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Despite dramatic improvements in outcomes arising from the introduction of targeted therapies and immunotherapies, metastatic melanoma is a highly resistant form of cancer with 5 year survival rates of <35%. Drug resistance is frequently reported to be associated with changes in oxidative metabolism that lead to malignancy that is non-responsive to current treatments. The current report demonstrates that triphenylphosphonium(TPP)-based lipophilic cations can be utilized to induce cytotoxicity in pre-clinical models of malignant melanoma by disrupting mitochondrial metabolism. In vitro experiments demonstrated that TPP-derivatives modified with aliphatic side chains accumulated in melanoma cell mitochondria; disrupted mitochondrial metabolism; led to increases in steady-state levels of reactive oxygen species; decreased total glutathione; increased the fraction of glutathione disulfide; and caused cell killing by a thiol-dependent process that could be rescued by N-acetylcysteine. Furthermore, TPP-derivative-induced melanoma toxicity was enhanced by glutathione depletion (using buthionine sulfoximine) as well as inhibition of thioredoxin reductase (using auranofin). In addition, there was a structure-activity relationship between the aliphatic side-chain length of TPP-derivatives (5–16 carbons), where longer carbon chains increased melanoma cell metabolic disruption and cell killing. In vivo bio-distribution experiments showed that intratumoral administration of a C 14 -TPP-derivative (12-carbon aliphatic chain), using a slow-release thermosensitive hydrogel as a delivery vehicle, localized the drug at the melanoma tumor site. There, it was observed to persist and decrease the growth rate of melanoma tumors. These results demonstrate that TPP-derivatives selectively induce thiol-dependent metabolic oxidative stress and cell killing in malignant melanoma and support the hypothesis that a hydrogel-based TPP-derivative delivery system could represent a therapeutic drug-delivery strategy for melanoma.

During Easter 2009, almost 200 people resident in a small Swedish village fell ill with gastrointestinal symptoms. We conducted a retrospective cohort study and a molecular investigation in order to identify the source of the outbreak. Residents living in households connected to the public water network were at an increased risk of developing disease (relative risk 4·80, 95% confidence interval 1·68–13·73) compared to those with no connection to the public network. Norovirus genotype GI.3 was identified in stool samples from six patients and in a sample from the public water network. Contamination of one of the wells supplying the public water network was thought to be the source of the outbreak. This is a description of a norovirus outbreak linked to a municipal drinking-water supply in Sweden. Information from epidemiological and molecular investigations is of utmost importance to guide outbreak control measures and to prevent future outbreaks.

Outbreaks of acute gastroenteritis are frequently caused by caliciviruses. Electron microscopy was used to search for these viruses in fecal samples from patients with acute gastroenteritis. Of 5800 samples collected and analyzed from November 1994 to June 1998, 3700 were associated with outbreaks. A total of 676 outbreaks were analyzed, and viruses were found in 67%. Caliciviruses, usually Norwalk-like viruses (NLVs), were found in 407 (89%) of 455 outbreaks, while Sapporo-like viruses were identified in nine outbreaks, including six that were suspected to include foodborne transmission. Sixty percent of the 1041 patients with calicivirus infections were between 70 and 90 years of age. Food- and waterborne infections were associated with 66 calicivirus outbreaks. Virus-positive outbreaks were documented mainly during winter and spring. The longitudinal survey showed that caliciviruses, and especially the NLVs, cause most nosocomial and community-associated outbreaks in Sweden.

Soils are extremely rich in biodiversity, and soil organisms play pivotal roles in supporting terrestrial life, but the role that individual plants and plant communities play in influencing the diversity and functioning of soil food webs remains highly debated. Plants, as primary producers and providers of resources to the soil food web, are of vital importance for the composition, structure, and functioning of soil communities. However, whether natural soil food webs that are completely open to immigration and emigration differ underneath individual plants remains unknown. In a biodiversity restoration experiment we first compared the soil nematode communities of 228 individual plants belonging to eight herbaceous species. We included grass, leguminous, and non-leguminous species. Each individual plant grew intermingled with other species, but all plant species had a different nematode community. Moreover, nematode communities were more similar when plant individuals were growing in the same as compared to different plant communities, and these effects were most apparent for the groups of bacterivorous, carnivorous, and omnivorous nematodes. Subsequently, we analyzed the composition, structure, and functioning of the complete soil food webs of 58 individual plants, belonging to two of the plant species, Lotus corniculatus (Fabaceae) and Plantago lanceolata (Plantaginaceae). We isolated and identified more than 150 taxa/groups of soil organisms. The soil community composition and structure of the entire food webs were influenced both by the species identity of the plant individual and the surrounding plant community. Unexpectedly, plant identity had the strongest effects on decomposing soil organisms, widely believed to be generalist feeders. In contrast, quantitative food web modeling showed that the composition of the plant community influenced nitrogen mineralization under individual plants, but that plant species identity did not affect nitrogen or carbon mineralization or food web stability. Hence, the composition and structure of entire soil food webs vary at the scale of individual plants and are strongly influenced by the species identity of the plant. However, the ecosystem functions these food webs provide are determined by the identity of the entire plant community.

A 1-year prospective study was conducted to identify enteropathogens in adults with diarrhea (n = 851) and in healthy control subjects (n = 203) by use of conventional laboratory methods. Virulence factor genes for diarrheagenic Escherichia coli were detected by polymerase chain reaction. Enteropathogens were identified in 56% of patients and 16% of control subjects. The isolation rate was 65% for patients with symptoms for <1 week and for travelers; >1 pathogen was found in 11% of patients. The most frequent enteropathogens were Campylobacter (13% of patients), Clostridium difficile (13%), enterotoxigenic Escherichia coli (8%), Salmonella (7%), Shigella (4%), Blastocystis hominis (4%), calicivirus (3%), rotavirus (3%), enteroaggregative E. coli (2%), Aeromonas (2%), Giardia intestinalis (2%), Cryptosporidium (2%), and astrovirus (2%). Less frequently isolated (≤1% of patients) were verotoxigenic E. coli, enteropathogenic E. coli, enteroinvasive E. coli, Entamoeba histolytica/Entamoeba dispar, microsporidia, and adenovirus. Fifty percent of the patients were hospitalized, and 43% needed intravenous fluids. The median duration of diarrhea was 14 days. Clinical features were not helpful for predicting the etiology of diarrhea.

On-going human population growth and changing patterns of resource consumption are increasing global demand for ecosystem services, many of which are provided by soils. Some of these ecosystem services are linearly related to the surface area of pervious soil, whereas others show non-linear relationships, making ecosystem service optimization a complex task. As limited land availability creates conflicting demands among various types of land use, a central challenge is how to weigh these conflicting interests and how to achieve the best solutions possible from a perspective of sustainable societal development. These conflicting interests become most apparent in soils that are the most heavily used by humans for specific purposes: urban soils used for green spaces, housing, and other infrastructure and agricultural soils for producing food, fibres and biofuels. We argue that, despite their seemingly divergent uses of land, agricultural and urban soils share common features with regards to interactions between ecosystem services, and that the trade-offs associated with decision-making, while scale- and context-dependent, can be surprisingly similar between the two systems. We propose that the trade-offs within land use types and their soil-related ecosystems services are often disproportional, and quantifying these will enable ecologists and soil scientists to help policy makers optimizing management decisions when confronted with demands for multiple services under limited land availability.

Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A , PHF6 , ATRX , KDM6A , SMARCA4 , ASXL2 , CREBBP , EZH2 , MLL2 , USP7 , ASXL1 , NSD2 , SETD2 , SMC1A and ZMYM3 . We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. Collectively, our results help to define the landscape of mutations in epigenetic regulatory genes in paediatric cancer and yield a valuable new database for investigating the role of epigenetic dysregulations in cancer. Proteins involved in epigenetic regulation are frequently mutated in several paediatric cancers. Here, Huether et al. characterize the somatic mutation frequency across 21 paediatric cancer subtypes by sequencing 633 epigenetic genes in over 1,000 tumours; generating a rich data set for investigating epigenetic dysregulation.

Over 400 office workers from the same unit of a manufacturing company in Stockholm County, Sweden, fell ill with gastroenteritis. A retrospective cohort study of office workers in the affected unit demonstrated that canteen visitors on one day had an increased risk of illness [risk ratio (RR) 27·1, 95% confidence interval (CI) 15·7–46·8] compared to non-visitors. A second study, investigating canteen visitors' consumption of particular food items, showed that both tomatoes from the salad buffet (RR 5·6, 95% CI 3·2–9·6) and hamburgers (RR 4·9, 95% CI 2·4–9·8) were the most likely vehicles of infection. Norovirus GI.3 (Desert Shield) was identified in stool samples from three office workers and from a food handler who prepared the tomatoes for the salad buffet and hamburger ingredients before vomiting at the workplace on 12 November. The outbreak could have been prevented if the food items prepared by the food handler some hours before vomiting had not been served.

An outbreak of gastroenteritis due to Norwalk-like virus (NLV) affecting approximately 500 people occurred in a Swedish ski resort during February–March 2002. Epidemiological investigations were performed on cohorts of schoolchildren, permanent residents and skiers visiting the area. Attack rates were respectively 39·7, 29·9 and 38·5%. Drinking un-boiled water originating from one of the three communal water systems was a significant risk factor for all groups. For schoolchildren, the risk of illness increased with increasing amount of water consumed. Nine of 12 stool samples of patients analysed tested positive for NLV. The water tested negative for indicator bacteria and results of NLV tests were inconclusive. In the absence of microbiological findings, the environmental authorities were reluctant to act based on the epidemiological analysis alone, and intervention was delayed until mid-April, following the discovery of a crack in a sewage pipe 10 m from the well.

We examined the relationship between plant species diversity, productivity and the development of the soil community during early secondary succession on former arable land across Europe. We tested the hypothesis that increasing the initial plant species diversity enhances the biomass production and consequently stimulates soil microbial biomass and abundance of soil invertebrates. We performed five identical field experiments on abandoned arable land in five European countries (CZ, NL, SE, SP and UK) which allowed us to test our hypothesis in a range of climate, soil and other environmental factors that varied between the experimental sites. The initial plant diversity was altered by sowing seed mixtures of mid-successional grassland species with two or five grass species, one or five legumes and one or five forbs. The results of low and high sown diversity treatments were compared with plots that were naturally colonized by species present in the seed bank. In three out of the five field sites, there was no correlation between plant species number and plant biomass production, one site had a positive and the other a negative relation. Treatments with a high diversity seed mixture had a higher biomass than the naturally colonized plots. However, there was no significant difference between high and low sown diversity plots at four out of five sites. The three-year study did not give any evidence of a general bottom-up effect from increased plant biomass on biomass of bacteria, saprophytic fungi or abundance of microarthropods. The biomass of arbuscular mycorrhizal was negatively related to plant biomass. The abundance of nematodes increased after abandonment and was related to plant biomass at four sites. Our results support the hypothesis that plant species diversity may have idiosyncratic effects on soil communities, even though studies on a longer term could reveal time lags in the response to changes in composition and biomass production of plant communities.