bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-omic ADNI CSF and plasma data integration identifies distinct metabolic transitions in disease progression in Alzheimer’s Disease
Authors: Paterson Tom , Rohrs Jennifer , Hohman Timothy J. , Mapstone Mark , Levey Allan I. , Hood LeRoy ,   Alzheimer’s Disease Neuroimaging Initiative, Funk Cory C. 
Published: July 2024

AbstractAge and APOE allele status are the two greatest risk factors for Alzheimer’s disease, with microglial processing, recycling of debris and cholesterol transport emerging as other key genetic determinants from AD GWAS. How risk factors contribute to neuronal loss is an unanswered question. Using the ADNI dataset, we provide evidence for distinct processes driving neurodegeneration in AD across a range of ADAS13 scores binned into quartiles (Q1-4) found in ADNI. In Q1 individuals, we see evidence of white matter hyperintensities (WMH) associated with complement and HDL proteins, independent of tau and hippocampal atrophy rates. In Q2 individuals, we see specific protein/lipid correlation networks that are associated with tau and hippocampal atrophy. Also in Q2, we see variations in enzyme levels (LPA2G7, LPCAT2) that impact phosphatidylcholine availability for cholesterol efflux onto CNS lipoproteins. Low LPA2G7 and high LPCAT are associated with lower disruption of ANLS, while high LPA2G7 and low LPCAT are associated with higher disruption. In Q3 individuals, DHA and plasmalogens appear to be protective of astrogliosis, presumably by decreasing lipid droplet size, and increasing their lipid debris flux capacity. The networks we identify in this analysis provide evidence that progressively elevated cellular cholesterol levels, likely the result of accelerating neuronal and myelin debris, are perturbing homeostatic processes, resulting in disruption of astrocyte-neuron lactate shuttle (ANLS), contributing to lipid droplet formation, and astrogliosis. Existing studies have already identified elevated cellular cholesterol as the driver of increased access of APP to β- and γ-secretase for β-amyloid production in late-onset AD. Importantly, we provide evidence that points to actionable variations in lipids associated with slower disease progression and decreased metabolic disruption and inflammation. We believe this positive feedback loop (neurodegeneration → lipid debris processing → metabolic disruption → neurodegeneration) is a key destabilizing cycle responsible for disease progression in AD, reinforcing the perspective that Alzheimer’s is fundamentally a metabolic disease. Our findings are consistent with established lipid risk factor associations. We anticipate the mechanistic insights from our analysis will advance nutritional and pharmacological interventions and slow cognitive decline.
The battle of the sexes in humans is highly polygenic
Authors: Cole Jared M. , Scott Carly B. , Johnson Mackenzie M. , Golightly Peter R. , Carlson Jedidiah , Ming Matthew J. , Harpak Arbel , Kirkpatrick Mark 
Published: July 2024

AbstractSex-differential selection (SDS), which occurs when the fitness effects of alleles differ between males and females, can have profound impacts on the maintenance of genetic variation, disease risk, and other key aspects of natural populations. Because the sexes mix their autosomal genomes each generation, quantifying SDS is not possible using conventional population genetic approaches. Here, we introduce a novel method that exploits subtle sex differences in haplotype frequencies resulting from SDS acting in the current generation. Using data from 300K individuals in the UK Biobank, we estimate the strength of SDS throughout the genome. While only a handful of loci under SDS are individually significant, we uncover polygenic signals of genome-wide SDS for both viability and fecundity. An interesting life-history tradeoff emerges: alleles that increase viability more in one sex increase fecundity more in the other sex. Lastly, we find evidence of SDS on fecundity acting on alleles affecting arm fat-free mass. Taken together, our findings connect the long-standing evidence of SDS acting on human phenotypes with its impact on the genome.Significance statementSelection often acts differently on females and males, as evidenced by the striking sexual dimorphism found in many taxa. As a result, alleles can have different fitness effects in each sex. Consequences can include higher levels of genetic variation and higher disease burdens in populations. This study introduces a novel method to quantify this sex-differential selection (SDS) and reveals that it acts throughout the human genome. We discovered a life history tradeoff between survival and fecundity in females and males and that SDS on fecundity acts on alleles affecting arm fat-free mass.
Comprehensive chemotyping, and the gonadal regulation, of seven kisspeptinergic neuronal populations in the mouse brain
Authors: Hernández Vito S. , Zetter Mario A. , Hernández-Pérez Oscar R. , Hernández-González Rafael , Camacho-Arroyo Ignacio , Millar Robert P. , Eiden Lee E. , Zhang Limei 
Published: July 2024

AbstractBackgroundKisspeptinergic signaling is well-established as crucial for regulation of reproduction, but its potential broader role in brain function is less understood. This study investigates the distribution and chemotyping of kisspeptin-expressing neurons within the mouse brain.MethodsRNAscope singleplex, duplex and multiplexin situhybridization methods were used to assess kisspeptin mRNA (Kiss1)expression and its co-expression with other neuropeptides, excitatory and inhibitory neurotransmitter markers, and sex steroid receptors in intact and gonadectomized young adult mice.ResultsSeven distinct kisspeptin neuronal chemotypes were characterized, including within two novelKiss1-expressing groups described here for the first time: the ventral premammillary nucleus, and the nucleus of the solitary tract.Kiss1mRNA was also localized in the soma, and within the dendritic compartment, of hypothalamic neurons. AlteredKiss1expression following gonadectomy suggests a previously unappreciated role for androgen receptors in regulating kisspeptin signaling.ConclusionThis study provides a detailed chemoanatomical map of kisspeptin-expressing neurons in the brain, highlighting their potential functional diversity. The discovery of new kisspeptin-expressing neuronal populations, and gonadectomy-induced changes inKiss1expression patterns, provide a basis for further exploration of non-endocrine roles for kisspeptin in brain function.
Knowledge and beliefs about dietary inorganic nitrate in a representative sample of adults from the United Kingdom
Authors: Griffiths Alex , Grainger Evie , Matu Jamie , Alhulaefi Shatha , Whyte Eleanor , Hayes Eleanor , Brandt Kirsten , Mathers John C. , Siervo Mario , Shannon Oliver M. 
Published: July 2024

ABSTRACTObjectiveEvaluate knowledge and beliefs about dietary nitrate among United Kingdom (UK)-based adults.DesignAn online questionnaire was administered to evaluate knowledge/beliefs about dietary nitrate. Overall knowledge of dietary nitrate was quantified using a 21-point Nitrate Knowledge Index. Responses were compared between sociodemographic groups.SettingUK.ParticipantsA nationally representative sample of three hundred adults.ResultsOnly 19% of participants had heard of dietary nitrate prior to completing the questionnaire. Most participants (∼70%) were unsure about the effects of dietary nitrate on health parameters (e.g., blood pressure, cognitive function, cancer risk) or exercise performance. Most participants were unsure of the average population intake (78%) and acceptable daily intake (ADI) (83%) of nitrate. Knowledge of dietary sources of nitrate was generally low, with only ∼30% of participants correctly identifying foods with higher/lower nitrate contents. Almost none of the participants had deliberately purchased, or avoided purchasing, a food based around its nitrate content. Nitrate Knowledge Index scores were generally low (median[IQR]: 5[8]), but were significantly higher in individuals who were currently employed vs. unemployed (median[IQR]: 5[7]vs.4[7];p<0.001), in those with previous nutritional education vs. no nutritional education (median[IQR]: 6[7]vs.4[8];p=0.012), and in individuals who had heard of nitrate prior to completing the questionnaire vs. those who had not (median [IQR]: 9[8]vs.4 [7];p<0.001).ConclusionsThis study demonstrates low knowledge around dietary nitrate in UK-based adults. Greater education around dietary nitrate may be valuable to help individuals make more informed decisions about their consumption of this compound.
Markers of Biological Brain Aging Mediate Effects of Vascular Risk Factors on Cognitive and Motor Functions: A Multivariate Imaging Analysis of 40,579 Individuals
Authors: Petersen Marvin , Link Moritz A. , Mayer Carola , Nägele Felix L. , Schell Maximilian , Fiehler Jens , Gallinat Jürgen , Kühn Simone , Twerenbold Raphael , Omidvarnia Amir , Hoffstaedter Felix , Patil Kaustubh R. , Eickhoff Simon B. , Thomalla Götz , Cheng Bastian 
Published: July 2024

AbstractThe increasing global life expectancy brings forth challenges associated with age-related cognitive and motor declines. To better understand underlying mechanisms, we investigated the connection between markers of biological brain aging based on magnetic resonance imaging (MRI), cognitive and motor performance, as well as modifiable vascular risk factors, using a large-scale neuroimaging analysis in 40,579 individuals of the population-based UK Biobank and Hamburg City Health Study. Employing partial least squares correlation analysis (PLS), we investigated multivariate associative effects between three imaging markers of biological brain aging – relative brain age, white matter hyperintensities of presumed vascular origin, and peak-width of skeletonized mean diffusivity – and multi-domain cognitive test performances and motor test results. The PLS identified a latent dimension linking higher markers of biological brain aging to poorer cognitive and motor performances, accounting for 94.7% of shared variance. Furthermore, a mediation analysis revealed that biological brain aging mediated the relationship of vascular risk factors — including hypertension, glucose, obesity, and smoking — to cognitive and motor function. These results were replicable in both cohorts. By integrating multi-domain data with a comprehensive methodological approach, our study contributes evidence of a direct association between vascular health, biological brain aging, and functional cognitive as well as motor performance, emphasizing the need for early and targeted preventive strategies to maintain cognitive and motor independence in aging populations.
Host trees partially explain the complex bacterial communities of two threatened saproxylic beetles
Authors: Kolasa Michał , Krovi Rama Sarvani , Plewa Radosław , Jaworski Tomasz , Kadej Marcin , Smolis Adrian , Gutowski Jerzy M. , Sućko Krzysztof , Ruta Rafał , Olbrycht Tomasz , Saluk Sergey , Oczkowicz Maria , Kajtoch Łukasz 
Published: July 2024

ABSTRACTMicroorganisms are integral to ecosystem functioning and host adaptation, yet the understanding of microbiomes in diverse beetle taxa remains limited. We conducted a comprehensive study to investigate the microbial composition of two red flat bark beetle species,Cucujus haematodesandC. cinnaberinus, and assessed the influence of host taxonomic relatedness and host tree species on their microbiomes. Moreover, we summarize the available data on the microbiome of saproxylic beetles as a reference. We sampled 67 larvae of twoCucujustaxa taken from eleven host tree species. 16S rRNA V4 fragment sequencing revealed distinct microbial communities associated with eachCucujusspecies, with host tree species significantly influencing microbiome composition. Alpha and beta diversity metrics indicated significant differences between microbial communities in both, beetle and host tree species. Principal Component Analysis indicated distinct clustering based on host tree species but not for beetle species. This overlap could be attributed to the similar ecology of bothCucujusspecies. The detection of various bacteria, among which some have already been reported in saproxylophagous beetles, suggests that the red flat bark beetles ingest the bacteria via foraging on other wood-dwelling invertebrates. Our findings show the complex interplay between host taxonomy, microhabitat, and microbial composition inCucujus, providing insights into their ecological roles and conservation implications. This research helps to fill the gap in understanding the microbial dynamics of saproxylic beetles, sheds light on factors shaping their microbiomes, and highlights the importance of considering both host species and environmental conditions when studying insect-microbe interactions in forest ecosystems.
A systematic targeted genetic screen identifies proteins involved in cytoadherence of the malaria parasiteP. falciparum
Authors: Küster Nina , Roling Lena , Ouayoue Ardin , Steeg Katharina , Przyborski Jude M 
Published: July 2024

SUMMARYImmediately after invading their chosen host cell, the mature human erythrocyte, malaria parasites begin to export an array of proteins to this compartment, where they initiate processes that are prerequisite for parasite survival and propagation, including nutrient import and immune evasion. One consequence of these activities is the emergence of novel adhesive phenotypes that can lead directly to pathology in the human host. To identify parasite proteins involved in this process we used modern genetic tools to target genes encoding 15 exported parasite proteins, selected by anin-silicoworkflow. This resulted in 4 genetically modified parasite lines that were then characterised in detail. Of these lines, 3 could be shown to have aberrations in adhesion, and of these 1 appears to have a block in the transport and/or correct folding of the major surface adhesin PfEMP1 (Plasmodium falciparumerythrocyte membrane protein 1). Our data expand the known factors involved in this important process, and once again highlight the complexity of this phenomenon.
Nuclear FAK aggravates CD8+T cell exhaustion via the SP1-IL-6 axis in colorectal cancer
Authors: Kong Hao , Wu Xiangji , Yang Qingxin , Wu Chunwei , Yu Xin , Yang Jie , Xie Dai , Dai Yu , Chen Lang , Ma Panpan , Dai Siqi , Huang Libin , Chen Chong , Mi Peng , Peng Yong , Shi Hubing , Zhang Dunfang , Ke Nengwen , Zhou Zongguang , Cao Dan , Hu Bing , Wang Ping , Chen Lu , Liu Yun-Hua , Jiang Hong 
Published: July 2024

SUMMARYAlthough immune checkpoint blockade (ICB) therapy has shown promise in colorectal cancer patients with high microsatellite instability (MSI-H), response rates remain low for the majority of patients. Key challenges include the exhaustion of CD8+T cells and the presence of immunosuppressive cells within the tumor microenvironment. By integrating digital spatial profiling and scRNA sequencing, we found that the tumor-intrinsic activation of focal adhesion kinase (FAK) was strongly correlated with the heterogeneity and exhaustion of CD8+T cells within the spatial context of the tumor microenvironment and correlated with patient survival. Pharmacological inhibition or genetic loss of FAK enhanced antitumor immune responses and synergistically potentiated αPD-1 and αTIM-3 immunotherapy by augmenting CD8+T cell cytotoxicity and restoring exhaustion in preclinical models of colorectal cancer. Mechanistically, nuclear FAK was found to regulate SP1/IL-6-mediated T cell exhaustion and the transcription of proinflammatory cytokines/chemokines. These findings underscore FAK’s pivotal role in CD8+T cell exhaustion within the immunosuppressive tumor microenvironment, suggesting that FAK is a promising target for advancing cancer immunotherapy.
Microscale Spatial Dysbiosis in Oral biofilms Associated with Disease
Authors: Grodner Benjamin , Wu David T. , Hahm Sumin , Takayasu Lena , Wen Natalie , Kim David M. , Chen Chia-Yu , De Vlaminck Iwijn 
Published: July 2024

AbstractMicrobiome dysbiosis has largely been defined using compositional analysis of metagenomic sequencing data; however, differences in the spatial arrangement of bacteria between healthy and diseased microbiomes remain largely unexplored. In this study, we measured the spatial arrangement of bacteria in dental implant biofilms from patients with healthy implants, peri-implant mucositis, or peri-implantitis, an oral microbiome-associated inflammatory disease. We discovered that peri-implant biofilms from patients with mild forms of the disease were characterized by large single-genus patches of bacteria, while biofilms from healthy sites were more complex, mixed structures. Based on these findings, we propose a model of peri-implant dysbiosis where changes in biofilm spatial architecture allow the colonization of new community members. This model indicates that spatial structure could be used as a potential biomarker for community stability and has implications in diagnosis and treatment of peri-implant diseases. These results enhance our understanding of peri-implant disease pathogenesis and may be broadly relevant for spatially structured microbiomes.
Contrasting defense strategies of oligotrophs and copiotrophs revealed by single-cell-resolved virus–host pairing of freshwater bacteria
Authors: Okazaki Yusuke , Nishikawa Yohei , Wagatsuma Ryota , Takeyama Haruko , Nakano Shin-ichi 
Published: July 2024

ABSTRACTThe ecological importance of virus–host interactions is unclear due to the limited ability of metagenomics to resolve virus–host pairs and the infection state of individual cells. We addressed these problems using single-cell genomics combined with published metagenomic data on lake bacterioplankton. We obtained 862 medium- to high-quality single-cell amplified genomes (SAGs) from two water layers and two seasons in Lake Biwa, Japan. We assembled 176 viral (dsDNA phage) contigs in the SAGs, and identified novel virus–host pairs including the discovery of viruses infecting CL500-11, the dominant bacterioplankton lineage in deep freshwater lakes worldwide. A virus was detected in 133 (15.4%) SAGs through read mapping analysis. The viral detection rate showed little variation among samples (12.1–18.1%) but significant variation in host taxonomy (4.2–65.3%), with copiotrophs showing higher values than oligotrophs. The high infection rates of copiotrophs were achieved by collective infection by diverse viruses, suggesting weak density-dependent virus–host selections, presumably because of their non-persistent interactions with viruses due to their fluctuating abundance. In contrast, the low infection rates of oligotrophs supported the idea that their co-dominance with viruses is achieved by genomic microdiversification that diversifies the virus–host specificity, sustained by their large population size and persistent density-dependent fluctuating selection. Overall, we demonstrated that virus–host interactions are highly diverse within and between host lineages, which was overlooked by metagenomics analysis, as exemplified by the CL500-11 virus, which showed extremely high read coverages in cellular and virion metagenomes, but infected < 1% of host cells.Significance statementVirus–host interactions are among the most significant driving forces of microbial biogeochemical cycles and genomic diversification. Unlike experimental conditions, bacterial cells in the natural environment are not uniformly infected by a single virus, but interact with diverse viruses under heterogeneous eco-physiological and genetic conditions. The specificity and heterogeneity of infection are the keys to understanding complex virus–host interactions and the mechanisms behind their co-existence. However, these interactions remain unclear due to the limitations of conventional metagenomic approaches. We addressed this issue by detecting viral signals from single-cell-amplified genomes of lake bacterial communities. The results revealed novel virus–host pairs and their infection rates, suggesting that viral defense strategies differ among host lineages, reflecting their ecological characteristics.
Investigation of a Novel Mouse Model of Prader-Willi Syndrome with Invalidation ofNecdinandMagel2
Authors: Barelle Pierre-Yves , Sicardi Alicia , Schaller Fabienne , Buron Julie , Becquet Denis , Omnes Felix , Watrin Françoise , Santos Catarina , Menuet Clément , François-Bellan Anne-Marie , Caron Emilie , Klucznik Jessica , Prevot Vincent , Bouret Sebastien G , Muscatelli Françoise 
Published: July 2024

AbstractPrader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of seven contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. Knockout (KO) mouse models for each candidate gene were generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay betweenNecdinandMagel2“PWS” genes and generated a novel mouse model (named “Madin”) with a deletion including both genes. A subset ofMadinKO mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood.MadinKO mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance. Delayed sexual maturation and altered timing of puberty onset were observed in mutant mice. AdultMadinKO mice displayed increased ventilation and a persistent increase in apneas following a hypercapnic challenge. Transcriptomics analyses revealed a dysregulation of key circadian genes and alterations of genes associated with axonal function that were also found in the hypothalamus of patients with PWS. At neuroanatomical levels, we report an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that theMadinKO mouse is a reliable and more genetically relevant model for the study of PWS.
Unraveling the Role of Ctla-4 in Intestinal Immune Homeostasis: Insights from a novel Zebrafish Model of Inflammatory Bowel Disease
Authors: Qin Lulu , Hu Chongbin , Zhao Qiong , Wang Yong , Fan Dongdong , Lin Aifu , Xiang Lixin , Chen Ye , Shao Jianzhong 
Published: July 2024

AbstractInflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 homolog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4−/−) zebrafish line. These mutant zebrafish exhibited reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, our findings demonstrate the pivotal role of Ctla-4 in maintaining intestinal homeostasis. Additionally, they offer substantial evidence linking CTLA-4 to IBD and establish a novel zebrafish model for investigating both the pathogenesis and potential treatments.