bluuebunny/crossref_metadata_2025_split huggingface dataset:
A chromosome-level reference genome of a Fabaceae species yam bean (Pachyrhizus erosus)
Authors: Bu Fengjiao , Jiang Fan , Zhang Caishun , Yuan Lihua , Fan Wei , Xiong Xinyao 
Published: September 2023

AbstractYam bean (Pachyrhizus erosusL.), belonging to the family Fabaceae, is an important but underutilized root crop. Here, we generated a high-quality chromosome-level reference genome of yam bean by PacBio HiFi and Hi-C sequencing, with assembly size of 539.0 Mb, contig N50 of 25.6 Mb, and BUSCO complete rate of 99.3%. Then, we anchored 94.4% of the contig sequences into 11 pseudo-chromosomes, and assembled the telomeres at 86.4% (19/22) of the chromosome-ends. A total of 44,692 protein-coding genes were predicted, with the BUSCO complete rate of 99.3%, comparable to that of the genome assembly. Compared to the previously reported yam bean genome, the current assembly has a 1,388-fold increase in contig N50 size, and 12.2% and 24.3% increase in BUSCO complete rate for the genome sequence and gene set, respectively. Evolutionary analysis revealed that yam bean diverged from the clade of soybean andPueraria lobatavar.montana22.5 MYA. This high-quality genome assembly will greatly facilitate the breeding of yam bean based on the genetic and genomic methods.
Uninheritable but widespread bacterial symbiont mediates insecticide detoxification of an agricultural invasive pestSpodoptera frugiperda
Authors: Zhang Yunhua , Ju Feng 
Published: September 2023

AbstractIdentifying insecticide resistance-related insect bacterial symbiont is a vital compass for promoting symbiont-based insecticide resistance management and insecticide-free insect pest control. Known insecticide-resistance-related symbionts lack universality and genetic manipulation, as either not widespread or unculturable. Here, we discovered a widespread symbiontEnterococcus casseliflavusof a significant invasive insect pest,Spodoptera frugiperda. This symbiont enhances host insecticide resistance to chlorantraniliprole by amide bond breaking and dehalogenation-related insecticide degradation, suggesting its great potential for Lepidoptera pest insecticide resistance management. Complying with the increase in exposure risk of chlorantraniliprole, theE. casseliflavusof insects’ symbionts rather than mammals or environmental strains were notably enriched with putative chlorantraniliprole degradation genes. We also found thatE. casseliflavuscan transmit horizontally with high efficiency (100%) through cross-diet and cannibalism rather than vertical transmission from mother insect to offspring. Moreover, the widespread infection ofE. casseliflavusin the field populations not only implies that an underlying symbiont-host co-evolution process driven by insecticide pressure might be underway, but also provides a novel therapeutic target of agricultural pests based on symbiont-targeted insect control (STIC).
Widespread impact of natural genetic variations in CRISPR/Cas9 outcomes
Authors: Li Victoria , Tadych Alicja , Wong Aaron , Zhang Zijun 
Published: September 2023

AbstractCRISPR/Cas9 is a genome editing tool widely used in biological research and clinical therapeutics. Natural human genetic variations, through altering the sequence context of CRISPR/Cas9 target regions, can significantly affect its DNA repair outcomes and ultimately lead to different editing efficiencies. However, these effects have not been systematically studied, even as CRISPR/Cas9 is broadly applied to primary cells and patient samples that harbor such genetic diversity. Here, we present comprehensive investigations of natural genetic variations on CRISPR/Cas9 outcomes across the human genome. The utility of our analysis is illustrated in two case studies, on both preclinical discoveries of CD33 knockout in Chimeric Antigen Receptor (CAR)-T cell therapy, and clinical applications of TTR inactivation for treating ATTR amyloidosis. We further expand our analysis to genome scale, population stratified common variants that may lead to gene editing disparity. Our analyses demonstrate pitfalls of failing to account for the widespread genetic variations in Cas9 target selection, and how they can be effectively examined and avoided using our method. To facilitate broad access to our analysis, a web platform CROTONdb is developed, which provides predictions for all possible CRISPR/Cas9 target sites in the coding region, spanning over 5.38 million gRNA targets and 90.82 million estimated variant effects. We anticipate CROTONdb having broad clinical utilities in gene and cellular therapies.
Clinical prediction models combining routine clinical measures identify participants with youth-onset diabetes who maintain insulin secretion in the range associated with type 2 diabetes: The SEARCH for Diabetes in Youth Study
Authors: Jones Angus G , Shields Beverley M , Oram Richard A , Dabelea Dana M , Hagopian William A , Lustigova Eva , Shah Amy S , Knupp Julieanne , Mottl Amy K , D’Agostino Ralph B. , Williams Adrienne , Marcovina Santica M , Pihoker Catherine , Divers Jasmin , Redondo Maria J 
Published: September 2023

AbstractObjectiveWith the high prevalence of pediatric obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D).MethodsWe studied 2,966 youth with diabetes in the prospective SEARCH study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting c-peptide ≥250 pmol/L (≥0.75ng/ml) after >3 years (median 74 months) of diabetes duration. Models included clinical measures at baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL-C), with and without islet autoantibodies (GADA, IA-2A) and a Type 1 Diabetes Genetic Risk Score (T1DGRS).ResultsModels using routine clinical measures with or without autoantibodies and T1DGRS were highly accurate in identifying participants with c-peptide ≥0.75 ng/ml (17% of participants; 2.3% and 53% of those with and without positive autoantibodies) (area under receiver operator curve [AUCROC] 0.95-0.98). In internal validation, optimism was very low, with excellent calibration (slope=0.995-0.999). Models retained high performance for predicting retained c-peptide in older youth with obesity (AUCROC 0.88-0.96), and in subgroups defined by self-reported race/ethnicity (AUCROC 0.88-0.97), autoantibody status (AUCROC 0.87-0.96), and clinically diagnosed diabetes types (AUCROC 0.81-0.92).ConclusionPrediction models combining routine clinical measures at diabetes diagnosis, with or without islet autoantibodies or T1DGRS, can accurately identify youth with diabetes who maintain endogenous insulin secretion in the range associated with type 2 diabetes.
The Impact of Body Mass Index on Robotic Surgery Outcomes in Endometrial Cancer
Authors: Kadoch Eva , Brezinov Yoav , Levin Gabriel , Racovitan Florentin , Lau Susie , Salvador Shannon , Gotlieb Walter H. 
Published: September 2023

STRUCTURED ABSTRACTOBJECTIVESTo compare surgical outcomes of patients with endometrial cancer who underwent robotic surgery across different BMI categories.METHODSA retrospective study including all consecutive patients with endometrial cancer who underwent robotic surgery at a tertiary cancer center between December 2007 and December 2022. The study analyzed outcome measures, including blood loss, surgical times, length of hospitalization, perioperative complications, and conversion rates with the Kruskal-Wallis test for BMI group differences and the Chi-squared test for associations between categorical variables.RESULTSA total of 1,329 patients with endometrial cancer were included in the study. Patients were stratified by BMI: <30.0 (n=576; 43.3%), 30.0-39.9 (n=449; 33.8%), and ≥40.0 (n=304; 22.9%). There were no significant differences in post-anesthesia care unit (PACU) stay (p=0.105) and hospital stay (p=0.497) between the groups. The rate of post-op complications was similar across the groups, ranging from 8.0% to 9.5% (p=0.761). The rate of conversion to laparotomy was also similar across the groups, ranging from 0.7% to 1.0% (p=0.885). Women with a BMI ≥40.0 had a non-clinically relevant but greater median estimated blood loss (30 mL vs. 20 mL; p<0.001) and longer median operating room (OR) time (288 minutes vs. 270 minutes; p<0.001). Within the OR time, the median set-up time was longer for those with a higher BMI (58 minutes vs. 50 minutes; p<0.001). However, skin-to-skin time (209 minutes vs. 203 minutes; p=0.202) and post-op time (14 minutes vs. 13 minutes; p=0.094) were comparable between groups.CONCLUSIONBMI does not affect the peri-operative outcome of patients undergoing robotic staging procedures for endometrial cancer.
Clinically actionable pharmacogenomic landscape of antidepressants and antipsychotics in Qatar: A population-based cohort study
Authors: Velayutham Dinesh , Bastaki Kholoud ,   the Qatar Genome Program Research Consortium, Ghuloum Suhaila , Azeem Muhammad Waqar , Pirmohamed Munir , Jithesh Puthen Veettil 
Published: September 2023

AbstractAntidepressants and antipsychotics, commonly prescribed worldwide, exhibit significant variability in patient responses. Genetic variations contribute substantially to this variability, offering the potential for predicting individual responses through pharmacogenetic testing. Clinical guidelines provided by organizations like the Clinical Pharmacogenetic Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG) facilitate the application of pharmacogenomics in clinical settings. Understanding the prevalence of actionable genetic variants and their associated response phenotypes is vital for effective pharmacogenomic integration, especially in under-served populations.In this study, we analyzed the frequency distribution of actionable genetic variants in 6045 adult Qataris recruited by the Qatar Biobank, whose genomes were sequenced as part of the Qatar Genome Program, focusing on genes (CYP2C19, CYP2D6, CYP2B6, and CYP3A4) influencing psychotropic medication responses. Haplotypes and diplotypes were generated from 490 alleles, and metabolizer phenotypes were predicted based on established guidelines.Our findings revealed that over 52% of Qatari individuals may possess actionable metabolizer phenotypes associated with CYP2C19, CYP2B6, and CYP2D6, impacting their response to tricyclic antidepressants. The frequency of actionable genetic variants for serotonin reuptake inhibitors ranged from approximately 2% to 51%, and for antipsychotics, it ranged from 0.1% to 32%, based on genetic variations in CYP3A4 and CYP2D6.This study underscores the importance of assessing these genetic variants, particularly concerning commonly prescribed antidepressants like escitalopram and amitriptyline in Qatar. Implementing pharmacogenetic testing based on these findings can potentially enhance patient outcomes in psychiatric medication management.
Task performance to discriminate mild cognitive impairment from healthy aging
Authors: Stockbridge Melissa D. , Hillis Argye E. 
Published: September 2023

AbstractMild cognitive impairment (MCI) is clinical diagnosis that refers to individuals whose performance is below average on standardized cognitive tests, but who otherwise function independently in instrumental activities of daily living. Few prior studies have addressed the problem of selecting the optimal combination of behavioral instruments and cutoff scores for detecting MCI in an outpatient setting. The aim of this work is to provide insight into two related questions: (1) What is the relative sensitivity and specificity of a battery of standardized tests frequently used to assess for MCI, as defined using receiver operating characteristic (ROC)-based analysis? (2) What are the optimal “cut point” scores for distinguishing patients’ mildly impaired performance based on these instruments?Two hundred forty outpatient behavioral neurology evaluations were retrospectively analyzed. All work was conducted with the formal approval of the Johns Hopkins University School of Medicine Institutional Review Board. All instruments that were evaluated performed very well in the detection of dementia (mean AUC = 0.8). However, fewer tasks performed acceptably in the detection of MCI (mean AUC = 0.7). Instruments that performed best in the detection of MCI tended to have higher total possible scores or not to reflect a score out of a total number possible.Cognitive screening tools, like the MMSE, did not perform well in the detection of MCI, raising important considerations for their interpretation. No one task in isolation is sufficient to detect MCI, and behavioral performance is not the only relevant consideration in differential diagnosis. However, these findings highlight the relative weakness of many assessments when used to build a comprehensive profile of a very large portion of outpatients presenting at clinic, those whose deficits are more subtle.
Working together to control mutation: how collective peroxide detoxification determines microbial mutation rate plasticity
Authors: Green Rowan , Wang Hejie , Botchey Carol , Zhang Nancy , Wadsworth Charles , McBain Andrew J , Paszek Pawel , Krašovec Rok , Knight Christopher G 
Published: September 2023

AbstractMutagenesis is responsive to many environmental factors. Evolution therefore depends on the environment not only for selection but also in determining the variation available in a population. One such environmental dependency is the inverse relationship between mutation rates and population density in many microbial species. Here we determine the mechanism responsible for this mutation rate plasticity. Using dynamical computational modelling andin vivomutation rate estimation we show that the negative relationship between mutation rate and population density arises from the collective ability of microbial populations to control concentrations of hydrogen peroxide. We demonstrate a loss of this density-associated mutation rate plasticity whenEscherichia colipopulations are deficient in the degradation of hydrogen peroxide. We further show that the reduction in mutation rate in denser populations is restored in peroxide degradation-deficient cells by the presence of wild-type cells in a mixed population. Together, these model-guided experiments provide a mechanistic explanation for density-associated mutation rate plasticity, applicable across all domains of life, and frames mutation rate as a dynamic trait shaped by microbial community composition.
A SUMO E3 ligase promotes long non-coding RNA transcription to regulate small RNA-directed DNA elimination
Authors: Shehzada Salman , Noto Tomoko , Saksouk Julie , Mochizuki Kazufumi 
Published: September 2023

AbstractSmall RNAs target their complementary chromatin regions for gene silencing through nascent long non-coding RNAs (lncRNAs). In the ciliated protozoanTetrahymena, the interaction between Piwi-associated small RNAs (scnRNAs) and the nascent lncRNA transcripts from the somatic genome has been proposed to induce target-directed small RNA degradation (TDSD), and scnRNAs not targeted for TDSD later target the germline-limited sequences for programmed DNA elimination. In this study, we show that the SUMO E3 ligase Ema2 is required for the accumulation of lncRNAs from the somatic genome and thus for TDSD and completing DNA elimination to make viable sexual progeny. Ema2 interacts with the SUMO E2 conjugating enzyme Ubc9 and enhances SUMOylation of the transcription regulator Spt6. We further show that Ema2 promotes the association of Spt6 and RNA polymerase II with chromatin. These results suggest that Ema2-directed SUMOylation actively promotes lncRNA transcription, which is a prerequisite for communication between the genome and small RNAs.
A tale of two receptors: simultaneous targeting of NMDARs and 5-HT4Rs exerts additive effects against stress
Authors: Chen Briana K. , Luna Victor M. , Jin Michelle , Shah Abhishek , Shannon Margaret E. , Pauers Michaela , Williams Brenna L. , Pham Vananh , Hunsberger Holly C. , Gardier Alain M. , Mendez-David Indira , David Denis J. , Denny Christine A. 
Published: September 2023

ABSTRACTBACKGROUNDSerotonin (5-HT) receptors andN-methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of (R,S)-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT4R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia.METHODSA single injection of saline (Sal), (R,S)-ketamine (K), prucalopride (P), or a combined dose of (R,S)-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis.RESULTSWe found that a combination of K+P, given before or after stress, exerted additive effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC.CONCLUSIONSOur results indicate that combined K+P has additive benefits for combating stress-induced pathophysiology, both at the behavioral and neural level. Our findings provide preliminary evidence that future clinical studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.
PCR-based survey of methane-cycling archaea in methane-soaked subsurface sediments of Guaymas Basin, Gulf of California
Authors: Hinkle John E. , Mara Paraskevi , Beaudoin David , Edgcomb Virginia P. , Teske Andreas P. 
Published: September 2023

AbstractThe Guaymas Basin in the Gulf of California is characterized by active seafloor spreading, rapid deposition of organic-rich sediments, steep geothermal gradients, and abundant methane of mixed thermogenic and microbial origin. Subsurface sediment samples from eight drilling sites with distinct geochemical and thermal profiles were selected for DNA extraction and PCR amplicifation to explore the diversity of methane-cycling archaea in the Guaymas Basin subsurface. We performed PCR amplifications with general (mcrIRD), and ANME-1 specific primers that target the alpha (α) subunit of methyl coenzyme M reductase (mcrA). Diverse ANME-1 lineages associated with anaerobic methane oxidation were detected in seven out of the eight drilling sites, preferentially around the methane-sulfate interface, and in several cases showed preferences for specific sampling sites. Phylogenetically, most ANME-1 sequences from the Guaymas Basin subsurface were related to marine mud volcanoes, seep sites, and the shallow marine subsurface. The most frequently recovered methanogenic phylotypes were closely affiliated with the hyperthermophilicMethanocaldococcaceae, and found at the hydrothermally influenced Ringvent site. The coolest drilling site, in the northern axial trough of Guaymas Basin, yielded the greatest diversity of methanogen lineages. Our survey indicates potential for extensive microbial methane cycling within subsurface sediments of Guaymas Basin.
The herpesvirus UL49.5 protein hijacks a cellular C-degron pathway to drive TAP transporter degradation
Authors: Wąchalska Magda , Riepe Celeste , Ślusarz Magdalena J. , Graul Małgorzata , Borowski Lukasz S. , Qiao Wenjie , Foltynska Michalina , Carette Jan E. , Bieńkowska-Szewczyk Krystyna , Szczesny Roman J. , Kopito Ron R. , Lipińska Andrea D. 
Published: September 2023

ABSTRACTThe transporter associated with antigen processing (TAP) is a key player in the MHC class I-restricted antigen presentation and an attractive target for immune evasion by viruses. Bovine herpesvirus 1 (BoHV-1) impairs TAP-dependent antigenic peptide transport through a two-pronged mechanism in which binding of the UL49.5 gene product to TAP both inhibits peptide transport and promotes its proteasomal degradation. How UL49.5 promotes TAP degradation is unknown. Here, we use high-content siRNA and genome-wide CRISPR-Cas9 screening to identify CLR2KLHDC3as the E3 ligase responsible for UL49.5-triggered TAP disposal in human cells. We propose that the C-terminus of UL49.5 mimics a C-end rule degron that recruits the E3 to TAP and engages the CRL2 E3 in ER-associated degradation.SIGNIFICANCEHerpesviruses are masters of immune evasion. Most often, they hijack host cellular pathways to modulate the antiviral immune response. Varicellovirus UL49.5 orthologs have evolved as inhibitors of the transporter associated with antigen processing (TAP) and, this way, major modulators of the MHC class I-restricted antigen presentation. This study identifies the long-sought molecular mechanism exploited by bovine herpesvirus 1-encoded UL49.5 to trigger proteasomal degradation of TAP. Our findings demonstrate that the viral protein hijacks host cell CRL2-ubiquitin conjugation and ER-associated degradation pathways to promote TAP degradation. These findings advance the understanding of how herpesviruses can manipulate the cellular machinery.
Interpretable Metric Learning in Comparative Metagenomics: The Adaptive Haar-like Distance
Authors: Gorman Evan , Lladser Manuel E. 
Published: September 2023

AbstractRandom forests have emerged as a promising tool in comparative metagenomics because they can predict environmental characteristics based on microbial composition in datasets whereβ-diversity metrics fall short of revealing meaningful relationships between samples. Nevertheless, despite this efficacy, they lack biological insight in tandem with their predictions, potentially hindering scientific advancement. To overcome this limitation, we leverage a geometric characterization of random forests to introduce a data-driven phylogeneticβ-diversity metric, the adaptive Haar-like distance. This new metric assigns a weight to each internal node (i.e., split or bifurcation) of a reference phylogeny, indicating the relative importance of that node in discerning environmental samples based on their microbial composition. Alongside this, a weighted nearest-neighbors classifier, constructed using the adaptive metric, can be used as a proxy for the random forest while maintaining accuracy on par with that of the original forest and another state-of-the-art classifier, CoDaCoRe. As shown in datasets from diverse microbial environments, however, the new metric and classifier significantly enhance the biological interpretability and visualization of high-dimensional metagenomic samples.Author summaryTraditional phylogeneticβ-diversity metrics, particularly weighted and unweighted UniFrac, have had great success in comparing and visualizing high-dimensional metagenomic samples. Nonetheless, these metrics rely upon pre-established biological assumptions that might not capture key microbial players or relationships between some samples. On the contrary, supervised machine learning algorithms, such as random forests, can often capture intricate relationships between microbial samples; however, unveiling these relationships is often challenging due to the intricate inner mechanisms inherent to these algorithms.The adaptive Haar-like distance integrates the merits ofβ-diversity metrics and random forests, allowing for precise, intuitive, and visual comparison of metagenomic samples, offering valuable scientific insight into the distinctions and associations among microbial environments.