Acarbose improved survival for Apc+/Min mice

Acarbose blocks the digestion of complex carbohydrates, and the NIA Intervention Testing Program (ITP) found that it improved survival when fed to mice. Yet, we do not know if lifespan extension was caused by its effect on metabolism with regard to the soma or cancer suppression. Cancer caused death for ~80% of ITP mice. The ITP found rapamycin, an inhibitor to the pro‐growth mTORC1 (mechanistic target of rapamycin complex 1) pathway, improved survival and it suppressed tumors in Apc^+/Min mice providing a plausible rationale to ask if acarbose had a similar effect. Apc^+/Min is a mouse model prone to intestinal polyposis and a mimic of familial adenomatous polyposis in people. Polyp‐associated anemia contributed to their death. To address this knowledge gap, we fed two doses of acarbose to Apc^+/Min mice. Acarbose improved median survival at both doses. A cross‐sectional analysis was performed next. At both doses, ACA fed mice exhibited reduced intestinal crypt depth, weight loss despite increased food consumption and reduced postprandial blood glucose and plasma insulin, indicative of improved insulin sensitivity. Dose‐independent and dose‐dependent compensatory liver responses were observed for AMPK and mTORC1 activities, respectively. Only mice fed the high dose diet exhibited reductions in tumor number with higher hematocrits. Because low‐dose acarbose improved lifespan but failed to reduced tumors, its effects seem to be independent of cancer. These data implicate the importance of improved carbohydrate metabolism on survival.     

Rainfall manipulation experiments as simulated by terrestrial biosphere models: Where do we stand?

Changes in rainfall amounts and patterns have been observed and are expected to continue in the near future with potentially significant ecological and societal consequences. Modelling vegetation responses to changes in rainfall is thus crucial to project water and carbon cycles in the future. In this study, we present the results of a new model‐data intercomparison project, where we tested the ability of 10 terrestrial biosphere models to reproduce the observed sensitivity of ecosystem productivity to rainfall changes at 10 sites across the globe, in nine of which, rainfall exclusion and/or irrigation experiments had been performed. The key results are as follows: (a) Inter‐model variation is generally large and model agreement varies with timescales. In severely water‐limited sites, models only agree on the interannual variability of evapotranspiration and to a smaller extent on gross primary productivity. In more mesic sites, model agreement for both water and carbon fluxes is typically higher on fine (daily–monthly) timescales and reduces on longer (seasonal–annual) scales. (b) Models on average overestimate the relationship between ecosystem productivity and mean rainfall amounts across sites (in space) and have a low capacity in reproducing the temporal (interannual) sensitivity of vegetation productivity to annual rainfall at a given site, even though observation uncertainty is comparable to inter‐model variability. (c) Most models reproduced the sign of the observed patterns in productivity changes in rainfall manipulation experiments but had a low capacity in reproducing the observed magnitude of productivity changes. Models better reproduced the observed productivity responses due to rainfall exclusion than addition. (d) All models attribute ecosystem productivity changes to the intensity of vegetation stress and peak leaf area, whereas the impact of the change in growing season length is negligible. The relative contribution of the peak leaf area and vegetation stress intensity was highly variable among models.     

Climate change undermines the global functioning of marine food webs

Sea water temperature affects all biological and ecological processes that ultimately impact ecosystem functioning. In this study, we examine the influence of temperature on global biomass transfers from marine secondary production to fish stocks. By combining fisheries catches in all coastal ocean areas and life‐history traits of exploited marine species, we provide global estimates of two trophic transfer parameters which determine biomass flows in coastal marine food web: the trophic transfer efficiency (TTE) and the biomass residence time (BRT) in the food web. We find that biomass transfers in tropical ecosystems are less efficient and faster than in areas with cooler waters. In contrast, biomass transfers through the food web became faster and more efficient between 1950 and 2010. Using simulated changes in sea water temperature from three Earth system models, we project that the mean TTE in coastal waters would decrease from 7.7% to 7.2% between 2010 and 2100 under the ‘no effective mitigation’ representative concentration pathway (RCP8.5), while BRT between trophic levels 2 and 4 is projected to decrease from 2.7 to 2.3 years on average. Beyond the global trends, we show that the TTEs and BRTs may vary substantially among ecosystem types and that the polar ecosystems may be the most impacted ecosystems. The detected and projected changes in mean TTE and BRT will undermine food web functioning. Our study provides quantitative understanding of temperature effects on trophodynamic of marine ecosystems under climate change.     

Benthic ecoregionalization based on echinoid fauna of the Southern Ocean supports current proposals of Antarctic Marine Protected Areas under IPCC scenarios of climate change

The Southern Ocean (SO) is among the regions on Earth that are undergoing regionally the fastest environmental changes. The unique ecological features of its marine life make it particularly vulnerable to the multiple effects of climate change. A network of Marine Protected Areas (MPAs) has started to be implemented in the SO to protect marine ecosystems. However, considering future predictions of the Intergovernmental Panel on Climate Change (IPCC), the relevance of current, static, MPAs may be questioned under future scenarios. In this context, the ecoregionalization approach can prove promising in identifying well‐delimited regions of common species composition and environmental settings. These so‐called ecoregions are expected to show similar biotic responses to environmental changes and can be used to define priority areas for the designation of new MPAs and the update of their current delimitation. In the present work, a benthic ecoregionalization of the entire SO is proposed for the first time based on abiotic environmental parameters and the distribution of echinoid fauna, a diversified and common member of Antarctic benthic ecosystems. A novel two‐step approach was developed combining species distribution modeling with Random Forest and Gaussian Mixture modeling from species probabilities to define current ecoregions and predict future ecoregions under IPCC scenarios RCP 4.5 and 8.5. The ecological representativity of current and proposed MPAs of the SO is discussed with regard to the modeled benthic ecoregions. In all, 12 benthic ecoregions were determined under present conditions, they are representative of major biogeographic patterns already described. Our results show that the most dramatic changes can be expected along the Antarctic Peninsula, in East Antarctica and the sub‐Antarctic islands under both IPCC scenarios. Our results advocate for a dynamic definition of MPAs, they also argue for improving the representativity of Antarctic ecoregions in proposed MPAs and support current proposals of Conservation of Antarctic Marine Living Resources for the creation of Antarctic MPAs.     

Spatial synchrony in the response of a long range migratory species (Salmo salar) to climate change in the North Atlantic Ocean

A major challenge in understanding the response of populations to climate change is to separate the effects of local drivers acting independently on specific populations, from the effects of global drivers that impact multiple populations simultaneously and thereby synchronize their dynamics. We investigated the environmental drivers and the demographic mechanisms of the widespread decline in marine survival rates of Atlantic salmon (Salmo salar) over the last four decades. We developed a hierarchical Bayesian life cycle model to quantify the spatial synchrony in the marine survival of 13 large groups of populations (called stock units, SU) from two continental stock groups (CSG) in North America (NA) and Southern Europe (SE) over the period 1971–2014. We found strong coherence in the temporal variation in postsmolt marine survival among the 13 SU of NA and SE. A common North Atlantic trend explains 37% of the temporal variability of the survivals for the 13 SU and declines by a factor of 1.8 over the 1971–2014 time series. Synchrony in survival trends is stronger between SU within each CSG. The common trends at the scale of NA and SE capture 60% and 42% of the total variance of temporal variations, respectively. Temporal variations of the postsmolt survival are best explained by the temporal variations of sea surface temperature (SST, negative correlation) and net primary production indices (PP, positive correlation) encountered by salmon in common domains during their marine migration. Specifically, in the Labrador Sea/Grand Banks for populations from NA, 26% and 24% of variance is captured by SST and PP, respectively and in the Norwegian Sea for populations from SE, 21% and 12% of variance is captured by SST and PP, respectively. The findings support the hypothesis of a response of salmon populations to large climate‐induced changes in the North Atlantic simultaneously impacting populations from distant continental habitats.     

Long-read RNA sequencing of human and animal filarial parasites improves gene models and discovers operons

Filarial parasitic nematodes (Filarioidea) cause substantial disease burden to humans and animals around the world. Recently there has been a coordinated global effort to generate, annotate, and curate genomic data from nematode species of medical and veterinary importance. This has resulted in two chromosome-level assemblies (Brugia malayi and Onchocerca volvulus) and 11 additional draft genomes from Filarioidea. These reference assemblies facilitate comparative genomics to explore basic helminth biology and prioritize new drug and vaccine targets. While the continual improvement of genome contiguity and completeness advances these goals, experimental functional annotation of genes is often hindered by poor gene models. Short-read RNA sequencing data and expressed sequence tags, in cooperation with ab initio prediction algorithms, are employed for gene prediction, but these can result in missing clade-specific genes, fragmented models, imperfect mapping of gene ends, and lack of isoform resolution. Long-read RNA sequencing can overcome these drawbacks and greatly improve gene model quality. Here, we present Iso-Seq data for B. malayi and Dirofilaria immitis, etiological agents of lymphatic filariasis and canine heartworm disease, respectively. These data cover approximately half of the known coding genomes and substantially improve gene models by extending untranslated regions, cataloging novel splice junctions from novel isoforms, and correcting mispredicted junctions. Furthermore, we validated computationally predicted operons, manually curated new operons, and merged fragmented gene models. We carried out analyses of poly(A) tails in both species, leading to the identification of non-canonical poly(A) signals. Finally, we prioritized and assessed known and putative anthelmintic targets, correcting or validating gene models for molecular cloning and target-based anthelmintic screening efforts. Overall, these data significantly improve the catalog of gene models for two important parasites, and they demonstrate how long-read RNA sequencing should be prioritized for ongoing improvement of parasitic nematode genome assemblies.     

Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system

Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU) disease, is unique amongst human pathogens in its capacity to produce a lipid toxin called mycolactone. While previous studies have demonstrated that bacterially-released mycolactone diffuses beyond infection foci, the spatiotemporal distribution of mycolactone remained largely unknown. Here, we used the zebrafish model to provide the first global kinetic analysis of mycolactone’s diffusion in vivo, and multicellular co-culture systems to address the critical question of the toxin’s access to the brain.Zebrafish larvae were injected with a fluorescent-derivative of mycolactone to visualize the in vivo diffusion of the toxin from the peripheral circulation. A rapid, body-wide distribution of mycolactone was observed, with selective accumulation in tissues near the injection site and brain, together with an important excretion through the gastro-intestinal tract. Our conclusion that mycolactone reached the central nervous system was reinforced by an in cellulo model of human blood brain barrier and a mouse model of M. ulcerans-infection.Here we show that mycolactone has a broad but heterogenous profile of distribution in vivo. Our investigations in vitro and in vivo support the view that a fraction of bacterially-produced mycolactone gains access to the central nervous system. The relative persistence of mycolactone in the bloodstream suggests that assays of circulating mycolactone are relevant for BU disease monitoring and treatment optimization.     

Enantiopure ethyl 2,3-dibromopropionate: Enantioselective synthesis vs preparative HPLC enantioseparation of racemate on multigram scale

Racemic ethyl 2,3-dibromopropionate, commercially available at low price, is a key intermediate used in the synthesis of several heterocycle fragments, which are present in many biologically active compounds. Surprisingly, the enantiomers are not commercially available and have never been described in the literature. In this work, we undertook two different strategies to obtain these enantiomers, which are enantioselective synthesis and preparative HPLC enantioseparation of commercially available racemate on multigram scale. The first strategy has proved inadequate because racemization occurred during the synthesis (ee ≈ 9-50%). Conversely, the second strategy produced a very good enantioseparation of commercially available racemate (ee > 99.5% for both enantiomers) on multigram scale.     

Model-based design and control of a small-scale integrated continuous end-to-end mAb platform

A continuous integrated bioprocess available from the earliest stages of process development allows for an easier, more efficient and faster development and characterization of an integrated process as well as production of small-scale drug candidates. The process presented in this article is a proof-of-concept of a continuous end-to-end monoclonal antibody production platform at a very small scale based on a 200 ml alternating tangential flow filtration perfusion bioreactor, integrated with the purification process with a model-based design and control. The downstream process, consisting of a periodic twin-column protein A capture, a virus inactivation, a CEX column and an AEX column, was compactly implemented in a single chromatography system, with a purification time of less than 4 hr. Monoclonal antibodies were produced for 17 days in a high cell density perfusion culture of CHO cells with titers up to 1.0 mg/ml. A digital twin of the downstream process was created by modelling all the chromatography steps. These models were used for real-time decision making by the implementation of control strategies to automatize and optimize the operation of the process. A consistent glycosylation pattern of the purified product was ensured by the steady state operation of the process. Regarding the removal of impurities, at least a 4-log reduction in the HCP levels was achieved. The recovery yield was up to 60%, and a maximum productivity of 0.8 mg/ml/day of purified product was obtained.     

Elabela/toddler: New peptide with a promising future in cancer diagnostic and therapy

Elabela/toddler is the second endogenous ligand recently identified after Apelin, that binds to the G protein-coupled receptor APJ. Elabela is a 54-amino acid peptide initially identified in fish and human genomes and classified as noncoding. This precursor can be cleaved to shorter sequences (32, 21, and 11 amino acids), which bind and activate APJ, and can be blocked by APJ antagonists. Contrary to Apelin and APJ, widely distributed in organs and tissues, Elabela expression is more restricted, and different studies have revealed the potential role of Elabela in cancers. This review summarizes the current studies focusing on the role of Elabela in different cancers.