julilili42/papers huggingface dataset:
Spontaneous scalarization
2024-03-07

Scalarization is a mechanism that endows strongly self-gravitating bodies, such as neutron stars and black holes, with a scalar-field configuration. It resembles a phase transition in that the scalar configuration appears only when a certain quantity that characterizes the compact object, for example, its compactness or spin, is beyond a threshold. A critical and comprehensive review of scalarization, including the mechanism itself, theories that exhibit it, its manifestation in neutron stars, black holes and their binaries, potential extension to other fields, and a thorough discussion of future perspectives, is provided.
CD38–RyR2 axis–mediated signaling impedes CD8 + T cell response to anti-PD1 therapy in cancer
2024-03-07

PD1 blockade therapy, harnessing the cytotoxic potential of CD8 + T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8 + T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8 + T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8 + T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8 + T cells, revealed that CD38-expressing CD8 + T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8 + T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8 + T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8 + T cells elevated intracellular Ca 2+ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8 + T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.
Multivariate Analysis of Light-Activated SMOX Gas Sensors
2024-03-07

Chemoresistive gas sensors made from SnO<sub>2</sub>, ZnO, WO<sub>3</sub>, and In<sub>2</sub>O<sub>3</sub> have been prepared by flame spray pyrolysis. The sensors' response to CO and NO<sub>2</sub> in darkness and under illumination at different wavelengths, using commercially available LEDs, was investigated. Operation at room temperature turned out to be impractical due to the condensation of water inside the porous sensing layers and the irreversible changes it caused. Accordingly, for sensors operated at 70 °C, a characterization procedure was developed and proven to deliver consistent data. The resulting data set was so complex that usual univariate data analysis was intricate and, consequently, was investigated by correlation and principal component analysis. The results show that light of different wavelengths affects not only the resistance of each material, both under exposure to the target gases in humidity and in its absence, but also the sensor response to humidity and the target gases. It was found that each of the materials behaves differently under light exposure, and it was possible to identify conditions that need further investigations.
Characterisation of a customised 4-chip Timepix3 module for charged-particle tracking
2024-03-07

Ion-beam radiotherapy is a growing cancer treatment modality because it offers a superior dose distribution in the patient compared with conventional radiotherapy using X-rays. Thanks to their versatility, application-specific integrated circuits (ASIC) increasingly gain interest for research into ion imaging and ion-beam characterisation. Timepix3 is a hybrid semiconductor pixel detector, which offers nanosecond time binning as well as dead-time-free and noise-free data-driven readout at a pixel pitch of 55 μm × 55 μm. In this work, a novel 4-chip Timepix3 mini-tracker (quad module) was characterised in a therapeutic proton beam. The quad module has two detection layers equipped with two Timepix3 chips each, which are stacked like a particle telescope at a distance of 20.3 mm. In a detection layer, two Timepix3 chips share the same sensitive silicon sensor. The surface area of the silicon sensor is approximately 28 mm × 14 mm. Apart from the pixels at the chip edges and the masked pixels, the quad module showed a uniform counting response to the mono-energetic proton irradiation without noticeable defects. The measurement accuracy of the energy deposition was found to be better than 1 % at 340 keV. The synchronisation between the four chips of the quad module showed systematic delays of up to 25 ns. When these delays are corrected, the time resolution of the quad module is (1.17 ± 0.03) ns. The time resolution could be further improved with the implementation of a time-walk correction. It is concluded that the quad module fulfils the requirements to be used as a charged-particle tracker in ion-beam radiotherapy. Future testing will focus on the radiation hardness, dose-rate dependence and response to high-LET radiation.
Pulsar-wind-nebula-powered Galactic center X-ray filament G0.13–0.11
2024-03-07

We report the discovery of X-ray polarization from the X-ray-bright filament G0.13−0.11 in the Galactic center (GC) region. This filament features a bright, hard X-ray source that is most plausibly a pulsar wind nebula (PWN) and an extended and structured diffuse component. Combining the polarization signal from IXPE with the imaging/spectroscopic data from Chandra , we find that X-ray emission of G0.13−0.11 is highly polarized PD = 57(±18)% in the 3−6 keV band, while the polarization angle is PA = 21 ° ( ± 9 ° ). This high degree of polarization proves the synchrotron origin of the X-ray emission from G0.13−0.11. In turn, the measured polarization angle implies that the X-ray emission is polarized approximately perpendicular to a sequence of nonthermal radio filaments that may be part of the GC Radio Arc. The magnetic field on the order of 100 μG appears to be preferentially ordered along the filaments. The above field strength is the fiducial value that makes our model self-consistent, while the other conclusions are largely model independent.
Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing–remitting multiple sclerosis, the ProVal-MS study
2024-03-07

Abstract Introduction In Multiple Sclerosis (MS), patients ́ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. Methods ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing–Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing–Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (&gt; 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. Perspective Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)—ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034
Some new perspectives on the Kruskal–Szekeres extension with applications to photon surfaces
2024-03-07

Abstract It is a well-known fact that the Schwarzschild spacetime admits a maximal spacetime extension in null coordinates which extends the exterior Schwarzschild region past the Killing horizon, called the Kruskal–Szekeres extension. This method of extending the Schwarzschild spacetime was later generalized by Brill–Hayward to a class of spacetimes of “profile h ” across non-degenerate Killing horizons. Circumventing analytical subtleties in their approach, we reconfirm this fact by reformulating the problem as an ODE, and showing that the ODE admits a solution if and only if the naturally arising Killing horizon is non-degenerate. Notably, this approach lends itself to discussing regularity across the horizon for non-smooth metrics. We will discuss applications to the study of photon surfaces, extending results by Cederbaum–Galloway and Cederbaum–Jahns–Vičánek-Martínez beyond the Killing horizon. In particular, our analysis asserts that photon surfaces approaching the Killing horizon must necessarily cross it.
Epstein-Barr Virus Orchestrates Spatial Reorganization and Immunomodulation within the Classic Hodgkin Lymphoma Tumor Microenvironment
2024-03-07

Classic Hodgkin Lymphoma (cHL) is a tumor composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells nested within a T-cell rich inflammatory immune infiltrate. cHL is associated with Epstein-Barr Virus (EBV) in 25% of cases. The specific contributions of EBV to the pathogenesis of cHL remain largely unknown, in part due to technical barriers in dissecting the tumor microenvironment (TME) in high detail. Herein, we applied multiplexed ion beam imaging (MIBI) spatial pro-teomics on 6 EBV-positive and 14 EBV-negative cHL samples. We identify key TME features that distinguish between EBV-positive and EBV-negative cHL, including the relative predominance of memory CD8 T cells and increased T-cell dysfunction as a function of spatial proximity to HRS cells. Building upon a larger multi-institutional cohort of 22 EBV-positive and 24 EBV-negative cHL samples, we orthogonally validated our findings through a spatial multi-omics approach, coupling whole transcriptome capture with antibody-defined cell types for tu-mor and T-cell populations within the cHL TME. We delineate contrasting transcriptomic immunological signatures between EBV-positive and EBV-negative cases that differently impact HRS cell proliferation, tumor-immune interactions, and mecha-nisms of T-cell dysregulation and dysfunction. Our multi-modal framework enabled a comprehensive dissection of EBV-linked reorganization and immune evasion within the cHL TME, and highlighted the need to elucidate the cellular and molecular fac-tors of virus-associated tumors, with potential for targeted therapeutic strategies.
Predictive learning shapes the representational geometry of the human brain
2024-03-07

Predictive coding theories propose that the brain constantly updates its internal models of the world to minimize prediction errors and optimize sensory processing. However, the neural mechanisms that link the encoding of prediction errors and optimization of sensory representations remain unclear. Here, we provide direct evidence how predictive learning shapes the representational geometry of the human brain. We recorded magnetoencephalography (MEG) in human participants listening to acoustic sequences with different levels of regularity. Representational similarity analysis revealed how, through learning, the brain aligned its representational geometry to match the statistical structure of the sensory inputs, by clustering the representations of temporally contiguous and predictable stimuli. Crucially, we found that in sensory areas the magnitude of the representational shift correlated with the encoding strength of prediction errors. Furthermore, using partial information decomposition we found that, prediction errors were processed by a synergistic network of high-level associative and sensory areas. Importantly, the strength of synergistic encoding of precition errors predicted the magnitude of representational alignment during learning. Our findings provide evidence that large-scale neural interactions engaged in predictive processing modulate the representational content of sensory areas, which may enhance the efficiency of perceptual processing in response to the statistical regularities of the environment.
Intravenous MSC-Treatment Improves Impaired Brain Functions in the R6/2 Mouse Model of Huntington’s Disease via Recovered Hepatic Pathological Changes
2024-03-07

Huntington’s disease (HD), a congenital neurodegenerative disorder, extends its pathological damages beyond the nervous system. The systematic manifestation of HD has been extensively described in numerous studies, including dysfunction in peripheral organs and peripheral inflammation. Gut dysbiosis and the gut–liver–brain axis have garnered greater emphasis in neurodegenerative research, and increased plasma levels of pro-inflammatory cytokines have been identified in HD patients and various in vivo models, correlating with disease progression. In the present study, we investigated hepatic pathological markers in the liver of R6/2 mice which convey exon 1 of the human mutant huntingtin gene. Furthermore, we evaluated the impact of intravenously administered Mesenchymal Stromal Cells (MSCs) on the liver enzymes, changes in hepatic inflammatory markers, as well as brain pathology and behavioral deficits in R6/2 mice. Our results revealed altered enzyme expression and increased levels of inflammatory mediators in the liver of R6/2 mice, which were significantly attenuated in the MSC-treated R6/2 mice. Remarkably, neuronal pathology and altered motor activities in the MSC-treated R6/2 mice were significantly ameliorated, despite the absence of MSCs in the postmortem brain. Our data highlight the importance of hepatic pathological changes in HD, providing a potential therapeutic approach. Moreover, the data open new perspectives for the search in blood biomarkers correlating with liver pathology in HD.
Tuning Interactions to Control Molecular Down Conversion in [2.2]Paracyclophane Bridged Oligo‐Tetracenes
2024-03-07

Abstract In tetracene, the energies of the lowest singlet excited state and twice that of the lowest triplet excited state are similar, allowing both down‐conversion (i.e., singlet fission, SF) and up‐conversion (i.e., triplet‐triplet annihilation up‐conversion, TTA‐UC) processes. Through‐space and through‐bond contributions to the inter‐tetracene coupling in purposefully designed oligomers play a crucial role in determining which of the two processes dominates. In this work, the focus is exclusively on SF in newly synthesized oligo‐tetracenes linked by conjugated [2.2]paracyclophane (PCP) building blocks. By choosing different PCP substitution patterns and by varying the degree of substitution the inter‐tetracene couplings are addressed. An independent variable is connecting the tetracences to the PCP at different positions to alter the through‐bond and through‐space coupling of the resulting oligo‐tetracenes. The novel oligo‐tetracenes are investigated by means of steady‐state and time‐resolved absorption and fluorescence spectroscopies with respect to the initial events of SF, that is, the transformation of a singlet excited state into a correlated triplet pair state. Briefly, through‐space couplings are profoundly weaker than through‐bond couplings that enable the correlated triplet pair state formation. If interactions are through‐space, correlated triplet pair state formation is turned off, while it is turned on if through‐bond interactions are operative.
p62, the Receptor for Selective Autophagy, Contributes in ATXN3 Aggregate Formation in Spinocerebellar Ataxia Type 3
2024-03-07

Spinocerebellar ataxia type 3 is a neurodegenerative disease caused by an abnormal expansion of CAG repeats in the disease gene ATXN3, leading to prolonged polyglutamine (polyQ) tracts in the respective protein ataxin-3. The polyQ-expanded protein forms polyQ-containing aggregates in several brain regions which leads to neuronal cell loss. Autophagy is thought to play a significant role in clearing these polyQ-containing protein aggregates. Therefore, the autophagy mechanism was investigated in SCA3 with focus on the autophagic protein p62/sequestosome-1. Human and mouse RNA sequencing data were analyzed to determine RNA expression level of autophagic genes. Additionally, autophagy was studied in the SCA3 304Q knock-in mouse model and through several cell culture experiments using HEK-293T cells transfected with ATXN3 of differ-ent polyQ lengths. For cell culture experiments, autophagy was induced with rapamycin treat-ment, proteasomal degradation was blocked with MG132 and degradation of autophagic pro-teins was investigated using cycloheximide treatment. Here, we report an increased autophagy impairment with SCA3 disease progression seen in HEK-293T cells transfected with ATXN3 plasmid with expanded polyQ tracts, higher aged 304Q-knock-in mice, or human post-mortem brain material. Furthermore, co-localized aggregation of the autophagic protein p62 and the dis-ease protein ATXN3 was observed in the course of SCA3 disease. Therefore, we suggest a signifi-cant role for p62 in aggregate formation seen in the neurodegenerative disease SCA3.
Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights
2024-03-08

Background Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations. Methods Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings. Results We identified potentially disease-causing variants in the established dystonia genes ( PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP ; n=11 families (26%)), in the uncommon forms of dystonia-associated genes ( PCCB, CACNA1A, ALDH5A1, PRKN ; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis. Conclusions Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.
Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis
2024-03-08

Abstract Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1 . TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.
Spatio-temporal variations of climate along possible African-Arabian routes of H. sapiens expansion
2024-03-08

Eastern Africa and Arabia were major hominin hotspots and critical crossroads for migrating towards Asia during the late Pleistocene. To decipher the role of spatiotemporal environmental change on human occupation and migration patterns, we remeasured the marine core from Meteor Site KL 15 in the Gulf of Aden and reanalyzed its data together with the aridity index from ICDP Site Chew Bahir in eastern Africa and the wet-dry index from ODP Site 967 in the eastern Mediterranean Sea using linear and nonlinear time series analysis. These analyses show major changes in the spatiotemporal paleoclimate dynamics at 400 and 150 ka BP (thousand years before 1950), presumably driven by changes in the amplitude of the orbital eccentricity. From 400 to 150 ka BP, eastern Africa and Arabia show synchronized wet-dry shifts, which changed drastically at 150 ka BP. After 150 ka BP, an overall trend to dry climate states is observable, and the hydroclimate dynamics between eastern Africa and Arabia are negatively correlated. Those spatio-temporal variations and interrelationships of climate potentially influenced the availability of spatial links for human expansion along those vertices. We observe positively correlated network links during the supposed out-of-Africa migration phases of H. sapiens. Furthermore, our data do not suggest hominin occupation phases during specific time intervals of humid or stable climates but provide evidence of the so far underestimated potential role of climate predictability as an important factor of hominin ecological competitiveness.
Future null singularity due to gravitational collapse
2024-03-08

In the case of unhindered gravitational collapse of a matter cloud governed by the Lema\\^{\\i}tre-Tolman-Bondi (LTB) spacetime, the end-state singularity is either locally visible, globally visible, or completely hidden. We have a past null singularity in the first two cases while a future spacelike singularity in the last case. Here, we show an example of a gravitational collapse model whose end state is a future null singularity (it has a causal property that is unlike the cases involving LTB spacetime). We depict such a distinct causal structure of the singularity by conformal diagrams.