bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reactive oxygen species suppress phagocyte surveillance by oxidizing cytoskeletal regulators
Authors: Ferling Iuliia , Pfalzgraf Steffen , Moutounet Lea , Qiu Lanhui , Li Iris , Zhou Yuhuan , Grinstein Sergio , Freeman Spencer A. 
Published: February 2024

AbstractDespite their superficial similarities, the phagocytosis of pathogens differs from that of apoptotic cells in their recognition mechanisms and downstream signaling pathways. While the initial stages of these processes have been studied, the cytoskeletal reorganization that follows particle uptake is not well understood. By comparing the uptake of phosphatidylserine (PS)- coated targets versus IgG-opsonized targets of identical size, shape, and rigidity, we noted remarkable differences in the accompanying changes in cell morphology, adhesion and migration that persisted long after phagocytosis. While myeloid cells continued to survey their microenvironment after engulfing PS-coated targets, the uptake of IgG-opsonized targets caused phagocytes to round up, decreased their membrane ruffling, and led to the complete disassembly of podosomes. These changes were associated with increased activation of Rho and a concomitant decrease of Rac activity that collectively resulted in the thickening and compaction of the cortical F-actin cytoskeleton. Rho/formin-induced actin polymers were fastened to the membrane by their preferential interaction with Ezrin-Radixin-Moesin (ERM) proteins, which were necessary for cell compaction and podosome disassembly following ingestion of IgG-coated particles. The source of the distinct responses to PS- versus IgG-targets was the differential activation of the respiratory burst mediated by the NADPH oxidase: reactive oxygen species (ROS), emanating from phagosomes containing IgG-opsonized targets – but not those containing PS-coated ones – directly led to the activation of Rho. Similar findings were made with phagocytes that encountered pathogens or microbial-associated molecular patterns (MAMPS) that instigate the activation of the NADPH oxidase. These results implicate a connection between sensing of harmful particulates, the oxidation of cytoskeletal regulators, and the immune surveillance by myeloid cells that have potentially important consequences for the containment of pathogens.
The correlation between Rate of Force Development Maximal Strength and Electromyography Variables of Basketball Athletes
Authors: Pinheiro Brandão Hiury Caio , de Andrade Marcelino Monteiro , do Carmo Jake Carvalho 
Published: February 2024

AbstractThe rate of force development (RFD), is seen as a determining characteristic in fast actions present in basketball. However, we observed different relationships between RFD and maximum strength, as well as different relationships between RFD and neuromuscular variables according to the evaluated population. The aim of the present study is to evaluate the degree of determination of maximum strength (Tmax) and neuromuscular recruitment variables (RMS), Absolute Energy (AE) and the motor units firing frequencies (MPF) in rate of force development (RFD) for basketball athletes. Nine basketball athletes from the same team (mean ± SD; age: 20.8 ± 2.08 years; body mass: 84.33 ± 8.80kg; height: 1.86 ± 0.095 meters; practice time: 11.67 ± 1.65 years) were evaluated through maximum isometric contraction with highest value of maximum force among 3 attempts. The RFD were evaluated and correlated with the RMS and AE values and the MPF values of the electromyographic signal at instants 0-50; 50-100, 100-150 and 150-200 milliseconds. The results show a reduction in RFD and MPF over the evaluated time windows and also a correlation between MPF and TDF in the 0-50ms time window (R20.67p<0.05). The results show no relationship between RFD and RMS and AE, in addition to these variables not showing significant reductions in the evaluated time windows. The levels of RFD show to be more related to the firing frequency of the motor units than the maximum force and the level of recruitment of the motor units.
Hypothalamic dopamine neuron activity is modulated by caloric states and amphetamine abuse in zebrafish larvae
Authors: Bansal Pushkar , Jung Erica E. 
Published: February 2024

AbstractDopaminergic (DA) neuron activity is affected by reward and stress-inducing entities such as food and drugs of abuse, and different DA neuron populations can respond distinctly to these stimuli. Interaction between both stimuli significantly alters the dynamics of DA release in different DA populations. Additionally, these stimulating entities can affect the interconnections among different DA populations by impairing their correspondence with each other. However, limited studies have been performed that could point to the effect of interaction between AMPH and caloric states on DA neurons and their inter-correlation. This study explores the individual and interactive effect of two caloric states, ad-libitum fed (AL) and food deprived (FD), and acute exposure to a stimulant drug (amphetamine) in two different DA neurons in the hypothalamus of zebrafish larvae. We used a transgenic zebrafish line Tg(th2:GCaMP7s), which expresses a calcium indicator (GCaMP7s) in A11(Posterior Tuberculum) and a part of A14 (Caudal Hypothalamus and Intermediate Hypothalamus) DA populations located in the hypothalamus of the larval zebrafish. The larvae were subjected to acute FD and ad AL feeding followed by acute treatment with 0.7uM and 1.5uM doses of AMPH. We recorded calcium activity and quantified fluorescence change, activity duration, peak rise/fall time, and latency in the spikes of the DA neurons. Our results show that baseline DA neuron activity amplitude, spike duration, and correlation between inter- and intra-DA neurons were higher in the FD than in the AL state. Dose-dependent AMPH treatment further increased the activity intensity of the aforementioned parameters in the neuron spikes in the FD state. The DA activity correlation and spike latency were dose-dependently impaired in both DA populations. These results suggest that different DA populations in the brain exhibit a similar activity trend in response to caloric states and AMPH, where the AMPH-mediated intensity change in the activity was dose-dependent.
ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3’UTR Length
Authors: Alessandrini Francesco , Wright Matthew , Kurosaki Tatsuaki , Maquat Lynne E. , Kiskinis Evangelos 
Published: February 2024

SUMMARYUPF1-mediated decay entails several mRNA surveillance pathways that play a crucial role in cellular homeostasis. However, the precise role of UPF1 in postmitotic neurons remains unresolved, as does its activity in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by TDP-43 pathology and disrupted mRNA metabolism. Here, we used human iPSC-derived spinal motor neurons (MNs) to identify mRNAs subject to UPF1 degradation by integrating RNA-seq before and after UPF1 knockdown with RIP-seq to identify RNAs that co-immunoprecipitate with the active form of phosphorylated UPF1. We define a stringent set ofbona fideUPF1 targets in MNs that are functionally enriched for autophagy and structurally enriched for GC-rich and long 3’ UTRs but not for premature termination codon (PTC)-containing transcripts. TDP-43 depletion in iPSC-derived MNs reduces UPF1 phosphorylation and consequently post-transcriptional upregulation of UPF1 targets, suggesting that TDP-43 dysfunction compromises UPF1-mediated mRNA surveillance. Intriguingly, our datasets reveal that UPF1 and TDP-43 regulate alternative polyadenylation and 3’UTR length of mRNAs associated with synaptic and axonal function, a process that we find to be compromised in ALS modelsin vitroand ALS patient tissue. Our study provides a comprehensive description of UPF1-mediated mRNA decay activity in neurons, reveals overlapping roles between UPF1 and TDP-43 in regulating 3’UTR length, and offers novel insight into the intricate interplay between RNA metabolism and neurodegeneration in ALS.
AAV-based delivery of RNAi targeting Ataxin-2 improves survival, strength, and pathology in mouse models of rapidly and slowly progressive sporadic ALS
Authors: Amado Defne A. , Robbins Ashley B. , Smith Alicia R. , Whiteman Katherine R. , Chillon Bosch Guillem , Chen Yonghong , Fuller Joshua A. , Izda Aleksandar , Nelson Shareen , Dichter Abigail I. , Monteys Alex Mas , Davidson Beverly L. 
Published: February 2024

AbstractAmyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targetedAtxn2knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliverAtxn2-targeting miRNAs. Mouse dosing studies demonstrated 55%Atxn2knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi againstAtxn2as a robust and translatable treatment strategy for sporadic ALS.
A machine-learning model to harmonize brain volumetric data for quantitative neuro-radiological assessment of Alzheimer’s disease
Authors: Archetti Damiano , Venkatraghavan Vikram , Weiss Béla , Bourgeat Pierrick , Auer Tibor , Vidnyánszky Zoltán , Durrleman Stanley , van der Flier Wiesje M. , Barkhof Frederik , Alexander Daniel C. , Altmann Andre , Redolfi Alberto , Tijms Betty M. , Oxtoby Neil P. ,   Australian Imaging Biomarkers and Lifestyle Study,   Alzheimer’s Disease Neuroimaging Initiative,   the E-DADS Consortium
Published: February 2024

AbstractBackgroundStructural MRI plays a pivotal role in the radiological workup for assessing neurodegeneration. Scanner-related differences hinder quantitative neuroradiological assessment of Alzheimer’s disease (QNAD). This study aims to train a machine-learning model to harmonize brain volumetric data of patients not encountered during model training.MethodNeuroharmony is a recently developed method that uses image quality metrics (IQM) as predictors to remove scanner-related effects in brain-volumetric data using random forest regression. To account for the interactions between AD-pathology and IQM during harmonization, we developed a multi-class extension of Neuroharmony. We performed cross-validation experiments to benchmark performance against existing approaches using data from 20,864 participants comprising cognitively unimpaired (CU) and impaired (CI) individuals, spanning 11 cohorts and 43 scanners. Evaluation metrics assessed ability to remove scanner-related variations in brain volumes (biomarker concordance), while retaining the ability to delineate different diagnostic groups (preserving disease-related signal).ResultsFor each strategy, biomarker concordances between scanners were significantly better (p < 10−6) compared to pre-harmonized data. The proposed multi-class model achieved significantly higher concordance than the Neuroharmony model trained on CU individuals (CI: p < 10−6, CU: p = 0.02) and preserved disease-related signal better than the Neuroharmony model trained on all individuals without our proposed extension (ΔAUC= −0.09). The biomarker concordance was better in scanners seen during training (concordance > 97%) than unseen (concordance < 79%), independent of cognitive status.ConclusionIn a large-scale multi-center dataset, our proposed multi-class Neuroharmony model outperformed other strategies available for harmonizing brain-volumetric data in a clinical setting. This paves the way for enabling QNAD in the future.
Does Education Sculpt Healthcare Choices? Exploring Factors Influencing Healthcare Utilization Among Female Youths in Eight Low and Lower-Middle-Income Countries
Authors: Nishan Nahid Hassan , Akter Khadiza , Sharmin Afroza , Tithi Tazmin Akter , Ahmed M Z E M Naser Uddin 
Published: February 2024

AbstractsIntroductionEmphasizing the global commitment to universal health coverage, this research addresses geographical variations and challenges faced by young females across low and lower-middle-income countries. Therefore, the objective of this study is to determine the factors that influence the decision-making of young females when it comes to seeking healthcare services in low or lower-middle-income countries.MethodologyWe examined healthcare usage among female youth across eight countries. We used data from the DHS and employed regression and Chi2tests for our analysis. Our focus was on females aged 15 to 24 and their visits to healthcare facilities. To ensure the validity of our findings, we used weighted sampling to represent the population.ResultsWe had a total sample of 51,298 female youth groups between the ages of 15 and 24 who participated in our study. When it comes to the demographics of the participants, most of those in the 15-19 age group were from Burkina Faso (54.26%), while most of those in the 20-24 age group were from Ghana (50.19%). The impact of education varied across countries; primary education led to increased healthcare utilization in Kenya, Tanzania, and Cambodia, but unexpected trends were observed in Burkina Faso.ConclusionsEducation significantly influences healthcare utilization, both primary and secondary education positively impacting this. Rural residents face challenges accessing timely healthcare. Geographical challenges, like diseases and limited accessibility, contribute to varied healthcare usage in Kenya and the Philippines. Addressing infrastructure issues is critical, emphasizing education and promoting transparency to enhance healthcare equity.
VAL-1221 FOR THE TREATMENT OF PATIENTS WITH LAFORA DISEASE: STUDY PROTOCOL FOR A SINGLE-ARM, OPEN-LABEL CLINICAL TRIAL
Authors: Muccioli Lorenzo , Vignatelli Luca , Tappatà Maria , Mazzone Serena , Zenesini Corrado ,   DEFEAT-LD study group, Armstrong Dustin , Michelucci Roberto , Bisulli Francesca 
Published: February 2024

ABSTRACTIntroductionLafora Disease (LD) is an ultrarare fatal progressive myoclonic epilepsy, causing drug-resistant epilepsy, myoclonus, and psychomotor deterioration. LD is caused by mutations in EPM2A or NHLRC1, which lead to the accumulation of polyglucosans in the brain and neurodegeneration. There are no approved treatments for LD. VAL-1221 is a fusion protein comprised of the Fab portion of a cell-penetrating antibody and recombinant human acid alpha glucosidase, and has demonstrated an ability to clear polyglucosans. We hypothesize that intravenous infusion of VAL-1221 might be able to degrade cerebral polyglucosans and stabilize or improve disease outcomes. The aim of this study is to assess the safety and preliminary efficacy of VAL-1221 in patients with LD.Methods and analysisThe study is a phase 2, single-arm, open-label, baseline-controlled clinical trial which will be conducted in a single investigational study center in Italy, namely the sponsor “IRCCS Istituto delle Scienze Neurologiche di Bologna - Azienda USL di Bologna”. The study will enroll 6 genetically-confirmed patients with mid- to late stage LD. The global duration of the study for each participant will be 18 months, including screening period, open-label treatment (12 months), and follow-up period. VAL-1221 20 mg/kg will be administered as an intravenous infusion every week for 3 weeks, then every other week. Patients will undergo full clinical assessments at baseline, at an intermediate and at the end-of-treatment visit. The primary objective is to evaluate the safety. The exploratory efficacy endpoints will be related to epilepsy, neuropsychological and motor functions, global assessment and disease burden, in addition to biomarkers. Statistical analyses will be primarily descriptive.Ethics and disseminationThe study protocol was approved by the local ethics committee (number 232-2023-FARM-AUSLBO–23020, 22-Mar-2023). The results of this study will be disseminated by the investigators through presentations at international scientific conferences and reported in peer-reviewed scientific journals.Trial RegistrationEuropean Union Clinical Trials Register (EudraCT number 2023-000185-34).ARTICLE SUMMARYStrengths And Limitations Of This StudyThis was the first approved study protocol developed for a potential disease-modifying drug in Lafora diseaseThe study will be open label due to the serious and life-threatening nature of the disease and its rarityGiven the lack of a control group in this study, the exploratory endpoints observed will be baseline-controlled and compared with natural history studiesThe rationale for VAL-1221 dose and schedule comes from experience in Pompe disease clinical trials and expanded access programs
ETHICAL CONSIDERATIONS FOR CLINICAL CARE ON SHORT TERM MEDICAL MISSIONS IN LOW- AND MIDDLE-INCOME COUNTRIES: A SCOPING REVIEW
Authors: Smith M. , Graham R. , Vance C. , Coburn W. , Richards D. , Whitfield J. 
Published: February 2024

ABSTRACTIntroDespite short term medical missions (STMMs) to low- and middle-income countries (LMIC) becoming increasingly popular, ethical considerations for the provision of clinical care on STMMs are poorly defined. Clinicians are often unprepared to adapt care and ethical precepts to resource limited environments. There may be discord in interpretation of ethical principles between visiting providers and hosts. Clinical care provision has direct impact on the health of patients and communities and there is a need for guidelines regarding ethical clinical care.MethodsScoping review of the literature published from 2001-2021 restricted to English language identified 3072 records discussing ethical considerations of provision of clinical care on STMMs. Records were screened by title, abstract and finally full text by independent reviewers resulting in 40 records for inclusion.ResultsThirteen themes were identified as important considerations for provision of ethical clinical care on STMMs. These themes included: collaboration/longitudinal relationship, education, lack of follow up, cultural barriers, needs assessment/goal setting, capacity building, outcome evaluation, pre-departure preparation, scope of practice, resources allocation, detriment to local systems, bidirectionality, and formal ethical review. From these themes a list of guidelines is outlined.ConclusionWhile ideally clinical care on STMMs would be regulated by formal ethical review boards this is difficult to develop and enforce. Independent STMMs must evaluate their approach to clinical care in LMICs. Care should be given to focusing on collaboration, education, follow up, cultural barriers, and performing a needs assessment/goal setting. These efforts may be guided by the checklist included within.
Botryococcus brauniireduces algal grazing losses toDaphniaandPoterioochromonasthrough both chemical and physical interference
Authors: Thomas Patrick , Arn Finn , Freiermuth Micha , Narwani Anita 
Published: February 2024

AbstractCrop protection from algal grazers is a key area of concern, as grazing zooplankton and flagellates can decimate algal crops and impede economic viability of cultivation for biofuels and bioproducts. Inhibition of grazing by chemical and physical interference is one promising solution; however, there have been few empirical tests of this approach that use defense traits innate to algal crop species. Here we conduct an experiment to test whether the hydrocarbon excreting algaBotryococcus brauniican mitigate losses to grazing by two distinct grazers,Daphnia magnaandPoterioochromonas malhamensis, due to both chemical inhibition and physical interference linked to large/inedible colonies. We show that chemical and physical defenses interactively reduce the total effect of grazing, thus significantly increasing the biomass of cultures ofB. brauniiandNannochloropsis limneticawhen either grazer is present. Specifically,B. brauniifiltrate alone inhibits grazing and thus weakens top-down control ofN. limneticagrowth rates and final biomass by both grazers;B. brauniicolonies alone also inhibit biomass losses; and the combination of filtrate andB. brauniicolonies reveals an interactive effect of both chemical and physical defenses on grazing. Our study demonstrates how community engineering can identify synergies arising from algal cocultivation (e.g., by using industrially relevant strains for crop protection). Such ecological discoveries may help to reduce the costs of large-scale deployment of algal cultivation for sustainable foods, fuels, bioproducts (e.g., bioplastics), and carbon capture.
Development of a cell-based DIFF-rGFP assay system for generalized discovery of viral protease Inhibitors
Authors: Xiaoyan Wu , Yan Feng , Ruiting Chen , Chenjie Fang , Shuai Wang , huimin Sun , shuling Jian , jiiasheng Song , Beibei Wu 
Published: February 2024

1.AbstractViral protease is an attractive target for antiviral therapeutics, but current viral protease inhibitor screening methods still need to be improved. Here, we systematically investigated the sites that may accommodate exogenous short peptides within Enhanced Green Fluorescent Protein (EGFP) and constructed a series of recombinant green fluorescent proteins (rGFPs). Meanwhile, a cell-based, simple and reliable assay system named DIFF-rGFP was developed relying on the co-expression of rGFP and the protease for protease inhibitor screening with the example of 3CLpro, in which the fluorescence intensity increases with the action of the inhibitor. The DIFF-rGFP assay avoided the requirement of a higher biosafety lab and can be performed in a high-throughput manner. For proof of concept, we demonstrated this method to discover novel inhibitors against SARS-CoV-2. We believe the proposed method, in combination with available drug libraries, may accelerate the identification of novel antivirals.