The Exocyst Protein Sec10 Interacts with Polycystin-2 and Knockdown Causes PKD-Phenotypes

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by formation of renal cysts that destroy the kidney. Mutations in PKD1 and PKD2, encoding polycystins-1 and -2, cause ADPKD. Polycystins are thought to function in primary cilia, but it is not well understood how these and other proteins are targeted to cilia. Here, we provide the first genetic and biochemical link between polycystins and the exocyst, a highly-conserved eight-protein membrane trafficking complex. We show that knockdown of exocyst component Sec10 yields cellular phenotypes associated with ADPKD, including loss of flow-generated calcium increases, hyperproliferation, and abnormal activation of MAPK. Sec10 knockdown in zebrafish phenocopies many aspects of polycystin-2 knockdown—including curly tail up, left-right patterning defects, glomerular expansion, and MAPK activation—suggesting that the exocyst is required for pkd2 function in vivo. We observe a synergistic genetic interaction between zebrafish sec10 and pkd2 for many of these cilia-related phenotypes. Importantly, we demonstrate a biochemical interaction between Sec10 and the ciliary proteins polycystin-2, IFT88, and IFT20 and co-localization of the exocyst and polycystin-2 at the primary cilium. Our work supports a model in which the exocyst is required for the ciliary localization of polycystin-2, thus allowing for polycystin-2 function in cellular processes

Dynamic Switch of Negative Feedback Regulation in Drosophila Akt–TOR Signaling

Akt represents a nodal point between the Insulin receptor and TOR signaling, and its activation by phosphorylation controls cell proliferation, cell size, and metabolism. The activity of Akt must be carefully balanced, as increased Akt signaling is frequently associated with cancer and as insufficient Akt signaling is linked to metabolic disease and diabetes mellitus. Using a genome-wide RNAi screen in Drosophila cells in culture, and in vivo analyses in the third instar wing imaginal disc, we studied the regulatory circuitries that define dAkt activation. We provide evidence that negative feedback regulation of dAkt occurs during normal Drosophila development in vivo. Whereas in cell culture dAkt is regulated by S6 Kinase (S6K)–dependent negative feedback, this feedback inhibition only plays a minor role in vivo. In contrast, dAkt activation under wild-type conditions is defined by feedback inhibition that depends on TOR Complex 1 (TORC1), but is S6K–independent. This feedback inhibition is switched from TORC1 to S6K only in the context of enhanced TORC1 activity, as triggered by mutations in tsc2. These results illustrate how the Akt–TOR pathway dynamically adapts the routing of negative feedback in response to the activity load of its signaling circuit in vivo

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Absorption of calcium from milk and tempeh consumed by postmenopausal Malay women using the dual stable isotope technique

Assessment of calcium bioavailability from non-dairy foods containing moderate amounts of calcium is especially important in populations that have habitually low dairy consumption. Absorption of calcium from milk and tempeh (a traditional fermented soy product) was compared in a sample of Malay subjects. A randomized, crossover design was utilized to assess calcium absorption in 20 postmenopausal women from either a glass of milk (114 g) or from a meal of tempeh (206 g); each containing 130 mg calcium. At each study of Phase 1 (mid-July) and Phase 2 (mid-August), intravenous (42)Ca and oral (44)Ca were administered and calcium absorption was measured in 24-h urine collections post-dosing; with a 1-month washout period between phases. Absorption of calcium from tempeh did not differ significantly from milk (36.9 +/- 10.6% vs. 34.3 +/- 8.6%, respectively). Due to differences in the calcium content of tempeh, four servings of this product would be needed to get the same amount of absorbed calcium as that obtained from a 4-ounce glass of milk. Tempeh may provide readily available calcium for this population of women at risk for low bone mass

A social media intervention to improve nutrition knowledge and behaviors of low income, pregnant adolescents and adult women.

Pregnant adolescents are at increased risk of adverse pregnancy outcomes compared to adult women, necessitating a need for early and comprehensive health care. This study aimed to evaluate the effectiveness of a social media intervention (i.e. weekly prenatal health messages) on improving diet quality, and health beliefs and knowledge. Participants (10 adolescents and 12 adults) completed pre-post intervention interviews, nutrition knowledge and health belief questionnaires, and 24-hour diet recalls. Participants entering pregnancy as overweight or obese were more likely to experience excessive GWG during the intervention. The adults had greater participation during the study despite high levels of social media access among both groups. Participants were able to identify sugar-sweetened foods and acknowledged the benefits of whole grains; however, overall knowledge of MyPlate Guidelines was limited. Social media-based education was well received by participants but did not result in large changes in dietary intake and knowledge. Although larger studies are needed, social media appears to have the potential to reach high-risk women

Meals and dephytinization affect calcium and zinc absorption in Nigerian children with rickets

Nutritional rickets resulting from calcium insufficiency is common in Nigeria and high dietary phytate is thought to inhibit calcium and zinc absorption. We compared the effects of a high-phytate meal and enzymatic dephytinization on calcium and zinc absorption in Nigerian children with and without rickets. Nineteen children with rickets and 15 age-matched control children, aged 2-10 gamma, were given calcium (600 mg/d) and ergocalciferol (1250 mu g/wk). After 6 wk, calcium and zinc absorption were measured in both groups with and without maize porridge using stable isotopes. One week later, absorption measurements were repeated to assess the effects of enzymatic dephytinization and fermentation of the maize porridge. The phytate concentration of maize porridge (3.87 +/- 0.38 g/kg wet weight) was reduced by enzymatic dephytinization (2.83 +/- 0.41 g/kg; P < 0.001) but not by fermentation (3.35 +/- 0.27 g/kg; P = 0.08). Calcium and zinc absorption were unaffected by the presence of rickets or by fermentation of maize porridge. Calcium absorption was greater with a meal (61.3 +/- 25.1%) than without (27.8 +/- 14.6%; P < 0.001). Zinc absorption was lower with a meal (16.2 +/- 8.0%) than without (63.4 +/- 23.9%; P < 0.001). Enzymatic dephytinization increased relative zinc absorption from a meal by 101 +/- 81% (P < 0.001) but did not affect calcium absorption. Rickets was not associated with impaired calcium or zinc absorption. Calcium absorption was enhanced by maize porridge, but zinc absorption was reduced. Enzymatic dephytinization increased zinc absorption. Multiple strategies may be required to optimize calcium and zinc absorption in deficient populations. J. Nutr. 139: 926-932, 2009

The Effect of Vitamin D2 and Vitamin D3 on Intestinal Calcium Absorption in Nigerian Children with Rickets

Context: Children with calcium-deficiency rickets have high 1,25-dihydroxyvitamin D values

Calcium kinetics during bed rest with artificial gravity and exercise countermeasures

SUMMARY: We assessed the potential for countermeasures to lessen the loss of bone calcium during bed rest. Subjects ingested less calcium during bed rest, and with artificial gravity, they also absorbed less calcium. With exercise, they excreted less calcium. To retain bone during bed rest, calcium intake needs to be maintained. INTRODUCTION: This study aims to assess the potential for artificial gravity (AG) and exercise (EX) to mitigate loss of bone calcium during space flight. METHODS: We performed two studies: (1) a 21-day bed rest (BR) study with subjects receiving 1&nbsp;h/day AG (n&thinsp;=&thinsp;8) or no AG (n&thinsp;=&thinsp;7) and (2) a 28-day BR study with 1&nbsp;h/day resistance EX (n&thinsp;=&thinsp;10) or no EX (n&thinsp;=&thinsp;3). In both studies, stable isotopes of Ca were administered orally and intravenously, at baseline and after 10&nbsp;days of BR, and blood, urine, and feces were sampled for up to 14&nbsp;days post dosing. Tracers were measured using thermal ionization mass spectrometry. Data were analyzed by compartmental modeling. RESULTS: Less Ca was absorbed during BR, resulting in lower Ca balance in BR+AG (-6.04&thinsp;&plusmn;&thinsp;3.38&nbsp;mmol/day, P&thinsp;=&thinsp;0.023). However, Ca balance did not change with BR+EX, even though absorbed Ca decreased and urinary Ca excretion increased, because endogenous excretion decreased, and there was a trend for increased bone deposition (P&thinsp;=&thinsp;0.06). Urinary N-telopeptide excretion increased in controls during BR, but not in the EX group. Markers of bone formation were not different between treatment groups for either study. Ca intake decreased during BR (by 5.4&nbsp;mmol/day in the AG study and 2.8&nbsp;mmol/day in the EX study), resulting in lower absorbed Ca. CONCLUSIONS: During BR (or space flight), Ca intake needs to be maintained or even increased with countermeasures such as exercise, to enable maintenance of bone Ca