bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analytical and clinical validation of a targeted-enhanced whole genome sequencing-based comprehensive genomic profiling test
Authors: Ferguson Stephanie , Sriram Shruthi , Wallace Jonathan Kyle , Lee Jeonghoon , Kim Jung-Ah , Lee Yoonsuh , Oh Brian Baek-Lok , Lee Won Chul , Lee Sangmoon , Connolly-Strong Erin 
Published: December 2023

AbstractEvaluation of the test performance of the targeted enhanced whole-genome sequencing (TE-WGS) assay for comprehensive oncology genomic profiling. The analytical validation of the assay included sensitivity and specificity for single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs), revealing a revealed a sensitivity of 99.8% for SNVs and 99.2% for indels. The PPV was 99.3% for SNVs and 98.7% for indels. Clinical validation was benchmarked against established orthogonal methods and demonstrated high concordance with reference methods in variant characterization. The TE-WGS assay enhances personalized cancer treatment by offering detailed genomic insights and the adaptability to include emerging biomarkers.
Association between Binge Drinking Behaviors and Comorbidities in Brazil: Network Analysis of a National Health Survey
Authors: Zadey Siddhesh , Franca Diego , Coelho Pessoa Santos Pollyana , Pereira Natan David , Tchuisseu Yolande Pokam , Andrade Luciano , Nunes Bruno Pereira , Lara Machado Wagner De , Staton Catherine A. , Vissoci Joao Ricardo Nickenig 
Published: December 2023

AbstractAlcohol consumption is the sixth leading cause of death globally. Brazil ranks second in alcohol-related mortality within the American regions with a notable increase in binge drinking behavior from 2013 (5.9%) to 2019 (17.1%). Binge drinking, a form of alcohol misuse, is a known risk factor for several diseases. We aimed to understand the differences in binge drinking across various sociodemographic groups and the patterns of comorbidities in a national-level dataset by doing a cross-sectional network analysis of the 2013 Brazilian National Health Survey. Binge drinking was defined as a binary variable based on alcohol consumption of >5 (4) doses in a month for male (female) responders. Weighted undirected network analysis using Ising models was performed to discover the strength of inter-relations between nineteen chronic conditions. In the network, the nodes represented the conditions and the edges were formed by statistical associations derived using logistic regression. Community analyses identified the clusters within networks. A nationally representative sample of 60,202 people revealed the prevalence of binge drinking to be about 13.5%. The study revealed a less connected network among binge drinkers, potentially impacting disease associations. Binge drinking demonstrated unique correlations with comorbidities across age, gender, ethnicity, and education levels, highlighting the complex interplay between binge drinking and health outcomes. Recognizing the specific comorbidities associated with binge drinking, such as hypertension and chronic spinal problems, allows healthcare professionals to tailor preventive measures and early interventions. In this sense, differences in binge drinking and its direct association with comorbidities as well as in comorbidity structures across sociodemographic characteristics point to the utility of network models to identify specific populations at various health risks.
LowIGFBP7expression identifies a subset of breast cancers with favorable prognosis and sensitivity to IGF-1 receptor targeting with ganitumab: Data from I-SPY2 and SCAN-B
Authors: Godina Christopher , Pollak Michael N , Jernström Helena 
Published: December 2023

AbstractThere has been a long-standing interest in targeting the insulin-like growth factor-1 receptor (IGF-1R) signaling system in breast cancer due to its key role in neoplastic proliferation and survival. However, no IGF-1R targeting agent has shown substantial clinical benefit in controlled trials, and no treatment predictive biomarkers for IGF-1R targeting agents exist. IGFBP7 is an atypical insulin-like growth factor binding protein as it has a higher affinity for the IGF-1R than IGF ligands. We report that lowIGFBP7gene expression identifies a subset of breast cancers for which the addition of ganitumab (an anti-IGF-1R monoclonal antibody) to chemotherapy substantially improved the pathological complete response rate compared to neoadjuvant chemotherapy alone. Furthermore, highIGFBP7expression predicted increased distant metastasis risk. If our findings are confirmed, decisions to halt the development of IGF-1 targeting drugs, which were based on disappointing results of prior trials that did not use predictive biomarkers, should be reviewed.
High-throughput structure determination of an intrinsically disordered protein using cell-free protein crystallization
Authors: Kojima Mariko , Abe Satoshi , Furuta Tadaomi , Hirata Kunio , Yao Xinchen , Kobayashi Ayako , Kobayashi Ririko , Ueno Takafumi 
Published: December 2023

AbstractIntrinsically disordered proteins (IDPs) play a crucial role in various biological phenomena, dynamically changing their conformations in response to external environmental cues. To gain a deeper understanding of these proteins, it is essential to identify the determinants that fix their structures at the atomic level. Here, we developed a pipeline for rapid crystal structure analysis of IDP using a cell-free protein crystallization (CFPC) method. Through this approach, we successfully demonstrated the determination of the structure of an IDP to uncover the key determinants that stabilize its conformation. Specifically, we focused on the 11-residue fragment of c-Myc, which forms an α-helix through dimerization with a binding partner protein. This fragment was strategically fused with an in-cell crystallizing protein and was expressed in a cell-free system. The resulting crystal structures of the c-Myc fragment were successfully determined at a resolution of 1.92 Å and we confirmed that they are identical to the structures of the complex with the native binding partner protein. This indicates that the environment of the scaffold crystal can fix the structure of c-Myc. Significantly, these crystals were obtained directly from a small reaction mixture (30 μL) incubated for only 72 hours. Analysis of 8 crystal structures derived from 22 mutants revealed two hydrophobic residues as the key determinants responsible for stabilizing the α-helical structure. These findings underscore the power of our CFPC screening method as a valuable tool for determining the structures of challenging target proteins and elucidating the essential molecular interactions that govern their stability.
A hyperparameter-randomized ensemble approach for robust clustering across diverse datasets
Authors: Goggin Sarah M. , Zunder Eli R. 
Published: December 2023

AbstractClustering analysis is widely used to group objects by similarity, but for complex datasets such as those produced by single-cell analysis, the currently available clustering methods are limited by accuracy, robustness, ease of use, and interpretability. To address these limitations, we developed an ensemble clustering method with hyperparameter randomization that outperforms other methods across a broad range of single-cell and synthetic datasets, without the need for manual hyperparameter selection. In addition to hard cluster labels, it also outputs soft cluster memberships to characterize continuum-like regions and per cell overlap scores to quantify the uncertainty in cluster assignment. We demonstrate the improved clustering interpretability from these features by tracing the intermediate stages between handwritten digits in the MNIST dataset, and between tanycyte subpopulations in the hypothalamus. This approach improves the quality of clustering and subsequent downstream analyses for single-cell datasets, and may also prove useful in other fields of data analysis.
Novelin vivoTDP-43 stress reporter models to accelerate drug development in ALS
Authors: Ferro Febe , Wolf C. Roland , Henstridge Chris , Inesta-Vaquera Francisco 
Published: December 2023

AbstractThe development of therapies to combat neurodegenerative diseases is widely recognised as a research priority, with conditions like Alzheimer’s, Amyotrophic lateral sclerosis (ALS) and Parkinson’s set to place an ever-heavier burden on healthcare systems in the near future. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility ofin vivoreporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS. The activation occurs in Purkinje neurons and other parvalbumin-positive (PV+) cells within the cerebellum of mice, before moderate clinical signs are observed. In addition, reporter expression in hTDP-43tg hom peripheral tissues was not observed at the tested mouse ages (15 and 17 days postnatally). Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters’ expression. Our current studies suggest that these reporters may represent a powerful approach to accelerate preclinical studies targeting TDP-43 pathologies. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.
A cascade of sulfur transferases delivers sulfur to the sulfur-oxidizing heterodisulfide reductase-like complex
Authors: Tanabe Tomohisa Sebastian , Bach Elena , D’Ermo Giulia , Mohr Marc Gregor , Hager Natalie , Pfeiffer Niklas , Guiral Marianne , Dahl Christiane 
Published: December 2023

ABSTRACTA heterodisulfide reductase-like complex (sHdr) and novel lipoate-binding proteins (LbpAs) are central players of a wide-spread pathway of dissimilatory sulfur oxidation. Bioinformatic analysis demonstrate that the cytoplasmic sHdr-LbpA systems are always accompanied by sets of sulfur transferases (DsrE proteins, TusA, rhodaneses). The exact composition of these sets may vary depending on the organism and sHdr system type. To enable generalizations, we studied model sulfur oxidizers from distant bacterial phyla, i.e. Aquificota and Pseudomonadota. DsrE3C of the chemoorganotrophic AlphaproteobacteriumHyphomicrobium denitrificansand DsrE3B from the GammaproteobacteriaThioalkalivibriosp. K90mix, an obligate chemolithotroph, andThiorhodospira sibirica, an obligate photolithotroph, are homotrimers that donate sulfur to TusA. Additionally, the hyphomicrobial rhodanese-like protein Rhd442 exchanges sulfur with both TusA and DsrE3C. The latter is essential for sulfur oxidation inHm. denitrificans. TusA fromAquifex aeolicus(AqTusA) interacts physiologically with AqDsrE, AqLbpA and AqsHdr proteins. This is particularly significant as it establishes a direct link between sulfur transferases and the sHdr-LbpA complex that oxidizes sulfane sulfur to sulfite.In vivo,it is unlikely that there is a strict unidirectional transfer between the sulfur-binding enzymes studied. Rather, the sulfur transferases form a network, each with a pool of bound sulfur. Sulfur flux can then be shifted in one direction or the other depending on metabolic requirements. A single pair of sulfur-binding proteins with a preferred transfer direction, such as a DsrE3-type protein towards TusA, may be sufficient to push sulfur into the sink where it is further metabolized or needed.SIGNIFICANCE STATEMENTA network of bacterial sulfur transferases is uncovered and characterized that ultimately delivers sulfur to a complex cytoplasmic sulfur-oxidizing metalloenzyme, sHdr, that resembles heterodisulfide reductase from methanogenic archaea and interacts with lipoate-binding proteins. Similar sets of sulfur transferases occur in phylogenetically distant bacteria, underscoring the fundamental importance of the work.
Understanding Genome Structure Facilitates the Use of Wild Lentil Germplasm for Breeding: A Case Study with Shattering Loci
Authors: Cao Zhe , Socquet-Juglard Didier , Daba Ketema , Vandenberg Albert , Bett Kirstin E 
Published: December 2023

ABSTRACTPlant breeders are generally reluctant to cross elite crop cultivars with their wild relatives to introgress novel desirable traits due to associated negative traits such as pod shattering. This results in a genetic bottleneck that could be reduced through better understanding of the genomic locations of the gene(s) controlling this trait. We integrated information on parental genomes, pod shattering data from multiple environments, and high-density genetic linkage maps to identify pod shattering QTLs in three lentil interspecific recombinant inbred line (RIL) populations. The broad-sense heritability on a multi-environment basis varied from 0.46 (in LR-70,Lens culinaris x L. odemensis) to 0.77 (in LR-68,L. orientalis x L. culinaris). Genetic linkage maps of the interspecific populations revealed reciprocal translocations of chromosomal segments that differed among the populations, and which were associated with reduced recombination. Segregation distortion was also observed for clusters of SNPs on multiple chromosomes per population, further affecting introgression. Two major QTL, on chromosomes 4 and 7, were repeatedly detected in the three populations and contain several candidate genes. These findings will be of significant value for lentil breeders to strategically access novel superior alleles while minimizing the genetic impact of pod shattering from wild parents.
Bile is a route of excretion for homogentisic acid in alkaptonuria
Authors: Norman BP , Sutherland H , Wilson PJM , Rutland DA , Milan AM , Hughes AT , Davison AS , Khedr M , Jarvis JC , Gallagher JA , Bou-Gharios G , Ranganath LR 
Published: December 2023

AbstractAltered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of the metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type-1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in the bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, HPPA and HPLA are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion and possible metabolism of HGA by the gut microbiome. These data provide new insights into the pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism.Take-home messageThis paper presents the first observation of elevated hepatobiliary circulation of metabolites associated with disease in alkaptonuria, including homogentisic acid in addition to tyrosine and the tyrosine metabolites 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid on nitisinone treatment.
GTalign: Spatial index-driven protein structure alignment, superposition, and search
Authors: Margelevičius Mindaugas 
Published: December 2023

AbstractIn response to the challenge posed by vast protein structure repositories, GTalign offers an innovative solution to protein structure alignment and search—an algorithm that achieves optimal superposition at high speeds. Through the design and implementation of spatial structure indexing, GTalign parallelizes all stages of superposition search across residues and protein structure pairs, yielding rapid identification of optimal superpositions. Rigorous evaluation across diverse datasets reveals GTalign as the most accurate among structure aligners while presenting orders of magnitude in speedup at state-of-the-art accuracy. GTalign’s high speed and accuracy make it useful for numerous applications, including functional inference, evolutionary analyses, protein design, and drug discovery, contributing to advancing understanding of protein structure and function.
Unveiling Vaginal Fibrosis: A Novel Murine Model Using Bleomycin and Epithelial Disruption
Authors: McCracken Jennifer M , Calderon Gisele A , Kumar Lishore A , Balaji Swathi , Rivas Felipe , Erxleben Dorothea , Hall Adam , Hakim Julie CE 
Published: December 2023

ABSTRACTObjectiveDevelop, validate, and characterize a fibrotic murine vaginal wound healing model using bleomycin instillations and epithelial disruption.ApproachWe tested the effect of repeated bleomycin instillations with mucosal layer disruption on induction of vaginal fibrosis. Tissue samples collected at various time points were analyzed for fibrosis-related gene expression changes and collagen content.ResultsLow (1.5U/kg) and high-dose (2.5U/kg) bleomycin instillations alone did not induce fibrosis, but when high-dose bleomycin was combined with epithelial disruption, increased pro-fibrotic gene expression and trichrome staining were observed. To evaluate spatial and temporal changes in the ECM structure and gene expression, tissue samples were collected at 1 day, 3 weeks, and 6 weeks after bleomycin and epithelial disruption. Data analyses revealed a significant decrease in matrix metabolizing genes and an increase in pro-fibrotic genes and inhibitors of matrix metabolizing genes in the bleomycin plus epithelial disruption group at 3 weeks. Elevated levels of the profibrotic genesActa2,Col1a1, andCol3awere exclusively detected in this group at 3 weeks, and trichrome staining confirmed increased collagen content after 3 weeks. Hydroxyproline levels showed a tendency towards elevation at 3 weeks (p=0.12) and 6 weeks (p=0.14), indicating fibrosis manifestation at 3 weeks and resolution by 6 weeks post-instillation and epithelial disruption.InnovationWe combined bleomycin instillations with epithelial disruption to induce fibrosis and understand the mechanisms of the vaginal repair process.ConclusionsEpithelial disruption combined with bleomycin induces murine vaginal fibrosis within three weeks, characterized by increased collagen synthesis. Remarkably, the vaginal tissue fully recovers within six weeks, elucidating the regenerative capacity of the vagina.
Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention
Authors: Fan Siqi , Dal Monte Olga , Nair Amrita R. , Fagan Nicholas A. , Chang Steve W. C. 
Published: December 2023

AbstractThe prefrontal cortex is extensively involved in social exchange. During dyadic gaze interaction, multiple prefrontal areas exhibit neuronal encoding of social gaze events and context-specific mutual eye contact, supported by a widespread neural mechanism of social gaze monitoring. To explore causal manipulation of real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events to three prefrontal areas in monkeys. Microstimulations of orbitofrontal cortex (OFC), but not dorsomedial prefrontal or anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing distance of one’s gaze fixations relative to partner monkey’s eyes. In the temporal dimension, microstimulations of OFC reduced the inter-looking interval for attending to another agent and the latency to reciprocate other’s directed gaze. These findings demonstrate that primate OFC serves as a functionally accessible node in controlling dynamic social attention and suggest its potential for a therapeutic brain interface.
Optimized mucin-selective enrichment strategy to probe the mucinome
Authors: Mahoney Keira E. , Chang Vincent , Lucas Taryn M. , Maruszko Krystyna , Malaker Stacy A. 
Published: December 2023

AbstractMucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of healthy and diseasedriven biological functions. Previously, we developed a mucin-selective enrichment strategy by employing a catalytically inactive mucinase (StcE) conjugated to solid support. While this method was effective, it suffered from low throughput and high sample requirements. Further, the elution step required boiling in SDS, thus necessitating an in-gel digest with trypsin. Here, we optimized our previous enrichment method to include elution conditions amenable to mucinase digestion and downstream analysis with mass spectrometry. This increased throughput and lowered sample input while maintaining mucin selectivity and enhancing glycopeptide signal. We then benchmarked this technique against different O-glycan binding moieties for their ability to enrich mucins from various cell lines and human serum. Overall, the new method outperformed our previous procedure and all other enrichment techniques tested. This allowed for effective isolation of more mucin-domain glycoproteins, resulting in a high number of O-glycopeptides, thus enhancing our ability to analyze the mucinome.