In summary, our study supported the safety and durable potency of CRISPR-edited CART in patients, providing a novel platform for developing autologous or allogeneic CART to minimize GM-CSF-associated toxicity in addition to autonomous IL6/IL1 blockade.Early onset schizophrenia (EOS, defined as first onset of schizophrenia before age 18) is a rare form of schizophrenia (SCZ). Though genome-wide association studies (GWASs) have identified multiple risk variants for SCZ, most of the cases included in these GWASs were not stratified according to their first age at onset. To date, the genetic architecture of EOS remains largely unknown. To identify the risk variants and to uncover the genetic basis of EOS, we conducted a two-stage GWAS of EOS in populations of Han Chinese ancestry in this study. We first performed a GWAS using 1,256 EOS cases and 2,661 healthy controls (referred as discovery stage). The genetic variants with a P  less then  1.0 × 10-04 in discovery stage were replicated in an independent sample (903 EOS cases and 3,900 controls). We identified four genome-wide significant risk loci for EOS in the combined samples (2,159 EOS cases and 6,561 controls), including 1p36.22 (rs1801133, Pmeta = 4.03 × 10-15), 1p31.1 (rs1281571, Pmeta = 4.14 × 10-08), 3p21.31 (rs7626288, Pmeta = 1.57 × 10-09), and 9q33.3 (rs592927, Pmeta = 4.01 × 10-11). Polygenic risk scoring (PRS) analysis revealed substantial genetic overlap between EOS and SCZ. These discoveries shed light on the genetic basis of EOS. Deucravacitinib concentration Further functional characterization of the identified risk variants and genes will help provide potential targets for therapeutics and diagnostics.Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1 Mb of genes was evaluated using linear regression models for unrelated subjects and linear-mixed models for related subjects. Cell-type-specific eQTL (ct-eQTL) models included an interaction term for the expression of "proxy" genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell types is supported by the observation that a large portion of GWS ct-eQTLs map within 1 Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type-specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type-specific analysis.The cyclic GMP-AMP synthase (cGAS) is a widely used DNA sensor, which detects cytosolic DNA species without a preference of self or non-self microbial DNA in interphase to initiate innate immune response. How cGAS is regulated to avoid self-DNA sensing upon nuclear envelope breakdown (NEBD) during mitosis remains enigmatic. Here we show that cGAS is mostly localized in the cytoplasm in interphase and rapidly translocated to chromosomes upon NEBD in mitosis. The major mitotic kinase CDK1-cyclin B complex phosphorylates human cGAS at S305 or mouse cGAS at S291, which inhibits its ability to synthesize cGAMP upon mitotic entry. The type 1 phosphatase PP1 dephosphorylates cGAS upon mitotic exit to enable its DNA sensing ability. Our findings reveal a mechanism on how the DNA sensor cGAS is post-translationally regulated by cell cycle-dependent enzymes to ensure its proper activation for host defense of cytosolic DNA in interphase and inert to self-DNA in mitosis.Purines and their derivatives, most notably adenosine and ATP, are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis. Besides, these purines support, as chemical messengers, purinergic transmission throughout tissues and species. Purines act as endogenous ligands that bind to and activate plasmalemmal purinoceptors, which mediate extracellular communication referred to as "purinergic signalling". Purinergic signalling is cross-linked with other transmitter networks to coordinate numerous aspects of cell behaviour such as proliferation, differentiation, migration, apoptosis and other physiological processes critical for the proper function of organisms. Pathological deregulation of purinergic signalling contributes to various diseases including neurodegeneration, rheumatic immune diseases, inflammation, and cancer. Particularly, gout is one of the most prevalent purine-related disease caused by purine metabolism disorder and consequent hyperuricemia. Compelling evidence indicates that purinoceptors are potential therapeutic targets, with specific purinergic agonists and antagonists demonstrating prominent therapeutic potential. Furthermore, dietary and herbal interventions help to restore and balance purine metabolism, thus addressing the importance of a healthy lifestyle in the prevention and relief of human disorders. Profound understanding of molecular mechanisms of purinergic signalling provides new and exciting insights into the treatment of human diseases.We show for the first time that a single ultrasonic imaging fibre is capable of simultaneously accessing 3D spatial information and mechanical properties from microscopic objects. The novel measurement system consists of two ultrafast lasers that excite and detect high-frequency ultrasound from a nano-transducer that was fabricated onto the tip of a single-mode optical fibre. A signal processing technique was also developed to extract nanometric in-depth spatial measurements from GHz frequency acoustic waves, while still allowing Brillouin spectroscopy in the frequency domain. Label-free and non-contact imaging performance was demonstrated on various polymer microstructures. This singular device is equipped with optical lateral resolution, 2.5 μm, and a depth-profiling precision of 45 nm provided by acoustics. The endoscopic potential for this device is exhibited by extrapolating the single fibre to tens of thousands of fibres in an imaging bundle. Such a device catalyses future phonon endomicroscopy technology that brings the prospect of label-free in vivo histology within reach.