Digital Commons Network^™

Bioimpedance-Derived Membrane Capacitance: Clinically Relevant Sources Of Variability, Precision, And Reliability, Valene Garr Barry, Jasmine L Chiang, Kaylan G Bowman, Kristina D Johnson, Barbara A Gower

2020-Current year OA Pubs

Membrane capacitance (C

Clonally Related, Notch-Differentiated Spinal Neurons Integrate Into Distinct Circuits, Saul Bello-Rojas, Martha W Bagnall

2020-Current year OA Pubs

Shared lineage has diverse effects on patterns of neuronal connectivity. In mammalian cortex, excitatory sister neurons assemble into shared microcircuits. In

An Rna Interference (Rnai) Toolkit And Its Utility For Functional Genetic Analysis Of Leishmania (Viannia), Lon-Fye Lye, Katherine L Owens, Soojin Jang, Joseph E Marcus, Erin A Brettmann, Stephen M Beverley

2020-Current year OA Pubs

RNA interference (RNAi) is a powerful tool whose efficacy against a broad range of targets enables functional genetic tests individually or systematically. However, the RNAi pathway has been lost in evolution by a variety of eukaryotes including most Leishmania sp. RNAi was retained in species of the

Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective Of Chronological Age, Joan Jiménez-Balado, Carolina Soriano-Tárraga, Et Al.

2020-Current year OA Pubs

In this manuscript we studied the relationship between WMH and biological age (B-age) in patients with acute stroke. We included in this study 247 patients with acute stroke recruited at Hospital del Mar having both epigenetic (DNA methylation) and magnetic resonance imaging data. WMH were measured using a semi-automated method. B-age was calculated using two widely used methods: the Hannum and Horvath formulas. We used multiple linear regression models to interrogate the role of B-age on WMH volume after adjusting for chronological age (C-age) and other covariables. Average C-age of the sample was 68.4 (±11.8) and we observed a relatively …

In Silico Activity And Admet Profiling Of Phytochemicals From Ethiopian Indigenous Aloes Using Pharmacophore Models, Lemessa Etana Bultum, Gemechu Bekele Tolossa, Gwangmin Kim, Ohhyeon Kwon, Doheon Lee

2020-Current year OA Pubs

In silico profiling is used in identification of active compounds and guide rational use of traditional medicines. Previous studies on Ethiopian indigenous aloes focused on documentation of phytochemical compositions and traditional uses. In this study, ADMET and drug-likeness properties of phytochemicals from Ethiopian indigenous aloes were evaluated, and pharmacophore-based profiling was done using Discovery Studio to predict therapeutic targets. The targets were examined using KEGG pathway, gene ontology and network analysis. Using random-walk with restart algorithm, network propagation was performed in CODA network to find diseases associated with the targets. As a result, 82 human targets were predicted and found …

Trem2 Dependent And Independent Functions Of Microglia In Alzheimer's Disease, Jinchao Hou, Yun Chen, Gary Grajales-Reyes, Marco Colonna

2020-Current year OA Pubs

Microglia are central players in brain innate immunity and have been the subject of extensive research in Alzheimer's disease (AD). In this review, we aim to summarize the genetic and functional discoveries that have advanced our understanding of microglia reactivity to AD pathology. Given the heightened AD risk posed by rare variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2), we will focus on the studies addressing the impact of this receptor on microglia responses to amyloid plaques, tauopathy and demyelination pathologies in mouse and human. Finally, we will discuss the implications of recent discoveries on microglia …

A Genome-Wide Association Study Of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants, Harold Bae, Ping An, Mary Feitosa, Et Al.

2020-Current year OA Pubs

We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609,

Impact Of Cd4 T Cells On Intratumoral Cd8 T-Cell Exhaustion And Responsiveness To Pd-1 Blockade Therapy In Mouse Brain Tumors, Saad M. Khan, Rupen Desai, Andrew Coxon, Alexandra Livingstone, Gavin P Dunn, Allegra Petti, Tanner M Johanns

2020-Current year OA Pubs

BACKGROUND: Glioblastoma is a fatal disease despite aggressive multimodal therapy. PD-1 blockade, a therapy that reinvigorates hypofunctional exhausted CD8 T cells (T

METHODS: Single-cell RNA sequencing was performed on flow sorted tumor-infiltrating lymphocytes from female C57/BL6 mice implanted with each model, with and without PD-1 blockade therapy. CD8

RESULTS: The CD8 T-cell compartment of the models is composed of heterogenous CD8 T

CONCLUSIONS: Here, we describe that dysfunctional CD4 T cells are associated with terminal CD8 T-cell exhaustion, suggesting CD4 T cells impact PD-1 blockade efficacy by controlling the severity of exhaustion. Given that CD4 lymphopenia is frequently observed in …

Expanded Proteomic Survey Of The Human Parasite Leishmania Major Focusing On Changes In Null Mutants Of The Golgi Gdp-Mannose/Fucose/Arabinopyranose Transporter, Gloria Polanco, Nichollas E Scott, Lon F Lye, Stephen M Beverley

2020-Current year OA Pubs

The trypanosomatid protozoan parasite

Antibodies Targeting The Neuraminidase Active Site Inhibit Influenza H3n2 Viruses With An S245n Glycosylation Site, Daniel Stadlbauer, Ali H Ellebedy, Et Al.

2020-Current year OA Pubs

Contemporary influenza A H3N2 viruses circulating since 2016 have acquired a glycosylation site in the neuraminidase in close proximity to the enzymatic active site. Here, we investigate if this S245N glycosylation site, as a result of antigenic evolution, can impact binding and function of human monoclonal antibodies that target the conserved active site. While we find that a reduction in the inhibitory ability of neuraminidase active site binders is measurable, this class of broadly reactive monoclonal antibodies maintains protective efficacy in vivo.

Self-Hybridization In Leishmania Major, Tiago R Ferreira, Ehud Inbar, Jahangheer Shaik, Brendan M Jeffrey, Kashinath Ghosh, Deborah E. Dobson, Stephen M. Beverley, David Sacks

2020-Current year OA Pubs

Genetic exchange between different

Type Iv Pili Are A Critical Virulence Factor In Clinical Isolates Of Paenibacillus Thiaminolyticus, Christine Hehnly, Petra Erdmann Gilmore, R. Reid Townsend, David D. Limbrick, Et Al.

2020-Current year OA Pubs

Hydrocephalus, the leading indication for childhood neurosurgery worldwide, is particularly prevalent in low- and middle-income countries. Hydrocephalus preceded by an infection, or postinfectious hydrocephalus, accounts for up to 60% of hydrocephalus in these areas. Since many children with hydrocephalus suffer poor long-term outcomes despite surgical intervention, prevention of hydrocephalus remains paramount. Our previous studies implicated a novel bacterial pathogen, Paenibacillus thiaminolyticus, as a causal agent of neonatal sepsis and postinfectious hydrocephalus in Uganda. Here, we report the isolation of three

Quality Assessment And Refinement Of Chromatin Accessibility Data Using A Sequence-Based Predictive Model, Seong Kyu Han, Yoshiharu Muto, Parker C Wilson, Benjamin D Humphreys, Matthew G Sampson, Aravinda Chakravarti, Dongwon Lee

2020-Current year OA Pubs

Chromatin accessibility assays are central to the genome-wide identification of gene regulatory elements associated with transcriptional regulation. However, the data have highly variable quality arising from several biological and technical factors. To surmount this problem, we developed a sequence-based machine learning method to evaluate and refine chromatin accessibility data. Our framework, gapped k-mer SVM quality check (gkmQC), provides the quality metrics for a sample based on the prediction accuracy of the trained models. We tested 886 DNase-seq samples from the ENCODE/Roadmap projects to demonstrate that gkmQC can effectively identify "high-quality" (HQ) samples with low conventional quality scores owing to marginal …

Morphologic Design Of Nanostructures For Enhanced Antimicrobial Activity, Fatma Al-Zahraa Sayed, Noura G Eissa, Yidan Shen, David A Hunstad, Karen L Wooley, Mahmoud Elsabahy

2020-Current year OA Pubs

Despite significant progress in synthetic polymer chemistry and in control over tuning the structures and morphologies of nanoparticles, studies on morphologic design of nanomaterials for the purpose of optimizing antimicrobial activity have yielded mixed results. When designing antimicrobial materials, it is important to consider two distinctly different modes and mechanisms of activity-those that involve direct interactions with bacterial cells, and those that promote the entry of nanomaterials into infected host cells to gain access to intracellular pathogens. Antibacterial activity of nanoparticles may involve direct interactions with organisms and/or release of antibacterial cargo, and these activities depend on attractive interactions and …

A Unique High-Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance In Cantu Syndrome, Gautam K Singh, Conor Mcclenaghan, Manish Aggarwal, Hongjie Gu, Maria S Remedi, Dorothy K Grange, Colin G Nichols

2020-Current year OA Pubs

Background Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high-output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities. Methods and Results We sought to systematically characterize high-output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain-of-function variants in

Covid-19 Induces Cns Cytokine Expression And Loss Of Hippocampal Neurogenesis, Allison L Soung, Abigail Vanderheiden, Xiaoping Jiang, Traci Bricker, Adrianus C M Boon, Robyn S Klein, Et Al.

2020-Current year OA Pubs

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with acute and postacute cognitive and neuropsychiatric symptoms including impaired memory, concentration, attention, sleep and affect. Mechanisms underlying these brain symptoms remain understudied. Here we report that SARS-CoV-2-infected hamsters exhibit a lack of viral neuroinvasion despite aberrant blood-brain barrier permeability. Hamsters and patients deceased from coronavirus disease 2019 (COVID-19) also exhibit microglial activation and expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the medulla oblongata, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uraemia or trauma. In the …

A Whole-Genome Sequencing Study Implicates Gramd1b In Multiple Sclerosis Susceptibility, Federica Esposito, Bryan Bollman, Laura Piccio, Et Al.

2020-Current year OA Pubs

While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the

Mitochondrial Autophagy In Ischemic Aged Livers, Jae-Sung Kim, William C Chapman, Yiing Lin

2020-Current year OA Pubs

Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.

Human Nk Cells Confer Protection Against Hiv-1 Infection In Humanized Mice, Can M. Sungur, Qiankun Wang, Ayşe N. Ozantürk, Hongbo Gao, Aaron J. Schmitz, Marina Cella, Wayne M. Yokoyama, Liang Shan

2020-Current year OA Pubs

The role of NK cells against HIV-1 infections remains to be elucidated in vivo. While humanized mouse models potentially could be used to directly evaluate human NK cell responses during HIV-1 infection, improved functional development of human NK cells in these hosts is needed. Here, we report the humanized MISTRG-6-15 mouse model, in which NK cells were quick to expand and exhibit degranulation, cytotoxicity, and proinflammatory cytokine production in nonlymphoid organs upon HIV-1 infection but had reduced functionality in lymphoid organs. Although HIV-1 infection induced functional impairment of NK cells, antiretroviral therapy reinvigorated NK cells in response to HIV-1 rebound …

Mitochondria Clumping Vs. Mitochondria Fusion In Cmt2a Diseases, Antonietta Franco, Caroline E Walton, Xiawei Dang

2020-Current year OA Pubs

Phenotypic variations in Charcot-Marie-Tooth disease type 2A (CMT2A) result from the many mutations in the mitochondrial fusion protein, mitofusin 2 (MFN2). While the GTPase domain mutations of MFN2 lack the ability to hydrolyze GTP and complete mitochondrial fusion, the mechanism of dysfunction in HR1 domain mutations has yet to be explored. Using

Social Attention During Object Engagement: Toward A Cross-Species Measure Of Preferential Social Orienting, Claire Weichselbaum, Nicole Hendrix, Jordan Albright, Joseph D Dougherty, Kelly N Botteron, John N Constantino, Natasha Marrus

2020-Current year OA Pubs

BACKGROUND: A central challenge in preclinical research investigating the biology of autism spectrum disorder (ASD) is the translation of ASD-related social phenotypes across humans and animal models. Social orienting, an observable, evolutionarily conserved behavior, represents a promising cross-species ASD phenotype given that disrupted social orienting is an early-emerging ASD feature with evidence for predicting familial recurrence. Here, we adapt a competing-stimulus social orienting task from domesticated dogs to naturalistic play behavior in human toddlers and test whether this approach indexes decreased social orienting in ASD.

METHODS: Play behavior was coded from the Autism Diagnostic Observation Schedule (ADOS) in two samples …

Tissue Registration And Exploration User Interfaces In Support Of A Human Reference Atlas, Katy Börner, Andreas Bueckle, Bruce W Herr 2nd, Leonard E Cross, Ellen M Quardokus, Elizabeth G Record, Yingnan Ju, Jonathan C Silverstein, Kristen M Browne, Sanjay Jain, Clive H Wasserfall, Marda L Jorgensen, Jeffrey M Spraggins, N Heath Patterson, Griffin M Weber

2020-Current year OA Pubs

Seventeen international consortia are collaborating on a human reference atlas (HRA), a comprehensive, high-resolution, three-dimensional atlas of all the cells in the healthy human body. Laboratories around the world are collecting tissue specimens from donors varying in sex, age, ethnicity, and body mass index. However, harmonizing tissue data across 25 organs and more than 15 bulk and spatial single-cell assay types poses challenges. Here, we present software tools and user interfaces developed to spatially and semantically annotate ("register") and explore the tissue data and the evolving HRA. A key part of these tools is a common coordinate framework, providing standard …

Condensates Formed By Prion-Like Low-Complexity Domains Have Small-World Network Structures And Interfaces Defined By Expanded Conformations, Mina Farag, Samuel R Cohen, Wade M Borcherds, Anne Bremer, Tanja Mittag, Rohit V Pappu

2020-Current year OA Pubs

Biomolecular condensates form via coupled associative and segregative phase transitions of multivalent associative macromolecules. Phase separation coupled to percolation is one example of such transitions. Here, we characterize molecular and mesoscale structural descriptions of condensates formed by intrinsically disordered prion-like low complexity domains (PLCDs). These systems conform to sticker-and-spacers architectures. Stickers are cohesive motifs that drive associative interactions through reversible crosslinking and spacers affect the cooperativity of crosslinking and overall macromolecular solubility. Our computations reproduce experimentally measured sequence-specific phase behaviors of PLCDs. Within simulated condensates, networks of reversible inter-sticker crosslinks organize PLCDs into small-world topologies. The overall dimensions of PLCDs …

Tenotomy-Induced Muscle Atrophy Is Sex-Specific And Independent Of Nfκb, Gretchen A Meyer, Stavros Thomopoulos, Yousef Abu-Amer, Karen C Shen

2020-Current year OA Pubs

The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKβ effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NFκB in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKKβ was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a twofold gain or loss of NFκB signaling. Surprisingly, neither knockdown of …

Mendelian Randomization And Genetic Colocalization Infer The Effects Of The Multi-Tissue Proteome On 211 Complex Disease-Related Phenotypes, Chengran Yang, Anne M Fagan, Richard J Perrin, Herve Rhinn, Oscar Harari, Carlos Cruchaga

2020-Current year OA Pubs

BACKGROUND: Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. Previous MR studies using the brain proteome only reported protein effects on a set of pre-selected tissue-specific diseases. No studies, however, have used high-throughput proteomics from multiple tissues to perform MR on hundreds of phenotypes.

METHODS: Here, we performed MR and colocalization analysis using multi-tissue (cerebrospinal fluid (CSF), plasma, and brain from pre- and post-meta-analysis of several …

Defective Proteostasis In Induced Pluripotent Stem Cell Models Of Frontotemporal Lobar Degeneration, Sidhartha Mahali, Rita Martinez, Melvin King, Anthony Verbeck, Oscar Harari, Bruno A Benitez, Kanta Horie, Chihiro Sato, Sally Temple, Celeste M Karch

2020-Current year OA Pubs

Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau (MAPT) gene are sufficient to cause tau accumulation and neurodegeneration. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. Here, we show that molecular networks associated with lysosomal biogenesis and autophagic function are disrupted in brains from FTLD-tau patients carrying a MAPT p.R406W mutation. We …

Acaricidal Activity Of Tea Tree And Lemon Oil Nanoemulsions Against Rhipicephalus Annulatus, Samar M Ibrahium, Ahmed A Wahba, Ahmed A Farghali, Abdel-Azeem S Abdel-Baki, Shaimaa A A Mohamed, Saleh Al-Quraishy, Ahmed O Hassan, Shawky M. Aboelhadid

2020-Current year OA Pubs

Tick infestation is a serious problem in many countries since it has an impact on the health of animals used for food production and pets, and frequently affects humans. Therefore, the present study aimed to investigate the acaricidal effects of nanoemulsions of essential oils of

Zur And Zinc Increase Expression Of E. Coli Ribosomal Protein L31 Through Rna-Mediated Repression Of The Repressor L31p, Rebecca A Rasmussen, Suning Wang, Jeannie M Camarillo, Victoria Sosnowski, Byoung-Kyu Cho, Young Ah Goo, Julius B Lucks, Thomas V O'Halloran

2020-Current year OA Pubs

Bacteria can adapt in response to numerous stress conditions. One such stress condition is zinc depletion. The zinc-sensing transcription factor Zur regulates the way numerous bacterial species respond to severe changes in zinc availability. Under zinc sufficient conditions, Zn-loaded Zur (Zn2-Zur) is well-known to repress transcription of genes encoding zinc uptake transporters and paralogues of a few ribosomal proteins. Here, we report the discovery and mechanistic basis for the ability of Zur to up-regulate expression of the ribosomal protein L31 in response to zinc in E. coli. Through genetic mutations and reporter gene assays, we find that Zur achieves the …

The Protein Phosphatase 2a Holoenzyme Is A Key Regulator Of Starch Metabolism And Bradyzoite Differentiation In Toxoplasma Gondii, Jin-Lei Wang, Ting-Ting Li, Hany M Elsheikha, Qin-Li Liang, Zhi-Wei Zhang, Meng Wang, L David Sibley, Xing-Quan Zhu

2020-Current year OA Pubs

Phenotypic switching between tachyzoite and bradyzoite is the fundamental mechanism underpinning the pathogenicity and adaptability of the protozoan parasite Toxoplasma gondii. Although accumulation of cytoplasmic starch granules is a hallmark of the quiescent bradyzoite stage, the regulatory factors and mechanisms contributing to amylopectin storage in bradyzoites are incompletely known. Here, we show that T. gondii protein phosphatase 2A (PP2A) holoenzyme is composed of a catalytic subunit PP2A-C, a scaffold subunit PP2A-A and a regulatory subunit PP2A-B. Disruption of any of these subunits increased starch accumulation and blocked the tachyzoite-to-bradyzoite differentiation. PP2A contributes to the regulation of amylopectin metabolism via dephosphorylation …

Genetic Diversity Fuels Gene Discovery For Tobacco And Alcohol Use, Gretchen R B Saunders, Charles C Gu, John P Rice, Nancy L Saccone, Laura J Bierut, Et Al.

2020-Current year OA Pubs

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury