Digital Commons Network^™

5Β-Dihydrosteroids: Formation And Properties, Trevor M Penning, Douglas F Covey

2020-Current year OA Pubs

5β-Dihydrosteroids are produced by the reduction of Δ

Development Of Vla4 And Cxcr4 Antagonists For The Mobilization Of Hematopoietic Stem And Progenitor Cells, Peter G Ruminski, Michael P Rettig, John F Dipersio

2020-Current year OA Pubs

The treatment of patients diagnosed with hematologic malignancies typically includes hematopoietic stem cell transplantation (HSCT) as part of a therapeutic standard of care. The primary graft source of hematopoietic stem and progenitor cells (HSPCs) for HSCT is mobilized from the bone marrow into the peripheral blood of allogeneic donors or patients. More recently, these mobilized HSPCs have also been the source for gene editing strategies to treat diseases such as sickle-cell anemia. For a HSCT to be successful, it requires the infusion of a sufficient number of HSPCs that are capable of adequate homing to the bone marrow niche and …

Sac1 Links Phosphoinositide Turnover To Cryptococcal Virulence, Elizabeth A Gaylord, Hau Lam Choy, Guohua Chen, Sydney L Briner, Tamara L Doering

2020-Current year OA Pubs

No abstract provided.

Immunological Correlates Of Protection Mediated By A Whole Organism,Cryptococcus Neoformans, Vaccine Deficient In Chitosan, Charles A Specht, Ruiying Wang, Lorena V N Oliveira, Maureen M Hester, Christina Gomez, Zhongming Mou, Diana Carlson, Chrono K Lee, Camaron R Hole, Woei C Lam, Rajendra Upadhya, Jennifer K Lodge, Stuart M Levitz

2020-Current year OA Pubs

UNLABELLED: The global burden of infections due to the pathogenic fungus

IMPORTANCE: The fungus

An Integrated Structural Model Of The Dna Damage-Responsive H3k4me3 Binding Wdr76:Spin1 Complex With The Nucleosome, Xingyu Liu, Yixuan Xie, Benjamin A Garcia, Et Al.

2020-Current year OA Pubs

Serial capture affinity purification (SCAP) is a powerful method to isolate a specific protein complex. When combined with cross-linking mass spectrometry and computational approaches, one can build an integrated structural model of the isolated complex. Here, we applied SCAP to dissect a subpopulation of WDR76 in complex with SPIN1, a histone reader that recognizes trimethylated histone H3 lysine4 (H3K4me3). In contrast to a previous SCAP analysis of the SPIN1:SPINDOC complex, histones and the H3K4me3 mark were enriched with the WDR76:SPIN1 complex. Next, interaction network analysis of copurifying proteins and microscopy analysis revealed a potential role of the WDR76:SPIN1 complex in …

Neoantigen Landscape Supports Feasibility Of Personalized Cancer Vaccine For Follicular Lymphoma, Cody A Ramirez, Michelle Becker-Hapak, Kartik Singhal, David A Russler-Germain, Erica K Barnell, Ethan D Mcclain, Sweta Desai, Timothy Schappe, Onyinyechi C Onyeador, Susanna Kiwala, Jasreet Hundal, Zachary L Skidmore, Marcus P Watkins, Thomas B Mooney, Jason R Walker, Kilannin Krysiak, Felicia Gomez, Catrina C Fronick, Robert S Fulton, Robert D Schreiber, Neha Mehta-Shah, Amanda F Cashen, Brad S Kahl, Nancy L Bartlett, Malachi Griffith, Obi L Griffith, Todd A Fehniger, Et Al.

2020-Current year OA Pubs

Personalized cancer vaccines designed to target neoantigens represent a promising new treatment paradigm in oncology. In contrast to classical idiotype vaccines, we hypothesized that "polyvalent" vaccines could be engineered for the personalized treatment of follicular lymphoma (FL) using neoantigen discovery by combined whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Fifty-eight tumor samples from 57 patients with FL underwent WES and RNA-seq. Somatic and B-cell clonotype neoantigens were predicted and filtered to identify high-quality neoantigens. B-cell clonality was determined by the alignment of B-cell receptor (BCR) CDR3 regions from RNA-seq data, grouping at the protein level, and comparison with the BCR …

Dominance Analysis To Assess Solute Contributions To Multicomponent Phase Equilibria, Daoyuan Qian, Hannes Ausserwoger, Tomas Sneideris, Mina Farag, Rohit V Pappu, Tuomas P J Knowles

2020-Current year OA Pubs

Phase separation in aqueous solutions of macromolecules underlies the generation of biomolecular condensates in cells. Condensates are membraneless bodies, representing dense, macromolecule-rich phases that coexist with the dilute, macromolecule-deficient phases. In cells, condensates comprise hundreds of different macromolecular and small molecule solutes. How do different solutes contribute to the driving forces for phase separation? To answer this question, we introduce a formalism we term energy dominance analysis. This approach rests on analysis of shapes of the dilute phase boundaries, slopes of tie lines, and changes to dilute phase concentrations in response to perturbations of concentrations of different solutes. The framework …

Dual Role Of Neuroplastin In Pancreatic Β Cells: Regulating Insulin Secretion And Promoting Islet Inflammation, Rie Asada Kitamura, Devynn Hummel, Alessandro Ustione, David W. Piston, Fumihiko Urano

2020-Current year OA Pubs

No abstract provided.

A Simplified G-Csf-Free Procedure Allows For In Vivo Hsc Gene Therapy Of Sickle Cell Disease In A Mouse Model, Chang Li, Anna K Anderson, Peter Ruminski, Michael Rettig, Darja Karpova, Hans-Peter Kiem, John F Dipersio, André Lieber

2020-Current year OA Pubs

We have reported the direct repair of the sickle cell mutation in vivo in a disease model using vectorized prime editors after hematopoietic stem cell (HSC) mobilization with granulocyte colony-stimulating factor (G-CSF)/AMD3100. The use of G-CSF for HSC mobilization is a hurdle for the clinical translation of this approach. Here, we tested a G-CSF-free mobilization regimen using WU-106, an inhibitor of integrin α4β1, plus AMD3100 for in vivo HSC prime editing in sickle cell disease (SCD) mice. Mobilization with WU-106 + AMD3100 in SCD mice was rapid and efficient. In contrast to the G-CSF/AMD3100 approach, mobilization of activated granulocytes and …

Multimodal Mechanisms Of Pathogenic Variants In The Signal Peptide Of Fix Leading To Hemophilia B, Meng Gao, Long Chen, Jinlong Yang, Shixia Dong, Qing Cao, Zihan Cui, Yanyan Dong, Hongli Liu, Yan Shen, Haiping Yang, Zhenyu Hao, Lei Zhang, Weikai Li, Jian-Ke Tie, Guomin Shen

2020-Current year OA Pubs

Signal peptide (SP) is essential for protein secretion, and pathogenic variants in the SP of factor IX (FIX) have been identified in hemophilia B (HB). However, the underlying mechanism for the genotype-phenotype correlation of these variants has not been well studied. Here, we systematically examined the effects of 13 pathogenic point variants in the SP of FIX using different approaches. Our results showed that these point variants lead to HB by missense variants and/or aberrant premessenger RNA (pre-mRNA) splicing. The missense variants in a hydrophobic core (h-region) mainly affected the cotranslational translocation function of the SP, and those in C-terminal …

Infection Prevention And Control In 2030: A First Qualitative Survey By The Crystal Ball Initiative, Hugo Sax, Jonas Marschall, Crystal Ball Initiative

2020-Current year OA Pubs

BACKGROUND: Healthcare delivery is undergoing radical changes that influence effective infection prevention and control (IPC). Futures research (short: Futures), the science of deliberating on multiple potential future states, is increasingly employed in many core societal fields. Futures might also be helpful in IPC to facilitate current education and organisational decisions. Hence, we conducted an initial survey as part of the IPC Crystal Ball Initiative.

METHODS: In 2019, international IPC experts were invited to answer a 10-item online questionnaire, including demographics, housekeeping, and open-ended core questions (Q) on the "status of IPC in 2030" (Q1), "people in charge of IPC" (Q2), …

Signaling By A Bacterial Phytochrome Histidine Kinase Involves A Conformational Cascade Reorganizing The Dimeric Photoreceptor, E Sethe Burgie, Katherine Basore, Michael J Rau, Brock Summers, Alayna J Mickles, Vadim Grigura, James A J Fitzpatrick, Richard D Vierstra

2020-Current year OA Pubs

Phytochromes (Phys) are a divergent cohort of bili-proteins that detect light through reversible interconversion between dark-adapted Pr and photoactivated Pfr states. While our understandings of downstream events are emerging, it remains unclear how Phys translate light into an interpretable conformational signal. Here, we present models of both states for a dimeric Phy with histidine kinase (HK) activity from the proteobacterium Pseudomonas syringae, which were built from high-resolution cryo-EM maps (2.8-3.4-Å) of the photosensory module (PSM) and its following signaling (S) helix together with lower resolution maps for the downstream output region augmented by RoseTTAFold and AlphaFold structural predictions. The head-to-head …

Untargeted Lipidomics Reveals Racial Differences In Lipid Species Among Women, Ghazaleh Pourali, Liang Li, Kayla R Getz, Myung Sik Jeon, Jingqin Luo, Chongliang Luo, Adetunji T Toriola

2020-Current year OA Pubs

Understanding the biological mechanisms underlying racial differences in diseases is crucial to developing targeted prevention and treatment. There is, however, limited knowledge of the impact of race on lipids. To address this, we performed comprehensive lipidomics analyses to evaluate racial differences in lipid species among 506 non-Hispanic White (NHW) and 163 non-Hispanic Black (NHB) women. Plasma lipidomic profiling quantified 982 lipid species. We used multivariable linear regression models, adjusted for confounders, to identify racial differences in lipid species and corrected for multiple testing using a Bonferroni-adjusted p-value <  10

Epigenetic Reprogramming Driving Successful And Failed Repair In Acute Kidney Injury, Yoshiharu Muto, Eryn E Dixon, Yasuhiro Yoshimura, Nicolas Ledru, Yuhei Kirita, Haojia Wu, Benjamin D Humphreys

2020-Current year OA Pubs

Acute kidney injury (AKI) causes epithelial damage followed by subsequent repair. While successful repair restores kidney function, this process is often incomplete and can lead to chronic kidney disease (CKD) in a process called failed repair. To better understand the epigenetic reprogramming driving this AKI-to-CKD transition, we generated a single-nucleus multiomic atlas for the full mouse AKI time course, consisting of ~280,000 single-nucleus transcriptomes and epigenomes. We reveal cell-specific dynamic alterations in gene regulatory landscapes reflecting, especially, activation of proinflammatory pathways. We further generated single-nucleus multiomic data from four human AKI samples including validation by genome-wide identification of nuclear factor …

Kat2a And Kat2b Prevent Double-Stranded Rna Accumulation And Interferon Signaling To Maintain Intestinal Stem Cell Renewal, Mai-Uyen Nguyen, Angela Halstead, José B Sáenz, Et Al.

2020-Current year OA Pubs

Histone acetyltransferases

Postacute Sequelae Of Sars-Cov-2 Infection In The Pre-Delta, Delta, And Omicron Eras, Yan Xie, Taeyoung Choi, Ziyad Al-Aly

2020-Current year OA Pubs

BACKGROUND: Postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) can affect many organ systems. However, temporal changes during the coronavirus disease 2019 (Covid-19) pandemic, including the evolution of SARS-CoV-2, may have affected the risk and burden of PASC. Whether the risk and burden of PASC have changed over the course of the pandemic is unclear.

METHODS: We used health records of the Department of Veterans Affairs to build a study population of 441,583 veterans with SARS-CoV-2 infection between March 1, 2020, and January 31, 2022, and 4,748,504 noninfected contemporaneous controls. We estimated the cumulative incidence of …

Multi-Omic Analysis Of Huntington's Disease Reveals A Compensatory Astrocyte State, Fahad Paryani, Ji-Sun Kwon, Andrew S Yoo, Et Al.

2020-Current year OA Pubs

The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington's disease (HD) have not been fully defined. To explore the role of astrocytes in this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, and multiplexed immunofluorescence on HD and control post-mortem brains. We identified genes that correlated with CAG repeat length, which were enriched in astrocyte genes, and lipidomic signatures that implicated poly-unsaturated fatty acids in sensitizing neurons to cell death. Because astrocytes play essential roles in lipid metabolism, we explored the heterogeneity of astrocytic states in both protoplasmic and fibrous-like (CD44+) astrocytes. Significantly, …

The Neonatal Fc Receptor (Fcrn) Is A Pan-Arterivirus Receptor, Teressa M Shaw, Meagan E Sullender, Megan T Baldridge, Et Al.

2020-Current year OA Pubs

Arteriviruses infect a variety of mammalian hosts, but the receptors used by these viruses to enter cells are poorly understood. We identified the neonatal Fc receptor (FcRn) as an important pro-viral host factor via comparative genome-wide CRISPR-knockout screens with multiple arteriviruses. Using a panel of cell lines and divergent arteriviruses, we demonstrate that FcRn is required for the entry step of arterivirus infection and serves as a molecular barrier to arterivirus cross-species infection. We also show that FcRn synergizes with another known arterivirus entry factor, CD163, to mediate arterivirus entry. Overexpression of FcRn and CD163 sensitizes non-permissive cells to infection …

Identification Of Genetic Subtypes In Follicular Lymphoma, Victoria Shelton, Brad Kahl, Et Al.

2020-Current year OA Pubs

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated …

Distinct Regulation Of Atm Signaling By Dna Single-Strand Breaks And Ape1, Haichao Zhao, Jia Li, Zhongsheng You, Howard D Lindsay, Shan Yan

2020-Current year OA Pubs

In response to DNA double-strand breaks or oxidative stress, ATM-dependent DNA damage response (DDR) is activated to maintain genome integrity. However, it remains elusive whether and how DNA single-strand breaks (SSBs) activate ATM. Here, we provide direct evidence in Xenopus egg extracts that ATM-mediated DDR is activated by a defined SSB structure. Our mechanistic studies reveal that APE1 promotes the SSB-induced ATM DDR through APE1 exonuclease activity and ATM recruitment to SSB sites. APE1 protein can form oligomers to activate the ATM DDR in Xenopus egg extracts in the absence of DNA and can directly stimulate ATM kinase activity in …

Stroke Severity, Caregiver Feedback, And Cognition In The Regards-Cares Study, Jason A Blake, D Leann Long, Amy J Knight, Burel R Goodin, Michael Crowe, Suzanne E Judd, J David Rhodes, David L Roth, Olivio J Clay

2020-Current year OA Pubs

BACKGROUND: Cognitive impairment after stroke is common and is present in up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of 2 stroke severity ratings and a caregiver-report of poststroke functioning with longitudinal cognitive outcomes.

METHODS AND RESULTS: One hundred fifty-seven caregivers and stroke survivor dyads participated in the CARES (Caring for Adults Recovering From the Effects of Stroke) project, an ancillary study of the REGARDS (Reasons for Geographic and Racial Differences in …

Deltex Family E3 Ligases Specifically Ubiquitinate The Terminal Adp-Ribose Of Poly(Adp-Ribosyl)Ation, Matthew Kelly, Chase Dietz, Samuel Kasson, Yong Zhang, Michael J Holtzman, In-Kwon Kim

2020-Current year OA Pubs

Poly(ADP-ribose) polymerases (PARPs) are critical to regulating cellular activities, such as the response to DNA damage and cell death. PARPs catalyze a reversible post-translational modification (PTM) in the form of mono- or poly(ADP-ribosyl)ation. This type of modification is known to form a ubiquitin-ADP-ribose (Ub-ADPR) conjugate that depends on the actions of Deltex family of E3 ubiquitin ligases (DTXs). In particular, DTXs add ubiquitin to the 3'-OH of adenosine ribose' in ADP-ribose, which effectively sequesters ubiquitin and impedes ubiquitin-dependent signaling. Previous work demonstrates DTX function for ubiquitination of protein-free ADPR, mono-ADP-ribosylated peptides, and ADP-ribosylated nucleic acids. However, the dynamics of DTX-mediated …

Changes In Atherosclerotic Cardiovascular Disease Risk Scores In A Predominantly Black Cohort With Hiv And Associated Comorbidities: A Preliminary Study, Shana A B Burrowes, Erin Zisman, Lori E Fantry, Quoc Bui, Angela Wu, John Sorkin, Michael Miller, Shashwatee Bagchi

2020-Current year OA Pubs

INTRODUCTION: People with HIV (PWH) have an increased risk of atherosclerotic cardiovascular disease (ASCVD) compared to non-PWH, but the reasons for this increased risk remain elusive. We investigated the change in ASCVD risk scores over 4 years to identify clinical factors associated with change in risk scores or high-risk scores.

METHODS: We conducted a preliminary study using retrospective analysis of PWH, between 40 and 75 years old, seen at the Evelyn Jordan Center with at least two routine HIV visits. We collected clinical and demographic data and calculated the ASCVD risk scores using the Pooled Cohort Equation. Exploratory analyses examined …

Tracking The Prevalence And Emergence Of Sars-Cov-2 Variants Of Concern Using A Regional Genomic Surveillance Program, Ana Jung, Lindsay Droit, Binita Febles, Catarina Fronick, Lisa Cook, Scott A Handley, Bijal A Parikh, David Wang

2020-Current year OA Pubs

UNLABELLED: SARS-CoV-2 molecular testing coupled with whole-genome sequencing is instrumental for real-time genomic surveillance. Genomic surveillance is critical for monitoring the spread of variants of concern (VOCs) as well as discovery of novel variants. Since the beginning of the pandemic, millions of SARS-CoV-2 genomes have been deposited into public sequence databases. This is the result of efforts of both national and regional diagnostic laboratories. In this study, we describe the results of SARS-CoV-2 genomic surveillance from February 2021 to June 2022 at a metropolitan hospital in the United States. We demonstrate that consistent daily sampling is sufficient to track the …

Benefits And Challenges Of Geographic Information Systems (Gis) For Data-Driven Outreach In Black Communities Experiencing Overdose Disparities: Results Of A Stakeholder Focus Group, Devin E Banks, Maria Paschke, Rashmi Ghonasgi, Vetta L Sanders Thompson

2020-Current year OA Pubs

BACKGROUND: Black individuals in the U.S. face increasing racial disparities in drug overdose related to social determinants of health, including place-based features. Mobile outreach efforts work to mitigate social determinants by servicing geographic areas with low drug treatment and overdose prevention access but are often limited by convenience-based targets. Geographic information systems (GIS) are often used to characterize and visualize the overdose crisis and could be translated to community to guide mobile outreach services. The current study examines the initial acceptability and appropriateness of GIS to facilitate data-driven outreach for reducing overdose inequities facing Black individuals.

METHODS: We convened a …

Brca1 Secondary Splice-Site Mutations Drive Exon-Skipping And Parp Inhibitor Resistance, Ksenija Nesic, John J Krais, Et Al.

2020-Current year OA Pubs

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift …

A Human Stat3 Gain-Of-Function Variant Drives Local Th17 Dysregulation And Skin Inflammation In Mice, Kelsey A Toth, Erica G Schmitt, Ana Kolicheski, Zev J Greenberg, Elizabeth Levendosky, Nermina Saucier, Kelsey Trammel, Vasileios Oikonomou, Michail S Lionakis, Eynav Klechevsky, Brian S Kim, Laura G Schuettpelz, Naresha Saligrama, Megan A Cooper

2020-Current year OA Pubs

Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without …

Maturation Of Germinal Center B Cells After Influenza Virus Vaccination In Humans, Katherine M Mcintire, Wooseob Kim, Sameer Kumar Malladi, Bassem M Mohammed, Julian Q Zhou, Aaron J Schmitz, Teresa Suessen, William D Middleton, Sharlene A Teefey, Rachel M Presti, Jackson S Turner, Ali H. Ellebedy, Et Al.

2020-Current year OA Pubs

Germinal centers (GC) are microanatomical lymphoid structures where affinity-matured memory B cells and long-lived bone marrow plasma cells are primarily generated. It is unclear how the maturation of B cells within the GC impacts the breadth and durability of B cell responses to influenza vaccination in humans. We used fine needle aspiration of draining lymph nodes to longitudinally track antigen-specific GC B cell responses to seasonal influenza vaccination. Antigen-specific GC B cells persisted for at least 13 wk after vaccination in two out of seven individuals. Monoclonal antibodies (mAbs) derived from persisting GC B cell clones exhibit enhanced binding affinity …

Resistance, Rebound, And Recurrence Regrowth Patterns In Pediatric Low-Grade Glioma Treated By Mapk Inhibition: A Modified Delphi Approach To Build International Consensus-Based Definitions-International Pediatric Low-Grade Glioma Coalition, Patricia O'Hare, David H Gutmann, Et Al.

2020-Current year OA Pubs

Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor …

Is Mild Really Mild?: Generating Longitudinal Profiles Of Stroke Survivor Impairment And Impact Using Unsupervised Machine Learning, Achini Adikari, Rashmika Nawaratne, Daswin De Silva, David L. Carey, Alistair Walsh, Carolyn Baum, Stephen Davis, Geoffrey A. Donnan, Damminda Alahakoon, Leeanne M. Carey

2020-Current year OA Pubs

No abstract provided.