Increased interferon alpha receptor 2 mRNA levels is associated with renal cell carcinoma metastasis

<p>Abstract</p> <p>Background</p> <p>Interferon-α (IFN-α) is one of the central agents in immunotherapy for renal cell carcinoma (RCC) and binds to the IFN-α receptor (IFNAR). We investigated the role of IFNAR in RCC.</p> <p>Methods</p> <p>We quantified IFNAR mRNA expression in paired tumor and non-tumor samples from the surgical specimens of 103 consecutive patients with RCC using a real-time reverse transcription polymerase chain reaction (RT-PCR), and IFNAR2 protein using Western blotting.</p> <p>Results</p> <p>The absolute level of IFNAR1 and IFNAR2 mRNAs in tumor and non-tumor tissues did not correlate with the malignant and metastatic profiles. The relative yields of the PCR product from the tumor tissue to that from the corresponding non-tumor tissue (T/N) for the expression of IFNAR mRNAs were calculated. While the T/N ratio of IFNAR1 did not correlate with any factor, a high T/N ratio of IFNAR2 correlated with poor differentiation (<it>P </it>< 0.05), local invasion (<it>P </it>< 0.001), and metastasis (<it>P </it>< 0.0001). By multivariate analysis, a high T/N ratio of IFNAR2 predicted a shortened overall survival in all cases (<it>P </it>< 0.05) and a shorter disease-free survival in those without metastasis (M0; 68 cases, <it>P </it>< 0.05). Impressively, patients with a poorer response to IFN-α treatment had a higher IFNAR2 T/N ratio than those who had a good response (P < 0.05). IFNAR2c protein expression was higher in the primary tumors in patients with metastases (M1; 35 cases) compared to those without ( P < 0.0001).</p> <p>Conclusion</p> <p>IFNAR2 is associated with the progression of RCC.</p

Magnetic and electronic phase transitions probed by nanomechanical resonators

The reduced dimensionality of two-dimensional (2D) materials results in characteristic types of magnetically and electronically ordered phases. However, only few methods are available to study this order, in particular in ultrathin insulating antiferromagnets that couple weakly to magnetic and electronic probes. Here, we demonstrate that phase transitions in thin membranes of 2D antiferromagnetic FePS3, MnPS3 and NiPS3 can be probed mechanically via the temperature-dependent resonance frequency and quality factor. The observed relation between mechanical motion and antiferromagnetic order is shown to be mediated by the specific heat and reveals a strong dependence of the Néel temperature of FePS3 on electrostatically induced strain. The methodology is not restricted to magnetic order, as we demonstrate by probing an electronic charge-density-wave phase in 2H-TaS2. It thus offers the potential to characterize phase transitions in a wide variety of materials, including those that are antiferromagnetic, insulating or so thin that conventional bulk characterization methods become unsuitable

A prevalent mutation with founder effect in Spanish Recessive Dystrophic Epidermolysis Bullosa families

<p>Abstract</p> <p>Background</p> <p>Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genodermatosis caused by more than 500 different mutations in the <it>COL7A1 </it>gene and characterized by blistering of the skin following a minimal friction or mechanical trauma.</p> <p>The identification of a cluster of RDEB pedigrees carrying the c.6527insC mutation in a specific area raises the question of the origin of this mutation from a common ancestor or as a result of a hotspot mutation. The aim of this study was to investigate the origin of the c.6527insC mutation.</p> <p>Methods</p> <p>Haplotypes were constructed by genotyping nine single nucleotides polymorphisms (SNPs) throughout the <it>COL7A1 </it>gene. Haplotypes were determined in RDEB patients and control samples, both of Spanish origin.</p> <p>Results</p> <p>Sixteen different haplotypes were identified in our study. A single haplotype cosegregated with the c.6527insC mutation.</p> <p>Conclusion</p> <p>Haplotype analysis showed that all alleles carrying the c.6527insC mutation shared the same haplotype cosegregating with this mutation (<b><it>CCGCTCAAA_6527insC</it></b>), thus suggesting the presence of a common ancestor.</p

Heritability of non-speech auditory processing skills

Recent insight into the genetic bases for autism spectrum disorder, dyslexia, stuttering, and language disorders suggest that neurogenetic approaches may also reveal at least one etiology of auditory processing disorder (APD). A person with an APD typically has difficulty understanding speech in background noise despite having normal pure-tone hearing sensitivity. The estimated prevalence of APD may be as high as 10% in the pediatric population, yet the causes are unknown and have not been explored by molecular or genetic approaches. The aim of our study was to determine the heritability of frequency and temporal resolution for auditory signals and speech recognition in noise in 96 identical or fraternal twin pairs, aged 6–11 years. Measures of auditory processing (AP) of non-speech sounds included backward masking (temporal resolution), notched noise masking (spectral resolution), pure-tone frequency discrimination (temporal fine structure sensitivity), and nonsense syllable recognition in noise. We provide evidence of significant heritability, ranging from 0.32 to 0.74, for individual measures of these non-speech-based AP skills that are crucial for understanding spoken language. Identification of specific heritable AP traits such as these serve as a basis to pursue the genetic underpinnings of APD by identifying genetic variants associated with common AP disorders in children and adults

Totally biological composite aortic stentless valved conduit for aortic root replacement: 10-year experience

<p>Abstract</p> <p>Objectives</p> <p>To retrospectively analyze the clinical outcome of a totally biological composite stentless aortic valved conduit (No-React^®BioConduit) implanted using the Bentall procedure over ten years in a single centre.</p> <p>Methods</p> <p>Between 27/10/99 and 19/01/08, the No-React^®BioConduit composite graft was implanted in 67 patients. Data on these patients were collected from the in-hospital database, from patient notes and from questionnaires. A cohort of patients had 2D-echocardiogram with an average of 4.3 ± 0.45 years post-operatively to evaluate valve function, calcification, and the diameter of the conduit.</p> <p>Results</p> <p>Implantation in 67 patients represented a follow-up of 371.3 patient-year. Males were 60% of the operated population, with a mean age of 67.9 ± 1.3 years (range 34.1-83.8 years), 21 of them below the age of 65. After a mean follow-up of 7.1 ± 0.3 years (range of 2.2-10.5 years), more than 50% of the survivors were in NYHA I/II and more than 60% of the survivors were angina-free (CCS 0). The overall 10-year survival following replacement of the aortic valve and root was 51%. During this period, 88% of patients were free from valved-conduit related complications leading to mortality. Post-operative echocardiography studies showed no evidence of stenosis, dilatation, calcification or thrombosis. Importantly, during the 10-year follow-up period no failures of the valved conduit were reported, suggesting that the tissue of the conduit does not structurally change (histology of one explant showed normal cusp and conduit).</p> <p>Conclusions</p> <p>The No-React^®BioConduit composite stentless aortic valved conduit provides excellent long-term clinical results for aortic root replacement with few prosthesis-related complications in the first post-operative decade.</p

Fabry disease in children and the effects of enzyme replacement treatment

Fabry disease is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficiency in the activity of the lysosomal enzyme, α-galactosidase A. In affected patients, the enzyme substrate, globotriaosylceramide (Gb3), accumulates in cells of various tissues and organs. Lysosomal accumulation of Gb3 begins in utero, and signs and symptoms of Fabry disease emerge in childhood and adolescence. The earliest presenting symptoms are typically neuropathic pain and gastrointestinal problems, which can have a substantial impact on health-related quality of life. Life-threatening major organ involvement is rare in young patients, but signs of kidney dysfunction (e.g., proteinuria), left ventricular hypertrophy, and stroke have been reported in children. There are two enzyme preparations for therapy: agalsidase alfa and beta. In two clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa, including 37 children, boys demonstrated reductions in plasma Gb3 levels, and both boys and girls reported reductions in neuropathic pain and in the use of neuropathic pain medications. Heart rate variability, which is reduced in boys with Fabry disease, was statistically significantly improved with 6 months of agalsidase alfa treatment. In a single clinical study of agalsidase beta in children (n =16), skin Gb3 deposits and plasma Gb3 levels were reduced in boys. Differences exist in the administration and the safety profile of these two enzyme formulations. Follow-up of these cohorts and additional studies will be necessary to fully evaluate long-term efficacy of ERT in children with Fabry disease

Directing the evolution of Rubisco and Rubisco activase: first impressions of a new tool for photosynthesis research

During the last decade the practice of laboratory-directed protein evolution has become firmly established as a versatile tool in biochemical research by enabling molecular evolution toward desirable phenotypes or detection of novel structure–function interactions. Applications of this technique in the field of photosynthesis research are still in their infancy, but recently first steps have been reported in the directed evolution of the CO2-fixing enzyme Rubisco and its helper protein Rubisco activase. Here we summarize directed protein evolution strategies and review the progressive advances that have been made to develop and apply suitable selection systems for screening mutant forms of these enzymes that improve the fitness of the host organism. The goal of increasing photosynthetic efficiency of plants by improving the kinetics of Rubisco has been a long-term goal scoring modest successes. We discuss how directed evolution methodologies may one day be able to circumvent the problems encountered during this venture

β-Actin and γ-Actin Are Each Dispensable for Auditory Hair Cell Development But Required for Stereocilia Maintenance

Hair cell stereocilia structure depends on actin filaments composed of cytoplasmic β-actin and γ-actin isoforms. Mutations in either gene can lead to progressive hearing loss in humans. Since β-actin and γ-actin isoforms are 99% identical at the protein level, it is unclear whether each isoform has distinct cellular roles. Here, we compared the functions of β-actin and γ-actin in stereocilia formation and maintenance by generating mice conditionally knocked out for Actb or Actg1 in hair cells. We found that, although cytoplasmic actin is necessary, neither β-actin nor γ-actin is required for normal stereocilia development or auditory function in young animals. However, aging mice with β-actin– or γ-actin–deficient hair cells develop different patterns of progressive hearing loss and distinct pathogenic changes in stereocilia morphology, despite colocalization of the actin isoforms. These results demonstrate overlapping developmental roles but unique post-developmental functions for β-actin and γ-actin in maintaining hair cell stereocilia

The Derived Allele of ASPM Is Associated with Lexical Tone Perception

The ASPM and MCPH1 genes have been implicated in the adaptive evolution of the human brain [Mekel-Bobrov N. et al., 2005. Ongoing adaptive evolution of ASPM, a brain size determinant in homo sapiens. Science 309; Evans P.D. et al., 2005. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science 309]. Curiously, experimental attempts have failed to connect the implicated SNPs in these genes with higher-level brain functions. These results stand in contrast with a population-level study linking the population frequency of their alleles with the tendency to use lexical tones in a language [Dediu D., Ladd D.R., 2007. Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and microcephalin. Proc. Natl. Acad. Sci. U.S.A. 104]. In the present study, we found a significant correlation between the load of the derived alleles of ASPM and tone perception in a group of European Americans who did not speak a tone language. Moreover, preliminary results showed a significant correlation between ASPM load and hemodynamic responses to lexical tones in the auditory cortex, and such correlation remained after phonemic awareness, auditory working memory, and non-verbal IQ were controlled. As in previous studies, no significant correlation between ASPM and cognitive measures were found. MCPH1 did not correlate with any measures. These results suggest that the association between the recently derived allele of ASPM is likely to be specific and is tied to higher level brain functions in the temporal cortex related to human communication

Contribution by Polymorphonucleate Granulocytes to Elevated Gamma-Glutamyltransferase in Cystic Fibrosis Sputum

Background: Cystic fibrosis (CF) is an autosomal recessive disorder characterized by a chronic neutrophilic airways inflammation, increasing levels of oxidative stress and reduced levels of antioxidants such as glutathione (GSH). Gammaglutamyltransferase (GGT), an enzyme induced by oxidative stress and involved in the catabolism of GSH and its derivatives, is increased in the airways of CF patients with inflammation, but the possible implications of its increase have not yet been investigated in detail. Principal Findings: The present study was aimed to evaluate the origin and the biochemical characteristics of the GGT detectable in CF sputum. We found GGT activity both in neutrophils and in the fluid, the latter significantly correlating with myeloperoxidase expression. In neutrophils, GGT was associated with intracellular granules. In the fluid, gel-filtration chromatography showed the presence of two distinct GGT fractions, the first corresponding to the human plasma b-GGT fraction, the other to the free enzyme. The same fractions were also observed in the supernatant of ionomycin and fMLPactivated neutrophils. Western blot analysis confirmed the presence of a single band of GGT immunoreactive peptide in the CF sputum samples and in isolated neutrophils. Conclusions: In conclusion, our data indicate that neutrophils are able to transport and release GGT, thus increasing GGT activity in CF sputum. The prompt release of GGT may have consequences on all GGT substrates, including major inflammatory mediators such as S-nitrosoglutathione and leukotrienes, and could participate in early modulation of inflammatory response