julilili42/papers huggingface dataset:
Age‐Associated Changes in Endothelial Transcriptome and Epigenetic Landscapes Correlate With Elevated Risk of Cerebral Microbleeds
2023-08-23

Background Stroke is a leading global cause of human death and disability, with advanced aging associated with elevated incidences of stroke. Despite high mortality and morbidity of stroke, the mechanisms leading to blood‐brain barrier dysfunction and development of stroke with age are poorly understood. In the vasculature of brain, endothelial cells (ECs) constitute the core component of the blood‐brain barrier and provide a physical barrier composed of tight junctions, adherens junctions, and basement membrane. Methods and Results We show, in mice, the incidents of intracerebral bleeding increases with age. After isolating an enriched population of cerebral ECs from murine brains at 2, 6, 12, 18, and 24 months, we studied age‐associated changes in gene expression. The study reveals age‐dependent dysregulation of 1388 genes, including many involved in the maintenance of the blood‐brain barrier and vascular integrity. We also investigated age‐dependent changes on the levels of CpG methylation and accessible chromatin in cerebral ECs. Our study reveals correlations between age‐dependent changes in chromatin structure and gene expression, whereas the dynamics of DNA methylation changes are different. Conclusions We find significant age‐dependent downregulation of the Aplnr gene along with age‐dependent reduction in chromatin accessibility of promoter region of the Aplnr gene in cerebral ECs. Aplnr is associated with positive regulation of vasodilation and is implicated in vascular health. Altogether, our data suggest a potential role of the apelinergic axis involving the ligand apelin and its receptor to be critical in maintenance of the blood‐brain barrier and vascular integrity.
Governance of biological nomenclature: mechanisms to address the needs of end-users are available and not onerous to implement
2023-08-23

Figueiredo, Estrela, Bae, Christopher J, Radović, Predrag, Wu, Xiu-Jie, Roksandic, Mirjana, Smith, Gideon F (2023): Governance of biological nomenclature: mechanisms to address the needs of end-users are available and not onerous to implement. Zoological Journal of the Linnean Society 199 (1): 3-4, DOI: 10.1093/zoolinnean/zlad056, URL: http://dx.doi.org/10.1093/zoolinnean/zlad056
Practice makes perfect: Restrained eaters' heightened control for food images
2023-08-23

Abstract Objective Restrained eaters (RE) show behaviourally unregulated food intake, which is often explained by a deficit in inhibitory control. Despite evidence for general inhibitory deficits in RE, it remains unclear how the variety of (food) cues in our environment can influence cognitive control. Method In this re‐analysis, we explored the inhibitory capacity of RE and unrestrained eaters (URE) on a stop‐signal task with modal (pictures) and amodal (word) food and non‐food stimuli. Results Although we did not find the expected inhibitory deficits in RE compared to URE, we found a significant Group × Modality × Stimulus Type interaction. This indicated that RE have relatively good inhibitory control for food, compared to non‐food modal cues, and that this relationship is reversed for amodal cues. Conclusions Hence, we showed differential processing of information based on food‐specificity and presentation format in RE. The format of food cues is thus an important new avenue to understand how the food environment impedes those struggling with regulating their eating behaviour.
Trim33 masks a non-transcriptional function of E2f4 in replication fork progression
2023-08-23

Abstract Replicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql. Replicative stress blunts Trim33-dependent ubiquitination of E2f4, which stimulates transient Recql recruitment to chromatin and facilitates recovery of DNA synthesis. In contrast, deletion of Trim33 induces chronic genome-wide recruitment of Recql and strongly accelerates DNA replication under stress, compromising checkpoint signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis controls progression of DNA replication forks along transcriptionally active chromatin to maintain genome integrity.
Admixture as a source for HLA variation in Neolithic European farming communities
2023-08-23

ABSTRACT The northern European Neolithic is characterized by two major demographic events: immigration of early farmers (EF) from Anatolia (5500 BCE) and their admixture (from ∼4200 BCE) with western hunter-gatherers (WHG) forming late farmers (LF). The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is understudied. Here, we conducted population and immunogenetic analyses on 83 individuals from six EF and LF sites located in present-day Germany. We observed significant shifts in HLA allele frequencies from EF to LF. The HLA diversity increased from EF to LF, likely due to admixture with WHG. However, it was considerably lower than in modern populations. Both EF and LF exhibited a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time. We additionally noted that LF resulted from sex-biased admixture from male WHG. TEASER More restricted HLA allele spectrum and lower diversity in Neolithic farmers than in modern populations
Resource Variation Within and Between Patches: Where Exploitation Competition, Local Adaptation, and Kin Selection Meet
2023-08-23

AbstractIn patch- or habitat-structured populations, different processes can favor adaptive polymorphism at different scales. While spatial heterogeneity can generate spatially disruptive selection favoring variation between patches, local competition can lead to locally disruptive selection promoting variation within patches. So far, almost all theory has studied these two processes in isolation. Here, we use mathematical modeling to investigate how resource variation within and between habitats influences the evolution of variation in a consumer population where individuals compete in finite patches connected by dispersal. We find that locally and spatially disruptive selection typically act in concert, favoring polymorphism under a wider range of conditions than when in isolation. But when patches are small and dispersal between them is low, kin competition inhibits the emergence of polymorphism, especially when the latter is driven by local competition for resources. We further use our model to clarify what comparisons between trait and neutral genetic differentiation (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>ST</mml:mi></mml:mrow></mml:msub><mml:mo>/</mml:mo><mml:msub><mml:mi>F</mml:mi><mml:mrow><mml:mi>ST</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> comparisons) can tell about the nature of selection. Overall, our results help us understand the interaction between two major drivers of polymorphism: locally and spatially disruptive selection, and how this interaction is modulated by the unavoidable effects of kin selection under limited dispersal.
Collective incentives reduce over-exploitation of social information in unconstrained human groups
2023-08-23

Collective dynamics emerge from countless individual decisions. Yet, we poorly understand the cognitive processes governing dynamically-interacting individuals in human collectives under realistic conditions. We present a naturalistic immersive-reality experiment where groups of participants searched for rewards in different environments, studying how individuals weigh personal and social information and how this shapes individual and collective outcomes. Capturing high-resolution visual-spatial data, behavioral analyses revealed individual-level gains -but group-level losses- of high social information use and spatial proximity in environments with concentrated (vs. distributed) resources. Incentivizing participants at the group (vs. individual) level facilitated adaptation to concentrated environments, buffering excessive scrounging. To infer discrete choices from unconstrained interactions and uncover the underlying decision mechanisms, we developed an unsupervised Social Hidden Markov Decision model. Computational results showed that participants were more sensitive to social information in concentrated environments frequently switching to a `social relocation' state where they approach successful group members. Group-level incentives reduced participants' overall responsiveness to social information and promoted higher selectivity over time. Finally, mapping group-level spatio-temporal dynamics through time-lagged regressions revealed a collective exploration-exploitation trade-off across different timescales. Our study unravels the processes linking individual-level strategies to emerging collective dynamics, and provides new tools to investigate decision-making in freely-interacting collectives.
Cortical Amyloid Burden Relates to Basal Forebrain Volume in Subjective Cognitive Decline
2023-08-23

Background: Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer’s disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. Objective: To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. Methods: The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. Results: Group differences approached significance for BF total volume ( p = 0.061) and the Ch4 subregion ( p = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. Conclusions: The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at “grey zone” levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings.
OpenMS 3 expands the frontiers of open-source computational mass spectrometry
2023-08-23

<title>Abstract</title> Mass spectrometry has become an indispensable tool in the life sciences. The new major version 3 of the computational framework OpenMS provides significant advancements regarding open, scalable, and reproducible high-throughput workflows for proteomics, metabolomics, and oligonucleotide mass spectrometry. OpenMS makes analyses from emerging fields available to experimentalists, enhances computational workflows, and provides a reworked Python interface to facilitate access for bioinformaticians and data scientists.
Augmenting MEK inhibitor Efficacy in BRAF Wild-Type Melanoma: Synergistic Effects of Disulfiram Combination Therapy
2023-08-23

Abstract Background MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells. Therefore, we investigated the combination of both therapeutics to test their effects on BRAF-WT melanoma cells and compared them with monotherapy using the MEKi trametinib. Methods The effects of combined therapy with disulfiram or its metabolite diethyldithiocarbamate and the MEKi trametinib were evaluated in a series of BRAF-WT melanoma cell lines by measuring cell viability and apoptosis induction. Cytotoxicity was additionally assessed in 3D spheroids, ex vivo melanoma slice cultures, and in vivo xenograft mouse models. The response of melanoma cells to treatment was studied at the RNA and protein levels to decipher the mode of action. Intracellular and intratumoral copper measurements were performed to investigate the role of copper ions in the antitumor cytotoxicity of disulfiram and its combination with the MEKi. Results Diethyldithiocarbamate enhanced trametinib-induced cytotoxicity and apoptosis induction in 2D and 3D melanoma culture models. Mechanistically, copper-dependent induction of oxidative stress and ER stress led to Janus kinase (JNK)-mediated apoptosis in melanoma cells. This mechanism was also detectable in patient-derived xenograft melanoma models and resulted in a significantly improved therapeutic effect compared to monotherapy with the MEKi trametinib. Conclusions Disulfiram and its metabolite represent an attractive pharmaceutical approach to induce ER stress in melanoma cells that potentiates the antitumor effect of MEK inhibition and may be an interesting candidate for combination therapy of BRAF WT melanoma.
Sentinel lymph node biopsy for lentigo maligna melanoma under local anaesthesia
2023-08-23

Abstract Background Lentigo maligna melanoma is mainly localized in the head and neck region in elderly patients. Due to its slow horizontal growth, it has a good prognosis compared to other melanoma subtypes, but specific data are rare. Objectives The aim of this study was to investigate sentinel lymph node biopsy in lentigo maligna melanoma under local anaesthesia and to discuss the benefit. Methods Investigation of patients with lentigo maligna melanoma and tumour thickness ≥1 mm treated at the Department of Dermatology, University Medical Centre Tuebingen, between January 2008 and October 2019. Results In total, 204 patients (126 SLNB, 78 non‐SLNB) with a median age of 75.7 years (SLNB: 73.3 years, non‐SLNB: 79.7 years) could be included. Sixteen of 126 (12.7%) sentinel lymph nodes were positive. Five‐year overall survival was 87.9% (88.5% SLNB; 87.4% non‐SLNB) and 5‐year distant metastasis‐free survival was 85.8% (85.4% SLNB; 86.7% non‐SLNB). There was no significant difference for distant metastasis‐free survival ( p = 0.861) and overall survival ( p = 0.247) between patients with and without sentinel lymph node biopsy. Conclusions Sentinel lymph node biopsy in lentigo maligna melanoma under local anaesthesia is a safe and simple method, even in very old patients. However, LMM has a very good 5‐year overall survival. In high‐risk patients with high tumour thickness and/or ulceration, adjuvant immunotherapy can now be offered without the need to perform this procedure.
Age-related biological differences in children’s and adolescents’ very rare tumors
2023-08-23

Very rare tumors (VRTs) in pediatric age represent many different diseases. They present an annual incidence &lt;&#13;\\n2/1000,000 and correspond to about 11% of all cancers in patients aged 0–14 years. They can be roughly divided&#13;\\ninto two groups: one including tumors that are also rare in adults, and the other group includes adult-type tumors&#13;\\nrarely encountered in children and adolescents. Although there is an obvious gap in knowledge regarding&#13;\\noncogenesis in pediatric cancers, there is some evidence of the involvement of various signalling pathways in the&#13;\\ndevelopment of tumors in children and adolescents and sometimes in young adults. In addition, despite the rarity&#13;\\nof these neoplasms, several attempts have been made to disclose the underlying mechanisms. More effort and&#13;\\nresources have urgently to be devoted to deepening current knowledge and integrating new findings into the&#13;\\ntherapeutic approach, which nowadays relies on the treatment modalities used in adult oncology. The aim of this&#13;\\npaper is to provide a review of the main solid VRTs occurring in both the pediatric and the adult age groups,&#13;\\nhighlighting the variability between groups in their biological and clinical course.
Functional diversification of a wild potato immune receptor at its center of origin
2023-08-24

Plant cell surface pattern recognition receptors (PRRs) and intracellular immune receptors cooperate to provide immunity to microbial infection. Both receptor families have coevolved at an accelerated rate, but the evolution and diversification of PRRs is poorly understood. We have isolated potato surface receptor Pep-13 receptor unit (PERU) that senses Pep-13, a conserved immunogenic peptide pattern from plant pathogenic Phytophthora species. PERU, a leucine-rich repeat receptor kinase, is a bona fide PRR that binds Pep-13 and enhances immunity to Phytophthora infestans infection. Diversification in ligand binding specificities of PERU can be traced to sympatric wild tuber-bearing Solanum populations in the Central Andes. Our study reveals the evolution of cell surface immune receptor alleles in wild potato populations that recognize ligand variants not recognized by others.
RNAPII-dependent ATM signaling at collisions with replication forks
2023-08-24

Abstract Deregulation of RNA Polymerase II (RNAPII) by oncogenic signaling leads to collisions of RNAPII with DNA synthesis machinery (transcription-replication conflicts, TRCs). TRCs can result in DNA damage and are thought to underlie genomic instability in tumor cells. Here we provide evidence that elongating RNAPII nucleates activation of the ATM kinase at TRCs to stimulate DNA repair. We show the ATPase WRNIP1 associates with RNAPII and limits ATM activation during unperturbed cell cycle. WRNIP1 binding to elongating RNAPII requires catalytic activity of the ubiquitin ligase HUWE1. Mutation of HUWE1 induces TRCs, promotes WRNIP1 dissociation from RNAPII and binding to the replisome, stimulating ATM recruitment and activation at RNAPII. TRCs and translocation of WRNIP1 are rapidly induced in response to hydroxyurea treatment to activate ATM and facilitate subsequent DNA repair. We propose that TRCs can provide a controlled mechanism for stalling of replication forks and ATM activation, instrumental in cellular response to replicative stress.
Neutron stars in Gauss-Bonnet gravity: Nonlinear scalarization and gravitational phase transitions
2023-08-24

It was recently discovered that scalarized neutron stars in scalar-tensor theories can undergo a gravitational phase transition to a nonscalarized (GR) state. Surprisingly, even though the driving mechanism is totally different, the process resembles closely the first-order matter phase transition from confined nuclear matter to deconfined quark matter in neutron star cores. The studies until now were limited, though, to only one theory of gravity and a limited range of parameters. With the present paper, we aim at demonstrating that gravitational phase transitions are more common than expected. More specifically, we show that the phenomenon of nonlinear scalarization is present for neutron stars in Gauss-Bonnet gravity leading to the possibility of gravitational phase transition. Moreover, it can be observed for a wide range of parameters so no fine-tuning is needed. This solidifies the conjecture that gravitational phase transitions are an important phenomenon for compact objects and their astrophysical implications deserve an in-depth study.
Generating realistic neurophysiological time series with denoising diffusion probabilistic models
2023-08-24

Abstract In recent years, deep generative models have had a profound impact in engineering and sciences, revolutionizing domains such as image and audio generation, as well as advancing our ability to model scientific data. In particular, Denoising Diffusion Probabilistic Models (DDPMs) have been shown to accurately model time series as complex high-dimensional probability distributions. Experimental and clinical neuroscience also stand to benefit from this progress, since accurate modeling of neurophysiological time series, such as electroencephalography (EEG), electrocorticography (ECoG), and local field potential (LFP) recordings, and their synthetic generation can enable or improve a variety of neuroscientific applications. Here, we present a method for modeling multi-channel and densely sampled neurophysiological recordings using DDPMs, which can be flexibly applied to different recording modalities and experimental configurations. First, we show that DDPMs can generate realistic synthetic data for a variety of datasets including different recording techniques (LFP, ECoG, EEG) and species (rat, macaque, human). DDPM-generated time series accurately capture single- and multi-channel statistics such as frequency spectra and phase-amplitude coupling, as well as fine-grained and dataset-specific features such as sharp wave-ripples. In addition, synthetic time series can be generated based on additional information like experimental conditions or brain states. We demonstrate the utility and flexibility of DDPMs in several neuroscience-specific analyses, such as brain-state classification and imputation of missing channels to improve neural decoding. In summary, DDPMs can serve as accurate generative models of neurophysiological recordings, and have a broad utility in the probabilistic generation of synthetic time series for neuroscientific applications.
Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer
2023-08-24

Triple–negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches. We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti–CD3 (NKG2D–CD3) or anti–CD16 (NKG2D–CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1–4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D–CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells. Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D–CD3/CD16. In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells. Therefore, NKG2D–based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients.