A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.     

FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair

Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.     

A selective role for dopamine in stimulus-reward learning

Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards can acquire motivational properties, becoming attractive and desirable incentive stimuli. However, whether a cue acts solely as a predictor of reward, or also serves as an incentive stimulus, differs between individuals. Thus, individuals vary in the degree to which cues bias choice and potentially promote maladaptive behaviour. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus-reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of stimulus-reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus-reward learning that confers increased susceptibility to disorders of impulse control.     

Hemmungswirkungen verschiedener Indophenole auf die Wasserstoff-peroxydzersetzung durch Blutkatalase

Summary Some indophenol derivatives inhibit strongly the activity of blood catalase. These effects were investigated quantitatively and compared with similar effects due to other oxidizing and reducing agents.     

Antibiotika als pflanzliche Plasmagifte

Summary The toxic action oflycomarasmine (a wilting agent produced byFusarium lycopersici Sacc., the causal organism of tomato-wilting) and ofpatulin (clavacin, an antibiotic produced byPenicillium patulum and by some other fungi) on some test-objects is studied (anthocyanin-test with red turnips, plasma-streaming test withSpirogyra etc.). Both substances are able to destroy for instance the semipermeability of the plasma boundary layer; but patulin proves to be more toxic for these objects than lycomarasmine, the specific poison of the tomato wilting disease.     

Hemmungswirkung verschiedener Chinone auf die Eiweißspaltung durch Papain

Summary With the intention to clarify the mechanism of action of the antibiotic effect of some quinones the inhibition of the activity of papain by various quinones was measured. The results let it appear improbable that there is any relation between the antibacterial effect of the quinones and their inhibition power on papain. On the other hand a close parallelism was found in the strength of inhibition of the same quinones on papain, urease and catalase. The mechanism of action of the quinone inhibition of these three enzymes must be regarded as a very similar one.

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Ausführliche Veröffentlichung mit weiteren Belegen folgt in den Monatsheften für Chemie (Wien).     

Glycoprotein misfolding in the endoplasmic reticulum: identification of released oligosaccharides reveals a second ER-associated degradation pathway for Golgi-retrieved proteins

Endoplasmic reticulum-associated degradation (ERAD) is a key cellular process whereby misfolded proteins are removed from the endoplasmic reticulum (ER) for subsequent degradation by the ubiquitin/proteasome system. In the present work, analysis of the released, free oligosaccharides (FOS) derived from all glycoproteins undergoing ERAD, has allowed a global estimation of the mechanisms of this pathway rather than following model proteins through degradative routes. Examining the FOS produced in endomannosidase-compromised cells following α-glucosidase inhibition has revealed a mechanism for clearing Golgi-retrieved glycoproteins that have failed to enter the ER quality control cycle. The Glc₃Man₇GlcNAc₂ FOS species has been shown to be produced in the ER lumen by a mechanism involving a peptide: N-glycanase-like activity, and its production was sensitive to disruption of Golgi-ER trafficking. The detection of this oligosaccharide was unaffected by the overexpression of EDEM1 or cytosolic mannosidase, both of which increased the production of previously characterised cytosolically localised FOS. The lumenal FOS identified are therefore distinct in their production and regulation compared to FOS produced by the conventional route of misfolded glycoproteins directly removed from the ER. The production of such lumenal FOS is indicative of a novel degradative route for cellular glycoproteins that may exist under certain conditions.     

Diel use of water by reintroduced bighorn sheep

Water sources are an important habitat component for populations of bighorn sheep ( Ovis canadensis ), and the technique of sampling at water sources has been used extensively to study behaviors and estimate parameters of bighorn populations. Little is known, however, concerning the time of day at which groups of bighorns visit water. Understanding when bighorns visit water sources will allow wildlife investigators to conduct sampling when bighorns are most likely to be present at this resource. We quantified use of 7 water sources by reintroduced bighorn sheep during summer 2005 and 2006 on Antelope Island State Park, Utah. Our purpose was to determine if female, male, or mixed-sex groups visited water at a particular time and if visits to this resource by all bighorns differed in time during drought conditions compared with nondrought conditions. The mean time that all bighorns visited water was 14:22 ( s = 3:08 hours). No time differences existed among female, male, or mixed-sex groups or between drought and nondrought conditions. Our results provide wildlife investigators with a time frame for activating motion-sensor cameras or sampling at water sources, which will increase the likelihood of photographing or observing reintroduced Rocky Mountain bighorn sheep at water sources in portions of the Great Basin Desert.     

Genetic differentiation of rare and common varieties of Eriogonum shockleyi (Polygonaceae) in Idaho using ISSR variability

Idaho populations of Eriogonum shockleyi are divided taxonomically into 2 varieties: E. shockleyi var. packardae , which is endemic to Idaho, and the typical variety, which is widespread in the western United States. Recent morphological investigations of E. shockleyi in Idaho have identified potentially reliable morphological characters for field identification of the subspecific taxa. This paper investigates the genetic basis for the separation of the 2 varieties of E. shockleyi using inter simple-sequence repeats (ISSR) markers. Although we found some morphological differences between the populations that correlated with the 2 varieties, we identified no molecular markers in this study to distinguish between them. Morphological measurements obtained in the field indicate that although a population may have an overall average morphology that defines the variety, some individuals in nearly all populations have putative diagnostic characters that define the other variety. The morphological characters used to distinguish the 2 varieties are most likely the result of environmental variability and could result from differences in precipitation and soil water retention. Alternatively, high levels of outcrossing through pollen flow could be obscuring selection for morphological characters at particular sites.