Essential role of GTP in the expression of adenylate cyclase activity after cholera toxin treatment

Expression of activation of rat liver adenylate cyclase by the A 1 peptide of cholera toxin and NAD is dependent on GTP. The nucleotide is effective either when added to the assay medium or during toxin (and NAD) treatment. Toxin treatment increases the V(max) for activation by GTP and the effect of GTP persists in toxin-treated membranes, a property seen in control membranes only with non-hydrolyzable analogs of GTP such as Gpp(NH)p. These observations could be explained by a recent report that cholera toxin acts to inhibit a GTPase associated with denylate cyclase. However, the authors have observed that one of the major effects of the toxin is to decrease the affinity of guanine nucleotides for the processes involved in the activation of adenylate cyclase and in the regulation of the binding of glucagon to its receptor. Moreover, the absence of lag time in the activation of adenylate cyclase by GTP, in contrast to by Gpp(NH)p, and the markedly reduced fluoride action after toxin treatment suggest that GTPase inhibition may not be the only action of cholera toxin on the adenylate cyclase system. The authors believe that the multiple effects of toxin action is a reflection of the recently revealed complexity of the regulation of adenylate cyclase by guanine nucleotides.link_to_subscribed_fulltex

Reversible activation of hepatic adenylate cyclase by guanyl-5'yl(α,β methylene)diphosphonate and guanyl-5'yl imidodiphosphate

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The Prion Protein Preference of Sporadic Creutzfeldt-Jakob Disease Subtypes

Fulltext embargoed for: 12 months post date of publicationSporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrP(C)). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrP(C) substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrP(C) substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrP(C) substrate was sourced, thus indicating that nuances in PrP(C) or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes

An integrated approach to mental health and disaster preparedness: a cluster comparison with earthquake affected communities in Nepal

Abstract Background On 25th April 2015, Nepal experienced a 7.8 magnitude earthquake, followed by countless aftershocks. Nearly 9000 people were killed and over 600,000 homes destroyed. Given the high frequency of earthquake and other natural hazards in Nepal, disaster preparedness is crucial. However, evidence suggests that some people exposed to prior disasters do not engage in risk reduction, even when they receive training and have adequate resources. Mental health symptoms, including those associated with prior disaster exposure, may influence engagement in preparedness. Perceived preparedness for future disasters may in turn influence mental health. Social cohesion may influence both mental health and preparedness. Methods We developed and tested a hybrid mental health and disaster preparedness intervention in two earthquake-affected communities in Nepal (N = 240), about 2.5 months after the April 25th, 2015 earthquake. The 3-day intervention was culturally adapted, facilitated by trained Nepalese clinicians and focused on enhancing disaster preparedness, mental health, and community cohesion. Communities were selected based on earthquake impacts and matched on demographic variables. The intervention was administered initially to one community, followed by the other receiving the intervention shortly thereafter. Survey data was collected across three time points. Focus groups were also conducted to examine intervention impact. Results At pre-intervention baseline, greater depression symptoms and lower social cohesion were associated with less disaster preparedness. Depression and PTSD were associated with lower social cohesion. Participation in the intervention increased disaster preparedness, decreased depression- and PTSD-related symptoms, and increased social cohesion. Mediation models indicated that the effect of intervention on depression was partially explained by preparedness. The effect of the intervention on disaster preparedness was partially explained by social cohesion, and the effect of intervention on depression and on PTSD was also partially explained by social cohesion. Data from focus groups illuminate participant perspectives on components of the intervention associated with preparedness, mental health and social cohesion. Conclusions This mental health integrated disaster preparedness intervention is effective in enhancing resilience among earthquake-affected communities in Nepal. This brief, cost-effective group intervention has the potential to be scaled up for use with other communities vulnerable to earthquakes and other natural hazards. Trial registration Clinical Trials Registry-India, National Institute of Medical Statistics. Registration number: CTRI/2018/02/011688. http://ctri.nic.in/Clinicaltrials/login.php Retrospectively registered February 5th, 2018. First participant enrolled July 2015

Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach

<div><p>Background</p><p>Non-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. These advantages however are not included in the classic frequentist approach of sample size calculation for non-inferiority trials. In contrast, the decision theory approach of sample size calculation does include these factors. The objective of this study is to compare the conceptual and practical aspects of the frequentist approach and decision theory approach of sample size calculation for non-inferiority trials, thereby demonstrating that the decision theory approach is more appropriate for sample size calculation of non-inferiority trials.</p><p>Methods</p><p>The frequentist approach and decision theory approach of sample size calculation for non-inferiority trials are compared and applied to a case of a non-inferiority trial on individually tailored duration of elastic compression stocking therapy compared to two years elastic compression stocking therapy for the prevention of post thrombotic syndrome after deep vein thrombosis.</p><p>Results</p><p>The two approaches differ substantially in conceptual background, analytical approach, and input requirements. The sample size calculated according to the frequentist approach yielded 788 patients, using a power of 80% and a one-sided significance level of 5%. The decision theory approach indicated that the optimal sample size was 500 patients, with a net value of €92 million.</p><p>Conclusions</p><p>This study demonstrates and explains the differences between the classic frequentist approach and the decision theory approach of sample size calculation for non-inferiority trials. We argue that the decision theory approach of sample size estimation is most suitable for sample size calculation of non-inferiority trials.</p></div