Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant defense were coordinately regulated in Stk25^–/– versus wild-type livers. We confirmed attenuated peroxisomal biogenesis and protection against oxidative and ER stress in STK25-deficient human liver cells, demonstrating the hepatocyte-autonomous manner of STK25’s action. In summary, our results suggest that regulation of peroxisomal function and metabolic stress response may be important molecular mechanisms by which STK25 controls the development and progression of NAFLD/NASH.

Contact between inflammatory cells and endothelial cells (ECs) is a crucial step in vascular inflammation. Recently, we demonstrated that the cell-surface level of endomucin (EMCN), a heavily O-glycosylated single-transmembrane sialomucin, interferes with the interactions between inflammatory cells and ECs. We have also shown that, in response to an inflammatory stimulus, EMCN is cleared from the cell surface by an unknown mechanism. In this study, using adenovirus-mediated overexpression of a tagged EMCN in human umbilical vein ECs, we found that treatment with tumor necrosis factor α (TNF-α) or the strong oxidant pervanadate leads to loss of cell-surface EMCN and increases the levels of the C-terminal fragment of EMCN 3- to 4-fold. Furthermore, treatment with the broad-spectrum matrix metalloproteinase inhibitor batimastat (BB94) or inhibition of ADAM metallopeptidase domain 10 (ADAM10) and ADAM17 with two small-molecule inhibitors, GW280264X and GI254023X, or with siRNA significantly reduced basal and TNFα-induced cell-surface EMCN cleavage. Release of the C-terminal fragment of EMCN by TNF-α treatment was blocked by chemical inhibition of ADAM10 alone or in combination with ADAM17. These results indicate that cell-surface EMCN undergoes constitutive cleavage and that TNF-α treatment dramatically increases this cleavage, which is mediated predominantly by ADAM10 and ADAM17. As endothelial cell-surface EMCN attenuates leukocyte–EC interactions during inflammation, we propose that EMCN is a potential therapeutic target to manage vascular inflammation.

Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role, and that hepatic amino acid metabolism and glucagon are linked in a mutual feed-back cycle, the liver-alpha cell axis. On this background, we hypothesized that hepatic steatosis might impair glucagon’s action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia.

We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism during basal and high physiological levels of glucagon. The degree of steatosis was evaluated from liver biopsies.

Total RNA sequencing of liver biopsies revealed perturbations in the expression of genes predominantly involved in amino acid metabolism in the obese steatotic individuals. This group was also characterized by fasting hyperglucagonemia, hyperaminoacidemia and an absent lowering of amino acid levels in response to high levels of glucagon. Endogenous glucose production was similar between lean and obese individuals.

Our results suggest that hepatic steatosis causes resistance to the effect of glucagon on amino acid metabolism resulting in increased amino acid concentrations as well as increased glucagon secretion providing a likely explanation of fatty liver-associated hyperglucagonemia.

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin’s effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.

Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is greater than TG output, resulting in the excess accumulation of TG. Dysregulation of lipogenesis therefore has the potential to increase lipid accumulation in the liver, leading to insulin resistance and type 2 diabetes. Recently, efforts have been made to examine the epigenetic regulation of metabolism by histone-modifying enzymes that alter chromatin accessibility for activation or repression of transcription. For regulation of lipogenic gene transcription, various known lipogenic transcription factors, such as USF1, ChREBP, and LXR, interact with and recruit specific histone modifiers, directing specificity toward lipogenesis. Alteration or impairment of the functions of these histone modifiers can lead to dysregulation of lipogenesis and thus hepatosteatosis leading to insulin resistance and type 2 diabetes.

Hepatic steatosis, the excess storage of intrahepatic lipids, is a rampant clinical problem associated with the obesity epidemic. Hepatic steatosis is linked to increased risk for insulin resistance, type 2 diabetes, and cardiovascular and advanced liver disease. Accumulating evidence shows that physical activity, exercise, and aerobic capacity have profound effects on regulating intrahepatic lipids and mediating susceptibility for hepatic steatosis. Moreover, exercise can effectively reduce hepatic steatosis independent of changes in body mass. In this perspective, we highlight 1) the relationship between obesity and metabolic pathways putatively driving hepatic steatosis compared with changes induced by exercise; 2) the impact of physical activity, exercise, and aerobic capacity compared with caloric restriction on regulating intrahepatic lipids and steatosis risk; 3) the effects of exercise training (modalities, volume, intensity) for treatment of hepatic steatosis, and 4) evidence for a sustained protection against steatosis induced by exercise. Overall, evidence clearly indicates that exercise powerfully regulates intrahepatic storage of fat and risk for steatosis.

Krim Pelangsing Badan Alami Green Tea adalah pelangsing herbal berbentuk krim berguna untuk melangsingkan dan mempercepat pembakaran lemak perut, lengan dl

Jamaica’s senior men’s ice hockey team’s historic championship win at last year’s Amerigol LATAM Cup is memorialised in a Canadian sports yearbook published earlier this year. The team copped the championship in its first international outing...

Do you want to become a certified Yoga Teacher? Just join our 200 Hour Yoga Teacher Training in Rishikesh and become a certified Yoga Teacher.

With passion, motivation and determination to go against what is deemed as conventional in today’s society, Flow hosted a staff summit ahead of the International Womens’ Day under the theme ‘Passion for Action’, which supports a collective will to...

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcr^m–/m–), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr^m–/m– mice than in control Hmgcr^fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr^m–/m– and Hmgcr^fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

Nicole Stott is an engineer, aquanaut and one of the 220 astronauts to have lived and worked on the International Space Station. In a confined space, under huge pressure, with no way out, it's important that teams maintain healthy dynamics, and individuals can manage their stress adequately, and in this podcast Nicole explains a little about...

Days after The Gleaner reported a clarion call from Port Maria Mayor Richard Creary for the quarantine of St Mary communities owing to growing concerns about the spread of COVID-19 in the parish, the Government responded with the lockdown of three...

We're bridging the gap between our Top 100 and organizational Top 30 lists this week with a look at each club's next best top prospect who didn't make the Top 100.

The D-backs will work to compete in 2019 while continuing to build up the farm system, which has some pitching at the top end with better position players at the lower levels.

By Michael Pershan, St. Ann’s School I. What do primary/secondary math educators think of the teaching that happens in colleges? And — the other way around — what do mathematics professors think of primary and secondary math teaching? I’m nearing … Continue reading →

By: Kristin Pfabe, Nebraska Wesleyan University “I am sad this class is going to be over,” said one student. “What am I going to do with myself?” asked another during the last week of an Intermediate Algebra class that I … Continue reading →

By: Yvonne Lai, University of Nebraska-Lincoln Ray Levy, Mathematical Association of America This is cross-posted in MathValues and Abbe Herzig has written a companion post. Additional resources and future meetings are also available here: https://tinyurl.com/OnlineTalkshop. In times of crisis we … Continue reading →

 By Abbe Herzig, AMS Director of Education Many of us are experiencing stress as schools, colleges and universities move instruction out of the classroom. Fortunately, even if distance learning is new to you, it isn’t new, and there is a … Continue reading →

The NFL outlined protocols Wednesday for the gradual reopening of team facilities amid the coronavirus pandemic.

Police in the Netherlands said officers responding to reports of a loose camel ended up capturing an emu running wild through the city of Rotterdam.

The Center for Research & Education in Technology is encouraging dental schools to find out how to participate in its program and learn about the benefits to the school and its students.

This year’s Institute for Teaching Learning program is scheduled for Aug. 23-26 in Atlanta. Now in its 14th year, with over 700 alumni, the program combines presentations, discussions, small group activities and peer-to-peer learnings to give participants new teaching skills. The onsite program is followed by a six-month distance learning experience that include online activities and interactive webinars.

When Dr. Gil Rivera became a dentist, he had no idea his career would take him to the bloodied and bruised front lines of the NHL, but nearly 18 years later, he continues to treat the ravaged mouths of professional hockey players as the team dentist of the Tampa Bay Lightning.

As some dental practices begin plans to reopen and provide nonemergency care — as some states reopen following the direction of their state — the Association is urging dentists to have robust communication and engage their dental team members to address any concerns related to returning to work amid the COVID-19 pandemic.

OBJECTIVE

To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes mellitus (T2DM).

Over the last few years I have been very busy working with teachers to create individualized behavior plans for several different elementary school students. There have been amazingly successful plans where some of the most significant behavior problems in the school have turned it around. Children who made daily trips to the office are only there now to receive praise from the administration. Teachers previously brought to tears from the behaviors have stopped me in the hall to say "Oh my goodness, he's like a different kid!" Students who were close to being sent to a day placement school are now succeeding in a regular classroom. It's very encouraging if I focus on those students. However, there have also been some plans that have been revised and revised and revised and the student is still struggling and the teacher is still severely frustrated. I have been reflecting on why some behavior plans work and others don't. Of course one of the biggest factors is the student. All students are different and the motivation for the misbehavior or lacking skill is different in each student. While this is important to consider, this particular article does not focus on this. I'm going to focus today on the teacher's role in making the behavior plan successful.

• Focus on the Positive!!! The behavior plans that have had the most dramatic success are plans that allow the teacher to focus on the positive. Classroom consequences are still in place, but are not connected to the plan. Here is an example: Johnny's teachers will offer positive reinforcement frequently in the classroom by giving Johnny a “warm fuzzy” pom pom when he is caught engaging in a desired behavior. Johnny will chose the bag to keep the “warm fuzzies” in and carry the bag with him to every class. Once the bag is full, he receives an immediate reward. There is no limit to how many “warm fuzzies” he can earn in a day. He does not loose “warm fuzzies” that he has already earned. All teachers and staff who work with Johnny can give him “warm fuzzies” for his bag. This plan works because Johnny who was used to receiving a lot of negative feedback, is now getting positive attention frequently throughout the day. He receives something tangible (the warm fuzzy) that he can put into his bag. This begins to change his perception of himself, which changes his behavior, which changes his teacher's perception of him, which can potentially change his future. Plans that offer positive rewards completely separate from the classroom consequences seem to have the most significant effects.




• Be Consistent. Teachers who are able to be consistent and are able to follow through every time have the most success with the plan. Oppositional children are excellent at pushing limits to see how far they can push. Consistent teachers have more success because they don't offer the wiggle room.




• Be Flexible. This is not the opposite of being consistent. This is having flexibility in your expectations and stating them upfront. If the student was able to behave like everyone else in the class she would be. She may need some flexibility in some areas. For example you may need to have area for her to work in the classroom for times she needs to cool down and get away from a stimulus. The teacher may need to allow her extra time to finish projects if it is the transition that sets her off. Being flexible and willing to make acceptable changes for the student sets everyone up for success.




• Remember that all students are different. The behaviors may be exactly the same as a student you had two years ago. However, that doesn't mean that the motivation for the behavior or the lacking skills are the same. What works for one student may not work for the next. That is the reason for the individualized plan. I strongly recommend doing a formal Functional Behavioral Assessment and a Behavior Intervention Plan.

Teachers have a HUGE part in making the Behavior Plan sucessful. It is the teacher who has to follow through and implement it consistently every day. It is the teacher who has to push forward even when it appears it isn't working at first. It is the teacher who has a tremendous positive impact on the student when the behavior starts turning around. It is the teacher who does the work to change lives!

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 have a hard time watching...

Netflix shared a premiere date and teaser trailer for its "Baby-Sitters Club" series, based on the Ann M. Martin book series.

The prolonged health and safety stressors of COVID-19 has many parents reaching out to mental health professionals with concern over their teenagers’ increased levels of anxiety. In the United States,...

It's lockdown after all. 

With America divided right down the middle for the third presidential election in a row, most people would not be surprised to hear that Democratic and Republican partisans perceive a widening gap between their presidential choices. In 2004, for example, die-hards in both parties felt that the...

Hi all, 2020 has been a complicated year so far, and things are only going to get more complicated as the COVID-19 pandemic. I’ve been thinking a lot about teaching recently, (as I’m the instructor for a class of undergrad … Continue reading →

In an era of stepped-up immigration enforcement, speakers at this event present their research on the impact of enforcement policies on children from immigrant families and U.S. public schools. 

Delicious steak with chimmi churri sauce

WHERE IS WINTER WITHOUT A GUTSY SAUCE TO ACCOMPANY A JUICY STEAK OR EVEN A ROAST CHICKEN? THIS IS MORE OF A RAGOUT TYPE SAUCE

Delicious gourmet steak, onion and cheese sandwich

Ricky Ponting believes South Africa could suffer from a lack of first-class preparation in the opening Test in Cape Town on Wednesday.

Steven B. Leichter
Jul 1, 2004; 22:129-131
The Business of Diabetes

David Willens
Apr 1, 2011; 29:60-68
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Massachusetts' new performance assessment for teacher candidates helps boost readiness.

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A sea of red-clad teachers took to the streets around North Carolina's legislative building in Raleigh to fight for higher pay and more school funding. See photos from the event.

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Thousands of teachers will head to the state capital on Wednesday to call for a nearly $10,000 raise over four years and an increase to per-pupil spending.

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A sea of red swept the capitals of North and South Carolina on Wednesday, as thousands of teachers turned out to demand higher pay and more school funding.