bluuebunny/crossref_metadata_2025_split huggingface dataset:
dsRNAEngineer: a web-based tool of comprehensive dsRNA design for pest control
Authors: Chen Yang , Shi Yufei , Wang Ziguo , An Xin , Wei Siyu , Andronis Christos , Vontas John , Wang Jin-jun , Niu Jinzhi 
Published: July 2024

AbstractRNA interference (RNAi) is a form of gene silencing triggered by double-stranded RNA (dsRNA) that operates in all eukaryotic organisms, including insects, mites, nematodes and fungi. In the last two decades, many dsRNAs have been synthesized to silence the target genes for exploration of the underlying function in these pests. Some of them are lethal to pests or inhibit the growth of the pest population, leading to a new concept of pesticides. The generation of these environment-friendly pesticides requires precisein silicodesign of dsRNA molecules that are specific to target pests but do not target non-pest organisms. Current efforts for dsRNA design are mostly focused on gene sequence level, lacking comprehensive analysis of RNAi-based mode-of-action at the whole transcriptome level of given species, causing low efficiency and imprecise dsRNA target exploration. To address these limitations, we have created dsRNAEngineer, a publicly available online tool that allows a comprehensive and rational dsRNA design, incorporating hundreds of pests and non-pests transcriptomes. Developed functionalities include screen-target (screen conserved genes for co-targets of various pest species), on-target, off-target, and multi-target to generate optimal dsRNA for precise pest control. dsRNAEngineer is available athttps://dsrna-engineer.cn/.Graphical abstract
Functional optimization in distinct tissues and conditions constrains the rate of protein evolution
Authors: Usmanova Dinara R. , Plata Germán , Vitkup Dennis 
Published: July 2024

AbstractUnderstanding the main determinants of protein evolution is a fundamental challenge in biology. Despite many decades of active research, the molecular and cellular mechanisms underlying the substantial variability of evolutionary rates across cellular proteins are not currently well understood. It also remains unclear how protein molecular function is optimized in the context of multicellular species and why many proteins, such as enzymes, are only moderately efficient on average. Our analysis of genomics and functional datasets reveals in multiple organisms a strong inverse relationship between the optimality of protein molecular function and the rate of protein evolution. Furthermore, we find that highly expressed proteins tend to be substantially more functionally optimized. These results suggest that cellular expression costs lead to more pronounced functional optimization of abundant proteins, and that the purifying selection to maintain high levels of functional optimality significantly slows protein evolution. We observe that in multicellular species both the rate of protein evolution and the degree of protein functional efficiency are primarily affected by expression in several distinct cell types and tissues. Specifically, in developed neurons with upregulated synaptic processes in animals and in young and fast-growing tissues in plants. Overall, our analysis reveals how various constraints from the molecular, cellular, and species’ levels of biological organization jointly affect the rate of protein evolution and the level of protein functional adaptation.
Localization ofDrosophilaformin, Cappuccino, influences posterior oocyte organization
Authors: Bailey Hannah M. , Cullimore Peter B. M. , Bailey Liam A. , Quinlan Margot E. 
Published: July 2024

AbstractCappuccino (Capu) and Spire build actin networks in numerous systems, including the mouse oocyte, melanocytes, and the Drosophila oocyte. As observed in mammalian systems, the localization of the Capu homologues (FMN1/2), influences the function of the actin network. Therefore, we established and interrogated the impact of altering Capu’s localization in the Drosophila oocyte to better understand its role and that of the actin mesh it builds. This mesh restricts bulk cytoplasmic flows, streaming, but otherwise remains undescribed functionally. Using a gene specific driver, capu-Gal4, to better study Capu transgenes, we found that fertility was markedly decreased when restricting Capu to membranes in the oocyte, although its canonical role in actin mesh assembly was apparently unaltered. Instead, we observed a defect in posterior anchoring of the mRNA oskar during mid-oogenesis. However, the defect did not fall into the traditional posterior group phenotype. The data suggest that Capu, independently of Spire, tethers the posterior determinants to the cortex but does not anchor them to each other, supporting that Capu localization influences the posterior oocyte organization.
Engineered microvasculature using maskless photolithography and on-chip hydrogel patterning: a facile approach
Authors: Kasi Dhanesh G. , de Graaf Mees N. S. , Nahon Dennis M. , van den Hil Francijna E. , van den Maagdenberg Arn M. J. M. , Mummery Christine L. , Orlova Valeria V. 
Published: July 2024

AbstractIn vitromodels of human microvasculature are increasingly used to understand blood vessel diseases and to support drug development. Most engineered models, however, are slow and labor-intensive to produce. Here, we used a single commercial digital micromirror device (DMD)-based setup for maskless photolithography to both fabricate microfluidic chips and pattern the inside of these chips with gelatin methacrylate (GelMA) hydrogels. These hydrogel scaffolds had tunable stiffness, could be generated rapidly and were suitable for forming perfusable microvasculature from human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs). When cultured in narrow channels, the hiPSC-ECs adopted a tubular morphology that was similar to capillariesin vivo, but they followed the square channel geometry in wider channels. Compartmentalization of the chips allowed co-culture of hiPSC-ECs with hiPSC-derived astrocytes, thereby increasing model complexity. Furthermore, valve-like structures could be patterned inside the channels, mimicking functional vascular valves, holding promise for thrombosis and lymphatic vasculature research.
Identification of novel loci regulating dormancy in barley and association with hypoxia sensitivity
Authors: Farquharson Lochlen , Samanfar Bahram , Khanal Raja , Bekele Wubishet , Brauer Elizabeth K. 
Published: July 2024

AbstractLow seed dormancy is an essential trait in malting barley since malting involves rapid and uniform induction of germination. At least two major QTLs on chromosome 5H, SD1 and SD2, regulate dormancy in multiple barley populations, and additional genetic regions are thought to be involved. To identify novel genetic loci that might be associated with dormancy, a panel of genotypes from diverse agro-ecosystems were evaluated alongside two Canadian biparental populations for germination rate. Association mapping revealed QTLs within the SD1 and SD2 loci in the Canadian populations, while neither of these loci were linked to dormancy in the diversity panel. The diversity panel identified 14 additional marker-trait associations, including novel genetic loci. An alanine aminotransferase (AlaAT1) underlies dormancy regulation at the SD1 allele and is thought to help mitigate the suppressive effects of hypoxia on respiration during grain fill. Additional testing with four genotypes carrying either dormant or non-dormantAlaAT1alleles revealed that dormant alleles had increased hypoxia sensitivity and hypoxia-responsive gene expression during grain fill. Together, this work indicates that multiple genetic regions influence dormancy and suggests that hypoxia influences dormancy establishment in barley.HighlightDormancy is regulated by distinct genetic regions in North American barley compared to African barley. The SD1 locus influences dormancy in North American lines and genotypes with the dormant SD1 allele are more sensitive to hypoxia.
Stimulation of locus coeruleus inputs to the frontal cortex in mice induces cell type-specific expression of theApoegene
Authors: Craig Genevieve E. , Ramos Lizbeth , Essig Samuel R. , Eagles Nicholas J. , Jaffe Andrew E. , Martinowich Keri , Hallock Henry L. 
Published: July 2024

AbstractDeficits in attention are common across a range of neuropsychiatric disorders. A multitude of brain regions, including the frontal cortex (FC) and locus coeruleus (LC), have been implicated in attention. Regulators of these brain regions at the molecular level are not well understood, but might elucidate underlying mechanisms of disorders with attentional deficits. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the FC, and subsequent bulk RNA-sequencing from the mouse FC. We found that stimulation of this circuit caused an increase in transcription of theApoegene. To investigate cell type-specific expression ofApoein the FC, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the FC, or a control virus, and found that increases inApoeexpression in the FC following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into howApoeexpression affects function in cortical microcircuits that are important for attention-guided behavior, and point to interneuron-specific expression ofApoeas a potential target for the amelioration of attention symptoms in disorders such as attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimer’s disease (AD).Significance StatementIdentifying patterns of gene expression in specific brain circuits is an important first step toward developing treatments for cognitive and behavioral symptoms that rely on those circuits. In this paper, we describe a transcriptome-scale motif in one such circuit - neurons in the LC that project to the FC. This circuit has been implicated in attention, and attentional deficits are common across many neuropsychiatric disorders, suggesting that targeting this circuit could have therapeutic potential for ameliorating attentional symptoms in these disorders. We further explored one of the top differentially expressed genes,Apoe,to identify how it is expressed in distinct cell types following stimulation of this circuit, paving the way for spatially- and genetically-specific targeting of this gene in attention.
A disinhibitory basal forebrain to cortex projection supports sustained attention
Authors: Li Shu-Jing , Hangya Balazs , Gupta Unmukt , Fischer Kyle B. , Sturgill James Fitzhugh , Callaway Edward M. , Kepecs Adam 
Published: July 2024

ABSTRACTSustained attention, as an essential cognitive faculty governing selective sensory processing, exhibits remarkable temporal fluctuations. However, the underlying neural circuits and computational mechanisms driving moment-to-moment attention fluctuations remain elusive. Here we demonstrate that cortex-projecting basal forebrain parvalbumin-expressing inhibitory neurons (BF-PV) mediate sustained attention in mice performing an attention task. BF-PV activity predicts the fluctuations of attentional performance metrics ― reaction time and accuracy ― trial-by-trial, and optogenetic activation of these neurons enhances performance. BF-PV neurons also respond to motivationally salient events, such as predictive cues, rewards, punishments, and surprises, which a computational model explains as representing motivational salience for allocating attention over time. Furthermore, we found that BF-PV neurons produce cortical disinhibition by inhibiting cortical PV+ inhibitory neurons, potentially underpinning the observed attentional gain modulation in the cortex. These findings reveal a disinhibitory BF-to-cortex projection that regulates cortical gain based on motivational salience, thereby promoting sustained attention.HIGHLIGHTSBF-PV activity predicts attentional performance metrics: reaction time and accuracyBF-PV responses reflect the computation of motivational salience-guided attention allocationOptogenetic activation of BF-PV neurons improves attentional performanceBF-PV neurons produce cortical disinhibition through topographic projections and mediate gain modulation
Efficacy and Safety of Middle Meningeal Artery Embolization for Patients with Chronic Subdural Hematoma: A Systematic Review and Meta-Analysis
Authors: Kabir N , Owais B , Trifan G , Testai FD 
Published: July 2024

BackgroundChronic subdural hematoma (CSDH) is characterized by the collection of blood beneath the dura mater. Traditional treatments involve surgical drainage of the hematoma, but recurrence rates can be high. A highly vascularized neo-membrane irrigated by the middle meningeal artery (MMA) may be involved in CSDH re-accumulation.ObjectiveWe conducted a systematic review and meta-analysis of studies that compared the efficacy and safety of MMA embolization to conventional treatment alone for CSDH.Material and MethodsA systematic search of PubMed, Embase Ovid, andClinicalTrials.govidentified observational and randomized clinical studies comparing MMA embolization to conventional treatment for chronic subdural hematoma. The efficacy outcomes were hematoma recurrence and good functional outcome (as defined by a modified Rankin Scale score (mRS) of 0-2). Safety outcomes were the rate of major complication and mortality. Heterogeneity among studies were evaluated using the I2statistic. Analyses were conducted using Cochrane Review Manager software, with risk ratios (RR) and 95% confidence intervals (95% CI) presented for key outcomes. Absolute risk reduction (ARR, 95% CI) 1000 patients were also calculated using GRADEpro software.ResultsThe analysis included data from 13 studies (4 RCTs and 9 observational studies) with a total number of 2960 patients (35.3% in the MMA group and 64.7% in the conventional treatment group). Compared to conventional treatment, MMA embolization decreased risk of hematoma recurrence by 60% (13 studies, RR=0.40, 95% CI 0.25-0.63; I2=50%), for an absolute effect of 119 fewer events/1000 patients (95% CI 70-149), with similar risk of major complications (9 studies, RR=0.82, 95% CI=0.54-1.25) and mortality risk (13 studies, RR=0.90, 95% CI=0.54-1.51). In subgroup analyses by study type, pooled results from RCTs showed similar direction effects as those from observational studies for both efficacy and safety outcomes.ConclusionMMA embolization in CSDH management is a safe and effective approach for CSDH.
A Data-Driven Sliding-window Pairwise Comparative Approach for the Estimation of Transmission Fitness of SARS-CoV-2 Variants and Construction of the Evolution Fitness Landscape
Authors: Pantho Md Jubair , Bauder Landen Alexander , Huang Sophia , Qin Hong 
Published: July 2024

SummaryEstimating the transmission fitness of SARS-CoV-2 variants and understanding their evolutionary landscape is important for epidemiological forecasting. Existing methods are often constrained by their parametric natures and do not satisfactorily align with the observations during COVID-19. Here, we introduce a sliding-window data-driven pairwise comparison method, Differential Population Growth Rate (DPGR), that uses viral strains as internal controls to mitigate sampling biases. DPGR is applicable in time windows in which the logarithmic ratio of two variant subpopulations is approximately linear. We apply DPGR to genomic surveillance data and focus on Variants of Concern (VOCs) in multiple countries and regions. We found the log-linear assumption of DPGR can be found in appropriate time windows in many regions. We show that DPGR can provide estimates of transmission fitness and quantify the transmission advantage of key variants such as Omicron by location. We show that DPGR estimates agree with other methods for estimating pathogenic transmission. Furthermore, DPGR allowed us to construct viral fitness landscapes that capture the evolutionary trends of SARS-CoV-2, reflecting the relative changes of transmission traits for key genotypic changes represented by major variants. The straightforward log-linear regression approach of DPGR may also facilitate its easy adoption. This study shows that DPGR is a promising new tool in our repertoire for addressing future pandemics.
Precision Education Tools for Pediatrics Trainees: A Mixed-Methods Multi-Site Usability Assessment
Authors: Fidel Alexander , Mai Mark V. , Muthu Naveen , Dziorny Adam C. 
Published: July 2024

ABSTRACTBackgroundExposure to patients and clinical diagnoses drives learning in graduate medical education (GME). Measuring practice data, how trainees each experience that exposure, is critical to planned learning processes including assessment of trainee needs. We previously developed and validated an automated system to accurately identify resident provider-patient interactions (rPPIs). In this follow-up study, we employ user-centered design methods to meet two objectives: 1) understand trainees’ planned learning needs; 2) design, build, and assess a usable, useful, and effective tool based on our automated rPPI system to meet these needs.MethodsWe collected data at two institutions new to the American Medical Association’s “Advancing Change” initiative, using a mixed-methods approach with purposive sampling. First, interviews and formative prototype testing yielded qualitative data which we analyzed with several coding cycles. These qualitative methods illuminated the work domain, broke it into learning use cases, and identified design requirements. Two theoretical models—the Systems Engineering Initiative for Patient Safety (SEIPS) and Master-Adaptive Learner (MAL)—structured coding efforts. Feature-prioritization matrix analysis then transformed qualitative analysis outputs into actionable prototype elements that were refined through formative usability methods. Lastly, qualitative data from a summative usability test validated the final prototype with measures of usefulness, usability, and intent to use. Quantitative methods measured time on task and task completion rate.ResultsWe represent GME work domain learnings through process-map-design artifacts which provide target opportunities for intervention. Of the identified decision-making opportunities, trainee-mentor meetings stood out as optimal for delivering reliable practice-area information. We designed a “mid-point” report for the use case of such meetings, integrating features from qualitative analysis and formative prototype testing into iterations of the prototype. A final version showed five essential visualizations. Usability testing resulted in high performance in subjective and objective metrics. Compared to currently available resources, our tool scored 50% higher in terms of Perceived Usability and 60% higher on Perceived Ease of Use.ConclusionsWe describe the multi-site development of a tool providing visualizations of log level electronic health record data, using human-centered design methods. Delivered at an identified point in graduate medical education, the tool is ideal for fostering the development of master adaptive learners. The resulting prototype is validated with high performance on a summative usability test. Additionally, the design, development, and assessment process may be applied to other tools and topics within medical education informatics.
Genetic ancestral patterns inCYP2D6alleles: structural variants, rare variants, and clinical associations in 479,144 UK Biobank genomes
Authors: Jiang Xiao , Hu Fengyuan , Zou Xueqing Zoe , Abbasi Ali , Deevi Sri V. V. , Atanur Santosh S. , O’Neill Amanda , Harrow Jen , Fabre Margarete , Wang Quanli , Petrovski Slavé , Rae William , Burren Oliver , Smith Katherine R. 
Published: July 2024

AbstractCytochrome P450 2D6 (CYP2D6) is involved in metabolising over 20% of clinical drugs, yet its genetic variation across ancestries is underexplored in large-scale whole-genome sequencing (WGS) datasets. We analysed WGS data from 479,144 UK Biobank participants, identifying 95 distinctCYP2D6star alleles across five biogeographic groups. Of these, 48 alleles had currently unknown effects. These alleles were more prevalent in African, admixed American, and South Asian groups (∼5%) compared to European and East Asian groups (∼2%), affecting the ability to provide pharmacogenomics recommendations across ancestries. We identified 99,656 (20.8%) individuals carryingCYP2D6structural variations and predicted theCYP2D6ultra-rapid metaboliser phenotype to be most common in Africans (4.5%) and rarest in East Asians (0.32%). Less than half (45.7%) of rare protein-truncating variant carriers were categorised as poor or intermediate metabolisers, indicating an underrepresentation of rare functional variants in the currentCYP2D6star allele evaluation. Phenome-wide association studies confirmed links with narcotic allergies and found new associations with plasma BAFFR and BAFF proteins, offering insights for the BAFF-targeted clinical therapy. Collectively, this largest WGS study ofCYP2D6to date highlights the importance of leveraging all genetic variations for pharmacogenomic insights affecting therapeutic safety and development.
Reevaluating the Role of ACE Inhibitors in Skin Fibrosis Risk: Evidence from Mendelian Randomization
Authors: Wei Yangyang , Wan Ziqi , Jiang Yiwen , Liu Zhengye , Yang Ming , Tang Jieying 
Published: July 2024

AbstractBackgroundSkin fibrosis, characterized by excessive extracellular matrix deposition, leads to hypertrophic scars and keloids, which are both common and often detrimental conditions. Angiotensin-converting enzyme (ACE) inhibitors have shown promise in animal studies and limited clinical trials for reducing scar formation. However, the causal relationship between ACE inhibition and skin fibrosis remains unclear.MethodsThis study employed two-sample Mendelian randomization (MR) analysis to investigate the causal effect of ACE inhibition on skin fibrotic diseases. We utilized genetic variants associated with serum ACE levels, ACE inhibition, and effect of decreasing blood pressure by ACE inhibition as instrumental variables. We analyzed the association between these exposures and the incidence of skin fibrosis, hypertrophic scars, and keloids using various MR methods.ResultsWe found no significant causal relationship between genetically proxied serum ACE levels, or local skin tissue ACE expression and the risk of skin fibrosis, hypertrophic scars, or keloids. Additionally, there was no direct causal relationship between the effect of ACE inhibitors on blood pressure reduction and the risk of skin fibrotic diseases. However, we observed a significant negative association between systolic blood pressure (SBP) and the risk of hypertrophic scars. Conversely, we found a positive association between β-blockers and the risk of skin fibrosis.ConclusionOur findings suggest that ACE inhibitors do not have a direct causal effect on the risk of skin fibrotic diseases, including hypertrophic scars and keloids. This challenges the potential of ACE inhibitors as a therapeutic option for preventing or treating these conditions.