197 research outputs found
Explaining the U-Shape of the Referral Hiring Pattern in a Search Model with Heterogeneous Workers
Evaporated manganese films as a starting point for the preparation of thin-layer MnO x water-oxidation anodes
A novel method to prepare anodes for water electrolysis cells has been developed, which starts from layers of elemental manganese deposited by physical vapour deposition (PVD) on indium-doped tin oxide (ITO). Oxidation in dry air at 300 °C transforms this metallic Mn layer into a manganese(II)-rich MnOx coating (x = 1â1.3), which also contains a buried layer of an InâSn alloy originating from reactions with the ITO support. The MnOx films are well connected to the underlying substrate and act as efficient catalysts for water-oxidation catalysis (WOC) at neutral pH. Detailed post-operando analyses using XRD, SEM, TEM and XAS revealed that the dense MnO/Mn3O4 film is virtually not affected by 2 h of electrochemical WOC at E â +1.8 V vs. RHE, corresponding well to the observed good stability of catalytic currents, which is unusual for such thin layers of a MnOx catalyst. The current densities during electrolyses are so far low (i â 50â100 ÎŒA cmâ2 at pH 7), but optimization of the preparation process may allow for significant improvements. This new, rather easy, and adaptable preparation method for stable, thin-layer MnOx water-oxidation anodes could thus prove to be very useful for a variety of applications
Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma
<p>Abstract</p> <p>Background</p> <p>Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC.</p> <p>Methods</p> <p>We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of <it>FGF19 </it>and <it>FGFR4 </it>to regulate their concentrations.</p> <p>Results</p> <p>We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (<it>P </it>< 0.05). Univariate and multivariate analyses revealed that the tumor <it>FGF19 </it>mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (<it>P </it>< 0.01, <it>n </it>= 12) and invasion (<it>P </it>< 0.01, <it>n </it>= 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (<it>P </it>< 0.01, <it>n </it>= 12). Inversely, decreasing <it>FGF19 </it>and <it>FGFR4 </it>expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (<it>P </it>< 0.01, <it>n </it>= 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (<it>P </it>< 0.01, <it>n </it>= 29).</p> <p>Conclusions</p> <p>FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.</p
Multi-Wavelength Variability of BL Lacertae Measured with High Time Resolution
In an effort to locate the sites of emission at different frequencies and
physical processes causing variability in blazar jets, we have obtained high
time-resolution observations of BL Lacertae over a wide wavelength range: with
the \emph{Transiting Exoplanet Survey Satellite} (TESS) at 6,000-10,000 \AA\
with 2-minute cadence; with the Neil Gehrels \emph{Swift} satellite at optical,
UV, and X-ray bands; with the Nuclear Spectroscopic Telescope Array at hard
X-ray bands; with the \emph{Fermi} Large Area Telescope at -ray
energies; and with the Whole Earth Blazar Telescope for measurement of the
optical flux density and polarization. All light curves are correlated, with
similar structure on timescales from hours to days. The shortest timescale of
variability at optical frequencies observed with TESS is hr. The
most common timescale is ~hr, comparable with the minimum timescale of
X-ray variability, 14.5 hr. The multi-wavelength variability properties cannot
be explained by a change solely in the Doppler factor of the emitting plasma.
The polarization behavior implies that there are both ordered and turbulent
components to the magnetic field in the jet. Correlation analysis indicates
that the X-ray variations lag behind the -ray and optical light curves
by up to days. The timescales of variability, cross-frequency lags,
and polarization properties can be explained by turbulent plasma that is
energized by a shock in the jet and subsequently loses energy to synchrotron
and inverse Compton radiation in a magnetic field of strength GComment: 33 pages, 25 figures, 14 tables. Accepted to Ap
Association study in the 5q31-32 linkage region for schizophrenia using pooled DNA genotyping
<p>Abstract</p> <p>Background</p> <p>Several linkage studies suggest that chromosome 5q31-32 might contain risk loci for schizophrenia (SZ). We wanted to identify susceptibility genes for schizophrenia within this region.</p> <p>Methods</p> <p>We saturated the interval between markers D5S666 and D5S436 with 90 polymorphic microsatellite markers and genotyped two sets of DNA pools consisting of 300 SZ patients of Bulgarian origin and their 600 parents. Positive associations were followed-up with SNP genotyping.</p> <p>Results</p> <p>Nominally significant evidence for association (p < 0.05) was found for seven markers (D5S0023i, IL9, RH60252, 5Q3133_33, D5S2017, D5S1481, D5S0711i) which were then individually genotyped in the trios. The predicted associations were confirmed for two of the markers: D5S2017, localised in the <it>SPRY4-FGF1 </it>locus (p = 0.004) and IL9, localized within the IL9 gene (p = 0.014). Fine mapping was performed using single nucleotide polymorphisms (SNPs) around D5S2017 and IL9. In each region four SNPs were chosen and individually genotyped in our full sample of 615 SZ trios. Two SNPs showed significant evidence for association: rs7715300 (p = 0.001) and rs6897690 (p = 0.032). Rs7715300 is localised between the <it>TGFBI </it>and <it>SMAD5 </it>genes and rs6897690 is within the <it>SPRY4 </it>gene.</p> <p>Conclusion</p> <p>Our screening of 5q31-32 implicates three potential candidate genes for SZ: <it>SMAD5</it>, <it>TGFBI </it>and <it>SPRY4</it>.</p
Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases
Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy
\ua9 The Author(s) 2024.In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3â/â; ttn.1+/â) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases
The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases.
Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes
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