julilili42/papers huggingface dataset:
Novel record of placodont remains including a Henodus cranium from the Upper Triassic Silves Group of the Algarve, southern Portugal
2024-09-02

Funding Information: We would like to thank anonymous reviewers for providing a detailed and very constructive review, contributing to the enhancement of the manuscript. We express our great gratitude to J. Graça for donating the skull ML. A9182 to the Museu Municipal de Loulé, making this study possible. Without this donation our knowledge of placodont material from the Algarve would be much poorer. We want to thank Geoparque Algarvensis for the support and promotion of this work. We want to thank Dinopark Lourinhã for enabling access to Dinopark’s preparatory lab, helping in the process of preparation of the fossil material. We thank S. Mateus, J. Marinheiro, and V. López Rojas for support during the preparation in Dinopark Lourinhã as well as Nathalie Rodrigues for assistance in the preparation of armor plate material at the Museum of Lourinhã. We would also like to thank C. Pessoa for helping with XRF analysis at the Departamento de Ciências da Terra of Faculdade de Ciências e Tecnologia of Universidade Nova de Lisboa. We are also grateful to J. Kowalski and P. Janecki for providing illustration of Henodus. IW was funded by Deutsche Forschungsgemeinschaft (grant: WE5440/6-1) as well as by E. and W. Datz-Stiftung. Publisher Copyright: © 2025. Maciej Ruciński, Hugo Campos, Octávio Mateus, Ingmar Werneburg.
Sub-optimal therapy of patients with primary biliary cholangitis (PBC) in the real-life stetting of the German PBC cohort
2024-09-03

Abstract Real-world data on the management of patients with primary biliary cholangitis (PBC) are so far scarce in Germany. Therefore, we aimed to establish a nationwide registry and describe the clinical characteristics and therapy of PBC patients. Three different cohorts defined as ursodeoxycholic acid (UDCA) responders, as inadequate responders according to Paris II criteria, and as newly diagnosed patients were prospectively recruited. This manuscript includes the baseline data of the project. In total, 33/77 (43%) contacted centres (58% of university hospitals, 38% of non-university hospitals, and 24% of private practices) recruited 515 patients including 204 UDCA responders, 221 inadequate responders to UDCA, and 90 newly diagnosed patients. All patients were treated with UDCA; however, a UDCA dosage below the recommended dosage of 13 mg/kg/d was observed in 38.5% of individuals after 12 months of treatment. UDCA dosages were lower in nonacademic compared to academic centres. Only 75/219 (38.5%) of inadequate responders to UDCA received a second-line therapy with obeticholic acid (OCA) and/or bezafibrate (BZF). OCA (13% vs. 4.5%) and BZF (14% vs. 6.5%) were significantly more often prescribed by academic vs. nonacademic centres. Pruritus (27% vs. 15.5%), fatigue (23% vs. 4.5%), and sicca syndrome (14% vs. 1%) were significantly more often reported by academic centres. The German PBC registry could be established, which indicates suboptimal therapy in a relevant proportion of patients and shows significant differences between academic and nonacademic centres. Results are fundamental to improving clinical management at different levels of care.
Re-name the Streets. Toponymic Struggles and Civic Belonging in Murcia (Spain) and Johannesburg (South Africa)
2024-09-03

Toponymic struggles are about forms of civic belonging that street names enable or prevent. Drawing on a moral economy perspective, this article examines similarities and differences between struggles over street names in the Spanish city of Murcia and the South African metropolis of Johannesburg. In contrasting these cases, a paradox becomes apparent: While actors in toponymic struggles have to evoke moral goods such as inclusivity, fairness and neutrality to advocate for change or in defense of the status quo, these values are rendered suspect in the very same process. Nonetheless, in the examined cases toponymic struggles lead in part to more inclusive solutions than those originally expected by actors that face each other as adversaries in the local moral economy of toponymic struggles. The article is based on intensive field research in both areas of study, including participant observation, qualitative interviews, online ethnography, and an analysis of newspaper articles and policy documents.
Assessment of the reliability, responsiveness, and meaningfulness of the scale for the assessment and rating of ataxia (SARA) for lysosomal storage disorders
2024-09-03

Abstract Objective To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change. Methods We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann–Pick disease type C (NPC) and GM2 Gangliosidoses (Tay–Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigator’s, Caregiver’s, and Patient’s Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale. Results The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was −0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator’s, Caregiver’s, and Patient’s CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient’s everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia. Conclusion Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.
Only a matter of time? Using logfile data to evaluate temporal motivation theory in university students' examination preparation
2024-09-03

Abstract Background While previous research has emphasized the importance of personal beliefs (expectancy‐value theories) for achievement‐motivated behaviour, it lacks the integration of temporal factors that are also discussed as important drivers of achievement‐motivated behaviour. Temporal Motivation Theory (TMT) combines both approaches in a formalized manner. Aims Although TMT is supported by empirical studies with self‐reported academic procrastination, it has not been tested on actual achievement‐motivated behaviour. Materials &amp; Methods We evaluated the predictive power of the TMT on N = 2351 learning days of 127 psychology students' self‐regulated examination preparation for statistics over the course of one semester using logfile data of an e‐learning system. Results The proposed TMT score, incorporating expectancy and value beliefs, sensivitiy to delay, and actual time till examination predicted students' achievement‐motivated behaviour significantly. Discussion Further analyses revealed that not the trait compositions of the TMT, but the temporal proximity of the statistics examination was the main driver of this association. Conclusion The results have important implications for understanding the factors that shape students' motivation to learn and subsequent academic success in actual learning situations. Thus, research should continue to take situational aspects, especially the temporal proximity of goals more into account.
Myositis -specific and -associated antibodies in neurological disorders - A retrospective study of 727 patients
2024-09-03

Testing MSA and MAA simultaneously may not be suitable as a primary screening method for myositis-linked diseases in clinical neurological groups. However, MSAs and MAAs may offer valuable diagnostic support, particularly in cases where myositis is strongly considered.
Medicago truncatula SOBIR1 controls pathogen immunity and specificity in the Rhizobium‐legume symbiosis
2024-09-03

Abstract Medicago truncatula Nod Factor Perception (MtNFP) plays a role in both the Rhizobium‐Legume (RL) symbiosis and plant immunity, and evidence suggests that the immune‐related function of MtNFP is relevant for symbiosis. To better understand these roles of MtNFP, we sought to identify new interacting partners. We screened a yeast‐2‐hybrid cDNA library from Aphanomyces euteiches infected and noninfected M. truncatula roots. The M. truncatula leucine‐rich repeat (LRR) receptor‐like kinase SUPPRESSOR OF BIR1 (MtSOBIR1) was identified as an interactor of MtNFP and was characterised for kinase activity, and potential roles in symbiosis and plant immunity. We showed that the kinase domain of MtSOBIR1 is active and can transphosphorylate the pseudo‐kinase domain of MtNFP. MtSOBIR1 could functionally complement Atsobir1 and Nbsobir1/sobir1‐like mutants for defence activation, and Mtsobir1 mutants were defective in immune responses to A. euteiches . For symbiosis, we showed that Mtsobir1 mutant plants had both a strong, early infection defect and defects in the defence suppression in nodules, and both effects were plant genotype‐ and rhizobial strain‐specific. This work highlights a conserved function for MtSOBIR1 in activating defence responses to pathogen attack, and potentially novel symbiotic functions of downregulating defence in association with the control of symbiotic specificity.
Anti-sulfatide antibodies in neurological disorders: should we test?
2024-09-03

Abstract Objective Neurological autoimmune peripheral and central nervous system disorders can be associated with anti-sulfatide antibodies. These antibodies are considered potential diagnostic biomarkers, although their additional diagnostic value in neurological fields has been increasingly questioned. Given the little evidence of anti-sulfatide antibodies’ frequency and diagnostic value in neurology, we aimed to fill this knowledge gap by investigating 10 years of data. Methods This retrospective study analyzed the results of the anti-ganglioside dot kits (GA Generic Assays GmbH) from 1318 serum samples and 462 cerebrospinal fluid (CSF) samples for the frequency, sensitivity, and specificity of anti-sulfatide antibodies in neurological disorders. Results Although anti-sulfatide antibodies are rarely present in neurological autoimmune disorders (serum IgM 2.5%, IgG 4.6%), they are also present in non-autoimmune diseases (serum IgM 1.2%, IgG 2.5%) and lack sensitivity and specificity towards being a diagnostic marker. Furthermore, anti-sulfatide antibodies are rarely found in CSF (e.g., no positive results for IgM), and including so-called borderline results ((+)) increases sensitivity and the false-positive rate in serum and CSF. Discussion While anti-sulfatide antibodies appear more frequently in neurological autoimmune diseases, they are rare overall and provide very limited diagnostic value in determining specific neurological diseases and—more importantly—if a neurological disease has a potential autoimmune etiology.
The mitochondrial unfolded protein response promotes senescence in human microglia by increasing S-adenosylmethionine availability for polyamine synthesis
2024-09-03

Abstract Mitochondria have developed a specialized mitochondrial unfolded protein response (UPR mt ) to maintain proteostasis and promote recovery under stress conditions. Research in simple organisms has demonstrated that UPR mt activation in glial cells promotes proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this knowledge gap, we profiled the cell type-specific roles of the UPR mt using human induced pluripotent stem cell-derived neuronal and glial cultures and brain organoids. We found that UPR mt activation induces metabolic rewiring in human microglia, resulting in a senescence phenotype mediated by S-adenosylmethionine availability for polyamine synthesis. Additionally, UPR mt disrupted microglial intercellular communication, leading to microglia-mediated dysfunction of phagocytic pathways and increased inflammatory signaling. Using microglia-brain-assembloids, we observed distinct contributions by microglia to brain senescence and neurodegenerative disease processes driven by mitochondrial stress responses. These findings underscore the profound impact of defects in mitochondrial proteostasis on intercellular networks during brain aging and disease.
Spatial and temporal variation in farmland bird nesting ecology: Implications for effective Corn Bunting Emberiza calandra conservation
2024-09-03

Farmland bird populations continue to decline despite intense conservation efforts, possibly also because of incomplete knowledge on the drivers of local productivity. We therefore investigated spatial and temporal variation in nest site selection, breeding phenology, and nest survival for 225 nests of the Corn Bunting, a species of conservation concern in Central and Western Europe, in cropland-dominated, mixed, and grassland-dominated landscapes in SW Central Europe. Nesting phenology spread from April to August, started earlier at lower altitudes and progressed from grassland habitats to arable crops and eco-scheme flower fields. Most nests were placed in cultivated land, with substantial variation between landscape types but also between years within sites, so that large fractions of breeding attempts are prone to fail through land use operations in particular years. When nests were individually protected from land use, 'apparent' and 'Mayfield' survival rates differed substantially between nest habitats, with lowest survival in 2nd year flower fields and highest survival in fallow grassland. Accounting for land use survival from patch-specific mowing, harvesting, and grazing dates, 'total Mayfield nest survival' estimates dropped by about half to 21 %, 13 %, and 20 % for (hay) meadows, alfalfa / clover-grass leys, and pastures, respectively, which held about 2/3 of nests in mixed landscapes. To enhance productivity beyond the thresholds required for local population persistence, we propose refined conservation schemes that improve survival within production farmland, best coupled with the development of prolific 'Corn Bunting Landscapes'.
Identifying Quinones in Complex Aqueous Environmental Media (Biochar Extracts) through Tagging with Cysteine and Cysteine-Contained Peptides and High Resolution Mass Spectrometry Analysis
2024-09-03

Quinones are among the most important components in natural organic matter (NOM) for redox reactions; however, no quinones in complex environmental media have been identified. To aid the identification of quinone-containing molecules in ultracomplex environmental samples, we developed a chemical tagging method that makes use of a Michael addition reaction between quinones and thiols (-SH) in cysteine (Cys) and cysteine-contained peptides (CCP). After the tagging, candidates of quinones in representative aqueous environmental samples (water extractions of biochar) were identified through high-resolution mass spectrometry (HRMS) analysis. The MS and UV spectra analysis showed rapid reactions between Cys/CCP and model quinones with β-carbon from the same benzene ring available for Michael addition. The tagging efficiency was not influenced by other co-occurring nonquinone representative compounds, including caffeic acid, cinnamic acid, and coumaric acid. Cys and CCP were used to tag quinones in water extractions of biochars, and possible candidates of quinones (20 and 53 based on tagging with Cys and CCP, respectively) were identified based on the HRMS features for products of reactions with Cys/CCP. This study has successfully demonstrated that such a Michael addition reaction can be used to tag quinones in complex environmental media and potentially determine their identities. The method will enable an in-depth understanding of the redox chemistry of NOM and its critical chemical compositions and structures.
Opportunities for Microphysiological Systems in Toxicity Testing of New Drug Modalities
2024-09-04

New drug modalities offer life-saving benefits for patients through access to previously undruggable targets. Yet these modalities pose a challenge for the pharmaceutical industry, as side effects are complex, unpredictable, and often uniquely human. With animal studies having limited predictive value due to translatability challenges, the pharmaceutical industry seeks out new approach methodologies. Microphysiological systems (MPS) offer important features that enable complex toxicological processes to be modeled in vitro such as ( a ) an adjustable complexity of cellular components, including immune components; ( b ) a modifiable tissue architecture; ( c ) integration and monitoring of dynamic mechanisms; and ( d ) a multiorgan connection. Here we review MPS studies in the context of four clinical adverse events triggered by new drug modalities: peripheral neuropathy, thrombocytopenia, immune-mediated hepatotoxicity, and cytokine release syndrome. We conclude that while the use of MPS for testing new drug modality–induced toxicities is still in its infancy, we see strong potential going forward.
Evaluation of an automated laminar cartilage T2 relaxation time analysis method in an early osteoarthritis model
2024-09-04

Abstract Objective A fully automated laminar cartilage composition (MRI-based T2) analysis method was technically and clinically validated by comparing radiographically normal knees with (CL-JSN) and without contra-lateral joint space narrowing or other signs of radiographic osteoarthritis (OA, CL-noROA). Materials and methods 2D U-Nets were trained from manually segmented femorotibial cartilages ( n = 72) from all 7 echoes (All E ), or from the 1st echo only (1 st E ) of multi-echo-spin-echo (MESE) MRIs acquired by the Osteoarthritis Initiative (OAI). Because of its greater accuracy, only the All E U-Net was then applied to knees from the OAI healthy reference cohort ( n = 10), CL-JSN ( n = 39), and (1:1) matched CL-noROA knees ( n = 39) that all had manual expert segmentation, and to 982 non-matched CL-noROA knees without expert segmentation. Results The agreement (Dice similarity coefficient) between automated vs. manual expert cartilage segmentation was between 0.82 ± 0.05/0.79 ± 0.06 (All E /1 st E) and 0.88 ± 0.03/0.88 ± 0.03 (All E /1 st E ) across femorotibial cartilage plates. The deviation between automated vs. manually derived laminar T2 reached up to − 2.2 ± 2.6 ms/ + 4.1 ± 10.2 ms (All E /1 st E ). The All E U-Net showed a similar sensitivity to cross-sectional laminar T2 differences between CL-JSN and CL-noROA knees in the matched (Cohen’s D ≤ 0.54) and the non-matched ( D ≤ 0.54) comparison as the matched manual analyses ( D ≤ 0.48). Longitudinally, the All E U-Net also showed a similar sensitivity to CL-JSN vs. CS-noROA differences in the matched ( D ≤ 0.51) and the non-matched ( D ≤ 0.43) comparison as matched manual analyses ( D ≤ 0.41). Conclusion The fully automated T2 analysis showed a high agreement, acceptable accuracy, and similar sensitivity to cross-sectional and longitudinal laminar T2 differences in an early OA model, compared with manual expert analysis. Trial registration Clinicaltrials.gov identification: NCT00080171.
Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification
2024-09-04

Abstract Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.
Whole genome analysis of Plasmodium malariae identifies reduced susceptibility to pyrimethamine, validated using ortholog replacement in P. knowlesi
2024-09-04

<title>Abstract</title> <italic>Plasmodium malariae</italic> parasites are widely observed across the tropics and sub-tropics. This slow-growing species, known to maintain chronic asymptomatic infections, has been associated with reduced antimalarial susceptibility. We analyse 251 <italic>P. malariae</italic> genomes, and leveraging 131,601 high-quality SNPs, demonstrate segregation of African and Asian isolates. Signals of recent evolutionary selection were identified in genes encoding putative surface proteins (<italic>pmmsp1</italic>) and putative erythrocyte invasion proteins (<italic>pmdpap3, pmrbp2, pmnif4</italic>). Amino acid substitutions were identified in orthologs of genes associated with antimalarial susceptibility including 2 amino acid substitutions in <italic>pmdhfr</italic> aligning with pyrimethamine resistance mutations in <italic>P. falciparum</italic>. Additionally, we characterise <italic>pmdhfr</italic> mutation F57L and demonstrate its involvement in reduced susceptibility to pyrimethamine for the first time in a parasite assay. We validate CRISPR-Cas9 mediated ortholog replacement in <italic>P. knowlesi</italic> parasites to determine the function of <italic>pmdhfr</italic> mutations and demonstrate that circulating <italic>pmdhfr</italic> genotypes are less susceptible to pyrimethamine.
Strategic Location and Manager Delegation with Concentrated Consumer Demand
2024-09-04

Abstract This paper studies how the separation of ownership and management affects firms’ location decisions in a model of price competition with concentrated consumer demand. Strategic location decisions are made by the owners themselves, whereas operational price decisions are delegated to managers. It is shown that the impact of manager delegation on locations, prices and profits crucially depends on the shape of the demand distribution. When the distribution is “broad-peaked”, delegation leads to more distant locations, higher prices and profits. However, “narrow-peaked” distributions reverse the delegation effect on location and can even lead to lower prices and profits.