Viral outbreak in corals associated with an in situ bleaching event: atypical herpes-like viruses and a new megavirus infecting Symbiodinium

Previous studies of coral viruses have employed either microscopy or metagenomics, but few have attempted to comprehensively link the presence of a virus-like particle (VLP) to a genomic sequence. We conducted transmission electron microscopy imaging and virome analysis in tandem to characterize the most conspicuous viral types found within the dominant Pacific reef-building coral genus Acropora. Collections for this study inadvertently captured what we interpret as a natural outbreak of viral infection driven by aerial exposure of the reef flat coincident with heavy rainfall and concomitant mass bleaching. All experimental corals in this study had high titers of viral particles. Three of the dominant VLPs identified were observed in all tissue layers and budding out from the epidermis, including viruses that were ∼70, ∼120, and ∼150 nm in diameter; these VLPs all contained electron dense cores. These morphological traits are reminiscent of retroviruses, herpesviruses, and nucleocytoplasmic large DNA viruses (NCLDVs), respectively. Some 300–500 nm megavirus-like VLPs also were observed within and associated with dinoflagellate algal endosymbiont (Symbiodinium) cells. Abundant sequence similarities to a gammaretrovirus, herpesviruses, and members of the NCLDVs, based on a virome generated from five Acropora aspera colonies, corroborated these morphology-based identifications. Additionally sequence similarities to two diagnostic genes, a MutS and (based on re-annotation of sequences from another study) a DNA polymerase B gene, most closely resembled Pyramimonas orientalis virus, demonstrating the association of a cosmopolitan megavirus with Symbiodinium. We also identified several other virus-like particles in host tissues, along with sequences phylogenetically similar to circoviruses, phages, and filamentous viruses. This study suggests that viral outbreaks may be a common but previously undocumented component of natural bleaching events, particularly following repeated episodes of multiple environmental stressors

Metabolic changes upon GLS inhibition by CB-839 in glioma cell lines

Many tumors use Gln for both energy generation and as a biosynthetic precursor. Glutaminases (GAs) catalyze the first step of glutaminolysis by converting glutamine (Gln) into glutamate and ammonia in the mitochondria. In humans, two genes encode for glutaminases: GLS and GLS2. We examined the metabolic consequences of inhibiting GLS activity in glioma cells by using the clinically relevant inhibitor CB-839. We treated three glioblastoma (GBM) cell lines with CB-839 and performed untargeted metabolomics and isotope tracing experiments using U-13C-labeled Gln and 15N-labeled Gln in the amido group to ascertain the metabolic fates of Gln carbon and nitrogen. Untargeted metabolomics results showed that CB-839 treatment significantly depleted tricarboxylic acid cycle (TCAC) intermediates and related metabolites in the three human glioblastoma cell lines assayed. This result was also confirmed by a lower labeling from U-13C- Gln in these metabolites. U-13C- Gln tracing also revealed reductive carboxylation-related labeling in these cell lines, and this pathways was also suppressed by CB-839. Metabolomics results showed an accumulation of the de novo purine biosynthesis intermediates inosine monophosphate and/or AICAR, and a decrease in uridine monophosphate, while 15N-Gln tracing results showed a decreased labeling from Gln amido group in AMP, GMP, UMP and CTP in T98G cell line when treated with CB-839. Finally, metabolomics showed higher levels of trimethyllysine and, in T98G cells, a 22-fold increase in 5-methyl-cytosine.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Interactions between Teladorsagia circumcincta infections and microbial composition of sheep with or without successful monepantel treatment:A preliminary study

Nematodes are one of the main impactors on the health, welfare and productivity of farmed animals. Teladorsagia circumcincta are endemic throughout many sheep-producing countries, particularly in the northern hemisphere, and contribute to the pathology and economic losses seen on many farms. Control of these nematode infections is essential and heavily reliant on chemotherapy (anthelmintics), but this has been compromised by the development of anthelmintic resistance. In mammals, the composition of the intestinal microbiota has been shown to have a significant effect on overall health. The interactions between host, microbiota and pathogens are complex and influenced by numerous factors. In this study, comparisons between intestinal and faecal microbiota of sheep infected with sensitive or resistant strains of T. circumcincta, with or without monepantel administration were assessed. The findings from both faecal samples and terminal ileum mucosal scrapings showed clear differences between successfully treated animals and those sheep that were left untreated and/or those carrying resistant nematodes. Specifically, the potentially beneficial genus Bifidobacterium was identified as elevated in successfully treated animals. The detection of these and other biomarkers will provide the basis for new therapeutic reagents particularly relevant to the problems of emerging multidrug anthelmintic resistance

Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines

Glioblastoma multiforme is the most common primary brain tumor. Unfortunately, it is also one of the cancer types that has the worst morbidity and mortality ratios, so new targets and treatments need to be found. The metabolism of glutamine is fundamental for the proliferation of many tumor cells, including glioblastomas. Glutaminase isoenzyme GLS is one of the responsible enzymes for the pro-oncogenic pathways that induce metabolic reprogramming and leads to altered levels of some amino acids and other key intermediary metabolites in glioblastoma. Using the clinically approved GLS inhibitor CB-839 (Telaglenastat), we found significant changes in glutamine metabolism, including both the oxidative and reductive fates of Gln-derived alpha-ketoglutarate in the tricarboxylic acid cycle, in three glioblastoma cell lines. One of them, the T98G glioblastoma cell line, showed the greatest modification of metabolite levels involved in the de novo biosynthetic pathways for nucleotides, as well as a higher content of methylated and acetylated metabolites.This research was funded by Ministerio de Ciencia y Tecnología of Spain, grant number RTI2018-096866-B-I00 (to J.M.M. and J.M.) and Junta de Andalucía, Grant UMA18-FEDERJA-082 (to J.M.). R.J.D. is supported by the Howard Hughes Medical Institute, the National Cancer Institute (R35CA220444901), the Cancer Prevention and Research Institute of Texas, and the Moody Foundation. J.D.l.S.-J. is granted by FPU17/04084, Ministerio de Ciencia, Innovación y Universidades. Partial funding for open access charge: Universidad de Málag

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase

Methodological strategies to understand smartphone practices for social connectedness in later life

Digital practices in later life are not yet well understood. Therefore, this paper discusses the framework for a research design project that aims at tracing differences and similarities in how older adults use their smartphones in circumstances in and outside their homes in Spain, the Netherlands, Sweden, and Canada. The research questions of this international research project focus on the extent to which digital mobile practices relate to perceived social connectedness among older adults aged 55–79 years old. While studies have shown that the subjective experience of ‘being connected’ supports continued wellbeing in later life, there remains an insufficient understanding of the processes through which digital mediated social interaction is effective for social connectedness. The analytical framework of the project prioritizes the co-constituency of (digital) technology and ageing, and takes digital practices in everyday life as its entry point. The main data collection tool will be the tracking of smartphone activity of 600 older adults (150 per country) during four weeks. An online survey and qualitative interviews will gather data about the meanings of the quantified digital practices, and how they shape (if they do) the participants’ connection to the world. This approach will allow us not only to get insight into what older adults say how they used their smartphone but also to gain insight into their real-life daily use. The assessment of the challenges, strengths, and weaknesses of the methods contributes towards an accurate and appropriate interpretation of empirical results and their implications

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone