bluuebunny/crossref_metadata_2025_split huggingface dataset:
A genetic safeguard for eliminating target genes in synthetic probiotics in response to a loss of the permissive signal in a gut environment
Authors: Nguyen Nhu , Wang Miaomiao , Li Lin , Chan Clement T. Y. 
Published: December 2024

SUMMARYFollowing the development of therapeutic probiotics, there is an emerging demand for constraining engineered microbial activities to ensure biosafety. Many biocontainment studies developed genetic devices that involve cell death and growth inhibition on the engineered microbes, which often create basal levels of cytotoxicity that hamper cell fitness and performance on therapeutic functions; furthermore, these toxic pathways may promote genetic instability that leads to mutations and breakdown of biocontainment circuit. To address this issue, here we explore a circuit design that destroys the engineered genetic materials in a probiotic strain, instead of killing these cells, under non-permissive conditions. Our safeguard circuit involves a two-layered transcriptional regulatory circuit to control the expression of a CRISPR system that targets the engineered genes for degradation. InEscherichia coli Nissle 1917(EcN), the biocontainment system continuously scavenged and destroyed the target until no engineered cellular function could be detected, suggesting this strategy has the potential to avoid escapee formation. Additionally, this safeguard circuit did not affectEcNcell fitness. We further demonstrated that the engineered probiotics inhabited in mouse guts and continued the engineered activities for at least 7 days when the permissive signal was supplied constantly; when the permissive signal was not provided, the engineered activities became undetectable within two days. Together, these studies support that our safeguard design is feasible for synthetic probiotic applications.HIGHLIGHTSOur safeguard system only destroys target genes and does not kill the host microbesIt terminated engineered activities in guts in response to a loss of a signalThis safeguard allowed synthetic probiotics to inhabit in guts for at least a weekCellobiose has great potential to serve as a continuous genetic signal in guts
Perinatal and maternal factors associated with Autism Spectrum Disorder
Authors: Edlund Susanna , Haglund Nils , Bornehag Carl-Gustaf , Gennings Chris , Kiviranta Hannu , Kolevzon Alexander , Lindh Christian , Rantakokko Panu , Reichenberg Abraham , Swan Shanna , Källén Karin 
Published: December 2024

AbstractThis study comprehensively examines maternal and perinatal conditions associated with autism spectrum disorder (ASD) in a total population sample with individually confirmed diagnoses from South Sweden. Following thorough review of medical records, 996 cases were ascertained and classified based on level of intellectual disability, ASD severity and family-history of ASD. 10 controls per case were randomly selected from the population (N=9,960). Multiple maternal and perinatal conditions were associated with increased risk for ASD, but associations varied by ASD comorbid conditions. Only high maternal BMI was associated with ASD risk across all ASD sub-groups. Results suggest differences in ASD etiology by comorbid subgroups and highlight potential modifiable risk factors.
Geometry-based BERT: an experimentally validated deep learning model for molecular property prediction in drug discovery
Authors: Zhang Xiang , Qian Chenliang , Yang Bochao , Jin Hongwei , Wu Song , Xia Jie , Yang Fan , Zhang Liangren 
Published: December 2024

AbstractVarious deep learning based methods have significantly impacted the realm of drug discovery. The development of deep learning methods for identifying novel structural types of active compounds has become an urgent challenge. In this paper, we introduce a self-supervised representation learning framework, i.e., GEO-BERT. GEO-BERT considers the information of atoms and chemical bonds in chemical structures as the input, and integrates the positional information of the three-dimensional conformation of the molecule for training. Specifically, GEO-BERT enhances its ability to characterize molecular structures by introducing three different positional relationships: atom-atom, bond-bond, and atom-bond. By benchmarking study, GEO-BERT has demonstrated optimal performance on multiple benchmarks. We also performed prospective study to validate the GEO-BERT model, with screening for DYRK1A inhibitors as a case. Two potent and novel DYRK1A inhibitors (IC50: <1 μM) were ultimately discovered at a hit rate of 10%. Taken together, we have developed the Geometry-based BERT model for molecular property prediction and proved its practical utility in early-stage drug discovery.Graphical AbstractGEO-BERT is a model pretrained on large-scale drug molecule data, while improving the accuracy of property prediction by using three-dimensional structural information within the molecule.
Mapping eukaryotic chromatin accessibility and histone modifications with DNA deaminase
Authors: Dong Wenyang , Zhang Jiankun , Dai Leyi , Chen Jinxin Phaedo , Wu Honggui , He Runsheng , Pang Yuxuan , Wang Zhi , Jian Fanchong , Ren Jun , Liu Yijun , Tian Yu , Liu Shuang , Zhao Xuechen , Xie Xiaoliang Sunney 
Published: December 2024

AbstractA variety of methods such as ATAC-seq and CUT&Tag have been developed for probing chromatin states. However, enzymatic cleavage of DNA in these methods hinders their multi-omics integration with other DNA profiling techniques. Here, by extending our use of dsDNA deaminase (FOOtprinting with DeamInasE, FOODIE), we introduce two new methods for mapping Chromatin Open region by DeamInasE (ChrODIE) and histone modification by ANtibody-associated DeamInasE (ANDIE), respectively. Unlike cleavage-based methods, both ChrODIE and ANDIE leave genomic DNA after deamination unfragmented and amplifiable. This offers the potential for simultaneous or downstream integration with other genomic profiling methods, such as mapping 3D genome interactions.
Experimental data supporting a novel hypothesis for the rhythmic initiation of proximal colon motor complexes
Authors: Morales-Soto Wilmarie , Stiglitz Emma S. , Edwards Brian S. , Smith-Edwards Kristen M. 
Published: December 2024

AbstractCurrent models of colon motility are largely based on studies of distal regions where distension-induced neural peristalsis predominates, but the proximal colon significantly differs in terms of cellular organization and its rhythmic motor activity that continues without external sensory input, emphasizing the need to define the unique mechanisms utilized by the proximal colon. With the long-term goal of developing a new model for the rhythmic initiation of proximal colon motor complexes (CMCs), we usedin situcalcium imaging to define activity patterns in key players for colon motility [i.e., submucosal interstitial cells of Cajal (ICC-SM) and myenteric neurons of the enteric nervous system (ENS)], while simultaneously monitoring motor output in the proximal mouse colon. We observed repeated patterns of activity in ICC-SM and ENS myenteric neurons during the intervals between CMCs that could be used to predict the timing of subsequent CMC events. Based on our findings, we propose a novel hypothesis that cyclical interactions between the ENS and ICC-SM act as an intrinsic pattern generator for the rhythmic initiation of proximal CMCs.
Morphological Plasticity and Reproductive Strategies ofKalanchoeSpecies in Invasive Spread
Authors: Zhang Zhe , Sugiura Daisuke , Yamori Wataru , Tang Yanhong 
Published: December 2024

AbstractKalanchoespecies, originally introduced worldwide as ornamentals, are now reported to be spreading in many regions, including China. It is hypothesized that morphological plasticity and the production of asexual plantlets contribute to their successful invasion. To address the hypothesis, four species -Kalanchoe delagoensisEckl. & Zeyh.,Kalanchoe × houghtoniiD. B. Ward,Kalanchoe laetivirensDesc. andKalanchoe daigremontianaRaym. - Hamet & H. Perrier - were cultivated under contrasting light and water conditions, and their reproductive and vegetative traits were examined. The plants subjected to high light tended to prioritize plantlet production, accompanied by a reduction in vegetative growth. Two distinct reproductive strategies were observed:K. delagoensisandK. × houghtoniisignificantly increased plantlet production under high light conditions, whereasK. daigremontianaandK. laetivirensenhanced the fresh weight of individual plantlets without altering the total number produced. These results highlight the high plasticity of vegetative and reproductive growth in response to light and water availability. The increased production of plantlets may contribute to the widespread occurrence ofKalanchoespecies in open fields.
A novel method for in vivo assessment of soft tissue weight in bivalves
Authors: Duan Shiyun , Gao Yunlong , Hu Xiaoli , Yin Xiaoshen 
Published: December 2024

AbstractAquaculture has been playing an increasingly important role in supplying proteins. To satisfy the rapidly growing demands for quality aquatic foods, the efficiency of aquaculture production needs to be improved. One strategy to achieve more efficient aquaculture production is to produce high-yielding seeds through breeding programs, for which in vivo assessment of target traits is indispensable to prevent candidate parents from being sacrificed for measurement and to track dynamically changing yield-related traits. Farmed mollusks, most of which are bivalves, rank the second among all aquatic animals in aquaculture production. Bivalves with heavier soft tissue, the major edible part, are preferable, target species for breeding and farming. A prerequisite for obtaining such species is to make accurate but nondestructive assessments of soft tissue weight, which cannot be accomplished using traditional dissection- or imaging-based methods. To resolve this issue, we take advantage of the complex relationships among shell dimension- and weight-related traits to construct classical, shell dimension- or wet weight-based models and novel, shell surface area-based models for in vivo assessment of soft tissue weight in Zhikong scallop (Chlamys farreri) and yesso scallop (Patinopecten yessoensis). Overall, soft tissue weight estimated by wet weight-involving models are highly correlated with observed values, indicating wet weight as a key proxy for soft tissue weight. While some models incorporating wet weight tend to systematically over- or under-estimate soft tissue weight despite the strong association between actual and estimated values, the novel, shell surface area-based model, MLR-log10Sshell-RR, generates accurate estimates free of systematic biases across populations of different ages for both species, suggesting it as a promising approach for in vivo assessment of soft tissue weight for scallops and other bivalves with bilaterally symmetrical shells.
An Expanded Registry of Candidate cis-Regulatory Elements for Studying Transcriptional Regulation
Authors: Moore Jill E. , Pratt Henry E. , Fan Kaili , Phalke Nishigandha , Fisher Jonathan , Elhajjajy Shaimae I. , Andrews Gregory , Gao Mingshi , Shedd Nicole , Fu Yu , Lacadie Matthew C , Meza Jair , Ganna Mohit , Choudhury Eva , Swofford Ross , Farrell Nina P. , Pampari Anusri , Ramalingam Vivekanandan , Reese Fairlie , Borsari Beatrice , Yu Michelle , Wattenberg Eve , Ruiz-Romero Marina , Razavi-Mohseni Milad , Xu Jinrui , Galeev Timur , Beer Michael A. , Guigó Roderic , Gerstein Mark , Engreitz Jesse , Ljungman Mats , Reddy Timothy E. , Snyder Michael P. , Epstein Charles B , Gaskell Elizabeth , Bernstein Bradley E , Dickel Diane E. , Visel Axel , Pennacchio Len A. , Mortazavi Ali , Kundaje Anshul , Weng Zhiping 
Published: December 2024

AbstractMammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression. Previously, The ENCODE consortium mapped biochemical signals across many cell types and tissues and integrated these data to develop a Registry of 0.9 million human and 300 thousand mouse candidate cis-Regulatory Elements (cCREs) annotated with potential functions1. We have expanded the Registry to include 2.35 million human and 927 thousand mouse cCREs, leveraging new ENCODE datasets and enhanced computational methods. This expanded Registry covers hundreds of unique cell and tissue types, providing a comprehensive understanding of gene regulation. Functional characterization data from assays like STARR-seq, MPRA, CRISPR perturbation, and transgenic mouse assays now cover over 90% of human cCREs, revealing complex regulatory functions. We identified thousands of novel silencer cCREs and demonstrated their dual enhancer/silencer roles in different cellular contexts. Integrating the Registry with other ENCODE annotations facilitates genetic variation interpretation and trait-associated gene identification, exemplified by discoveringKLF1as a novel causal gene for red blood cell traits. This expanded Registry is a valuable resource for studying the regulatory genome and its impact on health and disease.
Fast Myosin Binding Protein-C is a Vital Regulator in Young and Aged Fast Skeletal Muscle Homeostasis
Authors: Baby Akhil , Ananthamohan Kalyani , Song Taejeong 
Published: December 2024

AbstractBackgroundSkeletal muscle plays a vital role in voluntary motion and locomotion. Fast-twitch muscle fibers are characterized by their rapid contraction kinetics, high force generation capacity, and a distinct gene expression profile compared to slow-twitch fibers. Skeletal myosin binding protein-C (MyBP-C) paralogs, slow (sMyBP-C) and fast (fMyBP-C), interact with myosin and actin filaments within sarcomeres to modulate force development during contraction. These paralogs are differentially expressed in muscle fibers, with fMyBP-C predominantly expressed in the fast-twitch fibers. However, the role of fMyBP-C in skeletal muscle disease states and aging remains poorly understood. This study employs mouse models with fMyBP-C ablation to investigate its significance in skeletal muscle physiology.MethodsAdult skeletal muscle samples aged 2∼7 months from male and female wild-type, db/db, MDX, ECC injury model, were used to determine the differential expression of fMyBP-C. Next,Mybpc2knockout (C2-/-) young (3∼5 months) and old (22 months) male mice were used to define the role of fMyBP-C in aging. Western immunoblotting was employed to analyze the expression of fMyBP-C and sMyBP-C and the phosphorylation status of sMyBP-C. The impact of C2-/-and aging on the fiber type, size, and number as well as general muscle structure was assessed by immunohistochemistry and electron microscopy. The functional effect of C2-/-and aging was measured in terms of in vivo and ex vivo muscle force generation. Lastly, RNA sequencing was performed to identify the molecular pathways dysregulated in the C2-/-mediated muscle dysfunction in young and old mice.ResultsfMyBP-C was significantly reduced with a modest compensatory upregulation of sMyBP-C in the diseased fast-twitch muscles. fMyBP-C has a significantly higher expression in the male skeletal muscles compared to females. Further studies using young male C2-/-mice showed a significant reduction in isometric tetanic force generation and relaxation rate, fiber type switching, atrophy, and altered gene expressions related to muscle function and metabolism compared to wild-type mice. Similarly, compared to their wild-type counterparts, aged male C2-/-mice display significant deficits in muscle strength, endurance, and survival rate, accompanied by changes in muscle fiber size and molecular signaling pathways critical for muscle homeostasis.ConclusionfMyBP-C is an important regulator of muscle function and homeostasis in young and aged male fast-twitch muscle fibers. The absence of fMyBP-C aggravates the effect of aging on muscle structure and function. fMyBP-C has the potential to be a therapeutic target to modulate muscle wasting caused by aging and disease.
Longitudinal assessment of DREADD expression and efficacy in the monkey brain
Authors: Nagai Yuji , Hori Yukiko , Inoue Ken-ichi , Hirabayashi Toshiyuki , Mimura Koki , Oyama Kei , Miyakawa Naohisa , Hori Yuki , Iwaoki Haruhiko , Kumata Katsushi , Zhang Ming-Rong , Takada Masahiko , Higuchi Makoto , Minamimoto Takafumi 
Published: December 2024

AbstractDesigner Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantifiedin vivoDREADD expression in macaque monkeys using positron emission tomography with the DREADD-selective tracer [11C]deschloroclozapine (DCZ), complemented by functional studies. Twenty macaque monkeys were evaluated after being injected with adeno-associated virus vectors expressing the DREADDs hM4Di or hM3Dq, whose expression was quantified as changes in [11C]DCZ binding potential from baseline levels. Expression levels of both hM4Di and hM3Dq peaked around 60 days post-injection, remained stable for about 1.5 years, and declined gradually after two years. Significant chemogenetic control of neural activity and behavior persisted for about two years. Virus titer and the presence of protein tags significantly influenced expression levels, with co-expressed protein tags reducing overall expression levels. These findings provide valuable insights and guidelines for optimizing the use of DREADDs in long-term primate studies and potential therapeutic applications.
Dynamics of postnatal bone development and epiphyseal synostosis in the caprine autopod
Authors: Panebianco Christopher J. , Essaidi Maha , Barnes Elijah , Williams Ashley , Vancíková Karin , Labberté Margot C. , Brama Pieter , Nowlan Niamh C. , Boerckel Joel D. 
Published: December 2024

AbstractBones develop to structurally balance strength and mobility. Bone developmental dynamics are influenced by whether an animal is ambulatory at birth (i.e.,precocial). Precocial species, such as goats, develop advanced skeletal maturity in utero, making them useful models for studying the dynamics of bone formation under mechanical load. Here, we used microcomputed tomography and histology to characterize postnatal bone development in the autopod of the caprine lower forelimb. The caprine autopod features two toes, fused by metacarpal synostosis (i.e., bone fusion) prior to birth. Our analysis focused on the phalanges 1 (P1) and metacarpals of the goat autopod from birth through adulthood (3.5 years). P1 cortical bone densified rapidly after birth (half-life using one-phase exponential decay model (τ1/2= 1.6 ± 0.4 months), but the P1 cortical thickness increased continually through adulthood (τ1/2= 7.2 ± 2.7 mo). Upon normalization by body mass, the normalized polar moment of inertia of P1 cortical bone was constant over time, suggestive of structural load adaptation. P1 trabecular bone increased in trabecular number (τ1/2= 6.7 ± 2.8 mo) and thickness (τ1/2= 6.6 ± 2.0 mo) until skeletal maturity, while metacarpal trabeculae grew primarily through trabecular thickening (τ1/2= 7.9 ± 2.2 mo). Unlike prenatal fusion of the metacarpal diaphysis, synostosis of the epiphyses occurred postnatally, prior to growth plate closure, through a unique fibrocartilaginous endochondral ossification. These findings implicate ambulatory loading in postnatal bone development of precocial goats and identify a novel postnatal synostosis event in the caprine metacarpal epiphysis.
A practical DNA data storage using expanded alphabet introducing 5-methylcytosine
Authors: Liu Deruilin , Xu Demin , Shi Liuxin , Zhang Jiayuan , Bi Kewei , Luo Bei , Liu Chen , Li Yuxiang , Fan Guangyi , Wang Wen , Ping Zhi 
Published: December 2024

AbstractDNA molecular is a promising next-generation data storage medium. Recently, it has been theoretically proposed that non-natural or modified bases can serve as extra molecular letters to increase the information density. However, the feasibility of the strategy is challenging due to the difficulty in synthesizing and the complex structure of non-natural DNA sequences. Here, we described a practical DNA data storage transcoding scheme named R+ based on expanded molecular alphabet by introducing 5-methlcytosine(5mC). We also demonstrated the experimental validation by encoding one representative file into several 1.3~1.6 kbpsin vitroDNA fragments for nanopore sequencing. The results show an average data recovery rate of 98.97% and 86.91% with and without reference respectively. This work validates the practicability of 5mC in DNA storage systems, with a potentially wide range of applications.Availability & ImplementationR+ is implemented in Python and the code is available under the MIT license athttps://github.com/Incpink-Liu/DNA-storage-R_plus
GP-ML-DC: An Ensemble Machine Learning-Based Genomic Prediction Approach with Automated Two-Phase Dimensionality Reduction via Divide-and-Conquer Techniques
Authors: Liu Quanzhong , Ma Haofeng , Zhang Zhuangbiao , Hu Zhunhao , Wang Xihong , Li Ran , Cai Yudong , Jiang Yu 
Published: December 2024

AbstractTraditional machine learning (ML) and deep learning (DL) methods for genome prediction often face challenges due to the imbalance between the limited number of samples (n) and the large number of single nucleotide polymorphisms (SNPs) (p), wherenis much smaller thanp. To address this, we propose GP-ML-DC, an innovative genome predictor that combines traditional ML and DL models with a unique two-phase, parameter-free dimensionality reduction technique. Initially, GP-ML-DC reduces feature dimensionality by characterizing genes as features. Building on big data methodologies, it employs a divide-and-conquer approach to segment gene regions into multiple haplotypes, further decreasing dimensionality. Each haplotype segment is processed by a sub-task based on traditional ML, followed by integration via a neural network that synthesizes the results of all sub-tasks. Our experiments, conducted on four cattle milk-related traits using ten-fold cross-validation and independent testing, show that GP-ML-DC significantly surpasses current state-of-the-art genome predictors in prediction performance.