bluuebunny/crossref_metadata_2025_split huggingface dataset:
WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma
Authors: Mitchell Kelly , Shakya Sajina , Arora Sonali , Sprowls Samuel A. , Silver Daniel J. , Goins Christopher M. , Wallace Lisa , Roversi Gustavo , Schafer Rachel , Kay Kristen , Miller Tyler E. , Lauko Adam , Bassett John , Kashyap Anjali , D’Amato Kass J. , Mulkearns-Hubert Erin E. , Johnson Sadie , Alvarado Joseph , Rich Jeremy N. , Paddison Patrick J. , Patel Anoop P. , Stauffer Shaun R. , Hubert Christopher G. , Lathia Justin D. 
Published: September 2021

AbstractGlioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1-family-mediated Lys4 methylation of histone H3, associated with positive regulation of transcription. In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment diminished reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSCin vitrogrowth and self-renewal as well asin vivotumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.SignificanceIn this study, we perform an epigenetic-focused functional genomics screen in glioblastoma organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche.Graphical Abstract
Interferon induction and not replication interference mainly determines anti-influenza virus activity of defective interfering particles
Authors: Arora Prerna , Bdeir Najat , Gärtner Sabine , Reiter Stefanie , Pelz Lars , Felgenhauer Ulrike , Reichl Udo , Ludwig Stephan , Weber Friedemann , Hoffmann Markus , Winkler Michael , Pöhlmann Stefan 
Published: September 2021

AbstractDefective interfering (DI) RNAs arise during influenza virus replication, can be packaged into particles (DIPs) and suppress spread of wildtype (WT) virus. However, the molecular signatures of DI RNAs and the mechanism underlying antiviral activity are incompletely understood. Here, we show that any central deletion is sufficient to convert a viral RNA into a DI RNA and that antiviral activity of DIPs is inversely correlated with DI RNA length when induction of the interferon (IFN) system is disfavored. When induction of the IFN system was allowed, it was found to be the major contributor to DIP antiviral activity. Finally, while both DIPs and influenza virus triggered expression of IFN-stimulated genes (ISG) only virus stimulated robust expression of IFN. These results suggest a key role of innate immune activation in DIP antiviral activity and point towards previously unappreciated differences in DIP- and influenza virus-mediated activation of the effector functions of the IFN system.ImportanceDefective interfering (DI) RNAs naturally arise during RNA virus infection. They can be packaged into defective interfering particles (DIPs) and exert antiviral activity by suppressing viral genome replication and inducing the interferon (IFN) system. However, inhibition of influenza virus infection by DI RNAs has been incompletely understood. Here, we show that induction of the IFN system and not suppression of genome replication is the major determinant of DIP antiviral activity. Moreover, we demonstrate that DIPs induce IFN-stimulated genes (ISG) but not IFN with high efficiency. Our results reveal unexpected major differences in influenza virus and DIP activation of the IFN system, a key barrier against viral infection, and provide insights into how to design DIPs for antiviral therapy.
Successive pandemic waves with more virulent strains, and the effects of vaccination for SARS-CoV-2
Authors: Castro-e-Silva Alcides , Bernardes Américo T , Gonçalves Barbosa Eduardo Augusto , Dáttilo Wesley , Ribeiro Sérvio P. 
Published: September 2021

AbstractHundred years after the flu pandemic of 1918, the world faces an outbreak of a new severe acute respiratory syndrome, caused by a novel coronavirus. With a high transmissibility, the pandemic spreads worldwide, creating a scenario of devastation in many countries. By the middle of 2021, about 3% of the world population has been infected and more than 4 million people have died. Different from the H1N1 pandemic, which had a deadly wave and cessed, the new disease is maintained by successive waves, mainly produced by new virus variants, and the small number of vaccinated people. In the present work, we create a version of the SIR model with spatial localization of persons, their movements, and taking into account social isolation probabilities. We discuss the effects of virus variants, and the role of vaccination rate in the pandemic dynamics. We show that, unless a global vaccination is implemented, we will have continuous waves of infections.HighlightsThe COVID-19 has infected more than 200 millions and has killed more than 4 million persons.WHO has not been successful in defining a global vaccination policy.Many epidemic scenarios arise when different countries apply different vaccination strategies.Present model can show some insights on how vaccination programs can be managed.
Protective Transfer: Maternal passive immunization with a rotavirus-neutralizing dimeric IgA protects against rotavirus disease in suckling neonates
Authors: Langel SN , Steppe JT , Chang J , Travieso T , Webster H , Otero CE , Williamson LE , Crowe JE , Greenberg HB , Wu H , Hornik C , Mansouri K , Edwards RJ , Stalls V , Acharya P , Blasi M , Permar SR 
Published: September 2021

SUMMARYBreast milk secretory IgA antibodies provide a first line of defense against enteric infections. Despite this and an effective vaccine, human rotaviruses (RVs) remain the leading cause of severe infectious diarrhea in children in low- and middle-income countries (LMIC) where vaccine efficacy is lower than that of developed nations. Therapeutic strategies that deliver potently neutralizing antibodies into milk could provide protection against enteric pathogens such as RVs. We developed a murine model of maternal protective-transfer using systemic administration of a dimeric IgA (dIgA) monoclonal antibody. We confirmed that systemically-administered dIgA passively transferred into milk and stomach of suckling pups in a dose-dependent manner. We then demonstrated that systemic administration of an engineered potent RV-neutralizing dIgA (mAb41) in lactating dams protected suckling pups from RV-induced diarrhea. This maternal protective-transfer immunization platform could be an effective strategy to improve infant mortality against enteric infections, particularly in LMIC with high rates of breastfeeding.GRAPHICAL ABSTRACT
Multi-modal profiling of the extracellular matrix of human fallopian tubes and serous tubal Intraepithelial carcinomas
Authors: Renner Carine , Gomez Clarissa , Visetsouk Mike R , Taha Isra , Khan Aisha , McGregor Stephanie , Weisman Paul , Naba Alexandra , Masters Kristyn S , Kreeger Pamela K 
Published: September 2021

ABSTRACTRecent evidence supports the fimbriae of the fallopian tube as a potential origin site for high-grade serous ovarian cancer (HGSOC). The progression of many solid tumors is accompanied by changes in the microenvironment, including alterations of the extracellular matrix (ECM). The ECM of fallopian tube and HGSOC has not been well characterized. Therefore, we sought to determine the ECM composition of the benign fallopian tube and how it changes with the onset of serous intraepithelial carcinomas (STICs), precursor of HGSOC. The ECM composition of benign human fallopian tube was first defined from a meta-analysis of published proteomic datasets and identified 190 ECM proteins. We then conducted de novo proteomics using ECM enrichment and identified 88 proteins, 7 of which were not identified in prior studies. We further investigated the levels and localization of seven of these ECM proteins (type I, III, and IV collagens, fibronectin, laminin, versican, perlecan) and hyaluronic acid using multi-spectral immunohistochemical staining of fimbriae from patients with benign conditions or STICs. Quantification revealed an increase in stromal fibronectin and a decrease in epithelial versican in STICs. Our results provide an in-depth picture of the ECM in the benign fallopian tube and identified ECM changes that accompany STIC formation.
Functional Analysis of the Expanded Phosphodiesterase Gene Family in Toxoplasma gondii Tachyzoites
Authors: Moss William J. , Patterson Caitlyn E. , Jochmans Alexander K. , Brown Kevin M. 
Published: September 2021

AbstractToxoplasma motility is both activated and suppressed by 3’-5’ cyclic nucleotide signaling. Cyclic GMP (cGMP) signaling through TgPKG activates motility, whereas cyclic AMP (cAMP) signaling through TgPKAc1 inhibits motility. Despite their importance, it remains unclear how cGMP and cAMP levels are maintained in Toxoplasma. Phosphodiesterases (PDEs) are known to inactivate cyclic nucleotides and are highly expanded in the Toxoplasma genome. Here we analyzed the expression and function of the 18-member TgPDE family in tachyzoites, the virulent life-stage of Toxoplasma. We detected the expression of 11 of 18 TgPDEs, confirming prior expression studies. A knockdown screen of the TgPDE family revealed four TgPDEs that contribute to lytic Toxoplasma growth (TgPDE1, TgPDE2, TgPDE5, and TgPDE9). Depletion of TgPDE1 or TgPDE2 caused severe growth defects, prompting further investigation. While TgPDE1 was important for extracellular motility, TgPDE2 was important for host cell invasion, parasite replication, host cell egress, and extracellular motility. TgPDE1 displayed a plasma membrane/cytomembranous distribution, whereas TgPDE2 displayed an endoplasmic reticulum/cytomembranous distribution. Biochemical analysis of TgPDE1 and TgPDE2 purified from Toxoplasma lysates revealed that TgPDE1 hydrolyzes both cGMP and cAMP, whereas TgPDE2 was cAMP-specific. Interactome studies of TgPDE1 and TgPDE2 indicated that they do not physically interact with each other or other TgPDEs but may be regulated by kinases and proteases. Our studies have identified TgPDE1 and TgPDE2 as central regulators of tachyzoite cyclic nucleotide levels and enable future studies aimed at determining how these enzymes are regulated and cooperate to control Toxoplasma motility and growth.ImportanceApicomplexan parasites require motility to actively infect host cells and cause disease. Cyclic nucleotide signaling governs apicomplexan motility, but it is unclear how cyclic nucleotide levels are maintained in these parasites. In search of novel regulators of cyclic nucleotides in the model apicomplexan Toxoplasma, we identified and characterized two catalytically active phosphodiesterases, TgPDE1 and TgPDE2, that are important for Toxoplasma’s virulent tachyzoite lifecycle. Enzymes that generate, sense, or degrade cyclic nucleotides make attractive targets for therapies aimed at paralyzing and killing apicomplexan parasites.
Carbapenem-Resistant Acinetobacter baumannii in US hospitals: diversification of circulating lineages and antimicrobial resistance
Authors: Iovleva Alina , Mustapha Mustapha M. , Griffith Marissa P. , Komarow Lauren , Luterbach Courtney , Evans Daniel R , Cober Eric , Richter Sandra S. , Rydell Kirsten , Arias Cesar A. , Jacob Jesse T. , Salata Robert A. , Satlin Michael J. , Wong Darren , Bonomo Robert A. , van Duin David , Cooper Vaughn S. , Van Tyne Daria , Doi Yohei 
Published: September 2021

AbstractCarbapenem-resistant Acinetobacter baumannii (CRAb) are a major cause of healthcare-associated infections. CRAb are typically multidrug-resistant and infection is difficult to treat. Despite the urgent threat that CRAb pose, few systematic studies of CRAb clinical and molecular epidemiology have been conducted. The Study Network of Acinetobacter as a Carbapenem-Resistant Pathogen (SNAP) is designed to investigate the clinical characteristics and contemporary population structure of CRAb circulating in US hospital systems using whole genome sequencing (WGS). Analysis of the initial 120 SNAP patients from four US centers revealed that CRAb remain a significant threat to hospitalized patients, affecting the most vulnerable patients and resulting in 24% all-cause 30-day mortality. The majority of currently circulating isolates belonged to ST2Pas, a part of Clonal Complex 2 (CC2), which is the dominant drug-resistant lineage in the United States and Europe. We identified three distinct sub-lineages within CC2, which differed in their antibiotic resistance phenotypes and geographic distribution. Most concerning, colistin resistance (38%) and cefiderocol (10%) resistance were common within CC2 sub-lineage C (CC2C), where the majority of isolates belonged to ST2Pas/ST281Ox. Additionally, we identified a newly emergent lineage, ST499Pas that was the most common non-CC2 lineage in our study and had a more favorable drug susceptibility profile compared to CC2. Our findings suggest a shift within the CRAb population in the US during the past 10 years, and emphasize the importance of real-time surveillance and molecular epidemiology in studying CRAb dissemination and clinical impact.ImportanceCarbapenem-resistant Acinetobacter baumannii (CRAb) constitute a major threat to public health. To elucidate the molecular and clinical epidemiology of CRAb in the US, clinical CRAb isolates were collected along with data on patient characteristics and outcomes and bacterial isolates underwent whole genome sequencing and antibiotic susceptibility phenotyping. Key findings included emergence of new sub-lineages within the globally predominant clonal complex (CC) 2, increased colistin and cefiderocol resistance within one of the CC2 sub-lineages, and the emergence of ST499Pas as a previously unrecognized CRAb lineage in US hospitals.
Nationally Representative Social Contact Patterns among U.S. adults, August 2020-April 2021
Authors: Nelson Kristin N. , Siegler Aaron J , Sullivan Patrick S , Bradley Heather , Hall Eric , Luisi Nicole , Hipp-Ramsey Palmer , Sanchez Travis , Shioda Kayoko , Lopman Benjamin A 
Published: September 2021

AbstractThe response to the COVID-19 pandemic in the U.S prompted abrupt and dramatic changes to social contact patterns. Monitoring changing social behavior is essential to provide reliable input data for mechanistic models of infectious disease, which have been increasingly used to support public health policy to mitigate the impacts of the pandemic. While some studies have reported on changing contact patterns throughout the pandemic., few have reported on differences in contact patterns among key demographic groups and none have reported nationally representative estimates. We conducted a national probability survey of US households and collected information on social contact patterns during two time periods: August-December 2020 (before widespread vaccine availability) and March-April 2021 (during national vaccine rollout). Overall, contact rates in Spring 2021 were similar to those in Fall 2020, with most contacts reported at work. Persons identifying as non-White, non-Black, non-Asian, and non-Hispanic reported high numbers of contacts relative to other racial and ethnic groups. Contact rates were highest in those reporting occupations in retail, hospitality and food service, and transportation. Those testing positive for SARS-CoV-2 antibodies reported a higher number of daily contacts than those who were seronegative. Our findings provide evidence for differences in social behavior among demographic groups, highlighting the profound disparities that have become the hallmark of the COVID-19 pandemic.
Experimental reproducibility limits the correlation between mRNA and protein abundances in tumour proteomic profiles
Authors: Upadhya Swathi Ramachandra , Ryan Colm J. 
Published: September 2021

AbstractLarge-scale studies of human proteomes have revealed only a moderate correlation between mRNA and protein abundances. It is unclear to what extent this moderate correlation reflects post-transcriptional regulation and to what extent it reflects measurement error. Here, by analysing replicate profiles of tumours and cell lines, we show that there is considerable variation in the reproducibility of measurements of transcripts and proteins from individual genes. Proteins with more reproducible measurements tend to have higher mRNA-protein correlation, suggesting that measurement reproducibility accounts for a substantial fraction of the unexplained variation between mRNA and protein abundances. The reproducibility of individual proteins is somewhat consistent across studies and we exploit this to develop an aggregate reproducibility score that explains a substantial amount of the variation in mRNA-protein correlation across multiple studies. Finally, we show that pathways previously reported to have higher-than-average mRNA-protein correlation may simply contain members that can be more reproducibly quantified.
A science friction story – Molecular interactions in semiflexible polymer networks
Authors: Mollenkopf Paul , Prascevic Dusan , Glaser Martin , Smith David M. , Schnauß Jörg 
Published: September 2021

AbstractEstablished model theories, developed to capture the mechanical behavior of soft complex materials composed of semiflexible polymers assume entropic interactions between filaments to determine the mechanical response. In recent studies, the general accepted tube model has been challenged in terms of its basic assumption about filament-filament interactions, but also because of its predictions regarding the frequency dependence of the elastic modulus in the intermediate frequency regime. A central question is how molecular interactions and friction between network constituents influence the rheological response of isotropic entangled networks of semiflexible polymers. It was shown that friction forces between aligned pairs of actin filaments are not negligible. Here, we systematically investigate the influence of friction forces and attractive interactions on network rheology by means of a targeted surface modification. We show that these forces have a qualitative and quantitative influence on the viscoelastic properties of semiflexible polymer networks and contribute to the response to nonlinear deformations. By comparing two polymer model systems with respect to their surface compositions we give a possible explanation about the origin of acting forces on a molecular level.
Hsp40 Affinity to Identify Proteins Destabilized by Cellular Toxicant Exposure
Authors: Quanrud Guy M. , Montoya Maureen R. , Mei Liangyong , Awad Mohammad R. , Genereux Joseph C. 
Published: September 2021

AbstractEnvironmental toxins and toxicants can damage proteins and threaten cellular proteostasis. Most current methodologies to identify misfolded proteins in cells survey the entire proteome for sites of changed reactivity. We describe and apply a quantitative proteomics methodology to identify destabilized proteins based on their binding to the human Hsp40 chaperone DNAJB8. These protein targets are validated by an orthogonal limited proteolysis assay using parallel reaction monitoring. We find that brief exposure of HEK293T cells to meta-arsenite increases the affinity of two dozen proteins to DNAJB8, including known arsenite-sensitive proteins. In particular, arsenite treatment destabilizes both the pyruvate dehydrogenase complex E1 subunit and several RNA-binding proteins. This platform can be used to explore how environmental toxins impact cellular proteostasis, and to identify the susceptible proteome.
Swine H1N1 influenza virus variants with enhanced polymerase activity and HA stability promote airborne transmission in ferrets
Authors: Hu Meng , Jones Jeremy C. , Banoth Balaji , Ojha Chet Raj , Crumpton Jeri Carol , Kercher Lisa , Webster Robert G. , Webby Richard J. , Russell Charles J. 
Published: September 2021

ABSTRACTUnderstanding how animal influenza A viruses (IAVs) acquire airborne transmissibility in humans and ferrets is needed to prepare for and respond to pandemics. Here, we investigated in ferrets the replication and transmission of swine H1N1 isolates P4 and G15, whose majority population had decreased polymerase activity and poor HA stability, respectively. For both isolates, a minor variant was selected and transmitted in ferrets. Polymerase-enhancing variant PA-S321 airborne-transmitted and propagated in one ferret. HA-stabilizing variant HA1-S210 was selected in all G15-inoculated ferrets and was transmitted by contact and airborne routes. With an efficient polymerase and a stable HA, the purified minor variant G15-HA1-S210 had earlier and higher peak titers in inoculated ferrets and was recovered at a higher frequency after airborne transmission than P4 and G15. Overall, HA stabilization played a more prominent role than polymerase enhancement in the replication and transmission of these viruses in ferrets. The results suggest pandemic risk-assessment studies may benefit from deep sequencing to identify minor variants with human-adapted traits.IMPORTANCEDiverse IAVs circulate in animals, yet few acquire the viral traits needed to start a human pandemic. A stabilized HA and mammalian-adapted polymerase have been shown to promote the adaptation of IAVs to humans and ferrets (the gold-standard model for IAV replication, pathogenicity, and transmissibility). Here, we used swine IAV isolates of the gamma lineage a model to investigate the importance of HA stability and polymerase activity in promoting replication and transmission in ferrets. These are emerging viruses that bind to both α-2,6- and α-2,3-linked receptors. Using isolates containing mixed populations, a stabilized HA was selected within days in inoculated ferrets. An enhanced polymerase was also selected and propagated after airborne transmission to a ferret. Thus, HA stabilization was a stricter requirement, yet both traits promoted transmissibility. Knowing the viral traits needed for pandemic potential, and the relative importance of each, will help identify emerging viruses of greatest concern.