Identification of KD5170: a novel mercaptoketone-based histone deacetylase inhibitor

We report the identification of KD5170, a potent mercaptoketone-based Class I and II-histone deacetylase inhibitor that demonstrates broad spectrum cytotoxic activity against a range of human tumor-derived cell lines. KD5170 exhibits robust and sustained histone H3 hyperacetylation in HCT-116 xenograft tumors following single oral or i.v. dose and inhibition of tumor growth following chronic dosing.     

Involvement of a novel C-terminal kinase domain of Kir6.2 in the K-ATP channel rundown reactivation

Rundown is a generally encountered problem while recording K_ATP channel activity with inside-out patches. No assigned structural fragment related to this mechanism has yet been derived from any of the functional analyses performed. Therefore, based on a combined sequence and secondary structure alignment against known crystal structure of segments from closely related proteins, we propose here the three-dimensional structural model of an intracellular C-terminal domain of the Kir6.2 subunit in K_ATP channels. An E. coli CMP-kinase was suggested as template for the model building. The subdomain arrangement of this novel kinase domain and the structural correlation for UDP-docking are described. With structural-functional interpretation, we conclude that the reactivation of K_ATP channel rundown by MgATP or UDP is very possibly regulated by this intracellular kinase domain at the C-terminus of Kir6.2 subunit in K_ATP channels.     

Measurement of the size and orientation of human masseter and medial pterygoid muscles

To gain a better understanding of biting and chewing performance, the size and orientation of the masseter and medial pterygoid muscles in living humans were studied. Twenty-seven young males having complete dentition, class I dental occlusion and normal muscle and jaw function were examined using magnetic resonance images of the head between the zygomatic arch and hyoid bone. The sections were parallel to the palatal plane, and the thickness was 3 mm without a gap. A computer software program (Medical Dental Image, MDI) was developed to identify and calculate the area of each cross section of the muscle, and the volume of the muscle was then estimated. The axis of the muscle was determined by connecting the centroids of the sections in the lower and upper 1/3 of the whole muscle. The effective muscle cross section area was then calculated by resectioning the muscle perpendicularly to the muscle axis. It was found that the mean masseter muscle volume was around 31 cm3, and that the mean medial pterygoid muscle volume was 11 cm3. Their mean effective cross section areas were around 6.2 cm2 and 3.5 cm2, respectively. The axis of the masseter muscle was more perpendicular to the palatal plane and parallel to the sagittal plane than was the medial pterygoid muscle. The results suggest that the use of magnetic resonance images (MRI) is an effective noninvasive measurement technique for determining the size and orientation of masseter and medial pterygoid muscles. This technique can be employed in future studies on human bite force evaluation and masticatory function.     

Increase of dietary vitamin C improves haemocyte respiratory burst response and growth of juvenile grass shrimp,Penaeus monodon,fed with high dietary copper

Effects of dietary vitamin C (l-ascorbyl-2-monophosphate-Mg, C2MP-Mg) on growth, tissue copper (Cu) accumulation, and haemocyte superoxide anion production of juvenile grass shrimp, Penaeus monodon, fed with either adequate or high (8 x adequate) dietary Cu were studied. Three experimental diets were used: basal diet supplemented with adequate levels of both C2MP-Mg (40 mg kg diet(-1)) and Cu (20mg kg diet(-1)) (NC-NCu); basal diet supplemented with adequate C2MP-Mg and high Cu (8 x adequate) (NC-HCu); and basal diet supplemented with high C2MP-Mg (5 x adequate) and high Cu (HC-HCu). These were each fed to triplicate groups of shrimp (mean initial weight: 0.29+/-0.01 g) for 8 weeks. Highest (P< 0.01) weight gain, feed efficiency (FE) and protein efficiency ratio (PER) were observed in shrimp fed NC-NCu diet, intermediate in shrimp fed HC-HCu diet, and lowest in shrimp fed NC-HCu diet. Cu concentrations in hepatopancreas, muscle and haemolymph were highest in shrimp fed NC-HCu diet, followed by shrimp fed HC-HCu diet, and lowest for shrimp fed NC-NCu diet. Survival, total haemocyte count (THC) and intracellular superoxide anion (O-2) production were higher in shrimp fed NC-NCu diet than shrimp fed NC-HCu diet, whereas hepatosomatic index (HSI) was higher in shrimp fed NC-HCu diet than shrimp fed NC-NCu diet. However, all these parameters were similar in shrimp fed NC-NCu diet and shrimp fed HC-HCu diet. These data suggest that increase of dietary vitamin C improved haemocyte respiratory burst response and growth and prevented tissue Cu accumulation in P. monodon fed with high dietary Cu.     

Improving the thermostability of raw-starch-digesting amylase from a Cytophaga sp. by site-directed mutagenesis

A heat-stable raw-starch-digesting amylase (RSDA) was generated through PCR-based site-directed mutagenesis. At 65 degrees C, the half-life of this mutant RSDA, which, compared with the wild-type RSDA, lacks amino acids R178 and G179, was increased 20-fold. While the wild type was inactivated completely at pH 3.0, the mutant RSDA still retained 41% of its enzymatic activity. The enhancement of RSDA thermostability was demonstrated to be via a Ca(2+)-independent mechanism.     

Genetic association of single nucleotide polymorphisms in dystrobrevin binding protein 1 gene with schizophrenia in a Malaysian population

Dystrobrevin binding protein 1 (DTNBP1) gene is pivotal in regulating the glutamatergic system. Genetic variants of the DTNBP1 affect cognition and thus may be particularly relevant to schizophrenia. We therefore evaluated the association of six single nucleotide polymorphisms (SNPs) with schizophrenia in a Malaysian population (171 cases; 171 controls). Associations between these six SNPs and schizophrenia were tested in two stages. Association signals with p < 0.05 and minor allele frequency > 0.05 in stage 1 were followed by genotyping the SNPs in a replication phase (stage 2). Genotyping was performed with sequenced specific primer (PCR-SSP) and restriction fragment length polymorphism (PCR-RFLP). In our sample, we found significant associations between rs2619522 (allele p = 0.002, OR = 1.902, 95%CI = 1.266 – 2.859; genotype p = 0.002) and rs2619528 (allele p = 0.008, OR = 1.606, 95%CI = 1.130 – 2.281; genotype p = 6.18 × 10⁻⁵) and schizophrenia. Given that these two SNPs may be associated with the pathophysiology of schizophrenia, further studies on the other DTNBP1 variants are warranted.