The crystal structure of the phosphatidylinositol 4‐kinase IIα

Phosphoinositides are a class of phospholipids generated by the action of phosphoinositide kinases with key regulatory functions in eukaryotic cells. Here, we present the atomic structure of phosphatidylinositol 4‐kinase type IIα (PI4K IIα), in complex with ATP solved by X‐ray crystallography at 2.8 Å resolution. The structure revealed a non‐typical kinase fold that could be divided into N‐ and C‐lobes with the ATP binding groove located in between. Surprisingly, a second ATP was found in a lateral hydrophobic pocket of the C‐lobe. Molecular simulations and mutagenesis analysis revealed the membrane binding mode and the putative function of the hydrophobic pocket. Taken together, our results suggest a mechanism of PI4K IIα recruitment, regulation, and function at the membrane.     

Dysfonction érectile: profil épidémiologique dans une population de sujets retraités au Sénégal

Introduction

Erectile dysfunction (ED) presents particular profile among retired population. The purpose of this study is to report epidemiological aspects of that ED and analyze its risk factors.

Methods

It was a prospective study realized during a 12 months period, in the Centre medico-social of Institution de Prévoyance Retraite in Sénégal (IPRES). All data have been collected thanks to a questionnary that patients had to fill it themselves. Selected patients were at least 55 year-old. Among 552 given questionnary, 537 were selected.

Results

We found that 60,7 % (n=326) of this studied population presented an ED. The mean age of the subjects was 68 ± 6.7 years in the ED group versus 65 ± 6.2 years in the non-ED group. The average duration of tobacco abuse was 24.3 ± 14.4 years. The mean duration of alcohol exposure was 28.6 ± 15.5 years ranging from 3 to 63 years. Diabetes was reported in 67 cases (12.5 %) and 18 (3.3 %) of ED patients have been screened and diagnosted for diabete during the study. The ED lasted in average 4.2 ± 4 years with ranged from 6 months to 20 years.

Conclusion

ED is a good indicator of quality of life. However, psychological disturbances, socioeconomical and medical troubles noted during the period of compulsory retirement have a relevant impact in the appearance or worsening of ED.     

c-Met must translocate to the nucleus to initiate calcium signals

Hepatocyte growth factor (HGF) is important for cell proliferation, differentiation, and related activities. HGF acts through its receptor c-Met, which activates downstream signaling pathways. HGF binds to c-Met at the plasma membrane, where it is generally believed that c-Met signaling is initiated. Here we report that c-Met rapidly translocates to the nucleus upon stimulation with HGF. Ca(2+) signals that are induced by HGF result from phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol 1,4,5-trisphosphate formation within the nucleus rather than within the cytoplasm. Translocation of c-Met to the nucleus depends upon the adaptor protein Gab1 and importin beta1, and formation of Ca(2+) signals in turn depends upon this translocation. HGF may exert its particular effects on cells because it bypasses signaling pathways in the cytoplasm to directly activate signaling pathways in the nucleus.     

Effects of tocopherols and 2,2'-carboxyethyl hydroxychromans on phorbol-ester-stimulated neutrophils

Tocopherol vitamers [e.g., alpha-, gamma- and delta-tocopherol (-TOC, γ-TOC and δ-TOC, respectively)] and their water-soluble 2,2′-carboxyethyl hydroxychroman metabolites (e.g., -, γ- and δ-CEHC) all possess antioxidant properties. As a consequence, and similarly to other natural antioxidants, vitamin E compounds may be useful in preventing inflammatory and oxidative-stress-mediated diseases. In this study, we investigated the concentration-dependent effect of tocopherols and water-soluble metabolites on a key event in oxidative stress, for example, the oxidative burst in neutrophils. It was found that not only -TOC but also γ-TOC and δ-TOC as well as -, γ- and δ-CEHC at physiological concentrations inhibit superoxide anion (O₂^•−) production in phorbol-ester-stimulated neutrophils. This effect was mediated by the inhibition of the translocation and activation of protein kinase C (PKC) enzyme, which is the key event in the phorbol-ester signaling. Importantly, CEHCs were stronger inhibitors of PKC as compared with the vitamer precursors, and the gamma forms of both tocopherol and CEHC showed the highest inhibitory activities. Tocopherols, but not CEHCs, directly inhibit the fully activated nicotine–adenine–dinucleotide phosphate (NADPH) oxidase. However, none of the test compounds was able to directly scavenge O₂^•− when tested in a cell-free system. In conclusion, vitamin E compounds can control the neutrophil oxidative burst through the negative modulation of PKC-related signaling and NADPH oxidase activity. As an original finding, we observed that CEHC metabolites might contribute to regulate PKC activity in these cells. These results may have important implications in the anti-inflammatory and antioxidant role of vitamin E compounds.     

The Gambia has eliminated trachoma as a public health problem: Challenges and successes

Trachoma is the leading infectious cause of blindness in the world and has been known to be a major public health problem in The Gambia for over 60 years. Nationwide blindness surveys, including trachoma, in 1986 and 1996 provided the foundation for a comprehensive plan to implement a trachoma elimination strategy. Impact and pre-validation surveillance surveys in 2011–13 demonstrated that active trachoma was below WHO threshold for elimination but trichiasis remained a public health problem. Trichiasis-only surveys in 2019 demonstrated that trichiasis was below WHO thresholds for elimination and in 2020 the Government of The Gambia completed and submitted its dossier for validation of elimination as a public health problem. Challenges that The Gambia faced on the pathway to elimination included effective use of data for decision making, poor trichiasis surgical outcomes, lack of access to antibiotic treatment for low prevalence districts, high attrition of ophthalmic nurses trained as trichiasis surgeons, unexpected active trachoma in madrassas, the misalignment of elimination of active trachoma and trichiasis, trichiasis in urban settings, and maintaining the quality of surgery post-elimination when trichiasis cases are rare. Elimination of trachoma does not end with the submission of an elimination dossier; The Gambia will need to sustain monitoring and support over the coming years.     

Identification of QTLs conferring resistance to downy mildews of maize in Asia

Downy mildew is one of the most destructive diseases of maize in subtropical and tropical regions in Asia. As a prerequisite for improving downy mildew resistance in maize, we analyzed quantitative trait loci (QTLs) involved in resistance to the important downy mildew pathogens--Peronosclerospora sorghi (sorghum downy mildew) and P. heteropogoni (Rajasthan downy mildew) in India, P. maydis (Java downy mildew) in Indonesia, P. zeae in Thailand and P. philippinensis in the Philippines--using a recombinant inbred line population derived from a cross between Ki3 (downy mildew resistant) and CML139 (susceptible). Resistance was evaluated as percentage disease incidence in replicated field trials at five downy mildew 'hotspots' in the four countries. Heritability estimates of individual environments ranged from 0.58 to 0.75 with an across environment heritability of 0.50. Composite interval mapping was applied for QTL detection using a previously constructed restriction fragment length polymorphism linkage map. The investigation resulted in the identification of six genomic regions on chromosomes 1, 2, 6, 7 and 10 involved in the resistance to the downy mildews under study, explaining, in total, 26-57% of the phenotypic variance for disease response. Most QTL alleles conferring resistance to the downy mildews were from Ki3. All QTLs showed significant QTL x environment interactions, suggesting that the expression of the QTL may be environment-dependent. A strong QTL on chromosome 6 was stable across environments, significantly affecting disease resistance at the five locations in four Asian countries. Simple-sequence repeat markers tightly linked to this QTL were identified for potential use in marker-assisted selection.     

Drought tolerance in cereals in terms of water retention,photosynthesis and antioxidant enzyme activities

Experiments were carried out on three bread wheat varieties, one barley and one durum wheat variety grown in pots in the phytotron and subjected to water withdrawal for 7 days during grain-filling. Leaf water loss, net assimilation rate and transpiration showed marked differences, allowing the genotypes to be ranked. Although the most resistant variety had the highest activity for ascorbate peroxidase (APX), catalase (CAT), glutathione reductase (GR) and glutathione-S-transferase (GST), which did not rise further in response to drought and the most susceptible variety had the lowest values, which increased to the greatest extent under drought, the level of sensitivity could not be predicted for all the genotypes from the enzyme activity values alone. The largest increases were recorded for the APX, CAT and GR activities. In most genotypes the GR activity was correlated with that of GST, CAT and APX. Changes in the enzyme activities were observed after a decline in transpiration and photosynthesis. The range of soil moisture values over which the antioxidant enzyme activity levels remained relatively unchanged was a better indication of tolerance to drought than either basic or stress-induced activity levels.