julilili42/papers huggingface dataset:
Flexible inference in heterogeneous and attributed multilayer networks
2024-12-23

Abstract Networked datasets can be enriched by different types of information about individual nodes or edges. However, most existing methods for analyzing such datasets struggle to handle the complexity of heterogeneous data, often requiring substantial model-specific analysis. In this article, we develop a probabilistic generative model to perform inference in multilayer networks with arbitrary types of information. Our approach employs a Bayesian framework combined with the Laplace matching technique to ease interpretation of inferred parameters. Furthermore, the algorithmic implementation relies on automatic differentiation, avoiding the need for explicit derivations. This makes our model scalable and flexible to adapt to any combination of input data. We demonstrate the effectiveness of our method in detecting overlapping community structures and performing various prediction tasks on heterogeneous multilayer data, where nodes and edges have different types of attributes. Additionally, we showcase its ability to unveil a variety of patterns in a social support network among villagers in rural India by effectively utilizing all input information in a meaningful way.
Expanding the Chemical Space of Reverse Fosmidomycin Analogs
2024-12-23

Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for <i>Plasmodium falciparum</i>, <i>Escherichia coli</i>, and <i>Mycobacterium tuberculosis</i> that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin. Despite nanomolar target inhibition, the new DXR inhibitors demonstrated mainly weak or no <i>in vitro</i> growth inhibition of the pathogens. Crystallographic studies revealed that compounds <b>12a</b> and <b>12b</b> induce an open <i>Pf</i>DXR conformation and that the enzyme selectively binds the <i>S</i>-enantiomers. The study underscores the difficulties of achieving potent cellular activity despite strong DXR inhibition and emphasizes the need for novel structural optimization strategies and comprehensive pharmacokinetic studies.
Metabolic Biomarkers of Liver Failure in Cell Models and Patient Sera: Toward Liver Damage Evaluation In Vitro
2024-12-23

Recent research has concentrated on the development of suitable in vitro cell models for the early identification of hepatotoxicity during drug development in order to reduce the number of animal models and to obtain a better predictability for hepatotoxic reactions in humans. The aim of the presented study was to identify translational biomarkers for acute liver injury in human patients that can serve as biomarkers for hepatocellular injury in vivo and in vitro in simple cell models. Therefore, 188 different metabolites from patients with acute-on-chronic liver failure before and after liver transplantation were analyzed with mass spectrometry. The identified potential metabolic biomarker set, including acylcarnitines, phosphatidylcholines and sphingomyelins, was used to screen primary and permanent hepatocyte culture models for their ability to model hepatotoxic responses caused by different drugs with known and unknown hepatotoxic potential. The results obtained suggest that simple in vitro cell models have the capability to display metabolic responses in biomarkers for liver cell damage in course of the treatment with different drugs and therefore can serve as a basis for in vitro models for metabolic analysis in drug toxicity testing. The identified metabolites should further be evaluated for their potential to serve as a metabolic biomarker set indicating hepatocellular injury in vitro as well as in vivo.
Exploiting nonequilibrium phase transitions and strong symmetries for continuous measurement of collective observables
2024-12-23

Dissipative many-body quantum dynamics can feature strong symmetries which give rise to conserved quantities. We discuss here how a strong symmetry in conjunction with a nonequilibrium phase transition allows to devise a protocol for measuring collective many-body observables. To demonstrate this idea we consider a collective spin system whose constituents are governed by a dissipative dynamics that conserves the total angular momentum. We show that by continuously monitoring the system output the value of the total angular momentum can be inferred directly from the time-integrated emission signal, without the need of repeated projective measurements or reinitializations of the spins. This may offer a route towards the measurement of collective properties in qubit ensembles, with applications in quantum tomography, quantum computation and quantum metrology.
Systematic assessment of COVID-19 host genetics using whole genome sequencing data
2024-12-23

Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases. We observed the presence of autosomal-recessive or likely compound heterozygous monogenic disorders in six individuals, all of which were hospitalized and significantly younger than the rest of the cohort. We did not observe any suggestive causal variants in or around the established risk gene TLR7 . Burden testing in the largest population subgroup (i.e., Europeans) suggested nominal enrichments of rare variants in coding and non-coding regions of interferon immune response genes in the overall analysis and male subgroup. Case-control analyses of more common variants confirmed associations with previously reported risk loci, with the key locus at 3p21 reaching genome-wide significance. Polygenic scores accurately captured risk in an age-dependent manner. By enabling joint analyses of different types of variation across the entire frequency spectrum, this data will continue to contribute to the elucidation of COVID-19 etiology.
Probing the Protein Kinases′ Cysteinome by Covalent Fragments
2024-12-24

Abstract Protein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non‐covalent counterparts, covalent inhibitors offer the advantage of selectively targeting structurally similar kinases by modifying specific protein side chains, particularly non‐conserved cysteines. Previously, covalent fragment screens yielded potent and selective inhibitors for individual kinases such as ERK1/2 but have not been applied to the broader kinome. Furthermore, many of the accessible cysteine positions have not been addressed so far. Here, we outline a generalizable approach to sample ATP‐site cysteines with fragment‐like covalent inhibitors. We present the development of a kinase‐focused covalent fragment library and its systematic screening against a curated selection of 47 kinases, with 60 active site‐proximal cysteines using LC/MS and differential scanning fluorimetry (DSF) assays, followed by hit validation through various complementary techniques. Our findings expand the repertoire of targetable cysteines within protein kinases, provide insight into unique binding modes identified from crystal structures and deliver isoform‐specific hits with promising profiles as starting points for the development of highly potent and selective covalent inhibitors.
Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients: mutation frequencies, testing intention, and clinical impact
2024-12-24

Abstract Background Circulating cell-free tumor DNA (ctDNA) provides a non-invasive approach for assessing somatic alterations. The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice. In this context, ctDNA testing was included to understand the motivations of clinicians to initiate testing, to identify somatic alterations, and to assess the clinical impact of the results obtained. Methods Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting (PRAEGNANT study; NCT02338167). The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations. A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results. Results ctDNA from 49 patients was analyzed prospectively: 37 (76%) had at least one somatic alteration in the analyzed geneset; 14 patients (29%) harbored alterations in TP53, 12 (24%) in PIK3CA, and 6 (12%) in ESR1. Somatic mutations in BRCA1 or BRCA2 were detected in 3 (6%) and 4 (8%) patients, respectively, and 59% of patients had hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Questionnaires regarding test intentions and clinical impact were completed for 48 (98%) patients. These showed that ctDNA testing influenced treatment decisions for 35% of patients. Discussion The high prevalence of somatic alterations in TP53, PIK3CA, ESR1, and BRCA1/2 genes, identified by ctDNA genotyping, highlights their potential as biomarkers for targeted therapies. Detection of specific mutations affected treatment decisions, such as eligibility for alpelisib, and might further facilitate treatment with e.g. elacestrant or capiversatib in future treatment lines.
BIPE: A Bi-Layer Predictive Ensemble Framework for Forest Fire Susceptibility Mapping in Germany
2024-12-24

Forest fires diminish forests’ ecological services, including carbon sequestration, water retention, air cooling, and recreation, while polluting the environment and endangering habitats. Despite considerable economic advancements, firefighting strategies remain less than optimal. This paper introduces the Bi-layer Predictive Ensemble (BIPE), an innovative machine learning model designed to enhance the accuracy and generalization of forest fire susceptibility mapping. BIPE integrates model-centric and data-driven strategies, employing automated methods such as 10-fold cross-validation and meta-learning to improve stability and generalization. During its 10-fold cross-validation, BIPE demonstrated excellent performance, with the Area Under the Curve (AUC) values ranging from 0.990 to 0.996 and accuracy levels consistently high, around 97%, underscoring its robust class separation ability and strong generalization across different datasets. Our results confirm that BIPE outperforms traditional high-performance models like Support Vector Machine (SVM), Multilayer Perceptron (MLP), Extreme Gradient Boosting (XGBoost), Deep Neural Network (DNN), and Convolutional Neural Network (CNN), showcasing its practical effectiveness and reliability on the data of nonlinear, high-dimensional, and complex interactions. Additionally, our forest fire susceptibility maps offer valuable complementary information for German forest fire management authorities, enhancing their ability to assess and manage fire risks more effectively.
Predicting individual long-term prognosis of spatial neglect based on acute stroke patient data
2024-12-24

Abstract One of the most pressing questions after a stroke is whether an individual patient will recover in the long term. Previous studies demonstrated that spatial neglect—a common cognitive deficit after right hemispheric stroke—is a strong predictor for poor performance on a wide range of everyday tasks and for resistance to rehabilitation. The possibility of predicting long-term prognosis of spatial neglect is therefore of great relevance. The aim of the present study was to test the prognostic value of different imaging and non-imaging features from right hemispheric stroke patients: individual demographics (age, sex), initial neglect severity and acute lesion information (size, location). Patients’ behaviour was tested twice in the acute and the chronic phases of stroke and prediction models were built using machine learning-based algorithms with repeated nested cross-validation and feature selection. Model performances indicate that demographic information seemed less beneficial. The best variable combination comprised individual neglect severity in the acute phase of stroke, together with lesion location and size. The latter were based on individual lesion overlaps with a previously proposed chronic neglect region of interest that covers anterior parts of the superior and middle temporal gyri and the basal ganglia. These variables achieved a remarkably high level of accuracy by explaining 66% of the total variance of neglect patients, making them promising features in the prediction of individual outcome prognosis. An online tool is provided with which our algorithm can be used for individual outcome predictions (https://niivue.github.io/niivue-neglect/).
Environmental enrichment is associated with favorable memory-related functional brain activity patterns in older adults
2024-12-24

Background In humans, environmental enrichment (EE), as measured by the engagement in a variety of leisure activities, has been associated with larger hippocampal structure and better memory function. The present cross-sectional study assessed whether EE during early life (13–30 years) and midlife (30–65 years) is associated with better preserved memory-related brain activity patterns in older age. Methods In total, 372 cognitively unimpaired older adults (aged ≥60 years old) of the DZNE-Longitudinal Study on Cognitive Impairment and Dementia (DELCODE; DRKS00007966) were investigated. EE was operationalized using items of the Lifetime of Experiences Questionnaire (LEQ), which measures the self-reported participation in a variety of leisure activities in early life and midlife. The preservation of memory-related functional brain activity was assessed using single-value scores, which relate older adults’ brain activity patterns in the temporo-parieto-occipital memory network to those of young adults during visual memory encoding (FADE and SAME scores). Results EE during early life and midlife was significantly associated with higher SAME scores during novelty processing ( n = 372, β = 0.13, p = 0.011). Thus, older participants with higher EE showed greater similarity of functional brain activity patterns during novelty processing with young adults. This positive association was observed most strongly in participants with subjective cognitive decline (SCD, n = 199, β = 0.20, p = 0.006). Conclusion More frequent participation in a variety of leisure activities in early life and midlife is associated with more successful aging of functional brain activity patterns in the memory network of older adults, including participants at increased risk for dementia. Longitudinal studies are needed to clarify whether higher EE during life could help preserve memory network function in later life.
Determining the role of basophil activation testing in reported type 1 allergy to beta-lactam antibiotics
2024-12-24

Background Allergy to beta-lactam antibiotics (BLA), especially to penicillin, is the most commonly reported drug allergy by patients. Alternative antibiotics can yield negative consequences, such as extended hospitalization days due to less efficacy and overall higher costs. The basophil activation test (BAT) is an in vitro assay, in which activation of an individual's own basophils is quantified by flow cytometry. It is an increasingly applied in vitro method in allergy testing that is also gaining traction in drug allergies. Methods We correlated 37 BAT results with skin test results. The cohort exclusively included patients with suspected type I BLA allergy. In addition, we examined the concordance of these results with clinical symptoms reported in the BLA patients’ medical histories. Results BLA-BAT revealed a high specificity of 92.3% [95% confidence interval (CI) 66.7–98.6] but a low sensitivity of only 20.8% (95% CI 9.24–40.47) using BLA-skin tests as a comparator. Negative BLA-BAT in patients with a history of grade I anaphylaxis yielded doubt on the assumption of grading. The exclusion of grade I BLA anaphylaxis increased the sensitivity to 29.4% (95% CI 13.28–53.13) with a still high specificity of 85.7% (95% CI 48.69–97.43). When ImmunoCAP was available, we compared specific IgE and BAT results by using Cohens' kappa (κ) and revealed a moderate level of agreement (κ = 0.538, p = 0.029). Conclusion BAT reveals specific positive results exclusively in patients with cephalosporin anaphylaxis. However, these findings could not be generally confirmed in the heterogeneous group of BLA.
CSF biomarkers are differentially linked to brain areas high and low in noradrenaline, dopamine and serotonin across the Alzheimer’s disease spectrum
2024-12-24

Abstract Neurotransmitter systems of noradrenaline, dopamine, serotonin and acetylcholine are implicated in cognitive functions such as memory, learning and attention and are known to be altered in neurodegenerative diseases like Alzheimer’s disease. Specific brain structures involved in these systems, e.g. the locus coeruleus, the main source of noradrenaline in the cortex, are in fact affected earliest by Alzheimer’s disease tau pathology. Preserved volumetric neurotransmitter specific brain areas could therefore be an important neural resource for cognitive reserve in aging. The aim of this study was to determine whether volumes of brain areas known to be high in neurotransmitter receptors are relatively preserved in individuals with lower levels of Alzheimer’s disease pathology. Based on the Human Protein Atlas for neurotransmitter receptor distribution, we distinguished between ‘areas high and low’ in noradrenaline, dopamine, serotonin and acetylcholine and assessed associations of atrophy in those areas with CSF amyloid-ß 42/40, CSF phosphorylated tau protein and cognitive function across healthy controls (n = 122), individuals with subjective cognitive decline (n = 156), mild cognitive impairment or mild Alzheimer’s disease dementia (n = 126) using structural equation modelling. CSF pathology markers were inversely correlated and showed a stronger association with disease severity, suggesting distinguishable interrelatedness of these biomarkers depending on the stage of Alzheimer’s disease dementia. Across groups, amyloid pathology was linked to atrophy in areas high as well as low in neurotransmitter receptor densities, while tau pathology did not show any significant link to brain area volumes for any of the neurotransmitters. Within disease severity groups, individuals with more amyloid pathology showed more atrophy only in ‘areas high in noradrenaline’, whereas for dopamine tau pathology was linked to higher volumes in areas low in receptor density possibly indicating compensatory mechanisms. Furthermore, individuals with more tau pathology showed a selective decrease in memory function while amyloid pathology was related to a decline in executive function and language capacity as well as memory function. In summary, our analyses highlight the benefits of investigating disease-relevant factors in Alzheimer’s disease using a multivariate multigroup approach. Assessing multivariate dependencies in different disease stages and across individuals revealed selective links of pathologies, cognitive decline and atrophy in particular for areas modulated by noradrenaline, dopamine and serotonin.
Ovarian tissue cryopreservation for a girl with combined severe hemolytic anemia due to pyruvate kinase deficiency: a case report and literature review
2024-12-24

Hematopoietic stem cell transplantation is essential for effective treatment of pyruvate kinase deficiency. We assess OTC as the only possible fertility preservation method for children who cannot undergo embryo and oocyte cryopreservation.
Spectroelectrochemistry with Hydrogen-Doped Indium Oxide Electrodes Monitors Electron and Hole Injection into PbS Quantum Dots
2024-12-24

We combine potential-modulated absorption spectroscopy with working electrodes made of hydrogen-doped indium oxide on glass to study the electrochemically induced changes to the infrared absorption of ethanedithiol-crosslinked PbS quantum dot thin films. We demonstrate an electrochemical window of -1.5 V to 1 V vs. ferrocene/ferrocenium as well as a spectral window of 800 nm – 1900 nm, and we show how these ranges can be fine-tuned by tailoring the composition of the working electrode. We find evidence for the successful injection of electrons and holes into the quantum dots to a comparable degree. This enables us to locate the absolute positions of the band edges and the Fermi level for PbS quantum dots with different diameters, monitor how the band edge positions depend on the diameter and show a correlation between the position of the Fermi level with the appearance of in-gap states. We discuss the specific advantages of the technique presented here for monitoring the redox behaviour of IR-active quantum dots, detail the experimental challenges and devise strategies for their mitigation.
In Situ Vivianite Formation in Intertidal Sediments: Ferrihydrite-Adsorbed P Triggers Vivianite Formation
2024-12-25

Coastal sediments are a key contributor to oceanic phosphorus (P) removal, impacting P bioavailability and primary productivity. Vivianite, an Fe(II)-phosphate mineral, can be a major P sink in nonsulfidic, reducing coastal sediments. Despite its importance, vivianite formation processes in sediments remain poorly understood. Here, we applied a novel approach to detect and quantify in situ vivianite formation in three intertidal flats. We conducted 7-week long incubations of mesh-bags filled with sediments mixed with (1) <sup>57</sup>Fe-ferrihydrite, (2) <sup>57</sup>Fe-ferrihydrite with adsorbed phosphate, and (3) <sup>57</sup>Fe-ferrihydrite with adsorbed phosphate and some vivianite (natural Fe isotope abundance), which could serve as crystal growth sites. Synthesizing the ferrihydrite from <sup>57</sup>Fe (96.1%) enabled us to detect transformation products using <sup>57</sup>Fe-Mössbauer spectroscopy. Vivianite formed only in treatments containing adsorbed phosphate and only at the two sites where vivianite formation was thermodynamically feasible based on porewater chemistry. These results demonstrate vivianite formation within weeks when locally favorable Fe:P ratios exist. Although vivianite comprised a minor fraction of Fe (up to 15%), it represented a significant P pool (up to 72%), emphasizing its role in coastal P burial. Additionally, our results may apply to other environmental systems like limnic sediments.