bluuebunny/crossref_metadata_2025_split huggingface dataset:
The classic psychedelic DOI induces a persistent desynchronized state in medial prefrontal cortex
Authors: Olson Randall J. , Bartlett Lowell , Sonneborn Alex , Bretton-Granatoor Zachary , Firdous Ayesha , Harris Alexander Z. , Abbas Atheir I. 
Published: February 2023

AbstractAdministration or consumption of classic psychedelics (CPs) leads to profound changes in experience which are often described as highly novel and meaningful. They have shown substantial promise in treating depressive symptoms and may be therapeutic in other situations. Although research suggests that the therapeutic response is correlated with the intensity of the experience, the neural circuit basis for the alterations in experience caused by CPs requires further study. The medial prefrontal cortex (mPFC), where CPs have been shown to induce rapid, 5-HT2Areceptor-dependent structural and neurophysiological changes, is believed to be a key site of action. To investigate the acute neural circuit changes induced by CPs, we recorded single neurons and local field potentials in the mPFC of freely behaving mice after administration of the 5-HT2A/2Creceptor-selective CP, 2,5-Dimethoxy-4-iodoamphetamine (DOI). We segregated recordings into active and rest periods in order to examine cortical activity during desynchronized (active) and synchronized (rest) states. We found that DOI induced a robust decrease in low frequency power and decoupled rhythmic activity from neural population dynamics when animals were at rest, attenuating the usual synchronization that occurs during less active behavioral states. DOI also increased broadband gamma power and suppressed activity in fast-spiking neurons in both active and rest periods. Together, these results show that the CP DOI induces persistent desynchronization in mPFC, including during rest when mPFC typically exhibits more synchronized activity. This shift in cortical dynamics may in part underlie the longer-lasting effects of CPs on plasticity, and may be critical to their therapeutic properties.
Interpreting population and family-based genome-wide association studies in the presence of confounding
Authors: Veller Carl , Coop Graham 
Published: February 2023

AbstractA central aim of genome-wide association studies (GWASs) is to estimate direct genetic effects: the causal effects on an individual’s phenotype of the alleles that they carry. However, estimates of direct effects can be subject to genetic and environmental confounding, and can also absorb the ‘indirect’ genetic effects of relatives’ genotypes. Recently, an important development in controlling for these confounds has been the use of within-family GWASs, which, because of the randomness of Mendelian segregation within pedigrees, are often interpreted as producing unbiased estimates of direct effects. Here, we present a general theoretical analysis of the influence of confounding in standard population-based and within-family GWASs. We show that, contrary to common interpretation, family-based estimates of direct effects can be biased by genetic confounding. In humans, such biases will often be small per-locus, but can be compounded when effect size estimates are used in polygenic scores. We illustrate the influence of genetic confounding on population- and family-based estimates of direct effects using models of assortative mating, population stratification, and stabilizing selection on GWAS traits. We further show how family-based estimates of indirect genetic effects, based on comparisons of parentally transmitted and untransmitted alleles, can suffer substantial genetic confounding. In addition to known biases that can arise in family-based GWASs when interactions between family members are ignored, we show that biases can also arise from gene-by-environment (G×E) interactions when parental genotypes are not distributed identically across interacting environmental and genetic backgrounds. We conclude that, while family-based studies have placed GWAS estimation on a more rigorous footing, they carry subtle issues of interpretation that arise from confounding and interactions.
100 years of anthropogenic impact causes changes in freshwater functional biodiversity
Authors: Eastwood Niamh , Zhou Jiarui , Derelle Romain , Abdallah Mohamed Abou-Elwafa , Stubbings William A. , Jia Yunlu , Crawford Sarah E. , Davidson Thomas A. , Colbourne John K. , Creer Simon , Bik Holly , Hollert Henner , Orsini Luisa 
Published: February 2023

AbstractDespite efforts from scientists and regulators, biodiversity is declining at an alarming rate. Unless we find transformative solutions to preserve biodiversity, future generations may not be able to enjoy nature’s services.We have developed a conceptual framework that establishes the links between biodiversity dynamics and abiotic change through time and space using artificial intelligence. Here, we apply this framework to a freshwater ecosystem with a known history of human impact and study 100 years of community-level biodiversity, climate change and chemical pollution trends. We apply explainable network models with multimodal learning to community-level functional biodiversity measured with multilocus metabarcoding, to establish correlations with biocides and climate change records. We observed that the freshwater community assemblage and functionality changed over time without returning to its original state, even if the lake partially recovered in recent times. Insecticides and fungicides, combined with extreme temperature events and precipitation, explained up to 90% of the functional biodiversity changes. The community-level biodiversity approach used here reliably explained freshwater ecosystem shifts. These shifts were not observed when using traditional quality indices (e.g. Trophic Diatom Index).Our study advocates the use of high throughput systemic approaches on long-term trends over species-focused ecological surveys to identify the environmental factors that cause loss of biodiversity and disrupt ecosystem functions.
A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance
Authors: van der Krift Felix , Zijlmans Dick W. , Shukla Rhythm , Javed Ali , Koukos Panagiotis I. , Schwarz Laura L.E. , Timmermans-Sprang Elpetra P.M. , Maas Peter E.M. , Gahtory Digvijay , van den Nieuwboer Maurits , Mol Jan A. , Strous Ger J. , Bonvin Alexandre M.J.J. , van der Stelt Mario , Veldhuizen Edwin J.A. , Weingarth Markus , Vermeulen Michiel , Klumperman Judith , Maurice Madelon M. 
Published: February 2023

AbstractCancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later disease stages. Depletion of folylpolyglutamate synthase (FPGS), which normally promotes intracellular accumulation and activity of both natural folates and methotrexate, is linked to methotrexate and 5-fluorouracil resistance and its association with relapse illustrates the need for improved intervention strategies. In this study, we characterize a novel antifolate (C1) that, like methotrexate, potently inhibits dihydrofolate reductase (DHFR) and downstream one-carbon metabolism. Contrary to methotrexate, however, C1 displays optimal efficacy in FPGS-deficient contexts, due to decreased competition with intracellular folate concentrations for interaction with DHFR. Indeed, we show that FPGS-deficient patient-derived CRC organoids display enhanced sensitivity to C1-induced growth inhibition, while FPGS-high CRC organoids are more sensitive to methotrexate. Our results thus argue that polyglutamylation-independent antifolates can be applied to exert selective pressure on FPGS-deficient cells during chemotherapy, employing a vulnerability created by polyglutamylation deficiency.
The influence of generativity on purpose in life is mediated by social support and moderated by prefrontal functional connectivity in at-risk older adults
Authors: Walker Caitlin S. , Li Linda , Baracchini Giulia , Tremblay-Mercier Jennifer , Spreng R. Nathan ,   The PREVENT-AD Research Group, Geddes Maiya R. 
Published: February 2023

AbstractObjectivesGenerativity, the desire and action to improve the well-being of younger generations, is positively associated with purpose in life among older adults. However, the neural basis of generativity and the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults.MethodsFifty-eight cognitively healthy older adults (mean age = 70.78, 45 females) with a family history of Alzheimer’s disease were recruited from the PREVENT-AD aging cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS) and whether this rsFC moderated the relationship between generativity and purpose in life.ResultsAffectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus and vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC-rdlPFC connectivity moderated the association between generative desire and purpose in life.DiscussionThese findings provide insight into how the brain supports social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose and life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging.
NuSAP participates in metaphase spindle length control in mammalians
Authors: Wang Yao , Sun Mengjie , Xin Guangwei , Yang Biying , Jiang Qing , Zhang Chuanmao 
Published: February 2023

AbstractPrecise chromosome congression and segregation require proper assembly of a steady-state metaphase spindle, which is dynamic and maintained by continuous microtubule flux. NuSAP is a microtubule-stabilizing and -bundling protein that promotes chromosomedependent spindle assembly. However, its function in spindle dynamics remains unclear. Here, we demonstrate that NuSAP regulates the dynamics and length control of the metaphase spindle. Mechanistically, NuSAP facilitates kinetochore capture and spindle assembly via promoting Eg5 binding with microtubules. It also prevents excessive microtubule depolymerization through interacting with Kif2A and reduces its spindle-pole localization. NuSAP is phosphorylated by Aurora A at Ser-240 during mitosis, and this phosphorylation promotes its interaction with Kif2A on the spindle body and reduces its localization to the spindle poles, thus maintaining the proper spindle microtubule flux. NuSAP knockout resulted in shorter spindle formation with faster microtubule flux and chromosome misalignment. Taken together, we uncover that NuSAP participates in spindle assembly, dynamics, and metaphase spindle length control via affecting microtubule flux and Kif2A localization.
Kiwa is a bacterial membrane-embedded defence supercomplex activated by phage-induced membrane changes
Authors: Zhang Zhiying , Todeschini Thomas C. , Wu Yi , Kogay Roman , Naji Ameena , Rodriguez Joaquin Cardenas , Mondi Rupavidhya , Kaganovich Daniel , Taylor David W. , Bravo Jack P. K. , Teplova Marianna , Amen Triana , Koonin Eugene V. , Patel Dinshaw J. , Nobrega Franklin L. 
Published: February 2023

SummaryBacteria and archaea deploy diverse, sophisticated defence systems to counter virus infection, yet many immunity mechanisms remain poorly understood. Here, we characterise the Kiwa defence system as a membrane-associated supercomplex that senses changes in the membrane induced by phage infection and plasmid conjugation. This supercomplex, comprising KwaA tetramers bound to KwaB dimers, as its basic repeating unit, detects structural stress via KwaA, activating KwaB, which binds ejected phage DNA through its DUF4868 domain, stalling phage DNA replication forks and thus disrupting replication and late transcription. We show that phage-encoded DNA mimic protein Gam, which inhibits RecBCD, also targets Kiwa through KwaB recognition. However, Gam binding to one defence system precludes its inhibition of the other. These findings reveal a distinct mechanism of bacterial immune coordination, where sensing of membrane disruptions and inhibitor partitioning enhance protection against phages and plasmids.
Rapid and sensitive detection of native glycoRNAs
Authors: Hemberger Helena , Chai Peiyuan , Lebedenko Charlotta G. , Caldwell Reese M. , George Benson M. , Flynn Ryan A. 
Published: February 2023

AbstractChemical tools enable precise characterization of many biopolymers, including glycoconjugates. Metabolic chemical reporters enabled the discovery of glycoRNAs, however they have certain limitations due the requirement of having living cells to incorporate the modified sugar. Here we develop a periodate oxidation and aldehyde ligation method to detect and characterize native sialoglycoRNAs, termed rPAL. With optimized RNA biochemistry to enhance recovery and analysis of small RNAs, we show rPAL is at least an order of magnitude more sensitive than previous methods for detecting sialoglycoRNAs. These improvements allow rPAL to detect sialoglycoRNA from human clinical samples as demonstrated by defining the abundance and patterns of sialoglycoRNAs from sorted populations of peripheral blood mononuclear cells. The sensitivity, robustness, and flexibility of rPAL will allow greater access towards characterizing glycoRNA biology.
Substantial Downregulation of Mitochondrial and Peroxisomal Proteins during Acute Kidney Injury revealed by Data-Independent Acquisition Proteomics
Authors: Burton Jordan B. , Silva-Barbosa Anne , Bons Joanna , Rose Jacob , Pfister Katherine , Simona Fabia , Gandhi Tejas , Reiter Lukas , Bernhardt Oliver , Hunter Christie L. , Goetzman Eric S , Sims-Lucas Sunder , Schilling Birgit 
Published: February 2023

AbstractAcute kidney injury (AKI) manifests as a major health concern, particularly for the elderly. Understanding AKI-related proteome changes is critical for prevention and development of novel therapeutics to recover kidney function and to mitigate the susceptibility for recurrent AKI or development of chronic kidney disease. In this study, mouse kidneys were subjected to ischemia-reperfusion injury, and the contralateral kidneys remained uninjured to enable comparison and assess injury-induced changes in the kidney proteome. A fast-acquisition rate ZenoTOF 7600 mass spectrometer was introduced for data-independent acquisition (DIA) for comprehensive protein identification and quantification. Short microflow gradients and the generation of a deep kidney-specific spectral library allowed for high-throughput, comprehensive protein quantification. Upon AKI, the kidney proteome was completely remodeled, and over half of the 3,945 quantified protein groups changed significantly. Downregulated proteins in the injured kidney were involved in energy production, including numerous peroxisomal matrix proteins that function in fatty acid oxidation, such as ACOX1, CAT, EHHADH, ACOT4, ACOT8, and Scp2. Injured mice exhibited severely declined health. The comprehensive and sensitive kidney-specific DIA assays highlighted here feature high-throughput analytical capabilities to achieve deep coverage of the kidney proteome and will serve as useful tools for developing novel therapeutics to remediate kidney function.
Chromosome biorientation requires Aurora B’s spatial separation from its outer kinetochore substrates but not its turnover at kinetochores
Authors: Li Shuyu , Garcia-Rodriguez Luis J. , Tanaka Tomoyuki U. 
Published: February 2023

SummaryFor correct chromosome segregation in mitosis, sister kinetochores must interact with microtubules from opposite spindle poles (biorientation). For this, aberrant kinetochore– microtubule interaction must be resolved (error correction) by Aurora B kinase. Once biorientation is formed, tension is applied across sister kinetochores, stabilizing kinetochore– microtubule interactions. The mechanism for this tension-dependent process has been debated. Here we study how localizations of Aurora B at different kinetochore sites affect the establishment and maintenance of biorientation in budding yeast. In the absence of the physiological Aurora B–INCENP recruitment mechanisms, engineered recruitment of Aurora B–INCENP to the inner kinetochore (Mif2) prior to biorientation supports the subsequent establishment of biorientation. By contrast, an engineered Aurora B–INCENP recruitment to the outer kinetochore (Ndc80) fails to support biorientation establishment. Furthermore, when the physiological Aurora B–INCENP recruitment mechanisms are present, an engineered Aurora B–INCENP recruitment to Mif2 during metaphase (after biorientation establishment) does not affect biorientation maintenance. By contrast, an engineered Aurora B–INCENP recruitment to Ndc80 during metaphase leads to disruption of biorientation, which is dependent on the kinase activity of Aurora B. Taken together, our results suggest that spatial separation of Aurora B from its outer kinetochore substrates is required to stabilize kinetochore–microtubule interaction when biorientation is formed and tension is applied on this interaction. Meanwhile, Aurora B shows dynamic turnover (or exchange) on the centromere and kinetochore during early mitosis. It has been thought that this turnover is crucial for error correction and biorientation, as it may help Aurora B reach its substrates in distance and/or may facilitate the Aurora B activation on the mitotic spindle. However, using the engineered Aurora B–INCENP recruitment to the inner kinetochore, we demonstrate that, even without such a turnover, Aurora B–INCENP can efficiently support biorientation. Altogether, our study provides important insights into how Aurora B promotes error correction and biorientation in a tension-dependent manner.
Bactabolize: A tool for high-throughput generation of bacterial strain-specific metabolic models
Authors: Vezina Ben , Watts Stephen C. , Hawkey Jane , Cooper Helena B. , Judd Louise M. , Jenney Adam W. J. , Monk Jonathan M. , Holt Kathryn E. , Wyres Kelly L. 
Published: February 2023

AbstractMetabolic capacity can vary substantially within a bacterial species, leading to ecological niche separation, as well as differences in virulence and antimicrobial susceptibility. Genome-scale metabolic models are useful tools for studying the metabolic potential of individuals, and with the rapid expansion of genomic sequencing there is a wealth of data that can be leveraged for comparative analysis. However, there exist few tools to construct strain-specific metabolic models at scale.Here we describe Bactabolize (github.com/kelwyres/Bactabolize), a reference-based tool which rapidly produces strain-specific metabolic models and growth phenotype predictions. We describe a pan reference model for the priority antimicrobial-resistant pathogen,Klebsiella pneumoniae(github.com/kelwyres/KpSC-pan-metabolic-model), and a quality control framework for using draft genome assemblies as input for Bactabolize.The Bactabolize-derived model forK. pneumoniaereference strain KPPR1 performed comparatively or better than currently available automated approaches CarveMe and gapseq across 507 substrate and 2317 knockout mutant growth predictions. Novel draft genomes passing our systematically-defined quality control criteria resulted in models with a high degree of completeness (≥99% genes and reactions captured compared to models derived from matched complete genomes) and high accuracy (mean 0.97, n=10).We anticipate the tools and framework described herein will facilitate large-scale metabolic modelling analyses that broaden our understanding of diversity within bacterial species and inform novel control strategies for priority pathogens.
Metagenome diversity illuminates origins of pathogen effectors
Authors: Verhoeve Victoria I. , Lehman Stephanie S. , Driscoll Timothy P. , Beckmann John F. , Gillespie Joseph J. 
Published: February 2023

ABSTRACTRecent metagenome assembled genome (MAG) analyses have profoundly impacted Rickettsiology systematics. Discovery of basal lineages (Mitibacteraceae and Athabascaceae) with predicted extracellular lifestyles reveals an evolutionary timepoint for the transition to host dependency, which occurred independent of mitochondrial evolution. Notably, these basal rickettsiae carry the Rickettsialesvirhomolog (rvh) type IV secretion system (T4SS) and purportedly uservhto kill congener microbes rather than parasitize host cells as described for derived rickettsial pathogens. MAG analysis also substantially increased diversity for genusRickettsiaand delineated a basal lineage (Tisiphia) that stands to inform on the rise of human pathogens from protist and invertebrate endosymbionts. Herein, we probed Rickettsiales MAG and genomic diversity for the distribution ofRickettsia rvheffectors to ascertain their origins. A sparse distribution of mostRickettsia rvheffectors outside of Rickettsiaceae lineages indicates uniquervhevolution from basal extracellular species and other rickettsial families. Remarkably, nearly every effector was found in multiple divergent forms with variable architectures, illuminating profound roles for gene duplication and recombination in shaping effector repertoires inRickettsiapathogens. Lateral gene transfer plays a prominent role shaping thervheffector landscape, as evinced by the discover of many effectors on plasmids and conjugative transposons, as well as pervasive effector gene exchange betweenRickettsiaandLegionellaspecies. Our study exemplifies how MAGs can provide incredible insight on the origins of pathogen effectors and how their architectural modifications become tailored to eukaryotic host cell biology.
Keystone taxa responsible for the microbial community stability and performance of activated sludges
Authors: Liu Xiaonan , Wang Miaoxiao , Liu Bingwen , Chen Xiaoli , An Liyun , Nie Yong , Wu Xiao-Lei 
Published: February 2023

AbstractBackgroundThe functions and stability of a community depend on its species, which form complex interaction networks. The keystone taxa identified by network analysis are generally considered to play a vital role in the structure and function of microbial communities, but there is no uniformly accepted operational definition of such taxa. Further, what species and how they affect the community’s stability and function are still poorly understood.MethodsTo solve this problem, we performed a large-scale network analysis of the microbial communities residing in 1186 activated sludge (AS) samples.ResultsWe found that the AS co-occurrence network is a typical scale-free network. While most taxa in the AS co-occurrence network have little association, there are still a small number of taxa that are strongly interconnected. We defined a group of keystone taxa that have an important impact on network stability. Further analysis results indicate that the communities harboring the keystone taxa maintain higher stability, but these communities possess lower pollutant removal rates. In addition, we found that keystone taxa were more likely to appear in samples with lower sludge load.ConclusionsOur work identified the keystone taxa that maintain the stability of microbial communities in the AS systems but at the cost of reducing their function. This finding shed light on the relationship between composition, stability, and function within microbial communities. It also provides novel insights into manipulating the function of microbial communities by modifying their composition.