Explore the vast range of titles available.

This article explores the Kantian and Rousseauvian solutions to the conflict between autonomy and authority. First, I discuss how the categorical imperatives (CI) are the supreme source of the legitimate authority of a limited number of political laws. By extending the synthetic a priori nature of the CI, I demonstrate how Rousseau’s General Will (GW) can justify political laws in a broader sense. I also refer to the theory of H.L.A. Hart and John Rawls to show that all political laws are binding if they are within the limits of injustice and have some moral foundation. I discussed the limits of authority of on debatable laws such as banning abortion. I analyzed the possibility of GW by using Condorcet’s theorem. I conclude that GW cannot fully justify political laws based on majoritarian direct democracy, owing to problematic assumptions, although it may be an improvement to the current legislative procedure of the U.S.

Screencasts, which are screen-capture videos, have been created by teachers delivering instruction or feedback, reflecting a teacher-centered model of learning. Based on the constructivist principle, this study explores an innovative attempt to position students as screencast creators, who must demonstrate their knowledge by and explain their work in the screencast. This innovative approach has the potential to promote authentic learning and reduce dependence on generative artificial intelligence (GenAI) tools for completing assignments. However, it is uncertain whether students will have positive attitudes towards this new form of assessment. From 2022 to 2025, the authors used screencasts as assessments in computer programming and English language subjects. Survey results were obtained from 203 university students and analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM). The results show that students generally hold positive attitudes toward creating screencasts, with perceived usefulness for future applications exerting the strongest influence on acceptance, followed by perceived performance benefits and ease of use. It is also found that gender, discipline, and study mode did not significantly alter these relationships, although senior students perceived screencast production as more effortful. These findings suggest that student-created screencasts can serve as an effective, student-centered alternative to traditional written assessments. The research results imply that student-created screencasts have the potential to help students develop their skills in an increasingly GenAI-pervasive academic environment.

Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid cycle, but lower α-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation. Ex vivo incubation of platelets from both MPN patients and Jak2 V617F-knockin mice with α-KG supplementation significantly reduced platelet activation responses. Oral α-KG supplementation of Jak2 V617F mice decreased splenomegaly and reduced hematocrit, monocyte, and platelet counts. Finally, α-KG treatment significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling that contributes to platelet hyperreactivity in MPN patients.

Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by memory decline, cognitive impairment, and behavioral abnormalities. Pathologically, AD is marked by neurofibrillary tangles caused by excessive phosphorylation of Tau protein and abnormal deposition of β-amyloid (Aβ) in the brain. The PI3K/AKT signaling pathway plays a crucial role in the development, survival, and metabolic regulation of the central nervous system, particularly in neuronal growth, differentiation, and apoptosis. However, this pathway is often inhibited in AD patients.In recent years, studies have shown that herbal formulations and extracts derived from Traditional Chinese Medicine (TCM) can regulate the PI3K/AKT signaling pathway, thereby improving AD pathological models. This study reviews fundamental research on both active metabolites and compound formulations from TCM for the treatment of AD, targeting the PI3K/AKT signaling pathway.Keywords include “Alzheimer’s disease” “AD” “dementia” “PI3K” “AKT” “Traditional Chinese Medicine” “Chinese herbology” “Chinese medicine” and “TCM”.The study is based on relevant literature published over the past 15 years, primarily sourced from electronic databases such as Web of Science, PubMed, CNKI, Wanfang, and VIP databases.The findings indicate that herbal formulations and extracts derived from TCM can mitigate AD pathology by regulating the PI3K/AKT signaling pathway, reducing Tau protein phosphorylation and Aβ deposition, inhibiting inflammatory responses and oxidative stress, and alleviating neuronal apoptosis. This study enhances our understanding of the anti-AD mechanisms of TCM through the PI3K/AKT pathway and offers new insights for the future.

Due to the limitations on the capabilities of current robots regarding task learning and performance, imitation is an efficient social learning approach that endows a robot with the ability to transmit and reproduce human postures, actions, behaviors, etc., as a human does. Stable whole-body imitation and task-oriented teleoperation via imitation are challenging issues. In this paper, a novel comprehensive and unrestricted real-time whole-body imitation system for humanoid robots is designed and developed. To map human motions to a robot, an analytical method called geometrical analysis based on link vectors and virtual joints (GA-LVVJ) is proposed. In addition, a real-time locomotion method is employed to realize a natural mode of operation. To achieve safe mode switching, a filter strategy is proposed. Then, two quantitative vector-set-based methods of similarity evaluation focusing on the whole body and local links, called the Whole-Body-Focused (WBF) method and the Local-Link-Focused (LLF) method, respectively, are proposed and compared. Two experiments conducted to verify the effectiveness of the proposed methods and system are reported. Specifically, the first experiment validates the good stability and similarity features of our system, and the second experiment verifies the effectiveness with which complicated tasks can be executed. At last, an imitation learning mechanism in which the joint angles of demonstrators are mapped by GA-LVVJ is presented and developed to extend the proposed system.

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis factor (TNF) associated with MPN disease severity and transformation. We further evaluate a therapeutic approach utilizing a first-in-class RSK inhibitor, PMD-026, currently in Phase 2 development for breast cancer, for use in myeloid malignancies. Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML. Secondary acute myeloid leukemias (sAMLs) evolving from myeloproliferative neoplasms (MPNs) associate with poor prognosis. Here authors identify RSK1 as a vulnerability for MPN and sAML and show the efficacy of a first-in-class RSK inhibitor, PMD-026, against these types of myeloid malignancies.

Recent observational studies have found an association between Clonal Hematopoesis (CH) and strokes but with incomplete results. This study aims to comprehensively characterize mutation‐specific effects of CH on ischemic and hemorrhagic stroke subtypes and 90‐day functional outcomes through publicly available genome‐wide association study (GWAS) cohorts and Mendelian Randomization. TET2 is associated with an increased risk of overall stroke (OR = 1.06, P = 0.02), ischemic stroke (OR = 1.05, P = 0.03), transient ischemic attack (OR = 1.07, P = 0.01) and small vessel stroke (OR = 1.29, P = 0.01), as well as adverse 90‐day modified Rankin scale (mRS ≥ 3) before (OR = 1.34, P = 0.005) and after adjusted for age, sex, and stroke severity (OR = 1.30, P = 0.02). While the presence of any CH mutation is associated with intracerebral hemorrhage (ICH) (OR = 1.21, P = 0.02), specific mutations, SRSF2 and ASXL1 are protective against ICH (OR = 0.9, P = 0.04) and nontraumatic subarachnoid hemorrhage (OR = 0.92, P = 0.03), respectively. In conclusion, the study provided genetic evidence that TET2 is strongly associated with an increased risk of ischemic stroke and poor functional recovery. Future studies clarifying the relationship between CH and hemorrhagic stroke subtypes are needed. This study comprehensively evaluated the differential effect of clonal hematopoiesis (CH) mutations on the risk of various stroke subtypes and functional recovery. It shows that TET2 is associated with small vessel stroke possibly via a pro‐inflammatory pathway.

Conventional electrothermal floors suffer from low heating efficiency, uneven temperature distribution across the floor surface, local overheating, and severe heat accumulation. In order to improve the heating performance, an electrothermal composite floor with graphene as the heating layer was fabricated. The relationship between time and temperature rise, the relationship between power density and temperature rise, running stability, and surface temperature distribution were investigated and analyzed after heating, and the surface temperature profiles were simulated in two and three dimensions. The results were compared with the carbon fiber electrothermal composite floor and the resistance wire electrothermal composite floor. The results indicated that the temperature of the graphene electrothermal composite floor rose to 27.1 °C, the electrothermal conversion efficiency reached 90.1% after 40 min of electrification, and the temperature distribution unevenness was 4.4 °C, which were better than the carbon fiber electrothermal composite floor and the resistance wire electrothermal composite floor. The graphene electrothermal composite floor exhibited high heating performance, thus aiding the development and manufacture of such composite flooring.

Introduction Myeloid malignancies, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN), exhibit overlapping pathophysiology. Chronic MPNs can transform into secondary AML (sAML), which is associated with poor prognosis and limited treatment options. However, the process and prognostic significance of leukemic transformation remain incompletely understood. Method Through a two-sample bidirectional Mendelian randomization (MR) analysis, we showed that genetic liability to MPN significantly predicts the risk of developing AML, establishing MPN as the precursor to leukemia. To identify mediators of this risk, we integrated population-level plasma proteomics data, identifying 55 proteins associated with MPN. Upon integrative analysis with the BEAT-AML cohort, we developed a prognostic proteogenomic gene signature, showing that higher expression of CDCP1, CRISP3, and DCXR, alongside lower MPO levels, correlates with worse AML outcomes. We further performed pharmacogenomic analysis to identify vulnerability to PI3K/AKT/mTOR signaling pathway inhibition in high-risk AML. In vitro and in vivo experiments validated the efficacy of mTOR inhibition in myeloid malignancies. Results This gene signature effectively stratified patients by risk, with significant survival differences across the BEAT-AML and TCGA-LAML cohorts, and revealed immune alterations in high-risk groups, including elevated monocyte prevalence and cytokine signaling activity. Single-cell RNA sequencing (scRNA-seq) further suggested enrichment of these genes in progenitor cells and AML blasts. Drug sensitivity predictions suggested that high-risk AML patients may be particularly responsive to PI3K/AKT/mTOR signaling pathway inhibitors. Consistently, we observed upregulation of the genes in cell line models harboring MPN and AML mutations, which was suppressible via dual PI3K/mTOR inhibitor omipalisib. The efficiency of PI3K/mTOR inhibition in myeloid malignancies was further corroborated by results from multiple in vivo models. Conclusion Together, our findings revealed shared molecular features across MPN and AML, identified a prognostic gene signature for risk stratification, and provided rationale for PI3K/mTOR inhibition as a promising therapeutic strategy in myeloid malignancies.

Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome‐wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment‐resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation‐relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein‐coding region of HLA‐DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA‐DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin‐6 (IL‐6) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA‐DRB1 polymorphism, and enhanced IL‐6 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.