Antibacterial activity of glycine betaine analogues: involvement of osmoporters

Glycine betaine (GB) analogues were obtained using solid phase organic synthesis and assayed for their toxic activity against 15 Gram positive and Gram negative bacteria. Four benzyl derivatives of GB were selected to determine their effect on bacterial growth. Bacteriostatic and lethal effects were observed for compound 1 and compound 2, respectively. The importation of the two GB analogues into bacterial cells appeared strictly dependent on the presence of the powerful betaine membrane osmoporters; their capacity to be amassed intracellularly at molar levels from extremely dilute solutions might constitute a basis to design a new class of antimicrobial agents.     

Demographic processes affect HIV-1 evolution in primary infection before the onset of selective processes

HIV-1 transmission and viral evolution in the first year of infection were studied in 11 individuals representing four transmitter-recipient pairs and three independent seroconverters. Nine of these individuals were enrolled during acute infection; all were men who have sex with men (MSM) infected with HIV-1 subtype B. A total of 475 nearly full-length HIV-1 genome sequences were generated, representing on average 10 genomes per specimen at 2 to 12 visits over the first year of infection. Single founding variants with nearly homogeneous viral populations were detected in eight of the nine individuals who were enrolled during acute HIV-1 infection. Restriction to a single founder variant was not due to a lack of diversity in the transmitter as homogeneous populations were found in recipients from transmitters with chronic infection. Mutational patterns indicative of rapid viral population growth dominated during the first 5 weeks of infection and included a slight contraction of viral genetic diversity over the first 20 to 40 days. Subsequently, selection dominated, most markedly in env and nef. Mutants were detected in the first week and became consensus as early as day 21 after the onset of symptoms of primary HIV infection. We found multiple indications of cytotoxic T lymphocyte (CTL) escape mutations while reversions appeared limited. Putative escape mutations were often rapidly replaced with mutually exclusive mutations nearby, indicating the existence of a maturational escape process, possibly in adaptation to viral fitness constraints or to immune responses against new variants. We showed that establishment of HIV-1 infection is likely due to a biological mechanism that restricts transmission rather than to early adaptive evolution during acute infection. Furthermore, the diversity of HIV strains coupled with complex and individual-specific patterns of CTL escape did not reveal shared sequence characteristics of acute infection that could be harnessed for vaccine design.     

Same species,same habitat preferences? The distribution of aquatic plants is not explained by the same predictors in lakes and streams

1. Studying the geographical distribution of species can reveal conditions and processes that may drive species presence and abundance. Organism distribution has frequently been explained by climate, but the relative role of local environmental predictors is not fully understood. Moreover, in the freshwater realm, intrinsic differences existing between different categories of water bodies can lead to significant differences in species–environment relationships. Here, we tested the relative importance of broad-scale climate and local environmental predictors in explaining plant species distributions in freshwater lakes and streams.
2. We built species distribution models to investigate which predictors best explain aquatic plant distribution in two categories of water bodies. We used species inventories and records of three climate and eight local environmental predictors for 150 lakes and 150 streams in Finland.
3. We found that sets of predictors that explain the distribution of macrophyte species are unique depending on if species are in a lake or a stream. Overall, air temperature and ecosystem size were essential to predict aquatic plant species presence in both water body categories. Broad-scale climate predictors were always very important in explaining species distribution, while local environmental conditions such as water chemistry were of variable influence, depending on species and water body category.
4. These results are probably due to high spatial and temporal variability and range of water physico-chemical parameters, especially in streams. Nonetheless, despite a lower relative importance than climatic factors, local environmental predictors also strongly affected species distributions.
5. Our findings highlight that incorporating local environmental conditions to species distribution models in addition to climate predictors is necessary to improve predictions, particularly for distribution of stream flora. Considering the species-specific responses of aquatic plants to their environment, studying species individually with species distribution models represents a useful analysis.

     

Characterization of the Bubblegum acyl-CoA synthetase of Microchloropsis gaditana

The metabolic pathways of glycerolipids are well described in cells containing chloroplasts limited by a two-membrane envelope but not in cells containing plastids limited by four membranes, including heterokonts. Fatty acids (FAs) produced in the plastid, palmitic and palmitoleic acids (16:0 and 16:1), are used in the cytosol for the synthesis of glycerolipids via various routes, requiring multiple acyl-Coenzyme A (CoA) synthetases (ACS). Here, we characterized an ACS of the Bubblegum subfamily in the photosynthetic eukaryote Microchloropsis gaditana, an oleaginous heterokont used for the production of lipids for multiple applications. Genome engineering with TALE-N allowed the generation of MgACSBG point mutations, but no knockout was obtained. Point mutations triggered an overall decrease of 16:1 in lipids, a specific increase of unsaturated 18-carbon acyls in phosphatidylcholine and decrease of 20-carbon acyls in the betaine lipid diacylglyceryl–trimethyl–homoserine. The profile of acyl-CoAs highlighted a decrease in 16:1-CoA and 18:3-CoA. Structural modeling supported that mutations affect accessibility of FA to the MgACSBG reaction site. Expression in yeast defective in acyl-CoA biosynthesis further confirmed that point mutations affect ACSBG activity. Altogether, this study supports a critical role of heterokont MgACSBG in the production of 16:1-CoA and 18:3-CoA. In M. gaditana mutants, the excess saturated and monounsaturated FAs were diverted to triacylglycerol, thus suggesting strategies to improve the oil content in this microalga.

A heterokont Bubblegum acyl-CoA synthetase (ACSBG), or lipidosin, is essential in Microchloropsis (Nannochloropsis) gaditana and thio-esterifies 16:1 and 18:3 fatty acids to Coenzyme A in vivo.     

Live Imaging Reveals Listeria Hijacking of E-Cadherin Recycling as It Crosses the Intestinal Barrier

1. Download : Download high-res image (117KB)
2. Download : Download full-size image

     

LC3-associated phagocytosis in myeloid cells,a fireman that restrains inflammation and liver fibrosis,via immunoreceptor inhibitory signaling

ABSTRACT

Control of systemic and hepatic inflammation, in particular originating from monocytes/macrophages, is crucial to prevent liver fibrosis and its progression to end-stage cirrhosis. LC3-associated phagocytosis (LAP) is a non-canonical form of autophagy that shifts the monocyte/macrophage phenotype to an anti-inflammatory phenotype. In a recent study, we uncovered LAP as a protective mechanism against inflammation-driven liver fibrosis and systemic inflammation in the context of cirrhosis. We observed that LAP is enhanced in blood and liver monocytes from patients with liver fibrosis or those who progress to cirrhosis. Combining studies in which LAP was pharmacologically or genetically inactivated, we found that LAP limits inflammation in monocytes from cirrhotic patients, and the hepatic inflammatory profile in mice with chronic liver injury, resulting in anti-fibrogenic effects. Mechanistically, LAP-induced anti-inflammatory and antifibrogenic signaling results from enhanced expression of the Fc immunoreceptor FCGR2A/FcγRIIA and activation of an FCGR2A-mediated PTPN6/SHP-1 anti-inflammatory pathway, leading to increased engulfment of IgG into LC3 ⁺ phagosomes. In patients with cirrhosis progressing to multi-organ failure (acute-on chronic liver failure), LAP is lost in monocytes, and can be restored by targeting FCGR2A-mediated PTPN6/SHP-1 signaling. These data suggest that sustaining LAP may open novel therapeutic perspectives for patients with end-stage liver disease.     

How citizen science could improve species distribution models and their independent assessment

1. Species distribution models (SDM) have been increasingly developed in recent years, but their validity is questioned. Their assessment can be improved by the use of independent data, but this can be difficult to obtain and prohibitive to collect. Standardized data from citizen science may be used to establish external evaluation datasets and to improve SDM validation and applicability.
2. We used opportunistic presence‐only data along with presence–absence data from a standardized citizen science program to establish and assess habitat suitability maps for 9 species of amphibian in western France. We assessed Generalized Additive and Random Forest Models’ performance by (1) cross‐validation using 30% of the opportunistic dataset used to calibrate the model or (2) external validation using different independent datasets derived from citizen science monitoring. We tested the effects of applying different combinations of filters to the citizen data and of complementing it with additional standardized fieldwork.
3. Cross‐validation with an internal evaluation dataset resulted in higher AUC (Area Under the receiver operating Curve) than external evaluation causing overestimation of model accuracy and did not select the same models; models integrating sampling effort performed better with external validation. AUC, specificity, and sensitivity of models calculated with different filtered external datasets differed for some species. However, for most species, complementary fieldwork was not necessary to obtain coherent results, as long as the citizen science data were strongly filtered.
4. Since external validation methods using independent data are considered more robust, filtering data from citizen sciences may make a valuable contribution to the assessment of SDM. Limited complementary fieldwork with volunteer''s participation to complete ecological gradients may also possibly enhance citizen involvement and lead to better use of SDM in decision processes for nature conservation.

     

Potential impacts of climate change on the winter distribution of Afro-Palaearctic migrant passerines

We modelled the present and future sub-Saharan winter distributions of 64 trans-Saharan migrant passerines to predict the potential impacts of climate change. These predictions used the recent ensemble modelling developments and the latest IPCC climatic simulations to account for possible methodological uncertainties. Results suggest that 37 species would face a range reduction by 2100 (16 of these by more than 50%); however, the median range size variation is −13 per cent (from −97 to +980%) under a full dispersal hypothesis. Range centroids were predicted to shift by 500±373 km. Predicted changes in range size and location were spatially structured, with species that winter in southern and eastern Africa facing larger range contractions and shifts. Predicted changes in regional species richness for these long-distance migrants are increases just south of the Sahara and on the Arabian Peninsula and major decreases in southern and eastern Africa.     

High-resolution mapping of mitotic DNA synthesis regions and common fragile sites in the human genome through direct sequencing

DNA replication stress, a feature of human cancers, often leads to instability at specific genomic loci, such as the common fragile sites (CFSs). Cells experiencing DNA replication stress may also exhibit mitotic DNA synthesis (MiDAS). To understand the physiological function of MiDAS and its relationship to CFSs, we mapped, at high resolution, the genomic sites of MiDAS in cells treated with the DNA polymerase inhibitor aphidicolin. Sites of MiDAS were evident as well-defined peaks that were largely conserved between cell lines and encompassed all known CFSs. The MiDAS peaks mapped within large, transcribed, origin-poor genomic regions. In cells that had been treated with aphidicolin, these regions remained unreplicated even in late S phase; MiDAS then served to complete their replication after the cells entered mitosis. Interestingly, leading and lagging strand synthesis were uncoupled in MiDAS, consistent with MiDAS being a form of break-induced replication, a repair mechanism for collapsed DNA replication forks. Our results provide a better understanding of the mechanisms leading to genomic instability at CFSs and in cancer cells.Subject terms: Cancer, DNA damage and repair