NKD2 mediates stimulation-dependent ORAI1 trafficking to augment Ca2+ entry in T cells.

Sustained activation of the Ca2+-release-activated Ca2+ (CRAC) channel is pivotal for effector T cell responses. The mechanisms underlying this sustainability remain poorly understood. We find that plasma membrane localization of ORAI1, the pore subunit of CRAC channels, is limited in effector T cells, with a significant fraction trapped in intracellular vesicles. From a targeted screen, we identify an essential component of ORAI1+ vesicles, naked cuticle homolog 2 (NKD2). Mechanistically, NKD2, an adaptor molecule activated by signaling pathways downstream of T cell receptors, orchestrates trafficking and insertion of ORAI1+ vesicles to the plasma membrane. Together, our findings suggest that T cell receptor (TCR)-stimulation-dependent insertion of ORAI1 into the plasma membrane is essential for sustained Ca2+ signaling and cytokine production in T cells.

Standardized screening for periodontitis as an integral part of multidisciplinary management of adults with type 2 diabetes: an observational cross-sectional study of cohorts in the USA and UK.

OBJECTIVE: To determine prevalence and factors predictive of periodontitis by using a standardized assessment model in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed an observational cross-sectional study to determine the burden of periodontitis in adults with type 2 diabetes attending urban, ambulatory referral centers in the USA and UK. Full-mouth probing was performed and periodontitis was diagnosed based on either a low (≥5 mm at ≥1 site) or high pocket probing-depth threshold (≥6 mm at ≥1 site). Results were stratified into a five-stage schema and integrated with other clinical variables into the novel Diabetes Cross-Disciplinary Index to function as a balanced health scorecard. Corresponding demographic and routinely collected health data were obtained and comparisons were made between patients with and without periodontitis. Multivariable logistic regression was performed to identify factors predictive of the presence or absence of periodontitis. RESULTS: Between our two cohorts, 253 patients were screened. Caucasians comprised >90% and Hispanic Americans >75% of the UK and US cohorts, respectively. Males and females were equally distributed; mean age was 53.6±11 years; and 17 (6.7%) were edentulous. Of the 236 dentate patients, 128 (54.2%) had periodontitis by low threshold and 57 (24.2%) by high threshold. Just 17 (7.2%) were periodontally healthy. No significant differences in age, HbA1c, blood pressure, body mass index, low-density lipoprotein cholesterol, or smoking status (all p>0.05) were identified between those with or without periodontitis (regardless of threshold) and none was found to be a significant predictor of disease. CONCLUSIONS: Periodontitis is frequent in adults with type 2 diabetes and all should be screened. Periodontal health status can be visualized with other comorbidities and complications using a novel balanced scorecard that could facilitate patient-clinician communication, shared decision-making, and prioritization of individual healthcare needs.