bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete loss ofSLC30A8in humans improves glucose metabolism and beta cell function
Authors: Lamarche Lindsey B. , Koch Christopher , Khalid Shareef , Zaman Maleeha , Zessis Richard , Clement Matthew E. , Denning Daniel P. , Goldfine Allison B. , Abbasi Ali , Harrow Jennifer L , Underwood Christina , Tsunoyama Kazuhisa , Asaumi Makoto , Kou Ikuyo , Rodriguez-Flores Juan L , Shuldiner Alan R. , Rasheed Asif , Jahanzaib Muhammad , Mian Muhammad Rehan , Liaqat Muhammad Bilal , Abdulsalam Usman , Sultana Riffat , Jalal Anjum , Saeed Muhammad Hamid , Abbas Shahid , Memon Fazal Rehman , Ishaq Muhammad , Gurtan Allan M. , Dominy John E. , Saleheen Danish 
Published: April 2024

ABSTRACTGenetic association studies have demonstrated that partial loss ofSLC30A8function protects against type 2 diabetes (T2D) in humans, but the impact of complete loss ofSLC30A8function remains unknown. From whole-exome and genome sequencing of 100,814 participants in the Pakistan Genome Resource, we identified fifteenSLC30A8knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter) and 615 heterozygotes for loss-of-function (LoF) variants. T2D risk was lower inSLC30A8LoF hetero- and homozygotes, and the protective effect strengthens in a gene dose-dependent manner (ORadditive=0.63 [0.53-0.78, p=7.5E-07], ORrecessive=0.27 [0.09-0.80, p=0.018]). Recall-by-genotype ofSLC30A8LoF hetero- and homozygotes and their family members with oral glucose tolerance tests showed a gene dose-dependent reduction in glucose levels coupled with elevated insulin. Corrected Insulin Response, Disposition Index, and Insulin Sensitivity Index in LoF hetero- and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function. These data suggest that therapeutic knockdown ofSLC30A8, up to and including complete knockout, may treat T2D safely and effectively.
Real-world evaluation of deep learning algorithms to classify functional pathogenic germline variants
Authors: Chow Ryan D. , Parikh Ravi B. , Nathanson Katherine L. 
Published: April 2024

AbstractDeep learning models for variant pathogenicity prediction can recapitulate expert-curated annotations, but their performance remains unexplored on actual disease phenotypes in a real-world setting. Here, we apply three state-of-the-art pathogenicity prediction models to classify hereditary breast cancer gene variants in the UK Biobank. Predicted pathogenic variants inBRCA1, BRCA2andPALB2, but notATMandCHEK2, were associated with increased breast cancer risk. We explored gene-specific score thresholds for variant pathogenicity, finding that they could improve model performance. However, when specifically tasked with classifying variants of uncertain significance, the deep learning models were generally of limited clinical utility.
3D-Printing of Electroconductive MXene-based Micro-meshes in a Biomimetic Hyaluronic Acid-based Scaffold Directs and Enhances Electrical Stimulation for Neural Repair Applications
Authors: Woods Ian , Spurling Dahnan , Sunil Sandra , Maughan Jack , Gutierrez-Gonzalez Javier , McGuire Tara K. , Leahy Liam , Dervan Adrian , Nicolosi Valeria , O’Brien Fergal J 
Published: April 2024

AbstractNo effective treatments are currently available for central nervous system neurotrauma although recent advances in electrical stimulation suggest some promise in neural tissue repair. We hypothesized that structured integration of an electroconductive biomaterial into a tissue engineering scaffold could enhance electroactive signalling for neural regeneration.Electroconductive 2D Ti3C2TxMXene nanosheets were synthesized from MAX-phase powder, demonstrating excellent biocompatibility with neurons, astrocytes and microglia. To achieve spatially-controlled distribution of these MXenes, melt-electrowriting was used to 3D-print highly-organized PCL micro-meshes with varying fibre spacings (low-, medium-and high-density), which were functionalized with MXenes to provide highly-tunable electroconductive properties (0.081±0.053-18.87±2.94 S/m). Embedding these electroconductive micro-meshes within a neurotrophic, immunomodulatory hyaluronic acid-based extracellular matrix (ECM) produced a soft, growth-supportive MXene-ECM composite scaffold. Electrical stimulation of neurons seeded on these scaffolds promoted neurite outgrowth, influenced by fibre spacing in the micro-mesh. In a multicellular model of cell behaviour, neurospheres stimulated for 7 days on high-density MXene-ECM scaffolds exhibited significantly increased axonal extension and neuronal differentiation, compared to low-density scaffolds and MXene-free controls. The results demonstrate that spatial-organization of electroconductive materials in a neurotrophic scaffold can enhance repair-critical responses to electrical stimulation and that these biomimetic MXene-ECM scaffolds offer a promising new approach to neurotrauma repair.
Morphological Study of Left–right Head Asymmetry inDoubledaya bucculenta(Coleoptera: Erotylidae: Languriinae)
Authors: Oda Hiroki , Nakamura Taro , Toki Wataru , Niimi Teruyuki 
Published: April 2024

AbstractLeft–right asymmetry in paired organs is well-documented across various species, including the claws of fiddler crabs and snail-eating snakes’ dentition. However, the mechanisms underlying these asymmetries remain largely elusive. This study investigatesDoubledaya bucculenta(Coleoptera: Erotylidae), a lizard beetle species known for pronounced left-sided asymmetry in adult female mandible and gena. Given that insect mouthparts comprise multiple functionally significant appendages, we aimed to clarify the degree of asymmetry extending beyond the mandibles and genae. Phenotypic morphology was assessed through trait measurement and asymmetry index calculations. Our detailed morphometric analyses revealed left-longer asymmetry not only in mandibles and genae but also in maxillae and labium. Notably, the degree of asymmetry in other mouthparts was generally less pronounced compared to outer mandibles, suggesting a potential influence of left mandible development on other mouthparts. Additionally, male mandibles exhibited region-specific asymmetry, potentially indicative of constrained evolutionary adaptations. This study enhances a comprehensive understanding of adult phenotype morphology and offers insights into the developmental basis of asymmetrical mouthparts.
The impact of micro-habitat fragmentation on microbial populations growth dynamics
Authors: Mant Dina , Orevi Tomer , Kashtan Nadav 
Published: April 2024

AbstractMicrobial communities inhabit almost every habitat on Earth and are essential to the function of diverse ecosystems. Most microbial habitats are not spatially continuous and well-mixed, but rather composed, at the microscale, of many isolated or semi-isolated local patches, resulting in partitioning of microbial populations into discrete local populations. The impact of this spatial fragmentation on population dynamics is not well-understood. Here, we study how fragmentations affect the growth dynamics of clonal microbial populations and how dynamics in individual patches dictate those of the whole metapopulation. To investigate this, we developed the µ-SPLASH, a novel ecology-on-a-chip platform, enabling the culture of microbes in microscopic landscapes comprised of thousands of microdroplets, spanning a wide range of sizes. Using the µ-SPLASH, we cultured the model bacteriaE. coliand based on time-lapse microscopy, analyzed the population dynamics within thousands of individual droplets at single-cell resolution. Our results reveal that growth curves vary dramatically with droplet size. While growth rates generally increase with drop size, reproductive success and the time to approach carrying capacity, display non-monotonic patterns. Combining µ-SPLASH experiments with computational modeling, we show that these patterns result from both stochastic and deterministic processes, and demonstrate the roles of initial population density, patchiness, and patch size distribution in dictating the local and metapopulation dynamics. This study reveals basic principles that elucidate the effects of habitat fragmentation and population partitioning on microbial population dynamics. These insights are imperative for a deeper understanding of natural microbial communities and have significant implications for microbiome engineering.
RNA language models predict mutations that improve RNA function
Authors: Shulgina Yekaterina , Trinidad Marena I. , Langeberg Conner J. , Nisonoff Hunter , Chithrananda Seyone , Skopintsev Petr , Nissley Amos J. , Patel Jaymin , Boger Ron S. , Shi Honglue , Yoon Peter H. , Doherty Erin E. , Pande Tara , Iyer Aditya M. , Doudna Jennifer A. , Cate Jamie H. D. 
Published: April 2024

AbstractStructured RNA lies at the heart of many central biological processes, from gene expression to catalysis. While advances in deep learning enable the prediction of accurate protein structural models, RNA structure prediction is not possible at present due to a lack of abundant high-quality reference data1. Furthermore, available sequence data are generally not associated with organismal phenotypes that could inform RNA function2–4. We created GARNET (Gtdb Acquired RNa with Environmental Temperatures), a new database for RNA structural and functional analysis anchored to the Genome Taxonomy Database (GTDB)5. GARNET links RNA sequences derived from GTDB genomes to experimental and predicted optimal growth temperatures of GTDB reference organisms. This enables construction of deep and diverse RNA sequence alignments to be used for machine learning. Using GARNET, we define the minimal requirements for a sequence- and structure-aware RNA generative model. We also develop a GPT-like language model for RNA in which overlapping triplet tokenization provides optimal encoding. Leveraging hyperthermophilic RNAs in GARNET and these RNA generative models, we identified mutations in ribosomal RNA that confer increased thermostability to theEscherichia coliribosome. The GTDB- derived data and deep learning models presented here provide a foundation for understanding the connections between RNA sequence, structure, and function.
The RNA binding protein Nab2 regulates splicing of the RhoGEFtriotranscript to govern axon and dendrite morphology
Authors: Lancaster Carly L. , Yalamanchili Pranav S. , Goldy Jordan N. , Leung Sara W. , Corbett Anita H. , Moberg Kenneth H. 
Published: April 2024

ABSTRACTTheDrosophilaRNA binding protein (RBP) Nab2 acts in neurons to regulate neurodevelopment and is orthologous to the human intellectual disability-linked RBP, ZC3H14. Nab2 governs axon projection in mushroom body neurons and limits dendritic arborization of class IV sensory neurons in part by regulating splicing events in ~150 mRNAs. Analysis of theSex-lethal(Sxl) mRNA revealed that Nab2 promotes an exon-skipping event and regulates m6A methylation onSxlpre-mRNA by the Mettl3 methyltransferase. Mettl3 heterozygosity broadly rescuesNab2nullphenotypes implying that Nab2 acts through similar mechanisms on other RNAs, including unidentified targets involved in neurodevelopment. Here, we show that Nab2 and Mettl3 regulate the removal of a 5’UTR intron in thetriopre-mRNA. Trio utilizes two GEF domains to balance Rac and RhoGTPase activity. Intriguingly, an isoform of Trio containing only the RhoGEF domain, GEF2, is depleted inNab2nullnervous tissue. Expression of Trio-GEF2 rescues projection defects inNab2nullaxons and dendrites, while the GEF1 Rac1-regulatory domain exacerbates these defects, suggesting Nab2-mediated regulation Trio-GEF activities. Collectively, these data identify Nab2-regulated splicing as a key step in balancing Trio GEF1 and GEF2 activity and show that Nab2, Mettl3, and Trio function in a common pathway that shapes axon and dendrite morphology.Significance StatementDrosophilaNab2, ortholog of the human RBP ZC3H14 mutated in inherited intellectual disability, acts through unknown RNA targets to control axon and dendrite morphology.This study shows that Nab2 and the Mettl3 methyltransferase guide splicing oftriomRNA, which encodes a conserved GEF-domain protein. Intron retention intriomRNA leads to an imbalance in levels of two Trio GEF domains in Nab2-deficient neurons and restoring this balance rescues neuronal defects.The authors conclude that Nab2 control oftriosplicing is required to pattern axon and dendrite growth and suggests that ZC3H14 may play a similar role in the vertebrate brain.
Rapid profiling of transcription factor-cofactor interaction networks reveals principles of epigenetic regulation
Authors: Inge MM , Miller R , Hook H , Bray D , Keenan JL , Zhao R , Gilmore TD , Siggers T 
Published: April 2024

SummaryTranscription factor (TF)-cofactor (COF) interactions define dynamic, cell-specific networks that govern gene expression; however, these networks are understudied due to a lack of methods for high-throughput profiling of DNA-bound TF-COF complexes. Here we describe theCofactorRecruitment (CoRec) method for rapid profiling of cell-specific TF-COF complexes. We define a lysine acetyltransferase (KAT)-TF network in resting and stimulated T cells. We find promiscuous recruitment of KATs for many TFs and that 35% of KAT-TF interactions are condition specific. KAT-TF interactions identify NF-κB as a primary regulator of acutely induced H3K27ac. Finally, we find that heterotypic clustering of CBP/P300-recruiting TFs is a strong predictor of total promoter H3K27ac. Our data supports clustering of TF sites that broadly recruit KATs as a mechanism for widespread co-occurring histone acetylation marks. CoRec can be readily applied to different cell systems and provides a powerful approach to define TF-COF networks impacting chromatin state and gene regulation.
Accessory proteins increase the efficiency of RNA editing by Arabidopsis chloroplast editosomes
Authors: Lombana Jose , Hanson Maureen R. , Bentolila Stéphane 
Published: April 2024

ABSTRACTRNA editing modifies cytidines to uridines in plant organelle transcripts so that their sequences differ from the ones predicted from the genomic DNA. This process, conserved across most land plants, involves a family of RNA-binding proteins that has significantly expanded, the pentatricopeptide repeat (PPR)-containing proteins. In angiosperms, PPR proteins are found in editosomes associated with accessory proteins. The exact function of these accessory proteins has been unclear. Bacterial co-expression of an angiosperm synthetic factor and different accessory proteins, RIP2, RIP9, ORRM1 demonstrates their essential role in editing of an RNA target. The presence of ORRM1 and RIP2 or ORRM1 and RIP9 in bacteria with the PPR factor results in a target editing extent of 80%, which is similar to what is observedin planta. Accessory proteins increase the affinity of the PPR factor for the target RNA, likely the explanation of their role in improving editing efficiency. RNA-seq analysis of bacterial transcriptome in samples expressing various combinations of accessory proteins with the synthetic factor identified a total of 34 off-target editing events. Investigation of their upstream sequences that are recognized and bound by the synthetic factor allows the optimization of future designs to improve the specificity of this programmable RNA-editing factor.
Ribozyme-mediated gene-fragment complementation for non-destructive reporting of DNA transfer within soil
Authors: Selinidis Malyn A. , Corliss Andrew C. , Chappell James , Silberg Jonathan J. 
Published: April 2024

AbstractEnzymes that produce volatile metabolites can be coded into genetic circuits to report non-disruptively on microbial behaviors in hard-to-image soils. However, these enzyme reporters remain challenging to apply in gene transfer studies due to leaky off states that can lead to false positives. To overcome this problem, we designed a reporter that uses ribozyme-mediated gene-fragment complementation of a methyl halide transferase (MHT) to regulate the synthesis of methyl halides. We split themhtgene into two non-functional fragments and attached these to a pair of splicing ribozyme fragments. While the individualmht-ribozyme fragments did not produce methyl halides when transcribed alone inEscherichia coli, co-expression resulted in a spliced transcript that translated the MHT reporter. When cells containing onemht-ribozyme fragment transcribed from a mobile plasmid were mixed with cells that transcribed the secondmht-ribozyme fragment, methyl halides were only detected following rare conjugation events. When conjugation was performed in soil, it led to a 16-fold increase in methyl halides in the soil headspace. These findings show how ribozyme-mediated gene-fragment complementation can achieve tight control of protein reporter production, a level of control that will be critical for monitoring the effects of soil conditions on gene transfer and the fidelity of biocontainment measures developed for environmental applications.
NaV1.7 targeted fluorescence imaging agents for nerve identification during intraoperative procedures
Authors: Gonzales Junior , Adilbay Dauren , de Souza Franca Paula Demetrio , Artschwager Raik , Chow Chun Yuen , Viray Tara , Johnson Delissa S. , Jiang Yan , Patel Snehal G. , Ganly Ian , Schroeder Christina I. , Lewis Jason S. , King Glenn F. , Reiner Thomas , Pillarsetty Nagavarakishore 
Published: April 2024

ABSTRACTSurgeries and trauma result in traumatic and iatrogenic nerve damage that can result in a debilitating condition that approximately affects 189 million individuals worldwide. The risk of nerve injury during oncologic surgery is increased due to tumors displacing normal nerve location, blood turbidity, and past surgical procedures, which complicate even an experienced surgeon’s ability to precisely locate vital nerves. Unfortunately, there is a glaring absence of contrast agents to assist surgeons in safeguarding vital nerves. To address this unmet clinical need, we leveraged the abundant expression of the voltage-gated sodium channel 1.7 (NaV1.7) as an intraoperative marker to access peripheral nervesin vivo, and visualized nerves for surgical guidance using a fluorescently-tagged version of a potent NaV1.7-targeted peptide, Tsp1a, derived from a Peruvian tarantula. We characterized the expression of NaV1.7 in sensory and motor peripheral nerves across mouse, primate, and human specimens and demonstrated universal expression. We synthesized and characterized a total of 10 fluorescently labeled Tsp1a-peptide conjugates to delineate nerves. We tested the ability of these peptide-conjugates to specifically accumulate in mouse nerves with a high signal-to-noise ratioin vivo. Using the best-performing candidate, Tsp1a-IR800, we performed thyroidectomies in non-human primates and demonstrated successful demarcation of the recurrent laryngeal and vagus nerves, which are commonly subjected to irreversible damage. The ability of Tsp1a to enhance nerve contrast during surgery provides opportunities to minimize nerve damage and revolutionize standards of care across various surgical specialties.
Brain dynamics and spatiotemporal trajectories during threat processing
Authors: Misra Joyneel , Pessoa Luiz 
Published: April 2024

AbstractIn the past decades, functional MRI research has investigated task processing in a largely static fashion based on evoked responses during blocked and event-related designs. Despite some progress in naturalistic designs, our understanding of threat processing remains largely limited to those obtained with standard paradigms with limited dynamics. In the present paper, we applied Switching Linear Dynamical Systems to uncover the dynamics of threat processing during a continuous threat-of-shock paradigm. First, we demonstrated that the SLDS model learned the regularities of the experimental paradigm, such that states and state transitions estimated from fMRI time series data from 85 regions of interest reflected threat proximity and threat approach vs. retreat. After establishing that the model captured key properties of threat-related processing, we characterized the dynamics of the states and their transitions. Importantly, we characterized both endogenous and exogenous contributions to dynamics. The results revealed how threat processing can be viewed in terms of dynamic multivariate patterns whose trajectories are a combination of intrinsic and extrinsic factors that jointly determine how the brain temporally evolves during dynamic threat. Furthermore, we developed a measure ofregion importancethat quantifies the contributions of an individual brain region to system dynamics, which complements the system-level characterization that is obtained with the state-space SLDS formalism. Finally, we investigated the generalizability of the modeling approach. The successful application of the SLDS model trained on one paradigm to a separate experiment illustrates the potential of this approach to capture fMRI dynamics that generalize across related but distinct threat-processing tasks. We propose that viewing threat processing through the lens of dynamical systems offers important avenues to uncover properties of the dynamics of threat that are not unveiled with standard experimental designs and analyses.
Hierarchical determinants of the oxidation-induced mutational landscape in human cells
Authors: Cordero Cameron , Mehta Kavi P. M. , Weaver Tyler M. , Ling Justin A. , Freudenthal Bret D. , Cortez David , Roberts Steven A. 
Published: April 2024

Abstract8-oxoguanine (8-oxoG) is a common oxidative DNA lesion, which causes G>T substitutions that compose COSMIC single base substitution signature 18 (SBS18) in human cancers. Determinants of local and regional differences in 8-oxoG-induced mutability are currently unknown. To uncover factors influencing the topology of 8-oxoG-induced mutations, we assessed spontaneous and KBrO3-induced 8-oxoG mutagenesis in human cell lines. KBrO3exposure produced a SBS18-like substitution spectrum and a distinct never-before reported INDEL signature that we also observed in human cancers. KBrO3-induced 8-oxoG lesions occurred with similar sequence preference as KBrO3-induced substitutions, indicating that the reactivity of specific reactive oxygen species (ROS) dictates the trinucleotide motif specificity for 8-oxoG-induced mutagenesis. While 8-oxoG lesions occurred relatively uniformly across chromatin states and nucleosomes, 8-oxoG-induced mutations occurred more frequently in more compact regions of the genome, within nucleosomal DNA, and at inward facing guanines within strongly positioned nucleosomes. Cryo-EM structures of OGG1 bound to nucleosomes indicate that these effects originate from OGG1’s ability to flip outward positioned 8-oxoG lesions into the catalytic pocket with only minor alterations to nucleosome structure, while inward facing lesions occluded by the histone octamer are unrecognized. Mutation spectra from cells with DNA repair deficiencies revealed a hierarchical DNA repair network limiting 8-oxoG mutagenesis in human cells, where OGG1– and MUTY-mediated BER is supplemented by replication-associated factors participating in tolerance of 8-oxoG or derived repair intermediates (i.e. Pol η and HMCES). Surprisingly, analysis of transcriptional asymmetry of KBrO3-induced mutations demonstrated transcription-coupled repair of 8-oxoG in Pol η-deficient cells. Thus, radical chemistry, chromatin structures, and DNA repair processes combine to dictate the oxidative mutational landscape in human genomes.