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.

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.

Dysregulation of galectins and global protein glycosylation have been reported in various cancers, but their role in myeloproliferative neoplasms (MPNs) have remained incompletely understood. We performed single-cell RNA sequencing (scRNA-seq) which revealed significant enrichment of galectin genes in MPN monocytes. Cell-cell communication analysis predicted monocytes as a pivotal mediator of cell interactions and galectin signaling as a robust input/output pathway for monocytes. We identified elevated expression of galectin-1 (Gal-1, LGALS1) in monocytes from both human MPN samples and mouse models. Mass cytometry (CyTOF) profiling of MPN blood samples demonstrated that recombinant galectin-1 (rGal-1) significantly increased levels of multiple inflammatory cytokines in monocytes without affecting other cell types. Incubation of CD14+ monocytes from MPN patients with rGal-1 led to markedly increased transcription and secretion of inflammatory cytokines. Mechanistically, we uncovered crosstalk between the TLR4 and Gal-1 signaling pathways, as evidenced by protein 3D modeling and co-immunoprecipitation. Notably, TLR4 inhibition abrogated Gal-1 mediated proinflammatory effects in monocytes. We further identified NF-κB-dependent signaling as a key downstream effector of Gal-1, as reporter assays demonstrated rGal-1 mediated activation of NF-κB signaling in a TLR4-dependent manner. We corroborated these findings in vivo in a murine model driven by MPLW515L in which genetic abrogation of Lgals1 ameliorated key MPN disease features, including leukocytosis and splenomegaly. Additionally, Gal-1 inhibition suppressed carrageenan-induced thrombosis and inflammation in vivo. In summary, we identify Gal-1 enrichment in MPN monocytes as a driver of monocyte-mediated inflammation through TLR4 and NF-κB activation and uncover a novel therapeutic avenue for MPNs.

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 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.