Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus.

Hepatitis C virus (HCV) infection is a leading cause of hepatocellular carcinoma (HCC), mainly through cirrhosis induction, spurring research for a deeper understanding of HCV versus host interactions in cirrhosis. The present study investigated crosstalks between HCV infection and UNC5A, a netrin-1 dependence receptor that is inactivated in cancer. UNC5A and HCV parameters were monitored in patients samples (n=550) as well as in in vitro. In patients, UNC5A mRNA expression is significantly decreased in clinical HCV(+) specimens irrespective of the viral genotype, but not in (HBV)(+) liver biopsies, as compared to uninfected samples. UNC5A mRNA is downregulated in F2 (3-fold; P=0.009), in F3 (10-fold, P=0.0004) and more dramatically so in F4/cirrhosis (44-fold; P<0.0001) histological stages of HCV(+) hepatic lesions compared to histologically matched HCV(-) tissues. UNC5A transcript was found strongly downregulated in HCC samples (33-fold; P<0.0001) as compared with non-HCC samples. In vivo, association of UNC5A transcripts with polyribosomes is decreased by 50% in HCV(+) livers. Consistent results were obtained in vitro showing HCV-dependent depletion of UNC5A in HCV-infected hepatocyte-like cells and in primary human hepatocytes. Using luciferase reporter constructs, HCV cumulatively decreased UNC5A transcription from the UNC5 promoter and translation in a UNC5A 5'UTR-dependent manner. Proximity ligation assays, kinase assays, as well as knockdown and forced expression experiments identified UNC5A as capable of impeding autophagy and promoting HCV restriction through specific impact on virion infectivity, in a cell death-independent and DAPK-related manner. In conclusion, while the UNC5A dependence receptor counteracts HCV persistence through regulation of autophagy in a DAPK-dependent manner, it is dramatically decreased in all instances in HCC samples, and specifically by HCV in cirrhosis. Such data argue for the evaluation of the implication of UNC5A in liver carcinogenesis.

Precise control of thermal conductivity at the nanoscale through individual phonon-scattering barriers.

The ability to precisely control the thermal conductivity (kappa) of a material is fundamental in the development of on-chip heat management or energy conversion applications. Nanostructuring permits a marked reduction of kappa of single-crystalline materials, as recently demonstrated for silicon nanowires. However, silicon-based nanostructured materials with extremely low kappa are not limited to nanowires. By engineering a set of individual phonon-scattering nanodot barriers we have accurately tailored the thermal conductivity of a single-crystalline SiGe material in spatially defined regions as short as approximately 15 nm. Single-barrier thermal resistances between 2 and 4 x 10(-9) m(2) K W(-1) were attained, resulting in a room-temperature kappa down to about 0.9 W m(-1) K(-1), in multilayered structures with as little as five barriers. Such low thermal conductivity is compatible with a totally diffuse mismatch model for the barriers, and it is well below the amorphous limit. The results are in agreement with atomistic Green's function simulations.

"Nanoparticle-in-alloy" approach to efficient thermoelectrics: silicides in SiGe.

We present a "nanoparticle-in-alloy" material approach with silicide and germanide fillers leading to a potential 5-fold increase in the thermoelectric figure of merit of SiGe alloys at room temperature and 2.5 times increase at 900 K. Strong reductions in computed thermal conductivity are obtained for 17 different types of silicide nanoparticles. We predict the existence of an optimal nanoparticle size that minimizes the nanocomposite's thermal conductivity. This thermal conductivity reduction is much stronger and strikingly less sensitive to nanoparticle size for an alloy matrix than for a single crystal one. At the same time, nanoparticles do not negatively affect the electronic conduction properties of the alloy. The proposed material can be monolithically integrated into Si technology, enabling an unprecedented potential for micro refrigeration on a chip. High figure-of-merit at high temperatures (ZT approximately 1.7 at 900 K) opens up new opportunities for thermoelectric power generation and waste heat recovery at large scale.

Maturation of caffeine N-demethylation in infancy: a study using the 13CO2 breath test.

Four premature neonates and eight infants 1-19 months old received caffeine for apnea. The usual morning oral dose was substituted by 1,3,7 13C-trimethylxanthine (13C-tri CAF) as the citrate salt. Five breath samples were collected the day before (day 1) and the day of 13C-tri CAF administration (day 2). Plasma (after each breath collection) and urine were collected on day 2. 13C-CO2 exhalation was determined by isotope ratio mass spectrometry. Caffeine and its metabolites were measured using high-pressure liquid chromatography. Assessment of the labeled CO2 in the breath revealed no detectable 13C-tri CAF N-demethylation activity in infants before 45 wk postconceptional age. However, demethylation (as urinary metabolites) has been detected before that age. Two-, 4-, and 6-h cumulative excretion of 13C-tri CAF as 13C-CO2 increased with postnatal age and correlated with caffeine plasma clearance (r = 0.840, p less than 0.01). These results were consistent with those obtained for urinary metabolites. In one infant (19 months old) the cumulative excretion of 13C-CO2 while crying was 65% of the value observed during quiet breathing. The measurement of caffeine demethylation using the caffeine CO2 breath test is feasible in infants and is a safe and noninvasive method to determine age related changes in P4501-dependent N-demethylase activity.