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Itaconate (ITA) research began as an industrial application as a precursor for polymer synthesis and has advanced significantly since the discovery of the Irg1 gene in 1995. A deep exploration of ITA as an immunomodulatory metabolite has provided a profound understanding of the functional significance and mechanistic basis of metabolic reprogramming in the context of inflammatory responses and cancer development. ITA rapidly accumulates to high levels in myeloid cells during both infectious and sterile inflammatory conditions. This metabolite acts as a signaling molecule to modulate immune response by binding, covalently and noncovalently, to multiple proteins and regulating the oxidative response, cell metabolism, epigenetic modification, and gene expression intrinsically, and activating G protein-coupled receptor (GPCR) signaling via paracrine signaling. Genetic and preclinical studies in animal models support the therapeutic potential for treating a wide range of inflammatory diseases and cancer. Developing novel therapies based on ITA and targeting aconitate decarboxylase (ACOD1) holds exciting potential for treating many diseases that currently lack effective therapy. Immune cells undergo rapid and extensive metabolic changes during inflammation. In addition to contributing to energetic and biosynthetic demands, metabolites can also function as signaling molecules. Itaconate (ITA) rapidly accumulates to high levels in myeloid cells under infectious and sterile inflammatory conditions. This metabolite binds to and regulates the function of diverse proteins intracellularly to influence metabolism, oxidative response, epigenetic modification, and gene expression and to signal extracellularly through binding the G protein-coupled receptor (GPCR). Administration of ITA protects against inflammatory diseases and blockade of ITA production enhances antitumor immunity in preclinical models. In this article, we review ITA metabolism and its regulation, discuss its target proteins and mechanisms, and conjecture a rationale for developing ITA-based therapeutics to treat inflammatory diseases and cancer. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the SCN5A -encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies as well as bilateral stellate ganglionectomy. The patient's novel variant, p.F1760C-SCN5A, involves a critical residue of the Nav1.5's local anesthetic binding domain. The purpose of this study was to characterize functionally the p.F1760C-SCN5A variant using TSA-201 and patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Whole-cell patch clamp was used to assess p.F1760C-SCN5A associated sodium currents with/without lidocaine (Lido), flecainide, and phenytoin (PHT) in TSA-201 cells. p.F1760C-SCN5A and CRISPR-Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated. FluoVolt voltage dye was used to measure the action potential duration (APD) with/without mexiletine or PHT. V 1/2 of inactivation was right-shifted significantly in F1760C cells (–72.2 ± 0.7 mV) compared to wild-type (WT) cells (–86.3 ± 0.9 mV; P <.0001) resulting in a marked increase in window current. F1760C increased sodium late current 2-fold from 0.18% ± 0.04% of peak in WT to 0.49% ± 0.07% of peak in F1760C (P =.0005). Baseline APD to 90% repolarization (APD 90) was increased markedly in F1760C iPSC-CMs (601 ± 4 ms) compared to IC iPSC-CMs (423 ± 15 ms; P <.0001). However, 4-hour treatment with 10 μM mexiletine failed to shorten APD 90 , and treatment with 5μM PHT significantly decreased APD 90 of F1760C iPSC-CMs (453 ± 6 ms; P <.0001). PHT rescued electrophysiological phenotype and APD of a novel p.F1760C-SCN5A variant. The antiepileptic drug PHT may be an effective alternative therapeutic for the treatment of LQT3, especially for variants that disrupt the Lido/mexiletine binding site. [ABSTRACT FROM AUTHOR]

Curcumin, a polyphenolic dietary natural compound and active ingredient in turmeric, exerts antioxidant, anti-inflammatory, antidiabetic, anticancer, and antiarrhythmic properties. KCNE1-D85N, present in ∼1% of white, is a common, potentially proarrhythmic variant that predisposes individuals to drug-induced QT prolongation under certain conditions. The purpose of this article was to test the hypothesis that curcumin might cause action potential duration (APD) prolongation in KCNE1-D85N–derived human-induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Gene-edited/variant-corrected isogenic control and patient-specific KCNE1-D85N–containing iPSC-CMs were generated previously. Voltage-sensing dye, multielectrode array (MEA), and whole-cell patch clamp technique were used to measure APD without and with 4-hour incubation with 10 nM curcumin. KCNE1-D85N–derived iPSC-CMs demonstrated significant APD prolongation with treatment of 10 nM curcumin. Using voltage-sensing dye, action potential duration at 90% repolarization (APD90) was 578 ± 7 ms (n = 39) at baseline and was prolonged to 658 ± 13 ms (n = 35) with curcumin incubation (P <.0001). Using MEA, APD90 at baseline was 237 ± 6 ms (n = 24) compared with 280 ± 6 ms (n = 12) with curcumin incubation (P =.0002). The whole-cell patch clamp technique confirmed these results, with APD90 being 544 ± 37 ms at baseline and 664 ± 40 ms with treatment of curcumin (P <.005). However, APD from isogenic control iPSC-CMs remained unchanged with curcumin treatment. This study provides pharmacological and functional evidence to suggest that curcumin, a dietary natural supplement, might cause APD prolongation in patients with common, potentially proarrhythmic functional variants such as KCNE1-D85N. Whether this supplement is potentially dangerous for the Caucasian subpopulation that has this variant warrants further investigation. [ABSTRACT FROM AUTHOR]

To clarify the epidemiological characteristics and spatial distribution patterns of human norovirus outbreaks in China, identify high-risk areas, and provide guidance for epidemic prevention and control. This study analyzed 964 human norovirus outbreaks involving 50,548 cases in 26 provinces reported from 2012 to 2018. Epidemiological analysis and spatiotemporal scanning analysis were conducted to analyze the distribution of norovirus outbreaks in China. The outbreaks showed typical seasonality, with more outbreaks in winter and fewer in summer, and the total number of infected cases increased over time. Schools, especially middle schools and primary schools, are the most common settings of norovirus outbreaks, with the major transmission route being life contact. More outbreaks occurred in southeast coastal areas in China and showed significant spatial aggregation. The highly clustered areas of norovirus outbreaks have expanded northeast over time. By identifying the epidemiological characteristics and high-risk areas of norovirus outbreaks, this study provides important scientific support for the development of preventive and control measures for norovirus outbreaks, which is conducive to the administrative management of high-risk settings and reduction of disease burden in susceptible areas. [ABSTRACT FROM AUTHOR]

The catalytic activity of most epigenetic enzymes requires a metabolite produced by central carbon metabolism as a cofactor or (co-)substrate. The concentrations of these metabolites undergo dynamic changes in response to nutrient levels and environmental conditions, reprogramming metabolic processes and epigenetic landscapes. Abnormal accumulations of epigenetic modulatory metabolites resulting from mutations in metabolic enzymes contribute to tumorigenesis. In this review, we first present the concept that metabolite regulation of gene expression represents an evolutionarily conserved mechanism from prokaryotes to eukaryotes. We then review how individual metabolites affect epigenetic enzymes and cancer development. Lastly, we discuss the advancement of and opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy. [Display omitted] Epigenetic and metabolic alterations occur frequently in cancer cells. Wang et al. present the concept that metabolite regulation of gene expression represents an evolutionary conserved mechanism, review how individual metabolites affect epigenetic enzymes and cancer development, and discuss the opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy. [ABSTRACT FROM AUTHOR]

The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy. [Display omitted] • Macrophage L2HGDH deficiency restricts tumor progression • S-2HG accumulation caused by L2HGDH blockage guides macrophage antitumoral polarization • S-2HG promotes macrophage antitumoral polarization dependent on α-KG inhibition • S-2HG increases macrophage antigen presentation and enhances antitumor T cell immunity How immunometabolism shapes the macrophage immune response remains to be explored. Feng et al. demonstrate that blockage of L2HGDH-mediated S-2HG catabolism in macrophages drives antitumoral polarization via competitive inhibition of α-KG, thereby enhancing CD8+ T cell-mediated antitumor immunity to overcome resistance to anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

Background: Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%.Objective: The purpose of this study was to determine whether a phenotype-enhanced (PE) variant classification approach could reduce the VUS burden in LQTS genetic testing.Methods: Retrospective analysis was performed on 79 KCNQ1 missense variants in 356 patients from Mayo Clinic and an independent cohort of 42 variants in 225 patients from Amsterdam University Medical Center (UMC). Each variant was classified initially using the ACMG guidelines and then readjudicated using a PE-ACMG framework that incorporated the LQTS clinical diagnostic Schwartz score plus 4 "LQT1-defining features": broad-based/slow upstroke T waves, syncope/seizure during exertion, swimming-associated events, and a maladaptive LQT1 treadmill stress test.Results: According to the ACMG guidelines, Mayo Clinic variants were classified as follows: 17 of 79 P variants (22%), 34 of 79 LP variants (43%), and 28 of 79 VUS (35%). Similarly, for Amsterdam UMC, the variant distribution was 9 of 42 P variants (22%), 14 of 42 LP variants (33%), and 19 of 42 variants VUS (45%). After PE-ACMG readjudication, the total VUS burden decreased significantly from 28 (35%) to 13 (16%) (P = .0007) for Mayo Clinic and from 19 (45%) to 12 (29%) (P = .02) for Amsterdam UMC.Conclusion: Phenotype-guided variant adjudication decreased significantly the VUS burden of LQT1 case-derived KCNQ1 missense variants in 2 independent cohorts. This study demonstrates the value of incorporating LQT1-specific phenotype/clinical data to aid in the interpretation of KCNQ1 missense variants identified during genetic testing for LQTS. [ABSTRACT FROM AUTHOR]

Purpose: The magnetic compression technique (MCT) is a new surgical method that has been used for gastrointestinal anastomosis, choledochojejunostomy, and intestinal anastomosis, but there are no reports on its use for esophagogastric anastomosis. This study aimed to investigate the feasibility of using MCT to fashion esophagogastric anastomoses in rabbits. Methods: Twenty rabbits were randomized into an MCT group (study group, n = 10) and a hand-sewn group (control group, n = 10). The magnetic compression anastomosis device used in this study was made of neodymium iron boron (NdFeB) and possessed parent (PMR) and daughter (DMR) magnetic rings. To fashion the anastomosis, the PMR and DMR were inserted into the lower esophagus and gastric fundus, respectively. The coupled magnets automatically compressed the sandwiched tissues and were expelled once the anastomosis was installed. The two groups were further compared in terms of the anastomosis construction time, survival rate, and postoperative complications. One month after the anastomosis was installed, the burst pressure and gross appearance of the anastomoses were evaluated. Results: The anastomosis construction time in the study group was significantly shorter than that in the control group (10.50 ± 1.58 min vs. 18.60 ± 2.22 min; P < 0.05), and the magnetic rings were defecated out in 10.70 ± 3.49 days. The incidence of anastomotic blockage in both the study and control groups did not differ significantly (0%, 0/10 vs. 20%, 2/10; P > 0.05). Anastomotic leakage was not found in either of the groups, and the anastomoses burst pressures were similar in the two groups. However, the magnetically compressed anastomoses in the study group had a relatively smoother gross appearance than the hand-sewn anastomoses. Conclusion: The magnetic compression anastomosis device is a safe and feasible tool for fashioning esophagogastric anastomoses in this animal model. [ABSTRACT FROM AUTHOR]

As a new form of tourist accommodation, Airbnb has gained widespread popularity worldwide in Hong Kong. Considering the spatial heterogeneity and multiscale effects, this study employs the Multiscale Geographically Weighted Regression (MGWR) approach to reveal the impact of the built environment on Airbnb distribution in Hong Kong. The main findings are as follows: i) The density of hotels, cultural facilities, and tourist attractions, as well as the supply of residential land and open space (or recreational land), have a significant impact on the spatial distribution of Airbnb and vary according to geographic location; ii) At the local level, open spaces (or recreational land) present positively correlated with Airbnb density in mature tourism areas, yet this correlation reverses in certain localized communities; iii) Factors, such as location, traffic accessibility and caterings, may become less critical for Airbnb's location in highly developed cities like Hong Kong; iv) The density of cultural facilities has a global impact on Airbnb distribution, followed by hotel density, and the effect scale of residential land supply and open spaces (or recreational land) tend to be local. This empirical study can support precise and differentiated planning interventions and policy-making to promote a healthier development of the Airbnb market. • Exploring built environment factors that might have an impact on Airbnb distribution in Hong Kong. • Comparing to OLS, SLM and GWR, the MGWR model has the best analytical performance. • Justifying the factors affecting Airbnb distribution are spatially heterogeneous and act on different scales. • Planning intervention of Airbnb should be focused on the corresponding spatial scales and spatial differences. [ABSTRACT FROM AUTHOR]

Caveolin-3 (Cav-3) is an essential scaffolding protein for caveolae formation in cardiomyocytes and targets multiple long QT syndrome (LQTS)-associated ion channels. Mutations in CAV3 have caused an LQT3-like accentuation in late sodium current, I Na (Nav1.5). Here, we characterize a novel CAV3-V37L variant and determine whether it is the substrate for the patient's LQTS. The proband was a 39-year-old female with drug-induced, sudden cardiac arrest (SCA) with profound QT prolongation (QTc > 600 ms). Genetic testing revealed a rare CAV3-V37L variant of uncertain significance (VUS). Whole-cell patch clamp technique was used to measure I Ks , I Kr , I Na , and I Ca, L currents co-expressed with either CAV3-WT or CAV3-V37L in TSA201 cells and to measure the action potential duration (APD) in control human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) overexpressed with CAV3-WT or CAV3-V37L. CAV3-V37L did not affect Nav1.5 late current. Instead, CAV3-V37L resulted in 1) I Ca, L with slower inactivation, a 1.5 fold increase in peak I Ca, L current density and a 1.1 fold increase in I Ca, L persistent current, 2) dramatically reduced I Ks peak current density by 74.9%, 3) significantly reduced I Kr peak current density by 31.1%, and 4) significantly prolonged the APD in hiPSC-CMs. These functional validation assays enabled the promotion of CAV3-V37L from VUS status to a likely pathogenic variant. Although Nav1.5 was spared, this monogenetic insult precipitated an oligo-proteomic impact with a concomitant gain-of-function of I Ca, L and loss-of-function of both I Ks and I Kr culminating in a marked prolongation of the cardiomyocyte's action potential duration. • Cav3-V37L did not increase Nav1.5 (SCN5A) late current. • CAV3-V37L increased I Ca, L inactivation tau, peak, and persistent current. • CAV3-V37L dramatically reduced the I Ks current and reduced I Kr peak current. • CAV3-V37L reduced intensity of CAV3 on the membrane and co-localization with Cav1.2 channel. • CAV3-V37L prolonged APD50 and APD90 when overexpressed in control hiPSC-CMs. [ABSTRACT FROM AUTHOR]