Cartilage-specific ablation of site-1 protease in mice results in the endoplasmic reticulum entrapment of type IIB procollagen and down-regulation of cholesterol and lipid homeostasis

The proprotein convertase site-1 protease (S1P) converts latent ER-membrane bound transcription factors SREBPs and ATF6 to their active forms. SREBPs are involved in cholesterol and fatty acid homeostasis whereas ATF6 is involved in unfolded protein response pathways (UPR). Cartilage-specific ablation of S1P in mice (S1Pcko) results in abnormal cartilage devoid of type II collagen protein (Col II). S1Pcko mice also lack endochondral bone development. To analyze S1Pcko cartilage we performed double-labeled immunofluorescence studies for matrix proteins that demonstrated that type IIB procollagen is trapped inside the ER in S1Pcko chondrocytes. This retention is specific to type IIB procollagen; other cartilage proteins such as type IIA procollagen, cartilage oligomeric matrix protein (COMP) and aggrecan are not affected. The S1Pcko cartilage thus exhibits COMP-, aggrecan-, and type IIA procollagen-derived matrices but is characterized by the absence of a type IIB procollagen-derived matrix. To understand the molecular reason behind S1Pcko phenotypes we performed genome-wide transcriptional profiling of cartilage isolated from S1Pcko and wild type littermates. While the UPR pathways are unaffected, the SREBPs-directed cholesterol and fatty acid pathways are significantly down-regulated in S1Pcko chondrocytes, with maximal down-regulation of the stearoyl-CoA desaturase-1 (Scd1) gene. However, mouse models that lack Scd1 or exhibit reduction in lipid homeostasis do not suffer from the ER retention of Col II or lack endochondral bone. These studies indicate an indispensable role for S1P in type IIB procollagen trafficking from the ER. This role appears not to be related to lipid pathways or other current known functions of S1P and is likely dependent on additional, yet unknown, S1P substrates in chondrocytes

A novel transversely isotropic strength criterion for soils based on a mobilized plane approach

The peak shear strength rules of transversely isotropic soils are stress state dependent and dependent on relative orientation between bedding plane and principal stress. Accordingly, the shear strength of transversely isotropic soils exhibits two primary characteristics: (i) the strength curve on the deviatoric plane is asymmetrical with respect to three principal stress axes; (ii) the shear strength changes with the direction angle of the bedding plane when the intermediate principal stress coefficient is a constant. In this paper, the mobilized plane is introduced and used to reveal the failure mechanism of soils. By projecting the microstructure tensor of transversely isotropic soils onto the normal of the mobilized plane, the directionality of the transversely isotropic soils is introduced into the friction rules on the mobilized plane, and a transversely isotropic strength parameter is proposed. The proposed strength parameter can extend isotropic strength criteria into transversely isotropic strength criteria. This mobilized plane approach is used to establish a novel transversely isotropic nonlinear unified strength criterion (TI-NUSC). The difficulty to establish a unified description of the asymmetrical strength curve and its evolution with direction angle is overcome by the established criterion. Comparisons between available test results and the TI-NUSC shows that the TI-NUSC can successfully describe these two primary peak strength characteristics

Identification of the Acyltransferase that Octanoylates Ghrelin, an Appetite-Stimulating Peptide Hormone

SummaryGhrelin is a 28 amino acid, appetite-stimulating peptide hormone secreted by the food-deprived stomach. Serine-3 of ghrelin is acylated with an eight-carbon fatty acid, octanoate, which is required for its endocrine actions. Here, we identify GOAT (Ghrelin O-Acyltransferase), a polytopic membrane-bound enzyme that attaches octanoate to serine-3 of ghrelin. Analysis of the mouse genome revealed that GOAT belongs to a family of 16 hydrophobic membrane-bound acyltransferases that includes Porcupine, which attaches long-chain fatty acids to Wnt proteins. GOAT is the only member of this family that octanoylates ghrelin when coexpressed in cultured endocrine cell lines with prepro-ghrelin. GOAT activity requires catalytic asparagine and histidine residues that are conserved in this family. Consistent with its function, GOAT mRNA is largely restricted to stomach and intestine, the major ghrelin-secreting tissues. Identification of GOAT will facilitate the search for inhibitors that reduce appetite and diminish obesity in humans

Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review

We report the case of a 2-year-old girl who was diagnosed with Mannose-6-phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) and provide a review of the relevant literature. The young girl presented with recurrent unexplained diarrhea, vomiting, hypoproteinemia, and elevated liver transaminases. Whole-exome sequencing revealed that the patient had compound heterozygous mutations in the MPI gene (NM_0024). An exon 4 (c.455G > T, p.R152l) mutation was inherited from the mother and an exon 7 (c.884G > A, p.R295H) mutation from the father. One week after the start of mannose treatment, the vomiting and diarrhea symptoms disappeared completely and did not show any side effects. We also provide a brief review of the relevant literature. Including the present case, a total of 52 patients from hospitals across 17 countries were diagnosed with MPI-CDG. Age at disease onset ranged from birth to 15 years, with an onset under 2 years in most patients (43/50). Overall, patients presented with at least one or more of the following symptoms: chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36), elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34), hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36), portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14), and abnormally elevated leukocytes (5). None of the patients was reported to have an intellectual disability (0/28). The majority of patients (26/30) showed clinical symptoms, and laboratory results improved after oral mannose administration. Our findings suggest that MPI-CDG should be considered in children with unexplained recurrent digestive and endocrine systems involvement, and gene examination should be performed immediately to obtain a definite diagnosis in order to begin treatment in a timely manner