Junctophilin-2 is a double-stranded RNA-binding protein that regulates cardiomyocyte-autonomous innate immune response.

Junctophilin-2 (JPH2) is traditionally recognized as a cardiomyocyte-enriched structural protein that anchors the junction between the plasma membrane and the endo/sarcoplasmic reticulum, facilitating excitation-induced cardiac contraction. In this study, we uncover a novel function of JPH2 as a double-stranded RNA (dsRNA)-binding protein, which forms complexes with dsRNA both in vitro and in cells. Stimulation by cytosolic dsRNA enhances the interaction of JPH2 with the dsRNA sensor MDA5.

Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells.

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers, characterized by extremely limited therapeutic options and a poor prognosis, as it is often diagnosed during late disease stages. Innovative and selective treatments are urgently needed, since current therapies have limited efficacy and significant side effects. Through proteomics analysis of extracellular vesicles, we discovered an imbalanced distribution of amino acids secreted by PDAC tumor cells.

Role of inflammatory lipid and fatty acid metabolic abnormalities induced by plastic additives exposure in childhood asthma.

Lipid metabolism play an essential role in occurrence and development of asthma, and it can be disturbed by phthalate esters (PAEs) and organophosphate flame retardants (OPFRs). As a chronic inflammatory respiratory disease, the occurrence risk of childhood asthma is increased by PAEs and OPFRs exposure, but it remains not entirely clear how PAEs and OPFRs contribute the onset and progress of the disease. We have profiled the serum levels of PAEs and OPFRs congeners by liquid chromatography coupled with mass spectrometry, and its relationships with the dysregulation of lipid metabolism in asthmatic, bronchitic (acute inflammation) and healthy (non-inflammation) children.

EvIPqPCR, Target Circulating Tumorous Extracellular Vesicles for Detection of Pancreatic Cancer.

Pancreatic cancer patients predominantly present with advanced disease at diagnosis, contributing to its high mortality. A noninvasive, fast screening method to detect this disease is an unmet need. Tumor-derived extracellular vesicles (tdEVs) bearing information from parental cells have emerged as a promising cancer diagnostic biomarker.

Delineating regions of interest for mass spectrometry imaging by multimodally corroborated spatial segmentation.

Mass spectrometry imaging (MSI), which localizes molecules in a tag-free, spatially resolved manner, is a powerful tool for the understanding of underlying biochemical mechanisms of biological phenomena. When analyzing MSI data, it is essential to delineate regions of interest (ROIs) that correspond to tissue areas of different anatomical or pathological labels. Spatial segmentation, obtained by clustering MSI pixels according to their mass spectral similarities, is a popular approach to automate ROI definition.

PFAS-induced lipidomic dysregulations and their associations with developmental toxicity in zebrafish embryos.

Per- and polyfluoroalkyl substances (PFASs) are persistent environmental contaminants, posing developmental toxicity to fish and human. PFAS-induced lipid metabolism disorders were demonstrated using the zebrafish (Danio rerio) embryo model, but the detailed changes of lipid compositions and the influence of these changes on the biological development are still unclear. Herein, lipidomics analysis was performed to reveal the dysregulations of lipid metabolism in zebrafish embryos exposed to perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) through microinjection.

Serum metabolomic abnormalities in survivors of non-severe COVID-19.

Metabolic reprogramming is a distinctive characteristic of SARS-CoV-2 infection, which refers to metabolic changes in hosts triggered by viruses for their survival and spread. It is current urgent to understand the metabolic health status of COVID-19 survivors and its association with long-term health consequences of infection, especially for the predominant non-severe patients. Herein, we show systemic metabolic signatures of survivors of non-severe COVID-19 from Wuhan, China at six months after discharge using metabolomics approaches.

Cytokine receptor gp130 promotes postnatal proliferation of cardiomyocytes required for the normal functional development of the heart.

Mammalian ventricular cardiomyocytes are premature at birth and exhibit substantial phenotypic changes before weaning. Mouse ventricular myocytes undergo cell division several times after birth; however, the regulatory mechanisms and roles of cardiomyocyte division in postnatal heart development remain unclear. Here, we investigated the physiological role of glycoprotein 130 (gp130), the main subunit of multifunctional receptors for the IL-6 family of cytokines, in postnatal cardiomyocyte proliferation.

β-Sheet Richness of the Circulating Tumor-Derived Extracellular Vesicles for Noninvasive Pancreatic Cancer Screening.

Tumor-derived extracellular vesicles (EVs) are under intensive study for their potential as noninvasive diagnosis biomarkers. Most EV-based cancer diagnostic assays trace supernumerary of a single cancer-associated marker or marker signatures. These types of biomarker assays are either subtype-specific or vulnerable to be masked by high background signals.

Sequence determinants of human junctophilin-2 protein nuclear localization and phase separation.

Junctophilin-2 (JPH2) was conventionally considered as a structural membrane binding protein. Recently, it was shown that proteolytically truncated mouse JPH2 variants are imported into nucleus to exert alternative functions. However, the intranuclear behaviors of human JPH2 (hJPH2) and underlying molecular determinants have not been explored.

High-Resolution Ion Microscope Imaging over Wide Mass Ranges Using Electrodynamic Postextraction Differential Acceleration.

A time-dependent postextraction differential acceleration (PEDA) potential was used to temporally focus increasingly heavy ions in a stigmatic imaging mass spectrometer, allowing them to be imaged with high mass and spatial resolutions over a broad mass-to-charge (/) range. By applying a linearly rising potential to the ion extraction electrode, sequential / ratios were subjected to a changing electric field, allowing their foci to coincide at the detector. Using this approach, at least 75% of the maximum mass resolution was obtained over a 300-600 Da range when the ion microscope was focused around 450 Da, representing more than a 10-fold increase over the conventional single-field PEDA method.

Microscope imaging mass spectrometry with a reflectron.

A time-of-flight microscope imaging mass spectrometer incorporating a reflectron was used to image mass-resolved ions generated from a 270 μm diameter surface. Mass and spatial resolutions of 8100 ± 700 m/Δm and 18 μm ± 6 μm, respectively, were obtained simultaneously by using pulsed extraction differential acceleration ion optical focusing to create a pseudo-source plane for a single-stage gridless reflectron. The obtainable mass resolution was limited only by the response time of the position-sensitive detector and, according to simulations, could potentially reach 30 200 ± 2900 m/Δm.

Microwave-Assisted Hydrothermal Synthesis of [Al(OH)(1,4-NDC)] Membranes with Superior Separation Performances.

In this study, we report a facile ligand-assisted in situ hydrothermal approach for preparation of compact [Al(OH)(1,4-NDC)] (1,4-NDC=1,4-naphthalenedicarboxylate) MOF membranes on porous γ-Al O substrates, which also served as the Al source of MOF membranes. Simultaneously, it was observed that the heating mode exerted significant influence on the final microstructure and separation performance of [Al(OH)(1,4-NDC)] membranes. Compared with the conventional hydrothermal method, the employment of microwave heating led to the formation of [Al(OH)(1,4-NDC)] membranes composed of closely packed nanorods with superior H /CH selectivity.

E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.

Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA, and controls expression of a spectrum of genes in cardiomyocytes.

Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models.

Heart failure remains a major cause of morbidity and mortality in developed countries. There is still a strong need to devise new mechanism-based treatments for heart failure. Numerous studies have suggested the importance of the Ca-dependent protease calpain in cardiac physiology and pathology.

Transient activation of PKC results in long-lasting detrimental effects on systolic [Ca] in cardiomyocytes by altering actin cytoskeletal dynamics and T-tubule integrity.

Aims: Protein kinase C (PKC) isozymes contribute to the development of heart failure through dysregulation of Ca handling properties and disruption of contractile function in cardiomyocytes. However, the mechanisms by which PKC activation leads to Ca dysfunction are incompletely understood.

Methods And Results: Shortly upon ventricular pressure overload in mice, we detected transient PKC activation that was associated with pulsed actin cytoskeletal rearrangement.

Chemically Cross-Linked MOF Membrane Generated from Imidazolium-Based Ionic Liquid-Decorated UiO-66 Type NMOF and Its Application toward CO Separation and Conversion.

Carbon dioxide capture and transformation are of great importance to make cuts in greenhouse gas emissions. Nanometal-organic frameworks (NMOFs) could serve as ideal fillers for polymer membranes owing to their structural diversity and regulable microenvironment of the nanocage. Herein, a bifunctional, robust, and chemically cross-linked NMOF-based membrane was successfully constructed by the postsynthetic polymerization of imidazolium-based ionic liquid (IL)-decorated UiO-66 type nanoparticles (NPs) and the isocyanate-terminated polyurethane oligomer under mild conditions.

MG53 is dispensable for T-tubule maturation but critical for maintaining T-tubule integrity following cardiac stress.

The cardiac transverse (T)-tubule membrane system is the safeguard for cardiac function and undergoes dramatic remodeling in response to cardiac stress. However, the mechanism by which cardiomyocytes repair damaged T-tubule network remains unclear. In the present study, we tested the hypothesis that MG53, a muscle-specific membrane repair protein, antagonizes T-tubule damage to protect against maladaptive remodeling and thereby loss of excitation-contraction coupling and cardiac function.

Analysis of Cardiac Myocyte Maturation Using CASAAV, a Platform for Rapid Dissection of Cardiac Myocyte Gene Function In Vivo.

Rationale: Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly understood. Previous studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation.

Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts.

Beat-to-beat alternations in the amplitude of the cytosolic Ca transient (Ca alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca release channel responsible for cytosolic Ca transients, in cardiac alternans.

Regional distribution of T-tubule density in left and right atria in dogs.

Background: The peculiarities of transverse tubule (T-tubule) morphology and distribution in the atrium-and how they contribute to excitation-contraction coupling-are just beginning to be understood.

Objectives: The objectives of this study were to determine T-tubule density in the intact, live right and left atria in a large animal and to determine intraregional differences in T-tubule organization within each atrium.

Methods: Using confocal microscopy, T-tubules were imaged in both atria in intact, Langendorf-perfused normal dog hearts loaded with di-4-ANEPPS.

Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes.

Backgrounds: Low serum cholesterol levels are associated with cardiac arrhythmias and poor prognosis in patients with chronic heart failure. However, the underlying mechanisms by which decreases in cholesterol content lead to cardiac dysfunction remain unclear. Multiple studies have implicated damage to cardiac transverse (T)-tubules as a key mediator of excitation-contraction (E-C) coupling dysfunction and heart failure.

Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model.

Aim: Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits.

Methods: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB).

Confinement of Ionic Liquids in Nanocages: Tailoring the Molecular Sieving Properties of ZIF-8 for Membrane-Based CO2 Capture.

Fine-tuning of effective pore size of microporous materials is necessary to achieve precise molecular sieving properties. Herein, we demonstrate that room temperature ionic liquids can be used as cavity occupants for modification of the microenvironment of MOF nanocages. Targeting CO2 capture applications, we tailored the effective cage size of ZIF-8 to be between CO2 and N2 by confining an imidazolium-based ionic liquid [bmim][Tf2 N] into ZIF-8's SOD cages by in-situ ionothermal synthesis.

Molecular Determinants of Calpain-dependent Cleavage of Junctophilin-2 Protein in Cardiomyocytes.

Junctophilin-2 (JP2), a membrane-binding protein that provides a structural bridge between the plasmalemma and sarcoplasmic reticulum, is essential for precise Ca(2+)-induced Ca(2+) release during excitation-contraction coupling in cardiomyocytes. In animal and human failing hearts, expression of JP2 is decreased markedly, but the molecular mechanisms underlying JP2 down-regulation remain incompletely defined. In mouse hearts, ischemia/reperfusion injury resulted in acute JP2 down-regulation, which was attenuated by pretreatment with the calpain inhibitor MDL-28170 or by transgenic overexpression of calpastatin, an endogenous calpain inhibitor.