bluuebunny/crossref_metadata_2025_split huggingface dataset:
Talaromyces marneffei suppresses human macrophages inflammatory by producing the truncated protein NCOR2-013 via TUT1-regulated alternative splicing
Authors: Wei Wudi , Wang Gang , Zhang Hong , Bao Xiuli , An Sanqi , Luo Qiang , He Jinhao , Chen Lixiang , Liu Yuxuan , Ning Chuanyi , Lai Jingzhen , Yuan Zongxiang , Chen Rongfeng , Jiang Junjun , Ye Li , Liang Hao 
Published: July 2022

ABSTRACTTalaromyces marneffei (T. marneffei) immune-escaping is an important factor for high mortality of talaromycosis. It is currently known that T. marneffei performs these functions through a variety of strategies, however, the role of alternative splicing (AS) in this process is poorly understood. Here we depicted the AS landscape in the macrophage upon T. marneffei infection via high-throughput RNA sequencing. Moreover, we identified a truncated protein of NCOR2/SMRT, namedly NCOR2-013, was significantly upregulated upon T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1/TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Also, we identified TUT1 as the AS regulator that involved in facilitating T. marneffei immune evasion via regulation of NCOR2-013 production. Collectively, the findings indicate that T. marneffei escapes macrophages killing through the TUT1-mediated the alternative splicing of NCOR2-013, which providing a new insight into the molecular mechanisms of T. marneffei immune evasion, and a potential targets for talaromycosis therapy.
Conditional forest models built using metagenomic data could accurately predictSalmonellacontamination in Northeastern streams
Authors: Chung Taejung , Yan Runan , Weller Daniel L. , Kovac Jasna 
Published: July 2022

ABSTRACTThe use of water contaminated withSalmonellafor produce production contributes to foodborne disease burden. To reduce human health risks, there is a need for novel, targeted approaches for assessing the pathogen status of agricultural water. We investigated the utility of water microbiome data for predictingSalmonellacontamination of streams used to source water for produce production. Grab samples were collected from 60 New York streams in 2018 and tested forSalmonella. Separately, DNA was extracted from the samples and used for Illumina shotgun metagenomic sequencing. Reads were trimmed and used to assign taxonomy with Kraken2. Conditional forest (CF), regularized random forest (RRF), and support vector machine (SVM) models were implemented to predictSalmonellacontamination. Model performance was determined using 10-fold cross-validation repeated 10 times to quantify area under the curve (AUC) and Kappa score. Taxa identified as the most informative for accurately predictingSalmonellacontamination based on conditional variable importance were compared to taxa identified by ALDEx2 as being differentially abundant betweenSalmonella-positive and - negative samples. CF models outperformed the other two algorithms based on AUC (0.82 - CF, 0.76 - RRF, 0.67 - SVM) and Kappa score (0.41- CF, 0.38 - RRF, 0.19 - SVM). CF and differential abundance tests both identifiedAeromonas(VI = 0.32) andTabrizicola(VI = 0.12) as the two most informative taxa for predictingSalmonellacontamination. The taxa identified in this study warrant further investigation as indicators ofSalmonellacontamination in Northeastern freshwater streams.IMPORTANCEUnderstanding the associations between surface water microbiome composition and the presence of foodborne pathogens, such asSalmonella, can facilitate the identification of novel indicators ofSalmonellacontamination. This study assessed the utility of microbiome data and three machine learning algorithms for predictingSalmonellacontamination of Northeastern streams. The research reported here both expanded the knowledge on the microbiome composition of surface waters and identified putative novel indicators (i.e.,AeromonasandTabrizicola) forSalmonellain Northeastern streams. These putative indicators warrant further research to assess whether they are consistent indicators ofSalmonellafor regions, waterways, and years not represented in the dataset used in this study.
Natural Variation in Diauxic Shift between Patagonian Saccharomyces eubayanus Strains
Authors: Molinet Jennifer , Eizaguirre Juan I. , Quintrel Pablo , Bellora Nicolás , Villarroel Carlos A. , Villarreal Pablo , Benavides-Parra José , Nespolo Roberto F. , Libkind Diego , Cubillos Francisco A. 
Published: July 2022

AbstractThe study of natural variation can untap novel alleles with immense value for biotechnological applications. Saccharomyces eubayanus Patagonian isolates exhibit differences in the diauxic shift between glucose and maltose, representing a suitable model to study their natural genetic variation for novel strains for brewing. However, little is known about the genetic variants and chromatin regulators responsible for these differences. Here, we show how genome-wide chromatin accessibility and gene expression differences underlie distinct diauxic shift profiles in S. eubayanus. We identified two strains with a rapid diauxic shift between glucose and maltose (CL467.1 and CBS12357) and one strain with a remarkably low fermentation efficiency and longer lag phase during diauxic shift (QC18). This is associated in the QC18 strain to lower transcriptional activity and chromatin accessibility of specific genes of maltose metabolism, and higher expression levels of glucose transporters. These differences are governed by the HAP complex, which differentially regulates gene expression depending on the genetic background. We found in the QC18 strain a contrasting phenotype to those described in S. cerevisiae, where hap411, hap511 and cin511 knockouts significantly improved the QC18 growth rate in the glucose-maltose shift. The most profound effects were found between CIN5 allelic variants, suggesting that Cin5p could strongly activate a repressor of the diauxic shift in the QC18 strain, but not necessarily in the other strains. The differences between strains could originate from the tree host from which the strains were obtained, which might determine the sugar source preference and the brewing potential of the strain.ImportanceThe diauxic shift has been studied in the budding yeast under laboratory conditions, however, few studies have addressed the diauxic shift between carbon sources under fermentative conditions. Here, we study the transcriptional and chromatin structure differences that explain the natural variation in fermentative capacity and efficiency during diauxic shift of natural isolates of S. eubayanus. Our results show how natural genetic variants in transcription factors impact sugar consumption preferences between strains. These variants have different effects depending on the genetic background, with a contrasting phenotype to those previously described in S. cerevisiae. Our study shows how relatively simple genetic/molecular modifications/editing in the lab can facilitate the study of natural variation of microorganisms for the brewing industry.
Spatio-temporal estimates of HIV risk group proportions for adolescent girls and young women across 13 priority countries in sub-Saharan Africa
Authors: Howes Adam , Risher Kathryn A. , Kính Nguyen Van , Stevens Oliver , Jia Katherine M. , Wolock Timothy M. , Esra Rachel T. , Zembe Lycias , Wanyeki Ian , Mahy Mary , Benedikt Clemens , Flaxman Seth R. , Eaton Jeffrey W. 
Published: July 2022

AbstractThe Global AIDS Strategy 2021-2026 identifies adolescent girls and young women (AGYW) as a priority population for HIV prevention, and recommends differentiating intervention portfolios geographically based on local HIV incidence and individual risk behaviours. We estimated prevalence of HIV risk behaviours and associated HIV incidence at health district level among AGYW living in 13 countries in sub-Saharan Africa. We analysed 46 geospatially-referenced national household surveys conducted between 1999-2018 across 13 high HIV burden countries in sub-Saharan Africa. Female survey respondents aged 15-29 years were classified into four risk groups (not sexually active, cohabiting, non-regular or multiple partner[s] and female sex workers [FSW]) based on reported sexual behaviour. We used a Bayesian spatio-temporal multinomial regression model to estimate the proportion of AGYW in each risk group stratified by district, year, and five-year age group. Using subnational estimates of HIV prevalence and incidence produced by countries with support from UNAIDS, we estimated new HIV infections in each risk group by district and age group. We then assessed the efficiency of prioritising interventions according to risk group. Data consisted of 274,970 female survey respondents aged 15-29. Among women aged 20-29, cohabiting (63.1%) was more common in eastern Africa than non-regular or multiple partner(s) (21.3%), while in southern countries non-regular or multiple partner(s) (58.9%) were more common than cohabiting (23.4%). Risk group proportions varied substantially across age groups (65.9% of total variation explained), countries (20.9%), and between districts within each country (11.3%), but changed little over time (0.9%). Prioritisation based on behavioural risk, in combination with location- and age-based prioritisation, reduced the proportion of population required to be reached in order to find half of all expected new infections from 19.4% to 10.6%. FSW were 1.3% of the population but 10.6% of all expected new infections. Our risk group estimates provide data for HIV programmes to set targets and implement differentiated prevention strategies outlined in the Global AIDS Strategy. Successfully implementing this approach would result in more efficiently reaching substantially more of those at risk for infections.
Efficient Tracing of the SARS-CoV-2 Omicron Variants in Santa Barbara County Using a Rapid Quantitative Reverse Transcription PCR Assay
Authors: Aralis Zach , Comer Stewart , Ansorg Henning , Palmer Carl , Smith Jennifer , Feinstein Stu , Fitzgibbons Lynn N. , Arias Carolina 
Published: July 2022

AbstractThe recent emergence of the SARS-CoV-2 Omicron variant is associated with a dramatic surge of cases around the globe in late 2021 and early 2022. The numerous mutations in this variant, particularly in the Spike protein, enhance its transmission, increase immune evasion, and limit treatment with monoclonal antibodies. Identifying a community’s introduction to a novel SARS-CoV-2 variant with new clinical features related to treatment options and infection control needs is imperative to inform decisions by clinicians and public health officials, and traditional sequencing techniques often take weeks to result. Here, we describe a quantitative reverse transcription PCR assay (RT-qPCR) to accurately and precisely detect the presence of the Omicron sublineages BA.1/BA1.1 and BA.2 viral RNA from patient samples in less than four hours. The assay uses primers targeting the BA.1/BA1.1 unique mutations N211del, L212I, and L214 insertion EPE in the Spike protein gene, and the BA.2 specific mutations T19I and L24/P25/P26 deletion in the Spike protein gene. Using this assay, we detected 169 cases of Omicron, 164 BA.1/BA1.1 and 5 BA.2, from 270 residual SARS-CoV-2 positive samples collected for diagnostic purposes from Santa Barbara County (SBC) between December 2021 to February 2022. The RT-qPCR results show concordance with whole viral genome sequencing. Our observations indicate that Omicron was the dominant variant in SB County and is likely responsible for the surge of cases in the area during the sampling period. Using this inexpensive and accurate test, the rapid detection of Omicron in patient samples allowed clinicians to modify treatment strategies and public health officers to enhance contact tracing strategies. This RT-qPCR assay offers an alternative to current variant-specific detection approaches, provides a template for the fast design of similar assays, and allows the rapid, accurate, and inexpensive detection of Omicron variants in patient samples. It can also be readily adapted to new variants as they emerge in the future.
APOEε4 carriership associates with microglial activation independently of Aβ plaques and tau tangles
Authors: Ferrari-Souza João Pedro , Lussier Firoza Z. , Leffa Douglas T. , Therriault Joseph , Tissot Cécile , Bellaver Bruna , Lukasewicz Ferreira Pâmela C. , Malpetti Maura , Wang Yi-Ting , Povala Guilherme , Benedet Andréa L. , Ashton Nicholas J. , Chamoun Mira , Servaes Stijn , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Poltronetti Nina Margherita , O’Brien John T. , Rowe James B. , Cohen Ann D. , Lopez Oscar L. , Tudorascu Dana L. , Karikari Thomas K. , Klunk William E. , Villemagne Victor L. , Soucy Jean-Paul , Gauthier Serge , Souza Diogo O. , Zetterberg Henrik , Blennow Kaj , Zimmer Eduardo R. , Rosa-Neto Pedro , Pascoal Tharick A. 
Published: July 2022

AbstractMicroglial activation is an early phenomenon in Alzheimer’s disease (AD) that may occur prior to and independently of amyloid-β (Aβ) aggregation. Recent studies in transgenic animal models suggest that the apolipoprotein E ε4 (APOEε4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOEε4 genotype is associated with microglial reactivity in the living human brain. Here, we tested whether APOEε4 carriership is associated with microglial activation in individuals across the aging and AD spectrum. We studied 118 individuals who had positron emission tomography (PET) for Aβ ([18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28), as well as clinical, genetic, and magnetic resonance imaging data. We found that APOEε4 carriership was associated with increased microglial activation mainly in early Braak-staging regions within the medial temporal cortex, and this effect of APOEε4 was independent of Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on downstream tau accumulation, neurodegeneration, and clinical impairment. Interestingly, the physiological distribution of APOE mRNA expression, obtained from the Allen Human Atlas, predicted the patterns of APOEε4-related microglial activation in our population, suggesting that the deleterious effects of APOEε4 occur at the level of gene expression. These results support a model in which the APOEε4 has Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition. Our findings provide a rationale for the development of novel AD therapies targeting the interplay between ApoE and neuroinflammation.
Urban pandemic response: survey results describing the experiences from twenty-five cities during the COVID-19 pandemic
Authors: Boyce Matthew R , Asprilla Melissa Cordoba , van Loenen Breanna , McClelland Amanda , Rojhani Ariella 
Published: July 2022

AbstractSince first being detected in Wuhan, China in late December 2019, the COVID-19 pandemic has demanded a response from all levels of government. While the role of local governments in routine public health functions is well understood, and the response to the pandemic has highlighted the importance of involving local governments in the response to and management of large, multifaceted challenges, their role in pandemic response remains more opaque. Accordingly, to better understand how local governments in cities were involved in the response to the COVID-19 pandemic, we conducted a survey involving cities in the Partnership for Healthy Cities to: (i) understand which levels of government were responsible, accountable, consulted, and informed regarding select pandemic response activities; (ii) document when response activities were implemented; (iii) characterize how challenging response activities were; and (iv) query about future engagement in pandemic and epidemic preparedness. Twenty-five cities from around the world completed the survey and we used descriptive statistics to summarize the urban experience in pandemic response. Our results show that national authorities were responsible and accountable for a majority of the activities considered, but that local governments were also responsible and accountable for key activities – especially risk communication and coordinating with community-based organizations and civil society organizations. Further, most response activities were implemented after COVID-19 had been confirmed in a city, many pandemic response activities proved to be challenging for local authorities, and nearly all local authorities envisioned being more engaged in pandemic preparedness and response following the COVID-19 pandemic. This descriptive research represents an important contribution to an expanding evidence base focused on improving the response to the ongoing COVID-19 pandemic, as well as future outbreaks.
Selective Regulation of Tuft Cell-Like Small Cell Lung Cancer by Novel Transcriptional Co-activators C11orf53 and COLCA2
Authors: Zhou Chen , Huang Hui , Wang Yunyi , Sendinc Erdem , Shi Yang 
Published: July 2022

AbstractThe DepMap project has generated a huge resource for investigating selectively essential genes, which represent potential cancer therapeutic targets. However, manually sorting out which of the hundreds of selectively essential genes is understudied and warrants investigations is time-consuming and probably not practical. To efficiently identify uncharacterized, selectively essential genes, we collected and ranked the 347 selectively essential genes from the DepMap dataset by their PubMed publication counts, based on the assumption that genes with low publication counts are un-studied or under-studied. We successfully validated two of the top candidates in our ranking system, C11orf53 and COLCA2, as new vulnerabilities that are selectively essential in the class II POU domain transcription factor POU2F3-dependent tuft cell-like small cell lung cancer (SCLC) cell lines. Importantly, we found that the sequence motif, which mediates physical interactions of the transcriptional co-activator POU2AF1 with two of the class II POU domain-containing family of transcription factors (POU2F1 and POU2F2), is also present in the N-terminal regions of C11orf53 and COLCA2. We further confirmed that 1) COLCA2 physically interacts with POU2F3 through this conserved sequence motif; 2) this interaction is important for COLCA2 to regulate tuft cell-like SCLC cell growth, and 3) both C11orf53 and COLCA2 contain transcriptional co-activator domains. Consistently, we find similar transcriptomic changes in response to the loss of COLCA2 or POU2F3 in SCLC cells. In summary, our analysis pipeline enables identification and prioritization of understudied but important, selectively essential genes, leading to the identification of two new transcriptional co-activators for the class II POU domain transcription factors. Disruption of this important physical interaction is predicted to be a potential therapeutic strategy to selectively inhibit tuft cell-like SCLCs.
Heterogeneity of RNA editing in mesothelioma and how RNA editing enzyme ADAR2 affects mesothelioma cell growth, response to chemotherapy and tumor microenvironment
Authors: Hariharan Ananya , Qi Weihong , Rehrauer Hubert , Wu Licun , Ronner Manuel , Wipplinger Martin , Kresoja-Rakic Jelena , Sun Suna , Oton-Gonzalez Lucia , Sculco Marika , Serre-Beinier Véronique , Meiller Clément , Blanquart Christophe , Fonteneau Jean-François , Vrugt Bart , Rüschoff Jan Hendrik , Opitz Isabelle , Jean Didier , de Perrot Marc , Felley-Bosco Emanuela 
Published: July 2022

AbstractWe previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. Tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3’UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.
A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis
Authors: Wang Yuqing , Zhu Duolong , Ortiz-Velez Laura C. , Perry J. Lance , Pennington Michael W. , Hyser Joseph M. , Britton Robert A. , Beeton Christine 
Published: July 2022

AbstractEngineered microbes for the delivery of biologics is a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers the small molecular biologic to the intestinal tract with high efficacy and minimized side effects. We constructed an inducible system in the probiotic Lactobacillus reuteri to secret functional Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 is capable of blocking Kv1.3 currents and preferentially inhibiting human T effector memory (TEM) cells proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in adequate functional ShK-235 in the circulation to reduce inflammation in a delayed-type hypersensitivity model of atopic dermatitis mediated by TEM cells. Furthermore, the daily oral gavage of LrS235 dramatically reduced clinical signs of disease and joint inflammation in rats with a model of rheumatoid arthritis without eliciting immunogenicity against ShK-235. This work demonstrates the efficacy of using probiotic L. reuteri as a novel oral delivery platform for the small molecule ShK-235, and provides a efficacious strategy to deliver other biologics with great translational potential.Significance StatementNew therapeutics that combine efficacy with limited side effects and can be delivered non-invasively are needed to adequately treat patients with rheumatoid arthritis (RA) and other autoimmune diseases. Kv1.3 channel-expressing CCR7- effector memory T (TEM) lymphocytes are significant players in the pathogenesis of multiple autoimmune diseases and blocking Kv1.3 reduces disease severity in rat models of RA and patients with plaque psoriasis. However, peptide therapeutics require repeated injections, reducing patient compliance. We used a bioengineered Lactobacillus reuteri as an oral delivery method of a Kv1.3 blocker for immunomodulation in rat models of atopic dermatitis and RA. This study demonstrates a novel approach for the non-invasive delivery of peptide-based therapeutics for the oral treatment of chronic inflammatory diseases.