bluuebunny/crossref_metadata_2025 huggingface dataset:
The Transmission of the Phenomenon of Herbal Medicine to China via Silk Roads in Medieval China
Authors: Mollahassani Ali , CHENG Aoyu , ZHANG Weidong , WU Ye
Published: February 2025

The Silk Road has long been recognized as a vital channel for cultural and intellectual exchange, profoundly influencing the cosmopolitan identity of High Tang culture. Beyond the trade of goods like tea, silk, and carpets, this network also fostered the transfer of medical knowledge. Traditional Chinese Medicine (TCM), with its extensive pharmacopoeia of over ten thousand herbal medicines, benefited significantly from exchanges with neighboring countries and regions. This review explores the intricate connections between TCM and other medical systems facilitated by the Silk Road, highlighting representative herbs introduced from regions along the route. It underscores the reciprocal influences that shaped medical practices in both Eastern and Western traditions, offering insights into the potential integration of traditional and modern biomedical approaches today.
Neuro-arterial variants of thoracic outlet syndrome manifesting with atypical chest pain in a professional air rifle shooter managed by physical therapy and rehabilitation: Case report
Authors: Mishra Abhishek , Mishra Anushree
Published: February 2025

Thoracic outlet syndrome (TOS) is a diverse group of clinical disorders manifested upon impingement or compression of the neurovascular structures at the thoracic outlet, presenting a wide spectrum of neurovascular signs and symptoms. A high index of clinical suspicion complemented with a detailed clinical examination and optimal use of radiologic and electrodiagnostic studies must be employed to reach an early diagnosis for successful management since the symptoms are severely disabling and a residual neurological or vascular sequelae is expected in cases with the delayed or wrong diagnosis. We are discussing an interesting case where an air rifle shooter who presented to us with intermittent episodes of right-sided precordial chest pain for the last 3 months with a short history of breathing difficulty and occasional episodes of tingling and numbness in the right arm, diagnosed with hydro-pneumothorax on initial imaging and with neurological and arterial variants of TOS on subsequent workup during the course of hospital stay. The article intends to explain the relation of chest pain in patients with TOS.
Wiping Catheter-Associated Urinary Tract Infections Away With Chlorhexidine Gluconate
Authors: Williams Latasha , Collins Felicia , Hall-Thomas Cynthia
Published: February 2025

Catheter-associated urinary tract infections (CAUTIs) continue to be a concern in health care. According to the Agency on Healthcare Research and Quality, the cost associated with a single CAUTI is estimated to be $13,793 on average but can be as high as $29,743. Decreasing CAUTIs through preventative strategies will benefit both the patient and the healthcare organization. There were limited studies utilizing 2% and 4% chlorhexidine gluconate (CHG) as an intervention for CAUTI prevention. There was also an insufficient research about indwelling catheters, also known as a Foley catheters, and use of CHG during bathing and indwelling catheter care outside intensive care and CHG benefits relating to indwelling catheter care. To address this issue, we developed and implemented a quality improvement project in an inpatient rehabilitation facility for patients requiring indwelling catheters by integrating Food and Drug Administration-approved CHG products to determine the effectiveness of using 2% versus 4% CHG during bathing and indwelling catheter care to decrease CAUTI occurrences. We observed two CAUTIs for the unit using 4% CHG and zero CAUTIs using the 2% CHG. CAUTIs were associated with chronic renal calculi, missed opportunities with bowel care management, and knowledge deficits of supplemental staff members.
Predictors of Reoperation After Orthognathic Surgery in Patients With Cleft Palate: Two Decades of Insight
Authors: Pekcan Asli , Turk Marvee , Patel Raina K. , Bakovic Melanie , Mejia Valeria , Vallurupalli Medha , Magee William P. , Shakoori Pasha , Urata Mark , Hammoudeh Jeffrey
Published: February 2025

Orthognathic surgery represents a critical intervention within the continuum of care for patients with cleft lip and palate (CLP). Postoperative relapse is a significant complication and often necessitates reoperation. This study assesses risk factors for reoperation due to relapse following cleft orthognathic surgery. A retrospective review was conducted of patients with CLP who underwent orthognathic surgery for correction of class III malocclusion between 2005 and 2024, excluding those with under 6 months of follow-up. Maxillary advancement techniques included surgically assisted maxillary protraction (SAMP), LeFort I advancement (LF1), and distraction osteogenesis (DO). The outcome of interest was reoperation for late relapse. Overall, 133 patients met the inclusion criteria. The median age at surgery was 18.4 years, and the median follow-up was 2.1 years. Sixteen patients (12.0%) underwent SAMP, 101 (76.9%) LF1, 7 (5.3%) DO, and 9 (6.8%) staged DO followed by LF1. Bilateral sagittal split osteotomy (BSSO) for mandibular setback was performed in 48.4%. The incidence of reoperation was 13.5%. Maxillary advancements >8.5 mm were 6.3 times more likely to require reoperation (P<0.001). Multivariable regression identified bilateral CLP (P=0.038) and multiple prior maxillary operations (P=0.009) as significant predictors of reoperation, while BSSO was associated with decreased odds of reoperation (P=0.027). Patients with bilateral CLP and multiple prior maxillary operations were significantly more likely to require reoperation for late relapse. Limiting sagittal movements to <8.5 mm or performing concurrent BSSO may mitigate the risk of reoperation.
The Bacillus subtilis putative LysR-type transcriptional regulator YybE and its connection to chromosome replication and segregation
Authors: Koh Alan
Published: February 2025

Duplication and segregation of genetic material are vital for cell proliferation. Deletion of DNA replication regulators, such as YabA and ParA, leads to over initiation of DNA replication. However, the viability of the ΔyabA ΔParA double mutant suggests additional regulatory mechanisms. Using a transposon mutagenesis library, we identified yybE as a potential candidate. Bioinformatic analysis of yybE suggest that it encodes a putative LysR-type transcriptional regulator (LTTR). LTTR are established regulators of metabolic processes, leading us to hypothesise that YybE might link metabolic processes to DNA replication. However, under the tested conditions, deletion of yybE did not result in detectable changes to DNA replication frequency, origin segregation, or chromosome architecture.
Methanobacterium aridiramus sp. nov., a methanogen isolated from potential methane hydrate bearing area offshore southwestern Taiwan
Authors: Lee Kuan-Yi , Lai Mei-Chin , Lin Saulwood , Lai Shu-Jung , Zhang Wei-Ling , Chen Wen-Chieh , You Yi-Ting , Wu Sue-Yao , Hung Chuan-Chuan , Ding Jiun-Yan , Zhou Yang-Zhi , Shih Chao-Jen , Wu Yen-Chi , Zhao Jingjing , Li Yin , Xiao Wangchuan , Wu Chih-Hung , Zhang Hangying , Dong Guowen , Qiu Wanling , Wang Song , Chen Sheng-Chung
Published: February 2025

A novel mesophilic, hydrogenotrophic methanogen, strain CWC-01T, was isolated from the sediment sample of the piston core collected at station 3 at Good Weather Ridge area offshore southwestern Taiwan from ORI-902A cruise in 2009. Cells of strain CWC-01T are rod-shaped, measuring 0.4–0.5 µm in width and 1.0–2.0 µm in length. Strain CWC-01T utilizes formate and H2/CO2 to produce methane, but not secondary alcohol, methanol, ethanol, methylamines or acetate as catabolic substrates. The optimal growth conditions are 37 °C, 0.043 M NaCl and pH 6.3. Growth effectors tests indicate tryptone, but not acetate and yeast extract, could stimulate the growth of strain CWC-01. Phylogenetic analysis of 16S rRNA gene reveals that strain CWC-01T is most closely related to Methanobacterium petrolearium Mic5c12T, with 96.63% identity. Genome size of strain CWC-01T is 1.98 Mb and it is the smallest genome size of genus. The genomic DNA G+C content obtained from the genome sequence of strain CWC-01T is 44.15 mol%. Based on these phenotypic, phylogenetic and genomic analyses, we propose that strain CWC-01T represents a novel species in genus Methanobacterium, for which the name Methanobacterium aridiramus sp. nov. is proposed. The type strain is CWC-01T (=BCRC AR10053T=NBRC 113991T).
microGWAS: a computational pipeline to perform large-scale bacterial genome-wide association studies
Authors: Burgaya Judit , Damaris Bamu F. , Fiebig Jenny , Galardini Marco
Published: February 2025

Identifying genetic variants associated with bacterial phenotypes, such as virulence, host preference and antimicrobial resistance, has great potential for a better understanding of the mechanisms involved in these traits. The availability of large collections of bacterial genomes has made genome-wide association studies (GWAS) a common approach for this purpose. The need to employ multiple software tools for data pre- and postprocessing limits the application of these methods by experienced bioinformaticians. To address this issue, we have developed a pipeline to perform bacterial GWAS from a set of assemblies and annotations, with multiple phenotypes as targets. The associations are run using five sets of genetic variants: unitigs, gene presence/absence, rare variants (i.e. gene burden test), gene-cluster-specific k-mers and all unitigs jointly. All variants passing the association threshold are further annotated to identify overrepresented biological processes and pathways. The results can be further augmented by generating a phylogenetic tree and predicting the presence of antimicrobial resistance and virulence-associated genes. We tested the microGWAS pipeline on a previously reported dataset on Escherichia coli virulence, successfully identifying the causal variants and providing further interpretation of the association results. The microGWAS pipeline integrates state-of-the-art tools to perform bacterial GWAS into a single, user-friendly and reproducible pipeline, allowing for the democratization of these analyses. The pipeline, together with its documentation, can be accessed at https://github.com/microbial-pangenomes-lab/microGWAS.
Proteomics-based models of gene expression and cellular control of cotton fiber development
Authors: Lee Youngwoo , Yang Pengcheng , Rani Heena , Miller Gideon , Grover Corrinne E , Swaminathan Sivakumar , Zabotina Olga A , Wendel Jonathan F , Xie Jun , Szymanski Daniel B
Published: February 2025

The cotton textile industry is based on the material properties of terminally differentiated trichoblasts. Tens of thousands epidermal trichoblasts emerge from the seed coat and march through a reproducible developmental program that includes interconversion between cell-autonomous and tissue-based morphogenesis. Proteomic analyses of purified fibers provide a way to associate molecules with cellular processes that directly affect morphological transitions and material properties of the harvested cells. However, insufficient temporal sampling and poor protein coverage have limited the extent to which proteomic data predict control mechanisms. Here we quantified the subcellular proteomes of purified fibers daily over a 20-day interval that includes diverse modes of elongation and cell wall remodeling. Thousands of reliable protein abundance profiles were assigned to expression groups and tested for associations with a broad array of phenotypes. Integration of proteomic and RNA-sequencing data revealed distinct modes of transcriptional and post-transcriptional control. Collectively these datasets provide large-scale gene function predictions that can serve as a toolkit to engineer cotton material properties.
How does DeepSeek-R1 perform on USMLE?
Authors: Faray de Paiva Lisle , Luijten Gijs , Puladi Behrus , Egger Jan
Published: February 2025

DeepSeek, a Chinese artificial intelligence company, released its first free chatbot app based on its DeepSeek-R1 model. DeepSeek provides its models, algorithms, and training details to ensure transparency and reproducibility. Their new model is trained with reinforcement learning, allowing it to learn through interactions and feedback rather than relying solely on supervised learning. Reports showcase that DeepSeek’s model shows competitive performances against established large language models (LLMs) such as Anthropic’s Claude and OpenAI’s GPT-4o on established benchmarks in language understanding, mathematics (AIME 2024) and programming (Codeforces) while trained at a fraction of the costs. Additionally, running inference shows significantly lower costs, leading to DeepSeek surpassing ChatGPT as the most downloaded free app on the American iOS App Store. This development contributed to a nearly 17% drop in Nvidia’s share price, resulting in the most significant one-day loss in U.S. history, amounting to nearly $600 billion. The open-source models also bring a significant shift in the healthcare system, allowing cost-efficient medical LLMs to be deployed within hospital networks. To understand its performance in the healthcare sector, we analyse the new DeepSeek-R1 model on the United States Medical Licensing Examination (USMLE) and compare it to ChatGPT.
The Landscape of Prostate Tumour Methylation
Authors: Arbet Jaron , Yamaguchi Takafumi N. , Shiah Yu-Jia , Hugh-White Rupert , Wiggins Adriana , Oh Jieun , Gebo Tsumugi , Foucal Adrien , Lesurf Robert , Jung Chol-Hee , Dang Rachel M. A. , Agrawal Raag , Livingstone Julie , Salcedo Adriana , Yao Cindy Q. , Espiritu Shadrielle Melijah G. , Houlahan Kathleen E. , Yousif Fouad , Heisler Lawrence E , Fraser Michael , Kishan Amar , Berlin Alejandro , Chua Melvin LK , van der Kwast Theodorus , Hovens Christopher M. , Bristow Robert G. , Boutros Paul C.
Published: February 2025

Prostate cancer is characterized by profound heterogeneity in its clinical trajectory. While genomic heterogeneity has been well-characterized, epigenomic heterogeneity remains less understood. To fill this gap, we compiled 2,149 multi-ancestric prostate methylomes spanning normal tissue through localized disease of varying grades to poly-metastatic disease, most with multi-omic DNA and/or RNA characterization. We identify four subtypes that varied by stage, grade and mutational subtype. We identify extensive interplay between DNA ploidy and DNA methylation, with transcriptional consequences that vary across driver-genes. Each major prostate cancer driver gene mutation triggers a specific epigenetic dysregulation, and we define a set of 14 reusable models that accurately predict clinico-molecular features of a prostate cancer from DNA methylation data. Specific epigenetic features predict disease aggression, including metastasis, with epigenomic and genomic features synergizing to optimize predictions. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs, and subsequent clinical presentation.
Accelerated memory T cell decline and tolerogenic recall responses to SARS-CoV-2 vaccination in diabetes
Authors: Jones Emma M , Sourij Caren , Stradner Martin , Schlenke Peter , Sereban Nazanin , Moser Othmar , Quinlan Rachael , Short Charlotte-Eve , Harris Benjamin H L , Fertleman Michael , Taylor Graham P , Oliver Nick , Sourij Harald , Dominguez-Villar Margarita
Published: February 2025

Type 1 and type 2 diabetes are associated with increased severity and mortality from respiratory virus infections, including SARS-CoV-2. Vaccination in the general population significantly reduces the risk of severe respiratory viral infection and triggers a strong, polyfunctional and lasting T cell response in healthy individuals. However, vaccine effectiveness in people with diabetes is unclear. Here we studied the magnitude and functional characteristics of vaccine-specific CD4+and CD8+T cell responses to the full vaccination protocol, and the recall response after a third booster dose of SARS-CoV-2 vaccine in people with type 1 and type 2 diabetes, and compared them to those of people without diabetes. We found defects in both CD4+and CD8+T cell memory maintenance and the functionality of the vaccine specific T cells in people with diabetes compared to people without. In those individuals with diabetes that harbored detectable vaccine-specific T cells, they displayed an unfocused, tolerogenic phenotype characterized by increased expression of IL-13 and IL-10 in T1D and T2D compared to people without diabetes. These results have implications for vaccination strategies for people with diabetes.
Real-world visual search goes beyond eye movements: Active searchers select 3D scene viewpoints too
Authors: Wu Tiffany C. , Tsotsos John K.
Published: February 2025

Visual search is a ubiquitous task; people search for objects on a daily basis. However, the majority of the existing visual search literature focuses on passive search on a 2D computer screen, a far cry from emulating a real-world environment. Search is a real-world task that involves active observation. Search targets may be occluded, completely out of the observer’s line of sight, or oriented in unconventional ways. This is typically mitigated by actively selecting viewpoints, an important aspect of search behaviour with limited scope on a computer screen. Our goal was to explore viewpoint selection in active visual search. Subject eye and head movements were tracked as they moved freely while searching for toy objects in a controlled 3-dimensional environment, yielding the first such record of search-driven viewpoint selection. We found that subjects utilized their full range of eye and head motion to move from viewpoint to viewpoint, apparently employing a variety of objectives including changing viewing height and pose depending on object 3D pose. Subjects were also adept at selecting unobstructed views to search through otherwise occluded areas with objects. Furthermore, subjects completed the search task with high accuracy, even with no training on the environment. Although no learning was found in terms of accuracy over the duration of the experiment, increases in efficiency were found for other metrics such as response time, number of fixations, and distance travelled, particularly in target present trials where the target was not visible from the starting location. These results paint the story of a visual system that selects and moves to useful and informative views to facilitate the successful execution of an active visual search task, and stresses the significance of active vision research in understanding how vision is used in naturalistic environments.
Comprehensive analysis of αβT-cell receptor repertoires reveals signatures of thymic selection
Authors: Luppov Daniil V. , Vlasova Elizaveta K. , Chudakov Dmitry M. , Shugay Mikhail
Published: February 2025

Thymic selection is a multi-stage process that establishes a T-cell immunity that is efficient in fighting diverse foreign pathogens, while not being self-reactive. During the process, T-cell receptor (TCR)α and β chains are rearranged to form a highly diverse set of heterodimers that are selected based on their affinity to peptides presented by major histocompatibility molecules (MHC) in the thymus. Here we employ high-throughput TCR sequencing data, theoretical model of TCR rearrangement and dedicated statistical methods to infer how the selection process affects human TCR repertoire on different scales. On a global scale, our results indicate differences in V(D)J gene usage, complementarity determining region 3 (CDR3) amino acid composition, CDR3 physicochemical properties, k-mer composition and differences in loop structure induced by the selection process. On a local scale, we were able to determine enriched TCR motifs and “holes” in repertoire induced by positive and negative selection and characterize their features. Finally, we demonstrated how TCR sequence composition affects lineage commitment via thymic selection and highlighted the effect of individual MHC haplotype. Our results can aid in identification of potentially self-reactive TCRs in donor repertoires in autoimmunity and immunotherapy studies.

Graphical abstract

Study overview.

A.Datasets used in the study and the way TCR sequences were analyzed.B.Main directions in which thymic selection shapes TCR repertoire. Selection results in TCR-CDR3 losing positively charged and large amino-acids while increasing its flexibility. Unlike CDR3 of the TCRα chain, CDR3β hydrophobicity is also increased by selection. CDR3s carrying Cysteines and glycosylation sites are unlikely to pass the selection. In contrast, CDR3 carrying poly-Glycine regions are more likely to be selected for both chains. T-cells committed to CD8+ lineage were more likely to feature bulged CDR3s compared to CD4+.C.CDR3s enriched after thymic selection guide lineage commitment according to single-cell RNA sequencing data analysis, e.g. the MAIT cells and CD8+ phenotypes.D.Enrichment and depletion of certain TCR motifs pinpoint fine-structure of post-selection repertoires, as inferred by sequence neighborhood analysis.E.Comparative analysis of enriched and depleted TCR clusters in monozygotic twins revealed that the selection process is shaped by HLA haplotype.
Spatio-temporal distribution patterns and ecological correlates of new mammal records in China
Authors: Ding Chenchen , Ding Jiale , Qiao Huijie , Jiang Zhigang , Wang Zhiheng
Published: February 2025

Abstract

Species’ geographic distributions are central to research in biogeography, macroecology, and conservation biology. However, incomplete or inaccurate knowledge about their spatiotemporal ranges—known as the Wallacean shortfall—hampers our understanding of biodiversity patterns and processes. In this study, we systematically reviewed 192 papers that reported new distribution records of China’s mammals from 2001 to 2023, covering 150 species in 26 families across 7 orders. We examined the taxonomic, spatiotemporal, and biogeographic characteristics of these newly recorded species. We used Bayesian Phylogenetic Generalized Linear Mixed Models (BPGLMM) to assess how intrinsic traits and extrinsic factors influenced the likelihood of discoveries and partial Poisson regressions to evaluate how species-level attributes, environmental and socio-economic factors shaped the number of new occurrence records across provinces. Our results showed that Chiroptera (n=69), Eulipotyphla (n=26) and Rodentia (n=23) had the highest number of new records. Among provinces, Yunnan (n=31), Guangdong (n=22), and Xizang (n=18) yielded the most newly recorded species. The amount of annual discoveries varied and peaked between 2017 and 2021. The Western Mountain and Plateau (n=39) and the East Hilly Plain (n=33) zoogeographic subregions had the greatest number of newly recorded species, including two new records extending into historically unrecognized zoogeographic realms. Notably, 61 (40.7%) species were found to extend towards the north or northeast of their known ranges, and 32 (21.3%) eastward, mainly due to the sampling bias. Smaller-bodied species and those with broader habitat ranges are more likely to yield new records, and the total number of new records was positively correlated with regional species richness and current survey efforts (r > 0.5, p < 0.05). These findings expand the known distributions of China’s mammals and provide essential data for mitigating the Wallacean shortfall. They underscore the urgent need for intensified surveys in biodiversity-rich, underexplored regions—especially targeting small-bodied, data-deficient taxa—and for timely updates and data-sharing to better inform conservation strategies.
Protein language models accelerate the discovery of Plastic-Degrading Enzymes
Authors: Medina-Ortiz David , Alvarez-Saravia Diego , Soto-García Nicole , Sandoval-Vargas Diego , Aldridge Jacqueline , Rodríguez Sebastián , Andrews Barbara , Asenjo Juan A. , Daza Anamaría
Published: February 2025

Plastic pollution presents a critical environmental challenge, necessitating innovative and sustainable solutions. In this context, biodegradation using microorganisms and enzymes offers an environmentally friendly alternative. This work introduces an AI-driven frame-work that integrates machine learning (ML) and generative models to accelerate the discovery and design of plastic-degrading enzymes. By leveraging pre-trained protein language models and curated datasets, we developed seven ML-based binary classification models to identify enzymes targeting specific plastic substrates, achieving an average accuracy of 89%. The framework was applied to over 6,000 enzyme sequences from the RemeDB to classify enzymes targeting diverse plastics, including PET, PLA, and Nylon. Besides, generative learning strategies combined with trained classification models in this work were applied forde novogeneration of PET-degrading enzymes. Structural bioinformatics validated potential candidates throughin-silicoanalysis, highlighting differences in physicochemical properties between generated and experimentally validated enzymes. Moreover, generated sequences exhibited lower molecular weights and higher aliphatic indices, features that may enhance interactions with hydrophobic plastic substrates. These findings highlight the utility of AI-based approaches in enzyme discovery, providing a scalable and efficient tool for addressing plastic pollution. Future work will focus on experimental validation of promising candidates and further refinement of generative strategies to optimize enzymatic performance.
RNA-EFM : Energy based Flow Matching for Protein-conditioned RNA Sequence-Structure Co-design
Authors: Abir Abrar Rahman , Zhang Liqing
Published: February 2025

Ribonucleic acids (RNAs) are essential biomolecules involved in gene regulation and molecular recognition. Designing RNA molecules that can bind specific protein targets is crucial for therapeutic applications but remains challenging due to the structural flexibility of RNA and the laborious nature of experimental techniques. We proposeRNA-EFM, a novelEnergy-basedFlowMatching framework for protein-conditioned RNA sequence and structure co-design. RNA-EFM integrates biophysical constraints, including the Lennard-Jones potential and sequence-derived free energy, to generate low-energy and biologically plausible RNA conformations. By incorporating an idempotent refinement strategy for iterative structural correction, RNA-EFM consistently outperforms existing baselines, achieving lower RMSD, higher lDDT, and superior sequence recovery across multiple evaluation splits.
Dual Translational Control in Cardiomyocytes by Heterogeneous mTORC1 and Hypertrophic ERK Activation
Authors: Uchida Keita , Scarborough Emily A. , Prosser Benjamin L.
Published: February 2025

Background

Cardiac hypertrophy allows post-mitotic cardiomyocytes to meet increased hemodynamic demands but can predispose the heart to adverse clinical outcomes. Despite its central role in cardiac adaptation, the translational control mechanisms that drive cardiac hypertrophy are poorly understood. In this study, we elucidate the relative contributions of the various translational control mechanisms operant during homeostasis and hypertrophic growth.

Methods

A combination of immunofluorescence and single myocyte protein synthesis assays were used to dissect the single-cardiomyocyte mechanisms of translational control under basal and hypertrophic conditions in isolated adult rat cardiomyocytes. Translational control mechanism were examined in a mouse model of acute hypertrophic phenylephrine (PE) stimulation prior to overt cardiac growth.

Results

We observed strikingly heterogeneous activity of mTORC1, the master regulator of translation, across cardiomyocytes bothin situandex vivo. Heterogeneous mTORC1 activity drove heterogeneous protein synthesis, with translation primarily controlled via canonical mTORC1-dependent 4EBP1 phosphorylation at Thr36/Thr45/Thr69 under baseline conditions. Hypertrophic PE stimulation recruited more cardiomyocytes into a high mTORC1 activity state. PE induced a switch in 4EBP1 phosphorylation by increasing mTORC1-dependent phosphorylation at Thr36/Thr45, but not Thr69. Further, PE induced a novel mTORC1-independent, but MEK-ERK-dependent, pathway driving 4EBP1 phosphorylation at Ser64 in both isolated cardiomyocytes andin vivo. Ribosome biogenesis was also observed within hours upon hypertrophic stimulation, while the mTORC1-S6K-eEF2K-eEF2 pathway was not found to be a major driver of protein translation.

Conclusions

Protein synthesis is heterogeneous across cardiomyocytes driven by heterogeneous mTORC1 activity. MEK-ERK signaling directly controls 4EBP1 phosphorylation to augment translation during cardiac hypertrophy and challenges the canonical model of translation initiation.

Key points:

mTORC1 activity is low and heterogeneous across cardiomyocytes at baseline.

Heterogeneous mTORC1 activity drives variable 4EBP1 phosphorylation at Thr36/Thr45/Thr69, resulting in heterogeneous protein translation.

Phenylephrine stimulation recruits more cardiomyocytes into a high mTORC1 activity state to augment protein synthesis through 4EBP1 phosphorylation at Thr36/Thr45, but not Thr69.

Phenylephrine stimulation boosts protein translation through mTORC1-independent but ERK-dependent phosphorylation of 4EBP1 at Ser64.

mTORC1-S6K-eEF2K-eEF2 pathway is not a major driver of global protein translation.

Ribosome biogenesis is observed within hours after hypertrophic stimulation.

The data demonstrates a dual input model of mTORC1 and ERK dependent phosphorylation of 4EBP1 to regulate protein translation in cardiomyocytes.
A fluorescent folding reporter uncovers myosin misfolding as a driver of Hypertrophic Cardiomyopathy
Authors: Arnese Renato , Dexheimer Philipp Julian , Escobar-Doncel Beatriz , Krüger Lotta , Adhikari Govinda , Krpan Nina , Sehr Daria , Kley Juliane , Deszcz Luiza , Meinhart Anton , Kirstein Janine , Clausen Tim
Published: February 2025

Hypertrophic cardiomyopathy (HCM) is a fatal genetic disorder causing the thickening of ventricular walls in the heart muscle. While certain mutations in cardiac myosin deregulate ATPase activity, the pathology mechanism of most HCM mutations is not known. Here, by designing a fluorescent reporter to monitor myosin folding in cells, we uncovered a distinct class of HCM mutations that cause graded defects in myosin maturation. UsingC. elegansas a disease model, we found that folding deficient HCM variants cause myofilament disruption, impaired motility, and reduced lifespan. Dietary restrictions resulted in a near-complete recovery from these detrimental defects by activating autophagy pathways through insulin/TOR signaling. In conclusion, our study identifies myosin misfolding as an important driver of HCM, revealing therapeutic opportunities to counteract muscle protein disorders.
From ancient fears to airborne threats: fMRI insights into neural fear responses
Authors: Rádlová Silvie , Pidnebesna Anna , Chomik Aleksandra , Tomeček David , Hlinka Jaroslav , Frynta Daniel , Landová Eva
Published: February 2025

Threat perception is a fundamental aspect of human cognition, shaped by evolutionary pressures and modern environmental demands. While ancestral threats (e.g., snakes) have been shown to elicit stronger neural responses than modern threats (e.g., guns), less is known about how the brain processes airborne threats, such as depictions of individuals wearing face masks. This fMRI study investigates neural responses to ancestral, modern, and airborne threats to identify shared and distinct activation patterns.

Sixty participants viewed visual stimuli from the three categories while undergoing fMRI scanning. Results showed heightened activation in the fear-processing network for all affective stimuli. In addition, activation of the ventral attention network was found for the ancestral threats. Modern threats elicited less intense responses, primarily engaging cortical regions associated with context-specific analysis. Notably, airborne threats elicited neural responses of similar intensity to ancestral threats but activated cortical regions overlapping with those for modern threats. This dual pattern highlights the brain’s capacity to integrate evolutionary biases with socially constructed threat awareness. These findings underscore the importance of recognizing airborne threats as a unique category of threat processing, with implications for public health and mental well-being.
Refining type and timing of measured crop variables for the calibration of a new winter wheat cultivar in the STICS crop model
Authors: Gawinowski Meije , Aubry Maël , Buis Samuel , Garcia Cécile , Deswarte Jean-Charles , Bancal Marie-Odile , Launay Marie
Published: February 2025

Crop models need to be regularly upgraded with parametrization for new cultivars but this requires calibration, which is a major challenge. With winter wheat cultivar Rubisko as a case study, we propose to apply a calibration protocol to estimate the parameters of this new cultivar with multi-trials experimental data. We tested the calibration protocol in different conditions including or not LAI and/or biomass experimental data and we found that the resulting LAI and biomass dynamics strongly diverge. Several key findings emerge from this study: (1) RUE parameters should be excluded from the calibration process, as their critical role in biomass dynamics causes the optimization algorithm to treat them as adjustment parameters, resulting in unrealistic values for multiple parameters; (2) either LAI or biomass variables alone are sufficient for calibration, enabling experimental efforts to focus on one variable rather than both; and (3) the use of a synthetic dataset has facilitated the identification of the optimal type and timing of data collection needed to parameterize a new variety in the model. Moreover, the proposed methodology offers extrapolatable solutions applicable to other contexts (e.g., different models or datasets) and provides guidance on acquiring the most effective dataset for optimal calibration. The unbalanced structure of our dataset also highlighted the need to mobilize other calibration criteria (weighted RMSE) and alternative solutions to bridge the gap between quantitative metrics and empirical visual assessments.
RAB23loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome
Authors: Leong WY , Tung WL , Chui WH , Wilkie Andrew O M , Hor CHH
Published: February 2025

The primary cilium is a signal transduction organelle whose dysfunction clinically causes ciliopathies in humans. RAB23 is a small GTPase known to regulate the Hedgehog signalling pathway and ciliary trafficking. Mutations ofRAB23in humans lead to Carpenter syndrome (CS), an autosomal recessive disorder clinically characterized by craniosynostosis, polysyndactyly, skeletal defects, obesity, and intellectual disability. Although the clinical features of CS bear some resemblance to those of ciliopathies, the exact relationship between the pathological manifestations of CS and the ciliary function ofRAB23remains ambiguous. Besides, thein vivociliary functions ofRAB23remain poorly characterised.

Here, we demonstratein vivoandin vitro Rab23loss-of-function mutants modelling CS, includingRab23conditional knockout (CKO) mouse mutants, CS patient-derived induced pluripotent stem cells (iPSCs), and zebrafish morphants. TheRab23-CKO mutants exhibit multiple developmental and phenotypical traits recapitulating the clinical features of human ciliopathies and CS, indicating a causal link between the loss ofRab23and ciliopathy. In line with the ciliopathy-like phenotypes, all three different vertebrate mutant models consistently show a perturbation of primary cilia formation, intriguingly, in a context-dependent manner.In vivoexamination of primary cilia inRab23-CKO mutants reveals profound cell-type specific ciliary abnormalities in chondrocytes and neocortical neurons, but not in epithelial cells, cerebellar granule cells and hippocampus neurons. A profound reduction in ciliation frequency and/or shortening of primary cilia was observed in the neurons and neural progenitor cells derived from CS patient iPSCs. Furthermore,Rab23-KO neural progenitor cells were desensitized to primary cilium-dependent activation of the Hedgehog signaling pathway. Collectively, these findings indicate that the absence ofRAB23causes dysfunctional primary cilia in a cell-type distinctive manner, which underlies the pathological manifestations of CS. Our findings present the firstin vivoevidence validating the unique context-specific function ofRAB23in the primary cilium. Through the use of patient-derived iPSCs differentiated cells, we present direct evidence of primary cilia anomalies in CS, thereby confirming CS as a ciliopathy disorder.
Dietary manipulation of intestinal microbes prolongs survival in a mouse model of Hirschsprung disease
Authors: Tjaden Naomi E. Butler , Liou Megan J. , Sax Sophie E. , Lassoued Nejia , Lou Meng , Schneider Sabine , Beigel Katherine , Eisenberg Joshua D. , Loeffler Emma , Anderson Sierra E. , Yan Guang , Litichevskiy Lev , Dohnalová Lenka , Zhu Yixuan , Jin Daniela Min Jing Che , Raab Jessica , Furth Emma E. , Thompson Zachary , Rubenstein Ronald C. , Pilon Nicolas , Thaiss Christoph A. , Heuckeroth Robert O.
Published: February 2025

Enterocolitis is a common and potentially deadly manifestation of Hirschsprung disease (HSCR) but disease mechanisms remain poorly defined. Unexpectedly, we discovered that diet can dramatically affect the lifespan of a HSCR mouse model (Piebald lethal,sl/sl) where affected animals die from HAEC complications. In thesl/slmodel, diet alters gut microbes and metabolites, leading to changes in colon epithelial gene expression and epithelial oxygen levels known to influence colitis severity. Our findings demonstrate unrecognized similarity between HAEC and other types of colitis and suggest dietary manipulation could be a valuable therapeutic strategy for people with HSCR.

Hirschsprung disease (HSCR) is a birth defect where enteric nervous system (ENS) is absent from distal bowel. Bowel lacking ENS fails to relax, causing partial obstruction. Affected children often have “Hirschsprung disease associated enterocolitis” (HAEC), which predisposes to sepsis. We discovered survival ofPiebald lethal(sl/sl) mice, a well-established HSCR model with HAEC, is markedly altered by two distinct standard chow diets. A “Protective” diet increased fecal butyrate/isobutyrate and enhanced production of gut epithelial antimicrobial peptides in proximal colon. In contrast, “Detrimental” diet-fedsl/slhad abnormal appearing distal colon epithelium mitochondria, reduced epithelial mRNA involved in oxidative phosphorylation, and elevated epithelial oxygen that fostered growth of inflammation-associatedEnterobacteriaceae. Accordingly, selective depletion ofEnterobacteriaceaewith sodium tungstate prolongedsl/slsurvival. Our results provide the first strong evidence that diet modifies survival in a HSCR mouse model, without altering length of distal colon lacking ENS.

Highlights

Two different standard mouse diets alter survival in thePiebald lethal(sl/sl) mouse model of Hirschsprung disease, without impacting extent of distal colon aganglionosis (the region lacking ENS).

Piebald lethalmice fed the “Detrimental” diet had many changes in colon epithelial transcriptome including decreased mRNA for antimicrobial peptides and genes involved in oxidative phosphorylation. Detrimental diet fedsl/slalso had aberrant-appearing mitochondria in distal colon epithelium, with elevated epithelial oxygen that drives lethalEnterobacteriaceaeovergrowth via aerobic respiration.

Elimination ofEnterobacteriaceaewith antibiotics or sodium tungstate improves survival ofPiebald lethalfed the “Detrimental diet”.

Graphical abstract
Non-target effects on the soil microbiome of a plant root exudate biocontrol for Fusarium wilt
Authors: Torres-Bedoya Eliana , Studholme David J. , Warmington Rachel , Bebber Daniel P.
Published: February 2025

Crop rotation and intercropping withAlliumspp. (e.g. garlic, onion) are recognized as biological controls of Fusarium wilt in several crops. However, the non-target effects of this strategy on the soil microbiome are largely unknown. We evaluated the effect of cultivatingMusa basjoo,Allium tuberosum(Chinese leek), and their co-cultivation on the rhizosphere and bulk soil microbiome under glasshouse conditions. We do not report the impact of Chinese leek on Foc abundances, as this has been previously reported. The bacterial and fungal communities in the rhizosphere and bulk soil varied depending on the plant type. The microbiomes of allium and bananas were consistently dissimilar, and the co-cultivation treatment contained constituent taxa from both. However, the effect of allium on soil community composition was outweighed by that of bananas in the co-cultivation scenario. Discriminative taxa for allium included members of the generaSphingomonas, Microbacterium, Flavihumibacter, Brevundimonas, Pseudolabrys, Ramlibacter, Trichoderma, MortierellaandFusarium. In the case of bananas, predominant biomarkers encompassed members ofRhizobacter, Noviherbaspirillum, Pseudarthrobacter, Aquabacterium, Pseudomonas, TausoniaandHumicolaBiomarkers and predictions of functional gene abundances suggest that shifts in the soil microbiome induced by allium are correlated with increases in microorganisms exhibiting potential disease suppression and antibiotic or antifungal traits, whereas those in bananas are associated with plant-growth-promoting microorganisms. The biocontrol efficacy of allium co-cultivation may there involve shifts in the soil microbiome as well as direct impacts of root exudate chemistry onFusariumplant pathogens.
Persistent Disruptions in Prefrontal Connectivity Despite Behavioral Rescue by Environmental Enrichment in a Mouse Model of Rett Syndrome
Authors: Ährlund-Richter Sofie , Harpe Jonathan , Fernandes Giselle , Lam Ruby , Sur Mriganka
Published: February 2025

Rett Syndrome, a neurodevelopmental disorder caused by loss-of-function mutations in theMECP2gene, is characterized by severe motor, cognitive and emotional impairments. Some of the deficits may result from changes in cortical connections, especially downstream projections of the prefrontal cortex, which may also be targets of restoration following rearing conditions such as environmental enrichment that alleviate specific symptoms. Here, using a heterozygousMecp2+/−female mouse model closely analogous to human Rett Syndrome, we investigated the impact of early environmental enrichment on behavioral deficits and prefrontal cortex connectivity. Behavioral analyses revealed that enriched housing rescued fine motor deficits and reduced anxiety, with enrichment-housedMecp2+/−mice performing comparably to wild-type (WT) controls in rotarod and open field assays. Anatomical mapping of top-down anterior cingulate cortex (ACA) projections demonstrated altered prefrontal cortex connectivity inMecp2+/−mice, with increased axonal density in the somatosensory cortex and decreased density in the motor cortex compared to WT controls. ACA axons revealed shifts in hemispheric distribution, particularly in the medial network regions, withMecp2+/−mice exhibiting reduced ipsilateral dominance. These changes were unaffected by enriched housing, suggesting that structural abnormalities in prefrontal cortex connectivity persist despite behavioral improvements. Enriched housing rescued brain-derived neurotrophic factor (BDNF) levels in the hippocampus but failed to restore BDNF levels in the prefrontal cortex, consistent with the persistent deficits observed in prefrontal axonal projections. These findings highlight the focal nature of changes induced by reduction of MeCP2 and by exposure to environmental enrichment, and suggest that environmental enrichment starting in adolescence can alleviate behavioral deficits without reversing abnormalities in large-scale cortical connectivity.
Neurons in the inferior colliculus use multiplexing to encode features of frequency-modulated sweeps
Authors: Drotos Audrey C. , Wajdi Sarah Z. , Malina Michael , Silveira Marina A. , Williamson Ross S. , Roberts Michael T.
Published: February 2025

Within the central auditory pathway, the inferior colliculus (IC) is a critical integration center for ascending sound information. Previous studies have shown that many IC neurons exhibit receptive fields for individual features of auditory stimuli, such as sound frequency, intensity, and location, but growing evidence suggests that some IC neurons may multiplex features of sound. Here, we used in vivo juxtacellular recordings in awake, head-fixed mice to examine how IC neurons responded to frequency-modulated sweeps that varied in speed, direction, intensity, and frequency range. We then applied machine learning methods to determine how individual IC neurons encode features of FM sweeps. We found that individual IC neurons multiplex FM sweep features using various strategies including spike timing, distribution of inter-spike intervals, and first spike latency. In addition, we found that decoding accuracy for sweep direction can vary with sweep speed and frequency range, suggesting the presence of mixed selectivity in single neurons. Accordingly, using static receptive fields for direction alone yielded poor predictions of neuron responses to vocalizations that contain simple frequency changes. Lastly, we showed that encoding strategies varied across individual neurons, resulting in a highly informative population response for FM sweep features. Together, our results suggest that multiplexing sound features is a common mechanism used by IC neurons to represent complex sounds.
Molecularly-guided spatial proteomics captures single-cell identity and heterogeneity of the nervous system
Authors: Dutta Sayan , Pang Marion , Coughlin Gerard M. , Gudavalli Sirisha , Roukes Michael L. , Chou Tsui-Fen , Gradinaru Viviana
Published: February 2025

Single-cell proteomics is an emerging field with significant potential to characterize heterogeneity within biological tissues. It offers complementary insights to single-cell transcriptomics by revealing unbiased proteomic changes downstream of the transcriptome. Recent advancements have focused on enhancing proteome coverage and depth, mostly in cultured cell lines, and a few recent studies have explored the potential of analyzing tissue micro-samples but were limited to homogenous peripheral tissues. In this current work, we utilize the power of spatial single cell-proteomics through immunostaining-guided laser capture microdissection (LCM) coupled with LC-MS to investigate the heterogenous central nervous system. We used this method to compare neuronal populations from cortex and substantia nigra, two brain regions associated with motor and cognitive function and various neurological disorders. Moreover, we used the technique to understand the neuroimmune changes associated with stab wound injury. Finally, we focus our application on the peripheral nervous system, where we compare the proteome of the myenteric plexus cell ganglion to the nerve bundle. This study demonstrates the utility of spatial single-cell proteomics in neuroscience research toward understanding fundamental biology and the molecular drivers of neurological conditions.