bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eligibility to COAPT trial in the daily practice: a real-world experience
Authors: Zancanaro Edoardo , Buzzatti Nicola , Denti Paolo , Guicciardi Nicolò Azzola , Melillo Enrico , Monaco Fabrizio , Agricola Eustachio , Ancona Francesco , Alfieri Ottavio , De Bonis Michele , Maisano Francesco 
Published: March 2024

ABSTRACTBackgroundThe COAPT Trial was the first ever to demonstrate a survival benefit in treating functional mitral regurgitation (FMR). That was achieved through transcatheter mitral repair in selected patient. The exact proportion of patients fulfilling COAPT selection criteria in the real-world is unknown.Objectivesto assess the applicability of COAPT criteria in real-world and its impact on patients’ survival.MethodsWe assessed the clinical data and follow-up results of all consecutive patients admitted for FMR at our Department between January 2016 and May 2021 according to COAPT eligibility. COAPT eligibility was retrospectively assessed by a cardiac surgeon and a cardiologist.ResultsAmong 394 patients, 56 (14%) were COAPT eligible. The most frequent reasons for exclusion were MR<=2 (22%), LVEF <20% or >50% (19%), and non-optimized GDMT (21.3%). Among NON-COAPT patients, weighted 4-year survival was higher in patients who received MitraClip compared to those who were left in optimized medical therapy (91.5% (CI: [0.864, 0.96] vs 71.8 % (CI = [0.509, 0.926]) respectively, p=0.027)ConclusionsOnly a minority (14%) of real-world patients with FMR referred to a tertiary hospital fulfilled the COAPT selection criteria. Among NON-COAPT patients, weighted 4-year survival was higher in patients who received MitraClip compared to those who were left in optimized medical therapy (91.5% (CI: [0.864, 0.96] vs 71.8 % (CI = [0.509, 0.926]) respectively, p=0.027)Condensed AbstractIn the present real-life single center experience, only a small proportion of patients with functional mitral regurgitation were COAPT-like. Non-COAPT like patients treated with MitraClip experienced improved survival compared to those left in medical therapy and similar survival compared to patients treated with MitraClip fulfilling COAPT criteria. While these findings require further validation, the numerous patients currently referred to percutaneous repair outside the COAPT criteria should not be denied intervention but should receive a tailored Heart-Team evaluation. Further refinement of patients selection for transcatheter mitral valve repair and longer follow-up remain necessary.Key messagesWhat is already known about this subject?It is established the efficacy of TEER in case of FMR and the results form the highly selective COAPT trial.What does this study add?This is the first article that prove the applicability of COAPT in real practice and shows the good outcomes also in patients excluded by the trial.How might this impact on clinical practice?This may help the operator not to exclude patients with anatomy and clinical features considered not fit from one of the most important trials in the last 10 years on TEER and medical therapy.
Genome-Wide Association Study Reveals Influence of Cell-specific Gene Networks on Soybean Root System Architecture
Authors: Sun Ying , Miller Charlotte , Rajurkar Ashish B. , Lynch Ryan C. , Alyward Anthony , Zhang Ling , Shaner Marieken , Copeland Charles D. , Ye Heng , Nguyen Henry T. , Busch Wolfgang , Michael Todd P. 
Published: March 2024

AbstractRoot system architecture (RSA) describes the shape and arrangement of a plant’s roots in the soil including the angle, rate of growth, and type of individual roots, which facilitates the uptake of nutrients and water. In crop improvement efforts, RSA has been less well studied due to the technical challenges associated with phenotyping roots as well as a focus on above-ground traits such as yield. We developed a gel-based root phenotyping system calledRADICYL(Root Architecture 3D Cylinder), which is a non-invasive, high-throughput approach that enabled us to measure 15 RSA traits. We leveragedRADICYLto perform a comprehensive genome-wide association study (GWAS) with a panel of 371 diverse soybean elite lines, cultivars, landraces, and closely related species to identify gene networks underlying RSA. We identified 54 significant single nucleotide polymorphisms (SNPs) in our GWAS, some of which were shared across multiple RSA traits while others were specific to a given trait. We generated a single cell atlas of the soybean root using single nuclei RNA sequencing (snRNAseq) to explore the associated genes in the context of root tissues. Using gene co-expression network (GCN) analyses applied to RNA-seq of soybean root tissues, we identified network-level associations of genes predominantly expressed in endodermis with root width, and of those expressed in metaphloem with lateral root length. Our results suggest that pathways active in the endodermis and metaphloem cell-types influence soybean root system architecture.
Insights into post-translational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP
Authors: Meyer Gretchen A. , Ferey Jeremie L.A. , Sanford James A. , Fitzgerald Liam S. , Greenberg Akiva E. , Svensson Kristoffer , Greenberg Michael J. , Schenk Simon 
Published: March 2024

AbstractMice with skeletal muscle-specific inducible double knockout of the lysine acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP-response element-binding protein binding protein), referred to as i-mPCKO, demonstrate a dramatic loss of contractile function in skeletal muscle and ultimately die within 7 days. Given that many proteins involved in ATP generation and cross-bridge cycling are acetylated, we investigated whether these processes are dysregulated in skeletal muscle from i-mPCKO mice and thus could underlie the rapid loss of muscle contractile function. Just 4-5 days after inducing knockout of p300 and CBP in skeletal muscle from adult i-mPCKO mice, there was ∼90% reduction inex vivocontractile function in the extensor digitorum longus (EDL) and a ∼65% reduction inin vivoankle dorsiflexion torque, as compared to wildtype (WT; i.e. Cre negative) littermates. Despite the profound loss of contractile force in i-mPCKO mice, there were no genotype-driven differences in fatigability during repeated contractions, nor were there genotype differences in mitochondrial specific pathway enrichment of the proteome, intermyofibrillar mitochondrial volume or mitochondrial respiratory function. As it relates to cross-bridge cycling, remarkably, the overt loss of contractile function in i-mPCKO muscle was reversed in permeabilized fibers supplied with exogenous Ca2+and ATP, with active tension being similar between i-mPCKO and WT mice, regardless of Ca2+concentration. Actin-myosin motility was also similar in skeletal muscle from i-mPCKO and WT mice. In conclusion, neither mitochondrial abundance/function, nor actomyosin cross-bridge cycling, are the underlying driver of contractile dysfunction in i-mPCKO mice.New & NoteworthyThe mechanism underlying dramatic loss of muscle contractile function with inducible deletion of both p300 and CBP in skeletal muscle remains unknown. Here we find that impairments in mitochondrial function or cross-bridge cycling are not the underlying mechanism of action. Future work will investigate other aspects of excitation-contraction coupling, such as Ca2+handling and membrane excitability, as contractile function could be rescued by permeabilizing skeletal muscle, which provides exogenous Ca2+and bypasses membrane depolarization.
Bioinformatic analysis of human ZPR1 gene pathogenic exome mutations
Authors: Abok Jeremiah I. , Garver William S. , Edwards Jeremy S. 
Published: March 2024

AbstractAdvanced sequencing technologies enable rapid detection of sequence variants, aiming to uncover the molecular foundations of human genetic disorders. The challenge lies in interpreting the influence of new exome variants that lead to diverse phenotypes. Our study introduces a detailed, multi-tiered method for assessing the impact of novel variants, particularly focusing on the zinc finger protein 1 (ZPR1) gene. Herein, we employed a combination of variant effect predictors, protein stability analyses, and the American College of Medical Genetics and Association of Molecular Pathology (ACMG/AMP) guidelines. Our structural analysis pinpoints specific amino acid residues in the ZPR1 zinc finger domains that are sensitive to changes, distinguishing between benign and disease-causing coding variants using rigorousin silicotools. We examined 223 germline ZPR1 exome variants, uncovering significant ethnic disparities in the frequency of heterozygous harmful ZPR1 variants, ranging from 0.04% in the Ashkenazi Jewish population to 0.34% in African/African Americans. Additionally, the discovery of three homozygous carriers in European and South Asian groups suggests a higher occurrence of ZPR1 variants in these demographics, meriting further exploration. This research provides insights into the prevalence and implications of amino acid substitutions in the ZPR1 protein.
Hydroxysteroid 17-beta dehydrogenase 13(Hsd17b13)knockdown attenuates liver steatosis in high-fat diet obese mice
Authors: Mahmood Shehroz , Morrice Nicola , Thompson Dawn , Milanizadeh Sara , Wilson Sophie , Whitfield Philip D. , Mcilroy George D. , Rochford Justin J. , Mody Nimesh 
Published: March 2024

ABSTRACTHydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) loss-of-function gene variants are associated with decreased risk of ‘metabolic dysfunction-associated steatotic liver disease’ (MASLD). Our RNA-seq analysis of steatotic liver from obese mice -/+ Fenretinide treatment identified major beneficial effects of Fenretinide on hepatic gene expression includingHsd17b13. We sought to determine the relationship between Hsd17b13 expression and MASLD and to validate it as a therapeutic target by liver-specific knockdown. Hsd17b13 expression, which is unique to hepatocytes and associated with the lipid-droplet, was elevated in multiple models of MASLD and normalised with prevention of obesity and steatotic liver. Direct, liver- specific, shRNA-mediated knockdown ofHsd17b13(shHsd17b13) in high-fat diet (HFD)-obese mice, markedly improved hepatic steatosis with no effect on body weight, adiposity or glycaemia.shHsd17b13decreased elevated serum ALT, serum FGF21 levels and markers of liver fibrosis e.g.Timp2.shHsd17b13knockdown in HFD-obese mice and Hsd17b13 overexpression in cells reciprocally regulated expression of lipid metabolism genes e.g.Cd36. Global lipidomic analysis of liver tissue revealed a major decrease in diacylglycerols (e.g. DAG 34:3) withshHsd17b13and an increase in phosphatidylcholines containing polyunsaturated fatty acids (PUFA) e.g. PC 34:3 and PC 42:10. Expression of key genes involved in phospholipid and PUFA metabolism e.g.Cept1, were also reciprocally regulated suggesting a potential mechanism of Hsd17b13 biological function and role in MASLD. In conclusion,Hsd17b13knockdown in HFD-obese adult mice was able to alleviate MASLD via regulation of fatty acid and phospholipid metabolism, thereby confirming HSD17B13 as a genuine therapeutic target for MASLD and development of liver fibrosis.KEY POINTSHSD17B13loss-of-function gene variants are associated with decreased risk of metabolic dysfunction-associated (MA) steatotic liver disease and steatohepatitis (MASLD and MASH).RNA-seq analysis of steatotic liver identified beneficial effects of Fenretinide on hepatic gene expression including downregulation ofHsd17b13.Liver-specific shRNA knockdown ofHsd17b13in obese mice markedly improved hepatic steatosis and markers of liver health e.g. serum ALT, serum Fgf21 levels.Hsd17b13 influenced expression of lipid/phospholipid metabolism genes e.g. Cd36 and Cept1 and phosphatidylcholines PC 34:3 and PC 42:10.Our study suggests a mechanism of HSD17B13’s biological function and the strong rationale behind targeting HSD17B13 for MASLD/MASH.
Premeiotic endoreplication is the mechanism of obligate parthenogenesis in rock lizards of the genusDarevskia
Authors: Dedukh Dmitrij , Altmanová Marie , Petrosyan Ruzanna , Arakelyan Marine , Galoyan Eduard , Kratochvíl Lukáš 
Published: March 2024

AbstractAmong vertebrates, obligate parthenogenesis occurs exclusively in squamate reptiles. Premeiotic endoreplication in a small subset of developing oocytes has been documented as the mechanism of production of unreduced eggs in minutely explored obligate parthenogenetic lineages, namely in teiids and geckos. The situation in the lacertid genusDarevskiahas been discussed for decades. Certain observations suggested that ploidy level is restored during egg formation through a fusion of egg and polar body nuclei inD. unisexualisandD. armeniaca. In this study, we re-evaluated the fusion hypothesis by studying diplotene chromosomes in adult females of sexual speciesD. raddei nairensisand obligate parthenogensD. armeniaca, D. dahliandD. unisexualis. We revealed 19 bivalents in the sexual species and 38 bivalents in the diploid obligate parthenogens, which uncovers premeiotic endoreplication as the mechanism of the production of non-reduced eggs in parthenogenetic females. The earlier contradicting reports can be likely attributed to the difficulty in identifying mispairing of chromosomes in pachytene, and the fact that in parthenogenetic reptiles relying on premeiotic endoreplication only a small subset of developing oocytes undergo genome doubling and overcome the pachytene checkpoint. This study highlights co-option of premeiotic endoreplication for escape from sexual reproduction in all independent hybrid origins of obligate parthenogenesis in vertebrates studied to date.
Taste evolution in an herbivorous drosophilid
Authors: Peláez Julianne N. , Bernstein Susan , Okoro Judith , Rodas Esteban , Liang Irene , Leipertz Anna , Marion-Poll Frédéric , Whiteman Noah K. 
Published: March 2024

ABSTRACTPlant secondary metabolites pose a challenge for generalist herbivorous insects because they are not only potentially toxic, they also may trigger aversion. On the contrary, some highly specialized herbivorous insects evolved to use these same compounds as ‘token stimuli’ for unambiguous determination of their host plants. Two questions that emerge from these observations are how recently derived herbivores evolve to overcome this aversion to plant secondary metabolites and the extent to which they evolve increased attraction to these same compounds. In this study, we addressed these questions by focusing on the evolution of bitter taste preferences in the herbivorous drosophilidScaptomyza flava, which is phylogenetically nested deep in the paraphyleticDrosophila. We measured behavioral and neural responses ofS. flavaand a set of non-herbivorous species representing a phylogenetic gradient (S. pallida, S. hsui, andD. melanogaster) towards host- and non-host derived bitter plant compounds. We observed thatS. flavaevolved a shift in bitter detection, rather than a narrow shift towards glucosinolates, the precursors of mustard-specific defense compounds. In a dye-based consumption assay,S. flavaexhibited shifts in aversion toward the non-mustard bitter, plant-produced alkaloids caffeine and lobeline, and reduced aversion towards glucosinolates, whereas the non-herbivorous species each showed strong aversion to all bitter compounds tested. We then examined whether these changes in bitter preferences ofS. flavacould be explained by changes in sensitivity in the peripheral nervous system and compared electrophysiological responses from the labellar sensilla ofS. flava,S. pallida, andD. melanogaster. Using scanning electron microscopy, we also created a map of labellar sensilla inS. flavaandS. pallida. We assigned each sensillum to a functional sensilla class based on their morphology and initial response profiles to bitter and sweet compounds. Despite a high degree of conservation in the morphology and spatial placement of sensilla betweenS. flavaandS. pallida, electrophysiological studies revealed thatS. flavahad reduced sensitivity to glucosinolates to varying degrees. We found this reduction only in I type sensilla. Finally, we speculate on the potential role that evolutionary genetic changes in gustatory receptors betweenS. pallidaandS. flavamay play in driving these patterns. Specifically, we hypothesize that the evolution of bitter receptors expressed in I type sensilla may have driven the reduced sensitivity observed inS. flava, and ultimately, its reduced bitter aversion. TheS. flavasystem showcases the importance of reduced aversion to bitter defense compounds in relatively young herbivorous lineages, and how this may be achieved at the molecular and physiological level.
FLYNC: A Machine Learning-Driven Framework for Discovering Long Non-Coding RNAs inDrosophila melanogaster
Authors: dos Santos Ricardo F. , Baptista Tiago , Marques Graça S. , Homem Catarina C. F. 
Published: March 2024

ABSTRACTNon-coding RNAs have increasingly recognized roles in critical molecular mechanisms of disease. However, the non-coding genome ofDrosophila melanogaster, one of the most powerful disease model organisms, has been understudied. Here, we present FLYNC – FLY Non-Coding discovery and classification – a novel machine learning-based model that predicts the probability of a newly identified RNA transcript being a long non-coding RNA (lncRNA). Integrated into an end-to-end bioinformatics pipeline capable of processing single-cell or bulk RNA sequencing data, FLYNC outputs potential new non-coding RNA genes. FLYNC leverages large-scale genomic and transcriptomic datasets to identify patterns and features that distinguish non-coding genes from protein-coding genes, thereby facilitating lncRNA prediction. We demonstrate the application of FLYNC to publicly availableDrosophilaadult head bulk transcriptome and single-cell transcriptomic data fromDrosophilaneural stem cell lineages and identify several novel tissue- and cell-specific lncRNAs. We have further experimentally validated the existence of a set of FLYNC positive hits by qPCR. Overall, our findings demonstrate that FLYNC serves as a robust tool for identifying lncRNAs inDrosophila melanogaster, transcending current limitations in ncRNA identification and harnessing the potential of machine learning.
Evidence for the independent evolution of a rectal complex within the beetle superfamily Scarabaeoidea
Authors: Beaven Robin , Denholm Barry , Fremlin Maria , Scaccini Davide 
Published: March 2024

AbstractRectal or cryptonephridial complexes have evolved repeatedly in arthropods, including in beetles where they occur in ∼190,000 species of Cucujiformia and Bostrichoidea, and Lepidoptera where they occur in ∼160,000 species. Sections of the Malpighian/renal tubules coat the outer surface of the rectum, acting as powerful recycling systems of the gut contents, recovering water and specific solutes. There are hints that a rectal complex evolved independently within another beetle group, Scarabaeoidea. Here we report our observations of rectal complexes in Scarabaeoidea, which support this view. We did not find a rectal complex in the related group, Staphylinoidea, or in Lucanidae, a basal group of Scarabaeoidea. We did observe rectal complexes inMelolontha melolontha(Melolonthini),Pachnoda marginataandCetonia aurata(Cetoniinae), consistent with previous reports from these groups. Intriguingly we found that rectal complexes occur in adult, but notM. melolonthalarvae, and larvae but not adults within Cetoniinae, indicating dramatic pupal remodelling of these organ systems. Insights into the structure of the rectal complexes of Scarabaeoidea are compared with the well-studied rectal complexes of Cucujiformia. Finally we discuss possible functions of the rectal complexes of beetles within Scarabaeoidea, and future approaches to address this question.
Nextflow vs. plain Bash: Different Approaches to the Parallelisation of SNP Calling from the Whole Genome Sequence Data
Authors: Sztuka Marek , Kotlarz Krzysztof , Mielczarek Magda , Hajduk Piotr , Liu Jakub , Szyda Joanna 
Published: March 2024

AbstractThis study compared computational approaches to parallelisation of an SNP calling workflow. Data comprised DNA from five Holstein-Friesian cows sequenced with the Illumina platform. The pipeline consisted of quality control, alignment to the reference genome, post-alignment, and SNP calling. Three approaches to parallelisation were compared: (i) a plain Bash script in which a pipeline for each cow was executed as separate processes invoked at the same time, (ii) a Bash script wrapped in a single Nextflow process, and (iii) a Nextflow script with each component of the pipeline defined as a separate process. The results demonstrated that on average, the multi-process Nextflow script performed 15% to 27% faster depending on the number of assigned threads, with the biggest execution time advantage over the plain Bash approach observed with 10 threads. In terms of RAM usage, the most substantial variation was observed for the multi-process Nextflow, for which it increased with the number of assigned threads, while RAM consumption of the other setups did not depend much on the numbers of threads assigned for computations. Due to intermediate and log files generated, disk usage was markedly higher for the multi-process Nextflow than for the plain Bash and for the single-process Nextflow.
Multi-COBRA hemagglutinin formulated with cGAMP microparticles elicit protective immune responses against influenza viruses
Authors: Zhang Xiaojian , Shi Hua , Hendy Dylan A. , Bachelder Eric M. , Ainslie Kristy M. , Ross Ted M. 
Published: March 2024

AbstractInfluenza viruses cause a common respiratory disease known as influenza. In humans, seasonal influenza viruses can lead to epidemics, with avian influenza viruses of particular concern because they can infect multiple species and lead to unpredictable and severe disease. Therefore, there is an urgent need for a universal influenza vaccine that provides protection against seasonal and pre-pandemic influenza virus strains. The cyclic GMP-AMP (cGAMP) is a promising adjuvant for subunit vaccines that promotes type I interferons production through the stimulator of interferon genes (STING) pathway. The encapsulation of cGAMP in acetalated dextran (Ace-DEX) microparticles (MPs) enhances its intracellular delivery. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to generate H1, H3, and H5 vaccine candidates. Monovalent and multivalent COBRA HA vaccines formulated with cGAMP Ace-DEX MPs were evaluated in a mouse model for antibody responses and protection against viral challenge. Serological analysis showed that cGAMP MPs adjuvanted monovalent and multivalent COBRA vaccines elicited robust antigen-specific antibody responses after a prime-boost vaccination and antibody titers were further enhanced after second boost. Compared to COBRA vaccine groups with no adjuvant or blank MPs, the cGAMP MPs enhanced HAI antibody responses against COBRA vaccination. The HAI antibody titers were not significantly different between cGAMP MPs adjuvanted monovalent and multivalent COBRA vaccine groups for most of the viruses tested in panels. The cGAMP MPs adjuvanted COBRA vaccines groups had higher antigen-specific IgG2a binding titers than the COBRA vaccine groups with no adjuvant or blank MPs. The COBRA vaccines formulated with cGAMP MPs mitigated disease caused by influenza viral challenge and decreased pulmonary viral titers in mice. Therefore, the formulation of COBRA vaccines plus cGAMP MPs is a promising universal influenza vaccine that elicits protective immune responses against human seasonal and pre-pandemic strains.