Mitochondria-immobilized fluorescent probes for viscosity and cellular imaging.

A mitochondria-immobilized fluorescent probe Mito-CDM was designed and synthesized for viscosity sensing via the twisted intramolecular charge transfer (TICT) mechanism. The N,N-diethylaminophenyl group is the viscosity-sensitive unit in the prepared Mito-CDM molecular structure, while the pyridinium cation is the mitochondria-targeting group that is responsible for monitoring mitochondrial viscosity. As the viscosity increased from 0.

Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis.

Targeted therapies have improved survival for lung adenocarcinoma patients. However, similar advances are lacking for lung squamous carcinoma (LUSC). Advances in immunotherapy have shown some promise, but the overall response rate remains low in LUSC.

Combining xQTL and genome-wide association studies from ethnically diverse populations improves druggable gene discovery.

Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing new treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies (GWAS). Gene-based association tests provide a more powerful alternative to traditional single nucleotide polymorphism (SNP)-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate functional genomic data.

Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth.

Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts antitumor cytolysis by transferring FAs into developing metastatic tumors.

Preparation of mitochondrial targeted near-infrared ratio fluorescent probe and its dual response detection for viscosity and ONOO and cell imaging.

The changes in viscosity and the concentration of ONOO in mitochondria can effectively reflect the physiological and pathological status of cells. Therefore, the development of effective fluorescent probes for the sensing of viscosity and the concentration of ONOO in mitochondria has great significance. In this article, a mitochondrial targeted fluorescent probe named Mito-RP was synthesized for the dual responsive sensing of viscosity and ONOO by introducing pyridine ring and phenylboronic acid ester structure into 4-dimethylamino-cinnamaldehyde with long conjugated chain structure as the parent material.

Regulation of fatty acid delivery to metastases by tumor endothelium.

Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth. Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs but impair the cytotoxicity of T cells in the tumor microenvironment (TME), thereby supporting metastatic progression.

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.

Background: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations.

Methods: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project.

Lipid kinase PIK3C3 maintains healthy brown and white adipose tissues to prevent metabolic diseases.

Adequate mass and function of adipose tissues (ATs) play essential roles in preventing metabolic perturbations. The pathological reduction of ATs in lipodystrophy leads to an array of metabolic diseases. Understanding the underlying mechanisms may benefit the development of effective therapies.

PIK3C3/VPS34 helps school T cells in the thymus.

The development of a broad repertoire of T cells in the immune system requires interaction of T cell receptors expressed by immature T cells with peptide/major histocompatibility complexes (MHCs) displayed by specialized epithelial cells in the thymus, in a process called T cell positive selection. Thymic epithelial cells (TECs) display unique antigen processing machinery which shapes the collection of self-peptides that drive positive selection. In our recent studies, we explored the contribution of the lipid kinase PIK3C3/VPS34 to the generation of positively selecting peptides in TECs.

Thymic epithelial cells require lipid kinase Vps34 for CD4 but not CD8 T cell selection.

The generation of a functional, self-tolerant T cell receptor (TCR) repertoire depends on interactions between developing thymocytes and antigen-presenting thymic epithelial cells (TECs). Cortical TECs (cTECs) rely on unique antigen-processing machinery to generate self-peptides specialized for T cell positive selection. In our current study, we focus on the lipid kinase Vps34, which has been implicated in autophagy and endocytic vesicle trafficking.

Innate and Innate-like Effector Lymphocytes in Health and Disease.

Lymphocytes can be functionally partitioned into subsets belonging to the innate or adaptive arms of the immune system. Subsets of innate and innate-like lymphocytes may or may not express Ag-specific receptors of the adaptive immune system, yet they are poised to respond with innate-like speed to pathogenic insults but lack the capacity to develop classical immunological memory. These lymphocyte subsets display a number of common properties that permit them to integrate danger and stress signals dispatched by innate sensor cells to facilitate the generation of specialized effector immune responses tailored toward specific pathogens or other insults.

Faraday Instability in Viscous Fluids Covered with Elastic Polymer Films.

Faraday instability has great application value in the fields of controlling polymer processing, micromolding colloidal lattices on structured suspensions, organizing particle layers, and conducting cell culture. To regulate Faraday instability, in this article, we attempt to introduce an elastic polymer film covering the surface of a viscous fluid layer and theoretically study the behaviors of the Faraday instability phenomenon and the effect of the elastic polymer film. Based on hydrodynamic theory, the Floquet theory is utilized to formulate its stability criterion, and the critical acceleration amplitude and critical wave number are calculated numerically.

Dendritic cell PIK3C3/VPS34 controls the pathogenicity of CNS autoimmunity independently of LC3-associated phagocytosis.

PIK3C3/VPS34 is a key player in macroautophagy/autophagy and MAP1LC3/LC3-associated phagocytosis (LAP), which play critical roles in dendritic cell (DC) function. In this study, we assessed the contribution of PIK3C3 to DC function during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We found that -deficient DCs exhibit attenuated capacity to reactivate encephalitogenic T cells in the central nervous system, leading to reduced incidence and severity of EAE in DC-specific -deficient mice.

Pik3c3 deficiency in myeloid cells imparts partial resistance to experimental autoimmune encephalomyelitis associated with reduced IL-1β production.

The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex plays a role in both canonical and noncanonical autophagy, key processes that control immune-cell responsiveness to a variety of stimuli. Our previous studies found that PIK3C3 is a critical regulator that controls the development, homeostasis, and function of dendritic and T cells. In this study, we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient mice.

Robust and Latch-Up-Immune LVTSCR Device with an Embedded PMOSFET for ESD Protection in a 28-nm CMOS Process.

Low-voltage-triggered silicon-controlled rectifier (LVTSCR) is expected to provide an electrostatic discharge (ESD) protection for a low-voltage integrated circuit. However, it is normally vulnerable to the latch-up effect due to its extremely low holding voltage. In this paper, a novel LVTSCR embedded with an extra p-type MOSFET called EP-LVTSCR has been proposed and verified in a 28-nm CMOS technology.

Phosphorylation of PLCγ1 by EphA2 Receptor Tyrosine Kinase Promotes Tumor Growth in Lung Cancer.

EphA2 receptor tyrosine kinase (RTK) is often expressed at high levels in cancer and has been shown to regulate tumor growth and metastasis across multiple tumor types, including non-small cell lung cancer. A number of signaling pathways downstream of EphA2 RTK have been identified; however, mechanisms of EphA2 proximal downstream signals are less well characterized. In this study, we used a yeast-two-hybrid screen to identify phospholipase C gamma 1 (PLCγ1) as a novel EphA2 interactor.

Host deficiency in ephrin-A1 inhibits breast cancer metastasis.

The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated.

Autophagy-related protein PIK3C3/VPS34 controls T cell metabolism and function.

The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex is a key early player in macroautophagy/autophagy. In this study, we assessed the contribution of PIK3C3 to T cell metabolism and function. We found that -deficient T cells exhibited impaired cellular metabolism, and -deficient CD4 T cells failed to differentiate into T helper 1 cells.

Disruption of the Scaffolding Function of mLST8 Selectively Inhibits mTORC2 Assembly and Function and Suppresses mTORC2-Dependent Tumor Growth .

mTOR is a serine/threonine kinase that acts in two distinct complexes, mTORC1 and mTORC2, and is dysregulated in many diseases including cancer. mLST8 is a shared component of both mTORC1 and mTORC2, yet little is known regarding how mLST8 contributes to assembly and activity of the mTOR complexes. Here we assessed mLST8 loss in a panel of normal and cancer cells and observed little to no impact on assembly or activity of mTORC1.

EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells.

Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific cofactors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells.

Elevated Slit2 Activity Impairs VEGF-Induced Angiogenesis and Tumor Neovascularization in EphA2-Deficient Endothelium.

Unlabelled: Angiogenic remodeling during embryonic development and in adult tissue homeostasis is orchestrated by cooperative signaling between several distinct molecular pathways, which are often exploited by tumors. Indeed, tumors upregulate proangiogenic molecules while simultaneously suppressing angiostatic pathways to recruit blood vessels for growth, survival, and metastatic spread. Understanding how cancers exploit proangiogenic and antiangiogenic signals is a key step in developing new, molecularly targeted antiangiogenic therapies.

Eph receptor tyrosine kinases in cancer stem cells.

Eph receptor tyrosine kinases (RTKs) and their ligands, ephrins, play critical roles in development, tissue homeostasis, and cancer. Because Eph receptors are expressed in most adult stem cell niches and in many types of cancers, it has been long suspected that this family of RTKs may also regulate the function of cancer stem-like cells (CSCs). This review will focus on recent studies to elucidate the contribution of Eph/ephrin molecules in CSC self-renewal and tumorigenicity, as well as describe efforts to target these molecules in cancer.