Cross-regulation of viral kinases with cyclin A secures shutoff of host DNA synthesis.

Herpesviruses encode conserved protein kinases (CHPKs) to stimulate phosphorylation-sensitive processes during infection. How CHPKs bind to cellular factors and how this impacts their regulatory functions is poorly understood. Here, we use quantitative proteomics to determine cellular interaction partners of human herpesvirus (HHV) CHPKs.

The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant.

Pandemic influenza A virus (IAV) outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular basis of this species barrier is incompletely understood. Here we combine metabolic pulse labeling and quantitative proteomics to monitor protein synthesis upon infection of human cells with a human- and a bird-adapted IAV strain and observe striking differences in viral protein synthesis.

A viral kinase counteracts in vivo restriction of murine cytomegalovirus by SAMHD1.

The deoxynucleotide triphosphate (dNTP) hydrolase SAMHD1 inhibits retroviruses in non-dividing myeloid cells. Although antiviral activity towards DNA viruses has also been demonstrated, the role of SAMHD1 during cytomegalovirus (CMV) infection remains unclear. To determine the impact of SAMHD1 on the replication of CMV, we used murine CMV (MCMV) to infect a previously established SAMHD1 knockout mouse model and found that SAMHD1 inhibits the replication of MCMV in vivo.

Synthetic lethal mutations in the cyclin A interface of human cytomegalovirus.

Generally, the antagonism between host restriction factors and viral countermeasures decides on cellular permissiveness or resistance to virus infection. Human cytomegalovirus (HCMV) has evolved an additional level of self-imposed restriction by the viral tegument protein pp150. Depending on a cyclin A-binding motif, pp150 prevents the onset of viral gene expression in the S/G2 cell cycle phase of otherwise fully permissive cells.

PUL21a-Cyclin A2 interaction is required to protect human cytomegalovirus-infected cells from the deleterious consequences of mitotic entry.

Entry into mitosis is accompanied by dramatic changes in cellular architecture, metabolism and gene expression. Many viruses have evolved cell cycle arrest strategies to prevent mitotic entry, presumably to ensure sustained, uninterrupted viral replication. Here we show for human cytomegalovirus (HCMV) what happens if the viral cell cycle arrest mechanism is disabled and cells engaged in viral replication enter into unscheduled mitosis.

Chronic kidney disease in adolescent and adult patients with phenylketonuria.

Objectives: A lifelong phenylalanine-restricted diet with supplementation of a phenylalanine-free amino acid formula is recommended in patients with phenylketonuria (PKU). The effect of a long-term PKU diet on renal function and blood pressure has not been investigated yet.

Design: We analyzed renal function in 67 patients with PKU, aged 15-43 years, by measuring glomerular filtration rate (GFR) and effective renal plasma flow by isotope clearance ((51)Cr-EDTA, (123)J-Hippuran), estimated GFR, blood retention parameters, urinary protein and electrolyte excretion.

Long-term treatment with tetrahydrobiopterin in phenylketonuria: treatment strategies and prediction of long-term responders.

Tetrahydrobiopterin (BH4) responsive phenylketonuria has been described more than 10 years ago. However, criteria for the identification of long-term BH4 responsive patients are not yet established. 116 patients with phenylketonuria, aged 4-18 years, were screened for potential long-term BH4 responsiveness by at least two of the following criteria: positive neonatal BH4 loading test, putative BH4 responsive genotype, and/or milder phenotype.

The latency-associated UL138 gene product of human cytomegalovirus sensitizes cells to tumor necrosis factor alpha (TNF-alpha) signaling by upregulating TNF-alpha receptor 1 cell surface expression.

Many viruses antagonize tumor necrosis factor alpha (TNF-α) signaling in order to counteract its antiviral properties. One way viruses achieve this goal is to reduce TNF-α receptor 1 (TNFR1) on the surface of infected cells. Such a mechanism is also employed by human cytomegalovirus (HCMV), as recently reported by others and us.

Features and outcome of galactokinase deficiency in children diagnosed by newborn screening.

Galactokinase deficiency (GALK-D), an autosomal recessive disorder in the Leloir pathway, results in accumulation of galactose, galactitol, and galactonate and leads to early onset of juvenile bilateral cataract. Highest incidence of GALK-D is found in Romani populations. The migration wave due to the Yugoslavian civil war has changed the spectrum of inborn errors of metabolism within Europe.

Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria.

Hyperphenylalaninemia caused by phenylalanine hydroxylase (PAH) deficiency requires lifelong rigorous diet starting in early infancy to prevent severe neurodevelopmental handicap. In a considerable number of children with mild hyperphenylalaninemia, long-term tetrahydrobiopterin (BH4) treatment significantly improves phenylalanine (phe) tolerance, but it has never been investigated in classic phenylketonuria (PKU). We performed a BH4-loading test in 40 consecutive infants with phe serum concentrations exceeding 240 microM, who had been detected by newborn screening programs.

[The influence of normobaric hyperoxia on hepatic oxygenation--experience with an animal model].

We investigated the effect of a ventilation with an FiO2 of 1.0 on arterial and hepatic venous oxygenation in 23 Göttingen minipigs. Under balanced anaesthesia (isoflurane/fentanyl), a fibreoptic catheter was placed into a hepatic vein.

Homozygous and double heterozygous Factor V Leiden and Factor II G20210A genotypes predispose infants to thromboembolism but are not associated with an increase of foetal loss.

Prospective and controlled data about the individual risk profile in asymptomatic children with homozygous or double heterozygous risk genotypes for Factor V Leiden (FVL) and factor II (FII) G20210A are currently unavailable. The systematic and prospective observational study presented here was designed to determine the impact of the homozygous and double heterozygous FVL and FII G20210A genotypes on the prenatal and postnatal risk profiles of affected children. Risk infants and heterozygous controls were identified by screening of 85,304 neonates.

An unexpectedly high frequency of hypergalactosemia in an immigrant Bosnian population revealed by newborn screening.

In galactokinase (GALK) deficiency, galactose cannot be phosphorylated into galactose-1-phosphate, which leads to cataract formation. Neonatal screening for hypergalactosemia in Berlin has been performed by thin-layer chromatography since 1978, which detects classical galactosemia and GALK deficiency. Until 1991, GALK deficiency has not been identified in a total of approximately 260,000 samples.