bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insights into Ancestral Diversity in Parkinson’s Disease Risk: A Comparative Assessment of Polygenic Risk Scores
Authors: Saffie-Awad Paula , Makarious Mary B , Elsayed Inas , Sanyaolu Arinola O. , Crea Peter Wild , Schumacher Schuh Artur F , Levine Kristin S , Vitale Dan , Koretsky Mathew J , Kim Jeffrey , Leal Thiago Peixoto , Periñan María Teresa , Dey Sumit , Noyce Alastair J , Reyes-Palomares Armando , Rodriguez-Losada Noela , Foo Jia Nee , Mohamed Wael , Heilbron Karl , Norcliffe-Kaufmann Lucy , Rizig Mie , Okubadejo Njideka , Nalls Mike A , Blauwendraat Cornelis , Singleton Andrew , Leonard Hampton , Mata Ignacio F. , Bandres-Ciga Sara ,   the Global Parkinson’s Genetics Program (GP2)
Published: November 2023

ABSTRACTObjectivesTo evaluate and compare different polygenic risk score (PRS) models in predicting Parkinson’s disease (PD) across diverse ancestries, focusing on identifying the most suitable approach for each population and potentially contributing to equitable advancements in precision medicine.MethodsWe constructed a total of 105 PRS across individual level data from seven diverse ancestries. First, a cross-ancestry conventional PRS comparison was implemented by utilizing the 90 known European risk loci with weighted effects from four independent summary statistics including European, East Asian, Latino/Admixed American, and African/Admixed. These models were adjusted by sex, age, and principal components (28 PRS) and by sex, age, and percentage of admixture (28 PRS) for comparison. Secondly, a novel and refined multi-ancestry best-fit PRS approach was then applied across the seven ancestries by leveraging multi-ancestry meta-analyzed summary statistics and using a p-value thresholding approach (49 PRS) to enhance prediction applicability in a global setting.ResultsEuropean-based PRS models predicted disease status across all ancestries to differing degrees of accuracy. Ashkenazi Jewish had the highest Odds Ratio (OR): 1.96 (95% CI: 1.69-2.25, p < 0.0001) with an AUC (Area Under the Curve) of 68%. Conversely, the East Asian population, despite having fewer predictive variants (84 out of 90), had an OR of 1.37 (95% CI: 1.32-1.42) and an AUC of 62%, illustrating the cross-ancestry transferability of this model. Lower OR alongside broader confidence intervals were observed in other populations, including Africans (OR =1.38, 95% CI: 1.12-1.63, p=0.001). Adjustment by percentage of admixture did not outperform principal components. Multi-ancestry best-fit PRS models improved risk prediction in European, Ashkenazi Jewish, and African ancestries, yet didn’t surpass conventional PRS in admixed populations such as Latino/American admixed and African admixed populations.InterpretationThe present study represents a novel and comprehensive assessment of PRS performance across seven ancestries in PD, highlighting the inadequacy of a ‘one size fits all’ approach in genetic risk prediction. We demonstrated that European based PD PRS models are partially transferable to other ancestries and could be improved by a novel best-fit multi-ancestry PRS, especially in non-admixed populations.
Interactions between the gut microbiome, dietary restriction, and aging in genetically diverse mice
Authors: Litichevskiy Lev , Considine Maya , Gill Jasleen , Shandar Vasuprada , Cox Timothy O. , Descamps Hélène C. , Wright Kevin M. , Amses Kevin R. , Dohnalová Lenka , Liou Megan J. , Tetlak Monika , Galindo-Fiallos Mario R. , Wong Andrea C. , Lundgren Patrick , Kim Junwon , Uhr Giulia T. , Rahman Ryan J. , Mason Sydney , Merenstein Carter , Bushman Frederic D. , Raj Anil , Harding Fiona , Chen Zhenghao , Prateek G.V. , Mullis Martin , Deighan Andrew G. , Robinson Laura , Tanes Ceylan , Bittinger Kyle , Chakraborty Meenakshi , Bhatt Ami S. , Li Hongzhe , Barnett Ian , Davenport Emily R. , Broman Karl W. , Cohen Robert L. , Botstein David , Freund Adam , Francesco Andrea Di , Churchill Gary A. , Li Mingyao , Thaiss Christoph A. 
Published: November 2023

SummaryThe intestinal microbiome changes with age, but the causes and consequences of microbiome aging remain unclear. Furthermore, the gut microbiome has been proposed to mediate the benefit of lifespan- extending interventions such as dietary restriction, but this hypothesis warrants further exploration. Here, by analyzing 2997 metagenomes collected longitudinally from 913 deeply phenotyped, genetically diverse mice, we provide new insights into the interplay between the microbiome, aging, dietary restriction, host genetics, and a wide range of health parameters. First, we find that microbiome uniqueness increases with age across datasets and species. Moreover, age-associated changes are better explained by cumulative exposure to stochastic events (neutral theory) than by the influence of an aging host (selection theory). Second, we unexpectedly find that the majority of microbiome features are significantly heritable and that the amount of variation explained by host genetics is as large as that of aging and dietary restriction. Third, we find that the intensity of dietary restriction parallels the extent of microbiome changes and that dietary restriction does not rejuvenate the microbiome. Lastly, we find that the microbiome is significantly associated with multiple health parameters — including body composition, immune parameters, and frailty — but not with lifespan. In summary, this large and multifaceted study sheds light on the factors influencing the microbiome and aspects of host physiology modulated by the microbiome.
Stress Knowledge Map: A knowledge graph resource for systems biology analysis of plant stress responses
Authors: Bleker Carissa , Ramšak Živa , Bittner Andras , Podpečan Vid , Zagorščak Maja , Wurzinger Bernhard , Baebler Špela , Petek Marko , Križnik Maja , Dieren Annelotte van , Gruber Juliane , Afjehi-Sadat Leila , Županič Anže , Teige Markus , Vothknecht Ute C. , Gruden Kristina 
Published: November 2023

AbstractStress Knowledge Map (SKM,https://skm.nib.si) is a publicly available resource containing two complementary knowledge graphs describing current knowledge of biochemical, signalling, and regulatory molecular interactions in plants: a highly curated model of plant stress signalling (PSS, 543 reactions) and a large comprehensive knowledge network (CKN, 488,390 interactions). Both were constructed by domain experts through systematic curation of diverse literature and database resources. SKM provides a single entrypoint for plant stress response investigations and the related growth tradeoffs. SKM provides interactive exploration of current knowledge. PSS is also formulated as qualitative and quantitative models for systems biology, and thus represents a starting point of a plant digital twin. Here, we describe the features of SKM and show, through two case studies, how it can be used for complex analyses, including systematic hypothesis generation, design of validation experiments, or to gain new insights into experimental observations in plant biology.
Regulators of health and lifespan extension in genetically diverse mice on dietary restriction
Authors: Di Francesco Andrea , Deighan Andrew G. , Litichevskiy Lev , Chen Zhenghao , Luciano Alison , Robinson Laura , Garland Gaven , Donato Hannah , Schott Will , Wright Kevin M. , Raj Anil , Prateek G.V. , Mullis Martin , Hill Warren , Zeidel Mark , Peters Luanne , Harding Fiona , Botstein David , Korstanje Ron , Thaiss Christoph A. , Freund Adam , Churchill Gary A. 
Published: November 2023

SummaryCaloric restriction (CR) delays aging and extends healthy lifespan in multiple species. Alternative forms of dietary restriction (DR) such as intermittent fasting (IF) have drawn significant interest as a more sustainable regimen, but the landscape of longevity-promoting dietary interventions remains largely unexplored. Identifying the most robust, efficacious, and experimentally tractable modes of DR is key to better understanding and implementing effective longevity interventions for human healthspan. To that end, we have performed an extensive assessment of DR interventions, investigating the effects of graded levels of CR (20% and 40%) and IF (1 day and 2 days of fasting per week) on the health and survival of 960 genetically diverse female mice. All interventions extended lifespan, although only CR significantly reduced the mortality doubling time. Notably, IF did not extend lifespan in mice with high pre-intervention bodyweight. We carried out extensive phenotyping to determine the health effects of long-term DR and to better understand the mechanisms driving within-diet heterogeneity in lifespan. The top within-diet predictor of lifespan was the ability of mice to maintain bodyweight through periods of handling, an indicator of stress resilience. Additional predictors of long lifespan include specific changes in immune cells, red blood cell distribution width (RDW), and retention of adiposity in late life. We found that lifespan is heritable (h2= 0.24), and that genetic background has a larger influence on lifespan than dietary interventions. We identified a significant association for lifespan and RDW on chromosome 18 that explained 4.3% of the diet-adjusted variation in lifespan. Diet-induced changes on metabolic traits, although beneficial, were relatively poor predictors of lifespan, arguing against the long-standing notion that DR works by counteracting the negative effects of obesity. These findings indicate that improving health and extending lifespan are not synonymous and that metabolic parameters may be inappropriate endpoints for evaluating aging interventions in preclinical models and clinical trials.
Pollen production, pollen viability and autofertility in faba bean (Vicia fabaL.) and their relationship with realized paternal success
Authors: Brünjes Lisa , Link Wolfgang 
Published: November 2023

AbstractIn animal-pollinated plants, pollen dispersal depends on several plant and animal characteristics which may influence a plant’s paternal success. Different paternal success influences the genetic contribution of a genotype to the next generation. In breeding of partially allogamous faba bean (Vicia fabaL.), synthetic populations are developed where equal contributions of genotypes to the next generation are desired to reduce inbreeding. Since direct assessments of paternity are elaborate and costly, we studied whether components of plant fitness such as pollen production and pollen viability can be used as estimates for paternity. In a field experiment and a caged outdoor pot experiment, a total of 18 genotypes (14 inbred lines, 4 F1 hybrids) of faba bean were evaluated for pollen production, pollen viability and autofertility. Pollen production was higher at the lower than at the upper inflorescences and we found mid-parent heterosis for this trait. The relative pollen viability was high (93 % – 97 % in pots, 88 % – 95 % in field) indicating that fertilization success is rather not limited by a low pollen quality. Only in the field, pollen of F1 hybrids was more viable than pollen of inbred lines. Autofertility ranged from 0 % – 98 %, with very marked average mid-parent heterosis for this trait. Autofertility did not seem to be related to either pollen production, pollen viability or paternal success. However, pollen production and pollen viability were highly correlated with paternal success. Hence, data on pollen production and viability might be useful in breeding of synthetic populations to choose parents with small differences in paternal successes, to reduce inbreeding and better exploit heterosis.
HCN channels enhance robustness of patterned activity propagation in heterogeneous conductance-based ring networks
Authors: Mittal Divyansh , Narayanan Rishikesh 
Published: November 2023

ABSTRACTContinuous attractor network (CAN) models lend a powerful framework that has provided deep insights about several aspects of brain physiology. However, most CAN models employ homogeneous, rate-based or artificially spiking neurons with precisely structured synaptic connectivity, precluding detailed analyses of the impact of specific neural-circuit components and associated heterogeneities on CAN dynamics. To address this caveat, we built populations of tunable and scalable conductance-based, physiologically constrained, ring network models consisting of distinct rings of excitatory and inhibitory neurons. We assessed the network for its ability to sustain robust propagation of patterned activity across the rings. First, in homogeneous ring networks, we found that robust activity propagation could be sustained through several different combinations of synaptic weights, demonstrating synaptic degeneracy in the emergence of robust activity propagation. We incorporated intrinsic heterogeneity through randomized perturbations to ion channel parameters of all neurons and synaptic heterogeneity by adding jitter to the Mexican-hat connectivity between inhibitory neurons. We found the number of networks exhibiting robust propagation of patterned activity to reduce with increase in the degree of synaptic or intrinsic heterogeneities. Motivated by the ability of intrinsic neuronal resonance to stabilize heterogeneous rate-based CAN models, we hypothesized that increasing HCN-channel (a resonating conductance) density would stabilize activity propagation in heterogeneous ring networks. Strikingly, we observed that increases in HCN-channel density resulted in a pronounced increase in the proportion of heterogeneous networks that exhibited robust activity propagation, across multiple trials and across three degrees of either form of heterogeneity. Together, heterogeneous networks made of neurons with disparate intrinsic properties and variable HCN channel densities yielded robust activity propagation, demonstrating intrinsic degeneracy in the emergence of robust activity propagation. Finally, as HCN channels also contribute to changes in excitability, we performed excitability-matched controls with fast HCN channels that do not introduce resonance. We found that fast HCN channels did not stabilize heterogeneous network dynamics over a wide range of conductance values, suggesting that the slow negative feedback loop introduced by HCN channels is a critical requirement for network stabilization. Together, our results unveil a cascade of degeneracy in ring-network physiology, spanning the molecular-cellular-network scales. These results also demonstrate a critical role for the widely expressed HCN channels in enhancing the robustness of heterogeneous neural circuits by implementing a slow negative feedback loop at the cellular scale.
permGWAS2: Enhanced and Accelerated Permutation-based Genome-Wide Association Studies
Authors: John Maura , Korte Arthur , Grimm Dominik G. 
Published: November 2023

AbstractMotivationPermutation-based significance thresholds have been shown to be a robust alternative to Bonferroni-based significance thresholds in genome-wide association studies (GWAS). However, the implementation of permutation-based thresholds is computationally demanding. The recently published methodpermGWASintroduced a batch-wise approach using 4D tensors to efficiently compute permutation-based GWAS. However, running multiple univariate tests in parallel leads to many repetitive computations and increased computational resources. More importantly, the previous version ofpermGWASdoes not take into account the population structure when permuting the phenotype.ResultsWe proposepermGWAS2, an improved and accelerated version that uses a block matrix decomposition to optimize computations, thereby reducing redundant computations. It also introduces an alternative permutation strategy that takes into account the population structure during permutation. We show that this improved framework provides a more streamlined approach to performing permutation-based GWAS with a lower false discovery rate compared to the previous version and the traditional Bonferroni correction.AvailabilitypermGWAS2is open-source and publicly available on GitHub for download:https://github.com/grimmlab/permGWAS.
A rolling circle-replicating plasmid as an Inovirus phage satellite
Authors: Schmid Nicole E , Brandt David , Walasek Claudia , Rolland Clara , Wittmann Johannes , Müsken Mathias , Kalinowski Jörn , Thormann Kai M 
Published: November 2023

AbstractBacterial viruses (phages) are potent agents of lateral gene transfer and thus are important drivers of evolution. A group of mobile genetic elements (MGEs), referred to as phage satellites, exploit phages to disseminate their own genetic material. Here we isolated a novel member of the genusInovirus,Shewanellaphage Dolos, along with an autonomous rolling circle-replicating plasmid, pDolos. Dolos causes a chronic infection in its hostShewanella oneidensisby phage production with only minor effects on the host cell proliferation. When present, plasmid pDolos hijacks Dolos functions to be predominantly packaged into phage virions and released into the environment. pDolos can disseminate further genetic material encoding, e.g., resistances, fluorophores, and metabolically active proteins, to host cells sensitive to Dolos infection. Given the rather simple requirements of a plasmid for takeover of an inovirus, the wide distribution of phages of this group and the broad spectrum of rolling circle-replicating plasmids, we speculate that similar phage-satellite systems are common among bacteria.
Humans rationally balance detailed and temporally abstract world models
Authors: Kahn Ari E. , Daw Nathaniel D. 
Published: November 2023

AbstractHow do people model the world’s dynamics to guide mental simulation and evaluate choices? One prominent approach, the Successor Representation (SR), takes advantage of temporal abstraction of future states: by aggregating trajectory predictions over multiple timesteps, the brain can avoid the costs of iterative, multi-step mental simulation. Human behavior broadly shows signatures of such temporal abstraction, but finer-grained characterization of individuals’ strategies and their dynamic adjustment remains an open question. We developed a novel task to measure SR usage during dynamic, trial-by-trial learning. Using this approach, we find that participants exhibit a mix of SR and model-based learning strategies that varies across individuals. Further, by dynamically manipulating the task contingencies within-subject to favor or disfavor temporal abstraction, we observe evidence of resource-rational reliance on the SR, which decreases when future states are less predictable. Our work adds to a growing body of research showing that the brain arbitrates between approximate decision strategies. The current study extends these ideas from simple habits into usage of more sophisticated approximate predictive models, and demonstrates that individuals dynamically adapt these in response to the predictability of their environment.
Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice
Authors: Downs Anthony M. , Kmiec Gracianne , McElligott Zoé A. 
Published: November 2023

AbstractThe number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having more withdrawal symptoms, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.
Temperature-dependence and genetic variation in resource acquisition strategies in a model freshwater plant
Authors: Gillies Graydon J. , Angert Amy L. , Usui Takuji 
Published: November 2023

ABSTRACTUnderstanding how competition varies with environmental stress is critical to anticipating species and community responses to rapid environmental change. While the stress-gradient hypothesis predicts the strength of competition to decrease with increasing stress, our understanding of how competition varies with stress is limited by a lack of mechanistic understanding of how resource-use traits underlying competitive dynamics respond to stress.Here, we use duckweeds in theLemnaspecies complex to measure how phenotypic and genetic variation inR*(a resource acquisition trait representing the minimum resource requirement for positive population growth) varies with high-temperature stress to better understand how stress alters competitive ability for essential resources.We found that heat stress increased theR*ofLemnaplants for nitrogen acquisition. Because lowerR*values predict dominance in competitive dynamics where resources are limiting, this indicates that under stressful, high temperatures, plants could experience increased sensitivity to competition due to the higher resources required to sustain positive population growth rates.We found minimal genetic variation inR*across 11 local genotypes within theLemnaspecies complex, indicating that selection on resource acquisition strategies for essential resources such as nitrogen may be constrained in nature. The expression of genetic variation inR*for nitrogen was further reduced under heat stress, suggesting that the response to selection forR*could be particularly constrained under high-temperature stress.Contrary to predictions drawn from the gleaner-opportunist trade-off, we did not find evidence for a trade-off in resource acquisition strategies under benign conditions or high-temperature stress. Plants with lowerR*(i.e., higher growth rates under lower nitrogen levels) were not constrained to have lower growth rates under higher nitrogen levels, possibly because the chosen genotypes have not diverged across resource acquisition strategies or becauseLemnaspp. has escaped this constraint.Importantly, our work outlines that high-temperature stress could increase sensitivity to competition through increased requirement for resources while reducing the evolutionary potential forLemnaspecies to respond to selection for resource traits. This study acts as a key step to understanding the mechanistic traits behind competitive dynamics in resource-limited and stressful environments.