julilili42/papers huggingface dataset:
Deficiency in nucleoside diphosphate kinase B leads to endothelial activation of the hexosamine biosynthesis pathway and cardiac dysfunction
2025-02-21

Abstract Background Nucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) promotes the activation of the hexosamine biosynthesis pathway (HBP), leading to vascular damage in the retina. The aim of this study was to investigate the consequences of NDPKB deficiency in the mouse heart. Methods NDPKB deficient mice were used in the study. Echocardiography was employed to assess cardiac function in vivo. Characterization of contractility in hiPSC-derived cardiomyocytes (hiPSC-CMs) was measured with the IonOptix contractility system. Immunoblotting and immunofluorescence were carried out to analyze the expression and localization of proteins in cultured cells and left ventricles (LVs). Results NDPKB deficient mice displayed impaired glucose tolerance and increased heart weight compared to controls. Echocardiographic analysis revealed an increase in the diastolic diameter of the left ventricular posterior wall (LVPW), a decrease in the early diastolic mitral valve E and E′ wave, and in the ratios of E/A and E′/A′ in NDPKB deficient hearts, suggesting cardiac hypertrophy and diastolic dysfunction. In line with cardiac dysfunction, the phosphorylation of myocardial phospholamban (PLN) and the expression of sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2 (SERCA2) in the NDPKB deficient LVs were significantly reduced. Moreover, the accumulation of collagen, fibronectin as well as the upregulation of transforming growth factor β (TGF-β), were detected in NDPKB deficient LVs. In addition, activation of the HBP and its downstream O-GlcNAc cycle was observed in the LVs and cardiac ECs (CECs) isolated from the NDPKB −/− mice. Furthermore, a bipolar O-GlcNAc regulation was identified in CMs. O-GlcNAc was decreased in NDPKB-depleted CMs, while conditioned medium from NDPKB-depleted ECs significantly increased O-GlcNAc levels, along with contractile and relaxation dysfunction of the hiPSC-CMs, which was attenuated by inhibiting endothelial HBP activation. Conclusions Deficiency in NDPKB leads to endothelial activation of the HBP and cardiac dysfunction. Our findings may highlight the crucial role of proper endothelial HBP in maintaining cardiovascular homeostasis.
Preoperative Adult-Type Diffuse Glioma Subtype Prediction with Dynamic Contrast-Enhanced MR Imaging and Diffusion Weighted Imaging in Tumor Cores and Peritumoral Tissue—A Standardized Multicenter Study
2025-02-21

Background/Objectives: The non-invasive identification of glioma subtypes is useful for initial diagnosis, treatment planning, and follow-up. The aim of this study was to evaluate the performance of diffusion kurtosis imaging (DKI) and dynamic contrast-enhanced (DCE)-MRI in differentiating subtypes of adult-type diffuse gliomas. Methods: In a prospective multicenter study, standardized MRI was analyzed in 59 patients with adult-type diffuse glioma. DKI and DCE-MRI parameter values were quantitatively evaluated in ROIs of contrast-enhancing/solid tumor and four concentric shells of peritumoral tissue. The parameter means of glioblastomas, IDH wildtype; astrocytomas, IDH mutant; and oligodendrogliomas, IDH mutant were compared. Binary logistic regression analyses were performed to differentiate between IDH mutant and IDH wildtype gliomas and between IDH mutant astrocytomas and oligodendrogliomas. ROC curves were analyzed for each parameter and for combined regression. Results: Significant differences between the three aforementioned subtypes were found for the DKI and DCE-MRI parameters, depending on the distance to the tumor core. A combination of the parameters’ apparent diffusion coefficient (ADC) and fractional volume of extravascular extracellular space (ve) revealed the best prediction of IDH mutant vs. wildtype gliomas (AUC = 0.976 (0.943–1.000)) and astrocytomas vs. oligodendrogliomas (AUC = 0.840 (0.645–1.000)) with the lowest Akaike information criterion. Conclusions: The combined evaluation of DKI and DCE-MRI at different distances to the contrast-enhancing/solid tumor seems to be helpful in predicting glioma subtypes according to the WHO 2021 classification.
Modeling conditional distributions of neural and behavioral data with masked variational autoencoders
2025-02-21

Extracting the relationship between high-dimensional neural recordings and complex behavior is a ubiquitous problem in neuroscience. Encoding and decoding models target the conditional distribution of neural activity given behavior and vice versa, while dimensionality reduction techniques extract low-dimensional representations thereof. Variational autoencoders (VAEs) are flexible tools for inferring such low-dimensional embeddings but struggle to accurately model arbitrary conditional distributions such as those arising in neural encoding and decoding, let alone simultaneously. Here, we present a VAE-based approach for calculating such conditional distributions. We first validate our approach on a task with known ground truth. Next, we retrieve conditional distributions over masked body parts of walking flies. Finally, we decode motor trajectories from neural activity in a monkey-reach task and query the same VAE for the encoding distribution. Our approach unifies dimensionality reduction and learning conditional distributions, allowing the scaling of common analyses in neuroscience to today's high-dimensional multi-modal datasets.
Temperature-Enhanced Ordering in Plate-like Semicrystalline Block Copolymer Single-Crystal Suspensions Studied by Real-Time SAXS/WAXS
2025-02-21

Self-assembly of hard platelet colloids into liquid crystalline phases is typically driven by entropy, making them less sensitive to temperature changes. However, soft interaction potentials often exist in real colloidal systems, which can lead to temperature-sensitive phase transitions. Despite significant progress in understanding phase behavior in the past 2 decades, studies on temperature-dependent phase behavior remain rare, and there is limited knowledge about how soft interactions influence phase transitions upon temperature changes. In this work, we investigated a platelet colloid system in isotropic and nematic phases using small- and wide-angle X-ray scattering techniques (SAXS/WAXS) and polarized optical microscopy (POM). The system consisted of polystyrene-<i>block</i>-poly(l-lactide) (PS-<i>b</i>-PLLA) block copolymer single crystals (BCSCs) with varying sizes dispersed in <i>p</i>-xylene. These crystals were truncated lozenge-shaped with effective diameters of 500 and 1000 nm and a uniform dry thickness of 18.0 nm. The ordering behaviors of BCSC500 in the isotropic phase and BCSC1000 in the N phase were monitored through SAXS/WAXS during heating, quenching, self-seeding, crystal growth, and final quenching. Enhanced ordering, specifically face-to-face correlation, was observed during heating prior to crystal melting. For BCSC500, ordering emerged at 105 °C during heating. In the case of BCSC1000 in the N phase, ordering was enhanced with increased heating and reached up to the ninth order of correlation peaks, indicating the formation of lamellar domains within the N phase. After seeding and crystal growth, both systems exhibited ordering. However, during the final cooling to room temperature, ordering disappeared for BCSC500 but persisted for BCSC1000. POM observations revealed that for both systems, initial heating resulted in a decrease in overall brightness; however, enhanced nematic domains or tactoids emerged prior to melting. Subsequent thermal treatments did not induce noticeable changes in the observed order. While both techniques revealed increased order, discrepancies were noted. SAXS indicated intensified short-range correlations, while POM showed the formation of local nematic domains or tactoids. We propose three distinct ordering regimes to reconcile these observations: large-scale nematic order, enhanced short-range order, and short-range clusters. We attributed the temperature-enhanced ordering phenomenon to lateral interactions between the BCSCs, annealing, and memory effects during melting and crystallization.
Elevated Plasma Complement Factors in CRB1-Associated Inherited Retinal Dystrophies
2025-02-21

CRB1-IRDs are characterized by changes in plasma levels of complement factors and proteins of the innate immune system, and linkage between CRB1 and CFH genes implicates functional variants of the CFH-CFHR locus with specific pathogenic variants of CRB1.
Frequencies of Circulating Immune Cells in Patients with Parkinson’s Disease: Correlation with MDS-UPDRS Scores
2025-02-21

Background: Parkinson’s Disease (PD) is associated with dysregulated/chronic inflammation. The immune system has multiple roles including beneficial effects such as clearing alpha synuclein aggregates. However, peripheral immune cells entering the brain may also contribute to inflammation and neurodegeneration. To identify which cells might have a negative impact and could be potential therapeutic targets, we compared immune signatures of patients and healthy controls. Methods: Multicolor flow cytometry was used to determine the frequencies of major immune cell subsets in peripheral blood mononuclear cells (PBMCs) of PD patients and controls. Because of the major impact of Cytomegalovirus (CMV) infection on the distribution of immune cell subsets, particularly cluster of differentiation (CD)8+ T-cells, all participants were tested for CMV seropositivity. Results: Although the cohort of 35 PD patients exhibited the well-established T-cell differentiation signature driven by CMV infection, there were no differences in the frequencies of differentiated or pro-inflammatory T-cells, B-cells or natural killer cells (NK-cells) attributable to the disease. However, percentages of myeloid-derived suppressor cells (MDSCs) were higher in PD patients than controls. Moreover, percentages of CD14+CD16+ (intermediate) monocytes expressing the C-C chemokine receptor type 5 (CCR5) correlated with disease severity assessed by the Movement Disorder Society’s revised version of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score and disease duration. Conclusions: A comprehensive evaluation of the major subsets of circulating immune cells in PD patients revealed differences in myeloid cells between PD and healthy controls and some correlation of monocyte abundance with disease severity.
Profiling and semi-quantitation of urine sulfatides by UHPLC-Orbitrap-HRMS
2025-02-22

This study proves the feasibility of diagnosing MLD and severe MSD based on sulfatide excretion in urine. We established (gestational) age-specific cut-offs of the total sulfatide excretion and composition. Interpretation of the composition (e.g. by calculation the ratio (d18:1/C22:0+d18:1/C24:0)/(d18:1/C22:0-OH + d18:1/C24:0-OH)) may reduce false positives, especially when sampling at young age.
The Gender Gap in Economic and Financial Literacy: A Review and Research Agenda
2025-02-23

ABSTRACT Economic and financial literacy are crucial for both adults and adolescents due to their demonstrated impact on financial behavior, wealth accumulation, and retirement planning. However, studies indicate that financial literacy remains alarmingly low, especially among women. This disparity raises significant concerns about gender inequality in financial decision‐making and overall well‐being. This systematic literature review examines international research on the gender gap in economic and financial literacy and explores explanatory factors contributing to this gap. Applying the TCCM framework, we analyze 97 papers, including 185 individual studies. Findings confirm a gender gap favoring males across age groups and global contexts. Notably, the gap seems more pronounced in developed countries. Frequently reported explanatory factors are explored, including individuals' socialization, confidence, and computational skills, yet substantial parts of the gender gap remain unexplained by previous literature. Overall, this review contributes to the literature by providing a systematic overview of gender differences in economic and financial literacy and potential explanations.
Regulation of peripheral glucose levels during human sleep
2025-02-23

Abstract Studies in rats indicate that oscillatory signatures of memory processing during sleep, specifically hippocampal sharp wave-ripples, also regulate peripheral glucose concentration. Here, we examined whether there is a similar link between such signatures of memory processing and glucose regulation during sleep in healthy humans. We obtained polysomnographic recordings and continuous recordings of peripheral interstitial glucose levels (1 sample/minute) from 10 participants (5 females) during two consecutive nights. Temporal relationships between electroencephalography (EEG) events of interest and glucose levels were examined using cross-correlation functions and peri-event time histograms. Confirming the findings in rats, we found that sleep spindles, a core signature of sleep-dependent memory processing, were followed within 1–6 minutes by a robust decrease in glucose concentrations. By contrast, slow oscillation events hallmarking slow wave sleep were followed, with a lag of 5–11 minutes, by an increase in glucose levels. Transitions into rapid eye movement sleep were followed by a glucose decrease after 10–14 minutes, whereas awakenings and microarousals were linked to immediate glucose increases. These temporal relationships indicate a sleep-specific regulation of peripheral glucose concentrations that is linked to both signatures of sleep-dependent memory processing as well as the macro-architecture of sleep. They possibly reflect noradrenergic regulation of sympathetic activity via the brainstem locus coeruleus and may be of relevance in clinical conditions with concurrent disturbances of sleep and glucose regulation.
Abstract A017: Cysteine-Engineered CAR-T Cells to Counter Antigen Escape in B Cell Lymphoma
2025-02-23

Abstract The chimeric Antigen Receptor (CAR) T-cell approach has revolutionized the treatment of hematological malignancies, achieving remarkable success. However, despite its outstanding achievements, the technology still faces several challenges, including treatment-induced antigen escape. Thus, cancer cells often adapt to CAR-T therapy by suppressing target markers, leading to cancer relapse and treatment failure. This phenomenon renders CAR-T cells ineffective and poses a significant clinical challenge. Therefore, identifying alternative targets less prone to antigen escape is crucial. Abnormal expression of Protein Disulfide Isomerase (PDI) and other multifunctional redox enzymes in cancer cells alters the redox status of exofacial protein thiols or reactive disulfide. Our recent study identified abnormal redox states in B-cell lymphomas (BCL) as potential immunotherapy targets. In addition, we presented a single-domain antibody that specifically binds to BCL cells through a non-canonical cysteine in its complementarity-determining regions (CDRs). Building on these findings, we introduced a single-cysteine to a single-domain antibody fragment targeting the green fluorescent protein (GFP), inducing specific binding to BCL cells. We then expressed the cysteine-engineered single-domain antibodies as CARs on T cells, demonstrating their capacity to trigger cytotoxicity against BCL through their altered redox cell surface. Therefore, we generated bifunctional CAR-T cells by cysteine-engineering the clinically approved anti-CD19 single-chain variable fragment (scFv) CAR to overcome CD19 antigen escape. Our data demonstrate that T cells expressing the cysteine-engineered CD19-CAR effectively target various CD19-positive BCL subtypes. However, in contrast to their non-engineered counterparts, the inserted cysteine residue enables CAR-T cell activation and cytotoxicity against CD19-negative BCL cells in vitro and in a Mantle Cell Lymphoma (MCL) xenograft mouse model, extending survival in treated mice. Furthermore, we introduced cysteine mutations in different domains of the anti-CD19 scFv-CAR and meticulously assessed their activity and cytotoxicity against both CD19-positive and negative MCL cells. Based on the mutants varying cytotoxicity levels, we propose specific criteria for cysteine insertion to achieve optimal cytotoxicity of bi-specific CAR-T cells. Our findings present a novel class of bifunctional CAR-T cell therapy that targets both conventional antigens and altered redox states on the surface of BCLs, offering a promising strategy to mitigate the risk of antigen escape. Citation Format: Jost Lühle, Simon Krost, Felix Goerdeler, Christian Seitz, Peter H. Seeberger, Oren Moscovitz. Cysteine-Engineered CAR-T Cells to Counter Antigen Escape in B Cell Lymphoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A017.
Pharmacological Activation of NO-Sensitive Guanylyl Cyclase Ameliorates Obesity-Induced Arterial Stiffness
2025-02-23

ABSTRACT Objective Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD) 1 and dementia 2 . Akin to anti-hypertensive and lipid-lowering drugs, arterial de-stiffening therapies could be beneficial at decreasing CVD risk. We previously discovered that enhanced cytoskeletal actin polymerization in vascular smooth muscle cells (VSMCs) contributes to increased arterial stiffness 3 . In aortas and VSMCs, we previously found that decreased NO-sensitive guanylyl cyclase (NO-GC), the NO receptor which synthesizes cGMP, caused downregulation of cGMP-dependent protein kinase I (cGKI) and of its target vasodilator-stimulated phosphoprotein (pVASP S239 ), leading to increased cytoskeletal actin polymerization 3 . In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASP S239 and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness. Approach &amp; Results Cinaciguat administration (5 mg/kg) to high fat, high sucrose diet (HFHS)-fed mice, our established model of arterial stiffness 4 , (1) decreased pulse wave velocity, the in vivo index of arterial stiffness, without affecting blood pressure, (2) increased aortic pVASP S239 levels, and (3) decreased the ratio of filamentous (F) to globular (G) actin, compared to vehicle administration. In cultured VSMCs, cinaciguat (10 μmol/L) increased pVASP S239 levels and decreased the F/G actin ratio at baseline and after stimulation with the cytokine tumor necrosis factor α (TNFα), used to mimic the inflammatory milieu of HFHS aortas. These effects were abrogated in aortas and VSMCs from mice with smooth muscle-specific cGKI deletion (cGKI SMKO ), while being mimicked by a cell-permeable cGMP analog (8-Br-cGMP, 1 μmol/L), which also decreased VSMC stiffness in vitro . Conclusions Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need.
A Healed Arrowhead Injury in a Celtic Elite Burial Near the Heuneburg, Germany: Insights Into Ancient Warfare and Healthcare Practices
2025-02-23

ABSTRACT Utilizing imaging techniques opens new avenues for diagnosing paleopathological findings in archaeological human skeletal remains. This study presents a case of severe perforating trauma on the left ischial bone of an adult male Celtic elite burial from the late Hallstatt period, discovered within the central chamber of a burial mound near the Heuneburg hilltop settlement in southwest Germany. Despite the gravity of the injury, evidence of complete healing suggests meticulous medical intervention and intensive healthcare, indicative of the elevated social status accorded to elites during this period. Employing computer tomographic scanning, we created a three‐dimensional virtual negative imprint of the lesion and identified it as likely resulting from an arrowhead. Comparative analysis of the imprint with archaeological arrowheads typical for the era and region suggests a probable association with warfare rather than hunting purposes. This case study contributes to our understanding of protohistoric medical treatment practices and warfare techniques prevalent during the Hallstatt period.
Towards Explainable AI : Interpreting Soil Organic Carbon Prediction Models Using a Learning‐Based Explanation Method
2025-02-24

ABSTRACT An understanding of the key factors and processes influencing the variability of soil organic carbon (SOC) is essential for the development of effective policies aimed at enhancing carbon storage in soils to mitigate climate change. In recent years, complex computational approaches from the field of machine learning (ML) have been developed for modelling and mapping SOC in various ecosystems and over large areas. However, in order to understand the processes that account for SOC variability from ML models and to serve as a basis for new scientific discoveries, the predictions made by these data‐driven models must be accurately explained and interpreted. In this research, we introduce a novel explanation approach applicable to any ML model and investigate the significance of environmental features to explain SOC variability across Germany. The methodology employed in this study involves training multiple ML models using SOC content measurements from the LUCAS dataset and incorporating environmental features derived from Google Earth Engine (GEE) as explanatory variables. Thereafter, an explanation model is applied to elucidate what the ML models have learned about the relationship between environmental features and SOC content in a supervised manner. In our approach, a post hoc model is trained to estimate the contribution of specific inputs to the outputs of the trained ML models. The results of this study indicate that different classes of ML models rely on interpretable but distinct environmental features to explain SOC variability. Decision tree‐based models, such as random forest (RF) and gradient boosting, highlight the importance of topographic features. Conversely, soil chemical information, particularly pH, is crucial for the performance of neural networks and linear regression models. Therefore, interpreting data‐driven studies requires a carefully structured approach, guided by expert knowledge and a deep understanding of the models being analysed.
Ultrafast Hot Carrier Cooling Enabled van der Waals Photodetectors at Telecom Wavelengths
2025-02-24

Two-dimensional (2D) materials with high carrier mobility and picosecond intrinsic response times exhibit large potential for fast optoelectronics operating at telecom wavelengths. However, due to the inefficient utilization of hot carriers, 2D photodetectors for the telecom C-band have rarely been realized. Here, we report a high-performance and waveguide-free WS<sub>2</sub>/graphene photodetector operating at 1560 nm enabled by hot carrier injection and long-lived charge separation. The efficiently injected hot electrons from graphene to WS<sub>2</sub> exhibit ultrafast cooling dynamics with a 3 ps intrinsic response time. Simultaneous hole trapping in WS<sub>2</sub> ensures a long circulation of injected electrons, enabling a high responsivity of 0.26 A/W. In continuation, we present a vertical WS<sub>2</sub>/graphene/WSe<sub>2</sub> device with a built-in electric field and the same detection mechanism, for which a photocurrent on-off ratio of 3500 and an extrinsic response time of 1.71 ns are obtained. Our study highlights the benefit of combining 2D semiconductors and semimetals for high-speed photodetection.