bluuebunny/crossref_metadata_2025 huggingface dataset:
Video-evoked neuromarkers of visual function in age-related macular degeneration
Authors: Renton Angela I. , Klein David J. , Livezey Jesse A. , Nemrodov Dan , Wolfer Stephanie , Hanina Adam , Van De Ville Dimitri
Published: February 2025

Neural markers of visual function in age-related macular degeneration (AMD) allow clinicians and researchers to directly evaluate the functional changes in visual processing which occur as a result of the progressive loss of afferent input from the macula. Unfortunately, few protocols exist that elicit such neural markers, and most of these are poorly adapted to AMD. Here, we propose a novel method of embedding frequency tags into full colour and motion videos by periodically manipulating the contrast of visual information of different spatial frequencies at different temporal frequencies. These videos elicit steady-state visual evoked potentials (SSVEPS) in viewers which, when measured using electrophysiological neuroimaging methods, independently represent the responses of populations of neurons tuned to the tagged spatial frequencies. We used electroencephalography (EEG) to record the SSVEPs of 15 AMD patients and 16 age-matched healthy controls watching a 6-minute series of natural scene videos filtered with this spatial frequency tagging method. Compared with healthy controls, AMD patients showed a lower SSVEP response to high spatial frequency information, and a stronger response to the low spatial frequency information in the video set. The ratio of the SSVEP response to lower relative to higher spatial frequency information was strongly predictive of both visual acuity and contrast sensitivity, and the topographic distributions of these responses suggested retinotopic reorganisation of the neural response to spatial frequency information.
MYRF is Essential in Mesothelial Cells to Promote Lung Development and Maturation
Authors: Luna Gidsela , Verheyden Jamie , Tan Chunting , Kim Estelle , Hwa Michelle , Sahi Jugraj , Shen Yufeng , Chung Wendy , McCulley David , Sun Xin
Published: February 2025

The mesothelium is a squamous monolayer that ensheathes internal organs, lines the body cavity, and the diaphragm. It serves as a protective barrier, coated in glycocalyx, and secretes lubricants to facilitate tissue movement. How the mesothelium forms is poorly understood. Here, we investigateMyrf, a transcription factor gene expressed in the mesothelium, because it carries variants in patients with Congenital Diaphragmatic Hernia (CDH), a disorder that affects the diaphragm, lung, and other organs. In mice, inactivation ofMyrfearly in organogenesis resulted in CDH and defective mesothelial specification, compromising its function as a signaling center for lung growth. Inactivation ofMyrflater led to enhanced mesothelium differentiation into mesenchymal cell types through partial epithelial-to-mesenchymal transition (EMT), resulting in a unique accumulation of smooth muscle encasing the lung. In this role, MYRF functions in parallel with YAP/TAZ. Together, these findings establish MYRF as a critical regulator of mesothelium development, and when mutated, causes CDH.
A versatile miniature two-photon microscope enabling multicolor deep-brain imaging
Authors: Wu Runlong , Zhao Chunzhu , Qiu Shan , Zhu Yufei , Zhang Lifeng , Fu Qiang , Hu Yanhui , Wu Dakun , Yu Fei , Zhou Fangxu , Huang Haipeng , Zhang Yunfeng , Wang Xianhua , Wang Aiming , Cheng Heping
Published: February 2025

Here we present the FHIRM-TPM 3.0, a 2.6 g miniature two-photon microscope capable of multicolor deep-brain imaging in freely behaving mice. The system was integrated with a broadband anti-resonant hollow-core fiber featuring low transmission loss, minimal dispersion from 700-1060 nm, and high tolerance of laser power. By correcting chromatic and spherical aberrations and optimizing the fluorescence collection aperture, we achieved cortical neuronal imaging at depths exceeding 820 μm and, using a GRIN lens, hippocampal Ca2+imaging at single dendritic spine resolution. Moreover, we engineered three interchangeable parfocal objectives, allowing for a tenfold scalable field-of-view up to 1×0.8 mm², with lateral resolutions ranging from 0.68 to 1.46 μm. By multicolor imaging at excitation wavelengths of 780 nm, 920 nm and 1030 nm, we investigated mitochondrial and cytosolic Ca2+activities relative to the deposition of amyloid plaques in the cortex of awake APP/PS1 transgenic mice. Thus, the FHIRM-TPM 3.0 provides a versatile imaging system suitable for diverse brain imaging scenarios.
Pharmacophore modeling, 2D-QSAR, Molecular Docking and ADME studies for the discovery of inhibitors of PBP2a in MRSA
Authors: Mutie Musila Fredrick , Gitau Grace Wairimu , Amwayi Peris Wanza , Kingoo James Munyao , Kinyanyi Dickson Bennet , Njeru Patrisio Njiru
Published: February 2025

Methicillin-resistantStaphylococcus aureus(MRSA) is considered to be a worldwide threat to human health and the global spread of MRSA has been associated with the emergence of different types of infections and resultant selection pressure due to exposure to many antibiotics. In the current era characterized by incessant antibiotic resistance, assessment of multiple molecular targets represents notable therapeutic opportunities in the medical and pharmaceutical industry and can aid in the discovery of novel molecules that inhibit various receptors effectively to replace the current weak antimicrobial agents. Penicillin binding protein 2a (PBP2a) of MRSA is a major determinant of resistance to β-lactam antibiotics. The activity of PBP2a is not inhibited by β-lactam antibiotics, allowing the strain to survive in the presence of β-lactams leading to resistance to β-lactam antibiotics. The study aimed at identifying potential inhibitors of PBP2a receptor of MRSA through ligand-based pharmacophore modeling, 2D-QSAR, structure-based drug design docking and molecular dynamic (MD) simulations. The study led to the development of a satisfactory, predictive and significant 2D-QSAR model for predicting anti-MRSA activity of compounds and also led to the identification of two molecules: C21H25N7O4S2(ChEMBL30602) and C20H17NO6S (ChEMBL304837) with favorable pharmacophore features and ADME properties with potential to bind strongly to PBP2a receptor of MRSA. MD simulation analysis showed that the interactions of C20H17NO6S (ChEMBL304837) with PBP2a over 100 ns was more stable and similar to the interaction of ceftobiprole with PBP2a and may become potential drug candidate against MRSA which has developed a lot of resistance to current antibiotics.
Systematic Metaproteomics Mapping Reveals Functional and Ecological Landscapes of Human Gut Microbiota Responses to Therapeutic Drugs
Authors: Li Leyuan , Simopoulos Caitlin M.A. , Mayne Janice , Ning Zhibin , Zhang Xin , Hamada Mona , Butcher James , Serrana Joeselle M. , Wang Luman , Cheng Kai , Qin Hongye , Walker Krystal , Zhang Xu , Stintzi Alain , Figeys Daniel
Published: February 2025

Therapeutic compounds significantly alter the composition of the gut microbiota, yet their functional and ecological impacts, particularly at the protein level, remain largely unexplored. In this study, we systematically mapped metaproteomic responses ofex vivohuman gut microbiota to 312 compounds, generating 4.6 million microbial protein responses, available as an interactive resource (https://shiny.imetalab.ca/MPR_Viz/). Across protein-level, taxonomic composition-level, and ecosystem-level analyses, we simultaneously identified metaproteomic shifts in 47 compounds, a tri-stability taxonomic landscape, and, using our PhyloFunc beta-diversity metric, three distinct functional community state types with cross-individual ecological consistency. Notably, neuropharmaceuticals triggered profound metaproteomic alterations, marked by a decline in functional redundancy (FR) and an increase in antimicrobial resistance proteins (ARPs), shifting the community to alternative functional state on the functional landscape. We validated that enhancing FR maintained a microbiota’s resilience against neuropharmaceutical-induced ARP increase. These findings establish a novel landscape-based framework for understanding microbiome resilience and advancing targeted therapeutic interventions.
Transcranial Magnetic Stimulation Reduces Non-Decision Time in Perceptual Decisions
Authors: Gordleeva Susanna , Maksimenko Vladimir , Mohammad Usama , Grigoriev Nikita , Savosenkov Andrey , Kuc Alexander , Kurkin Semen , Udoratina Anna , Grubov Vadim , Hramov Alexander
Published: February 2025

Perceptual decision-making enables humans to process sensory information and translate it into goal-directed actions. A critical component of this process is response time, which declines with age due to the slowing of both non-decision processes and evidence accumulation. While perceptual learning has been shown to counteract these declines, it remains unclear whether non-decision processes can be accelerated through direct neural stimulation, bypassing the need for long training sessions. Here, we propose that Transcranial Magnetic Stimulation (TMS) can enhance perceptual decision-making by specifically reducing non-decision time. To test this hypothesis, we tracked response times during a perceptual learning task while recording brain activity. Using the Drift Diffusion Model, we quantified the effects of TMS on mental speed and non-decision time. Our findings reveal that perceptual learning decreases response time by simultaneously increasing mental speed and reducing non-decision time. Crucially, TMS application to brain regions associated with perceptual learning further shortened non-decision time without altering mental speed. These results demonstrate that TMS can selectively accelerate non-decision processes, offering a promising intervention for mitigating age-related cognitive slowing and enhancing decision efficiency.

Significance Statement

Perceptual decision-making is a fundamental cognitive process that slows with age due to declines in both non-decision processes and mental speed. While perceptual learning can mitigate these declines through practice, we propose that non-decision time can also be reduced by directly stimulating neural ensembles using Transcranial Magnetic Stimulation (TMS). Our study demonstrates that TMS applied to task-relevant brain areas decreases non-decision time, thereby accelerating response speed without affecting mental speed. These findings reveal a novel mechanism for enhancing perceptual decision-making efficiency and highlight TMS as a potential tool for counteracting age-related cognitive slowing.
Design of Protein Sequences with Precisely Tuned Kinetic Properties
Authors: Brotzakis Z. Faidon , Vendruscolo Michele , Skretas Georgios
Published: February 2025

Recent advances in computational biology have enabled solutions to the inverse folding problem - finding an amino acid sequence that folds into a target structure. An open question concerns the design of proteins that in addition to having the correct target structure also have precisely tuned kinetic properties, such as folding and unfolding rates. To address this problem, we formulate the inverse folding problem as a quest for a sequence with a target free energy landscape. To propose a procedure to address this problem, here we describe the Inverse Folding Molecular Dynamics (IF-MD) method, which combines inverse folding with enhanced sampling molecular dynamics and Bayesian optimization. IF-MD leverages ensemble averages from molecular dynamics simulations, reweighted according to a Bayesian framework, to guide the design of sequences exhibiting specific kinetic properties. We demonstrate the methodology by optisising the binding kinetics of H11, a nanobody against the SARS-CoV-2 spike receptor-binding domain (RBD), thus identifying nanobody variants with slower unbinding kinetics than H11. Mechanistic analysis reveals that this kinetic property arises from a shift towards configurations closer to the bound state and increased free energy barriers for dissociation. These findings highlight the power of IF-MD for efficiently navigating the vast sequence space to design proteins with a tailored free energy landscape.
CRISPR/Cas9-mediated elimination of theLMNAc.745C>G pathogenic mutation enhances survival and cardiac function inLMNA-associated congenital muscular dystrophy
Authors: Gómez-Domínguez Déborah , Epifano Carolina , Hernández Iván , Vilaplana-Martí Borja , Cesar Sergi , de Molina-Iracheta Antonio , Sena-Esteves Miguel , Sarquella-Brugada Georgia , Pérez de Castro Ignacio
Published: February 2025

LMNA-associated congenital muscular dystrophy is a currently incurable rare genetic disorder characterized by early-onset muscle weakness, dilated cardiomyopathy and respiratory failure, resulting from mutations in theLMNAgene. In this study, we assessed the potential of a CRISPR-mediated strategy to eliminate the mutant alleleLmnac.745C>T, p.R249W using a mutation specific guide (sg745T). Results from R249W-mutation-carrying cellular models showed specific activity of the Cas9/sg745T complex towards the mutant allele. This property varied depending on the concentration of CRISPR components, with a loss of specificity observed with increased dosage. We tested this strategyin vivousing adeno-associated virus delivery inLmnaR249Wmice. Despite being associated with a modest CRISPR activity, this therapeutic approach resulted in a 10% increase in the survival of R249W homozygous mice. Interestingly, a similar CRISPR activity improved the cardiac pathology developed byLmna+/R249Wanimals, significantly extending their median survival. These results represent the first therapeutic validation of a CRISPR/Cas9-mediated gene editing strategy for the treatment ofLMNA-associated congenital muscular dystrophy.
Genetic and pharmacological correction of impaired mitophagy in retinal ganglion cells rescues glaucomatous neurodegeneration
Authors: Maddineni Prabhavathi , Kodati Bindu , Kaipa Balasankara Reddy , Kesavan Karthikeyan , Cameron Millar J , Yacoub Sam , Kasetti Ramesh B , Clark Abbot F , Zode Gulab S
Published: February 2025

Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve axons are the pathological hallmarks of glaucoma. Ocular hypertension (OHT) and mitochondrial dysfunction are linked to neurodegeneration and vision loss in glaucoma. However, the exact mechanism of mitochondrial dysfunction leading to glaucomatous neurodegeneration is poorly understood. Using multiple mouse models of OHT and human eyes from normal and glaucoma donors, we show that OHT induces impaired mitophagy in RGCs, resulting in the accumulation of dysfunctional mitochondria and contributing to glaucomatous neurodegeneration. Using mitophagy reporter mice, we show that impaired mitophagy precedes glaucomatous neurodegeneration. Notably, the pharmacological rescue of impaired mitophagy via Torin-2 or genetic upregulation of RGC-specific Parkin expression restores the structural and functional integrity of RGCs and their axons in mouse models of glaucoma andex-vivohuman retinal-explant cultures. Our study indicates that impaired mitophagy contributes to mitochondrial dysfunction and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing mitophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration.Graphical Abstract
Post-mitotic transcriptional activation and 3D regulatory interactions show locus- and differentiation-specific sensitivity to cohesin depletion
Authors: Lee UkJin , Laguillo-Diego Alejandra , Wong Wilfred , Ni Zhangli , Cheng Lingling , Li Jieru , Pelham-Webb Bobbie , Pertsinidis Alexandros , Leslie Christina , Apostolou Effie
Published: February 2025

Prior studies showed that structural loops collapse upon acute cohesin depletion, while regulatory enhancer-promoter (E-P) loops largely persist, consistent with minimal transcriptional changes. However, these studies, conducted in asynchronous cells, could not resolve whether cohesin is required for the establishment of regulatory interactions and transcriptional activation during cell division or cell state transitions. To address this gap, we degraded RAD21, a core cohesin subunit, in naïve mouse embryonic stem cells (ESCs) transitioning from mitosis to G1 either in self-renewal condition or during differentiation toward formative pluripotency. Although most structural loops failed to be re-established without cohesin, about 35% of regulatory loops reformed at normal or higher frequencies. Cohesin-independent loops showed characteristics of strong active enhancers and promoters and a significant association with H3K27ac mitotic bookmarks. However, inhibition of CBP/p300 during mitotic exit did not impact these cohesin-independent interactions, suggesting the presence of complex compensatory mechanisms. At the transcriptional level, cohesin depletion induced only minor changes, supporting that post-mitotic transcriptional reactivation is largely independent of cohesin. The few genes with impaired reactivation were directly bound by RAD21 at their promoters, engaged in many structural loops, and located within strongly insulated TADs with low gene density. Importantly, degrading cohesin during the M-to-G1 transition in the presence of EpiLC differentiation signals revealed a larger group of susceptible genes, including key signature genes and transcription factors. Impaired activation of these genes was partly due to the failure to establishde novoEpiLC-specific interactions in the absence of cohesin. These experiments revealed locus-specific and context-specific dependencies between cohesin, E-P interactions, and transcription.
Cryo-EM structure of endogenousPlasmodium falciparumPfs230 and Pfs48/45 fertilization complex
Authors: Dietrich Melanie H. , Chmielewski Jill , Chan Li-Jin , Tan Li Lynn , Adair Amy , Lyons Frankie M. T. , Gabriela Mikha , Lopaticki Sash , Dite Toby A , Dagley Laura F , Pazzagli Lucia , Gupta Priya , Kamil Mohd , Vaughan Ashley M. , Rojrung Rattanaporn , Abraham Anju , Mazhari Ramin , Longley Rhea J. , Zeglinski Kathleen , Gouil Quentin , Mueller Ivo , Fabb Stewart A. , Shandre-Mugan Rekha , Pouton Colin W. , Glukhova Alisa , Shakeel Shabih , Tham Wai-Hong
Published: February 2025

Plasmodium falciparumPfs230 and Pfs48/45, part of a core fertilization complex, are leading malaria transmission-blocking vaccine candidates. However, how the two proteins interact is unknown. Here we report a 3.36 Å resolution cryo-electron microscopy structure of the endogenous Pfs230-Pfs48/45 complex. We show that Pfs48/45 interacts with Pfs230 domains 13 and 14, domains that are not included in current Pfs230 vaccine immunogens. Using a transgenic parasite line with a domain 13 to 14 deletion, we show that these domains are essential for Pfs230 localization on the gamete surface. Nanobodies against domains 13 and 14 inhibit Pfs230-Pfs48/45 complex formation, reduce transmission and structural analyses reveal their binding epitopes. Furthermore, domains 13 and 14 are targets of naturally acquired immunity and when delivered as mRNA-LNP vaccines induce potent immune responses. Our comprehensive structural insights on a coreP. falciparumfertilization complex will guide the design of novel transmission-blocking vaccine candidates against malaria.
Nuclear regulatory disturbances precede and predict the development of Type-2 diabetes in Asian populations
Authors: Jain Pritesh R , Ng Hong Kiat , Tay Darwin , Mina Theresia , Low Dorrain , Sadhu Nilanjana , Kooner Ishminder K , Gupta Ananya , Li Tai Fei , Bertin Nicolas , Chin Calvin Woon Loong , Jin Fang Chai , Goh Liuh Ling , Mok Shi Qi , Peh Su Qin , Sabanayagam Charumathi , Jha Vinitaa , Kasturiratne Anuradhani , Katulanda Prasad , Khawaja Khadija I , Lim Weng Khong , Leong Khai Pang , Cheng Ching-Yu , Yuan Jian-Min , Elliott Paul , Riboli Elio , Eng Sing Lee , Lee Jimmy , Ngeow Joanne , Liu Jian Jin , Best James , Kooner Jaspal S , Tai E-Shyong , Tan Patrick , van Dam Rob M , Koh Woon-Puay , Xueling Sim , Loh Marie , Chambers John C
Published: February 2025

To identify biomarkers and pathways to Type-2 diabetes (T2D), a major global disease, we completed array-based epigenome-wide association in whole blood in 5,709 Asian people. We found 323 Sentinel CpGs (from 314 genetic loci) that predict future T2D. The CpGs reveal coherent, nuclear regulatory disturbances in canonical immune activation pathways, as well as metabolic networks involved in insulin signalling, fatty acid metabolism and lipid transport, which are causally linked to development of T2D. The CpGs have potential clinical utility as biomarkers. An array-based composite Methylation Risk Score (MRS) is predictive for future T2D (RR: 5.2 in Q4 vs Q1; P=7x10-25), and is additive to genetic risk. Targeted methylation sequencing revealed multiple additional CpGs predicting T2D, and synthesis of a sequencing-based MRS that is strongly predictive for T2D (RR: 8.3 in Q4 vs Q1; P=1.0x10-11). Importantly, MRS varies between Asian ethnic groups, in a way that explains a large fraction of the difference in T2D risk between populations. We thus provide new insights into the nuclear regulatory disturbances that precede development of T2D, and reveal the potential for sequence-based DNA methylation markers to inform risk stratification in diabetes prevention.
Development and validation of a machine learning model to predict cognitive behavioral therapy outcome in obsessive-compulsive disorder using clinical and neuroimaging data
Authors: van de Mortel Laurens A. , Bruin Willem B. , Alonso Pino , Bertolín Sara , Feusner Jamie D. , Guo Joyce , Hagen Kristen , Hansen Bjarne , Thorsen Anders Lillevik , Martínez-Zalacaín Ignacio , Menchón Jose M , Nurmi Erika L. , O’Neill Joseph , Piacentini John C. , Real Eva , Segalàs Cinto , Soriano-Mas Carles , Thomopoulos Sophia I. , Stein Dan J. , Thompson Paul M. , van den Heuvel Odile A. , van Wingen Guido A.
Published: February 2025

Cognitive behavioral therapy (CBT) is a first-line treatment for obsessive-compulsive disorder (OCD), but clinical response is difficult to predict. In this study, we aimed to develop predictive models using clinical and neuroimaging data from the multicenter Enhancing Neuro-Imaging and Genetics through Meta-Analysis (ENIGMA)-OCD consortium.

Baseline clinical and resting-state functional magnetic imaging (rs-fMRI) data from 159 adult patients aged 18-60 years (88 female) with OCD who received CBT at four treatment/neuroimaging sites were included. Fractional amplitude of low frequency fluctuations, regional homogeneity and atlas-based functional connectivity were computed. Clinical CBT response and remission were predicted using support vector machine and random forest classifiers on clinical data only, rs-fMRI data only, and the combination of both clinical and rs-fMRI data.

The use of only clinical data yielded an area under the ROC curve (AUC) of 0.69 for predicting remission (p=0.001). Lower baseline symptom severity, younger age, an absence of cleaning obsessions, unmedicated status, and higher education had the highest model impact in predicting remission. The best predictive performance using only rs-fMRI was obtained with regional homogeneity for remission (AUC=0.59). Predicting response with rs-fMRI generally did not exceed chance level. Machine learning models based on clinical data may thus hold promise in predicting remission after CBT for OCD, but the predictive power of multicenter rs-fMRI data is limited.
Magnetoencephalography Reveals Neuroprotective Effects of COVID-19 Vaccination in Non-Human Primates
Authors: Stapleton-Kotloski Jennifer R. , Rowland Jared A. , Davenport April T. , Epperly Phillip M. , Blevins Maria , Godwin Dwayne W. , Ewing Daniel F. , Liang Zhaodong , Sundaram Appavu K. , Petrovsky Nikolai , Porter Kevin R. , Gamble Christopher S. , Sanders John W. , Daunais James B.
Published: February 2025

SUMMARY PARAGRAPH

COVID-19, caused by the SARS-CoV-2 virus, can lead to widespread neurological complications, including cognitive deficits and neurodegenerative symptoms, even in the absence of significant structural brain abnormalities. The potential neuroprotective effects of SARS-CoV-2 vaccination remain underexplored. Here, we demonstrate the neuroprotective effects of a psoralen-inactivated SARS-CoV-2 vaccine in a non-human primate model using resting-state magnetoencephalography (MEG), a non-invasive neurophysiological recording technique with sub-millisecond temporal and submillimeter spatial resolution. MEG scans demonstrated substantial preservation of neural activity across multiple brain regions in vaccinated subjects compared to unvaccinated controls following viral challenge. This approach not only underscores the role of vaccination in mitigating severe neurological outcomes but also highlights the capability of MEG to detect subtle yet significant changes in brain function that may be overlooked by other imaging modalities. These findings advance our understanding of vaccine-induced neuroprotection and establish MEG as a powerful tool for monitoring brain function in the context of viral infections.
Are new beta-lactamases posing a potential future threat?
Authors: Mlynarcik Patrik , Zdarska Veronika , Kolar Milan
Published: February 2025

Antimicrobial resistance, a significant and escalating public health threat, has extended its reach beyond healthcare settings to diverse environments such as urban beaches, wastewater plants, and household pets. A recent study even found bacteria in permafrost with genes encoding beta-lactamases, enzymes that confer resistance to beta-lactam antibiotics. Our previous study identified 2340 potential beta-lactamases across 673 bacterial genera, with only 139 of these enzymes sharing more than 70% amino acid identity with known beta-lactamases. This study underscores the critical and widespread distribution of potential beta-lactamases across different bacterial genera, regions, and hosts. The role of horizontal gene transfer and mobile genetic elements in spreading antibiotic resistance is of utmost importance, highlighting the gravity of the situation and the urgent need for monitoring and research.
NF-κB dependent gene expression and plasma IL-1β, TNFα and GCSF drive transcriptomic diversity and CD4:CD8 ratio in people with HIV on ART
Authors: Wang Yingfan , Gornalusse German G. , Siegel David A. , Barbehenn Alton , Hoh Rebecca , Martin Jeffrey , Hecht Frederick , Pilcher Christopher , Semenova Lesia , Murdoch David M , Margolis David M , Levy Claire N. , Jerome Keith R. , Rudin Cynthia D , Hladik Florian , Deeks Steven G. , Lee Sulggi A. , Browne Edward P
Published: February 2025

Despite antiretroviral therapy (ART), people with HIV (PWH) on ART experience higher rates of morbidity and mortality vs. age-matched HIV negative controls, which may be driven by chronic inflammation due to persistent virus. We performed bulk RNA sequencing (RNA-seq) on peripheral CD4+ T cells, as well as quantified plasma immune marker levels from 154 PWH on ART to identify host immune signatures associated with immune recovery (CD4:CD8) and HIV persistence (cell-associated HIV DNA and RNA). Using a novel dimension reduction tool - Pairwise Controlled Manifold Approximation (PaCMAP), we defined three distinct participant transcriptomic clusters. We found that these three clusters were largely defined by differential expression of genes regulated by the transcription factor NF-κB. While clustering was not associated with HIV reservoir size, we observed an association with CD4:CD8 ratio, a marker of immune recovery and prognostic factor for mortality in PWH on ART. Furthermore, distinct patterns of plasma IL-1β, TNF-α and GCSF were also strongly associated with the clusters, suggesting that these immune markers play a key role in CD4+ T cell transcriptomic diversity and immune recovery in PWH on ART. These findings reveal novel subgroups of PWH on ART with distinct immunological characteristics, and define a transcriptional signature associated with clinically significant immune parameters for PWH. A deeper understanding of these subgroups could advance clinical strategies to treat HIV-associated immune dysfunction.
ThePseudomonas aeruginosaTse4 toxin assembles ion-selective and voltage-sensitive ion channels to couple membrane depolarisation with K+efflux
Authors: Rojas-Palomino Jessica , Velázquez Carmen , Altuna-Alvarez Jon , González-Magaña Amaia , Zabala-Zearreta Maialen , Müller Matthias , Queralt-Martín María , Alcaraz Antonio , Albesa-Jové David
Published: February 2025

Pseudomonas aeruginosaemploys the Type VI secretion system (T6SS) to outcompete other bacteria in its environment. Among the effectors secreted by the T6SS ofP. aeruginosaPAO1, Tse4 is known for its potent antibacterial activity. This study elucidates the molecular function of Tse4, which promotes cell depolarisation in competing bacteria. Our results show that Tse4 spontaneously incorporates into lipid monolayers and forms multiionic channels in planar bilayers, with either ohmic conduction or diode-like rectifying currents and a preference for cations over anions. These observations allow us to propose a model of action whereby Tse4 channels couple cell depolarisation with K+efflux. These insights into Tse4’s pore-forming activity enhance our understanding of bacterial competition and exemplify a finely tuned antibacterial strategy, coupling its ability to cause membrane depolarisation with potassium efflux that synergises with other T6SS effectors. These results highlight the sophistication ofPseudomonas aeruginosa’s competitive arsenal.
Misleading monitoring: more hatchlings do not represent turtle population recovery
Authors: Norris Darren
Published: February 2025

This article critiques a recent study by Lacava et al. (2024) that suggests the population ofPodocnemis expansahas recovered in Brazil based on increased hatchling releases across 11 nesting areas. I present three main challenges to the study conclusions. Firstly, hatchling counts alone should not be used to assess population recovery. Secondly, the study failed to consider alternative hypotheses that could explain the observed increases, including changes in methods and effort over time. Lastly, the statistical analysis was flawed, specifically neglecting temporal autocorrelation and failing to distinguish between statistical significance and biological relevance. Reanalysis of the original data, accounting for temporal autocorrelation, revealed sustained increases in hatchlings released in only five of eleven areas, contradicting the original claim of increases in most areas. Furthermore, reanalysis suggests that methodological changes influenced results in at least one area. The study published by Lacava et al. (2024) requires correction to avoid ingenuous and potentially misleading conclusions and to more closely reflect the reality of 21st-century freshwater turtle conservation efforts.
Proteomic characterisation of three independent series of sequential cystic fibrosis strains in an InternationalPseudomonas aeruginosareference panel indicates positive selection in late infection strains
Authors: Drabinska Joanna , Connor Lucia O’ , McClean Caoilin , McClean Siobhán
Published: February 2025

Pseudomonas aeruginosais a frequent cause of chronic opportunistic infections in people with cystic fibrosis (CF). It is a highly diverse and adaptable Gram-negative bacterium that thrives in many environments. It is well recognised thatP. aeruginosaadapts over time of colonisation to facilitate chronic infection including loss of virulence factors, however proteomic analyses of the adaptation to chronic infection have been limited. We previously collated and characterised an international panel ofP. aeruginosastrains from different clinical presentations and geographical regions. Within this panel were three series of sequential isolates from people with CF, comprising eight strains in total which present an excellent opportunity to seek potential conserved adaptations that may be involved in driving chronic colonisation in the CF lung. We compared the proteomes of all eight strains (early versus respective late) to examine whether there were any changes in the proteomes over time of colonisation that were common to the three series of chronicP. aeruginosainfection isolates from three different patients. We identified 11 proteins that showed increased abundance in late isolates from all three patient series, many of which are reported to be involved in virulence, regulation of virulence or response to hypoxia and include cystic fibrosis inhibitory factor repressor (CifR), WspR, two two-component response regulators (PA2572 and PA3702), and transcriptional regulator (PA2551). Moreover, we identified three proteins (PA2572, PA3819 and PA5028) that showed increased abundance in all five late isolates from three people with CF. The probability of this being a random event is 5.06 x 10-53and consequently is very strong evidence of positive selection. The increased abundance of PA2573 and PA3819 appears to improve the fitnessP. aeruginosato antibiotics and oxidative stress. Overall, despite the diversity within this species, there appear to be common mechanisms of adaptation in the cystic fibrosis lung.
Accurate predictions of conformational ensembles of disordered proteins with STARLING
Authors: Novak Borna , Lotthammer Jeffrey M. , Emenecker Ryan J. , Holehouse Alex S.
Published: February 2025

Intrinsically disordered proteins and regions (collectively IDRs) are found across all kingdoms of life and play critical roles in virtually every eukaryotic cellular process. In contrast to folded proteins, IDRs lack a stable 3D structure and are instead described in terms of a conformational ensemble, a collection of energetically accessible interconverting structures. This unique structural plasticity facilitates diverse molecular recognition and function; thus, a convenient way to view IDRs is through their ensembles. Here, we combine advances in physics-based force fields for IDPs with the power of modern multi-scale generative modeling to develop STARLING, an approach for the rapid and accurate prediction of IDR ensembles directly from sequence. STARLING enables ensembles of hundreds of conformers to be generated in seconds and works on GPUs and CPUs. This, in turn, dramatically lowers the barrier to the computational interrogation of IDR function through the lens of emergent biophysical properties complementing bioinformatic protein sequence analysis. We evaluate STARLING’s accuracy against extant experimental data and offer a series of vignettes illustrating how STARLING can enable rapid hypothesis generation for IDR function and aid the interpretation of experimental data.
Exploring Lymph Node Stroma Ageing: Immune Implications and Future Directions
Authors: Ng Yu Yang , Tay Andy
Published: February 2025

Ageing is an inevitable biological process that impacts the immune system, leading to immunosenescence and inflammaging, which contribute to increased susceptibility to infections, autoimmune diseases and cancers in individuals over the age of 65. This review focuses on the ageing of lymph node stromal cells (LNSCs), which are crucial for maintaining lymph node (LN) structure and function. Age‐related changes in LNs, such as fibrosis and lipomatosis, disrupt the LN architecture and reduce immune cell recruitment and function, impairing immune responses to infections and vaccinations. The review discusses the structural and functional decline of various LNSC subsets, including fibroblastic reticular cells (FRCs), lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), highlighting their roles in immune cell activation and homeostasis. Potential strategies to restore aged LNSC function, such as enhancing LNSC activation during vaccination and using senotherapeutics, are explored. Outstanding questions regarding the mechanisms of LNSC ageing and how ageing of the LN stroma might impact autoimmune disorders are also addressed. This review aims to stimulate further research into the characterisation of aged LNSCs and the development of therapeutic interventions to improve immune function in the older adults.
Transcriptional Heterogeneity and Differential Response of Rod Photoreceptor Pathway Uncovered by Single‐Cell RNA Sequencing of the Aging Mouse Retina
Authors: Campello Laura , Brooks Matthew J. , Fadl Benjamin R. , Choi Hyo Sub , Pal Soumitra , Swaroop Anand
Published: February 2025

Visual function deteriorates throughout the natural course of aging. Age‐related structural and functional adaptations are observed in the retina, the light‐sensitive neuronal tissue of the eye where visual perception begins. Molecular mechanisms underlying retinal aging are still poorly understood, highlighting the need to identify biomarkers for better prognosis and alleviation of aging‐associated vision impairment. Here, we investigate dynamics of transcriptional dysregulation in the retina and identify affected pathways within distinct retinal cell types. Using an optimized protocol for single‐cell RNA sequencing of mouse retinas at 3, 12, 18, and 24 months, we detect a progressive increase in the number of differentially expressed genes across all retinal cell types. The extent and direction of expression changes varies, with photoreceptor, bipolar, and Müller cells showing the maximum number of differentially expressed genes at all age groups. Furthermore, our analyses uncover transcriptionally distinct, heterogeneous subpopulations of rod photoreceptors and bipolar cells, distributed across distinct areas of the retina. Our findings provide a plausible molecular explanation for enhanced susceptibility of rod cells to aging and correlate with the observed loss of scotopic sensitivity in elderly individuals.
Do changes in MD&A tone predict financial restatements? Evidence from Chinese listed companies
Authors: Du Li , Tu Chengmin
Published: February 2025

We empirically examine whether changes in the Management Discussion and Analysis (MD&A) tone in annual reports can effectively predict financial restatements. The results indicate that changes in MD&A tone are significantly positively correlated with financial restatements; the greater the changes in MD&A tone, the higher the probability of financial restatements. Furthermore, an empirical test shows that the predictive power of MD&A tone changes for financial restatements is relatively stronger when companies (1) face tighter financial constraints, (2) have poorer governance, (3) operate in highly competitive industries and (4) receive a heightened level of external attention. This study not only provides empirical evidence of management tone manipulation based on practices of Chinese companies, but it also marginally expands research on accounting information manipulation.
On the persistence of law firm performance in securities class action lawsuits
Authors: Oliver Barry , Yang Chuyi , Zhang Lei
Published: February 2025

Using data from 1741 lawsuits filed in the United States, we show that the skill of plaintiff law firms, measured by the Dismissal Ratio, strongly predicts the outcomes of securities class action lawsuits. Skilled law firms weed out frivolous cases and achieve favourable outcomes. Lawsuits brought by skilled law firms are more likely to be settled and have larger settlement amounts, while the defendants experience a higher likelihood of CEO turnover. Less skilled law firms are more likely to have zero market share. Overall, the persistence of law firm performance implies traceable law firm skills.
Environmental Engagement: An Effective Way in Mitigation of Firms' Litigation Risks in China
Authors: Tao Qian , Jun Aelee , Ma Shiguang
Published: February 2025

The increasing incidence of environmental disasters has necessitated stricter government environmental legislation and heightened firms' environment‐related litigation risks. Firms with environmental engagements receive favourable treatment from the government as their efforts align with government environmental campaigns and comply with government initiatives. In this study, we examine the impact of firms' environmental engagement on their litigation risks in China. Using a sample of listed firms from 2006 to 2019, we find that firms with environmental engagement are less likely to experience lawsuits. This result is robust across alternative estimation methods. The main results are also more pronounced in non‐state‐owned enterprises (non‐SOEs), firms from high‐pollution industries, located in high‐pollution provinces and low‐trust provinces. Overall, this study provides evidence from a new perspective on how firms can mitigate their litigation costs through environmental engagement.
Neural, Motivational, and Psychological Measures of Pain Avoidance Predict Future Alcohol Use in Adult Drinkers
Authors: Le Thang M. , Hughes F. AnNa , Oba Takeyuki , Li Chiang‐Shan R.
Published: February 2025

Drinking as a coping method in response to pain is a complex behaviour, involving multiple neural, motivational, and psychological factors. Among these factors, pain sensitivity and pain‐related drinking motive can significantly promote alcohol use. In contrast, proactive avoidance – a beneficial strategy of initiating overt actions to avoid negative outcomes – reduces harmful consumption. Yet, these factors have not been assessed as potential predictors of future drinking behaviour. Here, in a longitudinal study we collected fMRI data in 50 drinkers who, at baseline, performed a probabilistic learning go/nogo task that involved proactive avoidance of painful electric shocks. Pain‐related psychological measures and the neural correlates of proactive avoidance were examined in relation to participants' alcohol use and craving in the following 12 months. We found that deficits in proactive avoidance were associated with future drinking severity. Importantly, diminished activation of the dorsal anterior cingulate cortex (dACC) during proactive avoidance also predicted subsequent percentage of heavy drinking days. Using Bayesian network modelling, we established a potential pathway in which drinkers' heightened pain sensitivity led to greater pain‐avoidance drinking motive and alcohol craving. Both craving and weakened dACC activation to proactive avoidance predicted higher levels of drinking during the follow‐up period. Taken together, our study identified pain sensitivity, pain‐avoidance drinking motive, and impaired proactive avoidance as predictors of future alcohol use severity. These findings highlight the roles of pain response, thus potentially informing interventions for individuals at risk of alcohol use disorders.
Diversity, Distribution and Habitat Suitability Assessment of Solanum Species of the Leptostemonum Clade in Uganda
Authors: Kawuma Carol , Stedje Brita , Katuura Esther , Ipulet Perpetua , Mulumba John Wasswa , Kakudidi Esezah , Mugizi Felly Tusiime , Bello Anifat Olayemi , Namaganda Mary
Published: February 2025

The diversity and distribution of Solanum species of the Leptostemonum clade in Uganda was updated based on field surveys, herbarium collections and literature. Distribution maps were generated using ArcMap software and Spatial Distribution Models generated using maximum entropy software (version 3.3.3). Predictions were based on five environmental variables, namely: temperature, rainfall, slope, soil and land use/cover. Model evaluations were based on Area Under Curve. Jack knife test assessed the importance of each environmental variable in predicting species occurrence. Twenty‐one species were recorded with Solanum chrysotrichum as a new record for Uganda. The highest species richness was recorded in southwestern Uganda. Karamoja had unique diversity with four species restricted to the region, thus: S. forskalii, S. lanzae, S. coagulans and S. hastifolium. Most of the species occur in disturbed habitats in the land use/cover areas defined as croplands, tree cover and grasslands. Temperature and rainfall were the most useful variables in predicting occurrence of Solanum species. Karamoja and South western sub regions are hotspots for conservation of the spiny Solanum species. Periodic field surveys should be carried out in order to monitor changes in the occurrence of Solanum particularly in the identified hotspots.
Clinical Features of Seven COL2A1 Variations in Chinese Children With Type II Collagen Disorders
Authors: Zhan Shumin , He Qin , Yuan Jinna , Xu Xiaoqin , Huang Ke , Dong Guanping , Fu Junfen , Wu Dingwen , Wu Wei
Published: February 2025

Aim

Type II collagen, encoded by the collagen type II alpha 1 (COL2A1) gene, is crucial for the structure of cartilage. This study aims to improve our understanding of Spondyloepiphyseal Dysplasia Congenita (SEDC) caused by mutations in COL2A1. We also aim to evaluate the safety and efficacy of growth hormone (GH) therapy in two SEDC patients.

Methods

We performed genetic analyses of seven paediatric patients from unrelated Chinese families. Two patients received GH therapy, and their growth trajectories were monitored over 3.5 and 3 years.

Results

Genetic screening identified six missense mutations (Gly1110Ser, Gly1107Glu, Gly873Arg, Gly456Ala, Gly1062Ser and Gly1182Arg) and one intron variant in COL2A1. All patients (five girls and two boys, ranging from 2 years and 7 months to 12 years) were diagnosed with SEDC, exhibiting disproportionate short stature and skeletal abnormalities. GH therapy resulted in height increases of 0.76 and 0.27 standard deviation scores over 3.5 and 3 years, respectively, with no significant side effects.

Conclusion

This study expands the mutation spectrum of COL2A1 and supports the efficacy and safety of GH therapy in SEDC patients, highlighting the need for multi‐center studies to further investigate GH's therapeutic potential.
LGBTQ+ conspiracy beliefs and collective actions: Factors and processes that (de)motivate support for LGBTQ+ equality
Authors: De Cristofaro Valeria , Costacurta Mirco , Pellegrini Valerio , Giacomantonio Mauro , Salvati Marco
Published: February 2025

Recent times are characterized by increased participation in collective action that either supports or opposes greater equality for LGBTQ+ individuals. In this research, we focus on the Italian context, where both forms of collective action are highly present, and examine the role of LGBTQ+ conspiracy beliefs (i.e., beliefs that a powerful LGBTQ+ lobby exist that operates secretly to pursue its plans against cis‐heterosexual people and spread homosexuality in society) in (de)motivating heterosexual cisgender individuals’ mobilization. We conducted two correlational studies (N = 1266) and tested whether participants who endorse LGBTQ+ conspiracy beliefs would be less motivated to mobilize in support of LGBTQ+ rights, through decreased identification with LGBTQ+ people, lower anger for LGBTQ+ inequality, and lower group efficacy to achieve LGBTQ+ equality (Studies 1 and 2). In addition, we tested whether participants who endorse LGBTQ+ conspiracy beliefs would be more motivated to mobilize against LGBTQ+ rights, through increased identification with heterosexual people, higher anger for LGBTQ+ equality, and higher group efficacy to contrast LGBTQ+ equality (Study 2). Results of mediation analyses supported these predictions, indicating conspiracy beliefs about the LGBTQ+ community as a social‐cognitive obstacle to the achievement of LGBTQ+ equality. Implications, limitations, and future research directions are discussed.