Vapor-Phase Stoichiometry and Heat Treatment of CdTe Starting Material for Physical Vapor Transport

Six batches of CdTe, having total amounts of material from 99 to 203 g and gross mole fraction of Te, X(sub Te), 0.499954-0.500138, were synthesized from pure Cd and Te elements. The vapor-phase stoichiometry of the assynthesized CdTe batches was determined from the partial pressure of Te2, P(sub Te2) using an optical absorption technique. The measured vapor compositions at 870 C were Te-rich for all of the batches with partial pressure ratios of Cd to Te2, P(sub Cd)/P(sub Te2), ranging from 0.00742 to 1.92. After the heat treatment of baking under dynamic vacuum at 870 C for 8 min, the vapor-phase compositions moved toward that of the congruent sublimation, i.e. P(sub Cd)/P(sub Te2) = 2.0, with the measured P(sub Cd)/P(sub Te2) varying from 1.84 to 3.47. The partial pressure measurements on one of the heat-treated samples also showed that the sample remained close to the congruent sublimation condition over the temperature range 800-880 C

Mass Flux of ZnSe by Physical Vapor Transport

Mass fluxes of ZnSe by physical vapor transport (PVT) were measured in the temperature range of 1050 to 1160 C using an in-situ dynamic technique. The starting materials were either baked out or distilled under vacuum to obtain near-congruently subliming compositions. Using an optical absorption technique Zn and Se, were found to be the dominant vapor species. Partial pressures of Zn and Se, over the starting materials at temperatures between 960 and 1140 C were obtained by measuring the optical densities of the vapor phase at the wavelengths of 2138, 3405, 3508, 3613, and 3792 A. The amount and composition of the residual gas inside the experimental ampoules were measured after the run using a total pressure gauge. For the first time, the experimentally determined partial pressures of Zn and Se, and the amount and composition of the residual gas were used in a one-dimensional diffusion limited analysis of the mass transport rates for a PVT system. Reasonable agreement between the experimental and theoretical results was observed

Joint relationship between renal function and proteinuria on mortality of patients with type 2 diabetes: The Taichung Diabetes Study

Abstract Background Estimated glomerular filtration rate (eGFR) is a powerful predictor of mortality in diabetic patients with limited proteinuria data. In this study, we tested whether concomitant proteinuria increases the risk of mortality among patients with type 2 diabetes. Methods Participants included 6523 patients > 30 years with type 2 diabetes who were enrolled in a management program of a medical center before 2007. Renal function was assessed by eGFR according to the Modification of Diet in Renal Disease Study equation for Chinese. Proteinuria was assessed by urine dipstick. Results A total of 573 patients (8.8%) died over a median follow-up time of 4.91 years (ranging from 0.01 year to 6.42 years). The adjusted expanded cardiovascular disease (CVD)-related mortality rates among patients with proteinuria were more than three folds higher for those with an eGFR of 60 mL/min/1.73 m2 or less compared with those with an eGFR of 90 mL/min/1.73 m2 or greater [hazard ratio, HR, 3.15 (95% confidence interval, CI, 2.0–5.1)]. The magnitude of adjusted HR was smaller in patients without proteinuria [1.98 (95% CI, 1.1–3.7)]. An eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 significantly affected all-cause mortality and mortality from expanded CVD-related causes only in patients with proteinuria. Similarly, proteinuria affected all outcomes only in patients with an eGFR of <60 mL/min/1.73 m2. Conclusion The risks of all-cause mortality, as well as expanded and non-expanded mortality from CVD-related causes associated with proteinuria or an eGFR of 90 mL/min/1.73 m2 or greater are independently increased. Therefore, the use of proteinuria measurements with eGFR increases the precision of risk stratification for mortality.http://deepblue.lib.umich.edu/bitstream/2027.42/112804/1/12933_2012_Article_558.pd

Post-Transcriptional Inhibition Of Hsc70-4/Hspa8 Expression Leads To Synaptic Vesicle Cycling Defects In Multiple Models Of Als

Amyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to ∼97% of ALS cases. Using a Drosophila model of ALS, we show that TDP-43 overexpression (OE) in motor neurons results in decreased expression of the Hsc70-4 chaperone at the neuromuscular junction (NMJ). Mechanistically, mutant TDP-43 sequesters hsc70-4 mRNA and impairs its translation. Expression of the Hsc70-4 ortholog, HSPA8, is also reduced in primary motor neurons and NMJs of mice expressing mutant TDP-43. Electrophysiology, imaging, and genetic interaction experiments reveal TDP-43-dependent defects in synaptic vesicle endocytosis. These deficits can be partially restored by OE of Hsc70-4, cysteine-string protein (Csp), or dynamin. This suggests that TDP-43 toxicity results in part from impaired activity of the synaptic CSP/Hsc70 chaperone complex impacting dynamin function. Finally, Hsc70-4/HSPA8 expression is also post-transcriptionally reduced in fly and human induced pluripotent stem cell (iPSC) C9orf72 models, suggesting a common disease pathomechanism. Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by synaptic failure. Coyne et al. show that in multiple models of ALS, ranging from Drosophila to mice to patient-derived motor neurons, deficits in synaptic vesicle cycling can be explained by dysregulation of the Hsc70-4/HSPA8 chaperone

Inappropriate p53 Activation During Development Induces Features of CHARGE Syndrome

CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome

Identified single-nucleotide polymorphisms and haplotypes at 16q22.1 increase diabetic nephropathy risk in Han Chinese population

Abstract Background Diabetic nephropathy (DN) has become one of the most common causes of end-stage renal disease (ESRD) in many countries, such as 44.5% in Taiwan. Previous studies have shown that there is a genetic component to ESRD. Studies attempting to determine which genetic variants are related to DN in Han Chinese are limited. A case–control study was conducted to identify DN susceptibility variants in Han Chinese patients with type 2 diabetes. Results We included 574 unrelated type 2 diabetes patients (217 DN cases and 357 controls), who were genotyped using Illumina HumanHap550-Duo BeadChip. In single-SNP association tests, the SNPs rs11647932, rs11645214, and rs6499323 located at 16q22.1 under the additive-effect disease model were significantly associated with an approximately 2-fold increased risk of DN. In haplotype association tests, identified haplotypes located in the chromosome 16q22.1 region (containing ST3GAL2, COG4, SF3B3, and IL34 genes) raised DN risk. The strongest association was found with haplotype rs2288491-rs4985534-rs11645214 (C-C-G) (adjusted odds ratio [AOR] 1.93, 95% confidence interval [CI] 1.83-2.03, p = 6.25 × 10−7), followed by haplotype rs8052125-rs2288491-rs4985534-rs11645214 (G-C-C-G) (AOR 1.92, 95% CI 1.82-2.02, p = 6.56 × 10−7), and haplotype rs2303792-rs8052125-rs2288491-rs4985534-rs11645214 (A-G-C-C-G) (AOR 1.91, 95% CI 1.81-2.01, p = 1.15 × 10−6). Conclusions Our results demonstrate that the novel SNPs and haplotypes located at the 16q22.1 region may involve in the biological pathways of DN in Han Chinese patients with type 2 diabetes. This study can provide new insights into the etiology of DN.http://deepblue.lib.umich.edu/bitstream/2027.42/109508/1/12863_2014_Article_113.pd

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy

Background: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. Methods: We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo. Results: We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. Conclusion: Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration. Graphical Abstract: [Figure not available: see fulltext.]

Anesthetic Propofol Reduces Endotoxic Inflammation by Inhibiting Reactive Oxygen Species-regulated Akt/IKKβ/NF-κB Signaling

BACKGROUND: Anesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS) induces inflammation through toll-like receptor (TLR) 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Non-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS) and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKβ (Ser180) and nuclear factor (NF)-κB (Ser536); the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473) partly by reducing reactive oxygen species (ROS) generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages. CONCLUSIONS/SIGNIFICANCE: These results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKβ/NF-κB signaling pathways

Association of body mass index, metabolic health status and clinical outcomes in acute myocardial infarction patients: a national registry-based study

IntroductionObesity is an important risk factor for acute myocardial infarction (AMI), but the interplay between metabolic health and obesity on AMI mortality has been controversial. In this study, we aimed to elucidate the risk of short- and long-term all-cause mortality by obesity and metabolic health in AMI patients using data from a multi-ethnic national AMI registry.MethodsA total of 73,382 AMI patients from the national Singapore Myocardial Infarction Registry (SMIR) were included. These patients were classified into four groups based on the presence or absence of metabolic diseases, diabetes mellitus, hyperlipidaemia, and hypertension, and obesity: (1) metabolically-healthy-normal-weight (MHN); (2) metabolically-healthy-obese (MHO); (3) metabolically-unhealthy-normal-weight (MUN); and (4) metabolically-unhealthy-obese (MUO).ResultsMHO patients had reduced unadjusted risk of all-cause in-hospital, 30-day, 1-year, 2-year, and 5-year mortality following the initial MI event. However, after adjusting for potential confounders, the protective effect from MHO on post-AMI mortality was lost. Furthermore, there was no reduced risk of recurrent MI or stroke within 1-year from onset of AMI by the MHO status. However, the risk of 1-year mortality was higher in female and Malay AMI patients with MHO compared to MHN even after adjusting for confounders.ConclusionIn AMI patients with or without metabolic diseases, the presence of obesity did not affect mortality. The exception to this finding were female and Malay MHO who had worse long-term AMI mortality outcomes when compared to MHN suggesting that the presence of obesity in female and Malay patients may confer worsened outcomes