S-(2-Succinyl)cysteine:a novel chemical modification of tissue proteins by a Krebs cycle intermediate

S-(2-Succinyl)cysteine (2SC) has been identified as a chemical modification in plasma proteins, in the non-mercaptalbumin fraction of human plasma albumin, in human skin collagen, and in rat skeletal muscle proteins and urine. 2SC increases in human skin collagen with age and is increased in muscle protein of diabetic vs. control rats. The concentration of 2SC in skin collagen and muscle protein correlated strongly with that of the advanced glycation/lipoxidation end-product (AGE/ALE), N(epsilon)-(carboxymethyl)lysine (CML). 2SC is formed by a Michael addition reaction of cysteine sulfhydryl groups with fumarate at physiological pH. Fumarate, but not succinate, inactivates the sulfhydryl enzyme, glyceraldehyde-3-phosphate dehydrogenase in vitro, in concert with formation of 2SC. 2SC is the first example of spontaneous chemical modification of protein by a metabolic intermediate in the Krebs cycle. These observations identify fumarate as an endogenous electrophile and suggest a role for fumarate in regulation of metabolism.

No major schizophrenia locus detected on chromosome 1q in a large multicenter sample

Reports of substantial evidence for genetic linkage of schizophrenia to chromosome 1q were evaluated by genotyping 16 DNA markers across 107 centimorgans of this chromosome in a multicenter sample of 779 informative schizophrenia pedigrees. No significant evidence was observed for such linkage, nor for heterogeneity in allele sharing among the eight individual samples. Separate analyses of European-origin families, recessive models of inheritance, and families with larger numbers of affected cases also failed to produce significant evidence for linkage. If schizophrenia susceptibility genes are present on chromosome 1q, their population-wide genetic effects are likely to be small.

Smoking is a major cause of premature death worldwide

Question. How many deaths were attributable to smoking in 2000 worldwide? Study design. Statistical extrapolation of epidemiological and clinical data. Main results. In the year 2000, about 12% of adults died prematurely from smoking (estimated 4.83 million uncertainty range 3.94-5.93 million). Leading causes of death attributable to smoking were cardiovascular diseases (1.69 million deaths), chronic obstructive pulmonary disease (0.97 million deaths) and lung cancer (0.85 million deaths; 71% of lung cancers were smoking related). Smoking related deaths in men were about 3 times more common than women in industrial countries, and about 7 times more common in developing countries. Authors' conclusions. Smoking was a major cause of death worldwide in 2000. © 2004 Elsevier Ltd. All rights reserved.

A single-component multidrug transporter of the major facilitator superfamily is part of a network that protects Escherichia coli from bile salt stress

Resistance to high concentrations of bile salts in the human intestinal tract is vital for the survival of enteric bacteria such as Escherichia coli. Although the tripartite AcrAB-TolC efflux system plays a significant role in this resistance, it is purported that other efflux pumps must also be involved. We provide evidence from a comprehensive suite of experiments performed at two different pH values (7.2 and 6.0) that reflect pH conditions that E. coli may encounter in human gut that MdtM, a single-component multidrug resistance transporter of the major facilitator superfamily, functions in bile salt resistance in E. coli by catalysing secondary active transport of bile salts out of the cell cytoplasm. Furthermore, assays performed on a chromosomal ΔacrB mutant transformed with multicopy plasmid encoding MdtM suggested a functional synergism between the single-component MdtM transporter and the tripartite AcrAB-TolC system that results in a multiplicative effect on resistance. Substrate binding experiments performed on purified MdtM demonstrated that the transporter binds to cholate and deoxycholate with micromolar affinity, and transport assays performed on inverted vesicles confirmed the capacity of MdtM to catalyse electrogenic bile salt/H(+) antiport.

Psychological responses after a major fatal earthquake: The effect of preitraumatic dissociation and posttraumatic stress symptoms on anxiety and depression.

Following trauma, most people with initial symptoms of stress recover, but it is important to identify those at risk for continuing difficulties so resources are allocated appropriately. There has been limited investigation of predictors of posttraumatic stress disorder following natural disasters. This study assessed psychological difficulties experienced in 101 adult treatment seekers following exposure to a significant earthquake. Peritraumatic dissociation, posttraumatic stress symptoms, anxiety, depression, and emotional support were assessed. Path analysis was used to determine whether the experience of some psychological difficulties predicted the experience of other difficulties. As hypothesized, peritraumatic dissociation was found to predict posttraumatic stress symptoms and anxiety. Posttraumatic stress symptoms then predicted anxiety and depression. Depression and anxiety were highly correlated. Contrary to expectations, emotional support was not significantly related to other psychological variables. These findings justify the provision of psychological support following a natural disaster and suggest the benefit of assessing peritraumatic dissociation and posttraumatic stress symptoms soon after the event to identify people in need of monitoring and intervention.

GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence

Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts.

The radiated energy budget of Chromospheric Plasma in a major solar flare deduced from multi-wavelength observations

This paper presents measurements of the energy radiated by the lower solar atmosphere, at optical, UV, and EUV wavelengths, during an X-class solar flare (SOL2011-02-15T01:56) in response to an injection of energy assumed to be in the form of nonthermal electrons. Hard X-ray observations from RHESSI were used to track the evolution of the parameters of the nonthermal electron distribution to reveal the total power contained in flare accelerated electrons. By integrating over the duration of the impulsive phase, the total energy contained in the nonthermal electrons was found to be >2 × 1031 erg. The response of the lower solar atmosphere was measured in the free–bound EUV continua of H i (Lyman), He i, and He ii, plus the emission lines of He ii at 304 Å and H i (Lyα) at 1216 Å by SDO/EVE, the UV continua at 1600 Å and 1700 Å by SDO/AIA, and the white light continuum at 4504 Å, 5550 Å, and 6684 Å, along with the Ca ii H line at 3968 Å using Hinode/SOT. The summed energy detected by these instruments amounted to ~3 × 1030 erg; about 15% of the total nonthermal energy. The Lyα line was found to dominate the measured radiative losses. Parameters of both the driving electron distribution and the resulting chromospheric response are presented in detail to encourage the numerical modeling of flare heating for this event, to determine the depth of the solar atmosphere at which these line and continuum processes originate, and the mechanism(s) responsible for their generation.

Biotransformation of zearalenone and zearalenols to their major glucuronide metabolites reduces estrogenic activity

Zearalenone (ZEN) is a mycotoxin produced by Fusarium fungi. Once ingested, ZEN may be absorbed andmetabolised to a- and b-zearalenol (a-ZOL, b-ZOL), and to a lesser extent a- and b-zearalanol (a-ZAL,b-ZAL). Further biotransformation to glucuronide conjugates also occurs to facilitate the elimination ofthese toxins from the body. Unlike ZEN and its metabolites, information regarding the estrogenic activityof these glucuronide conjugates in various tissues is lacking. ZEN-14-O-glucuronide, a-ZOL-14-O-glucuronide,a-ZOL-7-O-glucuronide, b-ZOL-14-O-glucuronide and b-ZOL-16-O-glucuronide, previouslyobtained as the major products from preparative enzymatic synthesis, were investigated for their potentialto cause endocrine disruption through interference with estrogen receptor transcriptional activity.All five glucuronide conjugates showed a very weak agonist response in an estrogen responsive reportergene assay (RGA), with activity ranging from 0.0001% to 0.01% of that of 17b-estradiol, and also lessthan that of ZEN, a-ZOL and b-ZOL which have previously shown estrogenic potencies of the order 17bestradiol> a-ZOL > ZEN > b-ZOL. Confirmatory mass spectrometry revealed that any activity observedwas likely a result of minor deconjugation of the glucuronide moiety. This study confirms that formationof ZEN and ZOL glucuronides is a detoxification reaction with regard to estrogenicity, serving as a potentialhost defence mechanism against ZEN-induced estrogenic activity.

Multidrug transporter proteins of the major facilitator superfamily: not only for drug efflux

Multidrug resistance in prokaryotes is due primarily to efflux of offending antimicrobials from the cell by representatives of several different families of integral membrane transporter proteins. Clearly, in evolutionary terms, these proteins did not arise specifically to pump human-made antimicrobials out of the cell and thereby confer resistance. Despite this, often only their role in antibiotic resistance is characterised and highlighted.
In recent years, however, a transition from the traditional anthropocentric perception of antibiotic resistance mechanisms in microorganisms has occurred, with naturally produced antimicrobials now generally regarded as physiologically important signalling molecules or sources of nutrition for bacteria rather than antimicrobial agents, and bacterial multidrug efflux proteins not merely as a defensive response to antimicrobials but as important players in fundamental physiological processes such as cellular homeostasis.
This emerging perspective supports the notion that a better understanding of the complexities of infection and multidrug resistance in bacteria can be achieved via a more detailed understanding of those physiological processes. In this chapter, we review the ‘true’ physiological roles of multidrug efflux proteins of the largest non-ATP-hydrolysing family of membrane transporters, the major facilitator superfamily, and explore the evidence for their function in processes such as pH and metal homeostasis, import and export of metabolites and biofilm formation

The British conservative party and Europe:The choosing of John Major

This article provides an empirical analysis of voting behaviour in the second ballot of the 1990 Conservative leadership contest that resulted in John Major becoming party leader and prime minister. Seven hypotheses of voting behaviour are generated from the extant literature relating voting to socio-economic variables (occupational and educational background), political variables (parliamentary experience, career status, age and electoral marginality) and ideological variables (drawn from survey data on MPs' positions on economic, European and moral issues). These hypotheses are tested using data on voting intentions gathered from published lists of MPs' declarations, interviews with each of the leadership campaign teams, and correspondence with MPs. Bivariate relationships are presented, followed by logistic regression analysis to isolate the unique impact that each variable had on voting. This shows that educational background, parliamentary experience and (especially) attitudes to Europe were the key factors determining voting. The importance of Europe in the contest is particularly instructive: the severe problems for Major's leadership which were caused by the issue can be attributed to, and understood in the context of, the 1990 contest in which he became leader.