ATP8A2 is a P4-ATPase that actively flips phosphatidylserine and to a lesser extent phosphatidylethanolamine across cell membranes to generate and maintain transmembrane phospholipid asymmetry. The importance of this flippase is evident in the finding that loss-of-function mutations in ATP8A2 are known to cause the neurodevelopmental disease known as cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (CAMRQ4) in humans and related neurodegenerative disorders in mice. Although significant progress has been made in understanding mechanisms underlying phospholipid binding and transport across the membrane domain, little is known about the structural and functional properties of the cytosolic N- and C-terminal segments of this flippase. In addition, there has been uncertainty regarding the methionine start site of ATP8A2 and accordingly the size of the N-terminal segment. Here, we have used mass spectrometry to show that bovine ATP8A2 like its human counterpart has an extended N-terminal segment not apparent in the mouse ortholog. This segment greatly enhances the expression of ATP8A2 without affecting its cellular localization or phosphatidylserine-activated ATPase activity. Using a cleavable C-terminal protein and site-directed mutagenesis, we further show that the conserved GYAFS motif in the C-terminal segment plays a role in autoinhibition as well as efficient folding of ATP8A2 into a functional protein.

Dialysis dysequilibrium syndrome (DDS) refers to neurological symptoms usually seen during or after new initiation or following reinitiation of haemodialysis (HD) after missing multiple sessions. DDS is associated with death and morbidity. We studied interventions aimed at preventing DDS. To evaluate the benefits and harms of different types of interventions for preventing DDS. We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 8 May 2024 using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. We included randomised controlled trials (RCTs) that compared any intervention against standard care, including individuals initiated on HD, regardless of age. Two authors independently determined study eligibility, assessed quality and extracted data. Data were collected on methods, interventions, participants, and outcomes (DDS incidence, severe DDS, death, adverse events). Risk ratios (RR) and confidence intervals (CI) were calculated. Study quality was assessed using the Cochrane Risk of Bias 2 (ROB2) tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We included two RCTs, enrolling 32 adult participants. Interventions included were slow dialysis, sodium modelling, standard sodium dialysate, and high sodium dialysate. The risk of bias was of some concern to high risk of bias in both studies. Slow dialysis compared to sodium modelling (1 study, 15 participants) may result in little to no difference in DDS, severe DDS, and death (low certainty evidence) and has uncertain effects on adverse events (RR 1.33, 95% CI 0.15 to 11.64; very low certainty evidence). Standard sodium dialysate compared to high sodium dialysate (1 study, 17 participants) has uncertain effects on the incidence of DDS (RR 0.07, 95% CI 0.00 to 1.12), severe DDS (RR 0.47, 95% CI 0.02 to 10.32), and adverse events (RR 0.29, 95% CI 0.08 to 1.02) (very low certainty evidence). In HD patients, sodium modelling, compared to slow dialysis, may result in little to no difference in DDS and death (low certainty evidence) and has uncertain effects on adverse events (very low certainty evidence). The evidence is very uncertain for the effect of high-sodium dialysate and standard sodium dialysate on DDS, death and adverse events (very low certainty evidence).

Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Response disequilibrium is the perturbation of unconstrained behavior with a contingency. For example, the imposition of advertisements before or after viewing TikTok videos. The purpose of this laboratory analogue was to determine the effects of two such response disequilibrium conditions: (1) which required participants to view 5 s increments of advertisements to access 2 s increments of TikTok videos and (2) which required participants to view 5 s increments of TikTok videos to access 15 s increments of advertisements. The disequilibrium condition in (1) is called a response deficit due to the restricted access to TikTok videos relative to baseline while (2) is called a response excess due to the overabundance of advertisements relative to baseline. Additionally, participants had access to a third activity that was freely available throughout. Participants could browse images of TikTok video thumbnails while in deficit and excess. As predicted, participants increased their viewing of advertisements when TikTok was in deficit and decreased their viewing of TikTok when advertisements were in excess. Furthermore, some participants substituted TikTok with browsing during the excess of advertisements. This investigation has implications for a behavioral economic analysis of social media use and the contingency management of time spent on these platforms.

Previous studies have highlighted the association between cannabis use and diabetes and its complications; however, the causality remains ambiguous. Univariate Mendelian randomization (MR), multivariate MR, mediation MR, and linkage disequilibrium score (LDSC) analysis to assess the causal relationship between cannabis use and 12 diabetic phenotypes. Summary statistics for lifetime cannabis use (N = 184,765) and cannabis use disorder (CUD) (N = 374,287) from genome-wide association studies. The primary method used was inverse-variance-weighted (IVW). A range of sensitivity analyses ensured the robustness of the results. LDSC analysis revealed a significant genetic correlation between CUD and T2DM, as well as between lifetime cannabis use and four diabetic phenotypes (P < 0.05). After correction by false discovery rate (FDR), the primary IVW analysis indicates that the genetically predicted CUD is positively associated with the risk of diabetic hypoglycemia (OR = 1.11, 95% CI 1.04-1.20, P = 0.003, PFDR = 0.04) and proliferative diabetic retinopathy (PDR) (OR = 1.12, 95% CI 1.04-1.19, P = 4.89×10-4, PFDR =0.01). Additionally, suggestive evidence links CUD with increased risks of diabetic nephropathy, type 1 diabetes mellitus (T1DM), diabetic retinopathy, and T1DM associated with diabetic ketoacidosis (P < 0.05 & PFDR > 0.05). No causal relationship was detected between lifetime cannabis use and diabetic phenotypes (P > 0.05 & PFDR > 0.05). Multivariable and mediation MR analyses revealed that glycated hemoglobin A1c partially mediates the causal effect of CUD on PDR and diabetic hypoglycemia. This MR study suggests that CUD may have a causal role in several diabetic disease phenotypes.