Taewook Kang
Apr 7, 2020; 0:RA119.001882v1-mcp.RA119.001882
Research

Samuel W Entwisle
Apr 6, 2020; 0:RA120.001946v2-mcp.RA120.001946
Research

Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 is important for regulating BAT metabolism, but its downstream targets have not been fully characterized. In this study, we apply proteomics and phosphoproteomics to investigate the downstream effectors of mTORC2 in brown adipocytes. We compare wild-type controls to isogenic cells with an induced knockout of the mTORC2 subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30-minute time course. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation. We also observe significant differences to basal phosphorylation due to chronic RICTOR loss including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. Finally, we observe mild dampening of acute insulin signaling response in Rictor-iKO cells, and a subset of AKT substrates exhibiting statistically significant dependence on RICTOR.

The onset of obesity-linked type 2 diabetes (T2D) is marked by an eventual failure in pancreatic β-cell function and mass that is no longer able to compensate for the inherent insulin resistance and increased metabolic load intrinsic to obesity. However, in a commonly used model of T2D, the db/db mouse, β-cells have an inbuilt adaptive flexibility enabling them to effectively adjust insulin production rates relative to the metabolic demand. Pancreatic β-cells from these animals have markedly reduced intracellular insulin stores, yet high rates of (pro)insulin secretion, together with a substantial increase in proinsulin biosynthesis highlighted by expanded rough endoplasmic reticulum and Golgi apparatus. However, when the metabolic overload and/or hyperglycemia is normalized, β-cells from db/db mice quickly restore their insulin stores and normalize secretory function. This demonstrates the β-cell’s adaptive flexibility and indicates that therapeutic approaches applied to encourage β-cell rest are capable of restoring endogenous β-cell function. However, mechanisms that regulate β-cell adaptive flexibility are essentially unknown. To gain deeper mechanistic insight into the molecular events underlying β-cell adaptive flexibility in db/db β-cells, we conducted a combined proteomic and post-translational modification specific proteomic (PTMomics) approach on islets from db/db mice and wild-type controls (WT) with or without prior exposure to normal glucose levels. We identified differential modifications of proteins involved in redox homeostasis, protein refolding, K48-linked deubiquitination, mRNA/protein export, focal adhesion, ERK1/2 signaling, and renin-angiotensin-aldosterone signaling, as well as sialyltransferase activity, associated with β-cell adaptive flexibility. These proteins are all related to proinsulin biosynthesis and processing, maturation of insulin secretory granules, and vesicular trafficking—core pathways involved in the adaptation of insulin production to meet metabolic demand. Collectively, this study outlines a novel and comprehensive global PTMome signaling map that highlights important molecular mechanisms related to the adaptive flexibility of β-cell function, providing improved insight into disease pathogenesis of T2D.

REGGAE ARTISTE Isha Blender is still coming to terms with the loss of her son, Josiah, on January 5, a mere two days after she celebrated her birthday. The daughter of legendary crooner Everton Blender said the death of a child can be one of the...

It wasn't just that there were new faces when Reds camp opened Tuesday with the reporting of pitchers and catchers for physicals, there was a different vibe that could be felt in the hallways and clubhouse.

Stony Brook School of Dental Medicine opened Dec. 5 its Center for Implant and Digital Technology, which will serve as a state-of-the-art space for digital dentistry-focused education, patient care and research.

Texas A&M College of Dentistry announced Jan. 17 it opened it’s a new 160,000-square-foot, nine-story clinic, which enables the dental school to increase underserved patients’ access to care.

While migration once was a lower-priority topic for African governments, the last decade has seen a deepening in governance. Policymakers have integrated migration into their national development strategies and mainstreamed it across policy domains such as health and education. The actions are promising on paper, yet questions remain about the extent to which they will translate to more effective migration management.

Here’s my Q&A column from the WSJ this week — and if you have any questions for me, you can tweet them to @danariely with the hashtag #askariely, post a comment on my Ask Ariely Facebook page, or email them to AskAriely@wsj.com. ___________________________________________________ Hi, Dan. I offered to purchase a computer...

A small, isolated country, Iceland has been home to a largely homogenous population for much of its history. But in recent years, a booming economy and expanding tourism sector have drawn rising numbers of immigrants to the island nation. This article explores Iceland's balancing act of maintaining economic growth through immigration while preserving its culture and language.

What if the government ran more like Silicon Valley? Engineer Matt Cutts shares why he decided to leave Google (where he worked for nearly 17 years) for a career in the US government -- and makes the case that if you really want to make an impact, go where your help is needed most.

Ohio Gov. John Kasich is expected to sign a bill into law that would ban suspensions and expulsions for children in prekindergarten through 3rd grade for minor offenses.

The final version of the bill reduces the cost-of-living raises and increases employee contributions to their retirement, among other changes.

Birmingham : printed by M. Billing, 1847.

Lipsiae : Sumtibus Baumgaertneri, 1829.

Argentorati : Sumtibus Amandi Koenig, 1786-1787.

Halifax : Milner and Sowerby, 1856.

Halifax : Milner and Sowerby, 1860.

London : printed for A. Strahan, T. Cadell, 1790.

London : And J. Balfour, and W. Creech, Edinburgh, 1791.

London : printed for A. Strahan and T. Cadell, London, 1794.

Edinburgh : printed for Thomas Nelson, 1820.

London : printed for A. Strahan, and T. Cadell jun. and W. Davies, (successors to Mr. Cadell,) in the Strand, 1797.

London : printed for A. Strahan, T. Cadell jun. and W. Davies, 1800.

London : And J. Balfour, and W. Creech, Edinburgh, 1805.

London : printed for A. Strahan, T. Cadell and W. Davies, 1803.

Manchester : printed by S. Russell, 1806.

London : J. Johnson, 1807.

London : F.C. and J. Rivington, 1813.

Dunbar : printed by and for G. Miller, 1817.

Edinburgh : And for C. Elliot and T. Kay, London, 1789.

Edinburgh : Bell & Bradfute, 1813.

A private pre-K-12 school in Idaho welcomes students back after its coronavirus shutdown, but with shortened days, a closed cafeteria, no bus service, and other signs that things aren't back to normal.

The state's budget bill, which Republican Gov. Bruce Rauner signed into law this week, caps annual raises for end-of-career-teachers, lowering the pension they can receive.

A union lobbyist who worked just one day as a substitute teacher is entitled to a pension worth potentially tens of thousands of dollars annually, the Illinois supreme court has ruled.

There’s a tussle over the right balance for who should pick up the tab for teacher retirements and how that affects wealthier and less-wealthy districts.

Thursday's collection of links.

Mississippi State hired former Old Dominion women’s basketball coach Nikki McCray-Penson to replace Vic Schaefer as the Bulldogs’ head coach. Athletic director John Cohen called McCray-Penson “a proven winner who will lead one of the best programs in the nation” on the department’s website. McCray-Penson, a former Tennessee star and Women’s Basketball Hall of Famer, said it’s been a dream to coach in the Southeastern Conference and she’s “grateful and blessed for this incredible honor and opportunity.”

Fan Li, Fan Li.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2389--2415.

Abstract:
Causal or unconfounded descriptive comparisons between multiple groups are common in observational studies. Motivated from a racial disparity study in health services research, we propose a unified propensity score weighting framework, the balancing weights, for estimating causal effects with multiple treatments. These weights incorporate the generalized propensity scores to balance the weighted covariate distribution of each treatment group, all weighted toward a common prespecified target population. The class of balancing weights include several existing approaches such as the inverse probability weights and trimming weights as special cases. Within this framework, we propose a set of target estimands based on linear contrasts. We further develop the generalized overlap weights, constructed as the product of the inverse probability weights and the harmonic mean of the generalized propensity scores. The generalized overlap weighting scheme corresponds to the target population with the most overlap in covariates across the multiple treatments. These weights are bounded and thus bypass the problem of extreme propensities. We show that the generalized overlap weights minimize the total asymptotic variance of the moment weighting estimators for the pairwise contrasts within the class of balancing weights. We consider two balance check criteria and propose a new sandwich variance estimator for estimating the causal effects with generalized overlap weights. We apply these methods to study the racial disparities in medical expenditure between several racial groups using the 2009 Medical Expenditure Panel Survey (MEPS) data. Simulations were carried out to compare with existing methods.

Kalu, in the Amhara region of northern Ethiopia, is home to 28-year-old Yimam Ali. However, many young people from this region of Ethiopia move to the Middle East looking for work and a better life. The amount of job opportunities in the country has not matched its growth. 71 percent of Ethiopia’s population is under the age of 30 and many [...]