VISTA suppresses T cell proliferation and cytokine production and can influence autoimmunity and antitumor responses in mice.

Using whole-cell recording from CA1 hippocampal pyramidal neurons and minimal stimulation of Schaffer collaterals, we have studied what seem to be single synapses. Although the transmission at a putative single synapses is quite unreliable, the synapse can be made to release transmitter reliably in response to the second stimulus in a pair of stimuli that re presented in rapid succession (e.g., 50 ms separation). Statistical analysis of transsmision failures seen with such paired pulse stimulation reveals that the majority of stimulus-evoked synaptic currents (> 90%) are produced by a single synapse under the conditions of minimal stimulation, even if multiple synapses are actually present. Individual synapses appear to release either zero or one quantum; that is, a single synapse seems to have only one functional release sit at any time. After the release site has been used, approximately 20 ms is required to refill the site so that it can be used again.

Rechargeable aqueous Zn‐ion batteries promise high capacity, low cost, high safety, and sustainability for large‐scale energy storage. The Zn metal anode, however, suffers from the dendrite growth and side reactions that are mainly due to the absence of an appropriate solid electrolyte interphase (SEI) layer. Herein, the in situ formation of a dense, stable, and highly Zn2+‐conductive SEI layer (hopeite) in aqueous Zn chemistry is demonstrated, by introducing Zn(H2PO4)2 salt into the electrolyte. The hopeite SEI (≈140 nm thickness) enables uniform and rapid Zn‐ion transport kinetics for dendrite‐free Zn deposition, and restrains the side reactions via isolating active Zn from the bulk electrolyte. Under practical testing conditions with an ultrathin Zn anode (10 µm), a low negative/positive capacity ratio (≈2.3), and a lean electrolyte (9 µL mAh−1), the Zn/V2O5 full cell retains 94.4% of its original capacity after 500 cycles. This work provides a simple yet practical solution to high‐performance aqueous battery technology via building in situ SEI layers.

SUMMARY The molecular circuits by which antigens activate quiescent T cells remain poorly understood. We combined temporal profiling of the whole proteome and phosphoproteome via multiplexed isobaric labeling proteomics technology, computational pipelines for integrating multi-omics datasets, and functional perturbation to systemically reconstruct regulatory networks underlying T cell activation. T cell receptors activated the T cell proteome and phosphoproteome with discrete kinetics, marked by early dynamics of phosphorylation and delayed ribosome biogenesis and mitochondrial activation. Systems biology analyses identified multiple functional modules, active kinases, transcription factors and connectivity between them, and mitochondrial pathways including mitoribosomes and complex IV. Genetic perturbation revealed physiological roles for mitochondrial enzyme COX10-mediated oxidative phosphorylation in T cell quiescence exit. Our multi-layer proteomics profiling, integrative network analysis and functional studies define landscapes of the T cell proteome and phosphoproteome and reveal signaling and bioenergetics pathways that mediate lymphocyte exit from quiescence.

No abstract

Synaptic transmission in the hippocampus is rather unreliable, with many presynaptic action potentials failing to release neurotransmitter. How is this unreliability affected by the alterations in synaptic strength seen in long-term potentiation (LTP) and long-term depression (LTD)? We find that LTP increases synaptic reliability, and LTD decreases it, both without a change in the size of those postsynaptic currents that do occur. Thus LTD is a functional inverse of LTP.

To clarify the significance of circulating tumor cells (CTC) undergoing epithelial-mesenchymal transition (EMT) in patients with hepatocellular carcinoma (HCC), we used an advanced CanPatrol CTC-enrichment technique and hybridization to enrich and classify CTC from blood samples. One hundred and one of 112 (90.18%) patients with HCC were CTC positive, even with early-stage disease. CTCs were also detected in 2 of 12 patients with hepatitis B virus (HBV), both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal-CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis. Postoperative CTC monitoring in 10 patients found that most had an increased CTC count and M-CTC percentage before clinically detectable recurrence nodules appeared. Analysis of HCC with high CTC count and high M-CTC percentage identified 67 differentially expressed cancer-related genes involved in cancer-related biological pathways (e.g., cell adhesion and migration, tumor angiogenesis, and apoptosis). One of the identified genes, BCAT1, was significantly upregulated, and knockdown in Hepg2, Hep3B, and Huh7 cells reduced cell proliferation, migration, and invasion while promoting apoptosis. A concomitant increase in epithelial marker expression (EpCAM and E-cadherin) and reduced mesenchymal marker expression (vimentin and Twist) suggest that BCAT1 may trigger the EMT process. Overall, CTCs were highly correlated with HCC characteristics, representing a novel marker for early diagnosis and a prognostic factor for early recurrence. BCAT1 overexpression may induce CTC release by triggering EMT and may be an important biomarker of HCC metastasis. In liver cancer, CTC examination may represent an important "liquid biopsy" tool to detect both early disease and recurrent or metastatic disease, providing cues for early intervention or adjuvant therapy. .

Regulatory T (Treg) cells express tumor necrosis factor receptor superfamily (TNFRSF) members, but their role in thymic Treg development is undefined. We demonstrate that Treg progenitors highly express the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors correlates directly with T cell receptor (TCR) signal strength, and requires CD28 and the kinase TAK1. Neutralizing TNFSF ligands markedly reduced Treg development. Conversely, TNFRSF agonists enhanced Treg differentiation by augmenting IL-2R/STAT5 responsiveness. GITR-ligand costimulation elicited a dose-dependent enrichment of lower-affinity cells within the Treg repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated Treg development. Thus TNFRSF expression on Treg progenitors translates strong TCR signals into molecular parameters that specifically promote Treg differentiation and shape the Treg repertoire.