Toll and interleukin-1 receptor (TIR) domain-containing proteins in plants: a genomic perspective

Toll and interleukin-1 receptor (TIR) domains were originally described from comparisons of proteins found in mammals and Drosophila. They are now known to occur in several organisms, with the most TIR proteins being found in ARABIDOPSIS: our analysis of the sequenced Arabidopsis genome has revealed the presence of at least 135 proteins containing TIR domains. Several novel types of TIR-domain-containing proteins are found in Arabidopsis that are not found in other genomes. Here, we discuss the roles of TIR-domain-containing proteins in pathogen resistance and as candidate signaling modules.     

Assessing the drivers of syphilis among men who have sex with men in Switzerland reveals a key impact of screening frequency: A modelling study

Over the last decade, syphilis diagnoses among men-who-have-sex-with-men (MSM) have strongly increased in Europe. Understanding the drivers of the ongoing epidemic may aid to curb transmissions. In order to identify the drivers of syphilis transmission in MSM in Switzerland between 2006 and 2017 as well as the effect of potential interventions, we set up an epidemiological model stratified by syphilis stage, HIV-diagnosis, and behavioral factors to account for syphilis infectiousness and risk for transmission. In the main model, we used ‘reported non-steady partners’ (nsP) as the main proxy for sexual risk. We parameterized the model using data from the Swiss HIV Cohort Study, Swiss Voluntary Counselling and Testing center, cross-sectional surveys among the Swiss MSM population, and published syphilis notifications from the Federal Office of Public Health. The main model reproduced the increase in syphilis diagnoses from 168 cases in 2006 to 418 cases in 2017. It estimated that between 2006 and 2017, MSM with HIV diagnosis had 45.9 times the median syphilis incidence of MSM without HIV diagnosis. Defining risk as condomless anal intercourse with nsP decreased model accuracy (sum of squared weighted residuals, 378.8 vs. 148.3). Counterfactual scenarios suggested that increasing screening of MSM without HIV diagnosis and with nsP from once every two years to twice per year may reduce syphilis incidence (at most 12.8% reduction by 2017). Whereas, increasing screening among MSM with HIV diagnosis and with nsP from once per year to twice per year may substantially reduce syphilis incidence over time (at least 63.5% reduction by 2017). The model suggests that reporting nsP regardless of condom use is suitable for risk stratification when modelling syphilis transmission. More frequent screening of MSM with HIV diagnosis, particularly those with nsP may aid to curb syphilis transmission.     

Design,Synthesis and Pharmacological Screening of Novel Antihypertensive Agents Using Hybrid Approach

Eight derivatives of general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate were synthesized and tested for electrocardiographic, antiarrhythmic, vasorelaxing and antihypertensive activity as well as for in-vitro nitric oxide (NO) releasing ability. Compound 8b 2-(2-(4-(3-(5-benzyliden-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate, was the most potent in this series. The pharmacological results suggested that the antiarrhythmic effects of these compounds were related to their adrenolytic properties which are believed to be due to the presence of the 5-(substituted)methylen-2-(phenylimino)thiazolidin-4-one moiety with less bulky, electron donating substituent on the phenyl ring at 5th position of the thiazolidin-4-one. In conclusion, most of the synthesized compounds were significantly potent as antiarrhythmic and antihypertensive; this might be due to the presence of different pharmacopores which might act at different locations with different mode of action. Further insights of the same can be obtained by doing investigation at receptor level. The potency of compounds 8a–8h were promising enough to continue further experiments.     

Organic carbon transport and C/N ratio variations in a large tropical river: Godavari as a case study,India

This study gives an insight into the source of organic carbon and nitrogen in the Godavari river and its tributaries, the yield of organic carbon from the catchment, seasonal variability in their concentration and the ultimate flux of organic and inorganic carbon into the Bay of Bengal. Particulate organic carbon/particulate organic nitrogen (POC/PON or C/N) ratios revealed that the dominant source of organic matter in the high season is from the soil (C/N = 8–14), while in the rest of the seasons, the river-derived (in situ) phytoplankton is the major source (C/N = l–8). Amount of organic materials carried from the lower catchment and flood plains to the oceans during the high season are 3 to 91 times higher than in the moderate and low seasons. Large-scale erosion and deforestation in the catchment has led to higher net yield of organic carbon in the Godavari catchment when compared to other major world rivers. The total flux of POC, and dissolved inorganic carbon (DIC) from the Godavari river to the Bay of Bengal is estimated as 756 × 10⁹ and 2520 × 10⁹ g yr^–1, respectively. About 22% of POC is lost in the main channel because of oxidation of labile organic matter, entrapment of organic material behind dams/sedimentation along flood plains and river channel; the DIC fluxes as a function of alkalinity are conservative throughout the river channel. Finally, the C/N ratios (12) of the ultimate fluxes of particulate organic carbon suggest the dominance of refractory/stable soil organic matter that could eventually get buried in the coastal sediments on a geological time scale.     

ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia

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Fibronectin binding to Salmonella strains

Abstract Recent investigations by many workers have elucidated the mechanisms which may explain the clinical observation that an excessive intake of dietary carbohydrates can aggravate oral candidosis. These include the enhancement of growth, multiplication and adherence of Candida species to oral surfaces and the production of excessive quantities of short-chain carboxylic acids as byproducts of sugar metabolism. The resultant acidic milieu, in addition to provoking a mucosal inflammatory reaction, could also activate the highly potent phospholipases and acid proteases of Candida and suppress the growth of normal commensal flora. A unifying hypothesis encompassing the above is proposed to explain the exacerbation of mucosal candidoses observed in environments replete with carbohydrates such as glucose and sucrose.     

The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes

Background

Newborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848).

Methods

TLRA-induced NF-κB activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2.

Results

Hybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-α, and IL-1β. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848.

Conclusions

Hybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization.