bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractPrior 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

SummaryPlasmodium 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

ABSTRACTTo 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

AbstractCognitive 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 PARAGRAPHCOVID-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

ABSTRACTAntimicrobial 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

AbstractDespite 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

ABSTRACTPseudomonas 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

AbstractThis 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

AbstractPseudomonas 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

ABSTRACTIntrinsically 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

ABSTRACTAgeing 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

ABSTRACTVisual 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

AbstractWe 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.