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Strains of the human gut bacterium Escherichia coli carrying the clb gene cluster produce a secondary metabolite dubbed colibactin and have been provocatively linked to colorectal cancer in some models. Colibactin has been difficult to isolate in full, but pieces of the structure have been worked out, including an electrophilic warhead. Xue et al. found that colibactin contains two conjoined warheads, which is consistent with its ability to alkylate and cross-link DNA. Chemical synthesis and comparison to cell coculture confirm the structure and properties of this unstable and potentially carcinogenic metabolite. Science , this issue p. eaax2685 A DNA cross-linking metabolite from gut microbes is made by joining two precursor units. Colibactin is a complex secondary metabolite produced by some genotoxic gut Escherichia coli strains. The presence of colibactin-producing bacteria correlates with the frequency and severity of colorectal cancer in humans. However, because colibactin has not been isolated or structurally characterized, studying the physiological effects of colibactin-producing bacteria in the human gut has been difficult. We used a combination of genetics, isotope labeling, tandem mass spectrometry, and chemical synthesis to deduce the structure of colibactin. Our structural assignment accounts for all known biosynthetic and cell biology data and suggests roles for the final unaccounted enzymes in the colibactin gene cluster.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.

European bat lyssavirus type 2 (EBLV-2) has been isolated once previously from a bat in the UK in June 1996. In September 2002, a Daubenton's bat (Myotis daubentonif) found in Lancashire developed abnormal behaviour, including unprovoked aggression, while it was in captivity. Brain samples from the bat were tested for virus of the Lyssavirus genus, which includes EBLV-2 (genotype 6), and classical rabies virus (genotype 1). A positive fluorescent antibody test confirmed that it was infected with a lyssavirus, and PCR and genomic sequencing identified the virus as an EBLV-2a. Phylogenetic comparisons with all the published sequences from genotype 6 showed that it was closely related to the previous isolate of EBLV-2 in the UK and suggested links to isolates from bats in the Netherlands. The isolation of EBLV-2 from a bat found on the west coast of England provides evidence that this virus may be present within the UK Daubenton's bat population at a low prevalence level.

Much evidence has been gathered in support of a critical role for p53 in the cellular response to DNA damage. p53 dysfunction is associated with progression and poor prognosis of many human cancers and with a high incidence of tumours in p53 knockout mice. The absence of a p53-dependent G1 arrest that facilitates DNA repair or apoptosis might impact critically on clinical cancer in two ways. First, by abrogating the impact on therapy that operates via genotoxic damage and apoptosis; and second, by encouraging progression either by inducing genomic instability and DNA mis-repair or by permitting survival of mutants. However, experiments examining the relationship between p53 deficiency and mutation frequency have so far failed to confirm these predictions. The precise role played by p53 is therefore unclear. We now report use of a short term in vitro approach to assess the influence of p53 on radiation-induced mutations at the hprt locus in murine B cell precursors that are normally radiation ultrasensitive. We find a high number of hprt mutants among X-irradiated p53 null cells, which results from preferential survival as clonogenic mutants rather than from a p53-dependent increase in mutation rate. This result has important implications for genotoxic cancer therapy.

BackgroundThe aim was to assess the effect of a flexible dose of paroxetine, compared with clomipramine and placebo, in obsessive-compulsive disorder (OCD).MethodIn a multinational randomised study, 406 subjects with OCD of at least six months duration received double-blind mediation for up to 12 weeks. Doses were adjusted according to therapeutic effect and side-effects. Primary efficacy measures were the Yale–Brown Obsessive–Compulsive Scale and the National Institute of Mental Health Obsessive–Compulsive Scale. Secondary efficacy measures were the Montgomery–åsberg Depression Rating Scale, Symptom Check-List (90), Clinical Global Impression, and Patients' Global Evaluation.ResultsParoxetine was significantly more effective than placebo, and of comparable efficacy to clomipramine. Paroxetine had significantly superior tolerability to clomipramine on three measures: CGI efficacy index, anticholinergic adverse events, and adverse events leading to withdrawal.ConclusionParoxetine is as effective as clomipramine in the treatment of OCD. The comparable efficacy and better tolerability of paroxetine suggest that it would be an appropriate treatment for OCD.

Lymphatic malformations (LMs) are uncommon congenital lesions that may occur throughout the body, although the head and neck region is the most common site. Most LMs are seen at birth. However, they may present in adolescence or adulthood, mainly as a result of trauma or infection. We report the case of a 7-year-old boy who presented with an LM of the cervicofacial region causing airway compression. We discuss the causes of delayed presentation of these congenital lesions. An overview of the causation, natural history, diagnosis, and treatment options is presented.

Inherited myoclonus of Poll Hereford calves is characterized by hyperesthesia and myoclonic jerks of the skeletal musculature, which occur spontaneously and in response to sensory stimuli. The disease shows autosomal recessive inheritance, and significant proportions of the Poll Hereford herds in many countries are thought to be carriers of the mutant gene. Studies revealed a specific and marked (90 to 95 percent) deficit in [3H]strychnine binding sites in spinal cord membranes from myoclonic animals compared to controls, reflecting a loss of, or defect in, glycine/strychnine receptors. Spinal cord synaptosomes prepared from affected animals showed a significantly increased ability to accumulate [3H]glycine, indicating an increased capacity of the high-affinity neuronal uptake system for glycine. In contrast, stimulus-induced glycine release and spinal cord glycine concentrations were unaltered.