bluuebunny/crossref_metadata_2025_split huggingface dataset:
Personalized Molecular Signatures of Insulin Resistance and Type 2 Diabetes
Authors: Larsen Jeppe Kjærgaard , Stocks Ben , Henderson John , Andersson Daniel , Bäckdahl Jesper , Eriksson-Hogling Daniel , Stidsen Jacob V. , Sakamoto Kei , Højlund Kurt , Rydén Mikael , Zierath Juleen R. , Krook Anna , Deshmukh Atul S. 
Published: February 2024

AbstractHighlightsAdvanced proteomics analysis reveals personalized signatures of insulin resistanceFasting muscle proteome and phosphoproteome predicts whole-body insulin sensitivityInsulin-stimulated phosphoproteome reveals selective insulin resistance signaturesPhosphoproteome and proteome atlas explains sex-specific muscle metabolismGraphical AbstractInsulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deepin vivophenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes - even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings underscore the need for precision medicine approaches in type 2 diabetes care, acknowledging disease heterogeneity.
A Cautionary Note on Using STRUCTURE to Detect Hybridization in a Phylogenetic Context
Authors: Pang Xiao-Xu , Zhang Da-Yong 
Published: February 2024

AbstractPopulation genetic clustering methods are widely used to detect hybridization events between closely related populations within species, as well as between deeply diverged lineages across phylogenetic time-scales, although their strengths and limitations in the latter cases remain poorly explored. This study presents the first systematic evaluation of the performance of the most popular population clustering method, STRUCTURE, under a variety of cross-species hybridization scenarios, including hybrid speciation, as well as introgression involving ghost (i.e., extinct or unsampled) lineages or otherwise. Our simulations demonstrate that STRUCTURE performs well in identifying hybrids and their parental donors only when admixture happens very recently between sampled extant lineages. However, STRUCTURE generally fails to detect signals of admixture when hybridization occurs in deep time or when gene flow stems from ghost lineages. We find that symmetrical parental contribution in cases of hybrid speciation will often be revealed as extremely asymmetrical in STRUCTURE, especially when the admixture event occurred more than some time ago. Our results suggest that population-genetic clustering methods may be very inefficient for detecting either ancient or ghost admixtures, partly explaining why ghost introgression has escaped the attention of evolutionary biologists until recently.
miR-203 controls developmental timing and early fate restriction during preimplantation embryogenesis
Authors: González-Martínez José , Sánchez-Belmonte Agustín , Ayala Estefanía , García Alejandro , Nogueira Enrique , Muñoz Jaime , Melati Anna , Giménez Daniel , Losada Ana , Ortega Sagrario , Malumbres Marcos 
Published: February 2024

AbstractCommonly expressed at developmental transitions, microRNAs operate as fine tuners of gene expression to facilitate cell fate acquisition and lineage segregation. Nevertheless, how they might regulate the earliest developmental transitions in early mammalian embryogenesis remains obscure. Here, in a strictly in vivo approach based on novel genetically-engineered mouse models and single-cell RNA sequencing, we identify miR-203 as a critical regulator of timing and cell fate restriction within the totipotency to pluripotency transition in mouse embryos. Genetically engineered mouse models show that loss of miR-203 slows down developmental timing during preimplantation leading to the accumulation of embryos with high expression of totipotency-associated markers, including MERVL endogenous retroviral elements. A new embryonic reporter (eE-Reporter) transgenic mouse carrying MERVL-Tomato and Sox2-GFP transgenes showed that lack of miR-203 leads to sustained expression of MERVL and reduced Sox2 expression in preimplantation developmental stages. A combination of single-cell transcriptional studies and epigenetic analyses identified the central coactivator and histone acetyltransferase P300 as a major miR-203 target at the totipotency to pluripotency transition in vivo. By fine tuning P300 levels, miR-203 carves the epigenetic rewiring process needed for this developmental transition, allowing a timely and correctly paced development.
Dispensable regulation of brain development and myelination by the immune-related protein Serpina3n
Authors: Zhu Meina , Wang Yan , Park Joohyun , Titus Annlin , Guo Fuzheng 
Published: February 2024

AbstractSerine protease inhibitor clade A member 3n (Serpina3n) or its human orthologue SERPINA3 is a secretory immune-related molecule produced primarily in the liver and brain under homeostatic conditions and upregulated in response to system inflammation. Yet it remains elusive regarding its cellular identity and physiological significance in the development of the postnatal brain. Here, we reported that oligodendroglial lineage cells are the major cell population expressing Serpina3n protein in the postnatal murine CNS. Using loss-of-function genetic tools, we found that Serpina3n conditional knockout (cKO) from Olig2-expressing cells does not significantly affect cognitive and motor functions in mice. Serpina3n depletion does not appear to interfere with oligodendrocyte differentiation and developmental myelination nor affects the population of other glial cells and neuronsin vivo. Together, these data suggest that the immune-related molecule Serpina3n plays a minor role, if any, in regulating neural cell development in the postnatal brain under homeostatic conditions. We found that Serpina3n is significantly upregulated in response to oxidative stress, and it potentiates oxidative injury and cell senescence of oligodendrocytes. Our data raise the interest in pursuing its functional significance in the CNS under disease/injury conditions.
A reassessment of Hardy-Weinberg equilibrium filtering in large sample Genomic studies
Authors: Greer Phil J , Sedlakova Anastazie , Ellison Mitchell , Oranburg Talia DeFrancesco , Maiers Martin , David C Whitcomb , Busby Ben 
Published: February 2024

ABSTRACTHardy Weinberg Equilibrium (HWE) is a fundamental principle of population genetics. Adherence to HWE, using a p-value filter, is used as a quality control measure to remove potential genotyping errors prior to certain analyses. Larger sample sizes increase power to differentiate smaller effect sizes, but will also affect methods of quality control. Here, we test the effects of current methods of HWE QC filtering on varying sample sizes up to 486,178 subjects for imputed and Whole Exome Sequencing (WES) genotypes using data from the UK Biobank and propose potential alternative filtering methods.METHODSSimulations were performed on imputed genotype data using chromosome 1. WES GWAS (Genome Wide Association Study) was performed using PLINK2.RESULTSOur simulations on the imputed data from Chromosome 1 show a progressive increase in the number of SNPs eliminated from analysis as sample sizes increase. As the HWE p-value filter remains constant at p<1e-15, the number of SNPs removed increases from 1.66% at n=10,000 to 18.86% at n=486,178 in a multi-ancestry cohort and from 0.002% at n=10,000 to 0.334% at n=300,000 in a European ancestry cohort. Greater reductions are shown in WES analysis with a 11.91% reduction in analyzed SNPs in a European ancestry cohort n=362,192, and a 32.70% reduction in SNPs in a multi-ancestry dataset n=463,605. Using a sample size specific HWE p-value cutoff removes ∼ 2.25% of SNPs in the all ancestry cohort across all sample sizes, but does not currently scale beyond 300,000 samples. A hard cutoff of +/- 20% deviation from HWE produces the most consistent results and scales across all sample sizes but requires additional user steps.CONCLUSIONTesting for deviance from HWE may still be an important quality control step in GWAS studies, however we demonstrate here that using an HWE p-value threshold that is acceptable for smaller sample sizes will be inappropriate for large sample studies due to an unnecessarily high number of variants removed prior to analysis. Rather than exclude variants that fail HWE prior to analysis it may be better to include all variants in the analysis and examine their deviation from HWE afterward. We believe that adjusting the cutoffs will be even more important for large whole genome sequencing results and more diverse population studies.KEY TAKEAWAYSCurrent thresholds for assessing HWE are impractical for large sample sizes.Filtering imputed datasets for HWE regardless of sample size is unnecessary and in fact detrimental if you have a diverse, mixed, or unknown ancestry cohort.WES data shows more distributed deviation from HWE for all Minor Allele Frequencies (MAF).We present an alternative p-value filter for HWE for large sample sizes.We recommend that all genotype data (imputed, WES or WGS) should be analyzed, HWE computed, results combined, and then filtered post-hoc.
Heterogeneity of Diagnosis and Documentation of Post-COVID Conditions in Primary Care: A Machine Learning Analysis
Authors: Hendrix Nathaniel , Parikh Rishi V. , Taskier Madeline , Walter Grace , Rochlin Ilia , Saydah Sharon , Koumans Emilia H. , Rincón-Guevara Oscar , Rehkopf David H. , Phillips Robert L. 
Published: February 2024

AbstractBackgroundPost-COVID conditions (PCC) present clinicians with significant challenges due to their variable presentation.ObjectiveTo characterize patterns of PCC diagnosis in generalist primary care settings.DesignRetrospective observational studySetting519 primary care clinics around the United States who were in the American Family Cohort registry between October 1, 2021 and November 1, 2023.Patients6,116 with diagnostic code for PCC; 5,020 with PCC and COVID-19MeasurementsTime between COVID-19 and PCC (U09.9) diagnostic codes; count of patients with PCC diagnostic codes per clinician; patient-specific probability of PCC diagnostic code estimated by a tree-based machine learning model trained on clinician and specific practice visited, patient demographics, and other diagnoses; performance of a natural language classifier trained on notes from 5,000 patients annotated by two physicians to indicate probable PCC.ResultsOf patients with diagnostic codes for PCC and COVID-19, 43.0% were diagnosed with PCC less than 4 weeks after initial recorded COVID-19 diagnostic code. Six clinicians (out of 3,845 total) made 15.4% of all PCC diagnoses. The high-performing (F1: 0.98) tree-based model showed that patient demographics, practice visited, clinician visited, and calendar date of visit were more predictive of PCC diagnostic code than any symptom. Inter-rater agreement on PCC diagnosis was moderate (Cohen’s kappa: 0.60), and performance of the natural language classifiers was poor (best F1: 0.54).LimitationsCannot validate date of COVID-19 diagnosis, as it may not reflect when disease began and could have been coded retrospectively. Few options for medically focused language models.ConclusionWe identified multiple sources of heterogeneity in the documentation of PCC diagnostic codes in primary care practices after introduction of ICD-10 codes for PCC, which has created challenges for public health surveillance.Funding SourceUS CDC
Estimation of mean pulmonary artery pressure by cardiovascular magnetic resonance four-dimensional flow and compressed sensing
Authors: Abdula Goran , Bergqvist Pernilla , Castaings Jenny , Fyrdahl Alexander , Giese Daniel , Jin Ning , Testud Frederik , Sörensson Peder , Sigfridsson Andreas , Ugander Martin , Marlevi David 
Published: February 2024

AbstractBackgroundFour-dimensional (4D) phase-contrast cardiovascular magnetic resonance (CMR) allows for precise non-invasive estimation of mean pulmonary artery pressure (mPAP) by estimating the duration of pathological vortex persistence in the main pulmonary artery. This has previously been achieved with compressed sensing acceleration of a multiple two-dimensional (CS-M2D) flow sequence, but acquisition using a true time-resolved 3D excitation (CS-4D) offers theoretical advantages including spatiotemporal coherence. This study aimed to validate a state-of-the-art CS-4D sequence with a previously utilized CS-M2D sequence for estimating mPAP, and compare both to right heart catheterization (RHC).MethodsThe study included patients clinically referred for CMR (n=45), of which a subgroup (n=20) had prior mPAP of >16 mmHg confirmed by RHC. CMR was performed at 1.5T using CS-M2D and CS-4D sequences covering the main pulmonary artery. mPAP was estimated using a previously published linear relationship between vortex duration and mPAP. Agreement between CS-M2D and CS-4D estimates was quantified, including analysis of intra- and interobserver variabilities. The diagnostic performance of CS-M2D and CS-4D in predicting mPAP was further compared to gold-standard RHC.ResultsCS-M2D and CS-4D both had average scan durations under 3 minutes (175±36 and 135±34 seconds, respectively). Estimated mPAP by CS-4D and CS-M2D were strongly correlated (R2=0.93, p<0.001), with negligible mean±SD bias (0.0±2.7 mmHg) and good reproducibility. There was excellent agreement with RHC for both CS-M2D (R2=0.92, p<0.001, bias 0.6±3.1 mmHg) and CS-4D (R2=0.86, p<0.001, bias 1.1±4.5 mmHg).ConclusionsCS-4D and CS-M2D sequences effectively yield interchangeable non-invasive estimations of mPAP, with excellent agreement compared to invasive RHC. They can both be acquired in a scan time applicable to clinical workflow, offering a promising tool for non-invasive mPAP estimation in clinical practice.
High Initial Heart Rate Score is an Independent Predictor of New Atrial High-Rate Episodes in Pacemaker Patients with Sinus Node Dysfunction
Authors: Hayashi Katsuhide , Abe Haruhiko , Olshansky Brian , Sharma Arjun D. , Jones Paul W. , Wold Nicholas , Perschbacher David , Kohno Ritsuko , Lip Gregory Y. H. , Wilkoff Bruce L. 
Published: February 2024

AbstractBackgroundHeart Rate Score (HRSc), the percent of atrial beats in the largest paced/sensed 10-bpm histogram bin recorded in cardiac devices, is a metric of chronotropic incompetence. It remains uncertain if HRSc independently predicts atrial high-rate episodes (AHREs) in patients with sinus node dysfunction (SND) undergoing pacemaker (PM) implantation.ObjectiveTo determine the relationship between initial HRSc post-PM implant and new-onset AHREs in patients with SND.MethodsThe cohort included patients with Boston Scientific PMs implanted for SND from 2012-2021 at Cleveland Clinic, University of Occupational and Environmental Health, Japan, Kyushu Rosai Hospital, and JCHO Kyushu Hospital. Patients were excluded if they had atrial fibrillation before PM implant or AHREs in the initial 3-months post-implant. Subsequent AHREs post-implant (>1% of atrial beats>170 bpm) were evaluated.ResultsOver 48.9 (IQR 25.8-50.4) months, 136 consecutive PM patients (age 75±10 years, 42% male) were followed. The median initial HRSc was 73(55-86)%. AHREs developed in 28/136 (21%). Although %RA pacing and HRSc correlated, rate-responsive pacing was associated with a HRSc only in the patients with high %RA pacing. Patients with HRSc≥80% had higher occurrence of AHREs than those with HRSc<80% (p=0.01, log-rank test). After adjusting for age, race, comorbidities, left ventricular ejection fraction, left atrial diameter, %RA/RV pacing, and rate-response programming, HRSc (HR:2.84, 95% CI:1.17-6.92; P=0.02) and male sex (HR:2.55, 95% CI:1.15-6.19; P=0.04) were independent predictors of AHREs.ConclusionHRSc≥80% independently predicted new-onset, device-determined AHREs for patients undergoing PM implant for SND. HRSc may have prognostic and therapeutic implications.
Arktos: a simple tool for the design of polyhedral DNA nanostructures
Authors: Balaji Harshitha , Samprathi Anish Hemanth , Kolipakala Rakshita Sukruth , Pradeep Pushya , Nagarajan Deepesh 
Published: February 2024

ABSTRACTDNA nanostructures are a class of self-assembling nanomaterials with a wide range of potential applications in biomedicine and nanotechnology. The history of DNA nanotechnology can be traced back to the 1980s with the development of simple DNA polyhedra using either human intuition or simple algorithms. Today the field is dominated by DNA origami constructs to such an extent that the original algorithms used to design non-origami nanostructures have been lost. In this work we describe Arktos: an algorithm developed to design simple DNA polyhedra without the use of DNA origami. Arktos designs sequences predicted to fold into a desired structure using simulated annealing optimization. As a proof-of-concept, we used Arktos to design a simple DNA tetrahedron. The generated oligonucleotide sequences were synthesized and experimentally validated via polyacrylamide gel electrophoresis, indicating that they fold into the desired structure. These results demonstrate that Arktos can be used to design custom DNA polyhedra as per the needs of the research community.
Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus
Authors: Watanabe Mayumi , Uematsu Akira , Johansen Joshua P. 
Published: February 2024

AbstractTraumatic experiences produce powerful emotional memories which can subsequently be enhanced or reduced through cognitive control mechanisms. Noradrenaline from the brainstem locus coeruleus (LC) is activated during aversive emotion-inducing experiences and upregulated in individuals suffering from anxiety and trauma related disorders. The medial prefrontal cortex (mPFC) participates in cognitive and emotional control processes such as production of learned defensive responses and suppression of aversive memories through extinction. However, it is unclear whether or how distinct mPFC regions influence the LC to regulate learned emotional responding. Using viral based anatomical tracing techniques, we found that the LC receives topographically organized projections from the prelimbic (PL) and infralimbic (IL) subregions of mPFC. Furthermore, optogenetic approaches revealed that PL and IL inputs to LC are required to inhibit or facilitate, respectively, the extinction of aversive memories. Moreover, LC-projecting neurons in PL and IL exhibited distinct activity patterns during extinction learning, with IL-to-LC neurons displaying sustained, sensory cue-evoked activation, while activity in PL-to-LC inputs is elevated during periods of externally and internally generated aversive emotional responding. Together, these results demonstrate that mPFC subregions bidirectionally regulate extinction of emotional memories through differential modulation of the LC-noradrenaline system.
Loop-mediated Isothermal Amplification (LAMP) assay for reliable detection ofXanthomonas axonopodispv.vasculorum
Authors: Marabella Mitchell , Howard Julia , Bhandari Santosh , Do Sally , Montoya-Pimolwatana Maya , Dou Yichen , Dobhal Shefali , Arizala Dario , Montesinos Stefania , Andreason Sharon A. , Ochoa-Corona Francisco , Bingham Jon-Paul , Odani Jenee , Jenkins Daniel , Ma Li Maria , Fletcher Jacqueline , Stack James P. , Arif Mohammad 
Published: February 2024

AbstractXanthomonas axonopodispv.vasculorum(Xav), the causative agent of sugarcane gumming disease, represents a significant threat to global sugarcane production due to its systemic and destructive nature. Despite the economic implications, a field-deployable, Xav-specific diagnostic tool has not been developed. This resulted in a loop-mediated isothermal amplification (LAMP) assay targeting thepelLgene, unique to Xav strains, as a rapid and precise diagnostic assay. The selection of thepelLgene was informed by comprehensivein silicoanalyses of Xav genomes and relatedXanthomonasspecies and other close relatives. Validation against the NCBI GenBank database and internally sequenced genomes confirmed the gene’s exclusivity to Xav. Subsequent primers for both endpoint PCR and LAMP assays were designed using thepelLgene region. The LAMP assay underwent extensive testing against inclusivity and exclusivity panels. Use of exclusivity panel, comprising 81 strains from related species, other bacterial genera, and host genomes, demonstrated the assay’s specificity with no false positives. The assay exhibited a detection limit of 1 pg, and its effectiveness was unimpeded by crude host lysate (sugarcane). Further validation through multi-device and multi-operator testing underscored the assay’s 100% reproducibility and robustness. Application to infected plant samples resulted in the detection of all infected specimens without any false positives or negatives. This novel LAMP assay is accurate and reliable tool for Xav detection, with promising applications in routine diagnostics, biosecurity measures, microbial forensics, and epidemiological research.
Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators
Authors: Malone Taylor J. , Wu Jing , Zhang Yalan , Licznerski Pawel , Chen Rongmin , Nahiyan Sheikh , Pedram Maysam , Jonas Elizabeth A. , Kaczmarek Leonard K. 
Published: February 2024

SUMMARYNeuronal activity stimulates mRNA translation crucial for learning and development. While FMRP (Fragile X Mental Retardation Protein) and CYFIP1 (Cytoplasmic FMR1 Interacting Protein 1) regulate translation, the mechanism linking translation to neuronal activity is not understood. We now find that translation is stimulated when FMRP and CYFIP1 translocate to the potassium channel Slack (KCNT1, Slo2.2). When Slack is activated, both factors are released from eIF4E (Eukaryotic Initiation Factor 4E), where they normally inhibit translation initiation. A constitutively active Slack mutation and pharmacological stimulation of the wild-type channel both increase binding of FMRP and CYFIP1 to the channel, enhancing the translation of a reporter for β-actin mRNA in cell lines and the synthesis of β-actin in neuronal dendrites. Slack activity-dependent translation is abolished when both FMRP and CYFIP1 expression are suppressed. The effects of Slack mutations on activity-dependent translation may explain the severe intellectual disability produced by these mutations in humans.HIGHLIGHTSActivation of Slack channels triggers translocation of the FMRP/CYFIP1 complexSlack channel activation regulates translation initiation of a β-actin reporter constructA Slack gain-of-function mutation increases translation of β-actin reporter construct and endogenous cortical β-actinFMRP and CYFIP1 are required for Slack activity-dependent translationIN BRIEFMaloneet al. show that the activation of Slack channels triggers translocation of the FMRP/CYFIP1 complex from the translation initiation factor eIF4E to the channel. This translocation releases eIF4E and stimulates mRNA translation of a reporter for β-actin and cortical β-actin mRNA, elucidating the mechanism that connects neuronal activity with translational regulation.