bluuebunny/crossref_metadata_2025 huggingface dataset:
Variance spectrum scaling analysis for high-dimensional coordination in human movement
Authors: Dotov Dobromir , Gu Jingxian , Hotor Philip , Spyra Joanna
Published: January 2025

Coordinated movement has been essential to our evolution as a species but its study has been limited by ideas largely developed for one-dimensional data. The field is poised for a change by high-density recording tools and the popularity of data sharing. New ideas are needed to revive classical theoretical questions such as the organization of the highly redundant biomechanical degrees of freedom and the optimal distribution of variability for efficiency and adaptiveness. Methods have been focused on increasing dimensions: making inferences from one or few measured dimensions about the properties of a higher dimensional system. The opposite problem is to record 100+ kinematic degrees of freedom and make inferences about properties of the embedded manifold. We present an approach to quantify the smoothness and degree to which the manifold is distributed among embedding dimensions. The principal components of embedding dimensions are rank-ordered by variance. The power-law scaling exponent of this variance spectrum is a function of the smoothness and dimensionality of the embedded manifold. It defines a threshold value beyond which the manifold becomes non-differentiable. We verified this approach by showing that the Kuramoto model close to global synchronization in the upper critical end of the coupling parameter obeys the threshold. Next, we tested if the scaling exponent was sensitive to participants’ gait impairment in a full-body motion capture dataset containing short gait trials. Variance scaling was highest in the healthy individuals, followed by osteoarthritis patients after hip-replacement, and lastly, the same patients pre-surgery. Thinking about manifold dimensionality, smoothness, and scaling could inform classic problems in movement science and exploration of the biomechanics of full-body action.
Descriptron: Testing Artificial Intelligence for Automating Taxonomic Species Descriptions with a User-friendly Software Package
Authors: Van Dam Alex R. , Serbina Liliya Štarhová
Published: January 2025

Recent advances in Computer Vision, Convolutional Neural Networks (CNNs), Vision Transformers (ViTs) and Large Language Models (LLMs) suggest that it may be possible to approach mimicking the ability to decode knowledge about morphology and taxonomy to describe species in an automated way. Here we test for the first time a current state-of-the-art Vision Language Model (VLM) to approximate taxonomic species descriptions in an automated manner. The test utilizes a new graphical user interface,Descriptron, that collects data about biological images and transmits this highly specialized knowledge to a VLM to decode the taxonomic knowledge encoded in labeled biological images with text. Our results indicate that current state-of-the-art VLM (GPT-4o) can produce automated species descriptions that with error correction approximate taxonomists’ ability to describe morphological features of species and organize them in taxonomic keys. However, the results are not without significant errors and the VLM requires the input of the taxonomists knowledge to prevent widespread hallucinations by the VLM. We find here that the taxonomist is clearly needed to both teach and closely supervise the VLM. However, the time saved by utilizingDescriptronis also significant. Taxonomists remain essential for teaching and closely supervising the VLM. The time saved by utilizingDescriptronare nevertheless already very significant. TheDescriptronprogram and supporting example prompt files are free to use under an Apache2 License available from:https://github.com/alexrvandam/Descriptron.
Conformation-gated binding drives negative cooperativity in ATP:cob(I)alamin Adenosyltransferase for optimized cobalamin handling
Authors: Yan Guangjie , Pan Manhua , Keller Aaron M. , Santiago Ace George , Lofgren Michael , Banerjee Ruma , Chen Peng , Chen Tai-Yen
Published: January 2025

Vitamin B12(cobalamin) is a high-value yet scarce cofactor required for various metabolic processes, making its efficient handling important for maintaining metabolic homeostasis. While the involvement of ATP:cob(I)alamin adenosyltransferases (MMAB) in the synthesis, delivery, and repair of 5’-deoxyadenosylcobalamin (AdoCbl) is well established, the kinetic mechanisms that regulate this process, particularly its negative cooperativity, remain poorly understood. Understanding these mechanisms is key to clarifying how MMAB efficiently uses AdoCbl, prevents resource wastage, and supports bacterial survival in nutrient-limited environments. Using single-molecule relative fluorescence (SRF) spectroscopy, we found that conformation-gated binding is the driving force behind MMAB’s preference for AdoCbl over hydroxocobalamin and is the underlying mechanism for negative cooperativity. This mechanism significantly slows down the binding of the second equivalent of AdoCbl, favoring the singly bound state. Our findings indicate that MMAB predominantly binds a single AdoCbl, optimizing the AdoCbl loading to methylmalonyl-CoA mutase. Additionally, our SRF approach also serves as a tool to explore other cofactor interactions, such as those between riboswitches and cobalamin derivatives, to provide insights into regulatory mechanisms of cobalamin sensing and gene regulation, which are crucial for bacterial adaptation to changing nutrient conditions.

Significance Statement

MMAB is important for B12-dependent propionate metabolism in bacteria. Our findings reveal that conformation-driven binding mechanism underlines the negative cooperativity of MMAB, as it favors the binding of the first AdoCbl while limiting further binding. The largerkonfor the first site, combined with similar unbinding rates for both sites, could provide a solution for optimizing cobalamin handling and minimize unnecessary waste. Our single-molecule fluorescence approach offers a powerful tool for investigating other dynamic cofactor interactions, providing new insights into regulatory mechanisms in bacterial metabolism.
Backbone and Sidechain1H,15N and13C Resonance Assignments of a Multidrug Efflux Membrane Protein using Solution and Solid-State NMR
Authors: Harding Benjamin D. , Hiett Ashley , Tonelli Marco , Wang Songlin , Rienstra Chad M. , Henzler-Wildman Katherine A.
Published: January 2025

EmrE is a bacterial membrane-embedded multidrug transporter that functions as an asymmetric homodimer. EmrE is implicated in antibiotic resistance, but is now known to confer either resistance or susceptibility depending on the identity of the small molecule substrate. Here, we report both solution- and solid-state NMR assignments of S64V-EmrE at pH 5.8, below the pKa of critical residues E14 and H110. This includes1H,15N, and13C resonance assignments of the backbone, methyl groups (isoleucine, leucine, valine, threonine and alanine) from solution NMR experiments in bicelles, and backbone and side-chain assignments from solid-state NMR13C-detected experiments in liposomes.
Ustilaginoidea virenssuppresses floral immunity through promoting GA biosynthesis by the effector SCRE9
Authors: Yu Siwen , Zhang Shaoqi , Zheng Xinhang , Li Xiaoai , Wang Jiyang , Duan Guohua , Qiu Shanshan , Zhao Dan , Nan Nan , Yu Qianheng , Jiang Chunquan , Peng Zhao , Li Dayong , Sun Wenxian
Published: January 2025

Rice false smut caused byUstilaginoidea virenshas become one of the most important rice diseases.U. virensspecifically infects rice florets through stamen filaments. However, it is mysterious howU. virensinhibits floral immunity for successful colonization. Here, we show that a small cysteine-rich effector SCRE9 is a key virulence factor inU. virens. Expression of SCRE9 in rice not only suppresses immune responses and false smut resistance, but also significantly increases expression of expansin and gibberellin (GA) biosynthetic genes and GA content in young rice panicles. We further demonstrate that OsSIP1 (SCRE9-interacting protein 1) in rice is targeted by SCRE9 and interacts with the OsMADS63 and OsMADS68 transcription factors that transcriptionally regulate the GA synthesis geneGA3ox1. Interestingly, the chloroplast-localized OsSIP1 recruits OsMADS63/68 into the chloroplast. SCRE9 causes OsSIP1 to be translocated into the nucleus, thereby releasing OsMADS63/68 from the chloroplast into the nucleus to promoteGA3ox1transcription. Therefore, SCRE9 promotes GA biosynthesis and expression of expansins in rice florets, thus loosening cell walls and overcoming the physical barrier duringU. virensinfection. The finding uncovers an unidentified floret infection strategy that offsets the deficiency in cell wall degrading ability in the unique floret colonizing fungus.
Tandem duplication of serpin genes yields functional variation and snake venom inhibitors
Authors: Ward Meilyn S. , Holding Matthew L. , Haynes Laura M. , Ginsburg David
Published: January 2025

Tandem duplication of genes can play a critical role in the evolution of functional novelty, but our understanding is limited concerning gene duplication’s role in coevolution between species. Much is known about the evolution and function of tandemly duplicated snake venom genes, however the potential of gene duplication to fuel venom resistance within prey species is poorly understood. In this study, we characterize patterns of gene duplication of the SERPINA subfamily of genes across in vertebrates and experimentally characterize functional variation in the SERPINA3-like paralogs of a wild rodent. We find the hallmarks of rapid birth-death evolution of SERPINA1-like and SERPINA3-like genes within and between rodent lineages. Next, we recombinantly expressed the 2 paralogous duplicates of SERPINA1 and 12 paralogous duplicates of SERPINA3 found in the genome of the big-eared woodrat (Neotoma macrotis), a species known to be resistant to protease-rich rattlesnake venoms. We found that two SERPINA3 paralogs inhibit snake venom serine proteases, indicating that these proteins have potential as resistance factors in SERPIN-mediated venom resistance. In addition, functional variation is apparent among paralogs, including neofunctionalization to inhibit both chymotrypsin-like and and trypsin-like proteases simultaneously for one venom-inhibiting paralog. Our results provide further evidence that the rapid evolution of SERPINA1 and SERPINA3 gene copy number across rodents has adaptive potential by producing functionally-diverse inhibitors.
An intranasal, NLC-delivered self-amplifying RNA vaccine establishes protective immunity against pre-pandemic H5N1 and H7N9 influenza
Authors: Ykema Matthew R. , Davis Michael A. , Kasal Darshan N. , Jennewein Madeleine F. , Lo Ethan , Singh Jasneet , Beaver Samuel , Cross Noah , Melief Eduard , Reed Sierra , Press Christopher , Fusco Pauline , Bakken Julie , Casper Corey , Hartwig Airn Tolnay , Gerhardt Alana , Bowen Richard A. , Voigt Emily A.
Published: January 2025

Seasonal and pandemic influenzas are continuous threats to human health, requiring rapid development of vaccines to multiple evolving viral strains. New RNA vaccine technologies have the adaptability and manufacturability to facilitate pandemic preparedness but have limited flexibility in their route of administration, reducing the ability to establish local protective immune responses such as respiratory mucosal immunity. Here, we describe monovalent and bivalent self-amplifying RNA (saRNA) vaccines against A/Vietnam/1203/2004 H5N1 and A/Anhui/2013 H7N9. These saRNA vaccines express either H5 or H7 hemagglutinin and are formulated with a nanostructured lipid carrier (NLC) that permits both intramuscular (IM) and intranasal (IN) dosing. In mice, IM vaccination established systemic humoral and cellular responses but no detectable mucosal response, while IN administration induced robust systemic and mucosal immunity. The saRNA-NLC vaccines provided complete protection against morbidity and mortality in ferret challenge models, establishing this intranasally-administered saRNA-NLC vaccine platform as a potential pandemic response tool.

ONE SENTENCE SUMMARY

A self-amplifying RNA-NLC vaccine, delivered intranasally, induces robust mucosal immunity in mice and protects against H5N1 and H7N9 in ferrets
When Stopping Requires Going; Physiological Similarities Between Action Cancellation and the Cancellation of Action Cancellation
Authors: Weber Simon , Salomoni Sauro E. , Hinder Mark R.
Published: January 2025

The reactive cancellation of real-world actions typically requires complex combinations of both muscle contraction and/or muscle suppression. However, current experimental paradigms solely examine contexts in which action cancellation requires muscle suppression. To provide fundamental insights into inhibitory control mechanisms, we directly compared the latency of action cancellation in novel paradigms where ‘stopping’ required either suppression of planned activation or reinstatement of ongoing activity.

20 healthy adults (mean age = 32.2 years) completed novel variants of the stop signal task (SST) in which each trial began with tonic force production to depress two buttons. When a go signal appeared, participants were required to release these buttons. On a subset of trials, a stop signal occurred after a brief delay, and participants were required to cancel the release of one of the buttons. Data in these variants were compared to conventional response-selective SSTs, in which the go signal required bilateral button presses and stop signals necessitated cancellation of one of these responses. Electromyographic (EMG) recordings allowed detailed comparison of the characteristics of muscle contraction and suppression (i.e., stopping speed) across these tasks.

When physiological evidence of synchronous action cancellation in both hands was observed (supporting recent models of complex stopping), EMG measures of action cancellation speed did not differ (p = 0.863, BF01 = 8.49) between cancellation of releases and cancellation of presses conditions. This result suggests that response inhibition may broadly characterise reactive control to maintain a current physiological state rather than specific cancellation of a voluntary response.
Merging conformational landscapes in a single consensus space with FlexConsensus algorithm
Authors: Herreros D. , Mata C.P. , Sorzano C.O.S. , Carazo J.M.
Published: January 2025

The analysis of structural heterogeneity in CryoEM is experimenting a significant breakthrough toward estimating more accurate, richer, and interpretable conformational landscapes directly derived from experimental data. The increasing number of new methods designed to tackle the heterogeneity challenge reflects these new paradigms, allowing users to understand protein dynamics better. However, a question remains on how the estimation of different heterogeneity algorithms compare, which is essential to properly determine the reliability, stability, and correctness of the conformational landscapes and the structural transitions extracted from the CryoEM images. The intrinsic differences arising from the approximation and implementation of every heterogeneity algorithm make the definition of a consensus complex, a problem that remains unsolved. To overcome the challenges of comparing heterogeneity algorithms, we introduce our new FlexConsenus algorithm in this work. FlexConsensus relies on a multi-autoencoder architecture to learn the commonalities and differences of several conformational landscapes, allowing one to place them in a shared consensus space with enhanced reliability. In addition, FlexConsensus enables the derivation of error metrics from the consensus space to measure the reproducibility of the heterogeneity estimations. Thanks to the previous consensus metrics, it is possible to clean the original particle datasets further based on the differences in the estimation of their structural variability among different algorithms and/or different runs, allowing users to focus their analysis only on those particles with a stable estimation of their structural variability.
The research trends and hotspots of NLRP3 inflammasome in Alzheimer’s disease: a bibliometric and visualization analysis
Authors: Wen Xuanwei , Yang Huiye , Chen Shuangxi , Xiao Zijian
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, the NLRP3 inflammasome has been shown to play a pivotal role in the pathogenesis of AD, and with increasing attention to its involvement in AD. Therefore, we applied bibliometric methods to describe the current research status of the NLRP3 inflammasome in AD. This study aims to analyze the research trends and hotspots in this field from 2013 to 2024, providing valuable insights for AD research.

Methods

We have selected research on the NLRP3 inflammasome in Alzheimer’s disease from the Web of Science Core Collection, with the time range from January 1, 2013, to November 30, 2024, and exported all publications in plain text format. Visualization analysis was performed using CiteSpace 6.4.R1, VOSviewer 1.6.20, and Scimago Graphica 1.0.46.

Results

A total of 759 publications related to the NLRP3 inflammasome in Alzheimer’s disease were included in this study. The number of annual publications showed a general upward trend. The top three countries in terms of publication volume were China, the United States, and Italy. The University of Manchester was the institution with the highest number of publications. The author with the most publications was Michael Heneka, while the most cited author was Eicke Latz. The International Journal of Molecular Sciences published the highest number of articles and was also the most frequently cited journal. The most common keywords included Alzheimer’s disease, NLRP3 inflammasome, neuroinflammation, Aβ, and microglia.

Conclusion

The primary research hotspots in this field focus on the role of NLRP3 in AD pathology, its potential as a therapeutic target, and strategies to modulate neuroinflammation through targeting the NLRP3 inflammasome. Future research should further investigate the interactions between NLRP3 and other molecular pathways, assess its clinical therapeutic potential, and provide new insights and strategies for the early diagnosis and treatment of AD.
Structural and functional characterization of integrin α5-targeting antibodies for anti-angiogenic therapy
Authors: Nguyen Adam , Heim Joel B. , Cordara Gabriele , Chan Matthew C. , Johannesen Hedda , Charlesworth Cristine , Li Ming , Azumaya Caleigh M. , Madden Benjamin , Krengel Ute , Meves Alexander , Campbell Melody G.
Published: January 2025

Integrins are a large family of heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1, also known as the fibronectin receptor, is a key mediator of angiogenesis and its dysregulation is associated with tumor proliferation, progression, and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful in large part due to efficacy and off-target effects. To mediate activation and signaling, integrins undergo drastic conformational changes. However, how therapeutics influence or are affected by integrin conformation remains incompletely characterized. Using cell biology, biophysics, and electron microscopy, we shed light on these relationships by characterizing two potentially therapeutic anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity and reduce angiogenesisin vitro. We demonstrate BIIG2 reduces tumor growth in two human xenograft mouse models and exhibits a strong specificity for connective tissue-resident fibroblasts and melanoma cells. Using electron microscopy, we map out the molecular interfaces mediating the integrin-antibody interactions and reveal that although both antibodies have overlapping epitopes and block fibronectin binding via steric hindrance, the effect on the conformational equilibrium is drastically different. While MINT1526A constricts α5β1’s range of flexibility, BIIG2 binds without restricting the available conformational states. These mechanistic insights, coupled with the functional analysis, guide which aspects should be prioritized to avoid off-target effects or partial agonism in the design of future integrin-targeted therapeutics.
ERGA-BGE genome ofErebia palaricaChapman, 1905: a montane butterfly endemic to North-West Iberia
Authors: Vila Marta , Torrado-Blanco Laura , Ryrholm Nils , Romero-Pedreira David , Conejero María , Böhne Astrid , Monteiro Rita , Marcussen Thomas , Oomen Rebekah , Struck Torsten Hugo , Aguilera Laura , Gut Marta , Ferreira Francisco Câmara , Rodriguez Fernando Cruz , Gómez-Garrido Jèssica , Alioto Tyler S. , Bortoluzzi Chiara
Published: January 2025

The reference genome ofErebia palaricawill provide valuable insights into evolutionary and conservation genomics. On one hand, the reference genome paves the way to unravel the speciation process, reproductive barriers, and putative hybridisation ofE. palaricawith its closely related sister species:Erebica meolans. On the other hand, the reference genome will play an important role in the genetic monitoring of this endemic species, facilitating the use of genomics to estimate population genomics parameters. The genome was assembled into 14 contiguous chromosomal pseudomolecules (Z chromosome included). This chromosome-level assembly encompasses 0.49 Gb, composed of 38 contigs and 17 scaffolds, with contig and scaffold N50 values of 34.2 Mb and 38.4 Mb, respectively.
ERGA-BGE genome of the Spanish Moon MothGraellsia isabellaeGraells, 1849: a nocturnal lepidopteran protected by the Habitats Directive
Authors: Vila Marta , Marí-Mena Neus , Vila Roger , Riesgo Ana , García-Souto Daniel , Lopez-Vaamonde Carlos , Böhne Astrid , Monteiro Rita , Marcussen Thomas , Oomen Rebekah , Struck Torsten Hugo , Gut Marta , Aguilera Laura , Ferreira Francisco Câmara , Rodriguez Fernando Cruz , Gómez-Garrido Jèssica , Alioto Tyler S. , Bortoluzzi Chiara
Published: January 2025

The reference genome of the Spanish Moon Moth,Graellsia isabellae, will be of great importance for evolutionary and conservation genomics. Firstly, this reference genome, alongside phylogenomic analyses, may finally resolve the longstanding debate regarding the scientific name of this iconic species—whether it should beGraellsia isabellae(Graells, 1849) orActias isabellae(Graells, 1849). Secondly, the reference genome will be instrumental in the genetic monitoring of this protected species, enabling advanced methods to calculate contemporary population genomics estimates. The genome was assembled into 31 contiguous chromosomal pseudomolecules (Z chromosome included). The mitochondrial genome has also been assembled and is 15,247 bp in length. This chromosome-level assembly encompasses 0.56 Gb, composed of 38 contigs and 32 scaffolds, with contig and scaffold N50 values of 18.9 Mb and 20.4 Mb, respectively.
PARAS: high-accuracy machine-learning of substrate specificities in nonribosomal peptide synthetases
Authors: Terlouw Barbara R. , Huang Chuan , Meijer David , Cediel-Becerra José D. D. , Rothe Marlene L. , Jenner Matthew , Zhou Shanshan , Zhang Yu , Fage Christopher D. , Tsunematsu Yuta , van Wezel Gilles P. , Robinson Serina L. , Alberti Fabrizio , Alkhalaf Lona M. , Chevrette Marc G. , Challis Gregory L. , Medema Marnix H.
Published: January 2025

Nonribosomal peptides are chemically and functionally diverse natural products with important applications in medicine and agriculture. Bacterial and fungal genomes contain thousands of nonribosomal peptide biosynthetic gene clusters (BGCs) of unknown function, providing a promising resource for peptide discovery. Core structural features of such peptides can be inferred by predicting the substrate(s) of adenylation (A) domains in nonribosomal peptide synthetases (NRPSs). However, existing approaches to A domain prediction rely on limited datasets and often struggle with domains selecting large substrates or from less-studied taxa. Here, we systematically curate and computationally analyse 3,254 A domains and present two new high-accuracy specificity predictors, PARAS and PARASECT. A new type of A domain with unusually high L-tryptophan specificity was identified through the application of PARAS, and intact protein mass spectrometry to the corresponding NRPS showed it to direct the production of tryptopeptin-related metabolites inStreptomycesspecies. Together, these technologies will accelerate the characterisation of novel NRPSs and their metabolic products.

PARAS and PARASECT are available athttps://paras.bioinformatics.nl.
Sinusoidal regulation denoises circadian machinery
Authors: Kaji Hotaka , Mori Fumito , Maruyama Osamu , Ito Hiroshi
Published: January 2025

The rhythms transmitted from the circadian clock inevitably fluctuate because of molecular noise. The level of period fluctuations, observed not in the circadian clock, but in the output system that receives the transmitted rhythm, varies according to the organism and cell type, ranging from 0.5% to 10%. However, it remains unclear how the signal transduction involved in this transmission affects the fluctuations in the oscillation period of the output system. To address this, we investigated a coupled system consisting of a circadian clock and its output. We numerically and analytically demonstrated that the rhythmic regulation through which the clock controls downstream gene expression affects the level of fluctuations in the output system. Moreover, Gibbs sampling based on the analytically obtained fluctuation formula confirmed that the sine-wave-like regulatory functions effectively minimized the fluctuation of the output system. These theoretical insights provide new perspectives on signal transduction as a denoising mechanism embodied in the circadian system.

Author summary

Recent single-cell observations have revealed that individual cells exhibit circadian rhythms with intrinsic variability. In particular, the period fluctuation, evaluated using the coefficient of variation (CV), was studied. In this study, we investigated how signal transduction from the central clock affects period fluctuations in the output system. We identified a key factor influencing these fluctuations: the waveform of the regulatory function by which the circadian clock governs the downstream output. We numerically demonstrated that the fluctuations vary widely depending on the regulatory function and that the sinusoidal function significantly reduced fluctuations in the output system. Furthermore, Gibbs sampling revealed that sine-like regulatory functions effectively minimized fluctuations. These findings suggest a preference for near-sinusoidal waveforms in the regulation of circadian rhythms.
A hermetically closed sample chamber enables time-lapse nano-characterization of pathogenic microorganismsin-vitro
Authors: Braun Esther , Andany Santiago H. , Kangül Mustafa , Asmari Navid S. , McKinney John D. , Fantner Georg E.
Published: January 2025

Pathogenic microorganisms, such as pathogenic mycobacteria, pose a global health burden. Studying these organisms is crucial for gaining detailed knowledge about the pathogens and the diseases they cause. To handle pathogenic organisms, specific biosafety measures appropriate to the virulence of the organism must be fulfilled, most importantly ensuring that all manipulations of pathogenic material are performed within a confined environment. Atomic force microscopy (AFM) is a powerful technique to study biological samples at nanometer-scale resolution, yielding also mechanical properties, all while maintaining physiological conditions. However, standard AFM sample holders do not meet stringent biosafety requirements since they do not constitute a confined system. AFM imaging relies on direct contact between the cantilever and the sample and is sensitive to mechanical interference, rendering conventional containment systems for handling infectious substances inapplicable. Here, we introduce a hermetically sealed AFM sample chamber that meets biosafety demands while satisfying the mechanical and optical constraints of correlated optical microscopy and AFM. We imaged various pathogenic mycobacteria to demonstrate the chamber’s versatility and effectiveness in containing biohazardous materials. This sample chamber enables high-resolution, time-lapse correlated imaging and biomechanical characterization of pathogenic microorganismsin-vitro. It broadens the scope of research with pathogenic microorganisms under safe and controlled conditions.
Phosphorylation patterns modulate the transient secondary structure of RNA polymerase II CTD without altering its global conformation
Authors: Chen (陳瑋) Wei , Laremore Tatiana N. , Yennawar Neela H. , Showalter Scott A.
Published: January 2025

The intrinsically disordered C-terminal domain (CTD) of RNA polymerase II coordinates transcription and co-transcriptional events through dynamic phosphorylation patterns. While it has been long hypothesized that phosphorylation induces structural changes in the CTD, a direct comparison of how different phosphorylation patterns modulate the CTD conformation has been limited. Here, we generated two distinct phosphorylation patterns in an essentialDrosophilaCTD region with the kinase Dyrk1a: one where Ser2 are primarily phosphorylated, mimicking the state near transcription termination, and a hyperphosphorylation state where most Ser2, Ser5, and Thr4 residues are phosphorylated, expanding on our work on Ser5 phosphorylation, which mimics early transcription elongation. Using13C Direct-Detect NMR, we show that the CTD has a tendency to form transient beta strands and beta turns, which is altered differently by Ser2 and Ser5 phosphorylation. Small angle x-ray scattering (SAXS) revealed no significant changes in the CTD global dimensions even at high levels of phosphorylation, contradicting the common assumption of phosphorylation-induced chain expansion. Our findings support a transient beta model in which unphosphorylated CTD adopts transient beta strands at Ser2 during transcription pre-initiation. These transient structures are disrupted by Ser5 phosphorylation in early elongation, and later restored by Ser2 phosphorylation near termination for recruiting beta turn-recognizing termination factors.
APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence
Authors: Xie Jingyi , Chen Daniel G. , Chour William , Ng Rachel H. , Zhang Rongyu , Yuan Dan , Choi Jongchan , McKasson Michaela , Troisch Pamela , Smith Brett , Jones Lesley , Webster Andrew , Rasheed Yusuf , Li Sarah , Edmark Rick , Hong Sunga , Murray Kim M. , Logue Jennifer K. , Franko Nicholas M. , Lausted Christopher G. , Piening Brian , Algren Heather , Wallick Julie , Magis Andrew T. , Watanabe Kino , Mease Phil , Greenberg Philip D. , Chu Helen , Goldman Jason D. , Su Yapeng , Heath James R.
Published: January 2025

Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this unique, comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8+ T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.
A diagnostic support system based on interpretable machine learning and oscillometry for accurate diagnosis of respiratory dysfunction in silicosis
Authors: Machado do Amaral Jorge Luís , Moraes de Sá Sousa Cíntia , de Oliveira Ribeiro Caroline , Morisco de Sá Paula , Lopes Agnaldo José , Lopes de Melo Pedro
Published: January 2025

Silicosis, the most dangerous and common lung illness associated with breathing in mineral dust, is a significant health concern. Spirometry, the traditional method for evaluating pulmonary functions, requires high patient compliance. Respiratory Oscillometry and electrical models are being studied to evaluate the respiratory system. This study aims to harness the power of machine learning (ML) to enhance the accuracy and interpretability of oscillometric parameters in silicosis. The data was obtained from 109 volunteers (60 in the training and 49 in the validation groups). Some supervised ML algorithms were selected for tests: K-Nearest Neighbors, Logistic Regression, Random Forest, CatBoost (CAT), Explainable Boosting Machines (EBM), and a deep learning algorithm. Two synthetic data generation algorithms were also applied. Initially, this study revealed the most accurate oscillometric parameter: the resonant frequency (fr, AUC=0.86), indicating a moderate accuracy (0.70-0.90). Next, original oscillometric parameters were used as input in the selected algorithms. EBM (AUC=0.93) and HyperTab (AUC=0.95) demonstrated the best performance. When feature selection was applied, HyperTab (AUC=0.94), EBM (AUC=0.94), and Catboost (AUC=0.93) emerged as the most accurate results. Finally, external validation resulted in a high diagnostic accuracy (AUC=0.96). Machine learning algorithms introduced enhanced accuracy in diagnosing respiratory changes associated with silicosis. The HyperTab and EBM achieved a high diagnostic accuracy range, and EBM explains the importance of the features and their interactions. This AI-assisted workflow has the potential to serve as a valuable decision support tool for clinicians, which can enhance their decision-making process, ultimately leading to improved accuracy and efficiency.
Global dissection of the impact of Alzheimer’s disease on brain architecture and behavior: High resolution MRH resolves robust regional effects
Authors: Johnson G. Allan , Tian Yuqi , Hornburg Kathryn , Cook James J. , Qi Yi , White Leonard E. , Killmar John T. , Kaczorowski Catherine , Ashbrook David G. , Williams Robert W.
Published: January 2025

Alzheimer’s disease (AD) affects brain regions with remarkable heterogeneity, but the precise impact of this disease on hundreds of small cortical, subcortical, and brainstem regions remains poorly defined. Here, as a prelude to testing preclinical models to prevent AD, we systematically quantified effects of human AD mutations inAPPandPSEN1on 231 regions and comprehensively evaluated changes in volume with unprecedented resolution in genetically diverse mice as a function of sex and genetic background. We studied 34 5XFAD F1 hybrids and 23 sibling controls at 14 months, evaluating learning and memory behaviors, followed byex vivodiffusion tensor images (DTI) at 25 µm resolution. We delineated 231 regions of interest (ROIs) bilaterally with high precision. Remarkably, we found bidirectional changes: marked volume increases (up to 10%) in neocortex, hippocampus, amygdala, and sensory nuclei, contrasted with decreases in striatum, pallidum, thalamus, hypothalamus, and most fiber tracts. These opposing effects are unrelated to amyloid load and are likely to reflect temporal gradients in susceptibility of ROIs. Effects are similar in both sexes but far more prominent in females. Genetic background strongly modulates penetrance of the human mutations with the AD-BXD77 F1 type having the greatest sensitivity. Light sheet microscopy and stereological analysis of NeuN+ neurons and amyloid β aggregates in 22 regions revealed up to 20% loss of cells in CA3 and in anterior and intralaminar parts of the thalamus. Volumetric changes correlated with impaired fear acquisition and memory, with cases and controls often showing opposite relations between performance and regional volumes. These findings reveal unprecedented regional heterogeneity in AD progression and suggest therapeutic efficacy may vary substantially across genetic backgrounds and between sexes.
Exposure to a gradient of warming and acidification highlights physiological, molecular, and skeletal tolerance thresholds inPocillopora acutarecruits
Authors: Ashey Jill , Scucchia Federica , Huffmyer Ariana S. , Putnam Hollie M. , Mass Tali
Published: January 2025

Ocean warming and acidification are among the biggest threats to the persistence of coral reefs. Organismal stress tolerance thresholds are life stage specific, can vary across levels of biological organization, and also depend on natural environmental variability. Here, we exposed the early life stages ofPocillopora acutain Kāne‘ohe Bay, Hawai‘i, USA, a common reef-building coral throughout the Pacific, to projected ocean warming and acidification scenarios. We measured ecological, physiological, biomineralization, and molecular responses across the critical transition from larvae to newly settled recruits following 6 days of exposure to diel fluctuations in temperature and pH in Control (26.8-27.9°C, 7.82-7.96 pHTotal), Mid (28.4-29.5°C, 7.65-7.79 pHTotal) and High conditions (30.2-31.5°C, 7.44-7.59 pHTotal). We found thatP. acutaearly life stages are capable of survival, settlement, and calcification under all scenarios. The High conditions, however, caused a significant reduction in survival and settlement capacity, with changes in the skeletal fiber deposition patterns. In contrast to a limited impact on the expression of biomineralization genes, the dominant transcriptomic response to the High conditions relative to the two other treatments included depressed metabolism, reduced ATP production and increased activity of DNA damage-repair processes. Collectively, our findings indicate that corals living in environments with large diurnal fluctuations in seawater temperature and pH, such as Kāne‘ohe Bay, can tolerate exposure to moderate projected increased temperature and reduced pH. However, under more severe environmental conditions significant negative effects on coral cellular metabolism and overall organismal survival jeopardize species fitness and recruitment.
OcuPair, a novel photo-crosslinkable dendrimer-hyaluronic acid hydrogel bandage/bioadhesive for corneal injuries and temporary corneal repair
Authors: Kambhampati Siva P. , Sharma Rishi , Lin Hui , Appiani Santiago , Cleland Jeffrey L. , Yiu Samuel C , Kannan Rangaramanujam M.
Published: January 2025

Traumatic corneal injuries are a leading cause of blindness among military personnel. These injuries need immediate attention at the combat zone, but treatment options are limited as life-saving measures are often prioritized. To address this critical gap, we have developed OcupairTM, a two-component hydrogel system that consists of (i) an injectable viscoelastic filler that stabilizes the ocular cavity and prevents hypotony. (ii) Anin-situphoto-curable adhesive hydrogel comprising of methacrylated PAMAM dendrimer and hyaluronic acid engineered to form a transparent, flexible and robust bandage within 90 seconds, adhering to corneal surface and ensuring a water-tight seal securing full-thickness corneal wounds.Ex vivostudies demonstrated that the adhesive hydrogel is mechanically robust and withstands intraocular pressures beyond physiological range. In a rabbit corneal injury model, OcuPair™ effectively seals complex full thickness wounds and preserves the eye with favorable clinical outcomes for 5 days with no toxicity over 30 days. In this study, we have validated the pilot scale synthesis, formulation optimization, GMP scale-up and IDE-enabling GLP toxicity, essential for clinical translation as a battlefield-ready solution.
PSME3 Regulates Migration and Differentiation of Myoblasts
Authors: Kuhn Kenneth D , Cho Ukrae H , Hetzer Martin
Published: January 2025

The acquisition of cellular identity requires large-scale alterations in cellular state. The non-canonical proteasome activator PSME3 is known to regulate diverse cellular processes, but its importance for differentiation remains unclear. Here, we demonstrate that PSME3 binds dynamically to highly active promoters over the course of differentiation. However, loss of PSME3 does not globally affect mRNA transcription. We find instead that PSME3 interacts with the HSP90 co-chaperone NUDC and regulates the levels of several cell adhesion-related proteins, such that loss of PSME3 results in increased cell motility. Further, we show that PSME3 facilitates myoblast differentiation in a proteasome-independent manner. Our findings reveal several new facets of PSME3 functionality and highlight its particular importance for the differentiation of myogenic cells.
An autoantibody-based machine learning classifier for the detection of early-stage non-small cell lung cancer
Authors: Kung Andrew F , Didigu Chukwuka A , Wang Chung-Yu , Saxena Aditi , Castillo-Rojas Bryan , Mitchell Anthea M , Mann Sabrina A , Murillo Alyssa , Zorn Kelsey C , Bod Lloyd , Jablons David M , Kratz Johannes R , DeRisi Joseph L
Published: January 2025

The humoral immune system plays a significant role in the immune response to cancer but is challenging to study at scale. We used programmable phage immunoprecipitation sequencing (PhIP-Seq) to profile the autoantibody repertoire in non-small cell lung cancer (NSCLC) patients for the purpose of training a machine learning-based classifier to distinguish NSCLC patients from healthy controls using 301 primarily early-stage, asymptomatic NSCLC patients and 352 healthy controls. The classifier performed well in cross-validation (average ROC-AUC = 0.94) and in an independently analyzed clinical validation cohort of 134 NSCLC patients and 96 healthy controls (ROC-AUC = 0.84). Classification performance can be maintained with only a few hundred target peptides, provided a sufficiently large cohort is used for optimal training. Our findings suggest the existence of a measurable autoreactive humoral profile in NSCLC and demonstrate the potential for serum-based early detection of cancer independent of nucleic acids.
High Prevalence of Molecular Markers Associated with Artemisinin, Sulphadoxine and Pyrimethamine Resistance in Northern Namibia
Authors: Eloff Lydia , Aranda-Díaz Andrés , Routledge Isobel , Wesolowski Amy , Chisenga Mukosha , Mangena Brighton , Chimumbwa John , Sikaala Chadwick , Uusiku Petrina , Katokele Stark , Raman Jaishree , Smith Jennifer , Mumbengegwi Davis R.
Published: January 2025

Artemisinin-based combination therapies are a cornerstone of Namibia’s efforts to eliminate malaria, which has had an over 90% reduction in cases since their introduction in 2005. However, their efficacy has not been routinely monitored, with malaria outbreaks regularly reported since 2016. The recent emergence of artemisinin partial resistance in Africa has highlighted the role of malaria molecular surveillance in complementing efficacy studies. This cross-sectional genomic surveillance study was nested within Namibia’s routine surveillance system and aimed to determine the prevalence of antimalarial drug resistance markers in northern Namibia. Dried blood spots (DBS) and epidemiological data were collected from confirmedPlasmodium falciparumcases presenting at health facilities in the highest malaria-burden regions (Zambezi, Kavango East, Kavango West, Ohangwena, and Omusati) from April to September 2023. 12 genes associated with resistance to 7 antimalarial drugs were genotyped from 264 DBS using multiplexed targeted amplicon sequencing. Multiplepfk13mutations associated with artemisinin partial resistance were identified: the P441L candidate marker was the most abundant, at 33.2%, and the validated markers P574L and A675V were observed at 1.2%. The chloroquine resistance markerpfcrtCVIET haplotype was observed at 1%, while thepfmdr1N86 genotype, selected by lumefantrine use, was found in all samples. Although sulphadoxine-pyrimethamine is not used in Namibia, a high proportion of sulphadoxine-pyrimethamine resistance-associated mutations in thepfdhpsandpfdhfrgenes were observed. This study underscores the need for routine genomic surveillance to monitor emerging drug resistance markers and calls for further research to define their clinical implications.
Prevalence and Risk Factors of Comorbidities in Epilepsy Patients: A Meta-Analysis of Observational Studies in Asia
Authors: Hussain Zahabia Altaf , Aaqil Syeda Ilsa , Wen Cher Phoh , Khan Uneeb Ullah , Kaleem Safa , Tariq Rabeet , Ahmad Faizan
Published: January 2025

Background

Patients with epilepsy often present with multiple comorbidities, which can exacerbate the progression of the disease and reduce their quality of life. Despite the clinical significance, there is a scarcity of collective data to estimate the prevalence of comorbidities among patients with epilepsy in the Asian setting.

Methods

We conducted a comprehensive literature search in PubMed, Scopus, and Google Scholar to identify observational studies conducted in Asia that reported the prevalence of comorbidities among patients diagnosed with epilepsy. Only studies focusing on epilepsy patients were included, and participants were required to have epilepsy confirmed through clinical diagnosis or International Classification of Diseases (ICD) codes. Other neurological conditions, such as non-epileptic seizures, brain tumors, or stroke without concurrent epilepsy, were excluded from this analysis to maintain focus on epilepsy-specific outcomes.

Results

A total of nine studies were included in the meta-analysis based on inclusion criteria. The most prevalent comorbidities among patients with epilepsy in Asia were hypertension (28.6%, 95% CI: 25.3%–32.0%) and diabetes mellitus (16.2%, 95% CI: 12.5%–20.2%). Factors such as gender, alcohol use, family history, and education level were significantly lower in comparison to other factors.

Conclusions

Our study identified hypertension and diabetes mellitus as the most common comorbid conditions among epilepsy patients in Asian settings. These findings highlight the necessity for targeted interventions and comprehensive management strategies to address the high prevalence of comorbidities, ultimately improving patient outcomes. Further research is warranted to explore the underlying mechanisms and develop effective prevention strategies.