bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of the CIC-DUX4 fusion oncoprotein mimics human CIC-rearranged sarcoma in genetically engineered mouse models
Authors: Hendrickson Peter G. , Oristian Kristianne M. , Browne MaKenna R. , Lou Lixia , Ma Yan , Cardona Dianna M. , Linardic Corinne M. , Kirsch David G. 
Published: September 2023

AbstractCIC-DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of tissues and patients. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous tumors and widespread metastasis in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic CIC function and loxP site proximity. Characterization of primary and metastatic mouse tumors showed that they consistently expressed the CIC-DUX4 fusion protein as well as other downstream markers of the disease credentialing these models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-seq maps, validate CIC-DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS.
Physiologic Doses of TGF-β Improve the Composition of Engineered Articular Cartilage
Authors: Wang Tianbai , Dogru Sedat , Dai Zhonghao , Kim Sung Yeon , Vickers Nicholas A. , Albro Michael B. 
Published: September 2023

AbstractFor cartilage regeneration applications, transforming growth factor beta (TGF-β) is conventionally administered at highly supraphysiologic doses (10-10,000 ng/mL) in an attempt to cue cells to fabricate neocartilage that matches the composition, structure, and functional properties of native hyaline cartilage. While supraphysiologic doses enhance ECM biosynthesis, they are also associated with inducing detrimental tissue features, such as fibrocartilage matrix deposition, pathologic-like chondrocyte clustering, and tissue swelling. Here we investigate the hypothesis that moderated TGF-β doses (0.1-1 ng/mL), akin to those present during physiological cartilage development, can improve neocartilage composition. Variable doses of media-supplemented TGF-β were administered to a model system of reduced-size cylindrical constructs (Ø2-Ø3 mm), which mitigate the TGF-β spatial gradients observed in conventional-size constructs (Ø4-Ø6 mm), allowing for a novel assessment of the intrinsic effect of TGF-β doses on macroscale neocartilage properties and composition. The administration of physiologic TGF-β to reduced-size constructs yields neocartilage with native-matched sGAG content and mechanical properties while providing a more hyaline cartilage-like composition, marked by: 1) reduced fibrocartilage-associated type I collagen, 2) 77% reduction in the fraction of cells present in a clustered morphology, and 3) 45% reduction in the degree of tissue swelling. Physiologic TGF-β appears to achieve an important balance of promoting requisite ECM biosynthesis, while mitigating hyaline cartilage compositional deficits. These results can guide the development of novel physiologic TGF-β-delivering scaffolds to improve the regeneration clinical-sized neocartilage tissues.
The values of ecosystem services inside and outside of protected areas in Eastern and Southern Africa
Authors: Buschke Falko T. , Capitani Claudia 
Published: September 2023

AbstractConservation policies often take for granted the importance of protected areas for supplying ecosystem services. The 1stedition of theState of Protected and Conserved Areas in Eastern and Southern Africareport contained limited information on ecosystem services, so for the 2ndedition we compared statistically 561 standardised economic values of various types of ecosystem services inside and outside of protected areas. We found that data from local and sub-national case-studies in the Ecosystem Service Valuation Database were biased geographically, highlighting major evidence gaps for most of the region. For well-studied countries (Botswana, Ethiopia, Kenya, South Africa, Tanzania, Uganda), the value of ecosystem services varied considerably across different types of services but were – on average – three to six times higher outside protected areas. This trend was not universal, however, given that opportunities for recreation and tourism tended to be higher within protected areas. Combined, these findings suggest that conservation authorities across Eastern and Southern Africa (1) prioritise ecosystem service valuation studies; (2) expand the focus of ecosystem service policies to include wider landscapes beyond protected area boundaries; and (3) avoid making generic assumptions about ecosystem services by identifying which types of services are most compatible with the broader goals of protection.
Evidence of antigenic drift in the fusion machinery core of SARS-CoV-2 spike
Authors: Tan Timothy J.C. , Odle Abby , Lei Ruipeng , Matreyek Kenneth A. , Perlman Stanley , Wong Lok-Yin Roy , Wu Nicholas C. 
Published: September 2023

ABSTRACTAntigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding domain of spike protein. In contrast, whether antigenic drift occurs in the S2 domain remains largely elusive. Here, we perform a deep mutational scanning experiment to identify S2 mutations that affect binding of SARS-CoV-2 spike to three S2 apex public antibodies. Our results indicate that spatially diverse mutations, including D950N and Q954H, which are observed in Delta and Omicron variants, respectively, weaken the binding of spike to these antibodies. Although S2 apex antibodies are known to be non-neutralizing, we show that they confer partial protectionin vivo. We further demonstrate that suchin vivoprotection activity is diminished by the natural mutation D950N. Overall, this study indicates that the S2 domain of SARS-CoV-2 spike can undergo antigenic drift, which represents a potential challenge for the development of more universal coronavirus vaccines.
Best practices for perturbation MPRA—a computational evaluation framework of sequence design strategies
Authors: Liu Jiayi , Ashuach Tal , Inoue Fumitaka , Ahituv Nadav , Yosef Nir , Kreimer Anat 
Published: September 2023

ABSTRACTThe advent of the perturbation-based massively parallel reporter assays (MPRAs) technique has enabled delineating of the roles of non-coding regulatory elements in orchestrating gene expression. However, computational efforts remain scant to evaluate and establish guidelines for sequence design strategies for perturbation MPRAs. Here, we propose a framework for evaluating and comparing various perturbation strategies for MPRA experiments. Under this framework, we benchmark three different perturbation approaches from the perspectives of alteration in motif-based profiles, consistency of MPRA outputs, and robustness of models that predict the activities of putative regulatory motifs. Although our analyses show similar while significant results in multiple metrics, the method of randomly shuffling nucleotides outperform the other two methods. Thus, we still recommend designing sequences by randomly shuffling the nucleotides of the perturbed site in perturbation-MPRA. The evaluation framework, together with the benchmarking findings in our work, creates a resource of computational pipelines and illustrates the promise of perturbation-MPRA for predicting non-coding regulatory activities.
Inhibition of SARS-CoV-2 Infection in Human Airway Epithelium with a Xeno-Nucleic Acid Aptamer
Authors: Razi Niayesh , Li Weizhong , Ignacio Maxinne A. , Loube Jeffrey M. , Agostino Eva L. , Zhu Xiaoping , Scull Margaret A. , DeStefano Jeffrey J. 
Published: September 2023

AbstractBackgroundSARS-CoV-2, the agent responsible for the COVID-19 pandemic, enters cells through viral spike glycoprotein binding to the cellular receptor, angiotensin-converting enzyme 2 (ACE2). Given the lack of effective antivirals targeting SARS-CoV-2, we previously utilized systematic evolution of ligands by exponential enrichment (SELEX) and selected fluoro-arabino nucleic acid (FANA) aptamer R8-9 that was able to block the interaction between the viral receptor-binding domain and ACE2.MethodsHere, we further assessed FANA-R8-9 as an entry inhibitor in contexts that recapitulate infectionin vivo.ResultsWe demonstrate that FANA-R8-9 inhibits spike-bearing pseudovirus particle uptake in cell lines. Then, using anin-vitromodel of human airway epithelium (HAE) and SARS-CoV-2 virus, we show that FANA-R8-9 significantly reduces viral infection when added either at the time of inoculation, or several hours later. These results were specific to the R8-9 sequence, not the xeno-nucleic acid utilized to make the aptamer. Importantly, we also show that FANA-R8-9 is stable in HAE culture secretions and has no overt cytotoxic effects.ConclusionsTogether, these results suggest that FANA-R8-9 effectively prevents infection by specific SARS-CoV-2 variants and indicate that aptamer technology could be utilized to target other clinically-relevant viruses in the respiratory mucosa.
Myocardin-related transcription factors regulate morphogenetic events in vertebrate embryos by controlling F-actin organization and apical constriction
Authors: Itoh Keiji , Ossipova Olga , Matsuda Miho , Sokol Sergei Y. 
Published: September 2023

SummaryMyocardin-related transcription factors (Mrtfa and Mrtfb), also known as megakaryoblastic leukemia proteins (Mkl1/MAL and Mkl2), associate with serum response factor (Srf) to regulate transcription in response to actin dynamics, however, the functions of Mrtfs in early vertebrate embryos remain largely unknown. Here we document the requirement of Mrtfs for blastopore closure at gastrulation and neural plate folding in Xenopus early embryos. Both stimulation and inhibition of Mrtf activity caused similar gross morphological phenotypes, yet the effects on F-actin distribution and cell behavior were different. Suppressing Mrtf-dependent transcription reduced overall F-actin levels and inhibited apical constriction during gastrulation and neurulation. By contrast, constitutively active Mrtf caused tricellular junction remodeling and induced apical constriction in superficial ectoderm. The underlying mechanism appeared distinct from the one utilized by known apical constriction inducers. We propose that the regulation of apical constriction is among the primary cellular responses to Mrtf. Our findings highlight a dedicated role of specific transcription factors, Mrtfs, in early morphogenetic processes.
Neuroprotective Mechanism of Ribisin A on H2O2-induced PC12 cell injury model
Authors: Zhang Xin , Bao Mengyu , Zhang Jingyi , Zhu Lihao , Wang Di , Liu Xin , Xu Lingchuan , Luan Lijuan , Liu Yuguo , Liu Yuhong 
Published: September 2023

ABSTRACTRibisin A has been shown to have neurotrophic activity. The aim of this study was to evaluate the neuroprotective effect of Ribisin A on injured PC12 cells and elucidate its mechanism. In this project, PC12 cells were induced by H2O2to establish an injury model. After treatment with Ribisin A, the neuroprotective mechanism of Ribisin A was investigated by methyl tetrazolium (MTT) assay, Enzyme-linked immunosorbent assay (ELISA), flow cytometric analysis, fluorescent probe analysis, and western blot. We found that Ribisin A decreased the rate of lactate dehydrogenase (LDH) release, increased cellular superoxide dismutase (SOD) activity, decreased the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), Ca2+expression and reactive oxygen species (ROS). Moreover, Ribisin A significantly increased mitochondrial membrane potential (MMP) and inhibited apoptosis of PC12 cells. Meanwhile, Ribisin A activated the phosphorylation of ERK1/2 and its downstream molecule CREB by upregulating the expression of Trk A and Trk B, the upstream molecules of the ERK signaling pathway.Graphical Abstract
Altered motility in response to iron-limitation is regulated bylpdAin uropathogenicE. coliCFT073
Authors: Frick-Cheng A.E. , Shea A.E. , Roberts J.R. , Smith S.N. , Ohi M.D. , Mobley H.L.T. 
Published: September 2023

AbstractMore than half of all women will experience a urinary tract infection (UTI) in their lifetime with most cases caused by uropathogenicEscherichia coli(UPEC). Bacterial motility enhances UPEC pathogenicity, resulting in more severe disease outcomes including kidney infection. Surprisingly, the connection between motility and iron limitation is mostly unexplored, despite the lack of free iron available in the host. Therefore, we sought to explore the potential connection between iron restriction and regulation of motility in UPEC. We culturedE. coliCFT073, a prototypical UPEC strain, in media containing an iron chelator. Under iron limitation, CFT073 had elevatedfliC(flagella) promoter activity, driving motility on the leading edge of the colony. Furthermore, this iron-specific response was repressed by the addition of exogenous iron. We confirmed increased flagella expression in CFT073 by measuringfliCtranscript, FliC protein, and surface-expressed flagella under iron-limited conditions. To define the regulatory mechanism, we constructed single knockouts of eight master regulators. The iron-regulated response was lost incrp, arcA,andfismutants. Thus, we focused on the five genes regulated by all three transcription factors. Of the five genes knocked out, the iron-regulated motility response was most strongly dysregulated in anlpdAmutant, which also resulted in significantly lowered fitness in the murine model of ascending UTI. Collectively, we demonstrated that iron-mediated motility in CFT073 is regulated bylpdA, which contributes to the understanding of how uropathogens differentially regulate motility mechanisms in the iron-restricted host.ImportanceUrinary tract infections (UTIs) are ubiquitous and responsible for over five billion dollars in associated health care costs annually. Both iron acquisition and motility are highly studied virulence factors associated with uropathogenicE. coli(UPEC), the main causative agent of uncomplicated UTI. This work is innovative by providing mechanistic insight into the synergistic relationship between these two critical virulence properties. Here, we demonstrate that iron limitation has pleiotropic effects with consequences that extend beyond metabolism, and impact other virulence mechanisms. Indeed, targeting iron acquisition as a therapy may lead to an undesirable enhancement of UPEC pathogenesis through increased motility. It is vital to understand the full breadth of UPEC pathogenesis to adequately respond to this common infection, especially with the increase of antibiotic resistant pathogens.
Rare variant association analysis in 51,256 type 2 diabetes cases and 370,487 controls informs the spectrum of pathogenicity of monogenic diabetes genes
Authors: Schroeder Philip , Mandla Ravi , Huerta-Chagoya Alicia , Alkanak Ahmed , Nagy Dorka , Szczerbinski Lukasz , Madsen Jesper G.S. , Cole Joanne B. , Porneala Bianca , Westerman Kenneth , Li Josephine H. , Pollin Toni I. , Florez Jose C. , Gloyn Anna L. , Cebola Inês , Manning Alisa , Leong Aaron , Udler Miriam , Mercader Josep M. 
Published: September 2023

AbstractWe meta-analyzed array data imputed with the TOPMed reference panel and whole-genome sequence (WGS) datasets and performed the largest, rare variant (minor allele frequency as low as 5×10−5) GWAS meta-analysis of type 2 diabetes (T2D) comprising 51,256 cases and 370,487 controls.We identified 52 novel variants at genome-wide significance (p<5 × 10−8), including 8 novel variants that were either rare or ancestry-specific. Among them, we identified a rare missense variant inHNF4Ap.Arg114Trp (OR=8.2, 95% confidence interval [CI]=4.6-14.0,p= 1.08×10−13), previously reported as a variant implicated in Maturity Onset Diabetes of the Young (MODY) with incomplete penetrance. We demonstrated that the diabetes risk in carriers of this variant was modulated by a T2D common variant polygenic risk score (cvPRS) (carriers in the top PRS tertile [OR=18.3, 95%CI=7.2-46.9,p=1.2×10−9] vs carriers in the bottom PRS tertile [OR=2.6, 95% CI=0.97-7.09,p= 0.06]. Association results identified eight variants of intermediate penetrance (OR>5) in monogenic diabetes (MD), which in aggregate as a rare variant PRS were associated with T2D in an independent WGS dataset (OR=4.7, 95% CI=1.86-11.77],p= 0.001). Our data also provided support evidence for 21% of the variants reported in ClinVar in these MD genes as benign based on lack of association with T2D.Our work provides a framework for using rare variant imputation and WGS analyses in large-scale population-based association studies to identify large-effect rare variants and provide evidence for informing variant pathogenicity.
Suicide prediction with natural language processing of electronic health records
Authors: Korda Alexandra , Heide Marco , Nag Alena , Trulley Valerie-Noelle , Rogg Helena- Victoria , Avram Mihai , Eickhoff Sofia , Jauch-Chara Kamila , Wehkamp Kai , Song Xingyi , Martinetz Thomas , Conell Jörn , Roberts Angus , Stewart Robert , Andreou Christina , Borgwardt Stefan 
Published: September 2023

AbstractSuicide attempts are one of the most challenging psychiatric outcomes and have great importance in clinical practice. However, they remain difficult to detect in a standardised way to assist prevention because assessment is mostly qualitative and often subjective. As digital documentation is increasingly used in the medical field, Electronic Health Records (EHRs) have become a source of information that can be used for prevention purposes, containing codified data, structured data, and unstructured free text. This study aims to provide a quantitative approach to suicidality detection using EHRs, employing natural language processing techniques in combination with deep learning artificial intelligence methods to create an algorithm intended for use with medical documentation in German. Using psychiatric medical files from in-patient psychiatric hospitalisations between 2013 and 2021, free text reports will be transformed into structured embeddings using a German trained adaptation of Word2Vec, followed by a Long-Short Term Memory (LSTM) – Convolutional Neural Network (CNN) approach on sentences of interest. Text outside the sentences of interest will be analysed as context using a fixed size ordinally-forgetting encoding (FOFE) before combining these findings with the LSTM-CNN results in order to label suicide related content. This study will offer promising ways for automated early detection of suicide attempts and therefore holds opportunities for mental health care.
Effect of a gender-synchronized family planning intervention on inequitable gender norms in a cluster randomized control trial among husbands of married adolescent girls in Dosso, Niger
Authors: Boyce Sabrina C. , Minnis Alexandra M. , Deardorff Julianna , McCoy Sandra I. , Challa Sneha , Johns Nicole E. , Aliou Sani , Brooks Mohamad I. , Nouhou Abdoul-Moumouni , Baker Holly , Silverman Jay G. 
Published: September 2023

ABSTRACTGender inequity is pervasive globally and has severe consequences for health and well-being, particularly for women and girls in Niger. The Reaching Married Adolescents in Niger (RMA) intervention aimed to promote equitable gender norms in order to increase modern contraceptive use and reduce intimate partner violence among married adolescent girls and their husbands in Niger. Using data from a 4-arm factorial cluster randomized control trial of the RMA intervention (2016-2019), the current study assesses effects of the RMA intervention on gender norms among husbands. We used an adjusted hierarchical difference-in-differences linear regression model to assess these effects. The mean score for perceived gender inequitable norms at baseline was 4.1 (n=1,055; range: 0-5). Assignment to the RMA small groups intervention was associated with a 0.62 lower score (95% CI: −1.05, −0.18) relative to controls at follow-up, after adjusting for baseline differences. No significant effects were detected for other intervention arms. As a low-cost, simple, scalable, and transferrable intervention with rigorous evidence of being able to change such gender norms, this community health worker-based small group intervention could be valuable to the field of public health for reducing the negative impact of inequitable gender norms on health and wellbeing in similar settings.
Prevalence, clinical correlates and outcomes of cardiorenal anemia syndrome among patients with heart failure attending tertiary referral hospital in Dodoma, Tanzania: A protocol of a prospective observational study
Authors: Edwin Gidion , Alphonce Baraka , Meremo Alfred , Meda John 
Published: September 2023

ABSTRACTBackgroundCardiorenal anemia syndrome (CRAS) is a common complication among patients with heart failure and is associated with poor clinical outcomes. However, there is a paucity of published data concerning CRAS, despite of significant increase in heart failure patients attending medical services in developing countries. This study aims to assess the prevalence, clinical correlates, and outcomes of CRAS among patients with heart failure attending the Benjamin Mkapa Hospital in Dodoma, Tanzania.MethodologyA prospective observational study is ongoing at the Benjamin Mkapa Hospital in Dodoma, Tanzania. Currently, the study has enrolled 68 patients. The socio-demographic data, clinical correlates, and prevalence of CRAS will be determined at baseline meanwhile, the outcomes of CRAS will be determined during a follow-up period of six months from the date of enrollment. CRAS is the primary outcome of the study. Data will be categorized into CRAS and non-CRAS during analysis. Mean and standard deviation will be used for normally distributed continuous variables while median and interquartile range will be used for skewed data. Frequencies and percentages will summarize categorical variables. Clinical correlates and outcomes of CRAS will be analyzed and compared by using univariate and multivariate logistic regression models. A two-tailed p-value of less than 0.05 will indicate statistical significance.