The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

Priority Health Needs and Challenges in New Zealand Pacific Communities-A Qualitative Analysis of Healthcare Delivery during the COVID-19 Pandemic.

BACKGROUND: The Pacific community in New Zealand experienced an increased risk of COVID-19 transmission due to delayed contact tracing, along with a disproportionate prevalence of health challenges. The community is representative of a diverse population who proudly identify with the vibrant Pacific Island nations of Samoa, Tonga, Cook Islands, Niue, Fiji, etc. Pacific communities in New Zealand face a higher burden of health challenges compared to other groups. These challenges include obesity, high blood pressure, diabetes, mental health disorders, respiratory issues, smoking, excessive alcohol consumption, disabilities, and chronic conditions. Concerns were raised regarding the oversight of Pacific community views in the initial pandemic response planning. Pacific healthcare professionals expressed concerns about inadequate state support and the need for active involvement in decision making. METHODS: This article reports thematic analyses of text data gained from open-ended questions from a purposive anonymous online survey completed by Pacific healthcare professionals in New Zealand. RESULTS: The participants shared their experiences and opinions, which generated four major themes highlighting priority health needs and challenges. These themes included the necessity for a culturally appropriate healthcare plan, adequate resourcing, addressing discrimination, and emphasising a united and collaborative effort for consistency. The research's limitation is the narrow scope of open-ended questions in the questionnaire survey. However, conducting semi-structured face-to-face interviews can provide more in-depth data and offer further insights beyond the four broad themes identified in the analysis. CONCLUSIONS: The findings can inform the development of future research to provide more in-depth data and offer further insights beyond the four broad themes identified in the analysis. This will help develop future tailored healthcare delivery plans that address specific Pacific community needs.fals

The recent intellectual structure of geography

An active learning project in an introductory graduate course used multidimensional scaling of the name index in Geography in America at the Dawn of the 21st Century, by Gary Gaile and Cort Willmott, to reveal some features of the discipline\u27s recent intellectual structure relevant to the relationship between human and physical geography. Previous analyses, dating to the 1980s, used citation indices or Association of American Geographers spe- cialty-group rosters to conclude that either the regional or the methods and environmental subdisciplines bridge human and physical geography. The name index has advantages over those databases, and its analysis reveals that the minimal connectivity that occurs between human and physical geography has recently operated more through environmental than through either methods or regional subdisciplines

Service Uptake Challenges Experienced by Pasifika Communities during COVID-19 Lockdowns in New Zealand

Background: New Zealand was one of the first countries to adopt an elimination strategy based on a four-tier Alert Level system that included strict lockdowns at levels three and four. The lockdowns meant shutting out external social networks and being confining to individual household ‘bubbles’ only. This presented challenges for minority Pasifika communities in New Zealand as their cultural values are based on social bonding, interconnectedness, community engagement and caring for each other. The aim of this research was to conduct a small-scale pilot study to test and refine the study design and identify the major challenges faced by Pasifika communities in relation to accessing health, social and mental services while in lockdown. Methods: This exploratory study was designed using an online anonymous questionnaire survey targeting people who identified as Pasifika. A total of eighty-seven respondents were included in our analyses following the questionnaire survey. Results: Five main barriers to accessing health, social and mental health services during lockdowns were identified; (1) unavailability of or limited services; (2) fear of contracting the virus; (3) perception of high costs associated with seeking medical assistance; (4) transportation difficulties; and (5) lack of time. Almost a quarter of the respondents reported losing their jobs, 80% indicated a decline in their household income and more than half experienced some form of psychosocial distress while in lockdown. Conclusions: The findings of this research highlight existing challenges faced by Pasifika communities in adequately accessing essential services. Future research can focus on the key barriers to access identified in this research to gain a deeper understanding of services and its interaction with Pasifika communities during lockdowns.fals

Airway obstruction, serum vitamin D and mortality in a 33-year follow-up study

Background and objective: Chronic obstructive pulmonary disease and low vitamin D status predict mortality, but their combined effect on mortality remains inconclusive. We aimed to investigate a joint effect of airway obstruction and vitamin D status on mortality in a nationally representative cohort. Methods: We analysed data of 6676 Finnish adults participating between 1978 and 1980 in a national health examination survey, undergoing spirometry and having all necessary data collected. We followed them up in national registers through record linkage until 31 December 2011. We categorised the subjects with obstruction using the lower limit of normal (LLN) and the measured serum 25-hydroxyvitamin-D (s-25(OH)D) into tertiles. Results: Both obstruction and low s-25(OH) D independently predicted mortality in a multivariate model adjusted also for age, sex, smoking, education, leisure physical activity, body mass index, asthma and serum C-reactive protein. However, a statistically significant (p = 0.007) interaction emerged: the adjusted mortality HRs (95% CI's) for s-25(OH)D in tertiles among the subjects without and with obstruction were 1.00 (lowest), 0.96 (0.87-1.05) and 0.89 (0.81-0.98); and 1.00, 0.96 (0.71-1.31) and 0.57 (0.40-0.80), respectively. Conclusions: In conclusion, obstruction and low s-25(OH)D predict mortality independently of each other. Our findings suggest that low vitamin D status might be particularly detrimental among subjects with obstruction.Peer reviewe

P2 purinergic receptor modulation of cytokine production

Cytokines serve important functions in controlling host immunity. Cells involved in the synthesis of these polypeptide mediators have evolved highly regulated processes to ensure that production is carefully balanced. In inflammatory and immune disorders, however, mis-regulation of the production and/or activity of cytokines is recognized as a major contributor to the disease process, and therapeutics that target individual cytokines are providing very effective treatment options in the clinic. Leukocytes are the principle producers of a number of key cytokines, and these cells also express numerous members of the purinergic P2 receptor family. Studies in several cellular systems have provided evidence that P2 receptor modulation can affect cytokine production, and mechanistic features of this regulation have emerged. This review highlights three separate examples corresponding to (1) P2Y6 receptor mediated impact on interleukin (IL)-8 production, (2) P2Y11 receptor-mediated affects on IL-12/23 output, and (3) P2X7 receptor mediated IL-1β posttranslational processing. These examples demonstrate important roles of purinergic receptors in the modulation of cytokine production. Extension of these cellular observations to in vivo situations may lead to new therapeutic strategies for treating cytokine-mediated diseases

Effect of Monthly, High‐Dose, Long‐Term Vitamin D Supplementation on Central Blood Pressure Parameters: A Randomized Controlled Trial Substudy

Background: The effects of monthly, high‐dose, long‐term (≥1‐year) vitamin D supplementation on central blood pressure (BP) parameters are unknown. Methods and Results: A total of 517 adults (58% male, aged 50–84 years) were recruited into a double‐blinded, placebo‐controlled trial substudy and randomized to receive, for 1.1 years (median; range: 0.9–1.5 years), either (1) vitamin D3 200 000 IU (initial dose) followed 1 month later by monthly 100 000‐IU doses (n=256) or (2) placebo monthly (n=261). At baseline (n=517) and follow‐up (n=380), suprasystolic oscillometry was undertaken, yielding aortic BP waveforms and hemodynamic parameters. Mean deseasonalized 25‐hydroxyvitamin D increased from 66 nmol/L (SD: 24) at baseline to 122 nmol/L (SD: 42) at follow‐up in the vitamin D group, with no change in the placebo group. Despite small, nonsignificant changes in hemodynamic parameters in the total sample (primary outcome), we observed consistently favorable changes among the 150 participants with vitamin D deficiency (<50 nmol/L) at baseline. In this subgroup, mean changes in the vitamin D group (n=71) versus placebo group (n=79) were −5.3 mm Hg (95% confidence interval [CI], −11.8 to 1.3) for brachial systolic BP (P=0.11), −2.8 mm Hg (95% CI, −6.2 to 0.7) for brachial diastolic BP (P=0.12), −7.5 mm Hg (95% CI, −14.4 to −0.6) for aortic systolic BP (P=0.03), −5.7 mm Hg (95% CI, −10.8 to −0.6) for augmentation index (P=0.03), −0.3 m/s (95% CI, −0.6 to −0.1) for pulse wave velocity (P=0.02), −8.6 mm Hg (95% CI, −15.4 to −1.9) for peak reservoir pressure (P=0.01), and −3.6 mm Hg (95% CI, −6.3 to −0.8) for backward pressure amplitude (P=0.01). Conclusions: Monthly, high‐dose, 1‐year vitamin D supplementation lowered central BP parameters among adults with vitamin D deficiency but not in the total sample. Clinical Trial Registration URL: http://www.anzctr.org.au. Unique identifier: ACTRN12611000402943