julilili42/papers huggingface dataset:
Interhemispheric effects of iTBS on the fronto-parietal network: Evidence from dual-site stimulation
2025-07-01

This study investigated the neuromodulatory effects of Theta Burst Stimulation (TBS) on resting-state functional connectivity (FC) following psychosocial stress induced by the Trier Social Stress Test (TSST). Given its key role in cognitive control and emotion regulation - processes highly relevant for rumination - we focused on the frontoparietal network. Across two studies, intermittent (iTBS) and continuous (cTBS) protocols were applied to the left Dorsolateral Prefrontal Cortex (DLPFC; study 1) and right Ventrolateral Prefrontal Cortex (VLPFC; study 2) prior to stress induction. Functional Near-Infrared Spectroscopy (fNIRS) was used to assess neural changes. A total of 88 (study 1) and 89 (study 2) healthy participants were recruited, balanced for low and high trait rumination. Each participant received both active and sham TBS (iTBS or cTBS), in a randomized, counterbalanced design. Results indicated that iTBS elicited excitatory effects on prefrontal and fronto-parietal connectivity, whereas cTBS effects were more variable. Trait rumination emerged as a modulator of TBS effects: In study 1, significant interactions for FC between the right VLPFC and Somatosensory Association Cortex (SAC) when stimulating the left DLPFC emerged, while study 2 revealed similar interactions for FC between the left DLPFC and SAC and intra-SAC FC when stimulating the right VLPFC. Correlations between post-stress state rumination and FC changes further support these findings. These results underscore the importance of neural assessments in TBS research and highlight the complexity of individual differences in state and trait rumination. Understanding the interplay between TBS, fronto-parietal connectivity, and rumination may provide valuable insights into personalized neuromodulation strategies.
Disease stage–specific atrophy markers in Alzheimer's disease
2025-07-01

Abstract INTRODUCTION Structural magnetic resonance imaging (MRI) often lacks diagnostic, prognostic, and monitoring value in Alzheimer's disease (AD), particularly in early disease stages. To improve its utility, we aimed to identify optimal atrophy markers for different intended uses. METHODS We included 363 older adults; cognitively unimpaired individuals who were negative or positive for amyloid beta (Aβ) and Aβ‐positive patients with subjective cognitive decline, mild cognitive impairment, or dementia of the Alzheimer type. MRI and neuropsychological assessments were administered annually for up to 3 years. RESULTS Accelerated atrophy of medial temporal lobe subregions was evident already during preclinical AD. Symptomatic disease stages most notably differed in their hippocampal and parietal atrophy signatures. Atrophy–cognition relationships varied by intended use and disease stage. DISCUSSION With the appropriate marker, MRI can detect abnormal atrophy already during preclinical AD. To optimize performance, atrophy markers should be tailored to the targeted disease stage and intended use. Highlights Subregional atrophy markers detect ongoing atrophy in preclinical Alzheimer's disease (AD). Subjective cognitive decline in preclinical AD links to manifest atrophy. Optimal atrophy markers differ by the disease stage and intended use.
Durable effectiveness and safety of hybrid ablation versus catheter ablation: 2-year results from the randomized CEASE-AF trial
2025-07-01

Abstract OBJECTIVES The CEASE-AF trial demonstrated that epicardial-endocardial hybrid ablation (HA) had superior effectiveness compared to endocardial catheter ablation (CA) for non-paroxysmal atrial fibrillation (AF), without significantly increasing major complications during a 12-month period. Most contemporary AF ablation trials have not evaluated durability beyond 12 months. Therefore, 24-month effectiveness and safety of HA and CA are compared. METHODS CEASE-AF is a prospective, multicentre, randomized trial. Patients 18–75 years of age with symptomatic, drug refractory persistent AF and left atrial diameter &amp;gt;4.0 cm or long-standing persistent AF were randomized 2:1 to HA (posterior wall and pulmonary vein isolation with left atrial appendage exclusion) or CA (pulmonary vein isolation). Secondary effectiveness was freedom from AF/atrial flutter/atrial tachycardia off class I/III anti-arrhythmic drugs except for those who previously failed at doses not exceeding those previously failed through a 24-month follow-up period. Major complications and reinterventions were evaluated. RESULTS The intention-to-treat population was 102 patients with HA and 52 patients with CA. Seventy-five percent were male, 80.5% had persistent AF and 19.5% had long-standing persistent AF, with a mean age of 60.7 ± 7.9 years. Effectiveness for 24 months was 66.3% (63/95) with HA and 33.3% (17/51) with CA [absolute difference 33.0% (95% confidence interval 14.3%, 48.3%; P &amp;lt; 0.001)]. Major complication rates were 10.8% (11/102) with HA and 9.6% (5/52) with CA (P = 1.0), and fewer patients had reinterventions after HA than CA [18.9% (18/95) vs 52.9% (27/51), P &amp;lt; 0.001]. CONCLUSIONS CEASE-AF demonstrated that the 32.4% absolute benefit of HA over CA for 12 months was durable for 24 months at 33% with continued similar safety rates and fewer reinterventions after HA (funded by AtriCure, Inc.; NCT02695277). Clinicaltrials.gov registration NCT02695277
Long-read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons
2025-07-01

Long-read RNA sequencing has transformed transcriptome analysis by enabling comprehensive mapping of full-length transcripts, providing an unprecedented resolution of transcript diversity, alternative splicing and transcript-specific regulation. In this study, we employed nanopore long-read RNA sequencing to profile the transcriptomes of three cell types commonly used to model brain disorders, human fibroblasts, induced pluripotent stem cells and stem cell-derived cortical neurons, identifying extensive transcript diversity with 15 072 transcripts in stem cell-derived cortical neurons, 13 048 in fibroblasts and 12 759 in induced pluripotent stem cells. Our analyses uncovered 35 519 differential transcript expression events and 5135 differential transcript usage events, underscoring the complexity of transcriptomic regulation across these cell types. Importantly, by integrating differential transcript expression and usage analyses, we gained deeper insights into transcript dynamics that are not captured by gene-level expression analysis alone. Differential transcript usage analysis highlighted transcript-specific changes in disease-relevant genes such as APP , KIF2A and BSCL2 , associated with Alzheimer’s disease, neuronal migration disorders and degenerative axonopathies, respectively. This added resolution emphasizes the significance of transcript-level variations that often remain hidden in traditional differential gene expression analyses. Overall, our work provides a framework for understanding transcript diversity in both pluripotent and specialized cell types, which can be used to investigate transcriptomic changes in disease states in future work. Additionally, this study underscores the utility of differential transcript usage analysis in advancing our understanding of neurodevelopmental and neurodegenerative diseases, paving the way for identifying transcript-specific therapeutic targets.
Approaching the holistic transcriptome—convolution and deconvolution in transcriptomics
2025-07-01

Abstract Tissues, organs, and entire organisms are composed of diverse cell populations, which are characterized by cell-type-specific gene activities. Bulk RNA-seq represents a robust, cost-effective, scalable method to measure gene activity at the bulk tissue level. However, pathomolecular processes lead to divergent changes in tissue composition and cell-type-specific gene deregulations, which cannot be resolved at the tissue bulk level without information on either change in cell-type proportion or expression at the single-cell level. Accordingly, methods have been developed that constrain bulk deconvolution by information from single-cell expression or cell-type proportion. In parallel, convolution methods have been developed to project single-cell expression to bulk tissue level (pseudobulk simulation). In the present review, we provide an overview of existing convolution and deconvolution methods, their interconnectivity, and benchmarking. Our unique approach lies in the joint consideration of both directions in a “holistic transcriptome model.” Through analysis of published (de)convolution studies and benchmarks, we identified the reduced availability of suitable datasets and the use of inaccurate convolution-like methods for (de)convolution model assessment and training as key bottlenecks in the field. On that basis, we conclude with a holistic transcriptome model envisioning that a more integral approach to convolution and deconvolution is needed. With our suggestions for a unified framework we aim to spark collaborative efforts to enable major leaps forward in the field of (de)convolution.
Counterspeech encouraging users to adopt the perspective of minority groups reduces hate speech and its amplification on social media
2025-07-01

Abstract Online intergroup hostility is a pervasive and troubling issue, yet experimental evidence on how to curb it remains scarce. This study examines counterspeech as a user-driven strategy to reduce hate speech. Drawing on theories that suggest adopting the perspective of minority groups can reduce prejudice, we randomized four counterspeech strategies across the senders of 2102 xenophobic Twitter messages. Compared to a passive control group, we find that the pooled effect of the three perspective-centered strategies—traditional perspective-taking, analogical perspective-taking, and perspective getting—increased the likelihood that the sender deleted their xenophobic message by +0.14 SD ( ), decreased the number of likes the xenophobic message received by others (− 0.133 SD, ), but yielded a limited and not statistically significant estimate for the share of xenophobic messages the sender posted over the following four weeks (− 0.084 SD, ). Differences between the three perspective-centered strategies were generally small and not statistically significant, though analogical perspective-taking—encouraging senders to compare their own experiences of being attacked online with their discriminatory behavior toward outgroups—appears to have slightly larger effects across multiple outcomes. Disapproval messages without a perspective shift produced smaller and non-significant estimates. These findings advance our theoretical understanding of how counterspeech works and provide actionable insights for how users can contribute to reducing intergroup hostility and its amplification online—especially at a time when many platforms are scaling back content moderation.
Development and Evaluation of a Combined Driveline Oscillation and Traction Controller Using Model Predictive Control and Reinforcement Learning: A Comparative Case Study
2025-07-01

&lt;div class="section abstract"&gt;&lt;div class="htmlview paragraph"&gt;In electric vehicles, the control of driveline oscillations and tire traction is critical for guaranteeing driver comfort and safety. Yet, achieving sufficient driveline control performance remains challenging in the presence of rapidly varying road conditions. Two promising avenues for further improving driveline control are adaptive model predictive control (MPC) and model-based reinforcement learning (RL). We derive such controllers from the same non-linear vehicle model and validate them through pre-defined test scenarios. The MPC approach employs input and output trajectory tracking with soft constraints to ensure feasible control actions even in the presence of constraint violations and is further supported by a Kalman filter for robust state estimation and prediction. In contrast, the RL controller leverages the model-based DreamerV3 algorithm to learn control policies autonomously, adapting to different road conditions without relying on external information. The results indicate that both controllers achieve comparable overall performance although the MPC solution provides more precise input and output tracking and smoother control inputs, while the RL approach inherently adapts to changing road surfaces, eliminating the need for prior friction knowledge or online friction estimation. We discuss the trade-offs between MPC and RL in terms of complexity, adaptability and performance as well as avenues for future work, such as integrating road-condition estimation into the MPC framework and refining the RL controller for smoother, more precise control action.&lt;/div&gt;&lt;/div&gt;
Long-term organic fertilization shields soil prokaryotes from metal stress while mineral fertilization exacerbates it
2025-07-01

Metal contamination in agricultural soils threatens prokaryote dynamics essential for soil health and crop productivity. Yet, whether fertilization in the long-run affects their resilience to metals remains unclear. This study examined the biogeochemical impacts of realistically low-dose applications of cadmium, zinc, and lead in soils subjected to 119 years of non-fertilization, mineral-fertilization (NPK), organic-fertilization (manure), or combined mineral-organic fertilization. Amended metals remained in the mobile fraction with the order: mineral < unfertilized < mineral + organic < organic, mirroring the effects on soil prokaryotes. In both unfertilized and mineral-fertilized soils, 16S rRNA gene copy numbers declined by 30 % upon metal addition, but recovery timing differed: in unfertilized soil, recovery began after three days, whereas in mineral-fertilized soil, numbers declined until day seven before recovering. This coincided with an increase in metal-resistant taxa, particularly in mineral-fertilized soil, with 10 significantly affected OTUs, and to a lesser extent in unfertilized soil, with 5 affected OTUs. Carbon-, nitrogen-, and phosphorus-mining enzyme activities increased 50-100 % in mineral-fertilized soils, suggesting enhanced nutrient acquisition to mitigate metal toxicity. In contrast, organic-fertilized soil hosted stable enzymatic activities and microbial copy numbers with minimal community shifts (1 affected OTU), indicating greater resistance to metal amendment. Combined mineral-organic fertilization stabilized copy numbers and enzymatic activity upon metal amendment, but 8 OTUs were affected, including specialized nutrient cyclers, suggesting increased availability of previously adsorbed NPK cations. Our findings indicate that organic fertilization shields prokaryotes from metal stress, while mineral fertilization exacerbates it, highlighting the benefits of organic practices for maintaining soil health and productivity.
Microglial immune memory in Parkinson’s and Huntington’s diseases: epigenetics, triggers, and therapies
2025-07-01

Neurodegenerative disorders, like Parkinson's and Huntington's disease, have a profound global impact but currently lack effective treatments. Accumulations of misfolded proteins of <i>α</i>-synuclein and huntingtin are a common pathological hallmark in these diseases, respectiveley. Recently, the role of microglia and innate immune memory in modulating neurodegenerative diseases has been studied in more detail. This review explores the mechanisms of microglial activation in Parkinson's and Huntington's, emphasizing innate immune memory, epigenetic reprogramming, and the influence of external triggers such as lipopolysaccharides (LPS) and high-fat diets (HFD). The review also examines therapeutic strategies targeting microglia to mitigate neurodegeneration, including shifting microglial phenotypes from pro-inflammatory to anti-inflammatory states using epigenetic interventions. To support this review, a structured literature search was conducted using PubMed, Scopus, and Web of Science. Keywords included microglia, innate immune memory, epigenetics, neuroinflammation, and disease-specific terms. Future research should focus on improving animal models, investigating environmental stressors, and developing reliable biomarkers to strengthen translational approaches for neuroinflammatory-driven neurodegenerative diseases.
AK2‐Deficient Mice Recapitulate Impaired Lymphopoiesis of Reticular Dysgenesis Patients, but Also Lack Erythropoiesis
2025-07-01

ABSTRACT Reticular dysgenesis (RD) is a rare genetic disorder caused by mutations in the adenylate kinase 2 ( AK2 ) gene. It is characterized by a T − B − severe combined immunodeficiency, agranulocytosis, and sensorineural deafness. We established and characterized a haematopoiesis‐specific conditional Ak2 ‐knockout mouse model to provide a model system to study the molecular pathophysiology of RD. As expected from the human phenotype of RD, haematopoiesis‐specific AK2‐deficient embryos had a small, atrophic thymus consisting mainly of epithelial cells. No recognizable T‐cell component was observed, but B‐cell lineage precursor cells were present in the foetal liver. The effects of AK2 deficiency on myelopoiesis were less severe in mice than in humans. The absolute numbers of monocytes, macrophages, granulocytes and megakaryocytes in foetal liver as well as colony‐forming precursors were not reduced. In contrast to humans, haematopoiesis‐specific Ak2 ‐knockout mice exhibit embryonic lethality between E13 and E15 due to severe anaemia caused by an early block in definitive erythropoiesis. Murine erythroid progenitors mainly express AK2 and only low levels of functionally related kinases, which are unable to compensate for AK2 deficiency, in contrast to human erythroid progenitors.
Structure–Activity Relationships of Inactive‐Conformation Binding EGFR Inhibitors: Linking the ATP and Allosteric Pockets
2025-07-01

ABSTRACT The epidermal growth factor receptor (EGFR) tyrosine kinase is an important therapeutic target in non‐small cell lung cancer (NSCLC). However, the continual emergence of resistance mutations in the treatment of EGFR mutation‐positive NSCLC with currently approved tyrosine kinase inhibitors warrants the development of next‐generation inhibitors. Since research for ATP‐competitive EGFR tyrosine kinase inhibitors (TKIs) that extend into the back pocket has been neglected in the recent past, we survey the extent to which such binding functional groups can be incorporated into an ATP‐site imidazole scaffold. We find that meta ‐substituted amide linkers derivatized with fluorine in 2,6‐positions and/or a hydroxy group in 3‐position of the back pocket phenyl exhibit the highest potency. Structural insights into how the back pocket groups are bound through points of connection provide new directions for the discovery and optimization of inactive conformation targeting agents in EGFR and other kinases.
Structural and functional connectivity in tau mutation carriers: from presymptomatic to symptomatic frontotemporal dementia
2025-07-01

Abstract INTRODUCTION Microtubule‐associated protein tau ( MAPT ) mutations cause frontotemporal dementia (FTD), characterised by behavioural, language, and motor impairments due to brain connectivity disruptions. We investigated structural and functional connectivity in 86 mutation carriers and 272 controls to map connectivity changes at different disease stages. METHODS The CDR Dementia Staging Instrument plus National Alzheimer's Coordinating Center (NACC) Behaviour and Language domains (CDR plus NACC FTLD) stratified carriers into three groups: asymptomatic, prodromal, and symptomatic. We extracted measures of cortical thickness, white matter integrity, and functional connectivity, which were compared between each carrier group and controls using linear mixed models. RESULTS Early isolated functional disruptions in salience/visual networks were present in asymptomatic carriers, along with anterior cingulate gray matter reductions. In prodromal carriers, functional changes extended to other networks, with additional structural damage in temporal poles/cingulate. DISCUSSION This study shows that functional networks likely drive lifelong compensation for a genetically determined disease, manifesting clinically when structural damage reaches a critical threshold. This supports connectivity measures as potential biomarkers for MAPT ‐related neurodegeneration. Highlights Our findings reveal the progressive and staged nature of structural and functional connectivity alterations in MAPT mutation carriers, with distinct patterns at each disease stage. In asymptomatic carriers, we identified early functional connectivity alterations in salience and visual networks, despite preserved white matter and only subtle gray matter atrophy. These appear to represent both response to pathology and possible compensatory mechanisms. In prodromal carriers, functional connectivity alterations were accompanied by structural damage, including cortical atrophy and white matter tract disruptions, in regions directly connected to early‐affected networks. The sequential progression, from functional connectivity changes to structural degeneration, aligns with the hypothesis that tau propagates along axonal connections, disrupting neural network integrity before measurable atrophy occurs. We propose a theoretical data‐driven model of biomarker evolution in MAPT mutation carriers, highlighting functional disruptions as early indicators and structural damage as a later‐stage hallmark. These connectivity biomarkers have the potential to inform therapeutic strategies and clinical trial design.
A Possible Late Jurassic Final Closure of the Mongol‐Okhotsk Ocean in Its Eastern Segment: Constraints From New Paleomagnetic Investigations
2025-07-01

Abstract Closure of the Mongol‐Okhotsk Ocean (MOO) marks the final continental configuration of central Asia. Here we present a paleomagnetic study on the Upper Jurassic sedimentary rocks from the northern part of the Amuria Block (AMB) in northeastern China that is directly south of the Mongol‐Okhotsk suture to constrain the timing of its final closure in the eastern segment. Rock magnetic experiments reveal that magnetite and hematite are magnetic carriers of the characteristic remanent magnetization. Site‐mean directions isolated from 21 sites show antipodal normal and reversed polarities, passing both fold and reversal tests. After applying Elongation/Inclination correction of inclination shallowing, an age‐mean direction is calculated at D s / I s = 196.7°/−68.2° ( k = 71.9, α 95s = 1.3°) in stratigraphic coordinates, corresponding to a Late Jurassic paleomagnetic pole of λ / φ = 78.3°N/184.6°E ( A 95 = 2.0°) for the AMB. Combining paleomagnetic data with regional geological evidence, we propose a possible Late Jurassic closure of the MOO in its eastern segment, marking the final closure of the MOO and the formation of the central Asian continent.