In addition to forming gap-junction channels, a subset of connexins (Cxs) also form functional hemichannels. Most hemichannels are activated by depolarization, and opening depends critically on the external Ca 2؉ concentration. Here we describe the mechanisms of action and the structural determinants underlying the Ca 2؉ regulation of Cx32 hemichannels. At millimolar calcium concentrations, hemichannel voltage gating to the full open state of Ϸ90 pS is inhibited, and ion conduction at negative voltages of the partially open hemichannels (Ϸ18 pS) is blocked. Thus, divalent cation blockage should be considered as a physiological mechanism to protect the cell from the potentially adverse effects of leaky hemichannels. A ring of 12 Asp residues within the external vestibule of the pore is responsible for the binding of Ca 2؉ that accounts for both pore occlusion and blockage of gating. The residue Asp-169 of one subunit and the Asp-178 of an adjacent subunit must be arranged precisely to allow interactions with Ca 2؉ to occur. Interestingly, a naturally occurring mutation (D178Y) that causes an inherited peripheral neuropathy induces a complete Ca 2؉ deregulation of Cx32 hemichannel activity, suggesting that this dysfunction may be involved in the pathogenesis of the neuropathy.

NCT02159599.

X-linked Charcot-Marie-Tooth disease is one of a set of diseases caused by mutations in gap junction proteins called connexins. We identified a connexin32 missense mutation (F235C) in a girl with unusually severe neuropathy. The localization and trafficking of the mutant protein in cell culture was normal, but electrophysiological studies showed that the mutation caused abnormal hemichannel opening, with excessive permeability of the plasma membrane and decreased cell survival. Abnormal leakiness of connexin hemichannels is likely a mechanism of cellular toxicity in this and perhaps other diseases caused by connexin mutations.

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Background This study was designed to evaluate if patients with high risk for severe COVID-19 would benefit from treatment with TDF/FTC followed by baricitinib in case of hypoxemia and systemic inflammation. Methods PANCOVID is an open-label, double-randomized, phase 3 pragmatic clinical trial including adults with symptomatic COVID-19 with ≥ 2 comorbidities or older than 60 years conducted between 10 October 2020 and 23 September 2021. In the first randomization patients received TDF/FTC or not TDF/FTC. In the second randomization patients with room-air O2 saturation <95% and at least one increased inflammatory biomarker received baricitinib plus dexamethasone or dexamethasone alone. The primary endpoint was 28-day mortality. Main secondary endpoint was 28-day disease progression or critical care unit admission or mortality. The trial was stopped before reaching planned sample size due to the decrease in the number of cases and a mortality rate substantially lower than expected EudraCT registration number: 2020-001156-18. Results Of the 355 included participants 97% were hospitalized at baseline. Overall, 28-day mortality was 3.1%. The 28-day mortality relative risk (RR) for participants treated with TDF/FTC was 1.76 (95% CI 0.52-5.91; p= 0.379); it was 0.42 (95% CI 0.11-1.59; p= 0.201) for those treated with baricitinib. The 28-day RR for the main secondary combined endpoint for participants treated with TDF/FTC was 0.95 (95% CI 0.66-1.40; p = 0.774); it was 0.90 (95%CI 0.61-1.33; p = 0.687) for those treated with baricitinib. Conclusions Our results do not suggest a beneficial effect of TDF/FTC; nevertheless, they are compatible with the beneficial effect of baricitinib already established by other clinical trials.

Background & Aims Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and cirrhosis induce metabolic disorders. Here, we aimed to evaluate the association of plasma metabolites with Child‐Turcotte‐Pugh (CTP) score and hepatic decompensation in HIV/HCV‐coinfected and HCV‐monoinfected patients with advanced cirrhosis. Methods A cross‐sectional study was carried out in 62 HIV/HCV‐coinfected and 28 HCV‐monoinfected patients. Metabolomics analysis was performed by gas chromatography‐mass spectrometry (GC‐MS) and liquid chromatography‐mass spectrometry (LC‐MS). The statistical association analysis was performed by partial least squares discriminant analysis (PLS‐DA) and generalized linear model (GLM) with binomial distribution (to analyse HIV coinfection, high alcohol intake, treatment with statins, previous HCV therapy failure and decompensation) and ordinal logistic regression (OLR) models to analyse different stages of cirrhosis (CTP score). Results The statistical analysis identified plasma metabolites associated with HIV coinfection, high alcohol intake, CTP score and hepatic decompensation. Overall, fatty acids, bile acids, aromatic and sulphur amino acids, butyrate derivatives, oxidized phospholipids, energy‐related metabolites and bacterial fermentation‐related metabolites were increased in more advanced cirrhosis stages; while lysophosphatidylcholines and lysophosphatidylethanolamines, branched‐chain amino acids (BCAA) and metabolites of tricarboxylic acid cycle, among others, were decreased in more advanced cirrhosis. Most of the significant metabolites displayed a similar trend after stratifying for HIV/HCV‐ and HCV‐infected patients. Glycolic acid, LPC (16:0) and taurocholic acid had high accuracy for discriminating patients according to decompensated cirrhosis (CTP ≥ 7). Conclusion Altered plasma metabolomic profile was associated with advanced stages of cirrhosis in HIV/HCV‐coinfected and HCV‐monoinfected patients.

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