julilili42/papers huggingface dataset:
Genetic Risk of Axonal Neuropathy Following Infection
2024-10-06

Abstract Background Why some individuals experience severe neuropathy following infection is unknown. Nucleocytoplasmic trafficking (NCT) is an essential process in nucleated cells, and its disruption has been implicated in many neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Methods We performed genomic and clinical studies in 24 individuals from 12 families with acute onset axonal neuropathy. Genetic variants were characterized by thermal stability and enzymatic assays using recombinantly expressed protein. Protein localization was determined in patient fibroblasts using immunofluorescence following heat or oxidative stress. A humanized Drosophila model was generated to determine the effect of stress on in vivo function. Results We identified deleterious biallelic variants in human RCC1 , encoding a GTP exchange factor essential in maintaining Ran GTPase-dependent NCT function. Clinical presentations ranged from a rapidly progressive, fatal axonal neuropathy with encephalopathy to a mild motor neuropathy resulting in impaired walking. In most patients (n=22/24), neurological presentation was secondary to infection, resulting in prior diagnosis of Guillain-Barré syndrome (GBS) in 13. The efficiency of cellular Ran GDP-GTP exchange and the thermal stability of Rcc1 protein was reduced by disease-associated variants. Heat shock or oxidative stress revealed defects in Ran nuclear localization, impaired NCT, and TDP-43 mislocalization in patient fibroblasts. Disease associated variants were unable to rescue the thermosensitive phenotype of a rcc1 deficient hamster cell line. RCC1 Drosophila models revealed a fatal intolerance to oxidative stress. Conclusion We describe a novel autosomal recessive acute onset axonal neuropathy triggered by infection caused by biallelic RCC1 variants, which mimics GBS and has important mechanistic overlap with ALS.
ACKR3 agonism induces heterodimerization with chemokine receptor CXCR4 and attenuates platelet function
2024-10-07

Abstract Background Platelet receptors ACKR3 and CXCR4 play a crucial role in a variety of cardiovascular diseases. Like most chemokine receptors, CXCR4 is a G protein coupled receptor that induces platelet activation. In contrast, the atypical chemokine receptor 3 (ACKR3) lacks the ability to activate heterotrimeric G proteins and its activation leads to platelet inhibition and attenuates thrombus formation. In nucleated cells, heterodimerization of ACKR3 with CXCR4 regulates CXCL12‐dependent signalling. The aim of our study was to investigate the formation of ACKR3/CXCR4 heterodimers in platelets and the subsequent consequences for platelet function. Methods and Results Using a proximity ligation assay (PLA, Duolink®) to screen for CXCR4/ACKR3 heterodimerization inducing compounds, we found that ACKR3 agonism but not conventional platelet agonists or endogen ligands lead to heterodimer formation. To further characterize the formation of ACKR3/CXCR4 heterodimers, we studied the CXCL12‐dependent platelet activation via CXCR4. Both, CXCL12‐dependent platelet aggregation and collagen‐dependent ex vivo thrombus formation were significantly downregulated by ACKR3 agonism. Moreover, platelet intracellular calcium and Akt signalling were increased by CXCL12 and again suppressed by ACKR3‐specific agonists. Previously, CXCL12 was shown to decrease platelet cAMP levels via CXCR4. Treatment with a specific ACKR3 agonist counteracted this CXCL12/CXCR4‐dependent cAMP decrease. Conclusion Our results reveal that the formation of platelet ACKR3/CXCR4 heterodimers is dependent on ACKR3 rather than CXCR4. Furthermore, ACKR3 agonism induced heterodimerization is associated with mitigating CXCL12/CXCR4‐dependent platelet activation possibly by modulating CXCR4‐dependent G protein signalling. Our results indicate possible ACKR3 agonist functions and reinforce the potential therapeutic applications of ACKR3 agonists.
Multi-hazard susceptibility mapping in the karst context using a machine-learning method (MaxEnt)
2024-10-07

Abstract. In this study, we extend the application of the Maximum Entropy model (MaxEnt), traditionally applied to ecological research and less explored in natural hazard studies, to a novel context by characterising a multi-hazard scenario (i.e., flood-triggered sinkholes) in the Orléans karst region (Val d'Orléans) of France. Many regions of the world exhibit complex hazard landscapes where networks of multi-hazard interrelationships (cascades) pose challenges due to the potential interactions between hazards and the different temporal and spatial scales of hazard events. While mountainous, coastal and volcanic regions have been recognised as multi-hazard forming zones, karst terrains have received little attention despite being prone to multi-hazard events due to their distinct geology, geomorphology, hydrogeology and other environmental characteristics. Incorporating karst-specific multi-hazard scenarios supports disaster risk reduction efforts by raising the awareness of citizens, protecting elements at risk and facilitating decisions on disaster prevention. To support this aim, we developed a multi-hazard susceptibility map for the karst region of Val d'Orléans that characterises flood-triggered sinkholes. We applied MaxEnt, a machine learning method, to forecast the spatial probability distribution of flood-triggered sinkholes. Model inputs included the location of past sinkhole occurrences and geo-environmental factors contributing to sinkhole formation (e.g., topography, local geology, hydrology and flood hazard). We validated the performance of the model by initially using 70 % of the sinkhole inventory data and keeping the remaining 30 % for testing. This validation process assessed the model's performance using the Area Under the Curve of the Receiver Operating Characteristic (AUC-ROC). The resulting map reveals areas located up to 1 km south of the Loire River and areas with lowest elevation with highest susceptibility to flood-triggered sinkholes. We conclude that our approach to producing this type of multi-hazard scenario and map is useful for identifying flood-triggered sinkholes in Val d'Orléans and other karst areas around the globe, supporting effective land use planning.
Ta4SBr11: A Cluster Mott Insulator with a Corrugated, Van der Waals Layered Structure
2024-10-07

The compound Ta<sub>4</sub>SBr<sub>11</sub> was prepared by a comproportionation reaction of tantalum bromide with tantalum and elemental sulfur. The crystal structure, as refined by single-crystal X-ray diffraction, is composed of clusters with Ta<sub>4</sub>S cores, arranged in corrugated van der Waals layers. Individual layers appear to be displaced relative to each other along one direction. Successful crystal growth in a melt of CsBr yielded black platelets of Ta<sub>4</sub>SBr<sub>11</sub>, which were used to investigate the electrical properties of the compound. The electronic structure was studied by diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy and by density functional theory (DFT) band structure calculations, revealing this material to be a small-gap semiconductor. DFT results, in combination with magnetic susceptibility measurements, suggest that metallicity originating from the one unpaired Ta d electron per cluster is most likely suppressed by electronic correlations, forming a cluster Mott insulator.
Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial cochlea
2024-10-07

ABSTRACT Notch signaling patterns the cochlear organ of Corti, and individuals with the JAG1/NOTCH2-related genetic disorder Alagille syndrome can thus experience hearing loss. We investigated the function of Jag1 in cochlear patterning and signaling using Jag1Ndr/Ndr mice, which are a model of Alagille syndrome. Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells. Single cell RNA sequencing of the organ of Corti demonstrated a global dysregulation of genes associated with inner ear development and deafness. Analysis of individual cell types further revealed that Jag1 represses Notch activation in lateral supporting cells and demonstrated a function for Jag1 in gene regulation and development of outer hair cells. Surprisingly, ectopic ‘outer hair cell-like’ cells were present in the medial compartment and pillar cell region of Jag1Ndr/Ndr cochleae, yet they exhibited location-dependent expression of the inner hair cell fate-determinant Tbx2, suggesting Jag1 is required for Tbx2 to drive inner hair cell commitment. This study thus identifies new roles for Jag1 in supporting cells, and in outer hair cell specification and positioning.
Evaluating Ocular Healthcare Accessibility and the Severity of Emergencies during Times of Crisis
2024-10-07

Background/Objectives: The COVID-19 pandemic has profoundly impacted healthcare systems worldwide, including the delivery of ophthalmic emergency services. This study examines the impact of the COVID-19 pandemic on the clinical presentation of emergencies and the accessibility of healthcare in ophthalmology. Methods: The study employed a single-center, consecutive case series design with historical controls to examine electronic health records over a 21-day period during the COVID-19 pandemic and a matched period from the preceding year. Records were analyzed for demographic variables, diagnosis, length of stay, travel distance, and referral status. The urgency of cases was evaluated by three independent graders using the BaSe SCOrE (BAsic SEverity Score for Common OculaR Emergencies). Results: A total of 1229 patients were included in the study, with 786 patients in the 2019 cohort and 443 patients in the 2020 cohort. During the pandemic period, there was a significant decrease in the number of patients and the duration of their visits (p &lt; 0.0001, p &lt; 0.0001, respectively). There was an increase in walk-in patients (p = 0.03), who took significantly longer journeys to be treated as compared to referred patients (p &lt; 0.01). At the same time, the severity of emergencies increased (p = 0.02). The 2019 logistic regression model found that age (p = 0.003), referral status (p &lt; 0.001), distance (p = 0.009), and first presentation (p = 0.02) were significant predictors of the severity, while gender was not (p = 0.78). The 2020 model found that only age (p &lt; 0.001) and referral status (p &lt; 0.001) were significant predictors of severity. Conclusions: The observed decline in patient volume, increased severity of emergencies, and shifts in predictive variables within the logistic regression models are indicative of significant barriers to healthcare access. Therefore, enhancing health literacy and ensuring low-threshold access to emergency services are crucial, especially during crises.
Limes (the Roman Frontier): Developing a Video Game for History Learning
2024-10-07

The use of gaming technologies in education holds great promise to provide engaging learning experiences. Whereas video games have been successfully used to foster learning in several school subjects, the current understanding of the potential of video games for history learning is still limited. This paper details the development of Limes, a 2D top-down educational game created in Unity and rendered in pixel art. The game targets 5th/6th grade secondary school students and is set in the third century AD in southern Germany, a period characterized by political and social instabilities. Limes digs into the complex relations between the Roman Empire and the Alemanni tribe, one of the most powerful Germanic tribes of this period. The player can experience this pixelated world through the eyes of an Alemanni child, who forms a friendship with a Roman centurion. The unfolding narrative places the young protagonist in the precarious balance of peace and conflict, and the player needs to navigate the diplomatic tensions of the era. The gameplay consists of five levels, including primary missions and optional secondary missions which unlock special features (e.g., puzzles, quizzes). Limes incorporates a variety of game mechanics, ranging from running and interacting with characters to stealth missions, throwing rocks, and horse racing. These dynamics are integrated into the historical narrative of the game, enriching the player's experience. The game development process combined insights and methods from multiple disciplines, including game-based learning, educational, social, and cultural psychology, education sciences and pedagogy, and history education. Moreover, the game capitalizes on Unity’s wide array of development tools, which provide extensive customization possibilities, and employs pixel art, facilitating an engaging environment while maintaining a cost-conscious development process. Initial tests and expert feedback highlight the promise of Limes as a game that leverages historical accuracy and innovative educational tools to foster a deeper understanding of Roman history. Next steps include empirical studies with students to test the game's effectiveness (e.g., in improving interest in and knowledge of Roman history).
A novel approach to simultaneous genotyping of human platelet antigen systems and human leucocyte antigen class I loci using PacBio long‐read sequencing
2024-10-07

Abstract Background and Objectives Accurate human leucocyte antigen (HLA) and human platelet antigen (HPA) typing is essential for establishing a blood platelet donor bank to deal with refractoriness in patients undergoing multiple platelet transfusions. Current methods, such as Sanger and next‐generation sequencing, encounter difficulties in haplotyping. Herein, the aim of this study was to establish a method for HLA and HPA typing based on the long read sequencing. Study Design and Methods The HPA and HLA class I genotypes of 268 platelet donors from the Taiyuan Blood Center, China were identified using long‐read sequencing on the PacBio platform. Allele frequencies for HPA systems and HLA class I genes were calculated, and genetic variability within HPA system genes was analysed. Results Polymorphisms were identified in 8 of the 35 HPA systems (HPA‐1 to HPA‐6w, HPA‐15 and HPA‐21w), with the frequencies of the ‘b’ allele at 0.0187, 0.0709, 0.4086, 0.0075, 0.0149, 0.0317, 0.4310 and 0.0019, respectively. The alleles with the highest frequencies at the HLA‐A, HLA‐B and HLA‐C loci are HLA‐A02:01, B51:01, B46:01 and C06:02, respectively. Additionally, several genetic patterns in HPA systems were identified, including the c.166‐1029C&gt;T variant, which was found exclusively in samples carrying the HPA‐1b allele. Conclusion This study developed a targeted long‐read sequencing method characterized by high throughput and simultaneity, capable of resolving allele ambiguities for effective HLA class I genotyping in establishing a platelet donor bank.
Post-COVID-Syndrome patients might overestimate own cognitive impairment
2024-10-07

Abstract After a COVID-19 infection, some patients experience long-term consequences known as Post-Covid Syndrome, which often includes cognitive impairment. We investigated the congruence between subjectively experienced and objectively measured cognitive deficits after a COVID-19 infection in an unselected, successively admitted cohort of 38 patients reporting subjective cognitive complaints (SCC). We employed a comprehensive neuropsychological test battery to assess objective cognitive impairment across various cognitive domains. Three different cut-off criteria were applied commonly used in the literature to define objective neurocognitive disorder (NCD). We observed a notably low congruence between SCC and NCD in Post-Covid Syndrome, regardless of the cut-off criterion. Depending on the cognitive domain, only 5% to maximally 36% of the SCC could be objectified. One possible explanation for this discrepancy could be the high rate of depressive symptoms observed in the group of patients studied, which may negatively influence the perception of own cognitive abilities. These findings emphasize the need for careful evaluation of SCC in Post-Covid Syndrome and suggest that treating depressive symptoms may also alleviate some of the perceived cognitive deficits.
Applicability of Mean-Field Theory for Time-Dependent Open Quantum Systems with Infinite-Range Interactions
2024-10-08

Understanding quantum many-body systems with long-range or infinite-range interactions is of relevance across a broad set of physical disciplines, including quantum optics, nuclear magnetic resonance, and nuclear physics. From a theoretical viewpoint, these systems are appealing since they can be efficiently studied with numerics, and in the thermodynamic limit are expected to be governed by mean-field equations of motion. Over the past years the capabilities to experimentally create long-range interacting systems have dramatically improved permitting their control in space and time. This allows us to induce and explore a plethora of nonequilibrium dynamical phases, including time crystals and even chaotic regimes. However, establishing the emergence of these phases from numerical simulations turns out to be surprisingly challenging. This difficulty led to the assertion that mean-field theory may not be applicable to time-dependent infinite-range interacting systems. Here, we rigorously prove that mean-field theory in fact exactly captures their dynamics, in the thermodynamic limit. We further provide bounds for finite-size effects and their dependence on the evolution time.
Pioneering new paths: the role of generative modelling in neurological disease research
2024-10-08

Abstract Recently, deep generative modelling has become an increasingly powerful tool with seminal work in a myriad of disciplines. This powerful modelling approach is supposed to not only have the potential to solve current problems in the medical field but also to enable personalised precision medicine and revolutionise healthcare through applications such as digital twins of patients. Here, the core concepts of generative modelling and popular modelling approaches are first introduced to consider the potential based on methodological concepts for the generation of synthetic data and the ability to learn a representation of observed data. These potentials will be reviewed using current applications in neuroimaging for data synthesis and disease decomposition in Alzheimer’s disease and multiple sclerosis. Finally, challenges for further research and applications will be discussed, including computational and data requirements, model evaluation, and potential privacy risks.
Physical activity levels are positively related to progression-free survival and reduced adverse events in advanced ER+ breast cancer
2024-10-08

Abstract Background Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case–control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general. Methods In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into “active” and “insufficiently active” to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination. Results Compared to “insufficiently active” patients, “active” individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p = .0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be “active” at baseline revealed significantly fewer AEs compared to “insufficiently” active patients. In detail, both severe and non-severe AEs occurred less frequently in the “active” patients group. In line with that, QoL and fatigue were better in physical “active” patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels. Conclusions Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients’ QoL and fatigue. Trial registration EUPAS9462. Registered 30th October 2012 “retrospectively registered.”
Relationship between Prices and Quality of Essential Medicines from Different Manufacturers Collected in Cameroon, the Democratic Republic of the Congo, and Nigeria
2024-10-08

ABSTRACT. Achieving universal access to affordable medicines and at the same time ensuring the quality of medicines presents a challenge, especially in low- and middle-income countries. Here, the relationship between medicine prices and medicine quality was investigated in three African countries. From different types of health facilities and medicine vendors, 711 samples of 18 different essential medicines were purchased and analyzed for quality (assay and dissolution) according to the United States Pharmacopeia. Without exception, all originator brand medicines and all SRA generics (generic medicines manufactured in countries with stringent regulatory authorities [SRAs]) complied with pharmacopeial specifications. In contrast, 21.1% of the non-SRA generics (manufactured in countries without SRAs) were substandard. The median prices of originator brands and SRA generics were three times and two times higher than those of non-SRA generics, respectively. Within the non-SRA generics, no positive correlation was observed between medicine quality and medicine price. Medicines manufactured in India, China, or African countries showed similar quality and similar prices. Only a single WHO-prequalified medicine sample was found among the 711 samples. Non-SRA generic medicines produced by manufacturers for which WHO had published Public Inspection Reports showed a significantly lower rate of substandard medicines (7.3%) and, at the same time, significantly lower prices (by 33%) than other non-SRA generics. Falsified medicines (total 2.0%) were found among all categories of medicines and had prices similar to those of non-SRA generics. Our findings indicate that adequate quality assurance does not necessarily imply an increase in medicine prices.