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The respiratory epithelium is lined by a tightly balanced fluid layer that allows normal O and CO exchange and maintains surface tension and host defense. To maintain alveolar fluid homeostasis, both the integrity of the alveolar-capillary barrier and the expression of epithelial ion channels and pumps are necessary to establish a vectorial ion gradient. However, during pulmonary infection, auto- and/or paracrine-acting mediators induce pathophysiological changes of the alveolar-capillary barrier, altered expression of epithelial Na,K-ATPase and of epithelial ion channels including epithelial sodium channel and cystic fibrosis membrane conductance regulator, leading to the accumulation of edema and impaired alveolar fluid clearance. These mediators include classical pro-inflammatory cytokines such as TGF-β, TNF-α, interferons, or IL-1β that are released upon bacterial challenge with , or as well as in viral infection with influenza A virus, pathogenic coronaviruses, or respiratory syncytial virus. Moreover, the pro-apoptotic mediator TNF-related apoptosis-inducing ligand, extracellular nucleotides, or reactive oxygen species impair epithelial ion channel expression and function. Interestingly, during bacterial infection, alterations of ion transport function may serve as an additional feedback loop on the respiratory inflammatory profile, further aggravating disease progression. These changes lead to edema formation and impair edema clearance which results in suboptimal gas exchange causing hypoxemia and hypercapnia. Recent preclinical studies suggest that modulation of the alveolar-capillary fluid homeostasis could represent novel therapeutic approaches to improve outcomes in infection-induced lung injury.

We have recently shown that a linear current-to-voltage (I-V) relationship of membrane conductance (passive conductance) reflects the intrinsic property of K(+) channels in mature astrocytes. While passive conductance is known to underpin a highly negative and stable membrane potential (V M) essential for the basic homeostatic function of astrocytes, a complete repertoire of the involved K(+) channels remains elusive. TREK-1 two-pore domain K(+) channel (K2P) is highly expressed in astrocytes, and covalent association of TREK-1 with TWIK-1, another highly expressed astrocytic K2P, has been reported as a mechanism underlying the trafficking of heterodimer TWIK-1/TREK-1 channel to the membrane and contributing to astrocyte passive conductance. To decipher the individual contribution of TREK-1 and address whether the appearance of passive conductance is conditional to the co-expression of TWIK-1/TREK-1 in astrocytes, TREK-1 single and TWIK-1/TREK-1 double gene knockout mice were used in the present study. The relative quantity of mRNA encoding other astrocyte K(+) channels, such as Kir4.1, Kir5.1, and TREK-2, was not altered in these gene knockout mice. Whole-cell recording from hippocampal astrocytes in situ revealed no detectable changes in astrocyte passive conductance, V M, or membrane input resistance (R in) in either kind of gene knockout mouse. Additionally, TREK-1 proteins were mainly located in the intracellular compartments of the hippocampus. Altogether, genetic deletion of TREK-1 alone or together with TWIK-1 produced no obvious alteration in the basic electrophysiological properties of hippocampal astrocytes. Thus, future research focusing on other K(+) channels may shed light on this long-standing and important question in astrocyte physiology.

Cystic fibrosis (CF) is an autosomal recessive disease. The genetic transition occurs with CF transmembrane conductance regulator ( ) gene mutation. We aimed to determine the frequency of CF mutations and also new mutations in the gene in neonates with respiratory distress. Newborn babies hospitalized due to respiratory distress were included in the patient group. The control group consisted of infants who had no respiratory distress. The genes of both groups were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. A total of 40 patients (20 in the patient group and 20 in the control group) were evaluated. The gene analysis was normal in 16 neonates in the patient group, whereas in others: A46D (c.137C>A) ( = 1), D1312G (c.3935A>G) ( = 1), R117H (c.350G>A) ( = 1), S1426P (c.4276T>C) ( = 1) heterozygotes were detected; gene analysis was normal at 14 neonates in the control group, whereas in others: E1228G (c.3683A>G) ( = 1), E217G (c.650A>G) ( = 1), E632TfsX9 (c1894_1895delAG) ( = 1), I807M (c.2421 A>G) ( = 2), S573F (c.1718C>T) ( = 1) heterozygotes were detected. There was no significant difference in the patient and control groups’ gene analysis ( = 0.340). This study demonstrates the importance of gene analysis in asymptomatic newborn infants for follow-up and early diagnosis of -related disorders. In this study, a c.1894_1895delAG (E632TfsX9) heterozygous mutation detected in the gene in an asymptomatic newborn infant, was first encountered in the literature.

Photosynthesis is an important process in plants which influences their development and productivity. Many factors can control the efficiency of photosynthesis, including CO2 conductance of leaf mesophyll, which affects the CO2 availability for Rubisco. It is known that electrical stress signals can decrease this conductance, and the response is probably caused by inactivation of H+-ATPase in the plasma membrane. In the current work, we analyzed the influence of both CO2 conductance in the plasma membrane, and chloroplast envelopes and H+-ATPase activity on photosynthetic CO2 assimilation, using a two-dimensional mathematical model of photosynthesis in leaves. The model included a description of assimilation on the basis of the Farquhar–von Caemmerer–Berry model, ion transport through the plasma membrane, diffusion of CO2 in the apoplast, and transport of CO2 through the plasma membrane and chloroplast envelope. The model showed that the photosynthetic CO2 assimilation rate was mainly dependent on the plasma membrane and chloroplast envelope conductance; direct influence of the H+-ATPase activity (through changes in pH and CO2/HCO3− concentration ratio) on this rate was weak. In contrast, both changes in CO2 conductance of the plasma membrane and chloroplast envelopes and changes in the H+-ATPase activity influenced spatial heterogeneity of the CO2 assimilation on the leaf surface in the simulated two-dimensional system. These effects were also observed under simultaneous changes in the CO2 conductance of the plasma membrane and H+-ATPase activity. Qualitatively similar influence of changes in the CO2 conductance of the plasma membrane and chloroplast envelopes, and changes in the H+-ATPase activity on photosynthesis were shown for two different densities of stomata in the simulated leaf; however, lowering the density of stomata decreased the assimilation rate and increased the heterogeneity of assimilation. The results of the model analysis clarify the potential influence of H+-ATPase inactivation on photosynthesis, and can be the basis for development of new methods for remote sensing of the influence of electrical signals.

Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM. High-throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain (MSD) interfaces. Although individually these compounds marginally improve ΔF508-CFTR folding efficiency, function and stability, their combinations lead to ~50–100% of wild-type-level correction in immortalized and primary human airway epithelia and in mouse nasal epithelia. Likewise, corrector combinations were effective against rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application. Targeting different aspects of mutant CFTR structural defects with combination therapy leads to more potent rescue of function than that following single therapy.

Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational structure of the aggregate, as well as the oxidation state of the lipid membrane. We generated human stem cell-derived models of synucleinopathy, characterized by the intracellular formation of α-synuclein aggregates that bind to membranes. In human iPSC-derived neurons with SNCA triplication, physiological concentrations of glutamate and dopamine induce abnormal calcium signaling owing to the incorporation of excess α-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. α-synuclein oligomers further induce lipid peroxidation. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling. Inhibition of lipid peroxidation, and reduction of iron-dependent accumulation of free radicals, further prevents oligomer-induced toxicity in human neurons. In summary, we report that peroxidation of polyunsaturated fatty acids underlies the incorporation of β-sheet-rich aggregates into the membranes, and that additionally induces neuronal death. This suggests a role for ferroptosis in Parkinson’s disease, and highlights a new mechanism by which lipid peroxidation causes cell death.

COVID-19 is a disease with unique characteristics that include lung thrombosis 1 , frequent diarrhoea 2 , abnormal activation of the inflammatory response 3 and rapid deterioration of lung function consistent with alveolar oedema 4 . The pathological substrate for these findings remains unknown. Here we show that the lungs of patients with COVID-19 contain infected pneumocytes with abnormal morphology and frequent multinucleation. The generation of these syncytia results from activation of the SARS-CoV-2 spike protein at the cell plasma membrane level. On the basis of these observations, we performed two high-content microscopy-based screenings with more than 3,000 approved drugs to search for inhibitors of spike-driven syncytia. We converged on the identification of 83 drugs that inhibited spike-mediated cell fusion, several of which belonged to defined pharmacological classes. We focused our attention on effective drugs that also protected against virus replication and associated cytopathicity. One of the most effective molecules was the antihelminthic drug niclosamide, which markedly blunted calcium oscillations and membrane conductance in spike-expressing cells by suppressing the activity of TMEM16F (also known as anoctamin 6), a calcium-activated ion channel and scramblase that is responsible for exposure of phosphatidylserine on the cell surface. These findings suggest a potential mechanism for COVID-19 disease pathogenesis and support the repurposing of niclosamide for therapy. Lungs from patients who died from COVID-19 show atypical fused cells, the formation of which is mediated by the SARS-CoV-2 spike protein, and drugs that inhibit TMEM16F can prevent spike-induced syncytia formation.

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, ultimately leading to diminished transepithelial anion secretion and mucociliary clearance. CFTR correctors are therapeutics that restore the folding/trafficking of mutated CFTR to the plasma membrane. The large-conductance calcium-activated potassium channel (BKCa, l

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