bluuebunny/crossref_metadata_2025_split huggingface dataset:
WebGWAS: A web server for instant GWAS on arbitrary phenotypes
Authors: Zietz Michael , Gisladottir Undina , Brown Kathleen LaRow , Tatonetti Nicholas P. 
Published: December 2024

AbstractComplex disease genetics is a key area of research for reducing disease and improving human health. Genome-wide association studies (GWAS) help in this research by identifying regions of the genome that contribute to complex disease risk. However, GWAS are computationally intensive and require access to individual-level genetic and health information, which presents concerns about privacy and imposes costs on researchers seeking to study complex diseases. Publicly released pan-biobank GWAS summary statistics provide immediate access to results for a subset of phenotypes, but they do not inform about all phenotypes or hand-crafted phenotype definitions, which are often more relevant to study. Here, we present WebGWAS, a new tool that allows researchers to obtain GWAS summary statistics for a phenotype of interest without needing access to individual-level genetic and phenotypic data. Our public web app can be used to study custom phenotype definitions, including inclusion and exclusion criteria, and to produce approximate GWAS summary statistics for that phenotype. WebGWAS computes approximate GWAS summary statistics very quickly (<10 seconds), and it does not store private health information. We also show how the statistical approximation underlying WebGWAS can be used to accelerate the computation of multi-phenotype GWAS among correlated phenotypes. Our tool provides a faster approach to GWAS for researchers interested in complex disease, providing approximate summary statistics in short order, without the need to collect, process, and produce GWAS results. Overall, this method advances complex disease research by facilitating more accessible and cost-effective genetic studies using large observational data.
Evaluation of kindergarten through grade 12 school absenteeism data as an indicator and predictor of respiratory disease
Authors: Oberholtzer Zachary W. , Jeon Seonghye , Fineman Lillian , Adkins Susan Hocevar , Kang Gloria J. , Imberi-Olivares Kristi , Barrios Lisa C. , Meltzer Martin I. 
Published: December 2024

ABSTRACTObjectiveIncreases in school children absenteeism may precede increases in incidence of community-level respiratory diseases. This study assessed the correlations and predictive values between absenteeism in Kindergarten through Grade 12 students and community-level increases in influenza and COVID-19.MethodsAbsenteeism data from 4 districts between Fall 2018 and Spring 2022 was used to calculate correlations between school absenteeism and community-level cases of influenza, percent influenza-like-illnesses, and COVID-19. We estimated the positive predictive value (PPV) of a ≥20% increase in school absences to predict a ≥20% increase in community respiratory disease one or two weeks later.ResultsWe observed a median correlation of 0.4 between absenteeism and influenza cases across school years and districts, with a maximum of 0.8. COVID-19 cases had a median correlation of 0.1 with school absenteeism during the 2021-2022 school year. The median PPV for predicting increases in influenza 2 weeks ahead was 0.4 (maximum 0.6), and for COVID-19, the median PPV was 0.3.ConclusionsCorrelations and PPVs between school absenteeism and respiratory disease were variable, often below 0.5. School and public health officials may find absenteeism an inconsistent predictor of community-level respiratory diseases, limiting its utility for syndromic surveillance. Standardizing absence definitions and improving reporting timeliness may enhance its effectiveness.SUMMARY BOX1) What is the current understanding of this subject?Previous research has shown that K-12 student absenteeism may potentially anticipate surges in community influenza.2) What does this report add to the literature?Correlations and predictive values between school absenteeism and community levels of respiratory diseases (influenza, influenza-like illnesses, COVID-19) were found to be variable and often below 0.5, suggesting limitations in using school absences as a form of syndromic surveillance.3) What are the implications for public health practice?For school absenteeism to be a reliable syndromic surveillance tool, standardizing definitions of absences and improving reporting timeliness should be explored.
Fe starvation induces a second LHCI tetramer to photosystem I in green algae
Authors: Liu Helen W. , Khera Radhika , Grob Patricia , Gallaher Sean D. , Purvine Samuel O. , Nicora Carrie D. , Lipton Mary S. , Niyogi Krishna K. , Nogales Eva , Iwai Masakazu , Merchant Sabeeha S. 
Published: December 2024

AbstractIron (Fe) availability limits photosynthesis at a global scale where Fe-rich photosystem (PS) I abundance is drastically reduced in Fe-poor environments. We used single-particle cryo-electron microscopy to reveal a unique Fe starvation-dependent arrangement of light-harvesting chlorophyll (LHC) proteins where Fe starvation-induced TIDI1 is found in an additional tetramer of LHC proteins associated with PSI inDunaliella tertiolectaandDunaliella salina. These cosmopolitan green algae are resilient to poor Fe nutrition. TIDI1 is a distinct LHC protein that co- occurs in diverse algae with flavodoxin (an Fe-independent replacement for the Fe-containing ferredoxin). The antenna expansion in eukaryotic algae we describe here is reminiscent of the iron-starvation induced (isiA-encoding) antenna ring in cyanobacteria, which typically co-occurs withisiB, encoding flavodoxin. Our work showcases the convergent strategies that evolved after the Great Oxidation Event to maintain PSI capacity.
Direct Intercellular Vesicle Exchange between Adjacent Cells
Authors: Minakawa Tomohiro , Katsuno Tatsuya , Okamoto-Furuta Keiko , Ando Ryoko , Ishidate Fumiyoshi , Fujiwara Takahiro K. , Cho Dooseon , Takehana Sho , Sato Yoshikatsu , Tabata Yasuhiko , Miyawaki Atsushi , Yamashita Jun K. 
Published: December 2024

AbstractIntercellular communication plays a central role in the development and integrity of multicellular organisms. Vesicle transfer, especially through extracellular space, has recently been highlighted as a critical intercellular communication modality, carrying nucleic acids, proteins, and others to distant cells. Previously, we demonstrated that extracellular vesicles induce “phenotypic synchronization of cells (PSyC)” during stem cell differentiation. While examining the mechanism underlying PSyC, we discovered a novel form of cellular communication mediated by direct intercellular vesicle exchange (DIVE) between adjacent cells across the plasma membrane (PM). By achieving cell-wide and high-spatiotemporal resolution imaging of vesicles labeled with fusion proteins of CD63 or CD81 to StayGold, a photostable fluorescent marker, we observed small vesicles (50-500 nm in diameter) directly transferred between adjacent cells. These vesicles moved at approximately 1 µm/s and crossed PM in approximately 10-20 seconds. Furthermore, multiple vesicles traversed nearly identical sites of PM, suggesting the presence of specific routes or structures, potentially including a pore, mediating the vesicle transfer. Three-dimensional electron microscopy provided supportive observations for traversing vesicles with single membrane. These vesicles, named InterCellular Vesicles (InterCVs), were observed to colocalize with nucleic acids, including mRNA, microRNA, and DNA, suggesting the exchange of nucleic acid-mediated information, potentially inducing PSyC, between adjacent cells. Our discovery, DIVE, reveals a previously unknown modality of cell-cell communication, with the potential to reshape our understanding of cellular biology.
Constitutive differences in immune gene expression and energy storage phenotypes co-vary with winter environment in wood frogs
Authors: Vaziri Grace J. , Reid Noah M. , Rittenhouse Tracy A.G. , Bolnick Daniel I. 
Published: December 2024

AbstractMany terrestrial ectotherms have gone to great evolutionary lengths to adapt to long cold winters; some have even evolved the ability to tolerate the freezing of most of the water in the body. Now, however, high-elevation, and high-latitude winters are experiencing an accelerated period of warming. Specialized winter adaptations that promoted fitness in a seasonally frozen environment may soon be superfluous or even maladaptive. We ask whether winter adaptations include changes in immune functions, and whether changing winter conditions could exert disparate effects on populations of a wide-ranging terrestrial ectotherm, the wood frog (Lithobates sylvaticus). By rearing wood frogs from ancestral winter environments that vary in length and temperature in a common garden, and reciprocally exposing post-metamorphic frogs to unfrozen and frozen artificial winter conditions in the lab, we were able to decompose transcriptomic differences in ventral skin gene expression into those that were environmentally induced (responsive to temperature), genetically determined, and those that varied as an interaction between genotype and environment. We found that frogs from harsh ancestral winter environments constitutively upregulated immune processes, including cellular immunity, inflammatory processes, and adaptive immune processes, as compared to frogs from mild ancestral winter environments. Further, we saw that expression of several genes varied in an interaction between genotype and artificial winter. We suggest that just as winter climates likely served as the selective force resulting in remarkable winter adaptations such as freeze tolerance, they also induced constitutive changes in immune gene expression.
PlateletBase: A Comprehensive Knowledgebase for Platelet Research and Disease Insights
Authors: Luo Huaichao , Wu Changchun , Yu Sisi , Ren Hanxiao , Yin Xing , Zu Ruiling , Rao Lubei , zhang Peiying , Zhang Xingmei , Wu Ruohao , Leng Ping , Zhang Kaijiong , Peng Qi , Cao Bangrong , Qin Rui , Wei Hulin , Qiao Jianlin , Xu Shanling , Yi Qun , Zhang Yang , Huang Jian , Wang Dongsheng 
Published: December 2024

AbstractPlatelets are vital in many pathophysiological processes, yet there is a lack of a comprehensive resource dedicated specifically to platelet research. To fill this gap, we have developed PlateletBase, a knowledge base aimed at enhancing the understanding and study of platelets and related diseases. Our team retrieved information from various public databases, specifically extracting and analyzing RNA-seq data from 3,711 samples across 41 different conditions available on NCBI. PlateletBase offers six analytical and visualization tools, enabling users to perform gene similarity analysis, pair correlation, multi-correlation, expression ranking, clinical information association, and gene annotation for platelets. The current version of PlateletBase includes 10,278 genomic entries, 31,758 transcriptomic entries, 4,869 proteomic entries, 2,614 omics knowledge entries, 1,833 drugs, 97 platelet resources, 438 diseases/traits, and six analysis modules. Each entry has been carefully curated and supported by experimental evidence. Additionally, PlateletBase features a user-friendly interface designed for efficient querying, manipulation, browsing, visualization, and analysis of detailed platelet protein and gene information. Case study results, such as those from gray platelet syndrome and angina pectoris, demonstrate that this tool can aid in identifying diagnostic biomarkers and exploring disease mechanisms, significantly advancing research in platelet functionality and its applications. PlateletBase is accessible athttp://plateletbase.clinlabomics.org.cn/.
DNMT/G9a Complex Inhibition Uncovers Epigenetic Vulnerabilities and Induces IFN-Response in Acute Myeloid Leukemia
Authors: Schönefeld Angelique , Zanetti Costanza , Schmitt Eric C. , Woods Kevin , Westerback Ashley , Mitsch Sidney M. , Rühle Frank , Kelekci Simge , Fol Lisa , Shah Viral , Sanchez-Saez Miriam , Thevissen Sophia , Schäffer Alexander , Schmits Ulrike Regina , Sasca Daniel , Kindler Thomas , Wölfel Catherine , Feuerstein-Akgoz Clarissa , Gerhäuser Clarissa , Lutsik Pavlo , Rivière Jennifer , Hecker Judith S , Götze Katharina S , Platzbecker Uwe , Echchannaoui Hakim , Theobald Matthias , Plass Christoph , Padeken Jan , Medyouf Hind , Guezguez Borhane 
Published: December 2024

AbstractEpigenetic dysregulation is a hallmark of Acute Myeloid Leukemia (AML), with mutations in DNA Methyltransferases (e.g., DNMT3A) being frequent and promising therapeutic targets. DNMTs form complexes with Histone Methyltransferases (HMTs), driving gene silencing loop via chromatin methylation crosstalk. However, potential connections between this DNMTs/HMTs cooperative activity and oncogenic requirements across the AML mutational spectrum remain poorly understood. Here, we demonstrate that AMLs carrying DNMT3A and Nucleophosmin (NPM1) mutations exhibit a specific epigenetic vulnerability toward a complex formed by DNMTs and G9a, a specific histone H3 Lysine 9 Methyltransferase (H3K9-HMT). Dual inhibition of DNMT/G9a restores differentiation, reduces tumor growth, and spares healthy progenitors compared to standard hypomethylating agents. Mechanistically, DNMT/G9a regulates NPM1 stability, inhibits HOXA9/MEIS1 activity, and triggers interferons (IFN) response via viral mimicry pathways by modulating hypermethylated retrotransposons. Collectively, our data unravel specific epigenetic vulnerabilities within the complex AML mutational landscape and provide a compelling rationale for the design of personalized epigenetic therapies with enhanced efficacy and safer clinical outcomes.
Sex-Specific Regulation of Behavioral Responses to Single Prolonged Stress: Role of PACAP
Authors: Smail Marissa A. , Cotella Evelin M. , Martelle Susan E. , Chambers James B. , Parikh Ria K. , Moore Christine E. , Packard Ben A. , Nawreen Nawshaba , Moloney Rachel D. , Herman James P. 
Published: December 2024

ABSTRACTPost-Traumatic Stress Disorder (PTSD) is a debilitating condition in which a traumatic experience triggers symptoms related to re-experiencing, avoidance, arousal, and mood dysregulation. PTSD negatively impacts 6% of people during their lifetime, with women being disproportionally affected and exhibiting different, more severe symptoms than men. Despite this widespread impact, the molecular mechanisms underlying PTSD and its sex differences remain poorly understood. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a neuropeptide which participates in fine-tuning circuitry throughout the brain and has been associated with PTSD in humans, especially in women. Here, we use Single Prolonged Stress (SPS), an animal model of PTSD, to explore the roles of PACAP and sex in PTSD-like behaviors. Specifically, a PACAP agonist or antagonist was infused into the infralimbic (IL) prefrontal cortex, a region key to regulating fear- and anxiety-related behaviors, prior to SPS in male and female rats. One week later, rats were tested in open field/novel object, elevated plus maze, and social interaction. Utilizing a behavioral indexing method, we were able to uncover SPS effects in PTSD-related behavioral domains that were differentially impacted by PACAP manipulations in males and females. While both sexes exhibited increased threat avoidance and decreased threat assessment following SPS, females increased sociability while males decreased sociability. Males also appeared to be protected by IL PACAP antagonism while female SPS phenotypes were exacerbated by IL PACAP agonism. Furthermore, RNAscope revealed that PACAP in the prefrontal cortex responds differently to SPS in males and females. Together, these findings suggest complex relationships between SPS, sex, and IL PACAP which may have important implications for treating PTSD in men and women.HIGHLIGHTSSPS induces different PTSD-like phenotypes in male and female ratsSPS increases threat avoidance and decreases threat appraisal in both sexesSociability is decreased in males but increased in females following SPSIL PACAP manipulation exerts diverging SPS behavioral effects in males and femalesPrefrontal PACAP signaling plays a sex-specific role in SPS molecular mechanisms
An improved isochronous pulse after lentiviral knock-down of STEP in Area X of juvenile zebra finches
Authors: Norton Philipp , Breslav Daniel , Mendoza Ezequiel 
Published: December 2024

AbstractThe zebra finch is one of the most commonly used animal models for studying the genetic mechanisms underlying vocal learning. To investigate the genetic basis of vocal learning, various genes have been knocked down in Area X—a brain region involved in birdsong acquisition—during the critical learning period. All genes that affect speech when mutated in humans similarly impair song learning in zebra finches. To date, no study has demonstrated that not all genes downregulated in Area X result in decreased song learning. Therefore, we sought a candidate gene to knock down in Area X that could either have no effect or potentially improve song learning. STEP is a protein that dephosphorylates many targets in the brain, and its knockout in mice has resulted in enhanced learning. In this study, a lentiviral knockdown of STEP in Area X during song learning resulted in birds producing normal song in almost all parameters and levels of song analysis. This stands in contrast to the knockdown of other genes like all FoxP subfamily members, which resulted in diminished song learning in previous studies. The only parameter positively affected by STEP knockdown was song rhythmicity, as evidenced by a lower deviation of song element onsets from an isochronous pulse than even their tutors. These results demonstrate for the first time that not all knockdowns in Area X lead to deterioration of song learning and validate the specificity of the method and previous findings.Significance StatementThis is the first coding gene knockdown in Area X without negatively affecting song learning.
The adaptive state determines the impact of mutations on evolving populations
Authors: Weh Malgorzata Tyczynska , Kumar Pragya , Marusyk Viktoriya , Marusyk Andriy , Basanta David 
Published: December 2024

AbstractDarwinian evolution results from an interplay between stochastic diversification of heritable phenotypes, impacting the chance of survival and reproduction, and fitness-based selection. The ability of populations to evolve and adapt to environmental changes depends on rates of mutational diversification and the distribution of fitness effects of random mutations. In turn, the distribution of fitness effects of stochastic mutations can be expected to depend on the adaptive state of a population. To systematically study the impact of the interplay between the adaptive state of a population on the ability of asexual populations to adapt, we used a spatial agent-based model of a neoplastic population adapting to a selection pressure of continuous exposure to targeted therapy. We found favorable mutations were overrepresented at the extinction bottleneck but depleted at the adaptive peak. The model-based predictions were tested using an experimental cancer model of an evolution of resistance to a targeted therapy. Consistent with the model’s prediction, we found that enhancement of the mutation rate was highly beneficial under therapy but moderately detrimental under the baseline conditions. Our results highlight the importance of considering population fitness in evaluating the fitness distribution of random mutations and support the potential therapeutic utility of restricting mutational variability.
A Time Machine for Taxonomy
Authors: Davis-Richardson Austin , Reynolds Timothy 
Published: December 2024

AbstractThe NCBI Taxonomy Database is the primary resource for linking genomic information to taxonomic relationships, widely used across scientific disciplines and critically important to bioinformatics. This database is continuously changing as researchers discover and refine taxonomic relationships. Yet, tracking and comparing past taxonomic states is challenging due to frequent changes and the need to sift through numerous historical snapshots. To address this, we developed the Taxonomy Time Machine: a database for storing many snapshots of a taxonomic tree in a space-efficient manner. We have also created a web-based and programmatic (API) interface to make this data more accessible. This tool is capable of accurately reconstructing taxonomic lineages at any point in the history of the NCBI Taxonomy Database. We demonstrate that this tool is both perfectly accurate and significantly more efficient than loading and querying individual taxonomy snapshots, enabling its use on desktop computers as well as commodity web servers. We have made this tool available on the web (https://taxonomy.onecodex.com) as well as open source under the MIT license (https://github.com/onecodex/taxonomy-time-machine).
Cytosolic fructose - an underestimated player in the regulation of the sucrose biosynthesis?
Authors: Giesbrecht Oliver , Bonn Christina , Fürtauer Lisa 
Published: December 2024

AbstractPlants must continuously adapt to environmental fluctuations, which significantly influence their photosynthetic performance and overall metabolism. The sucrose cycling system within plant cells plays a critical regulatory role during stress conditions. This study employed a systems biology approach to analyze system stabilities mathematically under various regulatory conditions impacting sucrose cycling dynamics. We investigated the effects of mutations within this cycle, specifically HEXOKINASE1 (Arabidopsis thaliana gin2-1), alongside high-light exposure. Finally, we confirmed the modelling output in vitro by enzyme assays. The implementation of experimental subcellular metabolite data into a Structural Kinetic Model (SKM) enabled exploration of regulatory responses and system stabilities within a three-compartment model. Within system instabilities,gin2-1was more instable than its wild type. Thegin2-1mutation particularly was destabilized when fructokinase function was impaired by phosphorylated sugars. Additionally, we confirmed that phosphorylated sugars serve as stronger activators of sucrose-phosphate synthase (SPS) than glucose does. Interestingly, models with fructose SPS activation exhibited a similar stability pattern. Consequently, we proposed and confirmed in silico a triple activation of SPS by highly activating phosphorylated sugars and lower activating nonphosphorylated hexoses. Additionally, we biochemically confirmed the previously unknown, but now predicted, activation of SPS by fructose in vitro. In summary, our study highlights the essential role of sucrose cycling in plant cells under stress conditions. The in silico findings reveal that phosphorylated sugars are stronger activators of SPS than glucose and introduce a previously unknown activation mechanism by fructose. These potential activation capacities were confirmed in vitro through SPS enzyme activity assays, underscoring the efficiency of our systems biology approach. Overall, this research provides valuable insights into carbohydrate metabolism regulation and paves the way for future investigations to deepen our understanding of the complexities involved in sucrose cycling and biosynthesis in plants.