maintenance. Phosphorylation of RPA in DNA damage response (DDR) is a negative regulator of DNA ...


Evaluating The Occurrence Of Age-Related Peripheral Neuropathy In Het3 Mice And Development Of A Whole Tissue Imaging Technique For Analyzing Total Innervation In The Subcutaneous Adipose Depot, Jake Willows Dec 2019

Evaluating The Occurrence Of Age-Related Peripheral Neuropathy In Het3 Mice And Development Of A Whole Tissue Imaging Technique For Analyzing Total Innervation In The Subcutaneous Adipose Depot, Jake Willows

Electronic Theses and Dissertations

Adipose tissue can be characterized as either being a white (energy storing) depot or a brown (energy expending) depot and both have been found to contain dense networks of neural innervation. This adipose nerve supply regulates numerous metabolic functions and likely plays an important role in the function of adipose blood vessels. Recently our lab has shown in the C57BL/6 mouse model that peripheral neuropathy, or the dying back and dysfunction of the nerves in the superficial tissues such as the skin, can extend into the subcutaneous adipose tissue in conditions commonly associated with the neuropathic phenotype (i.e ...


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 ...


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 ...


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 ...


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 ...


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 ...


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 ...


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 ...


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 ...


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 ...


Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast Dec 2019

Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast

Senior Honors Theses

This paper reviews functions of Amyloid-β (Aβ) in healthy individuals compared to the consequences of aberrant Aβ in Alzheimer’s disease (AD). As extraneuronal Aβ accumulation and plaque formation are characteristics of AD, it is reasonable to infer a pivotal role for Aβ in AD pathogenesis. Establishing progress of the disease as well as the mechanism of neurodegeneration from AD have proven difficult (Selkoe, 1994). This thesis provides evidence suggesting the pathogenesis of AD is due to dysfunctional neuronal processes involving Aβ’s synaptic malfunction, abnormal interaction with tau, and disruption of neuronal homeostasis. Significant evidence demonstrates that AD symptoms ...


Quantitative Study Of The Antimicrobial Effects Of Silver On The Motility Of Escherichia Coli, Benjamin Russell Dec 2019

Quantitative Study Of The Antimicrobial Effects Of Silver On The Motility Of Escherichia Coli, Benjamin Russell

Theses and Dissertations

In recent decades, the number of antibiotic-resistant bacterial infections has grown to become a serious global threat. This rise can be attributed to the widespread misuse of antibiotics and the lack of newly developed drugs to fight resistant organisms. Novel bactericidal substances have, therefore, garnered significant research interest. Silver, due to its powerful antimicrobial effects, is one such substance. Silver is typically most effective in cationic form; however, advancements in nanotechnology have paved the way for the controlled fabrication of nano-silver. Silver nanoparticles have been shown to have increased antibacterial potency for a variety of reasons, including the release of ...


Methods To Evaluate Ruminant Animal Production Responses, Jose Manuel Diaz Gomez Dec 2019

Methods To Evaluate Ruminant Animal Production Responses, Jose Manuel Diaz Gomez

Theses and Dissertations

In experiment 1, 80 steers (197.0 kg initial body weight; BW for fall, 116.9 kg for spring), were stocked at 2.45 and 4.1 calves/ha in fall and spring, respectively in 16 tall fescue pastures [fall ergovaline (EV) = 1,475 ppb and spring EV = 1,173 ppb] under 2 treatments, mineral (MIN) (n = 8) and cumulative management (CM) (n = 8). Forage allowance did not differ (P = 0.76) between CM and MIN during fall but differed during spring (P ≤ 0.05, 2.55 vs. 3.22 kg DM/kg BW, for MIN and CM, respectively). For ...


Estimation Of Genetic Components Related To Infectious Bovine Keratoconjunctivitis Susceptibility In Angus And Angus Derived Cattle Produced In The Southern United States, Eric Oxford Dec 2019

Estimation Of Genetic Components Related To Infectious Bovine Keratoconjunctivitis Susceptibility In Angus And Angus Derived Cattle Produced In The Southern United States, Eric Oxford

Theses and Dissertations

The economic impact of infectious bovine keratoconjunctivitis (IBK) has been documented in many parts of the world. Many researchers have observed that prevention of this disease is very difficult given current methodologies. This is primarily due to the multifactorial nature of this disease. The objective of this dissertation was to determine the impact of IBK on calf performance and estimate genetic parameters, heritability and estimated breeding values for IBK susceptibility. Data were analyzed using PROC GLIMMIX of SAS; while genetic parameters were estimated using a linear animal model for both single- and two-traits through MTDFREML. Additional evaluations calculated heritability using ...


Production Of Poly(Ga) In C9orf72 Patient Motor Neurons Derived From Induced Pluripotent Stem Cells, Sandra Almeida, Gopinath Krishnan, Mia Rushe, Yuanzheng Gu, Mark W. Kankel, Fen-Biao Gao Dec 2019

Production Of Poly(Ga) In C9orf72 Patient Motor Neurons Derived From Induced Pluripotent Stem Cells, Sandra Almeida, Gopinath Krishnan, Mia Rushe, Yuanzheng Gu, Mark W. Kankel, Fen-Biao Gao

Open Access Articles

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A key pathological hallmark of C9ORF72-related ALS/FTD is the accumulation of dipeptide repeat (DPR) proteins synthesized from both sense and antisense repeat RNAs in affected neurons.To investigate how DPR proteins are synthesized in C9ORF72 human neurons, we used CRISPR-Cas9 technology to generate a homozygous deletion in the first intron of C9ORF72, 5′ to the G4C2 repeats to assess the effect of this deletion on DPR production.


The Difference In A1c Of Children And Adolescents With Type 1 Diabetes Mellitus Using Carbohydrate Counting Compared To Those Using A Structured Meal Plan, Alia El Kubbe Nov 2019

The Difference In A1c Of Children And Adolescents With Type 1 Diabetes Mellitus Using Carbohydrate Counting Compared To Those Using A Structured Meal Plan, Alia El Kubbe

Electronic Thesis and Dissertation Repository

Carbohydrate counting (CHO) is a nutrition education tool used by patients with type 1 diabetes mellitus (T1DM). The primary objective was to assess glycated hemoglobin (A1C) in participants with T1DM using CHO counting vs. those using a structured meal plan (SMP). The secondary objectives were to determine if BMI-for-age, parental income, parental involvement, and mothers’ educational level were associated with their children’s glycemic control. A cross sectional study was conducted, where participants aged 4-18 years, or their parents completed a survey. Total sample size was 88 participants (77 in the CHO counting group and 11 in the SMP group ...


Autophagy Protein Nrbf2 Has Reduced Expression In Alzheimer's Brains And Modulates Memory And Amyloid-Beta Homeostasis In Mice, Veronik Lachance, Qian Wang, Eric Sweet, Insup Choi, Cui-Zan Cai, Xu-Xu Zhuang, Jessica Li Jiang, Robert D. Blitzer, Ozlem Bozdagi-Gunal, Bin Zhang, Jia-Hong Lu, Zhenyu Yue Nov 2019

Autophagy Protein Nrbf2 Has Reduced Expression In Alzheimer's Brains And Modulates Memory And Amyloid-Beta Homeostasis In Mice, Veronik Lachance, Qian Wang, Eric Sweet, Insup Choi, Cui-Zan Cai, Xu-Xu Zhuang, Jessica Li Jiang, Robert D. Blitzer, Ozlem Bozdagi-Gunal, Bin Zhang, Jia-Hong Lu, Zhenyu Yue

Biology Faculty Publications

Background Dysfunctional autophagy is implicated in Alzheimer's Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. Methods To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-beta ...


Functionally Overlapping Variants Control Tuberculosis Susceptibility In Collaborative Cross Mice, Clare M. Smith, Megan K. Proulx, Rocky Lai, Michael C. Kiritsy, Timothy A. Bell, Pablo Hock, Fernando Pardo-Manuel De Villena, Martin T. Ferris, Richard E. Baker, Samuel M. Behar, Christopher M. Sassetti Nov 2019

Functionally Overlapping Variants Control Tuberculosis Susceptibility In Collaborative Cross Mice, Clare M. Smith, Megan K. Proulx, Rocky Lai, Michael C. Kiritsy, Timothy A. Bell, Pablo Hock, Fernando Pardo-Manuel De Villena, Martin T. Ferris, Richard E. Baker, Samuel M. Behar, Christopher M. Sassetti

Open Access Articles

Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine gamma interferon (IFN-gamma) in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 mouse susceptibility. Using a population derived from a CC001/Unc (CC001) x CC042 intercross, we mapped four quantitative trait loci (QTL) underlying tuberculosis immunophenotypes (Tip1 to Tip4). These included QTL ...


Differential Skewing Of Donor-Unrestricted And Gammadelta T Cell Repertoires In Tuberculosis-Infected Human Lungs, Paul Ogongo, Adrie Jc. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar Nov 2019

Differential Skewing Of Donor-Unrestricted And Gammadelta T Cell Repertoires In Tuberculosis-Infected Human Lungs, Paul Ogongo, Adrie Jc. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar

Open Access Articles

Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and gammadelta T cells. We exploited the distinctive nature of DURTs and gammadelta T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCRs in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and ...


Cdr3alpha Drives Selection Of The Immunodominant Epstein Barr Virus (Ebv) Brlf1-Specific Cd8 T Cell Receptor Repertoire In Primary Infection, Larisa Kamga, Anna Gil, Inyoung Song, Robin M. Brody, Dario Ghersi, Nuray Aslan, Lawrence J. Stern, Liisa K. Selin, Katherine Luzuriaga Nov 2019

Cdr3alpha Drives Selection Of The Immunodominant Epstein Barr Virus (Ebv) Brlf1-Specific Cd8 T Cell Receptor Repertoire In Primary Infection, Larisa Kamga, Anna Gil, Inyoung Song, Robin M. Brody, Dario Ghersi, Nuray Aslan, Lawrence J. Stern, Liisa K. Selin, Katherine Luzuriaga

Open Access Articles

The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response. Here, we seek to investigate factors that drive selection of TCR repertoires specific to the HLA-A2-restricted immunodominant epitope BRLF1109-117 (YVLDHLIVV) over the course of primary Epstein Barr virus (EBV) infection. Using single-cell paired TCRalphabeta sequencing of tetramer sorted CD8 T cells ex vivo, we show at the clonal level that recognition of the HLA-A2-restricted BRLF1 (YVL-BR, BRLF-1109) epitope is mainly driven by the TCRalpha chain. For the first time, we identify a CDR3alpha (complementarity determining region 3 alpha) motif, KDTDKL, resulting from an obligate ...


Statistical Analysis Of Variability In Tnseq Data Across Conditions Using Zero-Inflated Negative Binomial Regression, Siddharth Subramaniyam, Michael A. Dejesus, Anisha Zaveri, Clare M. Smith, Richard E. Baker, Sabine Ehrt, Dirk Schnappinger, Christopher M. Sassetti, Thomas R. Ioerger Nov 2019

Statistical Analysis Of Variability In Tnseq Data Across Conditions Using Zero-Inflated Negative Binomial Regression, Siddharth Subramaniyam, Michael A. Dejesus, Anisha Zaveri, Clare M. Smith, Richard E. Baker, Sabine Ehrt, Dirk Schnappinger, Christopher M. Sassetti, Thomas R. Ioerger

Open Access Articles

BACKGROUND: Deep sequencing of transposon mutant libraries (or TnSeq) is a powerful method for probing essentiality of genomic loci under different environmental conditions. Various analytical methods have been described for identifying conditionally essential genes whose tolerance for insertions varies between two conditions. However, for large-scale experiments involving many conditions, a method is needed for identifying genes that exhibit significant variability in insertions across multiple conditions.

RESULTS: In this paper, we introduce a novel statistical method for identifying genes with significant variability of insertion counts across multiple conditions based on Zero-Inflated Negative Binomial (ZINB) regression. Using likelihood ratio tests, we show ...


In Vivo Clonal Expansion And Phenotypes Of Hypocretin-Specific Cd4(+) T Cells In Narcolepsy Patients And Controls, Wei Jiang, James R. Birtley, Grant C. Weaver, Liying Lu, Lawrence J. Stern, Elizabeth D. Mellins Nov 2019

In Vivo Clonal Expansion And Phenotypes Of Hypocretin-Specific Cd4(+) T Cells In Narcolepsy Patients And Controls, Wei Jiang, James R. Birtley, Grant C. Weaver, Liying Lu, Lawrence J. Stern, Elizabeth D. Mellins

Open Access Articles

Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations of narcolepsy with the human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor alpha (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. Here, we present evidence of in vivo expansion of DQ6-HCRT tetramer(+)/TRAJ24(+)/CD4(+) T cells in DQ6(+) individuals with and without narcolepsy. We identify related TRAJ24(+) TCRalphabeta clonotypes encoded by identical alpha/beta gene regions from two patients and two controls. TRAJ24-G allele(+) clonotypes only expand in the two ...


Suppressing Aneuploidy-Associated Phenotypes Improves The Fitness Of Trisomy 21 Cells, Sunyoung Hwang, Jessica F. Williams, Maja Kneissig, Maria Lioudyno, Isabel Rivera, Pablo Helguera, Jorge Busciglio, Zuzana Storchova, Megan C. King, Eduardo M. Torres Nov 2019

Suppressing Aneuploidy-Associated Phenotypes Improves The Fitness Of Trisomy 21 Cells, Sunyoung Hwang, Jessica F. Williams, Maja Kneissig, Maria Lioudyno, Isabel Rivera, Pablo Helguera, Jorge Busciglio, Zuzana Storchova, Megan C. King, Eduardo M. Torres

Open Access Articles

An abnormal number of chromosomes, or aneuploidy, accounts for most spontaneous abortions, causes developmental defects, and is associated with aging and cancer. The molecular mechanisms by which aneuploidy disrupts cellular function remain largely unknown. Here, we show that aneuploidy disrupts the morphology of the nucleus. Mutations that increase the levels of long-chain bases suppress nuclear abnormalities of aneuploid yeast independent of karyotype identity. Quantitative lipidomics indicates that long-chain bases are integral components of the nuclear membrane in yeast. Cells isolated from patients with Down syndrome also show that abnormal nuclear morphologies and increases in long-chain bases not only suppress these ...