Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes

BACKGROUND: Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation. METHODS: Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes. FINDINGS: In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype. INTERPRETATION: MBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1. FUNDING: LV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02,364,358, Ricerca corrente Fondazione IRCCS Ca\u27 Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS- Liver Investigation: Testing Marker Utility in Steatohepatitis . MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) \u27Mario Coppo\u27 fellowship

The Outcome of a Multidimensional Intervention Strategy for the Management of Generalized Anxiety Disorder in an Internal Medicine Setting

Anxiety disorders are very prevalent in the United States. The most common type, Generalized Anxiety Disorder (GAD), affects 6.8 million adults every year. GAD can cause significant deficits in a person’s ability to function, decrease their quality of life and increases a person’s risk of attempting suicide. The purpose of this evidence-based practice (EBP) project was to improve the outcomes of adults diagnosed with GAD in an internal medicine setting by implementing a protocol composed of a combination of interventions. A thorough literature search was conducted to find the best available evidence to support the project. A total of 11 pieces of evidence were used and the Johns Hopkins Appraisal Tool was used to grade the evidence. After a thorough review of the literature, it was concluded that best practice for the treatment of GAD was a combination of interventions that included verbal and written education, cognitive behavioral therapy (CBT), using an online application, and medication therapy. This protocol was implemented in an internal medicine office in Indianapolis, IN. A total of 12 participants completed the project. Their anxiety was measured using the Generalized Anxiety Disorder-7 (GAD-7) questionnaire at baseline, then at two, four and eight weeks after implementation. To analyze the data, a one-way ANOVA will be used to measure the effectiveness of the protocol. Further recommendations should focus on the treatment of generalized anxiety disorder in non-psychiatric care settings

Ethnocentrism And Off Reservation Indian Boarding Schools

Ethnocentrism is a force to be reckoned with. The idea that one’s culture is morally and intellectually superior to another is a concept that has followed expanding civilizations for ages. The saga of the United States is no different. A society in a stage of expansion may think from a place of grandeur, and apply their cultural values to conquered people. This research will focus on three categories that will illustrate a holistic mindset of ethnocentrism from the point of view of the expanding United States to the original inhabitants of the continent. First, an exploration of federal government Indian policy. Second, an investigation into the personal memoirs of Richard H. Pratt, the originator of the first off-reservation boarding school. Finally, and possibly most effective, the voices of the students, and their decedents, of off-reservation boarding schools will be interpreted. The research is applied to high school social studies classrooms through analysis of primary sources via collaborative learning

Seasonal changes in nutritional condition of shorebirds (charadrii) during the non-breeding seasons

The nutritional condition (fat and protein reserves)of shorebirds was studied, mainly at Teesmouth and Lindisfarne, north-east England, during the non-breeding season. Normal patterns of fat and protein storage are similar in most coastal shorebird species. Fat reserves rise to a peak in midwinter. Fat is stored rapidly before both spring and autumn migrations. Protein reserves (measured as pectoral muscle size) remain steady during winter. Protein reserves increase before spring migration, but not before autumn migration. Most shorebirds regulate both fat and protein reserves during winter. Plovers (Charadriidae) have larger fat and protein reserves than Sandpipers (Scolopacidae). However rocky-shore species carry smaller reserves than species feeding on soft sediments. Interspecific differences are related to morphology, foraging behaviour, habitat use and winter movements. First-year shorebirds carry similar sized or larger reserves than adult conspecifics. Catabolism of nutritional reserves was studied during two periods of severe winter weather in north-east England. Reserves were catabolised faster by species that normally carried the largest regulated reserves. In eastern Britain some Redshanks cannot regulate their fat and protein reserves even during mild winters. Possible reasons are discussed. The condition of shorebirds that had starved to death during severe weather is examined. Redshanks, first-year Oystercatchers, inland species)and shorebirds that return early to breeding grounds are most at risk. Recovery of nutritional condition after starvation is examined. In addition to seasonal variation, differences in the size of regulated fat reserves occur in different wintering grounds. Total lean weights in relation to wing-length as a measure of body size are used to examine whether similar seasonal and latitudinal differences in protein reserves of shorebirds exist. Plovers have larger pectoral muscles than Sandpipers but similar total lean weight (measured in relation to body size). During winter, lean weights are lower in several equatorial and southern hemisphere areas than in northern temperate regions. Seasonal and latitutinal changes in lean weight are discussed in relation to periods of environmental stress

Cloning, expression, and localization of a rat brain high-affinity glycine transporter

A cDNA clone encoding a glycine transporter has been isolated from rat brain by a combined PCR and plaque-hybridization strategy. mRNA synthesized from this clone (designated GLYT1) directs the expression of sodium-and chloride-dependent, high-affinity uptake of [3H]glycine by Xenopus oocytes. [3H]Glycine transport mediated by clone GLYT1 is blocked by sarcosine but is not blocked by methylaminoisobutyric acid or L-alanine, a substrate specificity similar to that described for a previously identified glycine-uptake system called system Gly. In situ hybridization reveals that GLYT1 is prominently expressed in the cervical spinal cord and brainstem, two regions of the central nervous system where glycine is a putative neurotransmitter. GLYT1 is also strongly expressed in the cerebellum and olfactory bulb and is expressed at lower levels in other brain regions. The open reading frame of the GLYT1 cDNA predicts a protein containing 633 amino acids with a molecular mass of ≈70 kDa. The primary structure and hydropathicity profile of GLYT1 protein reveal that this protein is a member of the sodium- and chloride-dependent superfamily of transporters that utilize neurotransmitters and related substances as substrates

A six-coordinate aryl-germanium complex formed by the Kläui ligand

PhGeCl₃ reacts with Na{[OP(OEt)₂]₃CoCp} to give the six-coordinate complex PhCl₂Ge{[OP(OEt)₂]₃CoCp}, characterised spectroscopically and by an X-ray crystal structure determination which showed a firmly-attached tridentate ligand [Ge–O 1.973(2) Å]