Fishing, pollution, climate change, and the long-term decline of coral reefs off Havana, Cuba

Understanding temporal and spatial variation of coral reef communities allows us to analyze the relative effects of local stressors, such as fishing and eutrophication, and global stressors, such as ocean warming. To test for spatial and temporal changes in coral reef communities, we combined recent benthic and fish surveys from 2016 with long-term data, dating back to the late 1990s, from four zones located at different distances from Central Havana, Cuba’s largest population center. These changes may indicate the shifting importance of local vs global stressors affecting reef communities. Regardless of the distance from Havana, we found that coral cover was uniformly low (approximately 10%), whereas macroalgal abundance was often high (approximately 65%). Similarly, fish biomass was low across zones, particularly for herbivorous fishes (approximately 12 g m−2) that are critical ecological drivers of reef structure and coral resilience. Analyses of longer-term trends revealed that coral cover near Havana has been below about 10% since at least 1995, potentially because of local stressors. In contrast, reefs farther from Havana maintained relatively high coral cover (approximately 30%) until the early 2000s, but declined more recently to approximately 15%, putting them near the Caribbean-wide average. These distinct spatial and temporal trajectories of reef communities may be the result of the expansion of local stressors away from Havana as the human population increased, or as fishers ventured farther away to exploit new resources. Alternatively, the more recent decline of reefs farther from population centers may have resulted from increasingly frequent global stressors, such as bleaching events and hurricanes

Effet de différents systèmes de culture à couverture végétale sur le stockage du carbone dans un sol argileux des Hautes Terres de Madagascar

Stocker du carbone dans le sol permet d'améliorer ses propriétés physico-chimiques et de réduire les émissions de dioxyde de carbone vers l'atmosphère. L'effet des systèmes en semis direct avec couverture végétale (SCV) sur le stockage de C dans le sol est étudié sur un dispositif agronomique de longue durée (11 ans) à Antsirabe, Madagascar (16°C, 1 300 mm). Quatre systèmes sont étudiés: un système en labour conventionnel avec exportation des résidus de récolte [CT m/s, rotation maïs (Zea mays L.)-soja (Glycine max. L.)], et trois systèmes en SCV sans travail du sol, et avec restitution des résidus de récolte [NT m/s, rotation maïs-soja; NT m/m-d, rotation maïs-maïs avec une couverture végétale de Desmodium uncinatum; et NT h/s-k, rotation haricot (Phaseolus vulgaris)-soja avec une couverture végétale de Pennissetum clandestinum]. Le sol est très argileux, à faible capacité d'échange cationique mais possédant des propriétés andiques pouvant influencer les potentialités de stockage du C du sol. A 0-5 cm, les teneurs en C sont plus élevées sous SCV (NT m/s, NT m/m-d et NT his) que sous labour (CT m/s), et à 5-10 cm, elles sont plus élevées sous NT m/m-d et NT m/s que sous NT h/s-k et CT m/s. Le stockage annuel de C, à masse de sol équivalente, est de 0,69 et 1,01 mg C.ha-1.an-1, sous NT m/s et NT m/m-d pour l'horizon équivalent à 0-20 cm, alors qu'il n'y a pas d'effet SCV observé pour l'horizon équivalent à 0-40 cm. Ceci peut être dû à la fois à l'absence réelle de stockage comme à une variabilité initiale des teneurs en C dans les horizons de profondeurs, car le labour n'est effectué que jusqu'à 20 cm de profondeur. Les différences de stockage de C entre NT et CT dans la couche 0-20 cm sont essentiellement attribuées aux quantités beaucoup plus importantes de résidus organiques restituées par les systèmes NT par rapport au système labouré CT, mais on peut aussi envisager qu'une partie de cette différence soit le fait d'une perte de C par érosion sous labour. Les teneurs en macroagrégats stables (MA, 200-2 000 [mu]m) sont plus élevées sous NT m/s, NT h/s-k et NT m/m-d que sous CT m/s à 0-5 cm et à 5-10 cm. Cette teneur en MA est corrélée positivement (R = 0,408, p < 0,05, n = 24) avec la teneur en C du sol, ce qui pourrait induire (i) une amélioration de l'agrégation en fonction de l'augmentation de la teneur en C du sol et (ii) une protection du C se trouvant à l'intérieur de ces agrégats contre la minéralisation microbienne. Toutefois, la respirométrie ne montre pas une protection physique de C dans les sites de protection supérieurs à 200 [mu]m pour NT m/s et CT m/s. Dans cette étude, le C stocké dans le sol pourrait alors être protégé contre la minéralisation par d'autres processus comme l'adsorption sur les colloïdes du sol ou la recalcitrance biochimique de la matière organique du sol. (Résumé d'auteur

Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology

Anti-amyloid-β immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-β-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-β active immunization on neurite trajectories and the pathological hallmarks of Alzheimer's disease in the human hippocampus. Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and eight age-matched non-demented controls. Analyses included neurite curvature ratio as a quantitative measure of neuritic abnormalities, amyloid and tau loads, and a quantitative characterization of plaque-associated neuritic dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively). The curvature ratio in non-immunized patients with Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). In immunized patients, however, the curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls. In the non-immunized patients, neurites close to dense-core plaques (within 50 µm) were more abnormal than those far from plaques (i.e. beyond 50 µm) (P < 0.0001). By contrast, in the immunized group neurites close to and far from the remaining dense-core plaques did not differ, and both were straighter compared to the non-immunized patients (P < 0.0001). Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-β immunization on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 effectively improves a morphological measure of neurite abnormality in the hippocampus. This improvement is not just attributable to the decrease in plaque load, but also occurs within the halo of the remaining dense-core plaques. However, these remaining plaques still retain some of their toxic potential. Anti-amyloid-β immunization might also ameliorate the hippocampal tau pathology through a decrease in tau phosphorylation. These data agree with preclinical animal studies and further demonstrate that human anti-amyloid-β immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's diseas

Towards elucidating carnosic acid biosynthesis in Lamiaceae: Functional characterization of the three first steps of the pathway in Salvia fruticosa and Rosmarinus officinalis

Carnosic acid (CA) is a phenolic diterpene with anti-tumour, anti-diabetic, antibacterial and neuroprotective properties that is produced by a number of species from several genera of the Lamiaceae family, including Salvia fruticosa (Cretan sage) and Rosmarinus officinalis (Rosemary). To elucidate CA biosynthesis, glandular trichome transcriptome data of S. fruticosa were mined for terpene synthase genes. Two putative diterpene synthase genes, namely SfCPSand SfKSL, showing similarities to copalyl diphosphate synthase and kaurene synthase-like genes, respectively, were isolated and functionally characterized. Recombinant expression in Escherichia coli followed by in vitro enzyme activity assays confirmed that SfCPS is a copalyl diphosphate synthase. Coupling of SfCPS with SfKSL, both in vitro and in yeast, resulted in the synthesis miltiradiene, as confirmed by 1D and 2D NMR analyses (1H, 13C, DEPT, COSY H-H, HMQC and HMBC). Coupled transient in vivo assays of SfCPS and SfKSL in Nicotiana benthamiana further confirmed production of miltiradiene in planta. To elucidate the subsequent biosynthetic step, RNA-Seq data of S. fruticosa and R. officinalis were searched for cytochrome P450 (CYP) encoding genes potentially involved in the synthesis of the first phenolic compound in the CA pathway, ferruginol. Three candidate genes were selected, SfFS, RoFS1 and RoFS2. Using yeast and N. benthamiana expression systems, all three where confirmed to be coding for ferruginol synthases, thus revealing the enzymatic activities responsible for the first three steps leading to CA in two Lamiaceae genera

Elucidation of the biosynthesis of carnosic acid and its reconstitution in yeast

Rosemary extracts containing the phenolic diterpenes carnosic acid and its derivative carnosol are approved food additives used in an increasingly wide range of products to enhance shelf-life, thanks to their high anti-oxidant activity. We describe here the elucidation of the complete biosynthetic pathway of carnosic acid and its reconstitution in yeast cells. Cytochrome P450 oxygenases (CYP76AH22-24) from Rosmarinus officinalis and Salvia fruticosa already characterized as ferruginol synthases are also able to produce 11-hydroxyferruginol. Modelling-based mutagenesis of three amino acids in the related ferruginol synthase (CYP76AH1) from S. miltiorrhiza is sufficient to convert it to a 11-hydroxyferruginol synthase (HFS). The three sequential C20 oxidations for the conversion of 11-hydroxyferruginol to carnosic acid are catalysed by the related CYP76AK6-8. The availability of the genes for the biosynthesis of carnosic acid opens opportunities for the metabolic engineering of phenolic diterpenes, a class of compounds with potent anti-oxidant, anti-inflammatory and anti-tumour activities

The CanOE Strategy: Integrating Genomic and Metabolic Contexts across Multiple Prokaryote Genomes to Find Candidate Genes for Orphan Enzymes

Of all biochemically characterized metabolic reactions formalized by the IUBMB, over one out of four have yet to be associated with a nucleic or protein sequence, i.e. are sequence-orphan enzymatic activities. Few bioinformatics annotation tools are able to propose candidate genes for such activities by exploiting context-dependent rather than sequence-dependent data, and none are readily accessible and propose result integration across multiple genomes. Here, we present CanOE (Candidate genes for Orphan Enzymes), a four-step bioinformatics strategy that proposes ranked candidate genes for sequence-orphan enzymatic activities (or orphan enzymes for short). The first step locates “genomic metabolons”, i.e. groups of co-localized genes coding proteins catalyzing reactions linked by shared metabolites, in one genome at a time. These metabolons can be particularly helpful for aiding bioanalysts to visualize relevant metabolic data. In the second step, they are used to generate candidate associations between un-annotated genes and gene-less reactions. The third step integrates these gene-reaction associations over several genomes using gene families, and summarizes the strength of family-reaction associations by several scores. In the final step, these scores are used to rank members of gene families which are proposed for metabolic reactions. These associations are of particular interest when the metabolic reaction is a sequence-orphan enzymatic activity. Our strategy found over 60,000 genomic metabolons in more than 1,000 prokaryote organisms from the MicroScope platform, generating candidate genes for many metabolic reactions, of which more than 70 distinct orphan reactions. A computational validation of the approach is discussed. Finally, we present a case study on the anaerobic allantoin degradation pathway in Escherichia coli K-12

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

Forecasting Using Heterogeneous Panels with Cross-Sectional Dependence

In this paper, we focus on forecasting heterogeneous panels in presence of cross-sectional depen-dence in terms of both spatial error dependence and common factors. We propose two mainapproaches to estimate the factor structure, one using the residuals (“Residuals Based Approach”,RBA) while the second using a panel of some variables (“Auxiliary Variables Approach”, AVA)to extract the factors. Small sample properties of the methods proposed is investigated throughMonte Carlo simulation exercises and used in an application to predict house price inflation inOECD countries

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers