Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.

Targeted recruitment of E3 ubiquitin ligases to degrade traditionally undruggable proteins is a disruptive paradigm for developing new therapeutics. Two salient limitations are that <2% of the ~600 E3 ligases in the human genome have been exploited to produce proteolysis targeting chimeras (PROTACs), and the efficacy of the approach has not been demonstrated for a vital class of complex multi-subunit membrane proteins- ion channels. NEDD4-1 and NEDD4-2 are physiological regulators of myriad ion channels, and belong to the 28-member HECT (homologous to E6AP C-terminus) family of E3 ligases with widespread roles in cell/developmental biology and diverse diseases including various cancers, immunological and neurological disorders, and chronic pain. The potential efficacy of HECT E3 ligases for targeted protein degradation is unexplored, constrained by a lack of appropriate binders, and uncertain due to their complex regulation by layered intra-molecular and posttranslational mechanisms. Here, we identified a nanobody that binds with high affinity and specificity to a unique site on the N-lobe of the NEDD4-2 HECT domain at a location physically separate from sites critical for catalysis- the E2 binding site, the catalytic cysteine, and the ubiquitin exosite- as revealed by a 3.1 Å cryo-electron microscopy reconstruction. Recruiting endogenous NEDD4-2 to diverse ion channel proteins (KCNQ1, ENaC, and CaV2.2) using a divalent (DiVa) nanobody format strongly reduced their functional expression with minimal off-target effects as assessed by global proteomics, compared to simple NEDD4-2 overexpression. The results establish utility of a HECT E3 ligase for targeted protein downregulation, validate a class of complex multi-subunit membrane proteins as susceptible to this modality, and introduce endogenous E3 ligase recruitment with DiVa nanobodies as a general method to generate novel genetically-encoded ion channel inhibitors.

Knowledge, attitude and practice towards hepatitis B infection among high school students in Asante Mampong, Ghana.

BACKGROUND: Hepatitis B virus (HBV) infection is a serious global public health problem, with significant morbidity and mortality from acute and chronic complications. Increasing awareness and improving knowledge of HBV helps reduce the risk of the disease. Although many studies have been conducted on HBV in Ghana, few have focused on examining knowledge, attitude and preventive practices among adolescents towards the disease. OBJECTIVE: The objective of this study was to assess HBV knowledge, attitude and practice (KAP) among adolescents in high schools in the Asante Mampong Municipality in the Ashanti Region of Ghana. METHODS: A descriptive cross-sectional study was conducted among 398 adolescents from six senior high schools within the Asante Mampong Municipality. Data was collected using a 30-item structured questionnaire. Each item had two response options: "Yes" and "No". A scoring system was generated and respondents were given a score on each item answered. A positive response to an item was scored 1 point and a negative response was scored 0. Scores were then summed up and averaged to give the mean knowledge, attitude and practice scores. RESULTS: The majority of the respondents were male (60%), between 15 and 17 years (45%), Christian (93%) and in their first year of study. The adolescents had basic knowledge, positive attitude, and poor practices towards HBV. There was no significant relationship between the demographic variables of the respondents and KAP mean scores. CONCLUSION: There is the need to introduce health education and awareness programs in schools within the Asante Mampong Municipality to improve students' level of knowledge of HBV. Countrywide studies examining KAP towards HBV infection among adolescents are also warranted.

Influence of the Model of Care on the Outcomes of Diabetes Self-Management Education Program: A Scoping Review.

BACKGROUND: Type 2 diabetes mellitus (T2DM) accounts for approximately 95% of all diabetes cases, making the disease a global public health concern. The increasing prevalence of T2DM has highlighted the importance of evidence-based guidelines for effective prevention, management, and treatment. Diabetes self-management education (DSME) can produce positive effects on patient behaviors and health status. Study objective. We synthesized findings from the existing studies to find out whether or not the impact of DSME on patient health behaviors and outcomes differ by the different models of diabetes care. That is, we determined whether there are differences in DSME outcomes when patient's care provider is a general practitioner, a specialist, a nurse, or a combination of these health professionals. METHODS: Searches were made of six electronic databases to identify relevant English language publications on DSME from 2000 through 2019. Titles and abstracts of the search results were screened to select eligible papers for full-text screening. All eligible papers were retrieved, and full-text screening was done by three independent reviewers to select studies for inclusion in the final analysis. Twenty-one studies were included in the final analysis. The main outcome measures assessed were glycated hemoglobin (HbA1c), body mass index (BMI), diet, and physical activity. RESULTS: The majority of the patients with diabetes were seen by primary care physicians. In general, the studies reported significant improvements in patient health behaviors and outcomes. Some differences in outcomes between the different models of care were observed. CONCLUSION: Our findings suggest that the effects of DSME on patients' health behaviors and outcomes could differ by the different models of diabetes care. However, considering the limited sample of publications reviewed, and because none of the reviewed studies directly measured the impact of the DSME program on patient behaviors and outcomes, significant conclusions could not be reached.