bluuebunny/crossref_metadata_2025 huggingface dataset:
Global 3D simulations of magnetospheric accretion – II. Hotspots, equilibrium torque, episodic wind, and mid-plane outflow
Authors: Zhu Zhaohuan
Published: February 2025

Global 3D magnetohydrodynamical simulations have been conducted to study magnetospheric accretion around stars with various spin rates. For slow rotators, characterized by a fastness parameter $\omega _{\mathrm s}\lesssim 0.78$, the disc’s inner edge at the magnetospheric truncation radius becomes unstable to the interchange instability, leading to intruding filaments which produce hotspots closer to the stellar equator. Depending on spin rate, slow rotators can be in ‘chaotic’ or ‘ordered’ unstable regimes. For fast rotators, the interchange instability is suppressed by the super-Keplerian rotation beyond the corotation radius, and hotspots are generated only through polar accretion. Low- and mid-energy flux hotspots cover $\lesssim 20~{{\rm per\,cent}}$ and $\lesssim 3~{{\rm per\,cent}}$ of the surface, with faster rotators tending to produce hotter spots. Beyond the truncation radius, angular momentum transfers from the disc surface to the mid-plane, resulting in surface accretion and mid-plane outflow. The mid-plane outflow may transport thermally processed materials (e.g. those in chondrites) to the outer disc. Field inflation generates episodic winds with mass-loss rates $\sim$1–40 per cent of the accretion rate, depending on stellar spin. Frequent magnetic reconnections lead to efficient star–disc coupling. We derive the torque exerted by the disc on the star as a function of stellar spin. For fast rotators/propellers, both spin-down torque and disc wind rate increase dramatically with stellar spin. The equilibrium spin state occurs at $\omega _{\mathrm s}\sim 0.7$, with wind/jet speeds ($\sim$500 km s−1) and mass-loss rates ($\sim 10~{{\rm per\,cent}}$ accretion rate) aligning with observations. Most results are insensitive to disc thickness. Finally, we present testable predictions for how observables vary with stellar spin.
The stellar mass composition of galaxy clusters and dependencies on dark matter halo properties
Authors: Montenegro-Taborda Daniel , Avila-Reese Vladimir , Rodriguez-Gomez Vicente , Manuwal Aditya , Cervantes-Sodi Bernardo
Published: February 2025

We analyze 700 clusters from the TNG300 hydrodynamical simulation (M200 ≥ 5 × 1013 M⊙ at z = 0) to examine the radial stellar mass distribution of their central objects, consisting of the brightest cluster galaxy (BCG) and the intracluster light (ICL). The BCG+ICL mass fraction weakly anticorrelates with M200, but strongly correlates with the concentration, c200, the assembly redshift, z50, and the mass gap between the most massive and the fourth more massive member, $\Delta M_{\ast ,\rm 4th}$. We explore different aperture radii to nominally separate the ICL from the BCG and calculate ICL fractions. For rap = 2r*, half, where r*, half is the radius containing half the BCG+ICL mass, the ICL fraction is nearly independent of M200, c200, and z50 with values $\mbox{$M_{\rm \ast ,ICL}$}/(\mbox{$M_{\rm \ast ,ICL}$}+\mbox{$M_{\rm \ast ,BCG}$})= 0.33\pm 0.03$. Including the stellar mass of the satellites, the fraction $\mbox{$M_{\rm \ast ,ICL}$}/(\mbox{$M_{\rm \ast ,ICL}$}+\mbox{$M_{\rm \ast ,BCG}$}+M_{\rm \ast ,sat})$ weakly anticorrelates with M200 and strongly correlates with c200, z50, and $\Delta M_{\ast ,\rm 4th}$, suggesting that in more concentrated/earlier assembled/more relaxed clusters more stellar mass is lost from the satellites (by tidal stripping, and mergers) in favour of the ICL and BCG. Indeed, we find that ex-situ stars dominate both in the BCG and ICL masses, with mergers contributing more to the BCG, while tidal stripping contributes more to the ICL. We find that the difference between the projected and 3D ICL fractions are only a few per cent and suggest using 2$r_{\rm \ast ,half}^{\rm 2D}$ to separate the ICL from the BCG in observed clusters.
Formation and evolution of binary black holes in N-body simulations of star clusters with up to two million stars
Authors: Barber Jordan , Antonini Fabio
Published: February 2025

Understanding binary black hole (BBH) dynamics in dense star clusters is key to interpreting the gravitational wave detections by LIGO and Virgo. Here, we perform N-body simulations of star clusters, focusing on BBH formation mechanisms, dynamical evolution and merging properties. We explore a wide parameter space of initial conditions, with cluster masses ranging from 104 to 106 M⊙, densities from 103 to $10^{5}~\rm {M_{\odot }\, pc^{-3}}$, and up to 100% of massive stars in binaries. We show that most BBH mergers originate from the primordial binary population rather than being dynamically assembled, and that the evolution towards merger for most of these binaries is not significantly altered by dynamical encounters. As a result, the overall number of BBH mergers from the N-body simulations is nearly identical to that obtained when the same stellar population is evolved in isolation. Contrary to theoretical expectations, nearly all dynamically formed BBH mergers occur when the binary is still bound to its host cluster, with ≃ 90% of all dynamical mergers occurring within the cluster core region. In about half of these mergers the binary is part of a stable black hole-triple system. In one model, stellar mergers lead to the formation of a ≃ 200 M⊙ black hole, which then grows to ≃ 300 M⊙ through black hole mergers. Our study highlights the importance of detailed N-body simulations in capturing the evolution of black hole populations in dense clusters and challenges conclusions based on semi-analytical and Monte Carlo methods.
Particle acceleration and nonthermal emission at the intrabinary shock of spider pulsars. II: Fast-cooling simulations
Authors: Cortés Jorge , Sironi Lorenzo
Published: February 2025

Spider pulsars are binary systems composed of a millisecond pulsar and a low-mass companion. Their X-ray emission, varying with orbital phase, originates from synchrotron radiation produced by high-energy electrons accelerated at the intrabinary shock. For fast-spinning pulsars in compact binary systems, the intrabinary shock emission occurs in the fast cooling regime. Using global two-dimensional particle-in-cell simulations, we investigate the effect of synchrotron losses on the shock structure and the resulting emission, assuming that the pulsar wind is stronger than the companion wind (so, the shock wraps around the companion), as expected in black widows. We find that the shock opening angle gets narrower for greater losses; the lightcurve shows a more prominent double-peaked signature (with two peaks just before and after the pulsar eclipse) for stronger cooling; below the cooling frequency, the synchrotron spectrum displays a hard power-law range, consistent with X-ray observations.
Assessing the Dose of Regadenoson Required to Transiently Alter Blood-Brain Barrier Integrity in Patients with Infiltrating Gliomas
Authors: Grossman Stuart A , Romo Carlos G , Ye Xiaobu , Kral Brian , Strowd Roy E , Lesser Glenn , Raymond Catalina , Iacoboni Michaella , Desideri Serena , Fisher Joy , Danda Neeraja , Ellingson Benjamin M ,   ABTC
Published: February 2025

BACKGROUND

The blood brain barrier (BBB) severely limits delivery of therapeutic agents to the brain. Regadenoson, an FDA approved adenosine A2 agonist, transiently increases BBB permeability in rodents to a 70kDa dextran. This multi-institutional, NIH funded study examined regadenoson’s ability to transiently alter BBB permeability in patients with gliomas.

METHODS

Adults with supratentorial gliomas at low-risk for regadenoson complications were treated with one of seven dose levels known to be safe in humans. Successful BBB disruption was defined as 10-fold increase in vascular permeability (Ktrans) relative to historic benchmarks. This was assessed by dynamic contrast enhanced perfusion on MRI in normal appearing white matter (NAWM) changes in NAWM and non-enhancing tumor were also quantified using contrast enhanced T1 subtraction maps.

RESULTS

Seven patients <45 years old with low grade gliomas were accrued before the study was prematurely closed. Regadenoson was well tolerated. Following regadenoson, Ktrans in NAWM did not reach the targeted Ktrans threshold (0.04 min-1). Normalized subtraction maps of contrast enhanced T1-weighted MR signal intensity in NAWM did increase an average of 74%±22% (p= 0.016) after regadenoson.

CONCLUSIONS

No dose of regadenoson significantly elevated Ktrans in NAWM. However, the subtraction maps suggest that regadenoson may lead to a measurable change in gadolinium flux. This coupled with strong pre-clinical data suggests further investigation is warranted. Non-invasive quantification of BBB permeability in patients is feasible and could evaluate different regadenoson schedules, combination therapies, and other approaches to modify BBB permeability which is critical to improving outcomes in patients with brain tumors.
Reemergence Memory of Subtropical Mode Water Links Atlantic and Pacific Multidecadal Variability
Authors: Wu Baolan , Lin Xiaopei , Yu Lisan
Published: February 2025

Understanding how the ocean provides the memory for maintaining decadal to multidecadal variability is key to climate prediction. An important question is what process could provide the observed significant time-lag between the Pacific Decadal Oscillation (PDO) and the Atlantic Multidecadal Oscillation (AMO). Here we show that the Pacific Ocean could store climate anomalies within the subtropical recirculation gyre for a decadal duration, providing a ‘seeding’ link between the AMO and the PDO. The AMO-induced multidecadal temperature anomalies in the Northwestern Pacific Ocean are subducted into the thermocline and sequestered in the North Pacific subtropical mode water. These temperature anomalies propagate along the recirculation gyre and eventually re-join the Kuroshio one decade later. Once reemerged in the Kuroshio-Oyashio Extension region, the anomalies may engage with local air-sea feedbacks triggering the PDO. Our findings demonstrate that the mode water could provide a much-needed ocean memory for the prediction of multidecadal variability.
Worsened disparities in prenatal care among individuals with low educational attainment during the COVID-19 pandemic in the US: a repeated cross-sectional study
Authors: Lee Jusung , Manalew Wondimu Samuel
Published: February 2025

Background

The coronavirus pandemic was a major event that severely disrupted the health care system in the USA. Understanding the impact, especially among socioeconomically disadvantaged individuals, is necessary for informing health care and public health policy. This study evaluates changes in adequate prenatal care (PNC) across education levels after the 2020 pandemic.

Methods

The key outcome was adequate PNC utilization using the Kotelchuck index. A repeated cross-sectional study of before and after the COVID pandemic among individuals with low educational attainment compared to those with a college degree or above was used to estimate changes in adequate PNC use.

Results

A decrease in adequate PNC use after 2020 was greater (−4.4%) for less than high school graduation, compared to higher education levels (−2.0% to −0.8%). The difference in adjusted changes reaffirmed that having less than high school graduation was associated with a greater decrease in adequate PNC by −3.7 percentage points (95%CI −5.8, −1.5) compared to obtaining college degrees after 2020.

Conclusion

Disparities in access to care are persistent and further deteriorate among individuals of low educational attainment after the 2020 pandemic. An innovative, robust healthcare model is vital to reduce barriers to and disparities in access to care.
Crus control: Effective cerebello-cerebral connectivity during social action prediction using Dynamic Causal Modelling
Authors: Haihambo Naem , Baetens Kris , Deroost Natacha , Baeken Chris , Overwalle Frank Van
Published: February 2025

This dynamic causal modeling (DCM) analysis, comprising 99 participants from 4 studies, investigated effective neuronal connectivity during social action sequence prediction. The analysis focused on mentalizing areas within the cerebellum, specifically the bilateral Crus 1, Crus 2, and lobule IX, as well as cerebral mentalizing areas within the precuneus, temporo-parietal junction (TPJ), and dorsal medial prefrontal cortex (dmPFC). Consistent with previous research, we found robust bidirectional closed loop connections between the posterior cerebellar Crus and cerebral mentalizing areas. We also found previously unexplored unidirectional connections originating from cerebellar lobule IX to the dmPFC and left TPJ, and from the right TPJ to lobule IX. Furthermore, we uncovered many bidirectional closed loops within the cerebellum between the left and right Crus 1, and between Crus 1 and Crus 2, and for the first time, between the bilateral Crus 2 and lobule IX. Our findings illuminate the distinct role of cerebellar Crus and lobule IX, and cerebral mentalizing areas in predicting social action sequences.
Decoding affect in emotional body language: Valence representation in the action observation network
Authors: Keck Johannes , Bachmann Julia , Zabicki Adam , Munzert Jörn , Krüger Britta
Published: February 2025

Humans are highly adept at inferring emotional states from body movements in social interactions. Nonetheless, it is under debate how this process is facilitated by neural activations across multiple brain regions. The specific contributions of various brain areas to the perception of valence in biological motion remain poorly understood, particularly those within the action observation network (AON) and those involved in processing emotional valence. This study explores which cortical regions involved in processing emotional body language depicted by kinematic stimuli contain valence information, and whether this is reflected either in the magnitude of activation or in distinct activation patterns. Results showed that neural patterns within the AON, notably the inferior parietal lobule (IPL), exhibit a neural geometry that reflects the valence impressions of the observed stimuli. However, the representational geometry of valence-sensitive areas, mirrors these impressions to a lesser degree. Our findings also reveal that the activation magnitude in both AON and valence-sensitive regions does not correlate with the perceived valence of emotional interactions. Results underscore the critical role of the AON, particularly the IPL, in interpreting the valence of emotional interactions, indicating its essential function in the perception of valence, especially when observing biological movements.
Unveiling the role of KLF9‐mediated IFITM3 regulation in amyloidogenesis
Authors: Feng Yijia , Zhou Qian , Hu Bolang , Wang Shengya , Chen Lifen , Cai Wantong , Zhu Qinxin , Qin Xuemei , Zhou Weihui , Wu Yili , Song Weihong
Published: February 2025

Interferon‐induced transmembrane protein 3 (IFITM3) is implicated in the pathogenesis of Alzheimer's Disease (AD) by regulating γ‐secretase activity and subsequent amyloid β (Aβ) generation. However, the regulation of IFITM3 gene expression and the underlying mechanisms remain exclusive. In this study, we aimed to investigate the regulation of the IFITM3 and its role in amyloidogenesis. The functional active promoter of the IFITM3 gene was identified within the 1047 bp of 5′‐flanking regions by luciferase assays. Through chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA), we successfully identified a specific Krüppel‐like factor 9 (KLF9) binding site within the promoter region. Moreover, KLF9 overexpression significantly upregulates IFITM3 expression in vitro and in vivo, which promotes Aβ generation in the hippocampus of mice. Consistently, reduced IFITM3 expression results in a notable decrease of Aβ production. Together, we demonstrate that KLF9 plays a critical role in regulating IFITM3 expression and subsequent Aβ production. It highly suggests that inhibiting KLF9‐mediated IFITM3 expression may have therapeutic potential for AD by reducing Aβ production.
A Comparative Analysis of Dementia Strategies of Fifteen European Countries in the Context of Glasgow Declaration and WHO’s Global Action Plan
Authors: Bulsari Smruti , Hashim Nureen Izyani , Pandya Kiran , Kabir Russell
Published: February 2025

Dementia prevalence across the globe is in alarming proportion and it is even expected to rise in the future. The World Health Organisation (WHO) had declared dementia as a health priority, way back in 2009 and had recommended then, that at least high-income countries develop a dementia action plan, and other countries develop a national dementia strategy (NDS). Later in 2014, European Countries came together to sign the Glasgow Declaration and agreed to develop their respective NDSs. Yet, a few countries still do not have their NDS. Moreover, some countries do not have their NDS in English. This study attempts to compare the dementia strategies of 15 European countries, which has a comprehensive NDS in English language. The study further examines how well these NDSs comply with the Glasgow Declaration and the WHO’s Global Action Plan guidance. We undertake cluster analysis to classify NDSs of these countries in terms of similarity in the content. We make use of word clouds to get an overall idea about the clusterwise contents of the NDSs, and then use algorithmic approach to content analysis for identifying the clusterwise key focus areas of these dementia strategies. We make a comparative analysis of these NDSs in the perspective of dementia prevalence, demographic profile, per capita gross domestic product (GDP) and predominant healthcare financing model. We have found that irrespective of the prevalence, country’s demographic profile, GDP per capita or the predominant financing model, dementia strategies primarily focus on “care”. We discuss the cost-effectiveness of prevention and person-centered care (PCC) and suggest according priorities to these in the future NDSs, as these are also the focus areas of Glasgow Declaration and the GAP.
Multi-institutional Normal Tissue Complication Probability (NTCP) Prediction Model for Mandibular Osteoradionecrosis: Results from the PREDMORN Study
Authors: Humbert-Vidan Laia , Hansen Christian R. , Petit Steven , Muñoz-Montplet Carles , Mohamed Abdallah S. R. , Saunders Deborah P. , Patel Vinod , Verduijni Gerda M. , Heemsbergen Wilma D. , van der Schaaf Arjen , Witjes Max , de Vette Suzanne , Khan Abdul A. , Querol Jordi Marruecos , Cancio Irene Oliveras , Oliver Mike , Reich Peter , Santi Stacey A. , Pearce Andrew G. , Lai Stephen Y , King Andrew P. , Langendijk Johannes A. , Johansen Jørgen , Moreno Amy C , Fuller Clifton D. , van Dijk Lisanne V. , Urbano Teresa Guerrero
Published: February 2025

Background

Mandibular osteoradionecrosis (ORN) is a severe late complication affecting patients with head and neck cancer (HNC) treated with radiotherapy that significantly impacts patients’ quality of life and can require costly interventions. While radiation dose is a key factor, other clinical and demographic risk factors influence ORN development. Previous predictive models have primarily been single-institutional, limiting their generalizability. The PREDMORN Consortium was established to address these limitations. In this first analysis, we have aimed to reproduce existing statistical association and modelling analyses on the largest and most diverse mandibular ORN cohort worldwide to allow comparison with previous studies. As such, we have developed, tested and externally validated a multi-institutional normal tissue complication probability (NTCP) model for mandibular ORN.

Methods

This retrospective multi-institutional study included 1,184 HNC patients (389 ORN cases) from seven institutions. Clinical, demographic, and dosimetric (DVH) variables were analysed to develop a prediction model (any grade of ORN vs. no ORN) using forward stepwise logistic regression with correlation-based variable pre-selection. The ORN NTCP model was developed on 80% of data from six institutions, tested on the remaining unseen 20%, and externally validated on the seventh institution’s dataset.

Results

Key predictors of ORN were D30%, V70Gy, pre-RT dental extractions, and smoking status. The ORN NTCP model demonstrated good calibration and predictive performance, with AUCs of 0.69 for internal testing and external validation, which improved when tested on a sub-cohort of oropharyngeal and locally advanced larynx/hypopharynx cancer cases (AUCs of 0.75).

Conclusion

The PREDMORN NTCP model is the largest multi-institutional effort to predict ORN risk in HNC patients. We provide guidance on how to adjust the NTCP predicted probabilities for differences in target population baseline ORN risk to facilitate application of the model. Future research will focus on incorporating imaging-based spatial data and further external validation to enhance clinical applicability.
p16 expression confers sensitivity to CDK2 inhibitors
Authors: Sine Chance , Watts Lotte , Fernandez Brianna , Wang Jianxin , Knudsen Erik , Witkiewicz Agnieszka , Spencer Sabrina L
Published: February 2025

Blocking the cell cycle is a promising avenue for cancer therapy, with Cyclin-Dependent Kinase 2 (CDK2) emerging as a key target. However, in multiple cell types, CDK4/6 activity compensates for CDK2 inhibition and sustains the proliferative program, enabling CDK2 reactivation. Thus, we hypothesized that sensitivity to CDK2 inhibition is linked to the absence of this CDK4/6-mediated compensatory mechanism. Here we show that Cyclin E1-driven ovarian cancers often co-express the tumor suppressor p16, which inhibits CDK4/6. We show that ovarian cancer cells expressing p16 exhibit heightened sensitivity to CDK2 inhibitors and that depletion of p16 renders them significantly more resistant. Multiplexed immunofluorescence of 225 ovarian patient tumors reveals that at least 18% of tumors express high Cyclin E1 and high p16, a group that we expect to be particularly sensitive to CDK2 inhibition. Thus, p16 may be a useful biomarker for identifying the patients most likely to benefit from CDK2 inhibitors.
Role of the NuRD complex and altered proteostasis in cancer cell quiescence
Authors: Jiang Qi J , Ertel Michelle , Arrigo Austin , Sannino Sara , Goeckeler-Fried Jennifer L. , Sagan April , Varghese Betsy A , Brown Daniel D. , Stallaert Wayne , Lee Adrian , Clark Amanda , Brodsky Jeffrey , Osmanbeyoglu Hatice U. , Buckanovich Ronald J
Published: February 2025

Cytotoxic chemotherapy remains the primary treatment for ovarian cancer (OvCa). Development of chemoresistance typically results in patient death within two years. As such, understanding chemoresistance is critical. One underexplored mechanism of chemotherapy resistance is quiescence. Quiescent cells, which have reversibly exited the cell cycle, are refractory to most chemotherapies which primarily target rapidly proliferating cells. Here, we report that CHD4 and MBD3, components of the nucleosome remodeling and deacetylase (NuRD) complex, are downregulated in quiescent OvCa cells (qOvCa). Indicating a direct role for NuRD complex downregulation in the induction of quiescence, either CHD4 or MBD3 knockdown or histone deacetylase inhibitors (HDACi), such as vorinostat, induce quiescence in OvCa cells. RNA-Seq analysis of HDACi-treated cells confirmed expression changes consistent with induction of quiescence. We also find that both primary qOvCa and vorinostat-induced qOvCa demonstrate altered proteostasis, including increased proteasome activity and autophagy, and combination therapy of HDACi and proteasome inhibitors or autophagy inhibitors demonstrated profound synergistic death of OvCa cells. Finally, we overlapped RNA-Seq signatures from quiescent ovarian cancer cells with genes essential for quiescence in yeast to identify a "quiescent cell core signature." This core quiescent cell signature appeared to be conserved across multiple cancer types, suggesting new therapeutic targets.
Find Central Dogma Again: Leveraging Multilingual Transfer in Large Language Models
Authors: Liang Wang
Published: February 2025

In recent years, large language models (LLMs) have achieved state-of-the-art results in various biological sequence analysis tasks, such as sequence classification, structure prediction, and function prediction. Similar to advancements in AI for other scientific fields, deeper research into biological LLMs has begun to focus on using these models to rediscover important existing biological laws or uncover entirely new patterns in biological sequences. This study leverages GPT-like LLMs to utilize language transfer capabilities to rediscover the genetic code rules of the central dogma. In our experimental design, we transformed the central dogma into a binary classification problem of aligning DNA sequences with protein sequences, where positive examples are matching DNA and protein sequences, and negative examples are non-matching pairs. We first trained a GPT-2 model from scratch using a dataset comprising protein sequences, DNA sequences, and sequences from languages such as English and Chinese. Subsequently, we fine-tuned the model using the natural language sentences similarity judgment dataset from PAWS-X. When tested on a dataset for DNA and protein sequence alignment judgment, the fine-tuned model achieved a classification accuracy of 81%. The study also analyzed factors contributing to this zero-shot capability, including model training stability and types of training data. This research demonstrates that LLMs can, through the transfer of natural language capabilities and solely relying on the analysis of sequences themselves, rediscover the central dogma without prior knowledge of it. This study bridges natural language and genetic language, opening a new door for AI-driven biological research.
Supplementary motor area microstructure as measured by diffusion imaging defines the extent of gait impairment in Parkinson’s disease
Authors: Wróbel Paweł P. , Peter Annika , Kirsten Maja , Gulberti Alessandro , Bester Maxim , Goebell Einar , Cheng Bastian , Rathi Yogesh , Pasternak Ofer , Magnus Tim , Thomalla Götz , Quandt Fanny , Schulz Robert , Higgen Focko L. , Pötter-Nerger Monika
Published: February 2025

Background

Gait disorders are therapeutically challenging symptoms in Parkinson’s disease. However, the pathophysiological mechanisms and the interaction between cerebral structure and clinical burden are not yet fully understood. Objectives: Given that cortical microstructure is a crucial determinant of symptom burden in neurodegenerative diseases, we hypothesized that diffusion-imaging-based microstructural markers in the supplementary motor area, one cortical key hub in the gait network, are associated with gait performance. Methods: In this retrospective study, 29 patients (mean age 64.1 ± 6.9 years, 11 (37.9%) female, mean disease duration 10.9 ± 4.5 years) were included. Diffusion-tensor imaging measures and cortical thickness (fractional anisotropy, radial and axial diffusivity) in the supplementary motor area as defined by the Human Motor Area Template were correlated with quantitative gait performance parameters. Results: Lower anisotropy in the right supplementary motor cortex was significantly associated with better performance across various bilateral gait parameters during walking at natural speed, at maximal velocity and particularly during dual-tasking. There were no significant associations between cortical thickness and gait performance. Conclusions: Given the inverse relationship between anisotropy and cortical tissue complexity, the observed lower anisotropy in the right supplementary motor area of patients with better gait performance supports the assumption of the modulatory role of this cortical area in gait control suggesting a potential therapeutic target e.g. stimulation, in Parkinson’s disease patients with gait disorders.
Human Papilloma Virus does not fully inactivate p53 in HNSCC
Authors: Gencel-Augusto Jovanka , Li Hua , Woerner Liam C. , Borah Ashir A. , Myers Jeffrey N. , Johnson Daniel E. , Grandis Jennifer R.
Published: February 2025

Head and neck squamous cell carcinoma (HNSCC) is a major global health challenge. Inactivation of the tumor suppressor p53 is the most frequent molecular event in this malignancy. p53 inactivation occurs either throughTP53mutations in HPV-negative cases or via HPV-mediated p53 degradation in HPV-positive (HPV+) cases, where most retain a wild-type (WT)TP53allele. This underscores the critical role of p53-regulated processes in HNSCC pathogenesis. Clinically, HPV+ HNSCC is associated with significantly better outcomes than HPV-negative cases. Despite HPV E6-mediated degradation of p53, 10% of HPV+ HNSCC cases have mutantTP53alleles, suggesting an additional need to suppress p53 signaling. In this study, we demonstrate that HPV+TP53-WT HNSCC cells have residual p53 activity, with tumor-suppressive effects. Specifically, ablation of p53 in HPV+TP53-WT HNSCC cells lead to increased proliferation, migration, and invasion. RNA-sequencing revealed that p53 regulates gene transcription (both activation and repression) in the presence of HPV, and we confirmed that these functions are p53-specific. Human tumor data further reveal that among HPV+ HNSCC cases, those with WTTP53have significantly better survival outcomes than HPV+ cases withTP53mutations. Notably, HPV+TP53-WT HNSCC tumors show decreased PI3K-AKT signaling, increased gene methylation in oncogenic pathways, and fewer chromosomal alterations compared to HPV+TP53-mutant tumors. These findings challenge the prevailing notion that p53 is entirely inactivated in HPV+ HNSCC and provide critical insights into HNSCC-specific, p53-driven tumor suppression mechanisms with implications for targeted therapies in HNSCC.
Dynamic nucleosome redistribution and increases in nucleosome sensitivity underpin THP-1 macrophage response to LPS
Authors: Benoit Jane M , Buck Brandon D , Khadem Mahdi , Bass Hank W , Dennis Jonathan H
Published: February 2025

Macrophages detect lipopolysaccharide (LPS) through toll-like receptor 4 (TLR-4) on the cell surface which initiates a signaling cascade resulting in the recruitment of regulatory factors to chromatin and subsequent expression of chemokine and cytokine genes. Primary response genes, marked by poised promoters and enhancers, are rapidly expressed after LPS stimulation, and their gene products activate secondary response genes via paracrine and autocrine signaling pathways. While the signaling cascades following macrophage activation are well understood, the dynamics of nucleosome architecture and regulatory factor binding in promoter regions during early and late LPS responses remain unclear. Here, we stimulated THP-1 derived macrophages with LPS and assessed nucleosome distribution and MNase sensitivity across promoters at eight time points spanning primary and secondary responses. We found that while nucleosome distribution was static over most promoters, LPS stimulation resulted in transient remodeling of a subset of immune and DNA repair gene promoters. We also observed distinct MNase sensitivity alterations in two phases which aligned with early and late gene expression patterns. Notably, while most Pol II promoters showed altered chromatin sensitivity, only a subset exhibited transcriptional changes, suggesting that widespread alterations in nucleosome distribution and sensitivity occur at promoters with or without alterations in gene expression. These findings provide new temporal insights into the transient and long-term effects of immune stimulation on promoter architecture and offer a methodological framework for additional time-resolved studies of chromatin remodeling in other systems.

Summary sentence

Following LPS stimulation, a subset of nucleosomes in macrophage immune promoters undergo transient redistribution, whereas the majority of nucleosomes show changes in MNase sensitivity that are largely uncoupled from gene expression.

Abstract Figure

Graphical abstract.

LPS stimulation of THP-1 derived macrophages leads to altered nucleosome occupancy and positioning within a subset of promoters which are enriched for LPS response genes. Altered distribution patterns permit regulatory factor binding and gene expression. The majority of promoters have altered nucleosome sensitivity with a trend towards increased sensitivity after LPS stimulation. Altered sensitivity results in regulatory factor binding and expression of LPS response genes.
Dietary sterol depletion is associated with gut dysfunction inDrosophila melanogasterfemales
Authors: Zanco Brooke , Mirth Christen K , Sgro Carla M , Piper Matthew DW
Published: February 2025

Recent findings have shown that dietary restriction (DR) may extend lifespan by improving late life gut health. Given that recent work has shown that micronutrients such as sterols can mediate the effects of macronutrient ratios on longevity, we decided to examine the effects of sterol limitation on gut health. We found that mothers fed low sterol diets both suffer from increased incidence of intestinal permeability and reduced lifespans. Moreover, epithelial cells in the anterior region of the guts of flies fed low sterol diets showed signs of dysfunction prematurely when compared to flies fed adequate sterols. These findings indicate that the relationship between gut dysfunction and death inD. melanogasterfemales is conditional on dietary sterol limitation and may point to different paths of physiological decline with ageing that depend on the precise nutritional composition of the diet.
Lactobacillus acidophilusAttenuates Polyethylene Glycol-Induced Susceptibility toCitrobacter rodentiumInfection via Microbiota Modulation
Authors: Kou Guan-jun , Shen Jing , Li Guang-chao , Fu Shan-shan , Li Li-xiang , Zuo Xiu-li , Li Yan-qing
Published: February 2025

Objective

Polyethylene glycol (PEG), a globally prevalent laxative, is extensively utilized for bowel preparation prior to colonoscopy or abdominal surgery owing to its exceptional safety profile. Nevertheless, emerging evidence suggests that PEG administration may induce significant alterations in colonic microbiota composition, with dysbiotic effects persisting for over two weeks. The potential implications of such microbiota perturbations on the colonization and invasion of opportunistic pathogens remain underexplored.

Methods and Analysis

To investigate this, we employed a murine model infected withCitrobacter rodentium(C.R.), a surrogate for Enteropathogenic Escherichia coli(EPEC) andEnterohemorrhagic Escherichia coli(EHEC), following PEG-induced bowel preparation.

Results

The severity of infectious enteritis was assessed, and the prophylactic efficacy ofLactobacillus acidophilus (LAC) supplementation was evaluated. Our findings indicate that PEG administration significantly elevatedC.R.load, enhanced virulence gene expression, and exacerbated intestinal inflammation post-infection, with the infection window extending approximately 14 days. Through fecal metagenomic analysis and co-housing experiments, we demonstrated that PEG-associated enteritis is critically mediated by gut microbiota dysbiosis. Furthermore, supplementation withLACwas shown to mitigate susceptibility toC.R. infection.

Conclusions

These results suggest that PEG increases intestinal susceptibility to infection in a microbiota-dependent manner, highlighting the therapeutic potential ofLACin restoring microbial homeostasis.
Homeodomain protein Sxi1α regulates cell-cell fusion during distinct sexual reproduction modes inCryptococcus deneoformans
Authors: Huang Jun , Peterson Patricia P. , Xu Ziyan , Xiong Liping , Sun Sheng , Heitman Joseph
Published: February 2025

Sex-specific homeodomain (HD) proteins are key regulators of cell identity and sexual development in fungi, typically functioning as heterodimers to regulate transcription. In the human fungal pathogensCryptococcus neoformansandCryptococcus deneoformans, theHDproteins Sxi1α and Sxi2a(sex-induced 1α and 2a) have been characterized as interacting partners that play critical roles in sexual development duringax α sexual reproduction. Given the dominance of α cells in natural populations ofCryptococcus, the roles of Sxi1α and Sxi2ain unisexual reproduction, which predominantly involves same-sex (α x α) mating, remain unclear. To elucidate the functions of Sxi1α and Sxi2ain unisexual reproduction, we first used AlphaFold3 to predict their structures, which revealed the potential for both heterodimeric and homodimeric complexes. We subsequently deletedSXI1α andSXI2ain the hyperfilamentous self-fertileC. deneoformansstrains XL280aand XL280α. Disruption of these genes did not result in noticeable defects in vegetative growth, virulence-associated traits, colony morphology, sporulation, or competitiveness during eitherax α or α x α crosses. Surprisingly, the absence ofSXI1α significantly increased the cell–cell fusion rate during both α x α andax α mating, suggesting a novel inhibitory role for Sxi1α, independent of the partner Sxi2a. Together, our findings revealed an unexpected function of Sxi1α in regulating cell fusion, which may contribute to the predominance ofMATα isolates in globalCryptococcuspopulations and the conservation ofSXI1α in a population that is predominantly α mating type.
Exploring the causal role of the human gut microbiome in breast cancer risk
Authors: Edmunds Grace L. , Robinson Tim , Yarmolinsky James , Lee Matthew A , Hayes Bryony , Hughes David A , Gibbs Lara , Braybrooke Jeremy P. , Raes Jeroen , Timpson Nicholas J. , Wade Kaitlin H.
Published: February 2025

The relationship between the human gut microbiome and breast cancer (BC) risk is uncertain. We used Mendelian randomization (MR) and multivariable linear regression to investigate the causal relationship between the human gut microbiome and BC risk (overall and subtype-specific) and interrogate the role of circulating metabolites as potential mediators. Summary-level data from genome-wide association studies of gut microbial traits (N=3,890), circulating metabolites (N=7,824), overall (N=247,175) and subtype-specific (N=200,898) BC risk, including triple negative BC (TNBC; N=120,493), alongside individual-level data from the Flemish Gut Flora Project (N=2,242). Sensitivity analyses were applied to examine the robustness of causal estimates. Initial two-sample MR analyses suggested that the presence of bacteria within theRuminococcusgenus increased overall BC risk, that higher abundances of bacteria within theParabacteroidesgenus decreased and presence of unclassified bacteria within theBacteroidalesorder increased TNBC risk, and that several circulating metabolites altered BC risk (e.g., homostachydrine with overall BC and Luminal A BC, and betaine with TNBC). Whilst, in multivariable linear regression analyses, several of these metabolites were also associated with the microbial traits that influenced BC risk, importantly, given directional inconsistency of associations across analyses of microbial traits, metabolites and BC coupled with sensitivity analyses implying violations of MR assumptions, associations were unlikely to reflect causality nor a causal pathway between the gut microbiome, metabolites, and BC risk.
mRNA-LNP vaccines against Hepatitis B virus induce protective immune responses in preventive and chronic mouse challenge models
Authors: Limeres María José , Gambaro Rocio , Svensson Malin , Fraude-El Ghazi Silvia , Pretsch Leah , Frank Daniel , Islan German A. , Rivero Berti Ignacio , Bros Matthias , Tam Ying K. , Muramatsu Hiromi , Pardi Norbert , Gehring Stephan , Cacicedo Maximiliano L.
Published: February 2025

Over 300 million people worldwide suffer from chronic hepatitis B virus infections that can cause serious liver damage and hepatocellular carcinoma. Ineffective innate and adaptive immune responses characterize these chronic infections, making the development of a therapeutic vaccine an urgent medical need. While current vaccines can prevent HBV infections, they are ineffective in treating chronic disease. This study investigated lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines encoding Hepatitis B surface antigen (HBsAg) for prophylactic and therapeutic applications. We found that HBsAg mRNA-LNP vaccines induced robust humoral and cellular immune responses, outperforming the protein-based vaccine approved for human use. The incorporation of an MHC class I signal peptide further enhanced Th1-biased responses preventing HBV infections in a mouse model. Importantly, mRNA-LNP vaccination led to seroconversion, HBsAg clearance, and strong T cell responses in a chronically infected mouse model. These findings highlight the potential of mRNA-LNP as an alternative and effective vaccine modality for HBV prophylaxis and therapeutic use in treating chronic infections.
Unravelling the Core and Accessory Genome Diversity ofEnterobacteriaceaein Carbon Metabolism
Authors: Näpflin Nicolas , Schubert Christopher , Malfertheiner Lukas , Hardt Wolf-Dietrich , von Mering Christian
Published: February 2025

Enterobacteriaceaeare commonly colonizing animal guts and impact health. While strain-specific metabolic features can promote gut colonization, we lack systematic knowledge regarding metabolic diversity and the core metabolism shared amongEnterobacteriaceae. To address this gap, we have analyzed the pan-genome of nearly 20,000 genomes. We found that genes necessary for monosaccharide-fuelled mixed acid fermentation are part of theEnterobacteriaceaecore genome, while most genes for anaerobic respiration and most carbohydrate utilization genes belong to the accessory genome. UnderstandingEnterobacteriaceae’smetabolic capacity helps clarify the distinction of nutrients consumed by allEnterobacteriaceae, and niche-defining nutrient sources, which are genus-, species- or strain-specific. This knowledge sheds light on bacterial nutrient exploitation during gut colonization in health and disease, aiding in the development of targeted interventions for microbiome research and infectious disease control. The theoretical framework described here can also be adapted to analyze core physiological characteristics of other microbiota taxa.
A Clinically Aligned Murine Model of Electroconvulsive Stimulation Reverses Social Aversion and Displays Fear Memory Impairment After Chronic Social Defeat Stress
Authors: Kritzer Michael D , Maddox Stephanie , Chen Michelle X , Dan Shu , Covington Herbert , Miczek Klaus A , Camprodon Joan A , Klengel Torsten , Ressler Kerry J
Published: February 2025

Electroconvulsive therapy (ECT) remains the most effective treatment for patients with major depression, bipolar depression, mania, catatonia, and severe psychosis. Nonetheless, the mechanisms underlying the therapeutic effects of ECT largely remain unknown. While previous preclinical studies have noted a role for neurotropic signaling, neurogenesis, and alterations in monoamine neurotransmitter systems, these models were largely conducted using procedures that deviate from clinical practice. Therefore, we sought to develop a clinically relevant murine model of electroconvulsive stimulation (ECS), a model of ECT, which more closely replicates current clinical approaches and then employ this model to explore ECS mechanisms. Using the well-established chronic social defeat stress (CSDS) paradigm, known to disrupt reward and motivated behaviors, we investigated whether the behavioral changes after CSDS could be reversed following a clinically related course of ECS. Additionally, we observed induction of plasticity-related genes in the nucleus accumbens (NAcc) and amygdala, regions responsible for reward- and fear-related memory, respectively. Lastly, we investigated ECS-related changes in the NAcc with RNA-sequencing. This approach revealed a gene expression profile associated with ECS-related changes in NAcc. Pathway analysis demonstrated cellular changes primarily involved in regulating cell migration and differentiation. Therefore, utilizing our novel and clinically relevant model of ECS, we have begun to elucidate mechanisms that contribute to ECTs therapeutic outcomes by examining murine behavior and RNA from brain regions associated with stress-induced states that model anxiety and depression and the impact of ECS.
Moremi Bio Agent: Application of A Foundation Model and End-to-End Automation in the Design and Validation of Monoclonal Antibodies TargetingPlasmodium falciparumInvasion Complex
Authors: Akogo Darlington , Ayensu Jeremiah , Sam Nana , Hattoh Gertrude , Nyarko Prince , Eshun Solomon , Alhasan Mohammed , Mensah-Brown Henrietta , Quashie Peter
Published: February 2025

Malaria remains a significant global health challenge, withPlasmodium falciparumresponsible for the majority of severe cases and fatalities. Targeting the parasite’s invasion mechanisms offers a promising therapeutic strategy. In this study, we leveraged a novel agentic foundational model, Moremi Bio Agent, to design monoclonal antibodies targeting the AMA1-RON2 complex, a critical component in the parasite’s invasion of human red blood cells. Using advanced structural modeling, we generated 999 antibodies, which were evaluated for binding affinity, structural integrity, and physicochemical properties. Binding affinity analysis using PRODIGY identified 864 antibodies with successful target interactions, exhibiting binding free energies (ΔG) ranging from -116.8 kcal/mol to -5.6 kcal/mol. The strongest candidates demonstrated exceptionally tight binding, with dissociation constants (Kd) in the femtomolar to attomolar range, indicative of highly stable interactions. Additionally, structural validation confirmed that the antibodies were thermodynamically stable with robust fold reliability, essential for functional efficacy. Epitope mapping revealed highly conserved regions within the target complex, enhancing the likelihood of cross-strain efficacy. Glycosylation analysis identified key sites that could improve antibody stability and immune recognition, while BLAST comparison with known therapeutic antibodies demonstrated significant homology, underscoring their potential for clinical development. This study highlights the power of generative AI-driven computational pipelines in antibody discovery, providing a scalable and cost-effective framework for therapeutic development. The findings establish a foundation for experimental validation and optimization, with the potential to advance novel interventions against malaria and other infectious diseases.
WITHDRAWN: SA55 broadly neutralizes SARS-CoV-2 and robustly prevents viral escape by JN.1 sublineages
Authors: Shi Lanfang , Bowen Anthony , Han Juan , Zheng Xinhao , Luo Hongwei , Yao Tianjiao , Guo Ming , Yu Yuanling , Jian Fanchong , Cao Yunlong , Lan Ke , Guo Yicheng , Liu Lihong
Published: February 2025

Withdrawal Statement

The authors have withdrawn this manuscript because of a conflict of interest. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.