bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apolipoprotein E moderates the association between Non-APOEPolygenic Risk Score for Alzheimer’s Disease and Aging on Preclinical Cognitive Function
Authors: Xu Yuexuan , Sun Zhongxuan , Jonaitis Erin , Deming Yuetiva , Lu Qiongshi , Johnson Sterling C. , Engelman Corinne D. 
Published: June 2023

AbstractINTRODUCTIONVariation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer’s disease (e.g., a non-APOEpolygenic risk scores [PRS]) may interact with theAPOEε4 allele to influence cognitive decline.METHODSWe tested the PRSξAPOEε4ξage interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1,190 individuals.RESULTSWe found statistically significant PRSξAPOEε4ξage interactions on immediate learning (P=0.038), delayed recall (P<0.001), and Preclinical Alzheimer’s Cognitive Composite 3 score (P=0.026). PRS-related differences in overall and memory-related cognitive domains between people with and withoutAPOEε4 emerge around age 70, with a much stronger adverse PRS effect amongAPOEε4 carriers. The findings were replicated in a population-based cohort.DISCUSSIONAPOEε4 can modify the association between PRS and cognition decline.HighlightsAPOEε4 can modify the association between PRS and longitudinal cognition decline, with the modifying effects more pronounced when the PRS is constructed using a conservativeP-threshold (e.g.,P< 5e-8).The adverse genetic effect caused by the combined effect of the currently known genetic variants is more detrimental amongAPOEε4 carriers around age 70.Individuals who areAPOEε4 carriers with high PRS are the most vulnerable to the harmful effects caused by genetic burden.
Comparison of incidence and prognosis of myocardial injury in patients with COVID-19-related respiratory failure and other pulmonary infections: a contemporary cohort study
Authors: Vivan Manoela Astolfi , Hirakata Vania Naomi , Arteche Maria Antônia Torres , Araujo Débora Marques de , Fuchs Sandra Cristina Pereira Costa , Fuchs Flávio Danni 
Published: June 2023

ABSTRACTBackgroundMyocardial injury (MI) is frequent in critically ill patients with COVID-19, but its pathogenesis remains unclear. We hypothesized that MI is not solely due to viral infection by SARS-CoV-2, but rather due to the common pathophysiological mechanisms associated with severe pulmonary infections and respiratory failure.MethodsContemporary and comparative cohort study designed to compare the incidence of MI in patients with acute respiratory failure caused by COVID-19 to that of patients with other pulmonary infections. In addition, we aim to investigate whether MI is a distinct risk factor for in-hospital mortality in patients with COVID-19-related respiratory failure compared to those with non-COVID-19 infections.ResultsThe study included 1444 patients with COVID-19 [55.5% men; age 58 (46;68) years] and 182 patients with other pulmonary infections [46.9% men; age 62 (44;73) years]. The incidence of MI at ICU admission was lower in COVID-19 patients (36.4%) compared to non-COVID-19 patients (56%), and this difference persisted after adjusting for age, sex, coronary artery disease, heart failure, SOFA score, lactate, and C-reactive protein [RR 0.84 (95% CI, 0.71-0.99)]. MI at ICU admission was associated with a 59% increase in mortality [RR 1.59 (1.36-1.86); P<0.001], and there was no significant difference in the mortality between patients with COVID-19 and those with other pulmonary infections (P=0.271).ConclusionMyocardial injury is less frequent in patients with critical COVID-19 pneumonia and respiratory failure compared to those with other types of pneumonia. The occurrence of MI is a significant risk factor for in-hospital mortality, regardless of the etiology of the pulmonary infection.
Photoperiod regulates gonadotrope cell division in medaka via melatonin, Tsh and folliculostellate cells
Authors: Royan Muhammad Rahmad , Hodne Kjetil , Nourizadeh-lillabadi Rasoul , Weltzien Finn-Arne , Henkel Christiaan V. , Fontaine Romain 
Published: June 2023

ABSTRACTIn vertebrates, pituitary gonadotropins (follicle-stimulating and luteinizing hormones: FSH and LH) regulate gonadal development and maturation, therefore playing an essential role in reproduction. The seasonal regulation of gonadotropins has been widely studied in mammals and birds, and in these taxa thyroid-stimulating hormone (TSH) was found to play a critical role. By contrast, the seasonal regulation of gonadotropins remains unclear in teleost fish. In addition, the seasonal regulation of gonadotrope (gonadotropin-producing cell) proliferation has not been elucidated in any vertebrate group. Using the teleost fish medaka as a model, we show for the first time that long photoperiod enables reproduction by stimulating gonadotropin mRNA synthesis and gonadotrope cell proliferation. In female medaka, this proliferation is achieved by gonadotrope mitosis. We then demonstrate that in female medaka, photoperiod stimulates gonadotropin mRNA production and mitosis via an indirect intra-pituitary pathway, involving pituitary Tsh cells. We show that non-endocrine folliculostellate cells in the pituitary mediate the Tsh signal regulating gonadotrope activity and proliferation, as they are the only pituitary cells to express Tsh receptors and send projections to gonadotropes. Finally, we show that melatonin suppresses pituitarytshbaexpression in fish exposed to long photoperiod, suggesting that short photoperiod inhibits gonadotropin synthesis via melatonin in both fish and mammals. This study therefore demonstrates that in fish, photoperiod regulates gonadotrope cell activity and mitosis via a melatonin-Tsh pathway. It also reveals the existence of a novel intra-pituitary pathway for seasonal regulation of gonadotropes, involving folliculostellate cells, which we propose might also exist in other vertebrates.SIGNIFICANCEIn seasonally breeding mammals and birds, the production of the hormones that regulate reproduction (gonadotropins) by gonadotropes is controlled by the pituitary thyroid-stimulating hormone (TSH) through an indirect pathway via the brain. However, in fish, how seasonal environmental signals influence gonadotropins remains unclear. Here, we show that in a long day seasonally breeding fish, medaka, photoperiod not only regulates the activity (hormone production) of the gonadotropes but also their proliferation. We also reveal a novel intra-pituitary pathway that regulates gonadotrope cell activity and number. This pathway involves melatonin, Tsh, and folliculostellate cells. Interestingly, as all these components are also found in the mammalian pituitary, this study suggests the existence of an alternative regulatory mechanism of seasonal gonadotropin production across vertebrates.
Neuron Enriched Exosomal MicroRNA Expression Profiles as a Marker of Early Life Alcohol Consumption
Authors: Yakovlev Vasily , Lapato Dana M. , Rana Pratip , Ghosh Preetam , Frye Rebekah , Roberson-Nay Roxann 
Published: June 2023

AbstractBackgroundAlcohol consumption may impact and shape brain development through perturbed biological pathways and impaired molecular functions. We investigated the relationship between alcohol consumption rates and neuron-enriched exosomal microRNA (miRNA) expression to better understand the impact of alcohol use on early life brain biology.MethodsNeuron-enriched exosomal miRNA expression was measured from plasma samples collected from young people using a commercially available microarray platform while alcohol consumption was measured using the Alcohol Use Disorders Identification Test. Linear regression and network analyses were used to identify significantly differentially expressed miRNAs and to characterize the implicated biological pathways, respectively.ResultsCompared to alcohol naïve controls, young people reporting high alcohol consumption exhibited significantly higher expression of four neuron-enriched exosomal miRNAs including miR-30a-5p, miR-194-5p, and miR-339-3p, although only miR-30a-5p and miR-194-5p survived multiple test correction. The miRNA-miRNA interaction network inferred by a network inference algorithm did not detect any differentially expressed miRNAs with a high cutoff on edge scores. However, when the cutoff of the algorithm was reduced, five miRNAs were identified as interacting with miR-194-5p and miR-30a-5p. These seven miRNAs were associated with 25 biological functions; miR-194-5p was the most highly connected node and was highly correlated with the other miRNAs in this cluster.ConclusionsOur observed association between neuron-enriched exosomal miRNAs and alcohol consumption concurs with results from experimental animal models of alcohol use and suggests that high rates of alcohol consumption during the adolescent/young adult years may impact brain functioning and development by modulating miRNA expression.
Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules
Authors: Ma Bowen , Khan Khadija Shahed , Xu Tongyang , Amada Josefina Xeque , Guo Zhihao , Yan Yu , Cheng Alfred Sze-Lok , Ng Billy Wai-Lung 
Published: June 2023

ABSTRACTProtein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of O-GlcNAcylation homeostasis has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of O-GlcNAcylation challenging. To address this, we have developed first-in-class heterobifunctional small molecules, named O-GlcNAcylation targeting chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2in celluloby recruiting O-GlcNAc transferase (OGT), with temporal and magnitude control. Mass spectrometry data revealed that OGTACs induced site-selective O-GlcNAcylation of BRD4. Overall, OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.
Cell-free chromatin particles activate immune checkpoints in human T cells: Implications for cancer therapy
Authors: Shabrish Snehal , Pal Kavita , Khare Naveen Kumar , Satsangi Dharana , Pilankar Aishwarya , Jadhav Vishalkumar , Shinde Sushma , Raphael Nimisha , Sriram Gaurav , Lopes Relestina , Raghuram Gorantla V. , Tandel Harshali , Mittra Indraneel 
Published: June 2023

AbstractImmune checkpoint blockade is an exciting breakthrough in cancer therapy, but how immune checkpoints are activated is unknown. We have earlier reported that cell-free chromatin particles (cfChPs) that circulate in the blood, or those that are released locally from dying cells, are readily internalized by healthy cells with biological consequences. Here we show that treatment of human lymphocytes with cfChPs isolated from sera of cancer patients led to marked activation of immune checkpoints viz. PD-1, CTLA-4, LAG-3, NKG2A, and TIM-3. Concurrently activated were stress-related markers cJun, cFos, JunB, FosB, NFКB, and EGR1. The above immune checkpoints were also activated when lymphocytes were treated with cfChPs released from dying HeLa cells; the latter could be abrogated by three cfChPs deactivating agents. These results suggest that immune checkpoints are activated by lymphocytes as stress response to cfChPs. Simultaneous downregulation of multiple immune checkpoints may herald a new approach to immunotherapy of cancer.Statement of SignificanceWe show that cell-free chromatin particles (cfChPs) that circulate in the blood of cancer patients, or those released from dying cancer cells, simultaneously activate five immune checkpoints as a stress response by human lymphocytes. Activation of checkpoints was abrogated by cfChPs deactivating agents suggesting a novel approach to cancer treatment.
An atlas of protein homo-oligomerization across domains of life
Authors: Schweke Hugo , Levin Tal , Pacesa Martin , Goverde Casper A. , Kumar Prasun , Duhoo Yoan , Dornfeld Lars J. , Dubreuil Benjamin , Georgeon Sandrine , Ovchinnikov Sergey , Woolfson Derek N. , Correia Bruno E. , Dey Sucharita , Levy Emmanuel D. 
Published: June 2023

AbstractProtein structures are essential to understand cellular processes in molecular detail. While advances in AI revealed the tertiary structure of proteins at scale, their quaternary structure remains mostly unknown. Here, we describe a scalable strategy based on AlphaFold2 to predict homo-oligomeric assemblies across four proteomes spanning the tree of life. We find that 50% of archaeal, 45% of bacterial, and 20% of eukaryotic proteomes form homomers. Our predictions accurately capture protein homo-oligomerization, recapitulate megadalton complexes, and unveil hundreds of novel homo-oligomer types. Analyzing these datasets reveals coiled-coil regions as major enablers of quaternary structure evolution in Eukaryotes. Integrating these structures with omics data shows that a majority of known protein complexes are symmetric. Finally, these datasets provide a structural context for interpreting disease mutations, which we find enriched at interfaces. Our strategy is applicable to any organism and provides a comprehensive view of homo-oligomerization in proteomes, protein networks, and disease.Abstract Figure
Comparative analysis of gonadal transcriptomes between turtle and alligator identifies common molecular cues activated during the temperature-sensitive period for sex determination
Authors: Toyota Kenji , Akashi Hiroshi , Ishikawa Momoka , Yamaguchi Katsushi , Shigenobu Shuji , Sato Tomomi , Lange Anke , Tyler Charles R. , Iguchi Taisen , Miyagawa Shinichi 
Published: June 2023

AbstractThe mode of sex determination in vertebrates can be categorized as genotypic or environmental. In the case of genotypic sex determination (GSD), the sexual fate of an organism is determined by the chromosome composition with some having dominant genes, named sex-determining genes, that drive the sex phenotypes. By contrast, many reptiles exhibit environmental sex determination (ESD), whereby environmental stimuli drive sex determination, and most notably temperature. To date, temperature-dependent sex determination (TSD) has been found in most turtles, some lizards, and all crocodilians, but commonalities in the controlling processes are not well established. Recent innovative sequencing technology has enabled investigations into gonadal transcriptomic profiles during temperature-sensitive periods (TSP) in various TSD species which can help elucidate the controlling mechanisms. In this study, we conducted a time-course analysis of the gonadal transcriptome during the male-producing temperature (26L) of the Reeve’s turtle (Chinese three-keeled pond turtle)Mauremys reevesii. We then compared the transcriptome profiles for this turtle species during the TSP with that for the American alligatorAlligator mississippiensisto identify conserved reptilian TSD-related genes. Our transcriptome-based findings provide an opportunity to retrieve the candidate molecular cues that are activated during TSP and compare these target responses between TSD and GSD turtle species, and between TSD species.Highlights- A time-course gonadal RNA-seq was conducted usingMauremys reevesii.- Sexual differentiation genes in males were activated at an earlier stage than the ones in females.- Turtle-alligator comparative analysis revealed novel candidate TSD genes.
Physicochemical, functional, and evolutionary characteristics of protein loop regions in human andEscherichia coliproteomes
Authors: Zhang Lin , Nishi Hafumi 
Published: June 2023

AbstractProtein loops often play crucial roles in the formation of binding and enzyme active sites. However, the general structural and biological characteristics of these loops remain unclear. In this study, we investigated protein loop regions on a large scale from structural and evolutionary perspectives. After removing redundancy at the protein chain level, 555,516, 102,901, and 24,818 loops were extracted from the entire PDB, Homo sapiens, andEscherichia coliproteins, respectively. Regardless of whether they were isolated from humans orE. coli, numerous loop sequences tended to be unique among proteins or protein chains. However, loop properties exhibited high similarity or conservation, including length, distance, and stretch. The CATH classification analysis suggested that most loops connected the same superfamily, while the heterogeneity of superfamily context repertoires was not explained at the topology or homologous level. In contrast, the functions of conserved loops between human andE. coliproteins were not consistently conserved, with sequences exhibiting considerable divergence in enrichment. The amino acid composition profiles showed that loops from humans exhibited a preference for serine, whereasE. coliloops had biases for glycine and alanine. Although the amino acid composition was primarily determined by the species, the composition of certain special types of loops clustered separately from other classes, suggesting the existence of conserved loops with complex functions. Collectively, this study provides a detailed overview of protein loops from the structural, functional, and evolutionary perspectives and a vast natural loop repertoire for mining additional information.
Functional diversity reduces the risk of hydraulic failure in tree mixtures through hydraulic disconnection
Authors: Moreno Myriam , Simioni Guillaume , Cochard Hervé , Doussan Claude , Guillemot Joannès , Decarsin Renaud , Fernandez Pilar , Dupuy Jean-Luc , Trueba Santiago , Pimont François , Ruffault Julien , Martin-StPaul Nicolas K. 
Published: June 2023

AbstractForest ecosystems are increasingly threatened by anthropogenic pressures, especially by the increase in drought frequency and intensity. Tree species mixtures could improve resilience to diverse global anthropogenic pressures. However, there is still little consensus on how tree diversity affects water stress. Although some studies suggest that mixing species with different drought response strategies could be beneficial, the underlying mechanisms have seldom been identified. By combining a greenhouse experiment and a soil-plant-atmosphere hydraulic model, we explored whether mixing a drought avoidant (Pinus halepensis) and a drought tolerant (Quercus ilex) tree species could reduce plant water stress (defined as the risk of hydraulic failure) during extreme drought, compared to their respective monocultures. Our experiment showed that mixing species with divergent drought response strategies had a neutral effect on the drought-avoidant species and a positive effect on the drought-tolerant species. The model simulations further suggested that the beneficial effect of mixture on plant water stress during extreme drought was related to changes in the hydraulic connection of the plant from both the soil and the atmosphere. The ability of the drought-avoidant species to disconnect from the soil and the atmosphere limits its exposure to water stress, whereas the ability of the drought-tolerant species to increase its hydraulic connection to the soil lowers its hydraulic risk. This study brings a new insight on the mechanisms and traits combinations improving drought resistance in diversified forests and plantations, with important implications for forest management under climate change.
Assessing the Accuracy of a Smart Collar for Dogs: Predictive Performance for Heart and Breathing Rates on a Large Scale Dataset
Authors: Jarkoff Hugo , Lorre Guillaume , Humbert Eric 
Published: June 2023

AbstractWe present an evaluation of a smart collar for dogs that measures resting heart and breathing rates. The study involved 40 dogs of various breeds, ages, and sizes. The collar’s accuracy in estimating heart rates, breathing rates and detecting heart pulses was evaluated by comparing the measurements from the collar with those from a portable ECG device, completed by labels annotated by trained humans. The results show that the collar provides accurate and reliable measurements of heart and breathing rates, with a (symmetric) mean absolute percentage error of 0.38% and 1.42% respectively, and a F1 score of 98.04% for the detection of heart beats at 50ms precision.Our study demonstrates the potential of Invoxia’sSmart Dog Collaras a medical-grade tool for continuous, noninvasive, remote monitoring of vital signs in dogs, helping to improve the quality of life for dogs, detect early signs of illness, and strengthen the bond between dogs and their owners.
Alternative splicing of a potato disease resistance gene maintains homeostasis between development and immunity
Authors: Sun Biying , Huang Jie , Kong Liang , Gao Chuyun , Zhao Fei , Shen Jiayong , Wang Tian , Li Kangping , Wang Luyao , Wang Yuanchao , Halterman Dennis A. , Dong Suomeng 
Published: June 2023

AbstractPlants possess a robust and sophisticated innate immune system against pathogens. The intracellular receptors with nucleotide-binding, leucine-rich repeat (NLR) motifs recognize pathogen-derived effector proteins to trigger the immune response. To balance plant growth and rapid pathogen detection, NLR expression is precisely controlled in multifaceted ways. The alternative splicing (AS) of introns in response to infection is recurrently observed but poorly understood. Here we report that the potato NLR geneRBundergoes AS of its intron, resulting in two transcriptional isoforms, which coordinately regulate plant immunity and growth homeostasis. During normal growth,RBpredominantly exists as intron-retained isoformRB_IR, encoding a truncated protein containing only the N-terminus of the NLR. Upon late blight infection, the pathogen induces intron splicing ofRB, increasing the abundance ofRB_CDS, which encodes a full-length and active R protein. By deploying theRBsplicing isoforms fused with aluciferasereporter system, we identified IPI-O1 (also known as Avrblb1), the RB cognate effector, as a facilitator ofRBAS. IPI-O1 directly interacts with potato splicing factor StCWC15, resulting in altered localization of StCWC15 from the nucleoplasm to the nucleolus and nuclear speckles. Mutations in IPI-O1 that eliminate StCWC15 binding also disrupt StCWC15 re-localization andRBintron splicing. Thus, our study reveals that StCWC15 serves as a surveillance facilitator sensing the pathogen-secreted effector, and regulates the trade-off betweenRB-mediated plant immunity and growth, expanding our understanding of molecular plant-microbe interactions.One-sentence summaryPotato resistance geneRBbalances plant growth and immunity through AS (alternative splicing), while pathogen-secreted effector IPI-O1 mediates AS ofRBby targeting the conserved splicing factor StCWC15, further increasing theRB_CDSexpression level to activate immunity.