bluuebunny/crossref_metadata_2025_split huggingface dataset:
GTP signaling links metabolism, DNA repair, and responses to genotoxic stress
Authors: Zhou Weihua , Zhao Zitong , Lin Angelica , Yang John , Xu Jie , Kari Wilder-Romans , Yang Annabel , Li Jing , Solanki Sumeet , Speth Jennifer , Walker Natalie , Scott Andrew J. , Kothari Ayesha U. , Yao Yangyang , Peterson Erik R. , Korimerla Navyateja , Werner Christian K. , Liang Jessica , Jacobson Janna , Palavalasa Sravya , Obrien Alexandra M. , Elaimy Ameer L. , Ferris Sean P. , Zhao Shuang G. , Sarkaria Jann N. , Győrffy Balázs , Zhang Shuqun , Al-Holou Wajd N , Umemura Yoshie , Morgan Meredith A. , Lawrence Theodore S. , Lyssiotis Costas A. , Peters-Golden Marc , Shah Yatrik M. , Wahl Daniel R. 
Published: April 2023

ABSTRACTHow cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.
Understanding the link between functional profiles and intelligence through dimensionality reduction and graph analysis
Authors: Alberti F. , Menardi A. , Margulies D.S. , Vallesi A. 
Published: April 2023

AbstractThere is a growing interest in neuroscience for how individual-specific structural and functional features of the cortex relate to cognitive traits. This work builds on previous research which, using classical high-dimensional approaches, has proven that the interindividual variability of functional connectivity profiles reflects differences in fluid intelligence. To provide an additional perspective into this relationship, the present study uses a recent framework for investigating cortical organization:functional gradients.This approach places local connectivity profiles within a common low-dimensional space whose axes are functionally interretable dimensions. Specifically, this study uses a data-driven approach focussing on areas where FC variability is highest across individuals to model different facets of intelligence. For one of these loci, in the right ventral-lateral prefrontal cortex (vlPFC), we describe an association between fluid intelligence and relative functional distance from sensory and high-cognition systems. Furthermore, the topological properties of this region indicate that with decreasing functional affinity with the latter, its functional connections are more evenly distributed across all networks. Participating in multiple functional networks may reflect a better ability to coordinate sensory and high-order cognitive systems.Significant StatementThe human brain is highly variable. In particular, the way brain regions communicate to one another – that is, how they arefunctionallyconnected – constitutes a neural fingerprint of the individual. In this study, we make use of a recent methodological approach to characterize the connectivity patterns of transmodal (closely linked to abstract processing) and unimodal (closely linked to sensory processing) brain regions in an attempt to explain how this balance affects intelligence. We show that the more the functional profile of executive control regions is distant to that of abstract processing, the better they are at integrating information coming from widespread neural systems, ultimately leading to better cognitive performance.
Motor-targeted spinal stimulation promotes concurrent rebalancing of pathologic nociceptive transmission in chronic spinal cord injury
Authors: Bandres Maria F. , Gomes Jefferson L. , McPherson Jacob G. 
Published: April 2023

AbstractElectrical stimulation of spinal networks below a spinal cord injury (SCI) is a promising approach to restore functions compromised by inadequate excitatory neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared motor pathways and spinal motor networks rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by SCI. Debilitating spasms, spasticity, and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. But whereas spasms and spasticity can often be managed pharmacologically, SCI-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from etiologies other than SCI, and it has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for motor rehabilitation. Thus, we reasoned that spinal stimulation intended to increase transmission in motor pathways may simultaneously reduce transmission in spinal pain pathways. Using a well-validated pre-clinical model of SCI that results in severe bilateral motor impairments and SCI-related neuropathic pain, we show that the responsiveness of neurons integral to the development and persistence of the neuropathic pain state can be enduringly reduced by motor-targeted spinal stimulation while preserving spinal responses to non-pain-related sensory feedback. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with SCI.
Venomous Noodles: evolution of toxins in Nemertea through positive selection and gene duplication
Authors: Sonoda G.G , Tobaruela E.C. , Norenburg J.L. , Fabi J.P. , Andrade S.C.S. 
Published: April 2023

AbstractSome, probably most and perhaps all, members of the phylum Nemertea are venomous, documented so far from marine and benthic specimens. Although the toxicity of these animals has been long known, systematic studies on characterization of toxins, mechanisms of toxicity and toxin evolution for this group are relatively scarce compared to other venomous groups. Here we present the first investigation of the molecular evolution of toxins in Nemertea. Using a proteo-transcriptomic approach, we described toxins in the body and poisonous mucus of the pilidiophoranLineus sanguineusand the hoplonemerteanNemertopsis pamelaroeae. Using these new and publicly available transcriptomes, we investigated the molecular evolution of six selected toxin gene families. In addition, we have also characterizedin silicothe toxin genes found in the interstitial hoplonemertean,Ototyphlonemertes erneba, a first record for meiofaunal taxa. We identified 99 toxin transcripts in the pilidiophoranL. sanguineus,including previously known toxins, such as thealpha-nemertidesand theCytotoxins-A. However, for each of the hoplonemerteans, no more than 30 toxin transcripts were found. Genomic alignments and tree reconciliation methods supported the occurrence of at least one gene duplication in each analyzed toxin gene. Evidence of positive selection was observed in all investigated toxin genes. We hypothesized that an increased rate of gene duplications observed for Pilidiophora could be involved with the origin and expansion of toxin genes. Studies concerning the natural history of Nemertea are still needed to understand the evolution of their toxins. Nevertheless, our results show evolutionary mechanisms similar to those observed in other venomous groups.
Deletion ofPax1scoliosis-associated regulatory elements leads to a female-biased tail abnormality
Authors: Ushiki Aki , Sheng Rory R. , Zhang Yichi , Zhao Jingjing , Nobuhara Mai , Murray Elizabeth , Ruan Xin , Rios Jonathan J. , Wise Carol A. , Ahituv Nadav 
Published: April 2023

AbstractAdolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is sexually dimorphic, with increased incidence in females. A GWAS identified a female-specific AIS susceptibility locus near thePAX1gene. Here, we used mouse enhancer assays, three mouse enhancer knockouts and subsequent phenotypic analyses to characterize this region. Using mouse enhancer assays, we characterized a sequence, PEC7, that overlaps the AIS-associated variant, and found it to be active in the tail tip and intervertebral disc. Removal of PEC7 or Xe1, a known sclerotome enhancer nearby, and deletion of both sequences led to a kinky phenotype only in the Xe1 and combined (Xe1+PEC7) knockouts, with only the latter showing a female sex dimorphic phenotype. Extensive phenotypic characterization of these mouse lines implicated several differentially expressed genes and estrogen signaling in the sex dimorphic bias. In summary, our work functionally characterizes an AIS-associated locus and dissects the mechanism for its sexual dimorphism.
MUSSEL: Enhanced Bayesian Polygenic Risk Prediction Leveraging Information across Multiple Ancestry Groups
Authors: Jin Jin , Zhan Jianan , Zhang Jingning , Zhao Ruzhang , O’Connell Jared , Jiang Yunxuan ,   23andMe Research Team, Buyske Steven , Gignoux Christopher , Haiman Christopher , Kenny Eimear E. , Kooperberg Charles , North Kari , Koelsch Bertram L. , Wojcik Genevieve , Zhang Haoyu , Chatterjee Nilanjan 
Published: April 2023

AbstractPolygenic risk scores (PRS) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists a substantial performance gap across different populations. We propose MUSSEL, a method for ancestry-specific polygenic prediction that borrows information in the summary statistics from genome-wide association studies (GWAS) across multiple ancestry groups. MUSSEL conducts Bayesian hierarchical modeling under a MUltivariate Spike-and-Slab model for effect-size distribution and incorporates an Ensemble Learning step using super learner to combine information across different tuning parameter settings and ancestry groups. In our simulation studies and data analyses of 16 traits across four distinct studies, totaling 5.7 million participants with a substantial ancestral diversity, MUSSEL shows promising performance compared to alternatives. The method, for example, has an average gain in prediction R2across 11 continuous traits of 40.2% and 49.3% compared to PRS-CSx and CT-SLEB, respectively, in the African Ancestry population. The best-performing method, however, varies by GWAS sample size, target ancestry, underlying trait architecture, and the choice of reference samples for LD estimation, and thus ultimately, a combination of methods may be needed to generate the most robust PRS across diverse populations.
Biology of Coital Behavior: Looking Through the Lens of Mathematical Genomics
Authors: Sil Moumita , Nawn Debaleena , Hassan Sk. Sarif , Chakraborty Subhajit , Goswami Arunava , Basu Pallab , Roopesh Lalith , Wu Emma , Lundstrom Kenneth , Uversky Vladimir N. 
Published: April 2023

AbstractResearch has shown that genetics and epigenetics regulate mating behavior across multiple species. Previous studies have generally focused on the signaling pathways involved and spatial distribution of the associated receptors. However a thorough quantitative characterization of the receptors involved may offer deeper insight into mating behavioral patterns. Here oxytocin, arginine-vasopressin 1a, dopamine 1, and dopamine 2 receptors were investigated across 76 vertebrate species. The receptor sequences were characterized by polarity-based randomness, amino acid frequency-based Shannon entropy and Shannon sequence variability, intrinsic protein disorder, binding affinity, stability and pathogenicity of homology-based SNPs, structural and physicochemical features. Hierarchical clustering of species was derived based on structural and physicochemical features of the four receptor sequences separately, which eventually led to proximal relationships among 29 species. Humans were found to be significantly distant phylogenetically from the prairie voles, a representative of monogamous species based on coital behavior. Furthermore, the mouse (polygamous), the prairie deer mouse (polygamous), and the prairie vole (monogamous) although being proximally related (based on quantitative genomics of receptors), differed in their coital behavioral pattern, mostly, due to behavioral epigenetic regulations. This study adds a perspective that receptor genomics does not directly translate to behavioral patterns.
Effect of disease prevalence and growth stage on symptoms severity in theTurnip mosaic virus - Arabidopsis thalianapathosystem
Authors: de la Iglesia Francisca , Elena Santiago F. 
Published: April 2023

AbstractPlants emit volatile organic compounds (VOCs) in response to biotic and abiotic stimuli that provide information about their physiological status to other individuals in the community. Nearby receivers adjust their own defenses in response to these chemical cues. The majority of studies to date has concentrated on the communication of abiotic stressors (e.g. salinity or drought) or herbivory. Less attention had received the role of VOCs during microbial infections and almost nothing has been done for viruses. Here we investigated the function of VOCs during turnip mosaic virus infection ofArabidopsis thaliana. First, we looked at the influence of two factors on the kinetics of symptoms progression in receivers, namely the prevalence of infection in the population and the growth stage of the receiver plants at inoculation. We found that young plants were more sensitive to the protective effect of VOCs than older ones, and that high infection prevalence results in a slower disease progression in receivers. Second, we tested the possibility that jasmonates could be VOC candidates. To do this, we examined the kinetics of symptoms progression in jasmonate-insensitive and wild-type plants, and the results showed that the protective effect vanished in the mutant plants. Third, we investigated the possibility that root communication would be also relevant. We found that the kinetics of symptom progression across receivers was further slowed down in an age-dependent manner when plants were planted in the same pot. Together, these preliminary findings point to a potential function for disease prevalence in plant communities in regulating the severity of symptoms, this effect being mediated by VOCs.
Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain
Authors: Harris Noah J , Jenkins Meredith L , Nam Sung-Eun , Rathinaswamy Manoj K , Parson Matthew AH , Ranga-Prasad Harish , Dalwadi Udit , Moeller Brandon E , Sheekey Eleanor , Hansen Scott D , Yip Calvin K , Burke John E 
Published: April 2023

AbstractPI3Kγ is a critical immune signaling enzyme activated downstream of diverse cell surface molecules, including Ras, PKCβ activated by the IgE receptor, and Gβγ subunits released from activated GPCRs. PI3Kγ can form two distinct complexes, with the p110γ catalytic subunit binding to either a p101 or p84 regulatory subunit, with these complexes being differentially activated by upstream stimuli. Here using a combination of cryo electron microscopy, HDX-MS, and biochemical assays we have identified novel roles of the helical domain of p110γ in regulating lipid kinase activity of distinct PI3Kγ complexes. We defined the molecular basis for how an allosteric inhibitory nanobody potently inhibits kinase activity through rigidifying the helical domain and regulatory motif of the kinase domain. The nanobody did not block either p110γ membrane recruitment or Ras/Gβγ binding, but instead decreased ATP turnover. We also identified that p110γ can be activated by dual PKCβ helical domain phosphorylation leading to partial unfolding of an N-terminal region of the helical domain. PKCβ phosphorylation is selective for p110γ-p84 compared to p110γ-p101, driven by differential dynamics of the helical domain of these different complexes. Nanobody binding prevented PKCβ mediated phosphorylation. Overall, this works shows an unexpected allosteric regulatory role of the helical domain of p110γ that is distinct between p110γ-p84 and p110γ-p101 and reveals how this can be modulated by either phosphorylation or allosteric inhibitory binding partners. This opens possibilities of future allosteric inhibitor development for therapeutic intervention.
LinRace: single cell lineage reconstruction using paired lineage barcode and gene expression data
Authors: Pan Xinhai , Li Hechen , Putta Pranav , Zhang Xiuwei 
Published: April 2023

AbstractUnderstanding how single cells divide and differentiate into different cell types in developed organs is one of the major tasks of developmental and stem cell biology. Recently, lineage tracing technology using CRISPR/Cas9 genome editing has enabled simultaneous readouts of gene expressions and lineage barcodes in single cells, which allows for the reconstruction of the cell division tree, and even the detection of cell types and differentiation trajectories at the whole organism level. While most state-of-the-art methods for lineage reconstruction utilize only the lineage barcode data, methods that incorporate gene expression data are emerging, aiming to improve the accuracy of lineage reconstruction. However, effectively incorporating the gene expression data requires a reasonable model on how gene expression data changes along generations of divisions. Here, we present LinRace (LineageReconstruction with asymmetric cell division model), a method that integrates the lineage barcode and gene expression data using the asymmetric cell division model and infers cell lineage under a framework combining Neighbor Joining and maximum-likelihood heuristics. On both simulated and real data, LinRace outputs more accurate cell division trees than existing methods. Moreover, Lin Race can output the cell states (cell types) of ancestral cells, which is rarely performed with existing lineage reconstruction methods. The information on ancestral cells can be used to analyze how a progenitor cell generates a large population of cells with various functionalities. LinRace is available at:https://github.com/ZhangLabGT/LinRace.
Using dynamic oral dosing of rifapentine and rifabutin to simulate exposure profiles of long-acting formulations in a mouse model of tuberculosis preventive therapy
Authors: Chang Yong S. , Li Si-Yang , Pertinez Henry , Betoudji Fabrice , Lee Jin , Rannard Steven P. , Owen Andrew , Nuermberger Eric L. , Ammerman Nicole C. 
Published: April 2023

ABSTRACTAdministration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have anti-tuberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We utilized a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally-determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that has utility beyond latent tuberculosis infection.
Senescence suppresses the integrated stress response and activates a stress-enhanced secretory phenotype
Authors: Payea Matthew J. , Dar Showkat A. , Anerillas Carlos , Martindale Jennifer L. , Belair Cedric , Munk Rachel , Malla Sulochan , Fan Jinshui , Piao Yulan , Yang Xiaoling , Rehman Abid , Banskota Nirad , Abdelmohsen Kotb , Gorospe Myriam , Maragkakis Manolis 
Published: April 2023

AbstractSenescence is a state of indefinite cell cycle arrest associated with aging, cancer, and age-related diseases. Here, using label-based mass spectrometry, ribosome profiling and nanopore direct RNA sequencing, we explore the coordinated interaction of translational and transcriptional programs of human cellular senescence. We find that translational deregulation and a corresponding maladaptive integrated stress response (ISR) is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames. Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. Furthermore, absent a response, stress augments the senescence secretory phenotype, thus intensifying a proinflammatory state that exacerbates disease. Our results reveal a novel mechanism that senescent cells exploit to evade an adaptive stress response and remain viable.