julilili42/papers huggingface dataset:
Quality of Essential Medicines from Different Sources in Enugu and Anambra, Nigeria
2024-05-14

ABSTRACT. This study investigated the quality of 13 essential medicines in the states of Enugu and Anambra, Nigeria. A total of 260 samples were purchased from licensed pharmaceutical manufacturers and wholesalers and from vendors in pharmaceutical markets with unclear licensing status. Samples were analyzed for identity, content, and dissolution according to the United States Pharmacopeia (USP) 42 monographs. Forty-five samples of this study could be examined for authenticity with the Mobile Authentication Service scheme of the Nigerian National Agency for Food and Drug Administration and Control. Out of all samples, 25.4% did not comply with the USP 42 specifications. Strikingly, 21 out of 22 dexamethasone tablet samples (95%) were out of specification (OOS). Nine out of 19 glibenclamide samples (47%) failed dissolution testing, and 7 out of 17 cotrimoxazole samples (41%) failed assay testing. Medicines against noncommunicable diseases showed a slightly higher percentage of OOS samples than anti-infectives (21.2% versus 17.6%). The rates of OOS samples were similar in medicines stated to be produced in Nigeria, India, and China but were very different between individual manufacturers from each of these countries of origin. Therefore, prequalification of products, manufacturers, and suppliers are very important for quality assurance in medicine procurement. Unexpectedly, the total proportions of OOS samples were similar from licensed vendors (25.2%) and from markets (25.5%). Four samples (1.5%), all collected in markets, were clearly falsified and did not contain the declared active pharmaceutical ingredients. The proportion of falsified medicines was found to be lower than frequently reported in the media for Nigeria.
Black hole no-hair theorem for self-gravitating time-dependent spherically symmetric multiple scalar fields
2024-05-14

Abstract We prove under certain weak assumptions a black hole no-hair theorem in spherically symmetric spacetimes for self-gravitating time-dependent multiple scalar fields with an arbitrary target space admitting a Killing field with a non-empty axis and arbitrary non-negative potential invariant under the flow of the Killing field. It is shown that for such configurations the only spherically symmetric and asymptotically flat black hole solutions consist of the Schwarzschild metric and a constant multi-scalar map. In due course of the proof we also unveil the intrinsic connection of the time-dependence of the scalar fields with the symmetries of the target space.
Optimizing clinical interpretability of functional evidence in epilepsy-related ion channel variants
2024-05-14

Abstract Variants in genes encoding the voltage-gated ion channels are among the most common monogenic causes of epilepsy and neurodevelopmental disorders. Functional effects of a variant are increasingly important for diagnosis and therapeutic decisions. To incorporate knowledge regarding functional consequences in formal clinical variant interpretation, we developed an approach for evaluating multiple functional measurements within the Bayesian framework of the modified ACMG/AMP guidelines. We analyzed 216 functional assessments of 191 variants in SCN1A (n=74), SCN2A (n=66), SCN3A (n=18), and SCN8A (n=33). Of 20 commonly measured biophysical parameters, the most frequent drivers of overall functional consequence were persistent current (f=0.54), voltage dependence of activation (f=0.51), and voltage dependence of fast inactivation (f=0.40) for gain-of-function and peak current (f=0.87) for loss-of-function. By comparing measurements of 23 benign variants, we determined thresholds by which published data on these four parameters confer Strong evidence of variant pathogenicity (likelihood ratio &gt; 18.7) under the ACMG/AMP rubric. Similarly, we delineated evidence weights for the most common epilepsy-related potassium channel gene, KCNQ2 , through reports of 80 pathogenic and 24 benign variants, accounting for heterozygous and homozygous experimental conditions. We collected the resulting categorization of functional data into FENICS, a biomedical ontology of 152 standardized terms for coherent annotation of electrophysiological results. Across 271 variants in SCN1A/2A/3A/8A and KCNQ2 , 1,731 annotations are available in ClinVar, facilitating use of this evidence in variant classification. In summary, we introduce and apply an ACMG/AMP-calibrated framework for electrophysiological studies in epilepsy-related channelopathies to delineate the impact of functional evidence on clinical variant interpretation.
Single-cell and spatial atlas of steatotic liver disease-related hepatocellular carcinoma
2024-05-14

Summary Steatotic liver disease-related hepatocellular carcinoma (SLD-HCC) poses significant challenges in liver cancer management. Our current study investigates the tumor microenvironment (TME) of SLD-HCC using single-cell transcriptomic, proteomic and spatial transcriptomic analyses. We identified altered immune-related and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs) within the SLD-HCC microenvironment, suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. Cytometry by time-of-flight revealed a cold and immunosuppressive TME depleted with CD8 + T cells and enriched with Tregs, while spatial transcriptomics uncovered a unique spatial architecture with Treg/CAF clusters specifically located at the tumor margins in SLD-HCC. Crucially, we identified Treg-CAF interactions as a key mediator associated with lack of response to immunotherapy in SLD-HCC. Our findings highlight the intricate immune dynamics of SLD-HCC, indicating potential therapeutic targets to counteract immune evasion and restore anti-tumor immunity in SLD-HCC. Highlights The TME of SLD-HCC exhibits altered immune and lipid pathways Immunosuppressive SLD-HCC TME is depleted with CD8 + T cells and enriched with Tregs SLD-HCC has a unique spatial architecture with Treg-CAF clusters at tumor margins Treg-CAF interaction via TNFSF14-TNFRSF14 axis mediates immunotherapy resistance
Biallelic variants inARHGAP19cause a motor-predominant neuropathy with asymmetry and conduction slowing
2024-05-14

Abstract Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies, with over 100 causative genes identified to date. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Through international collaborations, we identified 16 recessive variants in Rho GTPase activating protein 19 ( ARHGAP19 ) causing motor-predominant neuropathy with conduction slowing in 25 individuals from 20 unrelated multi-ancestry families. ARHGAP19 is a GTPase-activating protein with activity towards RhoA. In vitro biochemical assays revealed that variants located within the GAP domain cause loss of GAP activity. iPSc-derived motor neurons exhibited 50% knockdown of ARHGAP19 protein. In vivo genetic perturbations of the Drosophila melanogaster ARHGAP19 ortholog RhoGAP54D reduced self-driven locomotor activity and startle responses to visual stimuli. Zebrafish loss-of-function models similarly exhibited movement deficits, coupled with increased motor neuron axonal branching but shorter caudal primary motor neurons. Together, these findings establish ARHGAP19 as a novel cause of early-onset neuropathy through a loss-of-function mechanism.
ACKR3 agonism induces heterodimerization with chemokine receptor CXCR4 and attenuates platelet function
2024-05-14

Abstract Background Platelet receptors ACKR3 and CXCR4 play a crucial role in a variety of cardio-vascular 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 signaling. 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 microscopy 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 signaling 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 signaling. Our results indicate possible ACKR3 agonist functions and reinforce the potential therapeutic applications of ACKR3 agonists. Abstract Figure Graphical abstract: CXCR4/ACKR3 heterodimerization in platelets.
The Fossils of Speothos Pacivorus (Carnivora: Canidae) at the Peter Lund/Quaternary Collection of the Natural History Museum of Denmark
2024-05-14

Speothos pacivorus is an extinct South American canid (Canidae: Cerdocyonina) from the Pleistocene of Lagoa Santa Karst, Central Brazil. This taxon is one of the hypercarnivore canids that vanished from the continent at the end of Pleistocene. Although all remains of Speothos pacivorus were collected in the 19th century by the Danish naturalist Peter W. Lund, few studies have committed to an in-depth analysis of the taxon and the known specimens. Here, we analyzed all biological remains of S. pacivorus hosted in the Peter Lund/Quaternary Collection at the Natural History Museum of Denmark, Copenhagen, by listing and illustrating all its specimens known to date. We also conducted a reconstruction of the holotype, an almost complete cranium, based on a μCT scan, producing an undeformed and crack-free three-dimensional model. With this data available we aim to foster new research on this elusive species.
Comparative Retrospective Assessment of the Effectiveness and Risk Factors of Fluoroquinolones, Cephalosporines, and Selective Antibiotic Prophylaxis for Transrectal Prostate Biopsy
2024-05-14

Introduction: Despite increasing resistance of enterobacteria against fluoroquinolones (FLU), they are still widely used during transrectal prostate biopsy (TRPB). This study was designed to analyse infectious complications and risk factors between FLU, cephalosporines (CEPH) and selective other antibiotics (O-AB) used during TRPB. Methods: 664 patients were included retrospectively (152 FLU, 452 CEPH and 60 O-AB). Infectious complications were defined as fever &amp;gt;38.0°C, the in-house definition of complicated urinary tract infection (cUTI) (if all applied: fever &amp;gt;38.0°C, leucocytosis &amp;gt;11.000/μL and positive urine dipstick) or postinterventional bacteriuria. Hospitalisation rate, duration and comorbidities were also assessed. χ2 and Fisher’s exact test were used for group comparison. Multivariate regression analysis assessed the association of comorbidities with infectious complications. Results: FLU and CEPH were indifferent regarding infectious complications, however in the O-AB group significantly more common compared to FLU and CEPH (11.6, 13.3, 25%, p &amp;lt; 0.05). Duration of hospital stay in CEPH was significantly shorter compared to FLU and O-AB (4.1 vs. 6.3 vs. 8.2 days, p &amp;lt; 0.05). Arterial hypertension showed increased association with fever (OR 6.002 (1.178; 30.597) p = 0.031) and cUTI (OR 6.006 (1.207; 29.891) p = 0.029). Conclusion: Infectious complications were low and indifferent between FLU and CEPH but significantly more frequent in O-AB. Arterial hypertension was significantly associated with postinterventional fever and cUTI.
Seasonal variation in the activity pattern of red squirrels and their mammalian predators
2024-05-14

Abstract Camera traps are a powerful tool to monitor the activity pattern of species over long time periods. Camera data can be used to analyze activity patterns of or temporal niche partitioning among species. Temporal niche partitioning plays an important role for species coexistence and is under constant evolutionary pressure from predator-prey relationships. Our study aimed to investigate temporal shifts in activity patterns of red squirrels and two mammalian predators, red fox and marten ( Martes spec .). Previous studies yielded different activity patterns for these species depending on location, season, predator-prey interactions, and food- availability. We used camera traps to monitor the activity of squirrels, red fox and martens throughout a whole year in a mountainous forest in southwestern Germany. We also investigated a possible difference in activity among different color morphs as coloration in mammals is often associated with concealment, for squirrels, however, such an effect could not be demonstrated so far. We found a diurnal activity for squirrels in all seasons with a bimodal activity pattern during spring, trimodal in summer and unimodal in fall and winter. Activity patterns did not differ between black and red color morphs. The activity of the squirrels showed only low to moderate overlaps with fox and marten, but there was still slight variation among seasons. Activity overlaps were higher in spring and summer, which coincides with breeding season. Our results suggest that predators might adjust their activity during squirrel breeding season to increase the chance of preying on their offspring. Squirrels in turn could benefit by minimizing the activity overlap during wintertime when they are highly visible to predators as trees are leaf-free or even snow might enhance the contrast between them and their background. Lastly, our results indicate that temporal niche portioning among red squirrel, red fox and martens might be rather fine scaled.
Porous Crystalline Organic Cages Made by Design
2024-05-15

Abstract Shape‐persistent organic cages are an intriguing class of molecular porous materials. Through hierarchical molecular design, size and shape of the intrinsic molecular voids are controlled by dynamic covalent chemistry, while pore structure and topology are governed by noncovalent alignment in the solid state. However, the predictable and reliable crystallization of organic cages is still challenging since long‐range superstructures are solely based on weak and rather unidirectional supramolecular interactions. In this tutorial review, we provide a general classification of porous solid‐state materials and discuss specific design principles regarding the dynamic covalent reactions, the small‐molecule building blocks and solid‐state engineering. Furthermore, we introduce the most important analytical techniques for porous materials with a special focus on organic cages.
Combined analysis of albumin in situ hybridisation and C reactive protein immunohistochemistry for the diagnosis of intrahepatic cholangiocarcinoma: towards a molecular classification paradigm
2024-05-15

Aims Intrahepatic cholangiocarcinoma (iCCA) is a diagnosis of exclusion that can pose a challenge to the pathologist despite thorough clinical workup. Although several immunohistochemical markers have been proposed for iCCA, none of them reached clinical practice. We here assessed the combined usage of two promising diagnostic approaches, albumin in situ hybridisation (Alb-ISH) and C reactive protein (CRP) immunohistochemistry, for distinguishing iCCA from other adenocarcinoma primaries. Methods We conducted Alb-ISH and CRP immunohistochemistry in a large European iCCA cohort (n=153) and compared the results with a spectrum of other glandular adenocarcinomas of different origin (n=885). In addition, we correlated expression patterns with clinicopathological information and mutation data. Results Alb-ISH was highly specific for iCCA (specificity 98.8%) with almost complete negativity in perihilar CCA and only rare positives among other adenocarcinomas (sensitivity 69.5%). CRP identified the vast majority of iCCA cases (sensitivity 84.1%) at a lower specificity of 86.4%. Strikingly, the combination of CRP and Alb-ISH boosted the diagnostic sensitivity to 88.0% while retaining a considerable specificity of 86.1%. Alb-ISH significantly correlated with CRP expression, specific tumour morphologies and small or large duct iCCA subtypes. Neither Alb-ISH nor CRP was associated with iCCA patient survival. 16 of 17 recurrent mutations in either IDH1, IDH2 and FGFR2 affected Alb-ISH positive cases, while the only KRAS mutation corresponded to an Alb-ISH negative case. Conclusions In conclusion, we propose a sequential diagnostic approach for iCCA, integrating CRP immunohistochemistry and Alb-ISH. This may improve the accuracy of CCA classification and pave the way towards a molecular-guided CCA classification.
Hydrothermal sulfidation of biogenic magnetite produces framboid-like pyrite
2024-05-15

Abstract Biogenic magnetite is a potential biosignature for microbial iron cycling in hydrothermal sulfide systems, critical environments for unraveling the emergence and early evolution of life. However, the preservation potential of biogenic magnetite under hydrothermal conditions is poorly understood. Here, we show that the hydrothermal sulfidation of abiogenic and biogenic magnetite (sulfide/iron = 4, 80 °C) yields pyrite with various distinct morphologies, including framboid-like spheroids. We demonstrate that the variability in pyrite morphologies resulted from the modulation of pyritization rates by interrelated effects between organic matter and elemental sulfur (crystalline or colloidal). Notably, framboid-like pyrite, commonly considered a potential fingerprint of microbial sulfur cycling, was exclusively produced from the hydrothermal sulfidation of biogenic (i.e., organic matter-associated) magnetite produced by iron-cycling microorganisms. Thus, framboid-like pyrite can additionally be a taphonomic fingerprint of microbial iron cycling, enabling a better understanding of the evolution of Earth’s biosphere in deep time.
Automated Scoring of Scientific Creativity in German
2024-05-15

ABSTRACT Automated scoring is a current hot topic in creativity research. However, most research has focused on the English language and popular verbal creative thinking tasks, such as the alternate uses task. Therefore, in this study, we present a large language model approach for automated scoring of a scientific creative thinking task that assesses divergent ideation in experimental tasks in the German language. Participants are required to generate alternative explanations for an empirical observation. This work analyzed a total of 13,423 unique responses. To predict human ratings of originality, we used XLM‐RoBERTa (Cross‐lingual Language Model‐RoBERTa), a large, multilingual model. The prediction model was trained on 9,400 responses. Results showed a strong correlation between model predictions and human ratings in a held‐out test set ( n = 2,682; r = 0.80; CI‐95% [0.79, 0.81]). These promising findings underscore the potential of large language models for automated scoring of scientific creative thinking in the German language. We encourage researchers to further investigate automated scoring of other domain‐specific creative thinking tasks.
[68Ga]Ga-NODAGA-TriGalactan, a low molecular weight tracer for the non-invasive imaging of the functional liver reserve
2024-05-15

Abstract Background Determination of the functional liver mass is important in a variety of clinical settings including liver surgery and transplantation. [ 99m Tc]Tc-diethylenetriamine-pentaacetic acid galactosyl human serum albumin ( 99m Tc-GSA) is a radiotracer targeting the asialoglycoprotein receptor (ASGR) and is routinely used in Japan for this purpose. Here we describe the development and evaluation of [ 68 Ga]Ga-NODAGA-TriGalactan a low molecular weight PET-tracer targeting this structure. Results For synthesis TRIS as branching unit and NODAGA as chelator for labelling with [ 68 Ga]Ga are included. Three galactose moieties are conjugated via a click chemistry approach resulting in the desired labelling precursor. 68 Ga-labelling could be accomplished in high radiochemical yield and purity. [ 68 Ga]Ga-NODAGA-TriGalactan is very hydrophilic and revealed high plasma stability and low plasma protein binding. Fluorescence imaging showed binding on ASGR-positive organoids and the IC 50 -value was in the nanomolar range. Most importantly, both biodistribution as well as animal imaging studies using normal mice demonstrated high liver uptake with rapid elimination from all other organs leading to even higher liver-to-background ratios as found for 99m Tc-GSA. Conclusion [ 68 Ga]Ga-NODAGA-TriGalactan shows high in vitro stability and selectively binds to the ASGR allowing imaging of the functional liver mass with high contrast. Thus, our first generation compound resulted already in an alternative to 99m Tc-GSA for imaging the functional liver reserve and might allow the broader use of this imaging technique.
Pedagogical approaches to health-related physical education (PE) in the context of digitalisation – a scoping review
2024-05-15

Introduction There are varied consequences of digital transformation processes within the fitness and health-related living environments of adolescents (e.g. increased physical activity through wearables, body dissatisfaction through social media) which could potentially provide fruitful health-related learning experiences within different pedagogical approaches to health in PE (e.g. biomedical vs. alternative, Mong and Standal, Citation2019, "Didactics of Health in Physical Education – a Review of Literature." Physical Education and Sport Pedagogy 24 (5): 506–518. https://doi.org/10.1080/17408989.2019.1631270). However, concerns have been raised that the integration of digital media into health-related PE could reinforce biomedical approaches to health and lead, for example, to a focus on increasing fitness through technology. This one-sided focus would not be in line with the demands for a comprehensive health education. This paper aims to map the current trend of pedagogical approaches to health-related PE in the context of digitalisation and to identify typical learning goals against this background.