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Recently, Manila clam, Ruditapes philippinarum, populations have suffered mortalities in Arcachon Bay (SW France). Mortality was associated with extensive lesions of the posterior adductor muscle, which become progressively brown and calcified. Ultrastructural observations by transmission electron microscopy revealed tissue degradation with necrotized muscle fibres and granulocytomas. Unenveloped virus-like particles (VLPs) were detected in muscle, granulocytic, epithelial and rectal cells. VLPs were abundant in the extracellular space, in the cytoplasm (free or enclosed in vesicles) and in the nucleoplasm of granulocytes. Nuclei and mitochondria of granulocytes displayed changes which suggested reactive oxygen species production and apoptosis induction. VLPs exhibited an icosahedral structure with a diameter of 25 to 35 nm. These observations suggest that the VLPs could belong to the family Picornaviridae or the Parvoviridae.

KRASis the most frequently mutatedrasfamily member in lung carcinomas1,2, whereasHRASmutations are common in tumours from stratified epithelia such as bladder or skin (www.sanger.ac.uk/genetics/CGP/cosmic/). Using a mouse model (HrasKI)3 in which theHrascoding sequence was inserted into theKraslocus, we demonstrate that specificity forKrasmutations in lung andHras mutations in skin tumours is determined by local regulatory elements in the targetrasgenes. We further show that, whileKras-4Ais dispensable for mouse development4,5, it is necessary both for lung carcinogenesisin vivoand for the previously reported6,7 inhibitory effect of wild-type (WT)Krason the transforming properties of the mutant allele. Kras-4A expression is detected in a sub-population of normal lung epithelial cells, but at very low levels in lung tumours, suggesting a role in tumour initiation rather than in tumour maintenance. The two Kras isoforms undergo different post-translational modifications8, therefore these findings can have important implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in the prevention and treatment of cancer.

Clonally transmissible cancers are tumour lineages that are transmitted between individuals via the transfer of living cancer cells. In marine bivalves, leukaemia-like transmissible cancers, called hemic neoplasia (HN), have demonstrated the ability to infect individuals from different species. We performed whole-genome sequencing in eight warty venus clams that were diagnosed with HN, from two sampling points located more than 1000 nautical miles away in the Atlantic Ocean and the Mediterranean Sea Coasts of Spain. Mitochondrial genome sequencing analysis from neoplastic animals revealed the coexistence of haplotypes from two different clam species. Phylogenies estimated from mitochondrial and nuclear markers confirmed this leukaemia originated in striped venus clams and later transmitted to clams of the species warty venus, in which it survives as a contagious cancer. The analysis of mitochondrial and nuclear gene sequences supports all studied tumours belong to a single neoplastic lineage that spreads in the Seas of Southern Europe. We thank the Galicia Supercomputing Centre (CESGA) for the availability of informatic resources. JMCT, SR, SD, and JT are supported by European Research Council (ERC) Starting Grant 716,290 SCUBA CANCERS. ALB is supported by MINECO PhD fellowship BES-2016-078166. DG-S is supported by postdoctoral contract ED481B/2018/091 from Xunta de Galicia. DP is supported by ERC grant ERC-617457-PHYLOCANCER and by Spanish Ministry of Economy and Competitiveness (MINECO) grant PID2019-106247GB-I00. This research was partially funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement 730984, ASSEMBLE Plus project. CESAM got financial support from FCT/MEC (UIDP/50017/2020, UIDB/50017/2020). Peer reviewed 20 Pág.

Makaluvamines are pyrroloiminoquinones isolated from Zyzzya sponges. Until now, they have been described as topoisomerase II inhibitors with cytotoxic effects in diverse tumor cell lines. In the present work, seven makaluvamines were tested in several antioxidant assays in primary cortical neurons and neuroblastoma cells. Among the alkaloids studied, makaluvamine J was the most active in all the assays. This compound was able to reduce the mitochondrial damage elicited by the well-known stressor H2O2. The antioxidant properties of makaluvamine J are related to an improvement of the endogenous antioxidant defenses of glutathione and catalase. SHSY5Y assays proved that this compound acts as a Nrf2 activator leading to an improvement of antioxidant defenses. A low concentration of 10 nM is able to reduce the reactive oxygen species release and maintain a correctmitochondrial function. Based on these results, non-substituted nitrogen in the pyrrole plus the presence of a p-hydroxystyryl without a double bond seems to be the most active structure with a complete antioxidant effect in neuronal cells. The research leading to these results received funding from the following FEDER cofounded-grants. From CDTI and Technological Funds, supported by the Ministerio de Economía y Competitividad, AGL2012-40185-CO2-01, AGL2014-58210-R, and the Consellería de Cultura, Educación e Ordenación Universitaria, GRC2013-016, and through the Axencia Galega de Innovación, Spain, ITC-20133020 SINTOX. From CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD. From the European Union’s Seventh Framework Programme managed by REA—Research Executive Agency (FP7/2007-2013) under grant agreement 312184 PHARMASEA. SI

Metabolomics and genomics are two complementary platforms for analyzing an organism as they provide information on the phenotype and genotype, respectively. These two techniques were applied in the dereplication and identification of bioactive compounds from a Streptomyces sp. (SM8) isolated from the sponge Haliclona simulans from Irish waters. Streptomyces strain SM8 extracts showed antibacterial and antifungal activity. NMR analysis of the active fractions proved that hydroxylated saturated fatty acids were the major components present in the antibacterial fractions. Antimycin compounds were initially putatively identified in the antifungal fractions using LC-Orbitrap. Their presence was later confirmed by comparison to a standard. Genomic analysis of Streptomyces sp. SM8 revealed the presence of multiple secondary metabolism gene clusters, including a gene cluster for the biosynthesis of the antifungal antimycin family of compounds. The antimycin gene cluster of Streptomyces sp. SM8 was inactivated by disruption of the antimycin biosynthesis gene antC. Extracts from this mutant strain showed loss of antimycin production and significantly less antifungal activity than the wild-type strain. Three butenolides, 4,10-dihydroxy-10-methyl-dodec-2-en-1,4-olide (1), 4,11-dihydroxy-10-methyl-dodec-2-en-1,4-olide (2), and 4-hydroxy-10-methyl-11-oxo-dodec-2-en-1,4-olide (3) that had previously been reported from marine Streptomyces species were also isolated from SM8. Comparison of the extracts of Streptomyces strain SM8 and its host sponge, H. simulans, using LC-Orbitrap revealed the presence of metabolites common to both extracts, providing direct evidence linking sponge metabolites to a specific microbial symbiont.

The association between fish consumption and new-onset type 2 diabetes is inconsistent and differs according to geographical location. We examined the association between the total and types of fish consumption and type 2 diabetes using individual participant data from 28 prospective cohort studies from the Americas (6), Europe (15), the Western Pacific (6), and the Eastern Mediterranean (1) comprising 956,122 participants and 48,084 cases of incident type 2 diabetes. Incidence rate ratios (IRRs) for associations of total fish, shellfish, fatty, lean, fried, freshwater, and saltwater fish intake and type 2 diabetes were derived for each study, adjusting for a consistent set of confounders and combined across studies using random-effects meta-analysis. We stratified all analyses by sex due to observed interaction (p = 0.002) on the association between fish and type 2 diabetes. In women, for each 100 g/week higher intake the IRRs (95% CIs) of type 2 diabetes were 1.02 (1.01–1.03, I2 = 61%) for total fish, 1.04 (1.01–1.07, I2 = 46%) for fatty fish, and 1.02 (1.00–1.04, I2 = 33%) for lean fish. In men, all associations were null. In women, we observed variation by geographical location: IRRs for total fish were 1.03 (1.02–1.04, I2 = 0%) in the Americas and null in other regions. In conclusion, we found evidence of a neutral association between total fish intake and type 2 diabetes in men, but there was a modest positive association among women with heterogeneity across studies, which was partly explained by geographical location and types of fish intake. Future research should investigate the role of cooking methods, accompanying foods and environmental pollutants, but meanwhile, existing dietary regional, national, or international guidelines should continue to guide fish consumption within overall healthy dietary patterns.

We thank D. Fatunmbi of Elementus Illustrations for creation of the illustration for Figure 2. We also acknowledge R. Etzel, M.D., Ph.D., for helpful feedback on Figure 2. K.S. acknowledges funding from the Research Council of Norway (project 288638) to the Centre for Global Health Inequalities Research at the Norwegian University of Science and Technology. T.V. acknowledges funding from the Research Council of Norway (project 303369) and SINTEF (strategic institute project on immunotherapy 102020958). M.W. acknowledges funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant (agreement 860720). Pregnancy, infancy, and childhood are sensitive windows for environmental exposures. Yet the health effects of exposure to nano- and microplastics (NMPs) remain largely uninvestigated or unknown. Although plastic chemicals are a well-established research topic, the impacts of plastic particles are unexplored, especially with regard to early life exposures. Peer reviewed

We hypothesized that Cholera (Vibrio cholerae) that appeared along Lake Kivu in the African Rift in the seventies, might be controlled by volcano-tectonic activity, which, by increasing surface water and groundwater salinity and temperature, may partly rule the water characteristics of Lake Kivu and promote V. cholerae proliferation. Volcanic activity (assessed weekly by the SO2 flux of Nyiragongo volcano plume over the 2007–2012 period) is highly positively correlated with the water conductivity, salinity and temperature of the Kivu lake. Over the 2007–2012 period, these three parameters were highly positively correlated with the temporal dynamics of cholera cases in the Katana health zone that border the lake. Meteorological variables (air temperature and rainfall), and the other water characteristics (namely pH and dissolved oxygen concentration in lake water) were unrelated to cholera dynamics over the same period. Over the 2016–2018 period, we sampled weekly lake water salinity and conductivity, and twice a month vibrio occurrence in lake water and fish. The abundance of V. cholerae in the lake was positively correlated with lake salinity, temperature, and the number of cholera cases in the population of the Katana health zone. V. cholerae abundance in fishes was positively correlated with V. cholerae abundance in lake water, suggesting that their consumption directly contaminate humans. The activity of the volcano, by controlling the physico-chemical characteristics of Lake Kivu, is therefore a major determinant of the presence of the bacillus in the lake. SO2 fluxes in the volcano plume can be used as a tool to predict epidemic risks. Author summary The area of the African Great Lakes has been an endemic area for cholera since the late 1970s. We focused on the Katana health zone, bordering Lake Kivu, as during outbreaks, this is, (together with the Kalemie health zone located along the west coast of the Tanganyika lake) the health zone in which the first cases of Cholera are usually observed, and the highest number of cases are also usually reached in this area. The persistence of this aquatic bacillus, usually associated with warm and salty waters, led us to formulate the hypothesis that the geothermal springs supplying Lake Kivu, mainly from the Nyiragongo volcano, should control the physico-chemical characteristics of the lake and promote the persistence of the bacillus. The lake would thus be a reservoir of the pathogen, which could contaminate local residents through the consumption of water and fish. Over the 2007–2012 period, we demonstrated a long-term unidirectional relationship between volcanic activity and cholera cases in the Katana health Zone. Contamination of the lake's water and fish was also correlated to the lake characteristics. The activity of the volcano can thus be used for predicting epidemic risks.

Background Chromatin structure can control gene expression and can define specific transcription states. For example, bivalent methylation of histone H3K4 and H3K27 is linked to poised transcription in vertebrate embryonic stem cells (ESC). It allows them to rapidly engage specific developmental pathways. We reasoned that non-vertebrate metazoans that encounter a similar developmental constraint (i.e. to quickly start development into a new phenotype) might use a similar system. Schistosomes are parasitic platyhelminthes that are characterized by passage through two hosts: a mollusk as intermediate host and humans or rodents as definitive host. During its development, the parasite undergoes drastic changes, most notable immediately after infection of the definitive host, i.e. during the transition from the free-swimming cercariae into adult worms. Methodology/Principal Findings We used Chromatin Immunoprecipitation followed by massive parallel sequencing (ChIP-Seq) to analyze genome-wide chromatin structure of S. mansoni on the level of histone modifications (H3K4me3, H3K27me3, H3K9me3, and H3K9ac) in cercariae, schistosomula and adults (available at http://genome.univ-perp.fr). We saw striking differences in chromatin structure between the developmental stages, but most importantly we found that cercariae possess a specific combination of marks at the transcription start sites (TSS) that has similarities to a structure found in ESC. We demonstrate that in cercariae no transcription occurs, and we provide evidences that cercariae do not possess large numbers of canonical stem cells. Conclusions/Significance We describe here a broad view on the epigenome of a metazoan parasite. Most notably, we find bivalent histone H3 methylation in cercariae. Methylation of H3K27 is removed during transformation into schistosomula (and stays absent in adults) and transcription is activated. In addition, shifts of H3K9 methylation and acetylation occur towards upstream and downstream of the transcriptional start site (TSS). We conclude that specific H3 modifications are a phylogenetically older and probably more general mechanism, i.e. not restricted to stem cells, to poise transcription. Since adult couples must form to cause the disease symptoms, changes in histone modifications appear to be crucial for pathogenesis and represent therefore a therapeutic target. Author Summary The blood fluke Schistosoma mansoni causes intestinal bilharzia. The parasite has a complex life cycle in which a freshwater snail serves as intermediate host from which the human infecting larvae hatch. These larvae will actively seek skin contact, penetrate through the epithelium and start developing straight away into adult worms. Development from larvae into adults needs thorough adjustment of gene expression through repositioning or modification of proteins that are associated with DNA (the chromatin). We decided to compare the chromatin of human infective larvae (cercariae), the first developmental stage after infection of the vertebrate host (schistosomula) and adults of S. mansoni. We found that cercariae possess chromatin structures (modifications of histone H3) around the beginning of genes that are very different from schistosomula and adults. We conclude that this structure serves to keep gene transcription in a poised state, i.e. transcription is initiated and can start immediately when the blocking histone modification is removed. A similar type of histone modification was found in embryonic stem cells of vertebrates and our data indicate that it is either a more ancient and/or more general means to poise transcription than previously assumed. Since many parasites possess infective stages that develop rapidly within the host, this particular chromatin structure could be a therapeutic target for a new class of antiparasitic drugs.

The inner membrane complex (IMC) is a defining feature of apicomplexan parasites, which confers stability and shape to the cell, functions as a scaffolding compartment during the formation of daughter cells and plays an important role in motility and invasion during different life cycle stages of these single celled organisms. To explore the IMC proteome of the malaria parasite Plasmodium falciparum we applied a proximity-dependent biotin identification (BioID)-based proteomics approach, using the established IMC marker protein Photosensitized INA-Labelled protein 1 (PhIL1) as bait in asexual blood-stage parasites. Subsequent mass spectrometry-based peptide identification revealed enrichment of twelve known IMC proteins and several uncharacterized candidate proteins. We validated nine of these previously uncharacterized proteins by endogenous GFP-tagging. Six of these represent new IMC proteins, while three proteins have a distinct apical localization that most likely represent structures described as apical annuli in Toxoplasma gondii. Additionally, various Kelch13 interacting candidates were identified, suggesting an association of the Kelch13 compartment and the IMC in schizont and merozoite stages. This work extends the number of validated IMC proteins in the malaria parasite and reveals for the first time the existence of apical annuli proteins in P. falciparum. Additionally, it provides evidence for a spatial association between the Kelch13 compartment and the IMC in late blood-stage parasites. This article is protected by copyright. All rights reserved.