Golgi pH elevation due to loss of V-ATPase subunit V0a2 function correlates with tissue-specific glycosylation changes and globozoospermia.

Loss-of-function variants in ATP6V0A2, encoding the trans Golgi V-ATPase subunit V0a2, cause wrinkly skin syndrome (WSS), a connective tissue disorder with glycosylation defects and aberrant cortical neuron migration. We used knock-out (Atp6v0a2) and knock-in (Atp6v0a2) mice harboring the R755Q missense mutation selectively abolishing V0a2-mediated proton transport to investigate the WSS pathomechanism. Homozygous mutants from both strains displayed a reduction of growth, dermis thickness, and elastic fiber formation compatible with WSS.

Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly.

Mammalian cells can acquire exogenous amino acids through endocytosis and lysosomal catabolism of extracellular proteins. In amino acid-replete environments, nutritional utilization of extracellular proteins is suppressed by the amino acid sensor mechanistic target of rapamycin complex 1 (mTORC1) through an unknown process. Here, we show that mTORC1 blocks lysosomal degradation of extracellular proteins by suppressing V-ATPase-mediated acidification of lysosomes.

Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified.

[Monoclonal gammopathies and kidney: a diagnostic challenge without any clues].

Diagnosis of monoclonal gammopathy of renal significance (MGRS) with histopathologic features of proliferative GN with monoclonal immunoglobulin deposits (PGNMID) is a challenge for clinicians because of the absence of laboratory findings suggestive of glomerular involvement in paraproteinemia. Renal biopsy remains the gold standard for diagnosis of PGNMID because it is a monoclonal gammopathy with kidney damage often "without a detectable serum/urine clone". Through this case report, we want to focus on the complexity both in the diagnostic process and in monitoring the renal-hematological response to therapy.

Two-Day ABPM-Derived Indices and Mortality in Hemodialysis Patients.

Background: Blood pressure (BP) and arterial stiffness are known cardiovascular risk factors in hemodialysis (HD) patients. This study examines the prognostic significance of 44-hour BP circadian rhythm and ambulatory arterial stiffness index (AASI) in this population.

Methods: A total of 80 HD patients underwent 44-hour ambulatory BP monitoring (ABPM) with a TM-2430 monitor during a standard midweek interdialytic interval and followed up for 4.