bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of EUROSCORE II to determine the prognosis of patients with moderate-to-severe aortic stenosis: a long-term retrospective study
Authors: Cai Xianzhen , Hu Danchun , Yan Baoxin , Chen Jinhao , Li Weiwen , Lin Ying , Lin Run , Ye Junjun , Huang Xiaojun , Xie Bin , Zhuang Xiaodong , Chen Jianying , Li Jilin 
Published: August 2024

Background and AimsAortic stenosis (AS) was a prevalent heart valve disease whose morbidity and mortality can be reduced by aortic valve replacement (AVR) . EUROSCORE II assesses the perioperative mortality of severe AS patients undergoing AVR. This study explored EUROSCORE II’s prognostic value for long-term all-cause mortality of Chinese patients with moderate-to-severe AS and determined whether AVR affects this.MethodsAllocated to four groups following the EUROSCORE II (cut-off value of 4%) and whether performed AVR, 544 patients with moderate-to-severe AS were enrolled. Baseline data, Kaplan–Meier, Cox regression and subgroup analysis were used to analyse the relationship between EUROSCORE II and participants’ all-cause mortality. Furthermore, ROC analysis determining the optimal cut-off value of EUROSCORE II was utilized.ResultsDuring a median follow-up of 41.4 months, 177 (21.5%) participants reached the endpoint, with higher risks (EUROSCORE II ≥4%) and no AVR exhibited significantly increased all-cause mortality rates compared to other groups (55.4% vs. 6.5%, 13.4%, and 32.7%; P<0.001). Kaplan-Meier curves confirmed these findings (log-rank test P<0.001). Cox regression analysis revealed a 6.891-fold higher risk (HR, 6.891; 95% CI, 3.083-15.401; P<0.001) in patients without AVR with higher EUROSCORE II. The adjusted model (P<0.01) and subgroup analyses (without AVR P=0.001; with AVR P=0.029) supported EUROSCORE II’s prognostic value for all-cause mortality. The optimal EUROSCORE II cut-off for predicting all-cause mortality in patients without AVR was 2.23% (AUC 0.675).ConclusionsEUROSCORE II (cut-off value 4%) and AVR independently impact the long-term prognosis of patients with moderate-to-severe AS.
THE POTENTIAL ROLE OF TAURINE IN ACETAMINOPHEN HEPATOTOXIC INDUCED RATS
Authors: Babalola Isaac Olamide , Adekunle Habeeb Kehinde , Adigun Muhammed Damola 
Published: August 2024

AbstractTaurine demonstrates an important cytoprotective function in the body, regulating oxidative and inflammation in various conditions. Taurine is actively synthesized in the hepatocyte, moreover, it confers protection to oxidative mediated injury in the liver. Acetaminophen, which has been shown to trigger oxidative related liver damage, is administered in its hepatotoxic dose to rats in this study. The preventive and regulatory role of taurine is investigated in this study. Twenty five adult male wistar rats were grouped into 5 distinct groups labeled the positive control group, negative control group, groups administered with taurine 12 hours prior acetaminophen administration, simultaneously with acetaminophen and an hour after acetaminophen was administered. The study indicated that taurine significantly reduced acetaminophen-induced liver injury in an in vivo rat model. Adding taurine either 12 hours before or at the time of acetaminophen treatment effectively prevented hepatocyte necrosis. Moreover, administering taurine 1 hour after the onset of acetaminophen-induced hepatotoxicity significantly improved liver injury, as evidenced by reduced hepatocyte necrosis, possibly through its unique cytoprotective properties such as antioxidant activity.
BCL2L13 Influences Autophagy and Ceramide Metabolism without Affecting Temozolomide Resistance in Glioblastoma
Authors: Clark Courtney , Barzegar Behrooz Amir , da Silva Rosa Simone C. , Jacobs Joadi , Weng Xiaohui , Srivastava Abhay , Vitorino Rui , Ande Sudharsan Rao , Ravandi Amir , Dhingra Sanjiv , Pecic Stevan , Miller Donald , Shojaei Shahla , Ghavami Saeid 
Published: August 2024

AbstractTemozolomide (TMZ) resistance in glioblastoma (GB) poses a significant therapeutic challenge. We developed a TMZ-resistant (TMZ-R) U251 GB model, revealing distinct differences in cell viability, apoptosis, autophagy, and lipid metabolism between TMZ-R and non-resistant (TMZ-NR) cells. TMZ-NR cells exhibited heightened sensitivity to TMZ-induced apoptosis, while TMZ-R cells-maintained viability. Autophagy flux was completely inhibited in TMZ-R cells, indicated by LC3βII and SQSTM1 accumulation. BCL2L13, which showed higher expression in TMZ-R cells, demonstrated increased interaction with Ceramide Synthase 6 (CerS6) and reduced interaction with Ceramide Synthase 2 (CerS2) in TMZ-NR cells. BCL2L13 knockdown (KD) disrupted autophagy flux, decreasing autophagosome accumulation in TMZ-R cells while increasing it in TMZ-NR cells. These changes contributed to altered ceramide profiles, where TMZ-R cells displayed elevated levels of Cer 16:0, 18:0, 20:0, 22:0, 24:0, and 24:1. Our findings highlight BCL2L13 and altered ceramide metabolism as potential therapeutic targets to overcome TMZ resistance in GB.
Improved genetic discovery and fine-mapping resolution through multivariate latent factor analysis of high-dimensional traits
Authors: Zhou Feng , Astle William J , Butterworth Adam S , Asimit Jennifer L 
Published: August 2024

SummaryGenome-wide association studies (GWAS) of high-dimensional traits, such as molecular phenotypes or imaging features, often use univariate approaches, ignoring information from related traits. Biological mechanisms generating variation in high-dimensional traits can be captured parsimoniously through GWAS of a smaller number of latent factors from factor analysis. Here, we introduce a zero-correlation multi-trait fine-mapping approach, flashfmZero, for any number of latent factors. In our application to 25 latent factors derived from 99 blood cell traits in the INTERVAL cohort, we show how GWAS of latent factors enables detection of signals that have sub-threshold associations with several blood cell traits. FlashfmZero resulted in 99% credible sets with the same size or fewer variants than those for blood cell traits in 87% of our comparisons, and all latent trait fine-mapping credible sets were subsets of those from flashfmZero. These analysis techniques give enhanced power for discovery and fine-mapping for many traits.
Genetically encoded fluorescent reporter for polyamines
Authors: Sharma Pushkal , Kim Colin Y. , Keys Heather R. , Imada Shinya , Joseph Alex B. , Ferro Luke , Kunchok Tenzin , Anderson Rachel , Yilmaz Omer , Weng Jing-Ke , Jain Ankur 
Published: August 2024

AbstractPolyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson’s disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a first-in-class genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conducted a genome-wide CRISPR screen and uncovered an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinson’s disease. By offering a new lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.
SynPull: a novel method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy
Authors: Kedia Shekhar , Fertan Emre , Wu Yunzhao , Zhang Yu P. , Meisl Georg , Lam Jeff Y. L. , Wiseman Francis , McEwan William A. , Quaegebeur Annelies , Spillantini Maria Grazia , Danial John S. H. , Klenerman David 
Published: August 2024

AbstractSynaptic dysfunction is one of the primary hallmarks of both Alzheimer’s and Parkinson’s disease, leading to cognitive and behavioural decline. While alpha-synuclein, beta-amyloid, and tau are involved in the physiological functioning of synapses, their pathological aggregation has been linked to synaptic dysfunction. However, the methodology for studying the small (sub-diffraction limit) and soluble aggregates -often called oligomers, formed by these proteins is limited. Here we describe SynPull, a novel method combining single-molecule pulldown, super-resolution microscopy, and advanced computational analyses, in order to reliably study the quantity and morphology of the oligomeric alpha-synuclein, beta-amyloid, and AT8-positive tau aggregates in synaptosomes harvested from post-mortem human brain samples and mouse models. Using SynPull, we show that AT8-positive tau is the predominant aggregate type in AD, with significantly more aggregates compared to the control samples, yet the aggregate size does not differ between disease and control samples. Meanwhile, the relatively smaller amount of alpha-synuclein and beta-amyloid aggregates found in the synapses are larger than the extra-synaptic ones. Collectively, these results show the utility of SynPull to study pathological aggregates in dementia, which can help further understand the disease mechanisms causing synaptic dysfunction.Abstract FigureGraphical abstract.Human post-mortem orbitofrontal cortex samples from subjects with neuropathological diagnosis of Alzheimer’s and Parkinson’s disease, as well as age-matched controls cut into ∼300 mg sections, and MI2, APPNL-G-F, P301S, and C57Bl/6J mouse brains were first homogenised in synaptosome buffer using a Dounce homogeniser and then filtered and centrifuged to separate nuclei and organelles from the synaptic fragments. Then, the isolated synaptosomes were incubated on the SiMPull surface with anti-neurexin antibody overnight, followed by fixation and permeabilisation. Imaging antibodies against beta-amyloid, alpha-synuclein, and AT8-positive tau were added to the samples anddSTORM imaging was performed to super-resolve the aggregates.
Optimization of Seizure Prevention by Cannabidiol (CBD)
Authors: Bhandari Bidhan , Naeini Sahar Emami , Rezaee Sholeh , Rogers Hannah M , Khodadadi Hesam , Bosomtwi Asamoah , Seyyedi Mohammad , MacKinnon Neil J , Dhandapani Krishnan M , Salles Évila Lopes , Hess David C , Yu Jack C , Moore-Hill Debra , Vale Fernando L. , Wang Lei P , Baban Babak 
Published: August 2024

AbstractObjectiveCannabidiol (CBD) is one of the most prominent non-psychotropic cannabinoids with known therapeutic potentials. Based on its anti-seizure efficacy, the first cannabis derived, pharmaceutical grade CBD-based medication was approved in the USA in 2018 for the treatment of seizures in patients 2 years and older. Despite the effectiveness in reducing seizures, there remain several major questions on the optimization of CBD therapy for epilepsy such as the optimal dosage, composition, and route of delivery, which are the main objective of this current study.MethodsWe evaluated the antiseizure effects of CBD through different compositions, routes of delivery, and dosages in a pre-clinical model. We used a kainic acid-induced epilepsy model in C57BL/6 mice, treated them with placebo and/or CBD through inhalation, oral and injection routes. We used CBD broad spectrum (inhaled and injection) versus CBD isolate formulations. We employed the Racine scaling system to evaluate the severity of the seizures, flow cytometry for measuring Immune biomarkers and neurotrophic factors, and histologic analysis to examine and compare the groups.ResultsOur findings showed that all forms of CBD reduced seizures severity. Among the combination of CBD tested. CBD broad spectrum via inhalation was the most effective in the treatment of epileptic seizures (p<0.05) compared to other forms of CBD treatments.ConclusionOur data suggest that route and CBD formulations affect its efficacy in the prevention of epileptic seizures. Inhaled broad spectrum CBD showed a potential superior effect compared to other delivery routes and CBD formulations in the prevention of epileptic seizures, warrants further research.
RESPIRATORY SYNCYTIAL VIRUS NON-STRUCTURAL PROTEIN EXPRESSION ARE LIMITED IN NEUTROPHILS
Authors: Thornhill Elena M , Verhoeven David 
Published: August 2024

AbstractRespiratory Syncytial Virus (RSV) is a negative stranded RNA virus with a high incidence of secondary bacterial infections. RSV contains two broad immune inhibitory proteins Ns1 and Ns2 which are not present in any other viruses of the Mononegavirales Order. Here we report that expression of Ns2 is attenuated during RSV infection of neutrophils and that RSV is indeed infecting neutrophils rather than simply being phagocytosed by them. Infection was determined by intracellular staining and coinfection studies of uninfected Hep2 cells. The significant attenuation of Ns2 in vivo along with the low abundance of coinfected cells indicates that RSV infection is likely functionally non permissive in in vivo infection. The implications of RSV infection of neutrophils may explain the previously observed phenomenon of decreased phagocytosis in neutrophils exposed to RSV and the lack of Ns2 expression within neutrophils may provide avenues of study to attenuate viral infection through therapy development.
Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty
Authors: Mak Jonathan K.L. , Qin Chenxi , Kuukka Anna ,   FinnGen, Hägg Sara , Lin Jake , Jylhävä Juulia 
Published: August 2024

AbstractFrailty is a clinically relevant phenotype with significant gaps in our understanding of its etiology. We performed a genome-wide association study of frailty in FinnGen (N=500,737) and replicated the signals in the UK Biobank (N=429,463) using polygenic risk scores (PRSs). We prioritized genes through proteomics integration (N∼45,000; UK Biobank) and colocalization of protein quantitative trait loci. Frailty was measured using the Hospital Frailty Risk Score (HFRS). We observed 1,588 variants associated with frailty (p<5×10-8) of which 1,242 were novel, i.e., previously unreported for any trait. The associations mapped to 106 genes of which 31 were novel. PRS replication validated the signals (β=0.074,p<2×10-16). Cell type enrichment analysis indicated expression in neuronal cells. Protein levels ofKHK,CGREF1,MET,ATXN2,ALDH2,NECTIN2,APOC1,APOEandFOSBwere associated with HFRS, whereas colocalized signals were observed withinAPOEandBRAP. Our results reveal novel genetic contributions and causal candidate genes for frailty.
The effect of dysautonomia on motor, behavioral and cognitive fluctuations in Parkinson’s disease
Authors: Mahajan Abhimanyu , Morrow Christopher B , Seemiller Joseph , Mills Kelly A , Pontone Gregory M 
Published: August 2024

AbstractBackgroundMotor and non-motor fluctuations adversely impact quality of life in Parkinson’s disease (PD). Dysautonomia, a feature frequently associated with PD and a possible adverse effect of dopaminergic therapy, may be comorbid with fluctuations.ObjectivesWe sought to evaluate the effect of dysautonomia on motor and non-motor fluctuations in PDMethodsTwo hundred subjects with PD were evaluated in both “on” and “off” dopamine states to assess changes in symptoms related to dopaminergic fluctuations. Multivariable logistic regression was performed to assess the association of dysautonomia with motor, cognitive, and psychiatric worsening from ON to OFF states with adjustment for disease duration, levodopa equivalent daily dosage (LEDD), and dopamine agonist LEDD.ResultsSubjects with dysautonomia had greater odds of clinically meaningful change in motor features (OR 3.0), cognition (OR 3.4) and anxiety (OR 4.3) compared to those without dysautonomia.ConclusionsDysautonomia may be a contributory mechanism behind fluctuations in PD. The exact nature of this relationship deserves further evaluation.
The public health co-benefits of strategies consistent with net-zero emissions: a systematic review of quantitative studies
Authors: Moutet Léo , Bernard Paquito , Green Rosemary , Milner James , Haines Andy , Slama Rémy , Temime Laura , Jean Kévin 
Published: August 2024

ABSTRACTMoving toward net-zero emission societies is projected to provide health co-benefits, yet their magnitude is not well documented and may be context-specific. Synthesizing the evidence on these co-benefits could enhance the engagement of decision-makers and populations in climate mitigation actions. We performed a systematic review including 58 quantitative studies exploring 125 scenarios. Across air quality, physical activity and dietary changes pathways, substantial health co-benefits were found, with half of scenarios showing a mortality reduction by more than 1.5%, in addition to benefits directly related to climate stabilization. However, these co-benefits varied with explored emission sectors, decarbonization levers, modelling approaches and locations. Among studies including a cost-benefit analysis, 11 of 13 estimated that monetized benefits outweighed the costs of implementing climate policies. This review highlights the need for a standardised framework to assess and compare health impacts of climate mitigation actions across sectors, and confirms that achieving net-zero goals supports far-reaching public health policies.
The role of protein shape in multiphasic separation within condensates
Authors: Pandey Vikas , Hosokawa Tomohisa , Hayashi Yasunori , Urakubo Hidetoshi 
Published: August 2024

AbstractLiquid–liquid phase separation (LLPS) of biological macromolecules leads to the formation of various membraneless organelles. LLPS can not only form homogenous condensates but also multilayered and multiphase condensates, which can mediate complex cellular functions. However, the factors that determine the topological features of multiphase condensates are not fully understood. Herein, we focused on Ca2+/calmodulin-dependent protein kinase II (CaMKII), a major postsynaptic protein that undergoes various forms of LLPS with other postsynaptic proteins, and present a minimalistic computational model that reproduces these forms of LLPS, including a form of two-phase condensates, phase-in-phase (PIP) organization. Analyses of this model revealed that the competitive binding of two types of client proteins is required for the PIP formation. The PIP only formed when CaMKII had high valency and a short linker length. Such CaMKII proteins exhibited a low surface tension, a modular structure, and slow diffusion. These properties are consistent with the functions required by CaMKII to store information at the synaptic level. Thus, the computational modeling reveals new structure–function relationships for CaMKII as a synaptic memory unit.
Impact of intragenicNRXN1deletions on early cortical development
Authors: Dutan Lucia , Gatford Nicholas J. F. , Carneiro Thaise , Nagy Roland , Higgs Victoria ,   APEX Consortia, Massrali Aicha , Paul Arkoprovo , Fasolino Maria , Zhou Zhaolan , Flinter Frances A , Adhya Dwaipayan , Bucan Maja , Baron-Cohen Simon , Srivastava Deepak P. 
Published: August 2024

AbstractBackgroundDeletions inNRXN1are strongly associated with neurodevelopmental and psychiatric conditions. While exonic deletions are well-studied, intragenic deletions, particularly in intron 5, are less understood and generally consider benign. Recent studies show exonic deletions impact isoform diversity during neurodevelopment, affecting neurogenesis and neuronal function. However, whether intragenic deletions impact isoform expression and neurodevelopment remains underexplored.MethodsWe used hiPSCs from typically developing individuals (control) and those withNRXN1intron 5 deletions to study neurodevelopment. HiPSCs were differentiated towards a cortical fate, withNRXN1isoform expression, molecular differences, and neuronal morphology examined.ResultsWe observed distinctNRXN1isoform expression dynamics during early neurodevelopment, with two expression peaks post-neuronal induction andNRXN1βbeing most highly expressed. BothNRXN1deletion and control lines showed similar acquisition of regional and cell fate identity, but significant differences inNRXN1isoform expression were observed between deletion and control lines, and between deletion lines. RNA sequencing revealed genotype-dependent alterations, particularly in pathways related to synaptic function and neuronal morphology. Consistent with these findings,NRXN1deletion lines exhibited altered dendrite outgrowth, with variations between deletion lines.ConclusionsOur results indicate a potential role for intron 5 in controllingNRXN1isoform expression during neurodevelopment. Alterations in gene expression profiles, correlated with morphological changes, suggest a role forNRXN1isoforms in shaping dendritic morphology. Molecular and cellular differences observed between lines with identical intronic deletions suggest that additional factors, such as genetic background or biological sex, may also play an important role in these phenotypes. Collectively, these findings indicate thatNRXN1intronic deletions are not benign, influencing isoform expression, cellular phenotypes, and neurodevelopment.
Substrate stress relaxation regulates monolayer fluidity and leader cell formation for collectively migrating epithelia
Authors: Charbonier Frank , Zhu Junqin , Slyman Raleigh , Allan Cole , Chaudhuri Ovijit 
Published: August 2024

AbstractCollective migration of epithelial tissues is a critical feature of developmental morphogenesis and tissue homeostasis. Coherent motion of cell collectives requires large scale coordination of motion and force generation and is influenced by mechanical properties of the underlying substrate. While tissue viscoelasticity is a ubiquitous feature of biological tissues, its role in mediating collective cell migration is unclear. Here, we have investigated the impact of substrate stress relaxation on the migration of micropatterned epithelial monolayers. Epithelial monolayers exhibit faster collective migration on viscoelastic alginate substrates with slower relaxation timescales, which are more elastic, relative to substrates with faster stress relaxation, which exhibit more viscous loss. Faster migration on slow-relaxing substrates is associated with reduced substrate deformation, greater monolayer fluidity, and enhanced leader cell formation. In contrast, monolayers on fast-relaxing substrates generate substantial substrate deformations and are more jammed within the bulk, with reduced formation of transient lamellipodial protrusions past the monolayer edge leading to slower overall expansion. This work reveals features of collective epithelial dynamics on soft, viscoelastic materials and adds to our understanding of cell-substrate interactions at the tissue scale.Significance StatementGroups of cells must coordinate their movements in order to sculpt organs during development and maintain tissues. The mechanical properties of the underlying substrate on which cells reside are known to influence key aspects of single and collective cell migration. Despite being a nearly universal feature of biological tissues, the role of viscoelasticity (i.e., fluid-like and solid-like behavior) in collective cell migration is unclear. Using tunable engineered biomaterials, we demonstrate that sheets of epithelial cells display enhanced migration on slower-relaxing (more elastic) substrates relative to faster-relaxing (more viscous) substrates. Building our understanding of tissue-substrate interactions and collective cell dynamics provides insights into approaches for tissue engineering and regenerative medicine, and therapeutic interventions to promote health and treat disease.