A TEM study on the microstructure of spark plasma sintered ZrB_2-based composite with nano-sized SiC dopant

Sintering behavior of ZrB_2 ceramic with nano-sized SiC dopant was studied. ZrB_2-25 vol% nano-sized SiC was selected as the starting mixture to fabricate the composite. The manufacturing process was accomplished at 1800℃ for 5 min under 25 MPa via spark plasma sintering(SPS). The as-sintered sample reached a relative density of 99%. Besides the initial phases, namely ZrB_2 and SiC, the high-resolution X-ray diffraction(HRXRD) was used to study the formation of an in-situ ZrC phase. The possible chemical interactions during the ZrC phase formation were scrutinized. The microstructure of the composite was studied by the field emission scanning electron microscopy(FESEM) and transmission electron microscopy(TEM). Elemental analysis through FESEM evaluations revealed the formation of amorphous phases, rich in Zr, C, Si, B, and O elements, which was in harmony with the thermodynamical assessments. TEM studies endorsed the formation of such phases, containing a glassy bed of Si–B–O with ZrC and C islands dispersed therein.     

The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast

The autosomal recessive disorder Shwachman-Diamond syndrome, characterized by bone marrow failure and leukemia predisposition, is caused by deficiency of the highly conserved Shwachman-Bodian-Diamond syndrome (SBDS) protein. Here, we identify the function of the yeast SBDS ortholog Sdo1, showing that it is critical for the release and recycling of the nucleolar shuttling factor Tif6 from pre-60S ribosomes, a key step in 60S maturation and translational activation of ribosomes. Using genome-wide synthetic genetic array mapping, we identified multiple TIF6 gain-of-function alleles that suppressed the pre-60S nuclear export defects and cytoplasmic mislocalization of Tif6 observed in sdo1Delta cells. Sdo1 appears to function within a pathway containing elongation factor-like 1, and together they control translational activation of ribosomes. Thus, our data link defective late 60S ribosomal subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition.     

Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy

Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.     

Sul meccanismo di azione della streptomicina

Summary A study was undertaken on the variations of the redox potential level produced by streptomycinin vitro andin vivo. We have been able to show that, owing to an oxidative effect, streptomycin produces an increase of the redox potential level. This oxidative effect varies in degree according to the condition of the patient.We also found that in the blood and in the spinal fluid of patients suffering from tubercular meningitis factors are present which inhibit the action of streptomycin.The results of our findings lead to the conclusion that the dose of streptomycin must be varied according to the condition of the patient if the constant level required for an efficient therapy is to be maintained in the blood and in the spinal fluid.     

Kondensationsprodukte von Oxyketonen und Aminoketonen mit 2,4,5-Triamino-6-oxy-pyrimidin

Summary By condensing 2:4:5-triamino-6-hydroxy-pyrimidine with dihydroxyacetone (diacetate), diaminoacetone or acetone-1,3-di (p-formylaminobenzoic acid) not the expected 8- or 9-oxymethyl resp. -aminomethyl-pteridines but 8-or 9-methyl-pteridines were obtained. With p-tolyl-d-isoglucosamine not a tetrahydroxybutyl-pteridine but a trihydroxybutyl-pteridine was formed. For an explanation of these results it is supposed that from the dihydro-pteridines formed at first by intramolecular splitting off of H₂O or R·NH₂ aromatization takes place.     

Phytanic acid impairs mitochondrial respiration through protonophoric action

Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts. Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007 J. C. Komen, F. Distelmaier: These authors contributed equally to this work.     

Regulation of insulin receptor function

Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human disease, is reviewed in this article. Received 3 August 2006; received after revision 1 December 2006; accepted 8 January 2007     

A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.