bluuebunny/crossref_metadata_2025_split huggingface dataset:
ITGB4 promotes the progression of colorectal cancer by activating Wnt/β-catenin signaling pathway via targeting EZR
Authors: Wang Jing , Si Yi , Xuan Mingda , Han Shuangshuang , Liu Kunyi , Jiao Jiao , Men XiaoYan , Li HongFei , Yu Weifang , Liu Ting , Wang Jia 
Published: December 2024

AbstractBackgroundIntegrin Beta 4 (ITGB4), a member of the integrin family, was found to be abnormally highly expressed in colorectal cancer tissues and serum in our previous research, and it was associated with clinicopathological types and overall survival. This study further explores the potential mechanisms of ITGB4 in the occurrence and development of colorectal cancer, seeks downstream target genes and signaling pathways, and provides new insights for precision treatment of colorectal cancer.MethodsThrough bioinformatics analysis, it was verified that ITGB4 and EZR are highly expressed in tumor tissues of CRC patients and are associated with poor patient prognosis. The effects of ITGB4 on the proliferation, migration, invasion, and apoptosis of CRC cells were validated using CCK-8, wound healing assay, Transwell migration, and invasion assays. A nude mouse tumor formation experiment was conducted to validate the tumor-promoting effect of ITGB4 in vivo. Transcriptome sequencing was performed in SW480 cells with ITGB4 knockdown, and potential downstream targets and signaling pathways of ITGB4 were screened using KEGG enrichment analysis and bioinformatics analysis. The interaction between ITGB4 and downstream target genes was further demonstrated by immunofluorescence co-staining and co-immunoprecipitation. Key proteins in the downstream signaling pathway (β-catenin, c-Myc, and cyclinD1) were detected by Western blot to clarify the potential signaling pathway through which ITGB4 functions in CRC. Rescue experiments were conducted to validate the role of ITGB4 and its downstream target genes in the proliferation, migration, and invasion of colorectal cancer.ResultsITGB4 is highly expressed in CRC tissues and cells. In vitro, downregulation of ITGB4 can inhibit the proliferation, migration, and invasion of CRC cells and promote apoptosis. In vivo, ITGB4 contributes to the growth of CRC tumor tissues and regulates the tumorigenic properties such as proliferation and invasion of CRC cells. Additionally, EZR has been preliminarily identified as a key downstream target of ITGB4, as the effects of ITGB4 knockdown on the proliferation, migration, and invasion of CRC cells can be rescued by overexpressing EZR. We also demonstrated that the ITGB4/EZR axis promotes the occurrence and development of CRC by activating the Wnt/β-catenin signaling pathway and regulating various biological functions of CRC cells.ConclusionsITGB4 targets and regulates EZR, and by activating the Wnt/β-catenin signaling pathway, it affects the proliferation, migration, and invasion of CRC, suggesting that ITGB4 may become a potential biomarker and therapeutic target.
Investigating Amino acid Enrichments and Patterns in Phase-Separating Proteins: Understanding Biases in Liquid-Liquid Phase Separation
Authors: Calvário Joana , Antunes Diogo , Cipriano Rita , Kalafatovic Daniela , Mauša Goran , Pina Ana S. 
Published: December 2024

AbstractLiquid-Liquid Phase Separation (LLPS) forms membraneless organelles, enhancing biochemical processes. The stickers-and-spacers model explains LLPS but is mainly validated in Prion-like RNA Binding Proteins. We explore peptide motifs in LLPS in broader protein contexts. We developed a computational approach for motif discovery, implemented in 178 Phase-Separating Proteins (PhSePs), complemented by the FuzDrop and CIDER servers, which identified droplet-promoting regions (DPRs) and examined disorder-related characteristics. Our database of PhSePs was analyzed against proteins with low propensity for LLPS. This comparative analysis revealed 129 enriched peptide motifs with folds higher than 0.2, consisting of 3 to 6 residues, with tetrapeptides being the most prevalent. Key features of the enriched motifs included Gly-rich sequences punctuated with aromatic, charged, and polar residues, as well as homopeptide repeats (e.g., GGDR, SRGG, YGGG, QQQQ, PPPP). Analysis of motif presence, frequency, and co-occurrence revealed widely distributed motifs across different DPRs, identified motifs with significant repetitive patterns, and highlighted motif trios that are more likely to co-occur within a sequence. By harvesting this analysis, we developed a data-driven approach for minimalistic peptide design with LLPS propensity, further using the CIDER server for peptide characterization and peptide design refinement. We designed 8 peptides with various motif combinations and amino acid distributions, which were experimentally validated to undergo LLPS, exhibiting liquid-like behavior with diverse molecular mobility patterns and droplet dynamics. Our approach bridges a non-biased computational approach with experimental validation, offering insights into sequence determinants of phase separation, with the potential for designing minimalistic synthetic condensates with tailored properties.
Personalization of Closed-Chain Shoulder Models Yields High Kinematic Accuracy for Multiple Motions
Authors: Hammond Claire V. , Henninger Heath B. , Fregly Benjamin J. , Gustafson Jonathan A. 
Published: December 2024

AbstractThe shoulder joint complex is prone to musculoskeletal issues, such as rotator cuff-related pain, which affect two-thirds of adults and often result in suboptimal treatment outcomes. Current musculoskeletal models used to understand shoulder biomechanics are limited by challenges in personalization, inaccuracies in predicting joint and muscle loads, and an inability to simulate anatomically accurate motions. To address these deficiencies, we developed a novel, personalized modeling framework capable of calibrating subject-specific joint centers and functional axes for the shoulder complex. Leveraging in vivo biplane fluoroscopy data and the recent Joint Model Personalization Tool from the Neuromusculoskeletal Modeling Pipeline, we optimized joint parameters and body scale factors for shoulder models with varying degrees of freedom (DOFs). We initially created and tested open-chain scapula-only models (3DOF, 4DOF, and 5DOF) and found that increasing DOFs improved accuracy, with the 5 DOF model yielding the lowest marker distance errors (average = 0.8 mm, maximum = 5.2 mm) as compared to biplane fluorscopy data of the scapula across eight movement trials. We subsequently created closed-chain shoulder models incorporating scapula, clavicle, and humerus bodies. We found closed-chain shoulder models with 5 DOFs for the scapula achieved the highest accuracy (average = 0.9 mm, maximum = 5.7 mm) and showed consistent performance across subjects (n=3) in leave-one-out cross-validation tests (average marker distance errors = 1.0–1.4 mm). This framework minimizes errors in joint kinematics and provides a foundation for future models incorporating personalized musculature and advanced simulations, enhancing its potential clinical utility for rehabilitation and surgical planning.
Segregated localization of target-SNARE proteins within presynaptic terminals of Munc18-1 deficient photoreceptors
Authors: Huang Mengjia , Chow Chun Hin , Charish Jason , Indrawinata Karen , Harada Hidekiyo , Wallace Valerie A. , Monnier Philippe P. , Sugita Shuzo 
Published: December 2024

AbstractSec1/Munc18 family proteins are essential for SNARE-mediated vesicular exocytosis. However, where SNARE proteins are localized in Munc18-1 deficient presynaptic terminals remains unclear due to the rapid degeneration of neurons lacking Munc18-1. Here, we found that removing Munc18-1 from photoreceptor cells did not result in major cellular loss until postnatal day 14, which allowed us to investigate the role of Munc18-1 in endogenous presynaptic terminals. In the absence of Munc18-1, even before major photoreceptor cell degeneration, functional impairments were present. While Munc18-1 was not required for the pre-synaptic enrichment of the t-SNARE proteins syntaxin-3 and SNAP-25, it played a critical role in their proper localization. In wild-type conditions, t-SNAREs are highly colocalized. However, in the absence of Munc18-1, their distribution becomes strikingly segregated. Immuno-electron microscopy revealed that without Munc18-1, syntaxin-3 is retained within various organelle membranes rather than being targeted to synaptic plasma membranes. These findings provide the first evidence that Munc18-1 is important to prevent segregation of syntaxin-3 and SNAP-25 within presynaptic terminals.
Global Biogeography of Prokaryotes in Mangrove Sediments: Spatial Patterns and Ecological Insights from 16S rDNA Metabarcoding
Authors: Jamon-Haon Emma , Cuny Philippe , Rossi Alix , Sylvi Léa , Fiard Maud , Militon Cécile 
Published: December 2024

AbstractThe global asymmetry in the floristic diversity distribution within mangrove ecosystems is well-documented. However, sediment microbial communities, which play crucial ecological roles, are often overlooked in mangrove biogeography studies. This study aimed to investigate the diversity, composition, and distribution of prokaryotic communities across distinct mangrove bioregions (12 countries and territories from the Caribbean bioregion, Southeast America, East Africa, Indo-Malaysia and Australasia). We conducted a meta-analysis by compiling 16S rDNA datasets from 17 previous studies (540 samples) over a six year period (2014-2020) and applied community ecology analyses combined with random forest models. Although no significant correlation was observed between tree richness and microbial diversity, a microbial hotspot was identified in the Indo-West Pacific region. Microbiota associated with different mangroves displayed opposite latitudinal diversity gradients and beta-dispersions. Distance-decay relationships were weak but statistically significant. Random forest models identified key microbial taxa, and the OTUs shared across all bioregions suggested the presence of a potential core mangrove microbiota. Taxonomic and statistical analyses underscored the great heterogeneity of microbiota composition, heavily influenced by the study (e.g., molecular and bioinformatic methodologies). Future research on mangrove microbiome would benefit from standardized sampling and sequencing methods. Despite current limitations, distance-decay relationship confirmed the influence of dispersal barriers for mangrove sediment microbiota. This study also suggests that environmental factors, rather than plant diversity alone, may play a prominent role in shaping the diversity, composition and distribution of prokaryotic communities in mangrove sediments.
Mapping the Genetic Architecture of the Adaptive Integrated Stress Response inS. cerevisiae
Authors: Baum Rachel , Kim Jinyoung , Muller Ryan Y. , Ingolia Nicholas T. 
Published: December 2024

AbstractThe integrated stress response (ISR) is a conserved eukaryotic signaling pathway that responds to diverse stress stimuli to restore proteostasis. The strength and speed of ISR activation must be tuned properly to allow protein synthesis while maintaining proteostasis. Here, we describe how genetic perturbations change the dynamics of the ISR in budding yeast. We treated ISR dynamics, comprising timecourses of ISR activity across different levels of stress, as a holistic phenotype. We profiled changes in ISR dynamics across thousands of genetic perturbations in parallel using CRISPR interference with barcoded expression reporter sequencing (CiBER-seq). We treated cells with sulfometuron methyl, a titratable inhibitor of branched-amino acid synthesis, and measured expression of an ISR reporter. Perturbations to translation such as depletion of aminoacyl-tRNA synthetases or tRNA biogenesis factors reduced cell growth and caused a strikingly proportionate activation of the ISR activation. In contrast, impaired ribosome biogenesis reduced basal ISR activity and weakened ISR dynamics. Reduced ribosome capacity may lower the demand for amino acids and thereby explain these changes. Our work illustrates how CiBER-seq enables high-throughput measurements of complex and dynamic phenotypes that shed light on adaptive and homeostatic mechanisms.
Modeling the Future Incidence of Preeclampsia under Climate Change and Population Growth Scenarios
Authors: Youssim Iaroslav , Nevo Daniel , Erez Offer , Garfinkel Chaim I. , Okun Barbara S. , Novack Lena , Kloog Itai , Raz Raanan 
Published: December 2024

AbstractPreeclampsia is a dangerous pregnancy disorder, with evidence suggesting that high ambient temperatures may increase its risk, making future incidence projections crucial for health planning. While temperature-related projections for all-cause mortality exist, disease-specific projections, especially for pregnancy complications, are limited due to data and methodological challenges. Vicedo-Cabrera et al. (2019) pioneered a time-series approach to project health impacts using the attributable fraction (AF) of cases due to climate change. We adjusted this method for preeclampsia, whose risk involves long-term exposures, with delivery as a competing event.We based our analysis on the exposure-response relationship estimated in our previous study in southern Israel using cause-specific hazard and distributed lag nonlinear models. In the current study, we modeled several demographic and climate scenarios in the region for 2020-2039 and 2040-2059. Scenario-specific AFs were calculated by comparing cumulative preeclampsia incidence with and without corresponding climate change. Finally, annual cases were estimated by applying climate scenario-specific AFs to cases projected under each demographic scenario.Our models show that climate change alone may increase preeclampsia by 3.2% to 4.3% in 2040-2059 relative to 2000-2019. Fertility trends are modeled to have a larger impact, with a 30% increase in cases by 2020-2039 under a low-fertility scenario. Extreme high-fertility and climate scenarios could result in a 2.3-fold rise in incidence, from 486 cases annually in 2000-2019 to 1,118 by 2040-2059.
Brown Bears activates a Satiety Hormone Cholecystokinin (CCK) pathway in adipose tissue during hibernation
Authors: Henriksen T.I , Engelhard C , Frøbert AM , Schrölkamp M , Friebe A , Overgaard MT , Poulsen SS , Rehfeld JF , Nielsen J , Fröbert O , Scheele C , Feizi A , Nielsen S 
Published: December 2024

AbstractThe brown bear (Ursus arctos) hibernates to survive cold winters without access to food. It builds enormous subcutaneous fat stores during summer and relies on it for energy during winter. Remarkably, the weight loss during winter occurs without muscle loss despite inactivity. Studying brown bear biology can therefore provide insights for improving human health in obesity and weight loss treatments. We here investigate subcutaneous adipose tissue biopsies obtained during summer and winter from free-living brown bears. During winter, a signature of genes involved in food intake and digestion is upregulated. Among these are several regulators of satiety, substrate transport and lipid metabolism. Interestingly, in humans these genes are enriched in distinct metabolic organs including, brain, intestine, stomach, liver and even salivary glands. We focused on the satiety brain/intestinal hormone cholecystokinin (CCK), which we demonstrate is produced in adipocytes, accompanied by an upregulation of the CCK receptor CCKBR. Importantly, CCK was undetectable in the circulation during winter and presence of sensory neurons suggest a neuronal feedback mechanism within the adipose tissue. Using RNA sequencing, we predict additionally 537 secreted proteins to be seasonally regulated, 37 of which could be confirmed with plasma proteomics. In conclusion, we propose that brown bears have developed a strategy of healthy fat burning and satiety regulation through an adipose tissue-contained mechanism which includes digestion factors and satiety mediators to provide safe energy turnover during hibernation-dependent weight loss.
Defining the high-translational readthrough stop codon context
Authors: Smoljanow Daniela , Lebeda Dennis , Hofhuis Julia , Thoms Sven 
Published: December 2024

AbstractTranslational termination is not entirely efficient and competes with elongation, which might result in translational readthrough (TR). TR occurs when a near-cognate tRNA binds to a stop codon, (mis)interpreting it as a sense codon and producing a C-terminal extension of the protein. This process is influenced by the stop codon itself and the surrounding nucleotide sequence, known as the stop codon context (SCC). To investigate the role of these cis-acting elements beyond the high-TR motif UGA CUA G, this study examines specific positions within the SCC, both upstream and downstream of the motif, that contribute to variations in basal and aminoglycoside-induced TR. In particular, we identified a surprisingly large influence of the upstream nucleotide positions -9 and -8 (relative to the stop codon) and positions +11 and +12 on readthrough levels, revealing a complex interplay between nucleotides in the expanded SCC. These findings support our understanding of translational termination and may benefit the development of pharmacological therapy for diseases caused by premature stop codon mutations.
Evolutionary conservation of midline axon guidance activity betweenDrosophilaandTriboliumFrazzled
Authors: Ghosh Piyasi , Wadsworth Benjamin C. , Terry Logan , Evans Timothy A. 
Published: December 2024

AbstractThe regulation of midline crossing of axons is of fundamental importance for the proper development of nervous system connectivity in bilaterian animals. A number of conserved axon guidance signaling pathways coordinate to attract or repel axons at the nervous system midline to ensure the proper regulation of midline crossing. The attractive Netrin-Frazzled/DCC (Net-Fra) signaling pathway is widely conserved among bilaterians, but it is not clear whether the mechanisms by which Net and Fra promote midline crossing are also conserved. InDrosophila, Fra can promote midline crossing via Netrin-dependent and Netrin-independent mechanisms, by acting as a canonical midline attractive receptor and also through a non-canonical pathway to inhibit midline repulsion via transcriptional regulation. To examine the conservation of Fra-dependent axon guidance mechanisms among insects, in this paper we compare the midline attractive roles of the Frazzled receptor in the fruit fly (Drosophila melanogaster) and flour beetle (Tribolium castaneum) using CRISPR/Cas9-mediated gene editing. We replace theDrosophila fragene with sequences encodingDrosophilaFra (DmFra) orTriboliumFra (TcFra) and examine midline crossing of axons in the ventral nerve cord of embryos carrying these modified alleles. We show thatTriboliumFra can fully substitute forDrosophilaFra to promote midline crossing of axons in the embryonic nervous system, suggesting that the mechanisms by which Frazzled regulates midline axon guidance may be evolutionarily conserved within insects.
Energy efficiency and sensitivity benefits in a motion processing adaptive recurrent neural network
Authors: Mohan Vishnu , Rideaux Reuben 
Published: December 2024

ABSTRACTMotion processing is a key function for the survival of many organisms and is initially implemented in areas V1 and MT of the primate visual cortex. Advances in machine learning approaches have led to the development of motion processing neural networks that have elucidated several aspects of this process. However, it remains unclear how adaptation, a canonical function of sensory processing, influences motion processing. In this study, we developed two recurrent neural networks to study motion processing: MotionNet-R, a baseline model, and AdaptNet, a model that employs adaptive mechanisms inspired by biological systems. Both networks were trained on natural image sequences to estimate motion vectors. We found that both networks developed response properties that resembled those of neurons found in areas V1 and MT, e.g., speed tuning, and AdaptNet recapitulated the motion aftereffect phenomenon (i.e.,the waterfall illusion). We show that the emergent computational properties that implement the phenomenon in AdaptNet confirm previous theoretical hypotheses. Further, we compared the performance of the two networks and found that AdaptNet processed motion more efficiently, operationalized as reduced activation. While AdaptNet incurred reduced accuracy in response to prolonged constant input, it was both more accurate and sensitive in response to changes in motion input. These results are consistent with theoretical explanations of adaptation as neural property that supports metabolic efficiency and increased sensitivity to change in the environment. Our findings provide novel insights into the neural mechanisms underlying motion adaptation and highlight the potential advantages of adaptive neural networks in modelling biological processes.
A molecularly defined brain circuit module for regulating the panic-like defensive state
Authors: Zhao Miao , Zhang Li , Chen Zhenhua , Zhang Shuangfeng , Cheng Xinyu , Huang Meizhu , Li Xiating , Gu Huating , Guan Xuyan , Geng Dandan , Li Yaning , Tu Yiheng , Xie Zhiyong , Zhang Fan , Ma Huijie , Li Dapeng , Wu Qingfeng , Cao Peng 
Published: December 2024

ABSTRACTPanic is an episode of strong defensive state, characterized by intense fear and severe physical symptoms such as elevated cardiorespiratory activities. How the brain generates panic state remains poorly understood. Here, we developed a robot-based experimental paradigm to evoke panic-like defensive state in mice. When stimulated by the robot, the mice exhibited jumping escapes and elevated cardiorespiratory activities. With this paradigm, we identifiedCbln2-expressing (Cbln2+) neurons in the posterior hypothalamic nucleus (PHN) as a key neuronal population essential for the induction of panic-like defensive state. Activation ofCbln2+ PHN neurons induced behavioral and physical symptoms of panic-like defensive state. These neurons were strongly activated by noxious mechanical stimuli and encode jumping escape vigor. They were synaptically innervated by anxiety-associated brain areas and provoked panic-like defensive state via their projection to the periaqueductal gray. Together, our results reveal a molecularly defined circuit module that regulates the panic-like defensive state in mice.
In VivoPathway Optimization in Yeast viaLoxPsym-Mediated Shuffling of Upstream Activating Sequences
Authors: Ruehmkorff Ciaran , Tafazoli Yazdi Ali , Hochrein Lena 
Published: December 2024

AbstractThe budding yeastSaccharomyces cerevisiaeplays an integral role in the bioeconomy as a powerful host for industrial bio-manufacturing, driving the production of diverse bio-based products. Achieving optimal product yields requires precise fine-tuning of the expression levels of multiple pathway genes, which often relies on cloning-intensive methods. Here, we present PULSE, anin vivopromoter engineering tool based on a streamlined workflow combining FACS-based screening of a randomized DNA library to identify active promoter elements, and their subsequent assembly into synthetic hybrid promoters where each element is flanked byloxPsymsites. Multiple promoter cassettes can be genome-integrated to generate “ready-to-use” platform strains, allowing users to easily place their genes of interest under the control of PULSE promoters. By activating Cre-mediated recombination,loxPsym-flanked promoter elements can be recombined, effectively bringing the target genes under control of a vast set of promoters spanning a wide range of expression levels in one simple step. Applying PULSE on two heterologous pathways, a threefold increase in β-carotene production and improved xylose utilization byS. cerevisiaewas achieved. These results demonstrate the power and efficiency of PULSE as a versatile platform for metabolic engineering, enabling rapid, cloning-free optimization of biosynthetic pathwaysin vivo.