bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sodium Benzoate Promotes Fat Accumulation and Aging via the SKN-1/Nrf2 Signaling Pathway: Evidence from theCaenorhabditis elegansModel
Authors: Lee Jiah D. , Lee Jiwoo , Vang Jerry , Pan Xiaoping 
Published: September 2024

ABSTRACTSodium benzoate (SB) is widely used in food products, cosmetics, and medical solutions due to its antimicrobial properties. While it is generally considered safe and has potential neuroprotective benefits, SB has also been linked to adverse effects, including hepatic oxidative stress and inflammation. However, the potential effects of SB on obesity and aging remain poorly understood. In this study, we investigated the effects of SB on fat accumulation and aging using the nematodeCaenorhabditis elegans(C. elegans) as a model system. Wild-type worms were exposed to various SB concentrations (0%, 0.0004%, 0.0008%, 0.004%, and 0.1%) and 0.016% glucose as a positive control for 72 hours in liquid or on NGM agar plates. Fat accumulation was assessed through the Oil Red O staining, which revealed that SB induced more fat accumulation compared to vehicle control, even at low concentrations, including the dosage of 0.0004%. Lifespan analysis also demonstrated that SB significantly accelerated aging in wild-type worms in a dose-dependent manner. Further investigations found that SKN-1 (an Nrf2 homolog) is necessary for SB-induced fat accumulation and aging. Moreover, SB inhibited the nuclear localization of SKN-1 under oxidative stress conditions. These findings suggest that SB may induce fat accumulation and aging by inhibiting the oxidative stress-mediated SKN-1 signaling pathway.
Antipsychotic-like effects of the selective Rho-kinase 2 inhibitor KD025 in genetic and pharmacological mouse models of schizophrenia
Authors: Tanaka Rinako , Liao Jingzhu , Liu Yue , Zhu Wenjun , Fukuzawa Kisa , Kondo Masamichi , Sawahata Masahito , Mori Daisuke , Mouri Akihiro , Kubota Hisayoshi , Tachibana Daiki , Kobayashi Yohei , Matsuzaki Tetsuo , Nagai Taku , Nabeshima Toshitaka , Kaibuchi Kozo , Ozaki Norio , Mizoguchi Hiroyuki , Yamada Kiyofumi 
Published: September 2024

1AbstractCopy number variations in theARHGAP10gene encoding Rho GTPase–activating protein 10 are significantly associated with schizophrenia. ARHGAP10 negatively regulates RhoA/Rho-kinase (ROCK) signaling. We previously demonstrated that fasudil, a non-selective ROCK inhibitor, exhibited antipsychotic-like effects in several mouse models of schizophrenia. ROCK has two subtypes, ROCK1 and ROCK2. ROCK1 is mainly expressed in the thymus and blood, while ROCK2 is predominantly expressed in the brain. Therefore, it is expected that like fasudil, selective ROCK2 inhibitors will exhibit antipsychotic-like effects, accompanied by a lower incidence of adverse effects due to ROCK1 inhibition. Here, we used genetic and pharmacological models of schizophrenia to investigate whether the selective ROCK2 inhibitor KD025 would show antipsychotic-like effects with a favorable adverse effect profile. Oral administration of KD025 suppressed the abnormal increase in the phosphorylation level of myosin phosphatase–targeting subunit 1, a substrate of ROCK, and ameliorated the decreased spine density of layer 2/3 pyramidal neurons in the medial prefrontal cortex ofArhgap10S490P/NHEJ mice. Furthermore, KD025 mitigated the methamphetamine-induced impairment of visual discrimination (VD) inArhgap10S490P/NHEJ and wild-type mice. KD025 also reduced MK-801–induced impairments of VD, novel object recognition, and hyperlocomotion. Regarding side effects that are commonly seen with typical antipsychotics, KD025 did not affect systolic blood pressure and did not induce extrapyramidal symptoms, hyperprolactinemia, or hyperglycemia at the effective dosage in naïve wild-type mice. Taken together, KD025 shows antipsychotic-like effects with a favorable adverse effect profile in genetic and pharmacological mouse models of schizophrenia.
Detection of statistically robust interactions from diverse RNA-DNA ligation data
Authors: Zehr Simonida , Seredinski Sandra , Walsh Emma C. , Bonetti Alessandro , Leisegang Matthias S. , Brandes Ralf P. , Schulz Marcel H. , Warwick Timothy 
Published: September 2024

AbstractChromatin-localized RNAs play diverse roles in gene regulation and nuclear architecture. Mapping genome-wide RNA-DNA interactions is possible using a variety of molecular methods, including using bridging oligonucleotides to ligate RNA and DNA in proximity. While molecular methods have progressed, a robust computational method for calling biologically meaningful RNA-DNA interactions from these data is lacking. Herein, we presentRADIAnT, a reads-to-interactions pipeline for analyzing RNA-DNA ligation data.RADIAnTcalls interactions against a dataset-specific, unified background which considers RNA binding site-TSS distance and genomic region bias. By scaling the background by RNA abundance,RADIAnTis sensitive enough to detect specific interactions of lowly expressed transcripts, while remaining specific enough to discount false positive interactions of highly abundant RNAs.RADIAnToutperforms previously proposed methods in the accurate recall of genome-wideMalat1-DNA interactions, and in a use case, was utilized to identify dynamic chromatin-associated RNAs in the physiologically- and pathologically-relevant process of endothelial-to-mesenchymal transition.
Post-transcriptional control of homeostatic B-cell signalling by HuR is required for innate B cell maintenance and function
Authors: Capitan-Sobrino Dunja , Mouysset Mailys , Maloudi Orlane , Aubert Yann , Osma-Garcia Ines C. , Nestor-Martin Maia , Nguyen Trang-My M. , Dunga Greta , Diaz-Muñoz Manuel D. 
Published: September 2024

SUMMARYInnate B-1 cells constitute a self-maintained layer of defence for early detection of bacteria, clearance of apoptotic cell debris and removal of autoantigens driving autoimmunity. B-1 cells are originated from foetal tissues but, as opposed to B-2 cells, the molecular mechanisms behind their development and homeostatic maintenance remain largely unknown. Here we demonstrate that post-transcriptional regulation by the RNA binding protein HuR is essential for the homeostatic self-replenishment of innate B-1 cells, the expansion of B-1 cell clones targeting self-antigens and the production of natural autoantibodies. HuR KO B-1 cells fail to express the high levels of surface BCR, TACI and BAFFR required for tonic signalling and cell survival. Mechanistically, HuR binds to the 3’UTRs of mRNAs encoding these surface receptors and of pro-survival molecules, like BCL-2 and MCL-1, promoting their translation into protein. In summary, we reveal the need of post-transcriptional regulation in BCR expression, tonic signalling and homeostatic maintenance of functional B-1 cells.
Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria
Authors: Bergquist Timothy , Stenton Sarah L. , Nadeau Emily A.W. , Byrne Alicia B. , Greenblatt Marc S. , Harrison Steven M. , Tavtigian Sean V. , O’Donnell-Luria Anne , Biesecker Leslie G. , Radivojac Predrag , Brenner Steven E. , Pejaver Vikas ,   ClinGen Sequence Variant Interpretation Working Group
Published: September 2024

ABSTRACTPurposeWe previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up toStrong. A new generation of tools using distinctive approaches have since been released, and these methods must be independently calibrated for clinical application.MethodUsing our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by three new tools (AlphaMissense, ESM1b, VARITY) and calibrated scores meeting each evidence strength. ResultsAll three tools reached theStronglevel of evidence for variant pathogenicity andModeratefor benignity, though sometimes for few variants. Compared to previously recommended tools, these yielded at best only modest improvements in the tradeoffs of evidence strength and false positive predictions.ConclusionAt calibrated thresholds, three new computational predictors provided evidence for variant pathogenicity at similar strength to the four previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.
Mitigating Cellular Dysfunction by Addressing Contaminants in Synthetic circRNA
Authors: Zhang Ziwei , Li Weiyu , Luo Dengwang , Yuan Xiushuang , Yu Li , Wang Daming , Cao Yuhong 
Published: September 2024

AbstractSynthetic circular RNA (circRNA) shows great potential in biomedical research and therapies, but impurities introduced during its synthesis can undermine circRNA efficacy. This study investigated the immunogenic potential of byproducts generated during its production. We found that trace amounts of double-stranded RNA in high molecular weight impurities, 5’ triphosphates of uncircularized RNA or small intron fragments, and hydrolyzed RNA fragments significantly impact the functionality of circRNA by activating innate immune responses through the sensory molecules involved in RNA sensing. To address this, we developed a novel multi-step purification process that employs enzymatic treatments and cellulose-based filtration to selectively remove these detrimental contaminants. This tailored approach minimizes cellular immune reactions and substantially improves circRNA yields with up to more than 10 times increase. Our findings underscore the critical impact of precise contaminant management in enhancing the expression and potential therapeutic utility of circRNA. This suggests a new direction for optimizing their production for both research and clinical applications.
BrainSTEM: A multi-resolution fetal brain atlas to assess the fidelity of human midbrain cultures
Authors: Toh Hilary SY , Xu Lisheng , Chen Carissa , Yang Pengyi , Sun Alfred X , Ouyang John F 
Published: September 2024

AbstractMany midbrain dopaminergic neuron (mDA) differentiation protocols aimed at Parkinson’s disease (PD) modeling and cell replacement therapy have been developed. However, comprehensive evaluations of the transcriptomic fidelity of these protocols at the single-cell level against a commonin vivoreference have been lacking. To this end, we constructed an integrated human fetal whole-brain atlas and a midbrain subatlas to use as a standard of comparison. From the whole-brain atlas, we observed distinct brain-region-specific gene expression in most neural cell types, emphasizing the need to first evaluatein vitroprotocols at the whole-brain level to identify midbrain-associated cells. These cells are then mapped to the midbrain subatlas for more refined neuronal subtype specification and trajectory analysis specific to the midbrain. We surveyed all publicly available single-cell datasets of human midbrain culture models and performed the two-tier mapping. Using this biologically-driven multi-resolution mapping strategy which we termed BrainSTEM (brain Single-cell Two tiEr Mapping), we confirmed the presence of multiple midbrain cell types (‘on-target’), but also a substantial proportion of cells associated with non-midbrain regions and subtypes (‘off-target’). This leads to an overall ‘inflation’ of mDA presence, stemming from non-midbrain-associated cells, across all published protocols. BrainSTEM thus offers an unbiased framework for understanding the current state of midbrain models and aids the improvement of midbrain differentiation protocols for PD studies.
The dynamics of capillary flow in an open-channel system featuring trigger valves
Authors: Tokihiro Jodie C. , Robertson Ingrid H. , Gregucci Denise , Shin Albert , Michelini Elisa , Nicholson Tristan M. , Olanrewaju Ayokunle , Theberge Ashleigh B. , Berthier Jean , Berthier Erwin 
Published: September 2024

AbstractTrigger valves are fundamental features in capillary-driven microfluidic systems that stop fluid at an abrupt geometric expansion and release fluid when there is flow in an orthogonal channel connected to the valve. The concept was originally demonstrated in closed-channel capillary circuits. We show here that trigger valves can be successfully implemented in open channels. We also show that a series of open-channel trigger valves can be placed alongside or opposite a main channel resulting in a layered capillary flow. We developed a closed form model for the dynamics of the flow at trigger valves based on the concept of average friction length and successfully validated the model against experiments. For the main channel, we discuss layered flow behavior in the light of the Taylor-Aris dispersion theory and in the channel turns by considering Dean theory of mixing. This work has potential applications in autonomous microfluidics systems for biosensing, at-home or point-of-care sample preparation devices, hydrogel patterning for 3D cell culture and organ-on-a-chip models.
A new comparative framework for estimating selection on synonymous substitutions
Authors: Verdonk Hannah , Pivirotto Alyssa , Pavinato Vitor , Hey Jody , Pond Sergei LK 
Published: September 2024

AbstractSelection on synonymous codon usage is a well known and widespread phenomenon, yet existing models often do not account for it or its effect on synonymous substitution rates. In this article, we develop and expand the capabilities of Multiclass Synonymous Substitution (MSS) models, which account for such selection by partitioning synonymous substitutions into two or more classes and estimating a relative substitution rate for each class, while accounting for important confounders like mutation bias. We identify extensive heterogeneity among relative synonymous substitution rates in an empirical dataset of ∼12,000 gene alignments from twelveDrosophilaspecies. We validate model performance using data simulated under a forward population genetic simulation, demonstrating that MSS models are robust to model misspecification. MSS rates are significantly correlated with other covariates of selection on codon usage (population-level polymorphism data and tRNA abundance data), suggesting that models can detect weak signatures of selection on codon usage. With the MSS model, we can now study selection on synonymous substitutions in diverse taxa, independent of anya prioriassumptions about the forces driving that selection.
Reconstruction of ancestral protein sequences using autoregressive generative models
Authors: De Leonardis Matteo , Pagnani Andrea , Barrat-Charlaix Pierre 
Published: September 2024

AbstractAncestral sequence reconstruction (ASR) is an important tool to understand how protein structure and function changed over the course of evolution. It essentially relies on models of sequence evolution that can quantitatively describe changes in a sequence over time. Such models usually consider that sequence positions evolve independently from each other and neglect epistasis: the context-dependence of the effect of mutations. On the other hands, the last years have seen major developments in the field of generative protein models, which learn constraints associated with structure and function from large ensembles of evolutionarily related proteins. Here, we show that it is possible to extend a specific type of generative model to describe the evolution of sequences in time while taking epistasis into account. We apply the developed technique to the problem of Ancestral Sequence Reconstruction (ASR): given a protein family and its evolutionary tree, we try to infer the sequences of extinct ancestors. Using both simulations and data coming from experimental evolution we show that our method outperforms state-of-the-art ones. Moreover, it allows for sampling a greater diversity of potential ancestors, allowing for a less biased characterization of ancestral sequences.
Entangled Evolution Model: Application to Adaptive Mutation
Authors: Ross Patrick 
Published: September 2024

AbstractAdaptive mutation, the phenomenon where organisms appear to increase beneficial mutation rates in response to environmental stress, has challenged the traditional understanding of random mutations in evolutionary biology. Here, we present a novel computational model, the Entangled Evolution Model, which integrates quantum game theory and quantum walks to provide a new approach to understanding mutation dynamics. By applying the Clauser-Horne-Shimony-Holt (CHSH) quantum game within a modified Lotka-Volterra framework, we simulate how quantum entanglement can accelerate the rate of adaptive mutations inEscherichia colipopulations. Our simulations reveal that entangled bacterial populations achieve successful adaptive mutations with an 85% probability, significantly surpassing the classical theoretical maximum. These results introduce a new perspective on computational approaches to evolutionary adaptation, offering an efficient algorithmic framework to explore the role of quantum effects in biological systems.
Ex vivoDHA supplementation suppresses prostaglandin E2 formation in primary human macrophages
Authors: Kirchhoff Rebecca , Kampschulte Nadja , Rothweiler Carina , Rohwer Nadine , Weylandt Karsten-Henrich , Schebb Nils Helge 
Published: September 2024

AbstractScopeThere is evidence that intake of long-chain n-3 polyunsaturated fatty acids (PUFA) is associated with improved prognosis for inflammatory diseases. However, the underlying mechanisms are still subject of ongoing research. For this purpose, we developed anex vivon-3 PUFA supplementation strategy to test n-3 PUFA supplementation under controlled conditions in primary human macrophages.Methods and resultsCells were supplemented with docosahexaenoic acid (DHA). Quality parameters to account for possible confounders were established for a reproducible and reliable supplementation. Following supplementation, PUFA pattern of cells was shifted towards a pattern reflecting that of subjects with a high n-3 PUFA status. This was accompanied by a decrease of arachidonic acid-derived oxylipins in a dose- and time-dependent manner in favor of n-3 PUFA ones. Stimulation with LPS resulted in decreased levels of pro-inflammatory prostaglandins in the DHA-supplemented cells, but no changes in cytokines.ConclusionIn vitrosupplementation studies with n-3 PUFA need rigorous controls to exclude background formation of oxylipins. By accounting for these possible confounders the desribedex vivoapproach is a promising tool for the mechanistic investigation of n-3 PUFA in primary human immune cells, offering an alternative for intervention studies in humans.
Beyond associations: A benchmark Causal Relation Extraction Dataset (CRED) of disease-causing genes, its comparative evaluation, interpretation and application
Authors: Bansal Nency , Sri Dhinesh R C , Pathak Ayush , Narayanan Manikandan 
Published: September 2024

AbstractInformation on causal relationships is essential to many sciences (including biomedical science, where knowing if a gene-disease relation is causal vs. merely associative can lead to better treatments); and can foster research on causal side-information-based machine learning as well. Automatically extracting causal relations from large text corpora remains less explored though, despite much work on Relation Extraction (RE). The few existing CRE (Causal RE) studies are limited to extracting causality within a sentence or for a particular disease, mainly due to the lack of a diverse benchmark dataset. Here, we carefully curate a new CRE Dataset (CRED) of 3553 (causal and non-causal) gene-disease pairs, spanning 284 diseases and 500 genes, within or across sentences of 267 published abstracts. CRED is assembled in two phases to reduce class imbalance and its inter-annotator agreement is 89%. To assess CRED’s utility in classifying causal vs. non-causal pairs, we compared multiple classifiers and found SVM to perform the best (F1 score 0.70). Both in terms of classifier performance and model interpretability (i.e., whether the model focuses importance/attention on words with causal connotations in abstracts), CRED outperformed a state-of-the-art RE dataset. To move from benchmarks to real-world settings, our CRED-trained classification model was applied on all PubMed abstracts on Parkinson’s disease (PD). Genes predicted to be causal for PD by our model in at least 50 abstracts got validated in textbook sources. Besides these well-studied genes, our model revealed less-studied genes that could be explored further. Our systematically curated and evaluated CRED, and its associated classification model and CRED-wide gene-disease causality scores, thus offer concrete resources for advancing future research in CRE from biomedical literature.
Optimizing the use of cryopreserved genetic resources for the selection and conservation of animal populations
Authors: Jacques Alicia , Tixier-Boichard Michèle , Restoux Gwendal 
Published: September 2024

AbstractBackgroundGenetic diversity is essential for the sustainability and adaptability of populations, and is thus a central pillar of the agro-ecological transition. However, within a population it is inevitable that some amount of genetic variability is lost, and efforts must be made to limit this as much as possible. A valuable tool in this endeavor could be the use of cryopreserved genetic resources in cryobanks, which could assist in the management of various animal populations in the contexts of both selection and conservation.ResultsWe performed simulations that revealed that the most appropriate use ofex situgenetic resources differs radically depending on characteristics of the target population and its management objectives. With populations under conservation, the aim is the management of genetic diversity, which was optimized by the regular use of cryopreserved genetic resources at each generation. For populations under selection, instead, the concern is the addition of additive genetic variability, which benefited from the use of cryopreserved collections over only a few generations based primarily on the genetic values of donors. In both cases, the use of cryopreserved individuals in animal populations requires a large amount of material: for breeds under selection because the number of offspring is high, and for breeds under conservation because the frozen semen is used repeatedly over a long period.ConclusionsThe use of cryopreserved material appears to be an effective means of managing the genetic variability of an animal population, either by slowing down the erosion of variability or by helping to redirect a selection objective. However, care must be taken with populations under selection to limit the disadvantages associated with the reintroduction of old genetic material, in particular the gap in breeding values for traits of interest. Finally, our study highlights the need for a sufficiently large stock of cryopreserved material in collections (e.g., number of doses, straws) to ensure the most efficient use.