Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.

ATP-dependent Lon proteases catalyze the degradation of various regulatory proteins and abnormal proteins within cells. Methanococcus jannaschii Lon (MjLon) is a homologue of Escherichia coli Lon (Ec-Lon) but has two transmembrane helices within its N-terminal ATPase domain. We solved the crystal structure of the proteolytic domain of Mj-Lon using multiwavelength anomalous dispersion, refining it to 1.9-Å resolution. The structure displays an overall fold conserved in the proteolytic domain of Ec-Lon; however, the active site shows uniquely configured catalytic Ser-Lys-Asp residues that are not seen in Ec-Lon, which contains a catalytic dyad. In Mj-Lon, the C-terminal half of the ␤4-␣2 segment is an ␣-helix, whereas it is a ␤-strand in Ec-Lon. Consequently, the configurations of the active sites differ due to the formation of a salt bridge between Asp-547 and Lys-593 in Mj-Lon. Moreover, unlike Ec-Lon, Mj-Lon has a buried cavity in the region of the active site containing three water molecules, one of which is hydrogen-bonded to catalytic Ser-550. The geometry and environment of the active site residues in Mj-Lon suggest that the charged Lys-593 assists in lowering the pK a of the Ser-550 hydroxyl group via its electrostatic potential, and the water in the cavity acts as a proton acceptor during catalysis. Extensive sequence alignment and comparison of the structures of the proteolytic domains clearly indicate that Lon proteases can be classified into two groups depending on active site configuration and the presence of DGPSA or (D/E)GDSA consensus sequences, as represented by Ec-Lon and Mj-Lon.In all cells, energy-dependent proteolysis plays a key role in the rapid turnover of short-lived regulatory proteins and in the elimination of defective and denatured proteins (1). Bacterial cells possess a number of ATP-dependent proteases, which are complex enzymes containing both ATPase and proteolytic activity as separate domains within a single polypeptide or as individual subunits within complex assemblies. Escherichia coli, for example, express five different ATP-dependent proteases: Lon, ClpAP, ClpXP, HslUV (ClpYQ), and FtSH (2). Homologous proteases have also been identified in archaea and eubacteria, as well as in numerous eukaryotes. Some archaeal Lons have one or two putative transmembrane regions, suggesting that they are membrane-associated (3). The proteolytic components of ATP-dependent proteases include several different types of active sites. For instance, ClpP is a classical serine protease (4), whereas HslV has a catalytic N-terminal Thr residue (5).Lon was the first ATP-dependent protease to be described (6). Similar to the molecular chaperon, Lon recognizes a broad range of proteins and mediates their turnover of abnormal and short-lived normal proteins. Indeed, through degradation of various specialized proteins, Lon is involved in the regulation of a number of biological functions (7). Moreover, it also reportedly acts as a DNA-binding protein, influencing the regulation of DNA replication and gene...

No abstract

Introduction. D-alanine:D-alanine ligase (Ddl) catalyses the dimerization of D-alanine before its incorporation in peptidoglycan precursors. The synthesis of D-alanine:Dalanine begins with an attack on the first D-alanine by the ␥-phosphate of adenosine triphosphate (ATP) to yield an acylphosphate. That is followed by attack by the amino group of the second D-alanine, which eliminates the phosphate and produces the D-alanine: D-alanine dipeptide.

No abstract

No abstract

BackgroundIn Korea, the prevalence, complications, and mortality rate of diabetes are rapidly increasing. However, investigations on the actual condition of diabetes management are very limited due to lack of nation-wide research or multicenter study. Hence, we have minutely inquired the current status of diabetes management and achievement of glucose target goal in general hospital offering education program. That way, we are able to furnish data for policy making of diabetes education and draw up guideline which may allow us to reduce the morbidity and mortality of diabetes.MethodsThe subjects consisted of 2,610 patients with type 2 diabetes who visited the 13 general hospital in Seoul or Gyeonggi region from March 19 to May 29, 2013. General characteristics, associated diseases, complications, and management status were investigated.ResultsThe mean age was 61.0±11.6 years, body mass index was 25.0±3.3 kg/m2, and family history of diabetes was 50.5%. The mean duration of diabetes was 10.7±7.9 years and 53% received education about diabetes. The prevalence of hypertension and dyslipidemia were 59.2% and 65.5%, respectively, and 18.3% of the subjects were accompanied by liver disease. Diabetic retinopathy appeared in 31.6%, nephropathy in 28.1%, and neuropathy in 19.9% of the subjects. The mean glycosylated hemoglobin (HbA1c) level was 7.3%±1.3% and the achieving rate based on Korean Diabetes Association guideline (HbA1c <6.5%) was 24.8%, blood pressure (130/80 mm Hg or less) was 49.4%, and low density lipoprotein cholesterol (<100 mg/dL) was 63.6%. The reaching rate to the target level in four parameters (blood glucose, blood pressure, lipids, and body weight) was 7.8%.ConclusionThe blood glucose control rate was lower than other parameters, and the implementation rate of diabetes education was only 53%. Thus more appropriate glucose control and systematic diabetes education are imperative.

No abstract