bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible by LPAR5 activation
Authors: Momoh Michael , Rathan-Kumar Sudiksha , Burman Andreanna , Brown Monica E , Adeniran Francisca , Ramos Cynthia , Goldenring James R , Roland Joseph T , Kaji Izumi 
Published: September 2024

AbstractFunctional loss of the motor protein, Myosin Vb (MYO5B), induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). Utilizing the MVID model mice,Vil1-CreERT2;Myo5bflox/flox(MYO5BΔIEC) andVil1-CreERT2;Myo5bflox/G519R(MYO5B(G519R)), we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5BΔIEC small intestine. Consistent with these observationsin vivo, RNA-sequencing of enteroids generated from two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, lysophosphatidic acid (LPA) signaling ameliorates epithelial cell defects in MYO5BΔIEC tissues and enteroids. The present study demonstrates that the highly soluble LPAR5-preferred agonist, Compound-1, improved sodium transporter localization and absorptive function, and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on intestine with MYO5B functional loss through epithelial cell-autonomous pathways that may improve the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for treatment of MVID symptoms induced by different point mutations in MYO5B.NEW & NOTEWOTHYThis study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, a previously unexplored function of MYO5B. Alterations in cellular metabolism may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID). To examine the therapeutic potential of progenitor-targeted treatments, the effects of LPAR5-preferred agonist, Compound-1, was investigated utilizing several MVID model mice and enteroids. Our observations suggests that Compound-1 may provide a therapeutic approach for treating MVID.Graphic Abstract
An independent base composition of each rate class for improved likelihood-based phylogeny estimation; the 5rf model
Authors: Waddell Peter J. , Bouckaert Remco 
Published: September 2024

AbstractThe combination of atimereversible Markov process with a “hidden” mixture ofgamma distributed relative site rates plusinvariant sites have become the most favoured options for likelihood and other probabilistic models of nucleotide evolution (e.g., tr4gi which approximates a gamma with four rate classes). However, these models assume a homogeneous and stationary distribution of nucleotide (character or base) frequencies. Here, we explore the potential benefits and pitfalls of allowing each rate category (rate class) of a 4gi mixture model to have its own base frequencies. This is achieved by starting each of the five rate classes, at the tree’sroot, with its own free choice of nucleotidefrequencies to create a 4gi5rf model or a 5rf model in shorthand.We assess the practical identifiability of this approach with a BEAST 2 implementation, aiming to determine if it can accurately estimate credibility intervals and expected values for a wide range of plausible parameter values. Practical identifiability, as distinguished from mathematical identifiability, gauges the model’s ability to identify parameters in real-world scenarios, as opposed to theoretically with infinite data.One of the most common types of phylogenetic data is mitochondrial DNA (mtDNA) protein coding sequence. It is often assumed current models analyse robustly such data and that higher likelihood/posterior probability models do better. However, this abstract shows that vertebrate mtDNA remains a very difficult type of data to fully model, and that dramatically higher likelihoods do not mean a model is measurably more accurate with respect to recovering key parameters of biological interest (e.g., monophyletic groups, their support and their ages). The 4gi5rf model considerably improves marginal likelihoods and seems to reverse some apparent errors exacerbated by the 4gi model, while introducing others. Problems appear to be linked to non-stationary DNA repair processes that alter the mutation/substitution spectra across lineages and time. We also show such problems are not unique to mtDNA and are encountered in analysing nuclear sequences. Non-stationarity of DNA repair processes mutation/substitution spectra thus pose an active challenge to obtaining reliable inferences of relationships and divergence times near the root of placental mammals, for example.An open source implementation is available under the LGPL 3.0 license in the beastbooster package for BEAST 2, available fromhttps://github.com/rbouckaert/beastbooster.
Mapping HIV-1 RNA Structure, Homodimers, Long-Range Interactions and persistent domains by HiCapR
Authors: Zhang Yan , Han Jingwan , Xie Dejian , Shen Wenlong , Li Ping , Lau Jian You , Li Jingyun , Li Lin , Kudla Grzegorz , Zhao Zhihu 
Published: September 2024

AbstractHuman Immunodeficiency Virus (HIV) persists as a leading global health issue. A significant gap in knowledge exists in our understanding of long-range interactions within the HIV-1 RNA genome. To bridge this gap, we introduce HiCapR, incorporating a psoralen crosslinking RNA proximity ligation and post-library hybridization for capturing HIV RNA-RNA interactions.Leveraging HiCapR, we confirm the presence of stem structures in the key regions, such as the 5’-untranslated region(5’-UTR) and Rev Response Element (RRE) stems, and dimer sites in 5’-UTR region, which is responsible for HIV packaging. Importantly, we reveal multiple previously unknown homodimers along the HIV genome, which may have important implications for viral RNA splicing and packaging processes. Also, we uncover a wealth of unprecedented long-range interactions, particularly within the 5’-UTR of infected cells.Intriguingly, our findings indicate a pronounced reduction in long-range RNA-RNA interactions, signifying a transition from a state of abundant interactions, hence a relative loose state within infected cells to a condensed structure within virions. Concurrently, we have demonstrated the presence of stable genomic domains within virions that are instrumental in the dimerization process. These domains are preserved throughout the packaging process.Our findings shed light on the functional significance of RNA organization, including stable and persistent genomic domains, homodimerization, and long-range RNA-RNA interactions, in the splicing, packaging as well as assembly of HIV.HighlightsHiCapR is a new proximity ligation method for mapping RNA structures and homodimers in the HIV genome with sufficient reliability and efficiency.Multiple homodimers were discovered along the genome, with potential implications for splicing and packaging processes.Long-range RNA-RNA interactions are abundant in infected cells but significantly reduced in virions.Stable genomic domains encluding homodimer sites are persistent in virions and are involved in dimerization.
A statistical-based method for the construction and analysis of gene network: application to bacteria
Authors: Zhang Zhiyuan , Chen Guozhong , Li Erguang 
Published: September 2024

ABSTRACTBacteria play a crucial role in environmental conservation, human health, and medicine. Whether in the gut or the soil, bacterial genomes are rich repositories of resources, such as exploring potential drugs and biopesticides. However, our ability to develop new therapies and deepen our understanding of the bacterial world is hindered by the largely unknown functions of bacterial genes. In this study, we proposed a method of gene network construction and analysis based on a Gaussian Graphical Model (GGM) and random sampling strategy to infer direct interactions at the genomic level in bacteria. UsingVibrio choleraeandStaphylococcus aureusas examples, we integrated partial correlation-based gene co-expression data with gene regulatory and essentiality information extracted from public databases to construct more comprehensive gene networks. Networks built upon bacterial different phenotypes, such as biofilm formation, flagellar assembly, and stress response, demonstrate the effectiveness of this method in deciphering unknown gene functions, uncovering new phenotype-associated factors, and identifying their corresponding interactions, thus providing new targets for experimental validation by researchers. Additionally, we extended this method to 14 bacteria, including 13 pathogens, supporting the investigation of gene functions and pathways at the genomic level in these bacteria. More importantly, for other species, this method of gene network construction can be easily implemented, provided that sufficient transcriptome sequencing samples are available.
Direct Nuclear Delivery of Proteins on Living Plant via Partial Enzymatic Cell Wall Digestion
Authors: Gu Qufei , Ming Nathan , Wei Xiaoyang , Aizezi Yalikunjiang , Yuan Yizhong , Esquivel Brian , Wang Zhiyong 
Published: September 2024

ABSTRACTWhile many variations of protein delivery methods have been described, it can still be difficult or inefficient to introduce exogenous proteins into plants. A major barrier to progress is the cell wall which is primarily composed of polysaccharides and thus only permeable to small molecules. Here, we report a partial enzymatic cell wall digestion-mediated uptake method that efficiently delivers protein into the nucleus of plant cells. Such a method allowed efficient nuclear delivery of GFP proteins into Arabidopsis root cells throughout all cell layers. This study establishes that a partial enzymatic cell wall degradation could enable a myriad of plant biotechnology applications that rely on functional protein delivery into walled plant cells.
Selective Agonism of Liver and Gut FXR Prevents Cholestasis and Intestinal Atrophy in Parenterally Fed Neonatal Pigs
Authors: Jiang Yanjun , Fang Zhengfeng , Guthrie Gregory , Stoll Barbara , Chacko Shaji , Lin Sen , Hartmann Bolette , Holst Jens J. , Dawson Harry , Pastor Jose J. , Ipharraguerre Ignacio R. , Burrin Douglas G. 
Published: September 2024

AbstractBACKGROUND & AIMSWe aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs.METHODSNewborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA), or increasing doses of obeticholic acid (OCA) for 19 days.RESULTSEnteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic cyp7a1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC$ and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP.CONCLUSIONSEnteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter FXR target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of FXR agonism in the prevention of PNALD in piglets.
Construction of Discrete Element Model of Different Moisture Hygroscopic Fertilizer Particles and Fertilizer Discharging Verification
Authors: Fei Chen Xiong , Yu Sun Ze , Ze Shi Yi , Hua Liu Mu , Jia Yu Jia , An Liu Jun 
Published: September 2024

AbstractThe hygroscopic fertilizer particles were characterized based on discrete element simulation, and its accuracy was verified by the simulation of fertilizer discharge. Firstly, the repose angle of the fertilizer particles served as the key metric for assessment. A mathematical model characterizing the relationship between fertilizer moisture content and the repose angle was established, R2=0.9935; and a mathematical representation of the repose angle for fertilizer moisture content was established, R2=0.9933. Then, the moisture absorbing fertilizer particles was developed utilizing the integrated Hertz Mindlin with JKR model within EDEM system to account for particle adhesion; A robust correlation model between the repose angle of hygroscopic fertilizers and the discrete element method was established, p <0.0001; Finally, a correlation model between moisture content and significant parameters within the discrete element method was established, drawing upon the models for moisture content repose angle and repose angle discrete element parameters. The moisture-absorbing fertilizer particles model at moisture contents of 2% and 6% were resolved, with a relative error of the repose angle not exceeding 1.42% and a single circle fertilizer discharge error below 8.32%. The results show that the moisture content discrete element significant parameter correlation model can reliably and precisely forecast the discrete element parameters of various moisture content hygroscopic fertilizers. The hygroscopic fertilizer particle model can represent surface interaction characteristics of hygroscopic fertilizer granules. which has guiding significance for the design of precision fertilizer discharge technology device.
Tissue-specific and functional loci analysis ofCASP14gene in the sheep horn
Authors: Lu Xiaoning , Zhang Guoqing , Yang Hao , Shan Mingzhu , Zhang Xiaoxu , Wang Yuqin , Bai Junyan , Pan Zhangyuan 
Published: September 2024

AbstractUnder the current context of intensive farming, small-horned animals are more suitable for large-scale breeding. TheCASP14gene, closely associated with skin and keratin formation, may influence horn size due to its link with skin development. This study comprehensively analyzed the tissue-specific expression ofCASP14using RNA-Seq data, identified functional sites through whole-genome sequencing (WGS), and investigated allele-specific expression (ASE) validated by KASP assays. Results showed significantly higherCASP14expression in the scurred group com-pared to the SHE group, with pronounced expression in the skin. Interbreed comparisons also revealed elevatedCASP14levels in the scurred group. Analysis of potential functional sites indicated structural similarities in theCASP14protein among horned mammals. Five ASE events were discovered, and intersecting these with SNPs and high fixation index loci (Fst > 0.05) identified three potential functional sites: 7941628, 7941817, and 7941830. The SNP site 7944295 was selected for T-test analysis and further validated through KASP assays, corroborating the role ofCASP14in sheep horn phenotypes. Our findings suggest thatCASP14plays a significant role in horn development, offering insights into breeding strategies for small-horned animals.
Evaluating Joint Angle Data for Clinical Assessment Using Multidimensional Inverse Kinematics with Average Segment Morphometry
Authors: Taitano Rachel I , Gritsenko Valeriya 
Published: September 2024

AbstractMovement analysis is a critical tool in understanding and addressing various disabilities associated with movement deficits. By analyzing movement patterns, healthcare professionals can identify the root causes of these alterations, which is essential for preventing, diagnosing, and rehabilitating a broad spectrum of medical conditions, disabilities, and injuries. With the advent of affordable motion capture technologies, quantitative data on patient movement is more accessible to clinicians, enhancing the quality of care. Nonetheless, it is crucial that these technologies undergo rigorous validation to ensure their accuracy in collecting and monitoring patient movements, particularly for remote healthcare services where direct patient observation is not possible. In this study, motion capture technology was used to track upper extremity movements during a reaching task presented in virtual reality. Kinematic data was then calculated for each participant using a scaled dynamic inertial model. The goal was to evaluate the accuracy of joint angle calculations using inverse kinematics from motion capture relative to the typical movement redundancy. Shoulder, elbow, radioulnar, and wrist joint angles were calculated with models scaled using either direct measurements of each individual’s arm segment lengths or those lengths were calculated from individual height using published average proportions. The errors in joint angle trajectories calculated using the two methods of model scaling were compared to the inter-trial variability of those trajectories. The variance of this error was primarily within the normal range of variability between repetitions of the same movements. This suggests that arm joint angles can be inferred with good enough accuracy from motion capture data and individual height to be useful for the clinical assessment of motor deficits.
AxonFinder: Automated segmentation of tumor innervating neuronal fibers
Authors: Ait-Ahmad Kaoutar , Ak Cigdem , Thibault Guillaume , Chang Young Hwan , Eksi Sebnem Ece 
Published: September 2024

SUMMARYNeurosignaling is increasingly recognized as a critical factor in cancer progression, where neuronal innervation of primary tumors contributes to the disease’s advancement. This study focuses on segmenting individual axons within the prostate tumor microenvironment, which have been challenging to detect and analyze due to their irregular morphologies. We present a novel deep learning-based approach for the automated segmentation of axons, AxonFinder, leveraging a U-Net model with a ResNet-101 encoder, based on a multiplexed imaging approach. Utilizing a dataset of whole-slide images from low-, intermediate-, and high-risk prostate cancer patients, we manually annotated axons to train our model, achieving significant accuracy in detecting axonal structures that were previously hard to segment. Our analysis includes a comprehensive assessment of axon density and morphological features across different CAPRA-S prostate cancer risk categories, providing insights into the correlation between tumor innervation and cancer progression. Our paper suggests the potential utility of neuronal markers in the prognostic assessment of prostate cancer in aiding the pathologist’s assessment of tumor sections and advancing our understanding of neurosignaling in the tumor microenvironment.
A Digital Microfluidic Platform for the Microscale Production of Functional Immune Cell Therapies
Authors: Little Samuel R. , Rahbari Niloufar , Hajiaghayi Mehri , Gholizadeh Fatemeh , Cloarec-Ung Fanny-Mei , Phillips Joel , Sinha Hugo , Hirukawa Alison , Knapp David J.H.F. , Darlington Peter J. , Shih Steve C.C. 
Published: September 2024

AbstractGenetically engineering human immune cells has been shown to be an effective approach for developing novel cellular therapies to treat a wide range of diseases. To expand the scope of these cellular therapies while solving persistent challenges, extensive research and development is still required. Electroporation has recently emerged as one of the most popular techniques for inserting biological payloads into human immune cells to perform genetic engineering. However, several recent studies have reported that electroporation can negatively impact cell functionality. Additionally, the requirement to use large amounts of cells and expensive payloads to achieve efficient delivery can drive up the costs of development efforts. Here we use a digital microfluidic enabled electroporation system (referred to as triDrop) and compare them against two state-of-the-art commercially available systems for the engineering of human T cells. We describe the ability to use triDrop for highly viable, highly efficient transfection while using substantially fewer cells and payload. Subsequently, we perform transcriptomic analysis on cells engineered with each of the three systems and show that electroporation with triDrop lead to less dysregulation of several functionally relevant pathways. Finally, in a direct comparison of immunotherapeutic functionality, we show that T cells engineered with triDrop have an improved ability to mount an immune response when presented with tumor cells. These results show that the triDrop platform is uniquely suited to produce functionally engineered immune cells while also reducing the costs of cell engineering compared to other commercially available systems.
Immunity against Mycobacterium avium induced by DAR-901 and BCG
Authors: Abate Getahun , Meza Krystal , Colbert Chase , Eickhoff Christopher 
Published: September 2024

AbstractThe prevalence of pulmonary nontuberculous mycobacteria (NTM) is increasing in Europe and North America. Most pulmonary NTM are caused byMycobacterium aviumcomplex (MAC). The treatment of pulmonary MAC is suboptimal with failure rates ranging from 30% to 40% and there is a need to develop new vaccines. In this study, we tested the ability of two whole cell vaccines, DAR-901 (heat killedM. obuense) and BCG (live attenuatedM. bovis), to induce MAC cross-reactive immunity by first immunizing BALB/c mice and then performing IFN-γ ELISPOT assay after overnight stimulation of splenocytes with live MAC. To study the ability of these vaccines to protect against MAC infection, BALB/c mice were vaccinated with DAR-901 (intradermal) or BCG (subcutaneous or intranasal) and challenged with aerosolized MAC 4 weeks later. Some mice vaccinated with BCG were treated with clarithromycin via gavage. Lung CFU in immunized mice and unvaccinated controls were quantified 4 weeks after infection. Our results showed that i) DAR-901 induced cross-reactive immunity to MAC and the level of MAC cross-reactive immunity was similar to the level of immunity induced by BCG, ii) DAR-901 and BCG protect against aerosol MAC, iii) mucosal BCG vaccination provided the best protection against MAC challenge, and iv) BCG vaccination did not interfere with anti-MAC activities of clarithromycin.