bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular characterization informs prognosis in patients with localized Ewing sarcoma: A report from the Children’s Oncology Group
Authors: Gillani Riaz , Shulman David S. , DelRocco Natalie J. , Klega Kelly , Han Ruxu , Krailo Mark D. , Slack Jonathan C. , Tanhaemami Mohammad , Ward Abigail , Bainer Victoria , Ricker Cora , Sparks Josee , Bailey Kelly M. , Reed Damon R. , DuBois Steven G. , Leavey Patrick , Mascarenhas Leo , Grohar Patrick J. , Church Alanna J. , Crompton Brian D. , Janeway Katherine A. 
Published: January 2025

ABSTRACTPURPOSEIdentification of discrete sub-groups associated with treatment response and resistance in localized Ewing sarcoma (EWS) remains a challenge. The primary objective of the Children’s Oncology Group biology study AEWS18B1-Q was to perform molecular characterization of a large cohort of patients with localized Ewing sarcoma treated on prospective trials with modern standard of care therapy.METHODSWe analyzed clinical and molecular features from patients with localized EWS enrolled on AEWS0031, AEWS1031, or INT-0154 frontline trials. All patients had available FFPE tissue, frozen tissue, or whole-genome amplified material. Sequencing was performed for identification of canonical fusions, recurrent copy number alterations (CNAs), and alterations inTP53andSTAG2. Where available, tissue was analyzed for loss of STAG2 protein expression. Molecular features were evaluated for their association with cumulative incidence of relapse in univariate and multivariable analyses.RESULTSThree hundred and fifty-one cases had sufficient tissue, which in most cases was extracted from two FFPE slides. EWS canonical fusions were identified in 282 cases (80.3%). Pathogenic mutations inTP53andSTAG2were identified in 5.1% and 7.6% of cases, respectively and 63.1% of cases were found to have recurrent CNAs. In univariate analysis, there was an increased cumulative incidence of relapse in patients withTP53mutation (5-year cumulative incidence of relapse 43%, CI [17%, 67%] vs. 22%, CI [17%, 27%]; Gray’s testP= 0.039),STAG2mutation (53%, CI [29%, 73%] vs. 21%, CI [16%, 26%];P< 0.001), and recurrent CNAs (30%, CI [22%, 37%] vs. 16%, CI [9%, 24%];P= 0.005). In a multivariable analysis,STAG2mutation was the only molecular biomarker that remained prognostic.CONCLUSIONThis is a prospective validation of the molecular prognostic features of localized EWS receiving standard of care therapy on therapeutic clinical trials. Building on prior work, patients withSTAG2mutations were at high risk of relapse.CONTEXTKey ObjectiveTo determine if molecular features can identify clinically relevant disease sub-groups applicable to frontline clinical trial design among patients with localized Ewing sarcoma.Knowledge GeneratedAmong 351 patients with localized Ewing sarcoma treated on prospective trials, canonical fusions were identified in 80% of cases. In a multivariable analysis of patients with genomically defined Ewing sarcoma, the presence ofSTAG2mutations identified a high-risk population.Relevance (added by Associate Editor)
A cholinergic spinal pathway for the adaptive control of breathing
Authors: Lin Minshan , Calabrese Giulia Benedetta , Incognito Anthony V. , Moore Matthew T. , Agarwal Aambar , Wilson Richard J.A. , Zagoraiou Laskaro , Sharples Simon A. , Miles Gareth B. , Philippidou Polyxeni 
Published: January 2025

AbstractThe ability to amplify motor neuron (MN) output is essential for generating high intensity motor actions. This is critical for breathing that must be rapidly adjusted to accommodate changing metabolic demands. While brainstem circuits generate the breathing rhythm, the pathways that directly augment respiratory MN output are not well understood. Here, we mapped first-order inputs to phrenic motor neurons (PMNs), a key respiratory MN population that initiates diaphragm contraction to drive breathing. We identified a predominant spinal input from a distinct subset of genetically-defined V0Ccholinergic interneurons. We found that these interneurons receive phasic excitation from brainstem respiratory centers, augment phrenic output through M2 muscarinic receptors, and are highly activated under a hypercapnia challenge. Specifically silencing cholinergic interneuron neurotransmission impairs the breathing response to hypercapnia. Collectively, our findings identify a novel spinal pathway that amplifies breathing, presenting a potential target for promoting recovery of breathing following spinal cord injury.
Multi-Region Brain Organoid –Fusion Organoid with Cerebral, Endothelial and Mid-Hindbrain Components
Authors: Kshirsagar Anannya , Mnatsakanyan Hayk , Kulkarni Sai , Guo John , Cheng Kai , Bohra Oce , Sagar Ram , Mahairaki Vasiliki , Badr Christian E , Kathuria Annie 
Published: January 2025

AbstractBrain organoid technology has revolutionized our ability to model human neurodevelopment in vitro. However, current techniques remain limited by their reliance on simplified endothelial cell populations rather than a complete endothelial system. We engineered Multi-Region Brain Organoids (MRBOs) that integrate cerebral, mid/hindbrain, and complex endothelial organoids into one structure. Different from the earlier approaches based on isolated HUVECs, our endothelial organoids contain diverse vascular cell types, including vascular progenitors, mature endothelial cells, pericytes, proliferating angiogenic cells and stromal cells. Our strategy employs a sequential modulation of key developmental pathways to generate individual organoids, followed by optimized fusion conditions that maintain regional identities while supporting cellular integration. Single-nucleus RNA sequencing shows that MRBOs develop discrete neural populations specific to each brain region alongside specialized endothelial populations that establish paracrine signalling networks. Integration analysis with human fetal brain data shows that MRBOs contribute to 80% of cellular clusters found in human fetal brain tissue (Carnegie stages 12-16), whereas CellChat analysis identifies 13 previously uncharacterized endothelial-neural signalling interactions. Notably, we uncover endothelial-derived factors that support the persistence of intermediate progenitor populations during hindbrain development, but not during the cerebral one thereby revealing a new role for complex endothelial populations in regional brain patterning. This platform enables matching multiple developmental regions, fully incorporating the endothelial nature at the same time providing opportunities for studying neurodevelopmental disorders in which neural-endothelial interactions are disrupted. Our engineered MRBO system establishes a foundation for investigating complex neurodevelopmental processes, providing an enabling context closer to physiological relevance.
AI-driven discovery of host thioredoxin as a CRISPR enhancer of phage-encoded miniature Cas12 hacker nuclease
Authors: Wang Zhipeng , Wang Yujue , Gao Hui , Dai Jiani , Tang Na , Wang Yannan , Ji Quanjiang 
Published: January 2025

AbstractThe evolutionary arms race between bacteriophages and their bacterial hosts has driven the evolution of sophisticated adaptive immune systems, such as CRISPR-Cas, as a crucial defense mechanism. While bacteriophages have developed various anti-CRISPR strategies to counteract these immune systems, the role of bacterial host factors in enhancing CRISPR-Cas functions has been relatively unexplored. In this study, we employ an artificial intelligence (AI)-driven approach to systematically analyze potential interactions betweenEscherichia coli(E. coli) proteins and fifteen previously uncharacterized Cas12 proteins, generating 65,715 predicted binary complex structures. Our findings reveal a previously unknown dimension of CRISPR immunity, demonstrating that the host’s ubiquitous redox enzyme, thioredoxin (TrxA), significantly enhances the DNA cleavage efficiency of a phage-encoded, miniature Cas12 nuclease (termed ‘Cas12 hacker’). This synergistic relationship represents a strategic inversion, where a bacteriophage hijacks a host protein to reinforce its own genome degradation machinery, possibly targeting rival nucleic acids. Through comprehensive biochemical characterizations, structural analyses of the Cas12 hacker-TrxA-sgRNA-dsDNA quaternary complex, andin vivobacterial defense assays, we uncover an intricate association in which thioredoxin binds to and activates the Cas12 hacker nuclease, intensifying its DNA cleavage capacity and bolstering CRISPR immunity. Our findings expand the understanding of the molecular interactions underlying host-phage conflicts and highlight the potential for harnessing endogenous host factors to enhance the capabilities of CRISPR-based genetic engineering tools.
Evasion of serum antibodies and complement bySalmonellaTyphi and Paratyphi A
Authors: Guerra Fermin E. , Karlinsey Joyce E. , Libby Stephen J. , Fang Ferric C. 
Published: January 2025

AbstractNontyphoidal and enteric fever serovars ofSalmonella entericadisplay distinctive interactions with serum antibodies and the complement system, which initiate the host immune response to invading microbes. This study examines the contributions of lipopolysaccharide O-antigen and theS.Typhi Vi polysaccharide capsule to serum resistance, complement activation and deposition, and immunoglobulin (Ig) binding in nontyphoidalS. entericaserovar Typhimurium and the enteric fever serovarsS.Typhi andS.Paratyphi A. Although all three serovars are resistant to serum killing,S.Typhi andS.Paratyphi A exhibit lower levels of Ig binding, complement binding and complement activation compared toS.Typhimurium. InS.Typhimurium, WzzB-dependent long O-antigen production and FepE-dependent very long O-antigen production are required for serum resistance but do not prevent IgM binding or complement deposition.S.Typhi lacks very long O-antigen, but its production of Vi capsule inhibits IgM binding and complement deposition, while acting in concert with long O-antigen to resist serum killing. InS.Paratyphi A, long O-antigen production is deficient due to a hypofunctional WzzB protein, but this is compensated by greater quantities of very long O-antigen, which are required for serum resistance. Restoration of WzzB function by exchange with theS.Typhimurium orS.TyphiwzzBalleles can restore long O-antigen production inS.Paratyphi A but decreases very long O-antigen production, resulting in increased IgM binding. Replacement of theS.Paratyphi A O2-type polysaccharide with theS.Typhi O9 polysaccharide further increases IgM binding ofS.Paratyphi A, which enhances complement activation but not complement deposition. Lastly, a gene duplication ofrfbVinS.Paratyphi A is necessary for higher levels of very long O-antigen and resistance to complement deposition and antibody binding. Collectively, these observations demonstrate fundamental differences between nontyphoidal and enteric feverSalmonellaserovars in their interactions with innate immune effectors.Author SummaryEnteric fever acquired by ingestion of food or water contaminated withSalmonellaTyphi or Paratyphi A is a significant cause of morbidity and mortality in low- and middle-income countries. In this study, we dissect the different mechanisms by which these bacteria avoid binding by serum proteins that are required for the initiation of protective immune responses. This is in contrast to the nontyphoidal serovarSalmonellaTyphimurium, a common cause of gastroenteritis, which does not avoid complement activation nor antibody binding but instead exploits host inflammation. Our observations provide new insights into the mechanisms responsible for the distinctive immunological features of human enteric fever and can inform the development ofSalmonellavaccines that target theSalmonellacell envelope.
The interplay between CB2and NMDA receptors in Parkinson’s disease
Authors: Lillo Jaume , Raïch Iu , Rebassa Joan Biel , Capó Toni , Badia Pau , Navarro Gemma , Reyes-Resina Irene 
Published: January 2025

AbstractParkinson’s disease (PD) is a progressive neurological disorder that affects movement, causing symptoms such as tremors, stiffness, slowness, and balance problems due to the degeneration of dopamine-producing neurons in the brain. Nowadays there is no cure for PD. Alpha synuclein (α-syn) aggregates, which are a hallmark of PD, are known to induce microglial activation, specifically the detrimental M1 microglial phenotype, which contributes to neuroinflammation and disease progression. Cannabinoid receptor 2 (CB2R) activation has been shown to counteract neuroinflammation. CB2R is able to interact with NMDA receptors (NMDAR), which has also attracted attention in PD research due to its role in excitotoxicity. Here we aimed to study the interaction between CB2R and NMDAR in a PD context. We observed that α-syn fibrils alter CB2R activation and CB2R-NMDAR heteromerization in a heterologous expression system. Furthermore, activation of CB2R counteracted NMDAR signaling. In neurons α-syn fibrils decreased CB2R-NMDAR heteromer expression, while increasing CB2R signaling. Importantly, CB2R activation counteracted the α-syn fibrils-induced increase in M1 activated microglia, while it favored the polarization of microglia to the beneficial M2 phenotype. These results reinforce the idea of using cannabinoids for treating PD, as they provide not only the anti-inflammatory effects of cannabinoids but also counteract the detrimental increase in NMDAR signaling present in this disease.
Characterisation of a touchscreen-based Go/No Go task for assessing cognitive judgement bias in mice: a new translational tool for affective state disorder drug screening
Authors: Lopez-Cruz L , Phillips BU , Saksida LM , Heath CJ , Bussey TJ 
Published: January 2025

AbstractA major obstacle in the pre-clinical study of mood-related disorders and novel affective state therapeutic evaluation is the lack of animal models that fully recapitulate human symptomatology.In this study, we developed a touchscreen-based Go/No Go cognitive judgement bias (CJB) task for mice. In this task, animals first learned to discriminate between two visual stimuli displayed on the touchscreen: one associated with a reward (S+) and one associated with a time-out and flashing house light (S−). Once mice learned to respond to the S+ and to withhold responding to the S− consistently, a set of four ambiguous stimuli ranging in visual similarity to the S+ and S− stimuli were randomly interspersed in the stimulus presentation sequence. Responses to these ambiguous stimuli were interpreted as a greater expectation of positive (‘optimistic bias’) or negative (‘pessimistic bias’) outcomes as a function of their similarity to the S+ or S− stimuli.The acute administration of the SSRIs fluoxetine and citalopram and the 5HT-2C receptor antagonist SB204048 did not produce any effects on CJB task performance. However, the noradrenaline/dopamine reuptake inhibitor, bupropion, increased responses to the ambiguous stimuli consistent with induction of an ‘optimistic bias’ and the pro-depressant tetrabenazine yielded the opposite effect.This study underscores the capacity of mice to respond to visually ambiguous stimuli in an ambiguity-dependent manner, a phenomenon observed across various species, including humans. Furthermore, it establishes and validates an operant behavioural task to assess CJB in mice delivered using the touchscreen platform which has significant intrinsic cross-species translational potential.
Statistical framework for assessing heterogeneous sensitivity of viruses to ultraviolet, ozone, and free chlorine
Authors: Yanagihara Miina , Smeets Patrick , Miura Fuminari , Torii Shotaro 
Published: January 2025

AbstractDisinfection is key to controlling the infection risk caused by viral contaminations. Recent disinfection guidelines often refer to a single virus resistant to the disinfectant of interest, despite a large variation in sensitivity to disinfectants between viruses or even strains within the same species. Here, we show a statistical framework to integrate multiple experimental datasets and measure the variation in sensitivity to disinfectants across different virus species by a parametric distribution, termed the disinfectant sensitivity distribution. To illustrate this framework, we collected 37, 9, and 28 species-dependent inactivation rate constants for ultraviolet (UV), ozone, and free chlorine from systematic reviews, and constructed the sensitivity distributions for those disinfectants. Our approach incorporated the uncertainty in individual inactivation rate constants using a Bayesian framework. The estimated sensitivity distributions suggested that 93.0% (95% CrI: 84.4–97.6%), 99.4% (95% CrI: 86.7–100%), and 90.3% (95% CrI: 78.2–96.6%) of the examined virus species for UV, ozone, and free chlorine are expected to be inactivated by 4-log if the disinfectant dose complies with the values recommended by USEPA Guidelines for 4-log inactivation, respectively. The proposed approach provides a reasonable extrapolation of observed inactivation kinetics to untested viruses and tools for more transparent risk assessments.Graphic for Table of Contents (TOC)/Abstract ArtOne sentence summaryWe propose a statistical framework to quantify the variation in sensitivity to common disinfectants across virus species synthesizing disinfection data.
Sound-Enhanced Sleep Depth Reduces Traumatic Brain Injury Damage and Sequelae and Supports Microglial Response
Authors: Moreira Carlos G. , Müllner Adrian , Gönel Meltem , Hofmann Pascal , Teixeira Filipe , Paolicelli Rosa C. , Dias Inês , Nemirovsky Sergio I. , Baumann Christian R. , Noain Daniela 
Published: January 2025

AbstractTraumatic brain injury significantly reduces the quality of life for millions of survivors worldwide, with no established treatments currently available. High slow-wave activity (SWA) sleep immediately after rodent TBI improves posttraumatic outcomes. However, pharmacological SWA-enhancing strategies are hindered by severe specificity and scalability issues that prevent it from effectively reaching clinical implementation. Alternatively, closed-loop auditory stimulation (CLAS) of sleep slow waves offers specific SWA enhancement with high translational potential. Our present results demonstrate that up-phase-targeted CLAS (upCLAS)-mediated SWA enhancement reduced diffuse axonal injury, decreased demyelination, and preserved cognitive ability in TBI rats. The alleviated posttraumatic phenotype was associated with increased microglia response, likely mediating CLAS’ neuroprotective effect in the acute injury phase. Auditory-enhanced SWA may thus constitute a novel noninvasive neuroprotective therapy preventing TBI sequelae via boosted cellular response to tissue damage.
Daily intermittent fasting is an effective multiscale treatment in preclinical models of absence epilepsy
Authors: Rulhe Coline , Thirard Steeve , Aparicio Arias Juri , Makrini Leila , Fauvelle Florence , Beyne Emmanuelle , Dauvé Alexandra , Bouschet Tristan , Valjent Emmanuel , Bertaso Federica 
Published: January 2025

ABSTRACTAbsence epilepsy (AE) is characterized by brief but frequent seizures with loss of consciousness. Existing treatments have heavy side effects, are only partially effective and do not address the comorbidities, including cognitive and social deficits. A tripartite link between seizures, cognitive deficits and diet has been established. We focused on intermittent fasting (IF), a regime where daily periods of fasting alternate with periods of food intake, with no restrictions in the type or quantity of food consumed. To date, the effects of IF on infantile epilepsy have not been addressed. We evaluated the therapeutic potential of a daily, one-month protocol of IF on three established mouse models of AE: the Grm7AAAKI mouse, the Scn2a haploinsufficiency mouse and the pharmacologically-induced AY-9944 mouse model. We show a reduction of the seizure frequency in all models, as well as an improvement of the sociability deficits observed in two of the models, with no adverse effects. Focusing on the Grm7AAAKI model, we performed RNA sequencing in a one of the key brain areas of the absence seizure circuit, the thalamus. We detected a deregulation of genes involved in vascularization associated with the development of malformed blood vessels in epileptic mice. Along with its anti-seizure effects, IF was able to counteract both abnormal gene expression and vessel morphology. This study demonstrates for the first time the positive effects of IF on AE and could facilitate the implementation of the diet in clinical trials.
The financial system and socio-economic development among emerging economies of Sub-Saharan Africa
Authors: Agyapong Elvis Kwame , Ohemeng Williams , Astu Francis , Boateng Sarah Serwah 
Published: January 2025

PurposeThis empirical work verifies the effect of the development of the financial sector on socio-economic development of the sub-region of Sub-Saharan Africa.Design/methodology/approachData were compiled from various sources for 40 countries from 2000 to 2020 and were analyzed using the two-step system generalized method of moments estimation technique. Socio-economic development is measured using the Human Development Index in order to focus on living standards and the welfare of individuals and households.FindingsEmpirical results indicate that financial development (efficiency, access and depth) has a significant positive effect on socio-economic development in the sub-region, all other things being equal. Again, the results reveal that improved governance structures positively moderate the nexus between the financial sector and development of economies in the sub-region. Financial stability, trade openness and financial freedom were also found to have a positive impact on living standards and welfare of the people in the sub-region.Originality/valueThe paper examines the nexus between the development of the financial sector and socio-economic development (living standards, welfare and health of the populace), with attention to the possible moderating role that quality of governance could play in the relationship.