julilili42/papers huggingface dataset:
Oligodendrocyte precursor cells establish regulatory contacts with the soma of active neurons
2025-03-31

ABSTRACT Oligodendrocyte precursor cells (OPCs) can generate myelinating oligodendrocytes life-long, a process that is dependent on neuronal activity. However, it is possible that OPCs have additional functions, influencing neuronal functions directly. We have used a mouse genetic model of juvenile seizures and chemical induction of neuronal activity to examine the morphological and molecular changes in OPCs around activated principal neurons. We found an increase in process extension of OPCs specifically toward the soma of activated neurons. Moreover, we found that the close proximity of OPC processes around neurons expressing the immediate early gene c-Fos decreased the calcium transients in these neurons, indicating a regulative function of OPCs. Analyses of transcriptome and chromatin accessibility revealed significant changes in genes involved in transforming growth factor beta (TGFβ) signaling. Extracellular matrix genes, particularly those encoding type VI collagen, an established binding partner for the OPC surface protein NG2, was increased around active neurons. Our findings indicate that OPCs are an integral part of the neural network and may help to decrease the activity of neurons that have previously been over-excited, in order to protect these neurons.
A space for time. Exploring temporal regulation of plant development across spatial scales
2025-03-31

SUMMARY Plants continuously undergo change during their life cycle, experiencing dramatic phase transitions altering plant form, and regulating the assignment and progression of cell fates. The relative timing of developmental events is tightly controlled and involves integration of environmental, spatial, and relative age‐related signals and actors. While plant phase transitions have been studied extensively and many of their regulators have been described, less is known about temporal regulation on a smaller, cell‐level scale. Here, using examples from both plant and animal systems, we outline time‐dependent changes. Looking at systemic scale changes, we discuss the timing of germination, juvenile‐to‐adult transition, flowering, and senescence, together with regeneration timing. Switching to temporal regulation on a cellular level, we discuss several instances from the animal field in which temporal control has been examined extensively at this scale. Then, we switch back to plants and summarize examples where plant cell‐level changes are temporally regulated. As time cannot easily be separated from signaling derived from the environment and tissue context, we next discuss factors that have been implicated in controlling the timing of developmental events, reviewing temperature, photoperiod, nutrient availability, as well as tissue context and mechanical cues on the cellular scale. Afterwards, we provide an overview of mechanisms that have been shown or implicated in the temporal control of development, considering metabolism, division control, mobile signals, epigenetic regulation, and the action of transcription factors. Lastly, we look at remaining questions for the future study of developmental timing in plants and how recent technical advancement can enable these efforts.
Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia
2025-04-01

Abstract INTRODUCTION Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females. METHODS We included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex. RESULTS Females with sporadic bvFTD showed worse compulsive behavior ( p = 0.026) and language impairments ( p = 0.024) compared to females with genetic bvFTD ( n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe. DISCUSSION Females with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation. Highlights Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.
MLKL activity requires a splicing-regulated, druggable intramolecular interaction
2025-04-01

Necroptosis is an inflammatory form of regulated cell death implicated in a range of human pathologies, whose execution depends on the poorly understood pseudokinase mixed lineage kinase domain-like (MLKL). Here, we report that splicing-dependent insertion of a short amino acid sequence in the C-terminal α-helix (Hc) of MLKL abolishes cell killing activity and creates an anti-necroptotic isoform that counteracts cell death induced by the necroptosis-proficient protein in mice and humans. We show that interaction of Hc with a previously unrecognized hydrophobic groove is essential for necroptosis, which we exploited in a strategy to identify small molecules that inhibit MLKL and substantially ameliorate disease in murine models of necroptosis-driven dermatitis and abdominal aortic aneurysm. Thus, alternative splicing of microexons controls the ability of MLKL to undergo an intramolecular rearrangement essential for necroptosis with potential to guide the development of allosteric MLKL inhibitors for the treatment of human disease.
Early increase of the synaptic blood marker β‐synuclein in asymptomatic autosomal dominant Alzheimer's disease
2025-04-01

Abstract INTRODUCTION β‐synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear. METHODS We investigated serum β‐synuclein in 69 cognitively unimpaired mutation non‐carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network. RESULTS β‐synuclein levels were already higher in asymptomatic AD mutation carriers compared to non‐carriers and highest in symptomatic carriers. Longitudinal trajectories and correlation analyses indicated that β‐synuclein levels start to rise after amyloid deposition preceding axonal degeneration, brain atrophy and hypometabolism, and cognitive decline. β‐synuclein levels were associated with cognitive impairment and gradually increased with declining cognition. DISCUSSION Our study supports the use of blood β‐synuclein to track synaptic changes in preclinical AD and as a surrogate marker for cognitive impairment which might be used in early diagnosis and to support patient selection and monitoring of treatment effects in clinical trials. Highlights Blood β‐synuclein levels were already higher in asymptomatic Alzheimer's disease (AD) mutation carriers. Blood β‐synuclein levels were highest in symptomatic AD mutation carriers. Blood β‐synuclein levels start to rise 11 years before symptom onset. Rise of β‐synuclein precedes axonal degeneration, brain atrophy, and cognitive decline. β‐synuclein levels gradually increased with declining cognition.
PCI-DB: a novel primary tissue immunopeptidome database to guide next-generation peptide-based immunotherapy development
2025-04-01

Background Various cancer immunotherapies rely on the T cell-mediated recognition of peptide antigens presented on human leukocyte antigens (HLA). However, the identification and selection of naturally presented peptide targets for the development of personalized as well as off-the-shelf immunotherapy approaches remain challenging. Methods Over 10,000 raw mass spectrometry (MS) files from over 3,000 tissue samples were analyzed, summing to approximately seven terabytes of data. The raw MS data were processed using the standardized and open-source nf-core pipelines MHCquant2 and epitopeprediction, providing a uniform procedure for data handling. A global false discovery rate was applied to minimize false-positive identifications. Results Here, we introduce the open-access Peptides for Cancer Immunotherapy Database (PCI-DB, https://pci-db.org/ ), a comprehensive resource of immunopeptidome data originating from various malignant and benign primary tissues that provides the research community with a convenient tool to facilitate the identification of peptide targets for immunotherapy development. The PCI-DB includes &gt;6.6 million HLA class I and &gt;3.4 million HLA class II peptides from over 40 tissue types and cancer entities. First application of the database provided insights into the representation of cancer-testis antigens across malignant and benign tissues, enabling the identification and characterization of cross-tumor entity and entity-specific tumor-associated antigens (TAAs) as well as naturally presented neoepitopes from frequent cancer mutations. Further, we used the PCI-DB to design personalized peptide vaccines for two patients suffering from metastatic cancer. In a retrospective analysis, PCI-DB enabled the composition of both a multi-peptide vaccine comprising non-mutated, highly frequent TAAs matching the immunopeptidome of the individual patient’s tumor and a neoepitope-based vaccine matching the mutational profile of a patient with cancer. Both vaccine approaches induced potent and long-lasting T-cell responses, accompanied by long-term survival of these patients with advanced cancer. Conclusion The PCI-DB provides a highly versatile tool to broaden the understanding of cancer-related antigen presentation and, ultimately, supports the development of novel immunotherapies.
High Agreement Across Laboratories Between Different Alpha‐Synuclein Seed Amplification Protocols
2025-04-01

ABSTRACT Background Seed amplification assays (SAA) detect alpha‐synuclein (aSYN) pathology in patient biomatrices such as cerebrospinal fluid (CSF)—potentially even before clinical manifestations. As CSF‐based SAA are approaching broader use in clinical trials and research, ensuring that different laboratories obtain the same results becomes increasingly important. Methods In this cross‐laboratory, cross‐aSYN‐recombinant substrate and cross‐protocol round‐robin test, we compared SAA results from a common set of 38 CSF samples measured independently in four research laboratories of the German Center for Neurodegenerative diseases. Three laboratories (A–C) used an assay protocol adapted from Parchi's group at ISNB (Bologna, Italy); laboratory D used an assay protocol adapted from Amprion Inc. Two different manufacturers of aSYN protein were used as substrates for the SAA reaction. Results Qualitative results were identical in at least three of the four laboratories for 37 out of 38 samples (20 positive, 17 negative). Fleiss Kappa for all four laboratories was 0.751 ( z = 12, p &lt; 0.001). For each laboratory, agreement with laboratory A was &gt; 92%. For the number of positive replicates, Fleiss Kappa was 0.45 for a score of zero positive replicates and 0.42 for a score of four positive replicates. Conclusions The qualitative SAA results showed a high level of agreement across research laboratories, aSYN monomers, and assay protocols. Small differences between laboratories were systematic, consistent with the notion that SAA reports biologically relevant properties. These results also underline that round‐robin tests can be helpful in assessing and ensuring SAA quality across laboratories.
The Antiviral Activity of Polyphenols
2025-04-01

ABSTRACT Polyphenols are secondary metabolites produced by a large variety of plants. These compounds that comprise the class of phenolic acids, stilbenes, lignans, coumarins, flavonoids, and tannins have a wide range of employment, from food production to medical usages. Among the beneficial applications of polyphenols, their antiviral activity is gaining importance due to the increased prevalence of drug‐resistant viruses such as herpes and hepatitis B viruses. In the present review, we provide an overview of the most promising or commonly used antiviral polyphenols and their mechanisms of action focusing on their effects on enveloped viruses of clinical importance (double‐stranded linear or partially double‐stranded circular DNA viruses, negative sense single‐stranded RNA viruses with nonsegmented or segmented genomes, and positive sense single‐stranded RNA viruses). The present work emphasizes the relevance of polyphenols, in particular epigallocatechin‐3‐gallate and resveratrol, as alternative or supportive antivirals. Polyphenols could interfere with virtually all steps of viral infection, from the adsorption to the release of viral particles. The activity of polyphenols against viruses is especially relevant given the risk of widespread outbreaks associated with viruses, remarked by the recent COVID‐19 pandemic.
Contactless measurement of muscle fiber conduction velocity—a novel approach using optically pumped magnetometers
2025-04-01

Abstract Objective . Muscle fiber conduction velocity (MFCV) describes the speed at which electrical activity propagates along muscle fibers and is typically assessed using invasive or surface electromyography. Because electrical currents generate magnetic fields, propagation velocity can potentially also be measured magnetically using magnetomyography (MMG), offering the advantage of a contactless approach. Approach . To test this hypothesis, we recorded MMG signals from the right biceps brachii muscle of 24 healthy subjects (12 male, 12 female) using a linear array of seven optically pumped magnetometers (OPMs). Subjects maintained muscle force for 30 s at 20%, 40%, and 60% of their maximum voluntary contraction. Main results . In 20 subjects, propagation of MMG signals was observable. Change in polarity and signal cancellation enabled localization of the innervation zone. We estimated the MFCV for each condition by cross-correlating double-differentiated MMG signals. To validate our results, we examined whether MFCV estimations increased with higher force levels, a well-documented characteristic of the neuromuscular system. The median MFCV significantly increased with force ( p = 0.007), with median values of 3.2 m s −1 at 20%, 3.8 m s −1 at 40%, and 4.4 m s −1 at 60% across all 20 subjects. Significance . Our results establish the first measurements of magnetic MFCV in MMG using OPMs. These findings pave the way for further developments and application of quantum sensors for contactless clinical neurophysiology.
Emergence of Trichophyton tonsurans—A Retrospective Multicentre Study of the Dermatophyte Spectrum in Germany
2025-04-01

ABSTRACT Background In mid‐2024, German media reported increasing fungal infections by Trichophyton tonsurans linked to visits to barbershops. However, epidemiological data confirming a rise in tinea capitis and tinea corporis due to Trichophyton tonsurans are lacking. Objectives This study assesses dermatophyte species and clinical types of infections in German university hospitals in 2018 and 2023. Patients/Methods This retrospective, multicentre study analyses mycological culture results from three Departments of Dermatology in Freiburg, Tübingen and Munich. The dermatophyte, along with the sampled body site, age and gender of the affected patient, was recorded. Results 1915 patients (male: 66.1%; mean age: 50 ± 24 years) with a dermatophyte‐positive culture were identified. The most common dermatophyte was Trichophyton rubrum (2018: 78.7%; 2023: 66.3%) with tinea pedis and tinea unguium being the most prevalent types of infection. An increase in tinea corporis and tinea capitis was observed , with tinea capitis doubling from 4.3% to 9.3%. In 2023, Trichophyton tonsurans emerged as the prevailing dermatophyte (67.6%) in tinea capitis and as the second most frequent agent in tinea corporis (26.3%). This dominance of Trichophyton tonsurans was consistently observed across all three study centres. Trichophyton tonsurans affected patients presented a median age of 18 years in 2023 (vs. 9 years in 2018) and an amplified imbalance towards the male gender. Conclusions The pathogen spectrum and infection patterns have changed in Germany due to the increase of Trichophyton tonsurans infections. Intensified screening and hygiene measures, as well as adaptation of initial empiric treatment of tinea capitis, should be considered.
Southwestern Tian Shan: 2. Timing of Cenozoic Mountain Building, Intra‐Montane Basin Inversion, and Relation to Lithospheric Mantle Indentation
2025-04-01

Abstract Cenozoic reactivation of the Paleozoic thick‐skinned fold‐thrust belt of the southwestern Tian Shan has—as the Afghan‐Tajik Basin inversion—been interpreted to be driven by Indian mantle‐lithosphere indentation beneath the Pamir. Herein, we date the reactivation and explore its temporal and spatial variations. Three structural domains emerged. In the Central Domain (Zeravshan‐Gissar, Vashan), apatite fission‐track (AFT) data—aided by Raman‐spectroscopic chemical‐composition discrimination of detrital apatites and vitrinite‐reflectance paleotemperature estimates—record a 15–10 Ma onset of shortening and &gt;4 km exhumation. The Northern Domain, with the southerly bounding N‐Zeravshan Fault as the major Cenozoic structural divide reactivating the Paleozoic Zirabulak Suture, exhumed from &lt;4 km. Apatite (U‐Th)/He (AHe) ages suggest a similar reactivation history as in the Central Domain. The synchronous structural reactivation implies rapid shortening propagation from the Pamir across the Afghan‐Tajik fold‐thrust belt into the southwestern Tian Shan. In the Southern Domain (Paleozoic Gissar Batholith), 9–7 Ma AFT and ∼4 Ma AHe ages suggest southward shortening propagation from both northern Domains and anew fault formation. In the hanging walls of major thrusts, 7–3 Ma AFT ages record significant and/or long‐lasting exhumation. Zircon (U‐Th)/He data limit exhumation to &lt;6 km. Most of the Southern and Central Domains cooled monotonously but temperature‐time models indicate northward‐decreasing reheating by syn‐orogenic deposition, consistent with stratigraphic data. The refined timing supports the synchroneity between major Cenozoic Tian‐Shan mountain building and India mantle‐lithosphere indentation beneath the Pamir and western Tibet, and the instantaneous transfer of shortening across a &gt;500‐km‐wide foreland, facilitated by structural reactivation.
Learning Training as a Cognitive Restructuring Intervention
2025-04-01

We suggest that personalized training, in conjunction with feedback based on interpretable computational model output, may provide a useful form of augmentation or learning support tool during therapy.
Influence of Mediterranean Oceanographic and Environmental Conditions on Molecular Proxy‐Based Sea Surface Temperature Reconstructions During the Last Interglacial
2025-04-01

Abstract We investigated the variability and phase relationship of two annually to subdecadally resolved sea surface temperature (SST) proxy records from the Mediterranean sapropel S5 deposited during the Last Interglacial. We compared our recently published alkenone‐based SST record, considered to reliably represent surface temperature, with a newly generated record of archeal glycerol dialkyl glycerol tetraether (GDGTs). GDGT‐based SST reconstruction in the Mediterranean Sea has been suggested to be affected by other parameters besides SST, and presumably represents subsurface temperature. Our investigation unveils notable differences between the two proxies; throughout most of the record, SST reconstructions derived from GDGTs and alkenones exhibit an anti‐phase relationship in the multicentennial time band. This suggests that during sapropel deposition, centennial‐scale alterations in the upper‐ocean temperature gradient, plausibly due to water column stratification, influenced both compound classes. While we expect a direct, thermal driver for the alkenone ratio, the effect on the GDGT‐based SST signal might have been mediated by ammonia oxidation rates that were positively correlated with changes in SST. A multidecadal comparison between GDGT‐ and alkenone‐based SSTs reveals distinct behaviors of the two proxies under different oceanographic conditions, indicating that changing oceanographic and environmental dynamics significantly impacted short‐term proxy variability. We demonstrate that during sapropel deposition in the Last Interglacial oceanographic, environmental and ecological factors played a crucial role in modulating the GDGT cyclization on both multidecadal and multicentennial time‐scales, suggesting strong non‐thermal forcing on GDGT‐based SST reconstruction during Mediterranean sapropel deposition.
The Sources of Necessity
2025-04-01

Abstract It is a currently popular view that essences, laws, and logic are among the grounds of necessity and possibility. Another currently popular idea relates essences, laws, and logic closely to causal explanations and to non-causal grounding explanations. This book combines those tenets within the view that certain phenomena establish explanations because they exert necessity, a modal force, on the facts. In form of a slogan, the explanatory phenomena are the sources of necessity. The book investigates this idea, and it argues that essences, laws, and logic are the sources of necessity. The investigation contains two different strands, one pertaining to explanation and one to necessity. In the first strand, the book uses different ways of exerting necessity to analyse the explanatory behaviour of essences, laws, and logic. It investigates the governance of natural laws, the interplay of essences and logic in the generation of absolute necessity, and the existence and nature of metaphysical laws. The second strand concerns the nature of necessity. It is argued that necessity is primitive and that there are several equally fundamental species of necessity. Two particularly thorny questions about necessity that arise from these insights are, ‘Why are the sources of necessity themselves necessary?’, and ‘Why are different kinds of necessity ordered by strength?’ The book develops a rationalist view to answer those questions. It says that contingent reality is the result of a cosmogenic sequence that unfolds from essences and logic through the other sources all the way to the contingent facts.
How Time Passes
2025-04-01

Abstract Time organizes things in a dynamic fashion, whereas space organizes things in a static fashion—things in time undergo passage, whereas things in space do not. What makes the temporal organization of things dynamic? What is the nature of the passage of time? Traditional discussions of passage have taken one of two perspectives. Some philosophers start with passage as a phenomenon that occurs in the physical world and ask what constitutes this objective phenomenon. Others start with passage as a phenomenon that is given in our experiences of the world and ask what constitutes this subjective phenomenon. In this book, both perspectives on passage are given equal weight. The first part of the book concerns the existence and nature of physical passage. The second part concerns the existence and nature of experiential passage. In both parts, the standard kind of explanation of passage is juxtaposed with a new kind of explanation. On the familiar tripartite approach, the denizens of time undergo passage in virtue of changing with respect to what is past, what is present, and what is future. On the geometrical approach, the denizens of time undergo passage in virtue of being temporally organized in a manner that does not involve the holding of any geometrical relations between them. In the book, two main claims are developed and defended. First, passage is not a phenomenon in the mind-independent world. Passage is an experiential illusion. Second, experiential passage is not tripartite passage. Experiential passage is geometrical passage.