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Background and Aims: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. Approach and Results: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD+/NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. Conclusions: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.

Cholera epidemics have a recorded history in eastern Congo dating to 1971. A study was conducted to find out the linkage between climate variability/change and cholera outbreak and to assess the related economic cost in the management of cholera in Congo.This study integrates historical data (20 years) on temperature and rainfall with the burden of disease from cholera in South-Kivu province, eastern Congo.Analyses of precipitation and temperatures characteristics in South-Kivu provinces showed that cholera epidemics are closely associated with climatic factors variability. Peaks in Cholera new cases were in synchrony with peaks in rainfalls. Cholera infection cases declined significantly (P<0.05) with the rise in the average temperature. The monthly number of new Cholera cases oscillated between 5 and 450. For every rise of the average temperature by 0.35 °C to 0.75 °C degree Celsius, and for every change in the rainfall variability by 10-19%, it is likely cholera infection risks will increase by 17 to 25%. The medical cost of treatment of Cholera case infection was found to be of US$50 to 250 per capita. The total costs of Cholera attributable to climate change were found to fall in the range of 4 to 8% of the per capita in annual income in Bukavu town.It is likely that high rainfall favor multiplication of the bacteria and contamination of water sources by the bacteria (Vibrio cholerae). The consumption of polluted water, promiscuity, population density and lack of hygiene are determinants favoring spread and infection of the bacteria among human beings living in over-crowded environments.

The continual spread of novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), posing a severe threat to the health worldwide. The main protease (Mpro, alias 3CLpro) of SARS-CoV-2 is a crucial enzyme for the maturation of viral particles and is a very attractive target for designing drugs to treat COVID-19. Here, we propose a multiple conformation-based virtual screening strategy to discover inhibitors that can target SARS-CoV-2 Mpro. Based on this strategy, nine Mpro structures and a protein mimetics library with 8960 commercially available compounds were prepared to carry out ensemble docking for the first time. Five of the nine structures are apo forms presented in different conformations, whereas the other four structures are holo forms complexed with different ligands. The surface plasmon resonance assay revealed that 6 out of 49 compounds had the ability to bind to SARS-CoV-2 Mpro. The fluorescence resonance energy transfer experiment showed that the biochemical half-maximal inhibitory concentration (IC50) values of the six compounds could hamper Mpro activities ranged from 0.69 ± 0.05 to 2.05 ± 0.92 μM. Evaluation of antiviral activity using the cell-based assay indicated that two compounds (Z1244904919 and Z1759961356) could strongly inhibit the cytopathic effect and reduce replication of the living virus in Vero E6 cells with the half-maximal effective concentrations (EC50) of 4.98 ± 1.83 and 8.52 ± 0.92 μM, respectively. The mechanism of the action for the two inhibitors were further elucidated at the molecular level by molecular dynamics simulation and subsequent binding free energy analysis. As a result, the discovered noncovalent reversible inhibitors with novel scaffolds are promising antiviral drug candidates, which may be used to develop the treatment of COVID-19.

Activated sludge from municipal wastewater treatment processes can be used directly for the production of biodegradable polyesters from the family of polyhydroxyalkanoates (PHAs). However, municipal activated sludge typically cannot accumulate PHAs to very high levels and often low yields of polymer produced on substrate are observed. In the present work, it was found that the presence of calcium promotes selective growth and enrichment of the PHA-storing biomass fraction and significantly improved both PHA contents and yields. Calcium addition resulted in PHA contents of 0.60 ± 0.03 gPHA/gVSS and average PHA yields on substrate of 0.49 ± 0.03 gCODPHA/gCODHAc compared to 0.35 ± 0.01 gPHA/gVSS and 0.19 ± 0.01 gCODPHA/gCODHAc without calcium addition. After 48 h, three times more PHA was produced compared to control experiments without calcium addition. Higher PHA content and selective biomass production is proposed to be a consequence of calcium dependent increased levels of passive acetate uptake. Such more efficient substrate uptake could be related to a formation of calcium acetate complexes. Findings lead to bioprocess methods to stimulate a short-term selective growth of PHA-storing microorganisms and this enables improvements to the techno-economic feasibility for municipal waste activated sludge to become a generic resource for industrial scale PHA production.

Abstract : Some serotonin 5‐HT3 receptor ligands of tropeine structure have been recently shown to modulate ionophore function and binding of glycine receptors. This led us to study the effects of the tropeines tropisetron and atropine on recombinant human glycine receptors transiently expressed in Xenopus oocytes by using whole‐cell voltage‐clamp electrophysiology. Glycine currents were inhibited by atropine in an apparently competitive manner and with considerable selectivity of the tropeines for α2 versus α1 subunits. Coexpression of β with α subunits and replacement of the N‐terminal region of the α1 subunits by the corresponding β segment resulted in similar increases in the inhibitory potencies. Our data suggest common sites of the tropeines for inhibition on the N‐terminal region of glycine receptors. The point mutations R271K and R271L of the α1 subunit decreased, whereas a T112A substitution increased, the inhibition constants (Ki) of the tropeines. These changes in the Ki values of the tropeines were associated with opposite changes in the EC50 of glycine. Selectivities for the tropeines versus glycine (EC50/Ki) varied within three orders of magnitude. These results, when expressed in terms of free energy changes, can be interpreted according to a two‐state receptor model.

Common ragweed (Ambrosia artemisiifolia L.) is a highly allergenic annual ruderal plant and native to Northern America, but now also spreading across Europe. Air pollution and climate change will not only affect plant growth, pollen production and duration of the whole pollen season, but also the amount of allergenic encoding transcripts and proteins of the pollen. The objective of this study was to get a better understanding of transcriptional changes in ragweed pollen upon NO2 and O3 fumigation. This will also contribute to a systems biology approach to understand the reaction of the allergenic pollen to air pollution and climate change. Ragweed plants were grown in climate chambers under controlled conditions and fumigated with enhanced levels of NO2 and O3. Illumina sequencing and de novo assembly revealed significant differentially expressed transcripts, belonging to different gene ontology (GO) terms that were grouped into biological process and molecular function. Transcript levels of the known Amb a ragweed encoding allergens were clearly up-regulated under elevated NO2, whereas the amount of allergen encoding transcripts was more variable under elevated O3 conditions. Moreover transcripts encoding allergen known from other plants could be identified. The transcriptional changes in ragweed pollen upon elevated NO2 fumigation indicates that air pollution will alter the transcriptome of the pollen. The changed levels of allergenic encoding transcripts may have an influence on the total allergenic potential of ragweed pollen.

Natural ecosystems are threatened by climate change, fragmentation, and non-native species. Dispersal-limitation potentially compounds impacts of these factors on plant diversity, especially in isolated vegetation patches. Changes in climate can impact the phenology of native species in distinct ways from non-natives, potentially resulting in cascading impacts on native communities. Few empirical studies have examined the combined effects of climate change and dispersal limitation on community diversity or phenology. Using a five-year dispersal-restriction experiment in an invaded semi-arid annual plant system in Western Australia, we investigated the interactive effects of dispersal-restriction and inter-annual rainfall variation on community composition, species dominance and seed production timing. We found inter-annual rainfall variation to be the principal driver of community dynamics. Drought years had long-term, stable effects on community composition, with evidence of shifts from native toward non-native dominance. Surprisingly, community composition remained largely unchanged under dispersal restriction. A subtle dispersal rescue effect was evident for a dominant native annual forb and a dominant annual non-native grass but only in average rainfall years. The timing of seed production was primarily driven by annual rainfall with native and non-native grasses having opposite responses. There was no evidence that inter-annual variation in seeding timing affected community diversity over time. Our study demonstrates that dispersal is not a major factor in driving community diversity in this invaded, semi-arid system. Results do suggest, however, that increases in drought frequency likely benefit non-native species over natives in the long term. Climate Change Ecology, 2 ISSN:2666-9005