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.     

多晶硅电阻中晶粒数、晶粒平均长度及激活能的确定

提出了一种基于实测伏安特性确定多晶硅电阻中晶粒数及晶粒平均长度的方法。用该法得出的结果同透射电子显微镜的实测统计结果符合较好，平均偏差小于１５％，给出了基于多晶硅电阻电流温度关系实测曲线得出的晶粒边界激活能。结果显示：经Ｈ２气氛４５０℃３０ｍｉｎ退火的样品，其激活能高于未退火的。     

Allometric degree distributions facilitate food-web stability

In natural ecosystems, species are linked by feeding interactions that determine energy fluxes and create complex food webs. The stability of these food webs enables many species to coexist and to form diverse ecosystems. Recent theory finds predator-prey body-mass ratios to be critically important for food-web stability. However, the mechanisms responsible for this stability are unclear. Here we use a bioenergetic consumer-resource model to explore how and why only particular predator-prey body-mass ratios promote stability in tri-trophic (three-species) food chains. We find that this 'persistence domain' of ratios is constrained by bottom-up energy availability when predators are much smaller than their prey and by enrichment-driven dynamics when predators are much larger. We also find that 97% of the tri-trophic food chains across five natural food webs exhibit body-mass ratios within the predicted persistence domain. Further analyses of randomly rewired food webs show that body mass and allometric degree distributions in natural food webs mediate this consistency. The allometric degree distributions hold that the diversity of species' predators and prey decreases and increases, respectively, with increasing species' body masses. Our results demonstrate how simple relationships between species' body masses and feeding interactions may promote the stability of complex food webs.     

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).     

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.     

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.     

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.     

The content of noradrenaline and adrenaline in the rat heart after administration of rauwolfia alkaloids

Zusammenfassung Die chemisch verwandten Rauwolfia-Alkaloide Raunescin, Isoraunescin, Deserpidin, Rescinnamin und Reserpin verursachen einen starken Abfall des Noradrenalingehaltes des Rattenherzens, wenn sie intraperitoneal in einer Dosis von 5 mg/kg gegeben werden. Der Adrenalingehalt wird nicht deutlich oder einheitlich ver?ndert. α-Yohimbin, das chemisch zu einer andern Gruppe geh?rt, hat keine Wirkung auf den Noradrenalingehalt des Herzens.

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This work was supported by a grant from the U. S. Public Health Service (H-2205) and by funds from the Eugene Higgins Trust.     

Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration

Tumor-necrosis factor (TNF), a pleiotropic cytokine, triggers physiological and pathological responses in several organs. Here we show that deletion of the mouse gene Timp3 resulted in an increase in TNF-alpha converting enzyme activity, constitutive release of TNF and activation of TNF signaling in the liver. The increase in TNF in Timp3(-/-) mice culminated in hepatic lymphocyte infiltration and necrosis, features that are also seen in chronic active hepatitis in humans. This pathology was prevented when deletion of Timp3 was combined with Tnfrsf1a deficiency. In a liver regeneration model that requires TNF signaling, Timp3(-/-) mice succumbed to liver failure. Hepatocytes from Timp3(-/-) mice completed the cell cycle but then underwent cell death owing to sustained activation of TNF. This hepatocyte cell death was completely rescued by a neutralizing antibody to TNF. Dysregulation of TNF occurred specifically in Timp3(-/-), and not Timp1(-/-) mice. These data indicate that TIMP3 is a crucial innate negative regulator of TNF in both tissue homeostasis and tissue response to injury.