Digital Commons Network^™

Challenges And Progress In Research, Diagnostics, And Therapeutics In Alzheimer's Disease And Related Dementias, Nikolay V Dokholyan, Richard C Mohs, Randall J Bateman

2020-Current year OA Pubs

The health, well-being, and financial security of Americans are greatly impacted by Alzheimer's disease. The forecast paints an upward trajectory with the number of Americans suffering from Alzheimer's disease and related dementia. To discuss the Alzheimer's crisis, The Senate Committee on Finance, Subcommittee on Health Care, held a hearing titled, "The Alzheimer's Crisis: Examining, Testing, and Treatment Pipelines and Fiscal Implications," on December 16, 2020. Here, we summarize and expand on the discussion of the panel and its review of recent progress, ongoing challenges associated with Alzheimer's disease, and potential initiatives that promise to speed progress in developing treatments and …

Cdc20 Regulates Sensitivity To Chemotherapy And Radiation In Glioblastoma Stem Cells, Diane D. Mao, Ryan T. Cleary, Amit Gujar, Tatenda Mahlokozera, Albert H. Kim

2020-Current year OA Pubs

Glioblastoma stem cells (GSCs) are an important subpopulation in glioblastoma, implicated in tumor growth, tumor recurrence, and radiation resistance. Understanding the cellular mechanisms for chemo- and radiation resistance could lead to the development of new therapeutic strategies. Here, we demonstrate that CDC20 promotes resistance to chemotherapy and radiation therapy. CDC20 knockdown does not increase TMZ- and radiation-induced DNA damage, or alter DNA damage repair, but rather promotes cell death through accumulation of the pro-apoptotic protein, Bim. Our results identify a CDC20 signaling pathway that regulates chemo- and radiosensitivity in GSCs, with the potential for CDC20-targeted therapeutic strategies in the treatment …

Comparative Analysis Of Dcas9-Vp64 Variants And Multiplexed Guide Rnas Mediating Crispr Activation, Kohei Omachi, Jeffrey H. Miner

2020-Current year OA Pubs

CRISPR/Cas9-mediated transcriptional activation (CRISPRa) is a powerful tool for investigating complex biological phenomena. Although CRISPRa approaches based on the VP64 transcriptional activator have been widely studied in both cultured cells and in animal models and exhibit great versatility for various cell types and developmental stages in vivo, different dCas9-VP64 versions have not been rigorously compared. Here, we compared different dCas9-VP64 constructs in identical contexts, including the cell lines used and the transfection conditions, for their ability to activate endogenous and exogenous genes. Moreover, we investigated the optimal approach for VP64 addition to VP64- and p300-based constructs. We found that MS2-MCP-scaffolded …

Preeclampsia Is Associated With Reduced Isg15 Levels Impairing Extravillous Trophoblast Invasion, Asli Ozmen, Anthony O Odibo, Et Al

2020-Current year OA Pubs

Among several interleukin (IL)-6 family members, only IL-6 and IL-11 require a gp130 protein homodimer for intracellular signaling due to lack of intracellular signaling domain in the IL-6 receptor (IL-6R) and IL-11R. We previously reported enhanced decidual IL-6 and IL-11 levels at the maternal-fetal interface with significantly higher peri-membranous IL-6 immunostaining in adjacent interstitial trophoblasts in preeclampsia (PE) vs. gestational age (GA)-matched controls. This led us to hypothesize that competitive binding of these cytokines to the gp130 impairs extravillous trophoblast (EVT) differentiation, proliferation and/or invasion. Using global microarray analysis, the current study identified inhibition of interferon-stimulated gene 15 (

Molecular Heterogeneity In Pediatric Malignant Rhabdoid Tumors In Patients With Multi-Organ Involvement, Katherine E Miller, Margaret Shatara, Et Al

2020-Current year OA Pubs

Rhabdoid tumors (RTs) of the brain (atypical teratoid/rhabdoid tumor; AT/RT) and extracranial sites (most often the kidney; RTK) are malignant tumors predominantly occurring in children, frequently those with

Glutathione S-Transferase Alpha 4 Promotes Proliferation And Chemoresistance In Colorectal Cancer Cells, Zhanhu Zhang, Lili Xu, Lin Huang, Tianqi Li, Jane Y Wang, Chunhua Ma, Xiaoyun Bian, Xiaoyan Ren, Haibo Li, Xingmin Wang

2020-Current year OA Pubs

Glutathione

Efficient T Cell Migration And Activation Require L-Plastin, Hemant Joshi, Sharon Celeste Morley

2020-Current year OA Pubs

Rapid re-organization of the actin cytoskeleton supports T-cell trafficking towards immune sites and interaction with antigen presenting cells (APCs). F-actin rearrangement enables T-cell trafficking by stabilizing adhesion to vascular endothelial cells and promoting transendothelial migration. T-cell/APC immune synapse (IS) maturation also relies upon f-actin-anchored LFA-1:ICAM-1 ligation. Therefore, efficient T-cell responses require tight regulation of f-actin dynamics. In this review, we summarize how the actin-bundling protein L-plastin (LPL) regulates T-cell activation and migration. LPL enhances f-actin polymerization and also directly binds to the β2 chain of the integrin LFA-1 to support intercellular adhesion and IS formation in human and murine T …

Combining Empirical Knowledge, In Silico Molecular Docking And Admet Profiling To Identify Therapeutic Phytochemicals From Brucea Antidysentrica For Acute Myeloid Leukemia, Lemessa Etana Bultum, Gemechu Bekele Tolossa, Doheon Lee

2020-Current year OA Pubs

Acute myeloid leukemia (AML) is one of the deadly cancers. Chemotherapy is the first-line treatment and the only curative intervention is stem cell transplantation which are intolerable for aged and comorbid patients. Therefore, finding complementary treatment is still an active research area. For this, empirical knowledge driven search for therapeutic agents have been carried out by long and arduous wet lab processes. Nonetheless, currently there is an accumulated bioinformatics data about natural products that enabled the use of efficient and cost effective in silico methods to find drug candidates. In this work, therefore, we set out to computationally investigate the …

Checkpoint Blockade-Induced Cd8+ T Cell Differentiation In Head And Neck Cancer Responders, Liye Zhou, Paul Zolkind, Obi Griffith, Et Al

2020-Current year OA Pubs

BACKGROUND: Immune checkpoint blockade (ICB) response in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is limited to 15%-20% of patients and underpinnings of resistance remain undefined.

METHODS: Starting with an anti-PD1 sensitive murine HNSCC cell line, we generated an isogenic anti-PD1 resistant model. Mass cytometry was used to delineate tumor microenvironments of both sensitive parental murine oral carcinoma (MOC1) and resistant MOC1esc1 tumors. To examine heterogeneity and clonal dynamics of tumor infiltrating lymphocytes (TILs), we applied paired single-cell RNA and TCR sequencing in three HNSCC models.

RESULTS: Anti-PD1 resistant MOC1esc1 line displayed a conserved cell intrinsic immune evasion signature. …

Subtyping Of Common Complex Diseases And Disorders By Integrating Heterogeneous Data. Identifying Clusters Among Women With Lower Urinary Tract Symptoms In The Lurn Study, Victor P. Andreev, H Henry Lai, Et Al

2020-Current year OA Pubs

We present a methodology for subtyping of persons with a common clinical symptom complex by integrating heterogeneous continuous and categorical data. We illustrate it by clustering women with lower urinary tract symptoms (LUTS), who represent a heterogeneous cohort with overlapping symptoms and multifactorial etiology. Data collected in the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN), a multi-center observational study, included self-reported urinary and non-urinary symptoms, bladder diaries, and physical examination data for 545 women. Heterogeneity in these multidimensional data required thorough and non-trivial preprocessing, including scaling by controls and weighting to mitigate data redundancy, while the various data …

Associations Of Polymorphisms In The Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With Subsequent Coronary Heart Disease: An Individual-Level Meta-Analysis, Tessa Schillemans, Sharon Cresci, Et Al

2020-Current year OA Pubs

No abstract provided.

A Polygenic Risk Score Based On A Cardioembolic Stroke Multitrait Analysis Improves A Clinical Prediction Model For This Stroke Subtype, Jara Cárcel-Márquez, Laura Ibañez, Laura Heitsch, Rajat Dhar, Carlos Cruchaga, Jin-Moo Lee, Et Al

2020-Current year OA Pubs

Background: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification.

Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (

Results: We found and replicated …

Uric Acid Predicts Recovery Of Left Ventricular Function And Adverse Events In Heart Failure With Reduced Ejection Fraction: Potential Mechanistic Insight From Network Analyses, Xiqiang Wang, Xiude Fan, Qihui Wu, Jing Liu, Linyan Wei, Dandan Yang, Xiang Bu, Xiaoxiang Liu, Aiqun Ma, Tomohiro Hayashi, Gongchang Guan, Yu Xiang, Shuang Shi, Junkui Wang, Jiansong Fang

2020-Current year OA Pubs

Background and Aims: Heart failure with reduced ejection fraction (HFrEF) still carries a high risk for a sustained decrease in left ventricular ejection fraction (LVEF) even with the optimal medical therapy. Currently, there is no effective tool to stratify these patients according to their recovery potential. We tested the hypothesis that uric acid (UA) could predict recovery of LVEF and prognosis of HFrEF patients and attempted to explore mechanistic relationship between hyperuricemia and HFrEF.

Methods: HFrEF patients with hyperuricemia were selected from the National Inpatient Sample (NIS) 2016-2018 database and our Xianyang prospective cohort study. Demographics, cardiac risk factors, and …

The Role Of Neutrophil Extracellular Traps In Acute Lung Injury, Davide Scozzi, Fuyi Liao, Alexander S Krupnick, Daniel Kreisel, Andrew E Gelman

2020-Current year OA Pubs

Acute lung injury (ALI) is a heterogeneous inflammatory condition associated with high morbidity and mortality. Neutrophils play a key role in the development of different forms of ALI, and the release of neutrophil extracellular traps (NETs) is emerging as a common pathogenic mechanism. NETs are essential in controlling pathogens, and their defective release or increased degradation leads to a higher risk of infection. However, NETs also contain several pro-inflammatory and cytotoxic molecules than can exacerbate thromboinflammation and lung tissue injury. To reduce NET-mediated lung damage and inflammation, DNase is frequently used in preclinical models of ALI due to its capability …

Where Do T Cell Subsets Stand In Sars-Cov-2 Infection: An Update, Mohammad Tarique, Mohd Suhail, Huma Naz, Naoshad Muhammad, Shams Tabrez, Torki A Zughaibi, Adel M Abuzenadah, Anwar M Hashem, Hari Shankar, Chaman Saini, Alpana Sharma

2020-Current year OA Pubs

An outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019 and spread so rapidly all around the globe. It's continued and spreading more dangerously in India and Brazil with higher mortality rate. Understanding of the pathophysiology of COVID-19 depends on unraveling of interactional mechanism of SARS-CoV-2 and human immune response. The immune response is a complex process, which can be better understood by understanding the immunological response and pathological mechanisms of COVID-19, which will provide new treatments, increase treatment efficacy, and decrease mortality associated with the disease. In this review we present a amalgamate viewpoint based on …

Advances In Understanding Interferon-Mediated Immune Responses To Enteric Viruses In Intestinal Organoids, Lila S Nolan, Megan T Baldridge

2020-Current year OA Pubs

Interferons (IFN) are antiviral cytokines with critical roles in regulating pathogens at epithelial barriers, but their capacity to restrict human enteric viruses has been incompletely characterized in part due to challenges in cultivating some viruses

A Recombinant Murine-Like Rotavirus With Nano-Luciferase Expression Reveals Tissue Tropism, Replication Dynamics, And Virus Transmission, Yinxing Zhu, Liliana Sánchez-Tacuba, Gaopeng Hou, Takahiro Kawagishi, Ningguo Feng, Harry B Greenberg, Siyuan Ding

2020-Current year OA Pubs

Rotaviruses (RVs) are one of the main causes of severe gastroenteritis, diarrhea, and death in children and young animals. While suckling mice prove to be highly useful small animal models of RV infection and pathogenesis, direct visualization tools are lacking to track the temporal dynamics of RV replication and transmissibility

Bsl2-Compliant Lethal Mouse Model Of Sars-Cov-2 And Variants Of Concern To Evaluate Therapeutics Targeting The Spike Protein, Mohanraj Manangeeswaran, Derek D C Ireland, Seth G Thacker, Ha-Na Lee, Logan Kelley-Baker, Aaron P Lewkowicz, Paul W Rothlauf, Marjorie Cornejo Pontelli, Louis-Marie Bloyet, Michael A Eckhaus, Mirian I Mendoza, Sean Whelan, Daniela Verthelyi

2020-Current year OA Pubs

Since first reported in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly acquiring mutations, particularly in the spike protein, that can modulate pathogenicity, transmission and antibody evasion leading to successive waves of COVID19 infections despite an unprecedented mass vaccination necessitating continuous adaptation of therapeutics. Small animal models can facilitate understanding host-pathogen interactions, target selection for therapeutic drugs, and vaccine development, but availability and cost of studies in BSL3 facilities hinder progress. To generate a BSL2-compatible

At-Home Blood Collection And Stabilization In High Temperature Climates Using Home Rna, Lauren G Brown, Amanda J Haack, Dakota S Kennedy, Karen N Adams, Jennifer E Stolarczuk, Meg G Takezawa, Erwin Berthier, Sanitta Thongpang, Fang Yun Lim, Damien Chaussabel, Mathieu Garand, Ashleigh B Theberge

2020-Current year OA Pubs

Expanding whole blood sample collection for transcriptome analysis beyond traditional phlebotomy clinics will open new frontiers for remote immune research and telemedicine. Determining the stability of RNA in blood samples exposed to high ambient temperatures (>30°C) is necessary for deploying home-sampling in settings with elevated temperatures (e.g., studying physiological response to natural disasters that occur in warm locations or in the summer). Recently, we have developed

Regulation Of Rod Photoreceptor Function By Farnesylated G-Protein Γ-Subunits, Alexander V. Kolesnikov, Elena Lobysheva, Jaya P. Gnana-Prakasam, Vladimir J. Kefalov, Oleg G. Kisselev

2020-Current year OA Pubs

Heterotrimeric G-protein transducin, Gt, is a key signal transducer and amplifier in retinal rod and cone photoreceptor cells. Despite similar subunit composition, close amino acid identity, and identical posttranslational farnesylation of their Gγ subunits, rods and cones rely on unique Gγ1 (Gngt1) and Gγc (Gngt2) isoforms, respectively. The only other farnesylated G-protein γ-subunit, Gγ11 (Gng11), is expressed in multiple tissues but not retina. To determine whether Gγ1 regulates uniquely rod phototransduction, we generated transgenic rods expressing Gγ1, Gγc, or Gγ11 in Gγ1-deficient mice and analyzed their properties. Immunohistochemistry and Western blotting demonstrated the robust expression of each transgenic Gγ in …

Genetic And Transcriptional Contributions To Relapse In Normal Karyotype Acute Myeloid Leukemia, Allegra A Petti, Saad M Khan, Ziheng Xu, Nichole Helton, Catrina C Fronick, Robert Fulton, Sai M Ramakrishnan, Sridhar Nonavinkere Srivatsan, Sharon E Heath, Peter Westervelt, Jacqueline E Payton, Matthew J Walter, Daniel C Link, John Dipersio, Christopher Miller, Timothy J Ley

2020-Current year OA Pubs

To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA sequencing on the same samples, which yielded 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes …

Socioecological Model-Based Design And Implementation Principles Of Lower Limb Preservation Programs As Partners For Limb-Loss Rehabilitation Programs- A Mini-Review, Vipul Khetarpaul, John P Kirby, Patrick Geraghty, John Felder, Prateek Grover

2020-Current year OA Pubs

People with lower limb loss, especially of dysvascular etiology, are at substantial risk for both ipsilateral and contralateral reamputation. Additionally, while not as well documented for reamputation, there is recognition that amputation incidence is influenced by not only sociodemographic factors such as sex, race, socioeconomic status, but also by system factors such as service access. A systems strategy to address this disparity within the field of limb-loss rehabilitation is for Limb-loss Rehabilitation Programs (LRP) to partner with medical specialists, mental health professionals, and Limb Preservation Programs (LPP) to provide comprehensive limb care. While LPPs exist around the nation, design principles …

Use Of Leishmania Major Parasites Expressing A Recombinant Trypanosoma Cruzi Antigen As Live Vaccines Against Chagas Disease, Catherine W Cai, Anne O'Shea, Christopher S Eickhoff, Hongjie Guo, Warren G Lewis, Stephen M Beverley, Daniel F Hoft

2020-Current year OA Pubs

INTRODUCTION:

METHODS: We generated recombinant

RESULTS: We demonstrate that mice inoculated with these recombinant TS-expressing

DISCUSSION: Altogether, these data indicate that

Islet Cilia And Glucose Homeostasis, Isabella Melena, Jing W Hughes

2020-Current year OA Pubs

Diabetes is a growing pandemic affecting over ten percent of the U.S. population. Individuals with all types of diabetes exhibit glucose dysregulation due to altered function and coordination of pancreatic islets. Within the critical intercellular space in pancreatic islets, the primary cilium emerges as an important physical structure mediating cell-cell crosstalk and signal transduction. Many events leading to hormone secretion, including GPCR and second-messenger signaling, are spatiotemporally regulated at the level of the cilium. In this review, we summarize current knowledge of cilia action in islet hormone regulation and glucose homeostasis, focusing on newly implicated ciliary pathways that regulate insulin …

Multi-Omics Insights Into The Biological Mechanisms Underlying Statistical Gene-By-Lifestyle Interactions With Smoking And Alcohol Consumption, Timothy D Majarian, Mary F Feitosa, Michael Province, Dabeeru C Rao, Karen Schwander, Yun Ju Sung, C Charles Gu, Et Al.

2020-Current year OA Pubs

Though both genetic and lifestyle factors are known to influence cardiometabolic outcomes, less attention has been given to whether lifestyle exposures can alter the association between a genetic variant and these outcomes. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium's Gene-Lifestyle Interactions Working Group has recently published investigations of genome-wide gene-environment interactions in large multi-ancestry meta-analyses with a focus on cigarette smoking and alcohol consumption as lifestyle factors and blood pressure and serum lipids as outcomes. Further description of the biological mechanisms underlying these statistical interactions would represent a significant advance in our understanding of gene-environment …

Implicating Genes, Pleiotropy, And Sexual Dimorphism At Blood Lipid Loci Through Multi-Ancestry Meta-Analysis, Stavroula Kanoni, Adam E. Locke, E Warwick Daw, Mary F. Feitosa, Mary K. Wojczynski, Bernhard Banas, Carsten A. Boger, Bettina Jung, D C. Rao, Michael A. Province, Et Al.

2020-Current year OA Pubs

No abstract provided.

Clinical And Molecular Characteristics Of A Novel Rare De Novo Variant In Ppp2ca In A Patient With A Developmental Disorder, Autism, And Epilepsy, Iris Verbinnen, Sara S Procknow, Lisa Lenaerts, Sara Reynhout, Aujan Mehregan, Chris Ulens, Veerle Janssens, Katherine A King

2020-Current year OA Pubs

PP2A-related (neuro) developmental disorders are a family of genetic diseases caused by a heterozygous alteration in one of several genes encoding a subunit of type 2A protein phosphatases. Reported affected genes, so far, are

Donor Chimerism And Immune Reconstitution Following Haploidentical Transplantation In Sickle Cell Disease, Yaya Chu, Brenda Grossman, Shalini Shenoy, Et Al

2020-Current year OA Pubs

INTRODUCTION: We previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.

METHODS: CD34 cells were enriched using the CliniMACS

RESULTS: HLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 …

Postnatal Osterix But Not Dmp1 Lineage Cells Significantly Contribute To Intramembranous Ossification In Three Preclinical Models Of Bone Injury, Evan G Buettmann, Susumu Yoneda, Pei Hu, Jennifer A Mckenzie, Matthew J Silva

2020-Current year OA Pubs

Murine models of long-bone fracture, stress fracture, and cortical defect are used to discern the cellular and molecular mediators of intramembranous and endochondral bone healing. Previous work has shown that Osterix (Osx

Top-Down And Bottom-Up Propagation Of Disease In The Neuronal Ceroid Lipofuscinoses, John R Ostergaard, Hemanth R Nelvagal, Jonathan D Cooper

2020-Current year OA Pubs

BACKGROUND: The Neuronal Ceroid Lipofuscinoses (NCLs) may be considered distinct neurodegenerative disorders with separate underlying molecular causes resulting from monogenetic mutations. An alternative hypothesis is to consider the NCLs as related diseases that share lipofuscin pathobiology as the common core feature, but otherwise distinguished by different a) initial anatomic location, and b) disease propagation.

METHODS: We have tested this hypothesis by comparing known differences in symptomatology and pathology of the CLN1 phenotype caused by complete loss of

RESULTS: Despite displaying similar pathological endpoints, the clinical phenotypes and the evidence of imaging and

DISCUSSION: The propagation of disease in these two …