bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction-powered Inference for Clinical Trials
Authors: Poulet Pierre-Emmanuel , Tran Maylis , Tezenas du Montcel Sophie , Dubois Bruno , Durrleman Stanley , Jedynak Bruno
Published: January 2025

Prediction-powered inference (PPI) [1] and its subsequent development called PPI++ [2] provide a novel approach to standard statistical estimation leveraging machine learning systems to enhance unlabeled data with predictions. We use this paradigm in clinical trials. The predictions are provided by disease progression models, providing prognostic scores for all the participants as a function of baseline covariates. The proposed method would empower clinical trials by providing untreated digital twins of the treated patients while remaining statistically valid. The potential implications of this new estimator of the treatment effect in a two-arm randomized clinical trial (RCT) are manifold. First, it leads to an overall reduction of the sample size required to reach the same power as a standard RCT. Secondly, it advocates for an imbalance of controls and treated patients, requiring fewer controls to achieve the same power. Finally, this technique directly transfers any disease prediction model trained on large cohorts to practical and scientifically valid use. In this paper, we demonstrate the theoretical properties of this estimator and illustrate them through simulations. We show that it is asymptotically unbiased for the Average Treatment Effect and derive an explicit formula for its variance. An application to an Alzheimer’s disease clinical trial showcases the potential to reduce the sample size.
The emerging fungal pathogenCandida aurisinduces IFNγ to colonize mammalian hair follicles
Authors: Merrill Eric Dean , Prudent Victoria , Moghadam Parna , Rodriguez Abram , Hurabielle Charlotte , Wells Elina K.C. , Basso Pauline , Scharschmidt Tiffany C. , Rosenblum Michael D. , Molofsky Ari B. , Noble Suzanne M.
Published: January 2025

Public health alarm concerning the emerging fungusCandida aurisis fueled by its antifungal drug resistance and propensity to cause deadly outbreaks. Persistent skin colonization drives transmission and lethal sepsis although its basis remains mysterious. We compared the skin colonization dynamics ofC. auriswith its relativeC. albicans, quantifying skin fungal persistence and distribution and immune composition and positioning.C. aurisdisplayed a higher propensity to colonize hair follicles and avidly bound to human hair. WhileC. albicanstriggered an effective sterilizing type 3/17 antifungal immune response driven by IL-17A/F-producing lymphocytes,C. auristriggered a type 1, IFNγ-driven immune response targeting hair follicles. Rather than promoting fungal clearance, IFNγ enhancedC. aurisskin colonization by acting directly on keratinocytes impairing epithelial barrier integrity and repressing antifungal defense programs.C. aurisexploits focal skin immune responses to create a niche for persistence in hair follicles.
Sequencing-based Spatial Transcriptomics with scRNA-seq Sensitivity
Authors: Liao Renjie , Fu Defeng , Xu Zaoxu , Liang Han , Zhou Xiaoran , Chen Yiling , Liu Xueqi , Cheng Jiajun , Guo Ruidong , Li Chen , Xia Huihua , Li Gailing , Feng Diewen , Chen Wei , Chen Yang , Chen Longchao , Huang Zihang , Zhou Yang , Chen Qingbin , Chen Dexia , Xuan Shuguang , Zhang Changling , Lu Yongyi , Wang Hui , Feng Taiqing , Bao Yuanye , Zhao Luyang , Liu Erkai , Wang Gufeng
Published: January 2025

The advent of spatial transcriptomics has dramatically expanded our ability to study the vast network of cell-cell interactions at the molecular level in tissue. Among current methods, sequencing-based approaches have great potential in discovering because of its unbiased capture. In the last couple of years, the spatial resolution for the capture addresses has been significantly improved from 100 μm to <1 μm, well below the size of a mammalian cell. However, the capture efficiency has always been a pain point, ∼one order of magnitude lower than that of single cell RNA sequencing (scRNA-seq). The low capture efficiency limits the depth and breadth of its applications in the study of complex biological systems and diseases. Here, we introduce Salus Spatial transcriptomic system (Salus-STS), which provides ∼1 μm capture resolution and a capture efficiency ∼1 order of magnitude higher than other current methods. Analysis with sub-cellular resolution becomes practical for sequencing-based spatial transcriptomics.
Comparison of TENS electrodes and textile electrodes for electrocutaneous warning
Authors: Dölker Eva-Maria , Cabuk Yasemin , Kühn Tino , Haueisen Jens
Published: January 2025

Electrocutaneous stimulation can be employed to alert workers in potentially hazardous situations. To determine the feasibility of a novel textile electrode cuff in comparison to previously used TENS electrodes, two studies were conducted. In a study onn= 30 participants, perception, attention, muscle twitch, and intolerance thresholds as well as qualitative and spatial perceptions, were determined for eight pairs of electrodes circumferentially placed around the upper right arm for TENS and for textile electrodes. In a second study onn= 36 participants, these thresholds were also determined during vibration, and a warning signal pattern was presented during vibration. We found smaller perception thresholds for the textile electrodes in comparison to the TENS electrodes for all 8 electrode pairs and occasional differences for the attention and intolerance thresholds, which might be mainly explained by the varying electrode sizes due to the manual production process of the textile electrodes. Stimulation using textile electrodes within the cuff showed less frequent muscle twitches compared to TENS electrodes. Other qualitative and spatial perceptions appeared comparable. The perception, attention, and intolerance thresholds increased during vibration comparable to previous results with TENS electrodes. The feasibility of using the textile electrodes during vibration and for the application of a warning signal was successfully demonstrated. Occasional cases occurred where the transition impedance was too high while using the textile electrodes. Future studies will focus on electrode optimization to achieve a wearable solution with both low electrode-skin transition impedance and minimal muscle twitching.
Oral prodrug of a novel glutathione surrogate reverses metabolic dysregulation and attenuates neurodegenerative process in APP/PS1 mice
Authors: Rao Swetha Pavani , Imam-Fulani Aminat O. , Xie Wei , Phillip Samuel , Chennavajula Krishna , Lind Erin B. , Zhang Ying , Vince Robert , Lee Michael K. , More Swati S.
Published: January 2025

Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer’s disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of non-enzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer’s disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reverses the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration in these mice. We also report the first metabolomics study of such a treatment, which yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study establishes pro-ψ-GSH as a viable, disease-modifying therapy for AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific clinically translatable biomarkers.

ABSTRACT GRAPHIC
Elevated SUN1 promotes aging-related polarity defects through mechanical coupling microtubules to the nuclear lamina
Authors: Li Yutao , Chen Mengqi , Antoku Susumu , Ding Junjun , Huang Kaiyao , Gundersen Gregg G. , Chang Wakam
Published: January 2025

In migratory fibroblasts, the front-rear polarity required for cell migration is defined by an anterior centrosome relative to the nucleus. To achieve this polarity, actin cables drive the nucleus backward by coupling to nuclear membrane proteins nesprin-2G and SUN2. Aging disrupts this cell polarity by increasing the protein levels of SUN1, a SUN2 homolog. Here, we investigated the molecular mechanisms behind this disruption and found that the dominant negative effect of SUN1 and progerin, an aging-related lamin A variant, required direct SUN1-lamin A interaction. Microtubule interaction and force transmission through a nesprin, identified as nesprin-2, are crucial for SUN1’s effect. We further discovered that stable microtubules are both necessary and sufficient to inhibit cell polarity. Using SUN1-SUN2 chimeric proteins, we demonstrated that the SUN domains determine their roles in cell polarization. Our findings reveal how elevated SUN1 disrupts cell polarity through coupling microtubule and nuclear lamina, emphasizing the impact of altered microtubule stability and nuclear mechanotransduction in aging.
Assessing the performance and suitability of wastewater based-surveillance for SARS-CoV-2 RNA in public schools
Authors: Acosta Nicole , Beaudet Alex Buchner , Westlund Paul , Hu Jia , Sedaghat Navid , Pradhan Puja , Man Lawrence , Hollman Jordan , Bautista María A. , Waddell Barbara J. , McCalder Janine , Penney Matthew , Chen Jianwei , Meddings Jon , Achari Gopal , Ryan M. Cathryn , Breton Dany , Wood Elizabeth A. , Cabaj Jason L. , Clark Rhonda C. , Frankowski Kevin , Hubert Casey R.J. , Parkins Michael D.
Published: January 2025

Municipal wastewater-based surveillance (WBS) programs for SARS-CoV-2 were valuable tools for epidemiological modelling and informing COVID-19 health policy during the pandemic. We conducted a “near to source” study to assess the capacity and performance of SARS-CoV-2 WBS programs in schools relative to municipal wastewater treatment plants (WWTP). Only 4/17 schools screened had plumbing systems that were amenable to WBS. From December 2020 - March 2021 composite wastewater collected 2X/week from four schools and three municipal WWTP were assessed for SARS-CoV-2 and fecal biomarkers. Schools had lower rates of successful sample collection relative to WWTP (44.7% vs 100%, p<0.001). In a time of low COVID-19 activity, 13/64 of school samples were positive of SARS-CoV-2-N1 vs 100% of WWTP. SARS-CoV-2-N1 detected in school wastewater associated with and preceded clinically identified infections, but did not correlate with rates of overall absenteeism. Notably levels of SARS-CoV-2-N1 and fecal biomarkers were markedly lower in wastewater from schools relative to WWTP. While our SARS-CoV-2 WBS program in schools did generate a leading signal relative to clinical disease, the significantly lower levels of SARS-CoV-2 and fecal biomarkers suggests that toileting habits of children who may avoid defecation at school adversely impact school-based WBS of targets shed in feces.
Multimodal Deep Learning Model to Estimate CT-based Body Composition Measures Using Chest radiographs and Clinical Data
Authors: Alipour Ehsan , Gratzl Samuel , Algohary Ahmad , Lin Hao , Bapat Manoj , Do Duy , Baker Charlotte , Rodriguez Tricia , Cartwright Brianna , Hadlock Jennifer , Tarczy-Hornoch Peter , Oka Anand , Stucky Nicholas
Published: January 2025

Body composition metrics such as visceral fat volume, subcutaneous fat volume and skeletal muscle volume, are important predictors for cardiovascular disease, diabetes, and cancer prognosis. Recent advances in artificial intelligence have enabled automatic calculation of body composition metrics from CT scans and MRIs.

In this study, we explore using deep learning to estimate body composition metrics from chest radiographs and a small set of variables that are easy to obtain in the clinical environment.

A retrospective cohort of patients with concurrent non-contrast abdominal CT scan and chest radiograph was selected using the Truveta dataset. TotalSegmentator was used to delineate various tissue components in the CT scan. Volumetric and mid-l3 level body composition measures including subcutaneous and visceral fat volume, skeletal muscle and bone related indices, and aortic calcification scores were calculated. A multitask, multimodal deep learning model using chest radiographs and select clinical variables was trained to estimate the ground truth body composition metrics. Three data fusion strategies were compared in this process: early, intermediate, and late.

Our final cohort consisted of 1,118 patients. Mean age of imaging was 67 years old, mean height was 1.67 meters and mean weight was 78 kgs. The late fusion multimodal model outperformed both unimodal clinical-only and imaging-only models, in addition to the early and intermediate fusion models. It achieved a Pearson correlation of 0.85 in prediction of subcutaneous fat volume and 0.76 and 0.72 in estimating visceral fat volume and vertebral bone volume in the hold-out test set.

While previous studies have used artificial intelligence to automate calculation body composition metrics in CT scans and MRIs, we introduce a novel strategy that utilizes simpler imaging modalities. Our models can be used in future studies to calculate body composition metrics for larger cohorts of patients using only a chest radiograph and readily available clinical variables.
Scaling data analyses in cellular cryoET using comprehensive segmentation
Authors: Last Mart G. F. , Voortman Lenard M. , Sharp Thomas H.
Published: January 2025

Automation and improved hardware have greatly accelerated the rate of data generation in cryoET. As the field moves towardsquantitative cryoET, the scale of the resulting datasets presents a significant challenge for analysis and interpretation. To explore ways of handling datasets comprising thousands of tomograms, we investigated a comprehensive segmentation strategy – assigning an ontology-based identity to every voxel in a dataset – that is based on the sequential application of multiple convolutional neural networks. Using an openly available dataset of over 1800Chlamydomonas reinhardtiitomograms as a test case, we demonstrate the segmentation of 25 different subcellular features across the full dataset, while requiring only a few seconds of processing time per tomogram. We show how the approach enables the representation of large datasets as searchable databases and propose the usage of ontology-based segmentations for improving two common processing tasks in cryoET. First, we explorecontext-aware particle pickingas a method to retain biological context when selecting particles for subtomogram averaging and other downstream analyses. Secondly, we demonstratearea-selective template matching, where we use segmentation-based masks to avoid redundant computations in template matching and enable >500-fold faster processing in specific cases. To illustrate the utility of the approach, all segmentation results have also been made available online viacryopom.streamlit.app.
Novel Deep Learning Framework for Simultaneous Assessment of Left Ventricular Mass and Longitudinal Strain: Clinical Feasibility and Validation in Patients with Hypertrophic Cardiomyopathy
Authors: Park Jiesuck , Yoon Yeonyee E. , Jang Yeonggul , Jung Taekgeun , Hong Youngtaek , Lee Seung-Ah , Choi Hong-Mi , Hwang In-Chang , Chun Eun Ju , Cho Goo-Yeong , Chang Hyuk-Jae
Published: January 2025

Aims

This study aims to present the Segmentation-based Myocardial Advanced Refinement Tracking (SMART) technique, a novel artificial intelligence (AI)-based approach for transthoracic echocardiography (TTE) that incorporates motion tracking and left ventricular (LV) myocardial segmentation throughout the cardiac cycle. The study evaluates its feasibility and accuracy in assessing LV mass (LVM) and global longitudinal strain (LVGLS) in hypertrophic cardiomyopathy (HCM) patients.

Methods and results

The study included 111 HCM patients (median age: 58 years, 69% male) who underwent TTE and cardiac magnetic resonance imaging (CMR). SMART-derived LVGLS (LVGLSSMART) showed strong correlation with conventional manual LVGLS measurements (LVGLSTTE-EchoPAC; Pearson’s correlation coefficient [PCC] 0.851; mean difference 0 [-2–0]). When compared to CMR as the reference standard for LVM measurement (LVMCMR), conventional dimension-based TTE calculations (LVMTTE-DB) overestimated LVM compared to CMR (PCC 0.652; mean difference: 106 [90–123]), while LVMSMARTdemonstrated excellent agreement with CMR (PCC 0.843; mean difference: 1 [-11–13]). For predicting extensive LGE (≥15% of LVM), LVGLSSMARTand LVMSMARTexhibited comparable predictive performance (AUC: 0.72 and 0.66, respectively) to conventional LVGLS and CMR. Patients identified as high-risk for extensive LGE by LVGLSSMART(≤11%) and LVMSMART(≥166g) had significantly higher rates of adverse outcomes, including heart failure hospitalization, new-onset atrial fibrillation, and defibrillator implantation.

Conclusion

The SMART technique provides a comparable evaluation of LVGLS and a more accurate assessment of LVM compared to conventional TTE, with additional predictive value for myocardial fibrosis and adverse outcomes, supporting its utility in HCM management.
Novel Risk Factors for Predicting Immune Effector Cell-Associated Neurotoxicity Syndrome
Authors: Friedman Alec R. , Tozlu Ceren , Gordillo Christian A. , Chan Hei Ton , Reshef Ran , Wesley Sarah Flanagan
Published: January 2025

ICANS is a common form of neurological immunotoxicity from CAR T-cell therapy (CAR-T). While high tumor burden, product type and cell dose are established risk factors, there are many unknowns. Our objective was to characterize novel neurological and non-neurological risk factors for the development of ICANS in subjects who received CAR-T. We retrospectively identified 93 subjects (60% men, mean age 60) who had undergone CD19 or BCMA-targeting CAR-T for hematological malignancy from 2018 to 2023 at a large academic hospital. Incidence of ICANS was 31.2%, high-grade in 9.7%. A low baseline MOCA score (p=0.008) was associated with ICANS when controlled for baseline ferritin, KPS, and age; loss of points on specific cognitive sub-scores was also significant, with poor attention testing of particular concern. Presence of preexisting cerebrovascular disease, active autoimmune disease, and neurological tumor involvement were not associated with increased risk. ICANS was also associated with older age (p=0.024), elevated baseline ferritin (p=0.006), low KPS (p=0.004), and preceding or concurrent CRS of any grade (<0.001). Increasing ferritin between baseline and Day 5+ (p=0.002) was associated with development of high-grade ICANS, along with prior tocilizumab exposure (p=0.015). Subjects who developed any grade of ICANS had higher 90-day mortality than those who did not (p<0.001). Identification of these additional baseline risk factors for ICANS will help identify high-risk patients ahead of treatment and allow for improved preventative planning and early identification of ICANS.

Key Points

Low baseline MOCA score is an independent risk factor for ICANS. Impaired baseline attention testing is of particular concern.

Baseline cerebrovascular disease, neurological exam focality, and active autoimmune disease are not associated with ICANS.
Associations between epilepsy-related polygenic risk and brain morphology in childhood
Authors: Ngo Alexander , Liu Lang , Larivière Sara , Kebets Valeria , Fett Serena , Weber Clara F. , Royer Jessica , Yu Eric , Rodríguez-Cruces Raúl , Zhang Zhiqiang , Rong Ooi Leon Qi , Yeo B. T. Thomas , Frauscher Birgit , Paquola Casey , Caligiuri Maria Eugenia , Gambardella Antonio , Concha Luis , Keller Simon S. , Cendes Fernando , Yasuda Clarissa L. , Bonilha Leonardo , Gleichgerrcht Ezequiel , Focke Niels K. , Kotikalapudi Raviteja , O’Brien Terence J. , Sinclair Benjamin , Vivash Lucy , Desmond Patricia M. , Lui Elaine , Vaudano Anna Elisabetta , Meletti Stefano , Kälviäinen Reetta , Soltanian-Zadeh Hamid , Winston Gavin P. , Tiwari Vijay K. , Kreilkamp Barbara A. K. , Lenge Matteo , Guerrini Renzo , Hamandi Khalid , Rüber Theodor , Bauer Tobias , Devinsky Orrin , Striano Pasquale , Kaestner Erik , Hatton Sean N. , Caciagli Lorenzo , Kirschner Matthias , Duncan John S. , Thompson Paul M. ,   ENIGMA Consortium Epilepsy Working Group, McDonald Carrie R. , Sisodiya Sanjay M. , Bernasconi Neda , Bernasconi Andrea , Gan-Or Ziv , Bernhardt Boris C.
Published: January 2025

Abstract

Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is associated with a complex genetic architecture, but the translation from genetic risk factors to brain vulnerability remains unclear. Here, we examined associations between epilepsy-related polygenic risk scores for HS (PRS-HS) and brain structure in a large sample of neurotypical children, and correlated these signatures with case-control findings in in multicentric cohorts of patients with TLE-HS. Imaging-genetic analyses revealed PRS-related cortical thinning in temporo-parietal and fronto-central regions, strongly anchored to distinct functional and structural network epicentres. Compared to disease-related effects derived from epilepsy case-control cohorts, structural correlates of PRS-HS mirrored atrophy and epicentre patterns in patients with TLE-HS. By identifying a potential pathway between genetic vulnerability and disease mechanisms, our findings provide new insights into the genetic underpinnings of structural alterations in TLE-HS and highlight potential imaging-genetic biomarkers for early risk stratification and personalized interventions.
Maternal motivation overcomes innate fear via prefrontal switching dynamics
Authors: Xie Yunyao , Li Yijia , Du Xinke , Huang Longwen
Published: January 2025

Parental care is altruistic. In natural environments, parents are often faced with challenging environmental conditions, such as severe weather, complex terrain and predatory threats, and therefore need to overcome the fear of adverse conditions to protect and raise the offspring. Although a few studies have reported risk-taking maternal behaviors1–3, it is unknown how maternal motivation and environmental threats are represented and integrated in neural circuits to resolve the conflict and dynamically drive behaviors. Here we report a novel risk-taking maternal behavior paradigm in a semi-naturalistic context, in which a female mouse has to overcome fear and jump off an elevated platform to retrieve pups outside a nest on the ground. We show that while fear of heights reduces the motivation to jump, the presence of pups dramatically facilitates overcoming such fear. A medial prefrontal-periaqueductal gray (mPFC-PAG) pathway is specifically required for the effect of pups on overcoming fear of height, and this circuit integrates conflicting cues about pup and height and encodes motivation to drive risk-taking jumping behaviors. In contrast to cued, fast and predictable reaction timing in typical structured tasks4,5, behaviors in our paradigm are highly spontaneous, characterized by stochastic transitions between low-motivation and high-motivation states. Our data reveal that such spontaneity is shaped by the switching ramping dynamics of neural activity in the motivation-encoding dimension, rather than continuous ramping dynamics. Pup and height cues modulate the switching ramping dynamics to influence, but not immediately evoke behaviors. Together, we propose that the prefrontal-brainstem pathway plays vital roles in encoding altruistic motivation to overcome innate fear, and the switching ramping dynamics might represent a general mechanism that gives rise to spontaneous behaviors in naturalistic and conflicting conditions.
Gonococcal aggregation causes upregulation of genes involved in antibiotic tolerance
Authors: Kraus-Römer Sebastian , Wielert Isabelle , Rathmann Isabel , Volkmann Thorsten E. , Higgins Paul G. , Maier Berenike
Published: January 2025

Aggregation and biofilm formation can increase the tolerance of bacteria to external stressors, including antibiotic treatment. While resistant bacteria grow at an elevated drug dose, tolerant bacteria survive longer-term treatment. The mechanisms by which aggregation confers tolerance are insufficiently characterized for most organisms, including the human pathogenNeisseria gonorrhoeae. We hypothesize that bacterial aggregation causes upregulation of genes involved in tolerance and that deletion of these genes increases killing rates during antibiotic treatment. To test this hypothesis and identify genes involved in gonococcal tolerance, we compared the transcriptome of aggregating and planktonicN. gonorrhoeaestrains. In general, the transcriptome analysis shows that aggregation causes a strong upregulation of prophage-related genes and a shift towards anaerobic respiration. We generated deletion strains for the twenty most upregulated genes and measured their killing kinetics during treatment with the clinically relevant antibiotics ceftriaxone or ciprofloxacin. We identified five genes and one multigene segment that are involved in gonococcal antibiotic tolerance. These include prophage genes whose deletion affects tolerance differently in aggregating and planktonic strains. Furthermore, deletion of genes encoding a putative multi-drug efflux pump, an alcohol dehydrogenase, and a DNA repair protein reduces tolerance. In summary, we have identified multiple genes that affect antibiotic tolerance and are upregulated in response to aggregation.

Author summary

Often bacterial infections recur after antibiotic treatment because not all of the bacteria were killed. The ability to survive treatment by bactericidal drugs is termed tolerance. It is well established that aggregation can increase tolerance by reducing growth and metabolism. However, the genes involved in tolerance are not well characterized, especially in the human pathogenNeisseria gonorrhoeae. Here, we aim to identify such genes by following the hypothesis that aggregation upregulates genes that cross-protectN. gonorrhoeaefrom antibiotic treatment. We show that prophage-associated genes are strongly upregulated in aggregates and that deletion of various phage genes affects tolerance to the currently administered drug, ceftriaxone. We identify three additional genes belonging to different functional classes whose deletion reduces tolerance to ciprofloxacin. Our study is an important step towards understanding the molecular mechanisms of gonococcal antibiotic tolerance. In particular, we propose that prophages could serve as a target for the treatment of tolerant gonococcal infections.
The C terminus of infectious bursal disease virus (IBDV) VP3 encodes a predicted intrinsically disordered region (IDR), which promotes the formation of cytoplasmic puncta and modulates their physical properties
Authors: Brodrick A.J. , Broadbent A. J.
Published: January 2025

The virus factories (VFs) of infectious bursal disease virus (IBDV) form through liquid-liquid phase separation (LLPS). A major component of the IBDV VF is the nonstructural protein VP3. Here, we predicted the full-length structure of the VP3 monomer and homodimer and employed molecular dynamics simulations to characterize their behavior. We identified the 36 amino acid carboxy(C)-terminus as a highly dynamic intrinsically disordered region (IDR). We then compared the cytoplasmic puncta that were made in the presence of the wild type (wt) VP3 with those made with a VP3 that lacked the C-terminus (VP3ΔC). Using live-cell imaging with fluorescent reporter tagged proteins, we found that VP3ΔC puncta were significantly less numerous (p<0.0001), smaller (p<0.0001), and more irregular in shape than puncta formed in the presence of wt VP3, demonstrating that the VP3 C terminal IDR promoted their formation. Moreover, by fluorescence recovery after photobleaching (FRAP), the VP3ΔC puncta had a significantly reduced mobile fraction (0.29) as compared to full-length VP3 puncta (0.70) (p<0.001), demonstrating that the VP3 C terminal IDR modulated their physical properties. However, the VP3ΔC puncta still exhibited liquid-like fusion events in the cytoplasm and were sensitive to treatment with aliphatic diols. Moreover, VP3 did not form puncta when expressed alone, and the removal of the C terminus did not abolish puncta formation completely. We propose that VP3 forms part of a higher order complex with other biomolecules to drive LLPS, and that the VP3 C terminal IDR modulates the physical properties of the resultant LLPS structures.

Importance

LLPS is a phenomenon of growing interest in cell biology. It is a part of the replication cycles of diverse viruses, but our understanding of the molecular basis that underpins the mechanism of phase separation is incomplete. We previously demonstrated that the birnavirus IBDV, a major agricultural pathogen, exploits LLPS in the formation of its VFs. Here, we have characterized the C-terminal 36 amino acid region of IBDV VP3 bioinformatically and by molecular dynamics simulations and found that it encodes a highly dynamic intrinsically disordered region (IDR). Furthermore, we found this region to promote the formation of cytoplasmic puncta and modulate their physical properties. This work contributes to a more detailed understanding of birnavirus replication at the molecular level, and to the study of LLPS as a phenomenon.
Sialic acid-containing glycolipids extend the receptor repertoire of Enterovirus-D68
Authors: Pereirinha da Silva Ashley K. , van Trijp Jacobus P. , Montenarie Anouk , Fok Jelle , Sooksawasdi Na Ayudhya Syriam , Pieters Roland J. , Boons Geert-Jan , van Riel Debby , de Vries Robert P. , Bauer Lisa
Published: January 2025

Enterovirus D68 (EV-D68) emerged as a pathogen of increasing health concern globally, particularly due to its association with outbreaks of severe respiratory diseases and acute flaccid myelitis (AFM) in children. Knowledge regarding the tissue tropism and pathogenesis of EV-D68 within the respiratory tract and central nervous system remains limited, primarily due to an incomplete understanding of the host factors that facilitate EV-D68 entry into host cells. Several cellular receptors involved in EV-D68 infections have been identified, including ICAM-5, sialylated glycoproteins, and heparan sulfate (HS). Here, we investigate the receptor requirement of a panel of EV-D68 strains covering all clades focusing on HS and sialosides utilizing glycan arrays. We found that all EV-D68 strains binding to HS harbour a cell culture adaptative substitution in the structural protein VP1 at position 271 which changes the amino acid into a positive charged one. Glycan array analyses revealed that EV-D68 strains either prefer α2,6-linked sialic acids presented on N-glycans, α2,8 linked sialic acids on gangliosides, or both. Inhibition of glycolipid biosynthesis or multivalent glycolipid mimics confirmed that ganglioside structures serve as entry receptors for certain EV-D68 strains. Lastly, we examined whether EV-D68 strains that bind to HS or glycolipids require different uncoating mechanisms. Bafilomycin A1 minimally affected cell entry of HS-binding EV-D68 strains B2/039 and B2/947 and the ganglioside preferring B1/2013 other viruses were strongly inhibited. Together, we identified that EV-D68 strains can use disialoglycolipids as novel receptors and that different EV-D68 strains show a promiscuous sialic acid binding repertoire.
Candida albicansenhances melanoma cell aggressiveness through p38-MAPK and HIF-1α pathways and metabolic reprogramming
Authors: Aparicio-Fernandez Leire , Cazalis-Bereicua Nahia , Areitio Maialen , Rodriguez-Erenaga Oier , Abio-Dorronsoro Lucia , Martin-Souto Leire , Buldain Idoia , Márquez Joana , Benedicto Aitor , Arteta Beatriz , Macias-Cámara Nuria , Gonzalez Monika , Martin Rodriguez Jose Ezequiel , Aransay Ana , Pellon Aize , Moyes David L. , Anguita Juan , Rementeria Aitor , Antoran Aitziber , Ramirez-Garcia Andoni
Published: January 2025

Recent studies have increasingly focused on the role of fungi, includingCandida albicans, in carcinogenesis. SinceC. albicansis a component of the human microbiota, particularly on the skin, we investigated its effect on the phenotype and signalling pathways of melanoma cells. Assays for migration, adhesion, angiogenesis, and hepatic metastasis showed thatC. albicanspromotes a more malignant phenotype in melanoma cells. At the transcriptomic level,C. albicansincreased the expression of VEGF (Vegfa), and genes associated with MAPK and HIF-1 signalling pathways, and with aerobic glycolysis. Further in vitro analysis revealed that TLRs and EphA2 receptors are involved in the recognition of liveC. albicans, stimulating VEGF secretion and expression of the AP-1 transcription factor component c-Fos through p38-MAPK and HIF-1α. These pathways also regulate the expression of other AP-1 constituents such asAtf3,Jun, andJund. Moreover, p38-MAPK regulates glycolytic genes likeHk2,Slc2a1, andEno2. In conclusion,C. albicansactivates the p38-MAPK/c-Fos/AP-1 and HIF-1/HIF-1α/c-Fos/AP-1 pathways in melanoma cells, promoting a pro-angiogenic environment and metabolic reprogramming. Therefore, this study clarifies the impact ofC. albicanson melanoma cells, which can lead to the use of antifungal therapies as complementary to traditional treatments for melanoma.
Astrocyte Ca2+activity regulates node of Ranvier length in the white matter
Authors: Lezmy Jonathan , Quintela-Lopez Tania , Woermann Nicholas , Mao Shuying , Thompson Caleb , Attwell David
Published: January 2025

Nodes of Ranvier generate action potentials along myelinated axons, but it is unclear whether they can modulate neural circuit function. Computer modelling previously predicted that adjusting node length can control axonal conduction speed1, but it is unknown whether mechanisms controlling nodal structure operate in the healthy brain. Here, in brain slices and in intact white matter tracts of live mice, we found that nodes elongate and shorten, while an overall stable mean node length is maintained. Changes in node length were only detected in nodes that were flanked by compact myelin sheaths, and more motile nodes were observed as myelination progressed during development. In the developing brain, but not in adult mice, neuronal activity caused the nodes to elongate. This occurred via astrocyte Ca2+-mediated adenosine generation, targeting A2breceptors expressed in myelin sheaths which raised cyclic AMP levels in oligodendrocytes. This activated NKCC1 cotransporters present in the myelin of the paranodes and internodes, the expression of which was upregulated in the developing brain compared to adults. NKCC1 activation elevated the membrane conductance and reduced the length of internodal myelin sheaths. Thus, nodal dynamics may continuously tune information flow along myelinated axons and drive activity-dependent white matter plasticity.
The Baldwin effect reloaded: Intermediate levels of phenotypic plasticity favor evolutionary rescue
Authors: Lambert Amaury , Achaz Guillaume , Le Rouzic Arnaud , Loison Laurent
Published: January 2025

Since the late 1890s and until today, how phenotypic plasticity interacts with genetic adaptation is a debated issue. Proponents of a positive causal role of phenotypic plasticity –James M. Bald-win in the first place– supported the view that, in altered environmental conditions, phenotypic plasticity is a key factor allowing a population to avoid extinction and then genetic evolution to catch up (“Original Baldwin Effect”, thereafter OBE). Opponents, like for instance Ernst Mayr, regularly pointed out that phenotypic plasticity, by masking genetic variation, slows gene-level evolution (“Mayr Effect”, thereafter ME). For decades this opposition remained only verbal and qualitative. To resolve it, we propose here a stochastic model that, following Baldwin’s intuitive take, combines the minimal number of ingredients to account for extinction, selection, mutation and plasticity. We study evolutionary rescue of the population (arrival and invasion of an adaptive genetic mutant) in the altered environment for different values of phenotypic plasticity, here quantified as the probabilitypthat the maladapted genotype develops into the adapted phenotype. Our claim is that OBE can be a genuine evolutionary mechanism, depending on the level of phenotypic plasticity with respect to a threshold valuep⋆: whenp < p⋆, increasingppromotes evolutionary rescue by delaying extinction (“Strong” OBE); whenp > p⋆, plasticity sustains population survival and increasingphas two antagonistic effects: to accelerate adaptation by increasing the supply of adaptive mutants (“Weak” OBE, intermediate values ofp), and to slow down adaptation by decreasing their fitness advantage (ME, high values ofp).
Identification of Evolutionary Trade-Offs Associated with High-Level Colistin Resistance inAcinetobacter baumannii
Authors: Acharya Kusumita , Bhattacharya Upasana , Biswas Shatarupa , Ghosh Mallika , Bhattacharya Arijit
Published: January 2025

ABSTRACT

Colistin (COL) belongs to the polymyxin group of drugs which possesses a positive charge and interacts with lipopolysaccharide (LPS) of Gram-negative bacterial outer membrane. Additionally, it can penetrate the cell membrane and disrupt the integrity of the phospholipid leading to cell death. Resistance against COL has been reported inAcinetobacter baumannii, a bacteria in the ‘ESKAPE’ group of ‘priority pathogens’ of the World Health Organization. Multiple and pan-drug-resistant strains ofA. baumanniiare rising in many medical facilities and they are becoming resistant to last-resort antibiotics including colistin. Though plasmid-encoded acquisition ofmcr-1 has been associated with clinical resistance, drug efflux, complete loss of LPS by inactivation of the biosynthetic pathway (lpxACD), and modifications of target LPS by-products of chromosomalpmrCAB genes has been ascribed with resistance evolution against COL. To further delve into the evolutionary dynamics of COL-resistance here we report experimental evolution of extreme COL-resistance by adaptive evolution of the reference strainA. baumannii ATCC19606. Phenotypic characterization has been performed for the evolved strains, which demonstrated hyperbiofilm phenotype and striking decrease in fitness. A comprehensive antibiotic susceptibility profiling has been performed on the evolved strains. Whole genome sequencing of the resistant strains led to the identification of mutations prospectively associated with COL resistance. Phenotypic characterization of three COL-resistant clinical isolates ofA. baumanniirevealed similarity with experimentally evolved resistant mutants at least in one of the isolates.
Multiple Types of Context-Specific Brain Causal Regulatory Networks and their Applications to Autism Spectrum Disorder
Authors: Wang Li , Yang Eric , Stolovitzky Gustavo , Schadt Eric , Zhu Jun
Published: January 2025

One of the primary goals of systems biology is to understand how different cell types are regulated at various developmental stages and how dysregulation in these cells contributes to disease. With advances in high-throughput omics profiling technologies, vast amounts of both bulk tissue and single-cell data have been generated to study cellular regulation. To investigate the types of gene-gene regulatory interactions that can be uncovered from bulk versus single-cell profiling data, we constructed multiple context-specific brain gene regulatory networks using brain bulk and single-cell RNA-seq datasets and applied two distinct computational methods: an integrative Bayesian Network (BN) and a deep learning model, Geneformer. A total of 39 networks were generated, comprising 13 brain region-specific Bayesian networks from bulk RNA-seq data (bulk_BNs), 13 cell-type and developmental stage-specific Bayesian networks, and 13 corresponding Geneformer-based networks from scRNA-seq data (sc_BNs and sc_GFs, respectively).

We compared these networks in terms of their topological features, biological pathway regulation, and known regulatory relationships among disease-related genes. Our analysis revealed distinct network properties driven by data source type (bulk vs. single-cell RNA-seq) and network inference method (integrative Bayesian Network vs. deep learning Geneformer). Neurodegenerative disease-related pathways were co-regulated in bulk_BNs, while sc_BNs and sc_GFs captured pathways associated with neuroactive ligand-receptor interactions. To demonstrate the utility of these networks, we leveraged them to investigate potential disease mechanisms of Autism Spectrum Disorder (ASD). We found that ASD risk genes were enriched among hub genes common across networks but were more frequently hubs in context-specific networks, underscoring the significance of inhibitory interneurons during early developmental stages in ASD. Additionally, we showed that these networks could effectively recapitulate context-specific ASD gene signatures.

In summary, this study highlights the complementary value of integrating multiple data types through different computational approaches to advance our understanding of disease-related molecular mechanisms, such as those involved in ASD. Our findings provide a framework for using context-specific gene regulatory networks to identify disease-causal genes and key regulators of signaling pathways, potentially guiding future therapeutic strategies.
The coordinated action of UFMylation and ribosome-associated quality control pathway clears arrested nascent chains at the endoplasmic reticulum
Authors: Mihailovic Milica , Anisimova Aleksandra S , Erte Bu , Zhan Ni , Styliara Ioanna , Dagdas Yasin , Karagöz G Elif
Published: January 2025

Clearance of incomplete nascent polypeptides resulting from ribosomal stalling is essential for protein homeostasis. While ribosome-associated quality control (RQC) mechanisms that degrade these polypeptides are well-characterized in the cytosol, how stalled endoplasmic reticulum (ER)-bound ribosomes are cleared remains poorly understood. Stalled ER-bound ribosomes are marked by ubiquitin-fold modifier 1 (UFM1) on large ribosomal subunit protein RPL26, but the precise function and regulation of this process are unclear. Here, we demonstrate that canonical RQC factors associate with ribosomes stalled at the ER. Functional cellular assays using ER-targeted stalling reporters reveal that while ribosome splitting is a prerequisite for UFMylation of RPL26, the UFMylation persists without late RQC components that are involved in the clearance of arrested nascent chains (NEMF and LTN1). The UFM1 E3 ligase complex binds to and UFMylates the 60S-peptidyl-tRNA complex and, in concert with the canonical RQC pathway, facilitates the clearance of arrested polypeptides. Our findings reveal that UFMylation acts to maintain translational integrity at the ER.
Fentanyl blockade of K+channels contribute to Wooden Chest Syndrome
Authors: Wei Aguan D. , Burgraff Nicholas J. , Oliveira Luiz M. , Moreira Thiago S. , Ramirez Jan-Marino
Published: January 2025

Fentanyl is a potent synthetic opioid widely used perioperatively and illicitly as a drug of abuse1,2. It is well established that fentanyl acts as a μ-opioid receptor agonist, signaling through Gαi/ointracellular pathways to inhibit electrical excitability, resulting in analgesia and respiratory depression3,4. However, fentanyl uniquely also triggers muscle rigidity, including respiratory muscles, hindering the ability to execute central respiratory commands or to receive external resuscitation. This potentially lethal condition is termed Wooden Chest Syndrome (WCS), the mechanisms of which are poorly understood5–7. Here we show that fentanyl directly blocks a subset of EAG-class potassium channels8. Our results also demonstrate that these channels are widely expressed in cervical spinal motoneurons, including those innervating the diaphragm. A significant fraction of these motoneurons is excited by fentanyl, concomitant with blockade of voltage-dependent non-inactivating K+currents. In vivoelectromyography revealed a persistent tonic component of diaphragmatic muscle activity elicited by fentanyl, but not morphine. Taken together our results identify a novel off-target mechanism for fentanyl action, independent of μ-opioid receptor activation, with a paradoxical excitatory effect that may underlie WCS. We anticipate these findings may inform the design of safer analgesics and generalize to other neuronal circuits implicated in fentanyl-related maladaptive behaviors.
Pediococcus pentosaceusdecreases α-synuclein accumulation and alleviates parkinsonism inCaenorhabditis elegansandOryzias latipes
Authors: Komura Tomomi , Yoshida Masayuki , Kurihara Rio , Kinoshita Masato , Yoshida Masaru , Nishikawa Yoshikazu
Published: January 2025

In Parkinson’s disease (PD), α-synuclein (αSyn) accumulation drives neuropathological progression, establishing it as a potential therapeutic target. Lactic acid bacteria (LAB) provide various health benefits to the host and are expected to offer protective effects on neurological functions through the brain–gut connection, as indicated by animal studies. However, the protective effects of LAB against αSyn are not well understood. We investigated whether LAB feeding could reduce αSyn accumulation and improve mobility in transgenicCaenorhabditis elegans, an invertebrate model organism that expresses human αSyn in muscle. Among the nine screened strains,Pediococcus pentosaceussuppressed αSyn accumulation and the decrease in bending counts, a locomotion index in nematodes. Additionally, feedingP. pentosaceustoOryzias latipes(medaka), a vertebrate model organism, alleviated PD-like behavioral defects induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.P. pentosaseusacts as a probiotic against PD, and PD model worms and medaka can be used to screen effective LAB for prevention.
Can we trigger radical lifestyle change in sustainable consumption? Exploring motivations, abilities and triggers of dietary changes
Authors: Csutora Maria , Vetőné Mózner Zsófia
Published: January 2025

Purpose

Reducing meat consumption requires significant effort from individuals. Such shifts in diet can be compelling examples of radical lifestyle change. The article explores factors that may trigger radical behavioural change. Decreased meat consumption yields environmental and health advantages; nevertheless, individuals often neglect to adopt this change in their diet.

Design/methodology/approach

The conceptual model is based on Fogg’s behavioural framework. The research is based on a survey, where respondents have already changed their lifestyles and reduced their meat consumption in the past. Respondents were recruited from social media groups in Hungary. Particular emphasis is put on the deeper analysis of open-ended questions. The coding process proposed by Strauss and Corbin was followed. Coding and analysis were supported by NVivo software.

Findings

Motivations, abilities and triggers of dietary changes were identified. Results revealed the prominent role of content creators. Influencers and social media can play an incubator role in diffusing new consumption patterns. Strong emotional experiences can also trigger radical lifestyle changes. Discouraging voices were mainly those of family and close acquaintances. Children tend to encourage parents, while parents tend to discourage children when it comes to reducing meat consumption.

Originality/value

Behaviour change theories primarily focus on incremental changes, yet there is a growing need to understand radical lifestyle changes related to food consumption. This article explores the triggering factors of such radical dietary changes. The study is a rare example of large-scale qualitative sustainable consumption research.