Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention

‘There is a Time to be Born and a Time to Die’ (Ecclesiastes 3:2a): Jewish Perspectives on Euthanasia

Reviewing the publications of prominent American rabbis who have (extensively) published on Jewish biomedical ethics, this article highlights Orthodox, Conservative and Reform opinions on a most pressing contemporary bioethical issue: euthanasia. Reviewing their opinions against the background of the halachic character of Jewish (biomedical) ethics, this article shows how from one traditional Jewish textual source diverse, even contradictory, opinions emerge through different interpretations. In this way, in the Jewish debate on euthanasia the specific methodology of Jewish (bio)ethical reasoning comes forward as well as a diversity of opinion within Judaism and its branches

Serum homocysteine, vitamin B 12 and folic acid levels in different types of glaucoma

BACKGROUND: This study was performed to compare levels of serum homocysteine (Hcy), vitamin B12 and folic acid in patients with primary open-angle glaucoma (POAG), pseudoexfoliative glaucoma (PEXG), normotensive glaucoma (NTG) and healthy controls. METHODS: Twentyfive patients with POAG, 24 with PEXG, and 18 with NTG, along with 19 control healthy subjects were included this prospective study. Levels of serum Hcy were measured using immunoassay, and those of serum vitamin B12 and folic acid were measured using competitive chemiluminescent enzyme immunoassay. RESULTS: The mean Hcy concentration in the PEXG group was significantly higher (P < 0.001) as compared to the other groups. There were no significant differences with respect to the mean Hcy concentrations among other groups (P > 0.05). There were no statistical differences in serum vitamin B12 levels among POAG, PEXG, NTG and control subjects (P > 0.05). The mean serum folic acid level was significantly lower in the subjects with PEXG (P < 0.009). However, the mean folic acid concentrations among the other groups did not differ significantly (P > 0.05). CONCLUSION: Elevated levels of Hcy in PEXG may explain the role of endothelial dysfunction among patients with PEXG

The publics' understanding of daily caloric recommendations and their perceptions of calorie posting in chain restaurants

<p>Abstract</p> <p>Background</p> <p>Calorie posting in chain restaurants has received increasing attention as a policy lever to reduce energy intake. Little research has assessed consumer understanding of overall daily energy requirements or perceived effectiveness of calorie posting.</p> <p>Methods</p> <p>A phone survey was conducted from May 1 through 17, 2009 with 663 randomly selected, nationally-representative adults aged 18 and older, including an oversample of Blacks and Hispanics in the United States. To examine differences in responses by race and ethnicity (White, Black, and Hispanic) and gender, we compared responses by conducting chi-squared tests for differences in proportions.</p> <p>Results</p> <p>We found that most Americans were knowledgeable about energy requirements for moderately active men (78%) and women (69%), but underestimated energy requirements for inactive adults (60%). Whites had significantly higher caloric literacy and confidence about their caloric knowledge than Blacks and Hispanics (p < 0.05). As compared to their counterparts, Blacks, Hispanics and women reported a significantly higher likelihood of eating at a chain restaurant and of selecting lower calorie foods where caloric information was posted. Most Americans favored the government requiring chain restaurants to post calorie information on menus at the point of purchase (68%). Support for government mandated calorie posting in chain restaurants was significantly higher among Blacks, Hispanics and women as compared to their counterparts. The public was divided about the mode of caloric information that would best help them make a lower calorie decision; a third favored number of calories (35%) which is the current standard mode of presenting caloric information in chain restaurants, a third favored a physical activity equivalent (26%), and a third favored percentage of total energy intake (39%).</p> <p>Conclusion</p> <p>Mandating calorie posting in chain restaurants may be a useful policy tool for promoting energy balance, particularly among Blacks, Hispanics and women who have higher obesity risk.</p

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease

This work was supported by a research fellowship grant from the Crohn’s and Colitis in Childhood Research Association (CICRA) and a small project grant from Crohn’s and Colitis UK (CCUK). We would like to acknowledge Professor Ian Sanderson, who helped with the initial design of this work, and provided important support throughout. We would also like to thank Dr Gary Warne for his advice and assistance in the use of the sorting by flow cytometry. We would also like to thank Dr Raj Lahiri and Professor Graham Foster for the kind gift of the primers for the ISGs (2’5’ OAS and MxA)

Arcuate Fasciculus Abnormalities and Their Relationship with Psychotic Symptoms in Schizophrenia

Disruption of fronto-temporal connections involving the arcuate fasciculus (AF) may underlie language processing anomalies and psychotic features such as auditory hallucinations in schizophrenia. No study to date has specifically investigated abnormalities of white matter integrity at particular loci along the AF as well as its regional lateralization in schizophrenia. We examined white matter changes (fractional anisotropy (FA), axial diffusivity (AD), asymmetry indices) along the whole extent of the AF and their relationship with psychotic symptoms in 32 males with schizophrenia and 44 healthy males. Large deformation diffeomorphic metric mapping and Fiber Assignment Continuous Tracking were employed to characterize FA and AD along the geometric curve of the AF. Our results showed that patients with schizophrenia had lower FA in the frontal aspects of the left AF compared with healthy controls. Greater left FA and AD lateralization in the temporal segment of AF were associated with more severe positive psychotic symptoms such as delusions and hallucinations in patients with schizophrenia. Disruption of white matter integrity of the left frontal AF and accentuation of normal left greater than right asymmetry of FA/AD in the temporal AF further support the notion of aberrant fronto-temporal connectivity in schizophrenia. AF pathology can affect corollary discharge of neural signals from frontal speech/motor initiation areas to suppress activity of auditory cortex that may influence psychotic phenomena such as auditory hallucinations and facilitate elaboration of delusional content

Will the Public's Health Fall Victim to the Home Foreclosure Epidemic?

Gary Bennett and colleagues discuss the ways in which the dramatic rise in home foreclosures, particularly in the US, may have health consequences