The vacuolar H(+)-ATPase (V-ATPase) is one of the most fundamental enzymes in nature. It functions in almost every eukaryotic cell and energizes a wide variety of organelles and membranes. In contrast to F-ATPases, whose primary function in eukaryotic cells is to form ATP at the expense of the proton-motive force, V-ATPases function exclusively as ATP-dependent proton pumps. The proton-motive force generated by V-ATPases in organelles and across plasma membranes of eukaryotic cells is utilized as a driving force for numerous secondary transport processes. The enzyme is also vital for the proper functioning of endosomes and the Golgi apparatus. In contrast to yeast vacuoles, which maintain an internal pH of approximately 5. 5, it is believed that the vacuoles of lemon fruit may have a pH as low as 2. Similarly, some brown and red algae maintain an internal pH as low as 1 in their vacuoles. It was yeast genetics that allowed the identification of the special properties of individual subunits and the discovery of the factors that are involved in V-ATPase biogenesis and assembly. Null mutations in genes encoding V-ATPase subunits of Saccharomyces cerevisiae result in a phenotype that is unable to grow at high pH and is sensitive to high and low metal-ion concentrations. Treatment of these null mutants with ethyl methanesulphonate causes mutations that suppress the V-ATPase null phenotype, and these cells are able to grow at pH 7.5. The suppressor mutants were denoted as svf (Suppressor of V-ATPase Function). The svf mutations are recessive: crossing the svf mutants with their corresponding V-ATPase null mutants resulted in diploid strains that were not able to grow at pH 7.5. A novel gene family in which null mutations cause pleiotropic effects on metal-ion resistance or on the sensitivity and distribution of membrane proteins in different targets was discovered. We termed this gene family VTC (Vacuolar Transporter Chaperon) and discovered four genes in S. cerevisiae that belong to the family. Inactivation of one of them, VTC1, in the background of V-ATPase null mutations resulted in an svf phenotype that was able to grow at pH 7.5. Apparently, Vtc1p is one of a few membrane organizers that determine the relative amounts of different membrane proteins in the various cellular membranes. We utilize the numerous yeast mutants generated in our laboratory to identify the specific organelle whose acidification is vital. The interaction between V-ATPase and the secretory pathway is investigated.

<b><i>Introduction:</i></b> Coronavirus disease is associated with increased morbidity and mortality in maintenance hemodialysis (MHD) patients. Recent breakthrough infection in vaccinated people has led some authorities to recommend a booster dose for patients fully vaccinated 5–8 months ago. We aimed to assess the humoral response of MHD patients following a booster dose with the BNT162b2 vaccine. <b><i>Methods:</i></b> The study included 102 MHD patients vaccinated with 2 doses of the BNT162b2 (Pfizer-BioNTech) vaccine. A third dose (booster) was recommended to all MHD patients in our center and was given to those who opted to receive it, resulting in a booster group and a control group that did not receive the booster. Previous exposure was excluded by testing for the presence of the anti-nucleocapsid antibody (SARS-CoV-2) or positive PCR. We assessed the humoral response before and after the booster dose. <b><i>Results:</i></b> Of 66 patients in the booster group, 65 patients (98.5%) developed a positive antibody response, from 472.7 ± 749.5 to 16,336.8 ± 15,397.3, as compared to a sustained decrease in the control group (695.7 ± 642.7 to 383.6 ± 298.6), <i>p</i> &#x3c; 0.0001. No significant adverse effects were reported. Prior antibody titers were positively correlated to IgG levels following the booster dose. There was a significant association between malnutrition-inflammation markers and the humoral response. <b><i>Conclusions:</i></b> Almost all MHD patients developed a substantial humoral response following the booster dose, which was significantly higher than levels reported for MHD patients following administration of 2 doses alone. Further studies and observations are needed to determine the exact timing and dosing schedule.

Background: Patients with end-stage renal disease (ESRD) undergoing chronic hemodialysis are at high mortality and cardiovascular risk. This study was aimed to assess whether the CHA 2 DS 2-VASc score may be used for risk stratification of this population. Methods: Included were patients undergoing chronic hemodialysis at Meir Medical Center. The CHA 2 DS 2-VASc score was calculated for each patient at the initiation of hemodialysis. Patients were classified into 3 groups according to the CHA 2 DS 2-VASc score: 0-3 (low), 4-5 (intermediate), and ≥6 (high). The primary endpoint was the composite of all-cause mortality, myocardial infarction, and stroke during the first year of hemodialysis. Results: Of the 457 patients with ESRD, 181 (40%) had low, 193 (42%) intermediate, and 83 (18%) high CHA 2 DS 2-VASc scores. During the first year of hemodialysis, 109 (23.8%) patients died, 17 (3.7%) had a stroke, and 28 (6.1%) had a myocardial infarction. Compared to patients in the low CHA 2 DS 2-VASc score group, those in the intermediate and high score groups had higher risk for the composite endpoint (OR: 2.6, 95% CI: 1.6-4.2, p < 0.01 and OR: 4.2, 95% CI: 2.3-7.5, p < 0.01, respectively). Each 1-point increase in CHA 2 DS 2-VASc score was associated with a 38% increased risk for the composite endpoint, a 19% increased risk for 1-year myocardial infarction, and a 29% increased risk for 1-year stroke. Conclusions: Patients with ESRD are at an extremely high mortality and cardiovascular risk within the first year of hemodialysis. The CHA 2 DS 2-VASc score was strongly associated with adverse outcomes and may be used for risk stratification of these patients.

The optimal SARS-CoV-2 vaccination schedule in dialysis patients and the potential need for a fourth vaccine dose are debatable. We prospectively assessed the humoral responses to three and four doses of BNT162b2 among dialysis patients. The study included 106 dialysis patients; 60 (56.6%) and 46 (43.4%) received 3 and 4 vaccine doses, respectively. Anti-spike (anti-S) antibody titers significantly increased after the third vaccine dose, followed by a decline, yet still remained higher than all previous measurements. The fourth vaccine dose led to another profound rise in anti-S titers. The absolute increase following the fourth dose correlated with response to the third dose. Infection risk however was similar between patients vaccinated with three or four doses.