Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

After you submit a stored process from the SAS Stored Process Web Application, the generated URL is placed into a cell in a Microsoft Excel worksheet. When you click this URL, you expect that the stored process is sub

The SAS Stored Process Server does not create a detailed log file by default. However, you can create a detailed SAS Stored Process Server log file (that will contain information about all of the code that was executed) by using this approach. AUTO

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

17 February 2020

Zinc metallopeptidase STE24 (ZMPSTE24) is essential for the conversion of farnesyl–prelamin A to mature lamin A, a key component of the nuclear lamina. In the absence of ZMPSTE24, farnesyl–prelamin A accumulates in the nucleus and exerts toxicity, causing a variety of disease phenotypes. By ~4 months of age, both male and female Zmpste24^–/– mice manifest a near-complete loss of adipose tissue, but it has never been clear whether this phenotype is a direct consequence of farnesyl–prelamin A toxicity in adipocytes. To address this question, we generated a conditional knockout Zmpste24 allele and used it to create adipocyte-specific Zmpste24–knockout mice. To boost farnesyl–prelamin A levels, we bred in the "prelamin A–only" Lmna allele. Gene expression, immunoblotting, and immunohistochemistry experiments revealed that adipose tissue in these mice had decreased Zmpste24 expression along with strikingly increased accumulation of prelamin A. In male mice, Zmpste24 deficiency in adipocytes was accompanied by modest changes in adipose stores (an 11% decrease in body weight, a 23% decrease in body fat mass, and significantly smaller gonadal and inguinal white adipose depots). No changes in adipose stores were detected in female mice, likely because prelamin A expression in adipose tissue is lower in female mice. Zmpste24 deficiency in adipocytes did not alter the number of macrophages in adipose tissue, nor did it alter plasma levels of glucose, triglycerides, or fatty acids. We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl–prelamin A, reduces adipose tissue stores, but only modestly and only in male mice.

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, is potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor of activated T cells (NFAT) in conduit and medium-sized resistance arteries and that NFAT blockade abolishes diabetes-driven aggravation of atherosclerosis. In this study, we test whether NFAT plays a role in the development of endothelial dysfunction in diabetes. NFAT-dependent transcriptional activity was elevated in skin microvessels of diabetic Akita (Ins2^+/–) mice when compared with nondiabetic littermates. Treatment of diabetic mice with the NFAT blocker A-285222 reduced NFATc3 nuclear accumulation and NFAT-luciferase transcriptional activity in skin microvessels, resulting in improved microvascular function, as assessed by laser Doppler imaging and iontophoresis of acetylcholine and localized heating. This improvement was abolished by pretreatment with the nitric oxide (NO) synthase inhibitor l-N^G-nitro-l-arginine methyl ester, while iontophoresis of the NO donor sodium nitroprusside eliminated the observed differences. A-285222 treatment enhanced dermis endothelial NO synthase expression and plasma NO levels of diabetic mice. It also prevented induction of inflammatory cytokines interleukin-6 and osteopontin, lowered plasma endothelin-1 and blood pressure, and improved mouse survival without affecting blood glucose. In vivo inhibition of NFAT may represent a novel therapeutic modality to preserve endothelial function in diabetes.

Former American Basketball Association commissioner and NBA executive Mike Storen died Thursday after a lengthy battle with a rare form of cancer. He was 84.

The Maryland State Department of Education "inappropriately stored" personal information of 1.4 million students and more than 230,000 teachers, leaving them vulnerable to potential bad actors, according to an audit published earlier this month.

Environmental economics.

The Spanish Surrealist painted a series of 100 watercolors inspired by Dante's "Divine Comedy"

But will that keep susceptible populations safe?

Buyers can ask for a mix of their favorite genre or seek booksellers’ recommendations

The village of La Loche is calling on the provincial government to force the closure of liquor stores in the community, which is in the throes of a COVID-19 outbreak. 

Retail stores in Fort William First Nation (FWFN) reopened to the general public on May 5, but they are under new operating requirements, the band council announced Friday. However, the residential area of the First Nation remains accessible only to people who live in the community.

As the province of Ontario starts to relax some COVID-19 restrictions, one Sudbury business owner says it feels great to be opening back up.

The University of Manitoba is laying off dozens of employees as it tries to find savings at a time when post-secondary schools have largely been closed since COVID-19 emerged on the Prairies, a union says.

One of the two grocery stores in La Loche, Sask., has shut temporarily after one of its employees tested positive for COVID-19, according to an executive at the North West Company. 

The NDP wants the Saskatchewan government to delay Phase 2 of its reopening plan, currently scheduled for May 19.

A woman found not criminally responsible for fatally stabbing a stranger in the heart at the makeup counter of a Toronto drugstore five years ago could ultimately be allowed to live in the community if the mental health facility where she is staying decides she can, the Ontario Review Board says.

Curbside pickups offer a bit of hope after months of being shuttered by COVID-19, but while retailers are happy to start getting back to business some are raising questions of fairness and access to opportunity.

Apple has reopened all of its operational Apple Stores in Australia, following their closure because of the coronavirus outbreak. Each of the stores has introduced social distancing and temperature checks.

Apple has now launched a new shop front online which is expressly for making it easier to buy, and get technical help, from home.

Apple is to reopen at least three of its stores in Germany on May 11, in line with the country's newly-announced measure for allowing shops to open with extra hygiene measures.

Apple has just declared that it is opening up a handful of Apple Stores in the US cautiously, with more to follow as conditions warrant.

Apple's upcoming reopening of some U.S.-based retail locations will be based around guidelines that the company developed for and refined at its open South Korea Apple Store.

Apple is preparing to reopen all four of its Apple Stores in Switzerland on May 12, as part of the iPhone maker's bid to slowly return its retail efforts back to normal around the world.

Walvis Bay, Namibia :: Logos Hope's volunteers rebuild a flimsy church and encourage the grieving pastor and congregation.

Teens gather in Warwick, Queensland this week for OM Australia's TeenStreet.

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Give your skin a tasty treat and cook up your own beauty recipes, says Sandra Dick

SCOTTISH energy storage start-up Gravitricity has received £300,000 from government agency Innovate UK to explore the potential to use gold mine shafts in South Africa as energy stores.

Newborn screening (NBS) programs may store bloodspot samples and use them for secondary purposes, such as research. Recent public controversies and lawsuits over storage and secondary uses underscore the need to engage the public on these issues.

This public engagement study identifies values underlying citizens’ acceptance of and discomfort with research from NBS samples. Well-designed methods of public education and civic discourse on the risks and benefits of storage and secondary uses of NBS samples are required. (Read the full article)

Youth exposure to retail tobacco advertisements and displays is associated with smoking initiation. The Family Smoking Prevention and Tobacco Control Act of 2009 gives states and local governments legal authority to regulate the time, place, and manner of tobacco advertising.

This is the first experimental study using a virtual store environment to provide evidence that a policy banning tobacco product displays at the point of sale may deter youth from attempting to purchase tobacco products at retail stores. (Read the full article)

Cow’s milk consumption has opposite effects on vitamin D and iron levels in children; however, the amount of cow’s milk intake required for sufficient stores of vitamin D and iron is poorly understood, and existing guidelines on consumption are unclear.

Two cups of cow’s milk per day is sufficient to maintain healthy vitamin D and iron stores for most children. Wintertime vitamin D supplementation appears particularly important among children with darker skin pigmentation. (Read the full article)

It was far too easy to accidentally start an app subscription if you own an iPhone with Touch ID. Apple just solved the problem with a pop-up.

In a 5-4 decision, the Supreme Court sided with four iPhone owners who contend the company has been inflating the prices on the App Store. Current antitrust laws allow the plaintiffs to recover three times the amount of damages.

Wix Stores has a smooth offering that's strongly geared toward beginners who just want to get off the ground quickly. More advanced users or those who need more in-depth customizability, however, will need to look elsewhere.

Given that GoDaddy's GoCentral Online Store is an add-on service to its web hosting product, you'll find its features a little more limited than much of the competition. But if you're a GoDaddy customer, then it's a great way to start quickly.

Is your favorite music missing on your iPhone or iPad? Maybe you inadvertently turned off syncing or accidentally deleted those tunes. All is not lost; here's how to recover your music.

Customers in the U.S. should begin noticing in-store changes starting today.

In a shocking display of ignorance, pay for performance has become reformers' blitzkrieg. Both common sense and research are being ignored.

Many consumers are facing limited hours and product shortages at their neighborhood grocery stores and naturally are worried about the availability and safety of their food. A Penn State Extension webinar planned for noon to 1 p.m. May 14 will address these concerns, as well as provide suggestions on alternative places and methods for sourcing food.

Retail stores, corporate offices, and contact centers in China are closed through February 9 as the coronavirus spreads globally. Apple's online store will remain open, though.

The books category has disappeared from the Microsoft Store and you'll no longer be able to access purchased or rented ebooks from July. Expect a full refund, though.

The House appropriations committee voted Wednesday to advance a bill providing a slight funding increase for the U.S. Department of Education, bringing overall funding to about $71 billion.

Apple on Friday said it will begin gradually reopening its retail shops in the US next week, taking pandemic precautions such as making sure everyone in them wears masks.