bluuebunny/crossref_metadata_2025_split huggingface dataset:
LOMETS3: integrating deep learning and profile alignment for advanced protein template recognition and function annotation
Authors: Zheng Wei , Wuyun Qiqige , Zhou Xiaogen , Li Yang , Freddolino Lydia , Zhang Yang 
Published: April 2022

Abstract
Deep learning techniques have significantly advanced the field of protein structure prediction. LOMETS3 (https://zhanglab.ccmb.med.umich.edu/LOMETS/) is a new generation meta-server approach to template-based protein structure prediction and function annotation, which integrates newly developed deep learning threading methods. For the first time, we have extended LOMETS3 to handle multi-domain proteins and to construct full-length models with gradient-based optimizations. Starting from a FASTA-formatted sequence, LOMETS3 performs four steps of domain boundary prediction, domain-level template identification, full-length template/model assembly and structure-based function prediction. The output of LOMETS3 contains (i) top-ranked templates from LOMETS3 and its component threading programs, (ii) up to 5 full-length structure models constructed by L-BFGS (limited-memory Broyden–Fletcher–Goldfarb–Shanno algorithm) optimization, (iii) the 10 closest Protein Data Bank (PDB) structures to the target, (iv) structure-based functional predictions, (v) domain partition and assembly results, and (vi) the domain-level threading results, including items (i)–(iii) for each identified domain. LOMETS3 was tested in large-scale benchmarks and the blind CASP14 (14th Critical Assessment of Structure Prediction) experiment, where the overall template recognition and function prediction accuracy is significantly beyond its predecessors and other state-of-the-art threading approaches, especially for hard targets without homologous templates in the PDB. Based on the improved developments, LOMETS3 should help significantly advance the capability of broader biomedical community for template-based protein structure and function modelling.
The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes
Authors: Hertweck Arnulf , Vila de Mucha Maria , Barber Paul R , Dagil Robert , Porter Hayley , Ramos Andres , Lord Graham M , Jenner Richard G 
Published: April 2022

Abstract
Lineage-determining transcription factors (LD-TFs) drive the differentiation of progenitor cells into a specific lineage. In CD4+ T cells, T-bet dictates differentiation of the TH1 lineage, whereas GATA3 drives differentiation of the alternative TH2 lineage. However, LD-TFs, including T-bet and GATA3, are frequently co-expressed but how this affects LD-TF function is not known. By expressing T-bet and GATA3 separately or together in mouse T cells, we show that T-bet sequesters GATA3 at its target sites, thereby removing GATA3 from TH2 genes. This redistribution of GATA3 is independent of GATA3 DNA binding activity and is instead mediated by the T-bet DNA binding domain, which interacts with the GATA3 DNA binding domain and changes GATA3′s sequence binding preference. This mechanism allows T-bet to drive the TH1 gene expression program in the presence of GATA3. We propose that redistribution of one LD-TF by another may be a common mechanism that could explain how specific cell fate choices can be made even in the presence of other transcription factors driving alternative differentiation pathways.
Nuclear and cytoplasmic poly(A) binding proteins (PABPs) favor distinct transcripts and isoforms
Authors: Nicholson-Shaw Angela L , Kofman Eric R , Yeo Gene W , Pasquinelli Amy E 
Published: April 2022

AbstractThe poly(A)-tail appended to the 3′-end of most eukaryotic transcripts plays a key role in their stability, nuclear transport, and translation. These roles are largely mediated by Poly(A) Binding Proteins (PABPs) that coat poly(A)-tails and interact with various proteins involved in the biogenesis and function of RNA. While it is well-established that the nuclear PABP (PABPN) binds newly synthesized poly(A)-tails and is replaced by the cytoplasmic PABP (PABPC) on transcripts exported to the cytoplasm, the distribution of transcripts for different genes or isoforms of the same gene on these PABPs has not been investigated on a genome-wide scale. Here, we analyzed the identity, splicing status, poly(A)-tail size, and translation status of RNAs co-immunoprecipitated with endogenous PABPN or PABPC in human cells. At steady state, many protein-coding and non-coding RNAs exhibit strong bias for association with PABPN or PABPC. While PABPN-enriched transcripts more often were incompletely spliced and harbored longer poly(A)-tails and PABPC-enriched RNAs had longer half-lives and higher translation efficiency, there are curious outliers. Overall, our study reveals the landscape of RNAs bound by PABPN and PABPC, providing new details that support and advance the current understanding of the roles these proteins play in poly(A)-tail synthesis, maintenance, and function.
Exonic splicing code and protein binding sites for calcium
Authors: Pengelly Reuben J , Bakhtiar Dara , Borovská Ivana , Královičová Jana , Vořechovský Igor 
Published: April 2022

Abstract
Auxilliary splicing sequences in exons, known as enhancers (ESEs) and silencers (ESSs), have been subject to strong selection pressures at the RNA and protein level. The protein component of this splicing code is substantial, recently estimated at ∼50% of the total information within ESEs, but remains poorly understood. The ESE/ESS profiles were previously associated with the Irving-Williams (I-W) stability series for divalent metals, suggesting that the ESE/ESS evolution was shaped by metal binding sites. Here, we have examined splicing activities of exonic sequences that encode protein binding sites for Ca2+, a weak binder in the I-W affinity order. We found that predicted exon inclusion levels for the EF-hand motifs and for Ca2+-binding residues in nonEF-hand proteins were higher than for average exons. For canonical EF-hands, the increase was centred on the EF-hand chelation loop and, in particular, on Ca2+-coordinating residues, with a 1&gt;12&gt;3∼5&gt;9 hierarchy in the 12-codon loop consensus and usage bias at codons 1 and 12. The same hierarchy but a lower increase was observed for noncanonical EF-hands, except for S100 proteins. EF-hand loops preferentially accumulated exon splits in two clusters, one located in their N-terminal halves and the other around codon 12. Using splicing assays and published crosslinking and immunoprecipitation data, we identify candidate trans-acting factors that preferentially bind conserved GA-rich motifs encoding negatively charged amino acids in the loops. Together, these data provide evidence for the high capacity of codons for Ca2+-coordinating residues to be retained in mature transcripts, facilitating their exon-level expansion during eukaryotic evolution.
DEPhT: a novel approach for efficient prophage discovery and precise extraction
Authors: Gauthier Christian H , Abad Lawrence , Venbakkam Ananya K , Malnak Julia , Russell Daniel A , Hatfull Graham F 
Published: April 2022

Abstract
Advances in genome sequencing have produced hundreds of thousands of bacterial genome sequences, many of which have integrated prophages derived from temperate bacteriophages. These prophages play key roles by influencing bacterial metabolism, pathogenicity, antibiotic resistance, and defense against viral attack. However, they vary considerably even among related bacterial strains, and they are challenging to identify computationally and to extract precisely for comparative genomic analyses. Here, we describe DEPhT, a multimodal tool for prophage discovery and extraction. It has three run modes that facilitate rapid screening of large numbers of bacterial genomes, precise extraction of prophage sequences, and prophage annotation. DEPhT uses genomic architectural features that discriminate between phage and bacterial sequences for efficient prophage discovery, and targeted homology searches for precise prophage extraction. DEPhT is designed for prophage discovery in Mycobacterium genomes but can be adapted broadly to other bacteria. We deploy DEPhT to demonstrate that prophages are prevalent in Mycobacterium strains but are absent not only from the few well-characterized Mycobacterium tuberculosis strains, but also are absent from all ∼30 000 sequenced M. tuberculosis strains.
A rationalized definition of general tumor suppressor microRNAs excludes miR-34a
Authors: Mockly Sophie , Houbron Élisabeth , Seitz Hervé 
Published: April 2022

Abstract
While several microRNAs (miRNAs) have been proposed to act as tumor suppressors, a consensual definition of tumor suppressing miRNAs is still missing. Similarly to coding genes, we propose that tumor suppressor miRNAs must show evidence of genetic or epigenetic inactivation in cancers, and exhibit an anti-tumorigenic (e.g., anti-proliferative) activity under endogenous expression levels. Here we observe that this definition excludes the most extensively studied tumor suppressor candidate miRNA, miR-34a. In analyzable cancer types, miR-34a does not appear to be down-regulated in primary tumors relatively to normal adjacent tissues. Deletion of miR-34a is occasionally found in human cancers, but it does not seem to be driven by an anti-tumorigenic activity of the miRNA, since it is not observed upon smaller, miR-34a-specific alterations. Its anti-proliferative action was observed upon large, supra-physiological transfection of synthetic miR-34a in cultured cells, and our data indicates that endogenous miR-34a levels do not have such an effect. Our results therefore argue against a general tumor suppressive function for miR-34a, providing an explanation to the lack of efficiency of synthetic miR-34a administration against solid tumors.
Fragment screening and structural analyses highlight the ATP-assisted ligand binding for inhibitor discovery against type 1 methionyl-tRNA synthetase
Authors: Yi Jia , Cai Zhengjun , Qiu Haipeng , Lu Feihu , Luo Zhiteng , Chen Bingyi , Gu Qiong , Xu Jun , Zhou Huihao 
Published: April 2022

Abstract
Methionyl-tRNA synthetase (MetRS) charges tRNAMet with l-methionine (L-Met) to decode the ATG codon for protein translation, making it indispensable for all cellular lives. Many gram-positive bacteria use a type 1 MetRS (MetRS1), which is considered a promising antimicrobial drug target due to its low sequence identity with human cytosolic MetRS (HcMetRS, which belongs to MetRS2). Here, we report crystal structures of a representative MetRS1 from Staphylococcus aureus (SaMetRS) in its apo and substrate-binding forms. The connecting peptide (CP) domain of SaMetRS differs from HcMetRS in structural organization and dynamic movement. We screened 1049 chemical fragments against SaMetRS preincubated with or without substrate ATP, and ten hits were identified. Four cocrystal structures revealed that the fragments bound to either the L-Met binding site or an auxiliary pocket near the tRNA CCA end binding site of SaMetRS. Interestingly, fragment binding was enhanced by ATP in most cases, suggesting a potential ATP-assisted ligand binding mechanism in MetRS1. Moreover, co-binding with ATP was also observed in our cocrystal structure of SaMetRS with a class of newly reported inhibitors that simultaneously occupied the auxiliary pocket, tRNA site and L-Met site. Our findings will inspire the development of new MetRS1 inhibitors for fighting microbial infections.
Pre-mRNA splicing factor U2AF2 recognizes distinct conformations of nucleotide variants at the center of the pre-mRNA splice site signal
Authors: Glasser Eliezra , Maji Debanjana , Biancon Giulia , Puthenpeedikakkal Anees Mohammed Keedakkatt , Cavender Chapin E , Tebaldi Toma , Jenkins Jermaine L , Mathews David H , Halene Stephanie , Kielkopf Clara L 
Published: April 2022

Abstract
The essential pre-mRNA splicing factor U2AF2 (also called U2AF65) identifies polypyrimidine (Py) tract signals of nascent transcripts, despite length and sequence variations. Previous studies have shown that the U2AF2 RNA recognition motifs (RRM1 and RRM2) preferentially bind uridine-rich RNAs. Nonetheless, the specificity of the RRM1/RRM2 interface for the central Py tract nucleotide has yet to be investigated. We addressed this question by determining crystal structures of U2AF2 bound to a cytidine, guanosine, or adenosine at the central position of the Py tract, and compared U2AF2-bound uridine structures. Local movements of the RNA site accommodated the different nucleotides, whereas the polypeptide backbone remained similar among the structures. Accordingly, molecular dynamics simulations revealed flexible conformations of the central, U2AF2-bound nucleotide. The RNA binding affinities and splicing efficiencies of structure-guided mutants demonstrated that U2AF2 tolerates nucleotide substitutions at the central position of the Py tract. Moreover, enhanced UV-crosslinking and immunoprecipitation of endogenous U2AF2 in human erythroleukemia cells showed uridine-sensitive binding sites, with lower sequence conservation at the central nucleotide positions of otherwise uridine-rich, U2AF2-bound splice sites. Altogether, these results highlight the importance of RNA flexibility for protein recognition and take a step towards relating splice site motifs to pre-mRNA splicing efficiencies.
ExPheWas: a platform forcis-Mendelian randomization and gene-based association scans
Authors: Legault Marc-André , Perreault Louis-Philippe Lemieux , Tardif Jean-Claude , Dubé Marie-Pierre 
Published: April 2022

AbstractEstablishing the relationship between protein-coding genes and phenotypes has the potential to inform on the molecular etiology of diseases. Here, we describe ExPheWas (exphewas.ca), a gene-based phenome-wide association study browser and platform that enables the conduct of gene-based Mendelian randomization. The ExPheWas data repository includes sex-stratified and sex-combined gene-based association results from 26 616 genes with 1746 phenotypes measured in up to 413 133 individuals from the UK Biobank. Interactive visualizations are provided through a browser to facilitate data exploration supported by false discovery rate control, and it includes tools for enrichment analysis. The interactive Mendelian randomization module in ExPheWas allows the estimation of causal effects of a genetically predicted exposure on an outcome by using genetic variation in a single gene as the instrumental variable.
Effect on Tobacco Use and Subjective Measures of Including E-cigarettes in a Simulated Ban of Menthol in Combustible Cigarettes
Authors: Kotlyar Michael , Shanley Ryan , Dufresne Sheena R , Corcoran Gretchen A , Hatsukami Dorothy K 
Published: April 2022

Abstract

Introduction
Bans of menthol characterizing flavor in tobacco products have been proposed; however, there is limited data regarding the impact on current menthol cigarette smokers of including e-cigarettes in such bans.

Methods
In this six-week pilot study, 47 menthol smokers were randomized to receive all tobacco products from an experimental marketplace simulating either no menthol ban, a menthol ban for cigarettes but not e-cigarettes, or a ban for both (“total menthol ban”).

Results
At the first visit, all but one participant selected cigarettes with e-cigarettes selected by 38%, 69%, and 40% of participants in the no ban, menthol cigarette ban, and total menthol ban groups, respectively. Over the study period, the total menthol ban group smoked more than the menthol cigarette ban group (estimated mean ratio [EMR] in cigarettes per day = 1.38; 95% CI: 1.1, 1.75; p = .006). Compared to the no ban condition, the menthol cigarette ban group smoked slightly fewer (EMR = 0.87; 95% CI: .68, 1.11) and the total menthol ban group smoked slightly more (EMR = 1.20; 95% CI: 1.00, 1.45) although neither difference reached statistical significance. In both menthol ban conditions, ratings were lower (vs. no ban) on several measures of craving and cigarette effects and liking.

Conclusions
Menthol bans that include e-cigarettes may result in different patterns of tobacco use than if only combustible cigarettes are included, although e-cigarettes were not extensively used in any group. Larger studies are needed to determine policies most likely to provide the largest public health benefit.

Implications
Bans of menthol characterizing flavor have been proposed, however, the effects on menthol cigarette smokers of including e-cigarettes in such bans are not clear. This study found that smokers randomized to a simulated ban on menthol in both cigarettes and e-cigarettes smoked more cigarettes per day over the 6-week study period than those randomized to a simulated ban on menthol in only cigarettes suggesting that smoking patterns among current menthol smokers differ depending on which products are included in a menthol ban. Larger studies are needed to determine the policies most likely to provide the largest public health benefit.
Road accidents: unexpected costs of stock market movements
Authors: Fry Jane M , Farrell Lisa 
Published: April 2022

AbstractRecent interest has grown in the link between stock market returns and health conditions. We extend this literature to road accidents as changes in returns may affect anxiety and stress, leading to driver fatigue and distraction, resulting in road accidents. Using Stats19 administrative data on accidents, we investigate the relationship between FTSE100 returns and accidents in British regions from 2008 to 2019. Accidents respond positively to decreases and increases in returns with effects up to 1.2%. Daily returns can be large, having substantial effect on accidents when returns are large. Compared with US results, we find no effects for fatal accidents. This could result from the UK’s very low fraction of fatalities and differences in road infrastructure, speed, and congestion. Unanticipated changes in returns represent an exogenous shock to individuals which may causally affect driving behaviour, and this is important to road safety stakeholders and for health promotion and policy.
Reaching Hard-to-Reach People Who Use Drugs: A Community-Based Strategy for the Elimination of Hepatitis C
Authors: Nagot Nicolas , D’Ottavi Morgana , Quillet Catherine , Debellefontaine Anne , Castellani Joëlle , Langendorfer Nicolas , Hanslik Bertrand , Guichard Sylvain , Baglioni René , Faucherre Vincent , Tuaillon Edouard , Pageaux Georges-Philippe , Laureillard Didier , Donnadieu-Rigole Hélène 
Published: April 2022

Abstract

Background
Elimination of hepatitis C virus (HCV) among people who use drugs (PWUD) remains a challenge even in countries in which HCV care is provided free of cost. We assessed whether an innovative community-based, respondent-driven sampling (RDS) survey, coupled with HCV screening and immediate treatment, could be efficient to detect and cure current PWUD with chronic HCV in a large city of Southern France.

Methods
At a community site with peers, PWUD (cannabis not included) were enrolled after confirmation by a urine drug test. Participants were then screened for hepatitis B virus, HCV, and human immunodeficiency virus and benefited from onsite HCV treatment evaluation and prescription. Peer support was provided during treatment, and a systematic visit was scheduled 12 weeks after the end of treatment. The cost of the intervention was estimated.

Results
Five hundred fifty-four participants were enrolled. Most were male (78.8%) with a median age of 39 years (interquartile range, 33–46). Cocaine (73.1%) and heroine (46.8%) were the main drugs consumed. Overall, 32.6% of PWUD (N = 181) were HCV seropositive, 49 (27.1%) of which had detectable HCV ribonucleic acid and were thus eligible for treatment. Ten of these patients had severe fibrosis. Hepatitis C virus treatment was initiated for 37 (75.5%) patients, 30 (81.1%) of whom completed their treatment and 27 (73.0%) achieved sustained viral response at week 12. The total cost was 161 euros € per screened patient and 1816€ per patient needing treatment.

Conclusions
A community-based RDS survey approach, involving peers, proved efficient and cost-effective to reach and cure PWUD for HCV. This innovative strategy could be key for the final step of HCV elimination.
Clinical trial registration. ClinicalTrials.gov, NCT04008927.
Phase I Trial of Regorafenib, Hydroxychloroquine, and Entinostat in Metastatic Colorectal Cancer
Authors: Karasic Thomas B , Brown Timothy J , Schneider Charles , Teitelbaum Ursina R , Reiss Kim A , Mitchell Tara C , Massa Ryan C , O’Hara Mark H , DiCicco Lisa , Garcia-Marcano Luis , Amaravadi Ravi K , O’Dwyer Peter J 
Published: April 2022

Abstract

Background
The antiangiogenic tyrosine kinase inhibitor regorafenib provides a survival benefit in patients with previously treated metastatic colorectal cancer (CRC). Antiangiogenic therapy causes hypoxic stress within tumor cells, which activates autophagy as a survival mechanism. The histone deacetylase inhibitor (HDAC) entinostat increases dependence on autophagy through epigenetic mechanisms. Hydroxychloroquine (HCQ) blocks autophagy by blunting lysosomal acidification. We hypothesized that HCQ and entinostat would be tolerable with regorafenib and potentiate the antitumor response.

Methods
This was a 3+3 phase I trial of HCQ and entinostat with regorafenib in patients with metastatic CRC. The primary objective was safety, and the secondary objective was clinical efficacy.

Results
Twenty patients received study therapy. Six evaluable patients were enrolled at each of the three planned dose levels, one patient at an intermediate dose level, and one additional patient withdrew consent after 4 days to receive treatment closer to home. One dose-limiting toxicity was noted in the study at dose level 2 (grade 3 fatigue). Seven patients discontinued therapy due to related toxicities; rapid weight loss was near universal, with a median weight loss of 4.4 kg (range 1.5-12.2 kg) in the first 2 weeks of treatment. No objective responses were observed.

Conclusion
The combination of regorafenib, HCQ, and entinostat was poorly tolerated without evident activity in metastatic CRC.

ClinicalTrials.gov Identifier
NCT03215264
Phase II Study of Cabozantinib in Patients With Bone Metastasis
Authors: Choy Edwin , Cote Gregory M , Michaelson M Dror , Wirth Lori , Gainor Justin F , Muzikansky Alona , Sequist Lecia V , Sullivan Ryan J , Fidias Panagiotis M , Shaw Alice , Heist Rebecca S 
Published: April 2022

Abstract
Bone metastases are often difficult to manage as they can be symptomatic and skeletal-related events (SREs) can contribute to significant morbidity and declines in performance status. We sought to identify a novel medical treatment for bone metastasis by testing the safety and efficacy of cabozantinib in patients with bone metastasis arising from non-breast, non-prostate, malignant solid tumors. Patients were administered cabozantinib as an oral drug starting at 60 mg per day and radiologic measurements were performed at baseline and every 8 weeks. Thirty-seven patients were enrolled. No SREs were observed throughout the study. Twenty patients had disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Four of 20 had a partial response by RECIST. An additional 12 patients had some decrease in tumor burden with nine of these having a decrease in tumor burden of at least 10% by RECIST. Six of the patients with at least a minor response had sarcoma. Sixteen patients had biomarkers of bone turnover measured before and after treatment. Most of these patients demonstrated decrease in urine and serum N-telopeptide and serum C-telopeptide. However, these changes in biomarkers of bone turnover did not correlate with radiographic changes measured by RECIST. This study demonstrates clinical activity and safety for cabozantinib in heavily pretreated patients with bone metastasis and shows activity for cabozantinib in patients with metastatic sarcoma.