A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.

Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers

Tandem Mass Spectrometry Measurement of the Collision Products of Carbamate Anions Derived from CO2 Capture Sorbents: Paving the Way for Accurate Quantitation

The reaction between CO2 and aqueous amines to produce a charged carbamate product plays a crucial role in post-combustion capture chemistry when primary and secondary amines are used. In this paper, we report the low energy negative-ion CID results for several anionic carbamates derived from primary and secondary amines commonly used as post-combustion capture solvents. The study was performed using the modern equivalent of a triple quadrupole instrument equipped with a T-wave collision cell. Deuterium labeling of 2-aminoethanol (1,1,2,2,-d4-2-aminoethanol) and computations at the M06-2X/6-311++G(d,p) level were used to confirm the identity of the fragmentation products for 2-hydroxyethylcarbamate (derived from 2-aminoethanol), in particular the ions CN−, NCO− and facile neutral losses of CO2 and water; there is precedent for the latter in condensed phase isocyanate chemistry. The fragmentations of 2-hydroxyethylcarbamate were generalized for carbamate anions derived from other capture amines, including ethylenediamine, diethanolamine, and piperazine. We also report unequivocal evidence for the existence of carbamate anions derived from sterically hindered amines (Tris(2-hydroxymethyl)aminomethane and 2-methyl-2-aminopropanol). For the suite of carbamates investigated, diagnostic losses include the decarboxylation product (−CO2, 44 mass units), loss of 46 mass units and the fragments NCO− (m/z 42) and CN− (m/z 26). We also report low energy CID results for the dicarbamate dianion (−O2CNHC2H4NHCO2−) commonly encountered in CO2 capture solution utilizing ethylenediamine. Finally, we demonstrate a promising ion chromatography-MS based procedure for the separation and quantitation of aqueous anionic carbamates, which is based on the reported CID findings. The availability of accurate quantitation methods for ionic CO2 capture products could lead to dynamic operational tuning of CO2 capture-plants and, thus, cost-savings via real-time manipulation of solvent regeneration energies

Altered Composition of Liver Proteasome Assemblies Contributes to Enhanced Proteasome Activity in the Exceptionally Long-Lived Naked Mole-Rat

The longest-lived rodent, the naked mole-rat (Bathyergidae; Heterocephalus glaber), maintains robust health for at least 75% of its 32 year lifespan, suggesting that the decline in genomic integrity or protein homeostasis routinely observed during aging, is either attenuated or delayed in this extraordinarily long-lived species. The ubiquitin proteasome system (UPS) plays an integral role in protein homeostasis by degrading oxidatively-damaged and misfolded proteins. In this study, we examined proteasome activity in naked mole-rats and mice in whole liver lysates as well as three subcellular fractions to probe the mechanisms behind the apparently enhanced effectiveness of UPS. We found that when compared with mouse samples, naked mole-rats had significantly higher chymotrypsin-like (ChT-L) activity and a two-fold increase in trypsin-like (T-L) in both whole lysates as well as cytosolic fractions. Native gel electrophoresis of the whole tissue lysates showed that the 20S proteasome was more active in the longer-lived species and that 26S proteasome was both more active and more populous. Western blot analyses revealed that both 19S subunits and immunoproteasome catalytic subunits are present in greater amounts in the naked mole-rat suggesting that the observed higher specific activity may be due to the greater proportion of immunoproteasomes in livers of healthy young adults. It thus appears that proteasomes in this species are primed for the efficient removal of stress-damaged proteins. Further characterization of the naked mole-rat proteasome and its regulation could lead to important insights on how the cells in these animals handle increased stress and protein damage to maintain a longer health in their tissues and ultimately a longer life

Modulating Pharmacokinetics, Tumor Uptake and Biodistribution by Engineered Nanoparticles

Inorganic nanoparticles provide promising tools for biomedical applications including detection, diagnosis and therapy. While surface properties such as charge are expected to play an important role in their in vivo behavior, very little is known how the surface chemistry of nanoparticles influences their pharmacokinetics, tumor uptake, and biodistribution.Using a family of structurally homologous nanoparticles we have investigated how pharmacological properties including tumor uptake and biodistribution are influenced by surface charge using neutral (TEGOH), zwitterionic (Tzwit), negative (TCOOH) and positive (TTMA) nanoparticles. Nanoparticles were injected into mice (normal and athymic) either in the tail vein or into the peritoneum.Neutral and zwitterionic nanoparticles demonstrated longer circulation time via both i.p. and i.v. administration, whereas negatively and positively charged nanoparticles possessed relatively short half-lives. These pharmacological characteristics were reflected on the tumor uptake and biodistribution of the respective nanoparticles, with enhanced tumor uptake by neutral and zwitterionic nanoparticles via passive targeting

Loneliness of Older Immigrant Groups in Canada: Effects of Ethnic-Cultural Background

This study aimed to explore the loneliness of several groups of older immigrants in Canadacompared to native-born older adults. Data from the Canadian General Social Survey, Cycle 22 (Nolder adults = 3,692) were used. The dependent variable is the 6 item De Jong Gierveld lonelinessscale. Determinants of loneliness included country of birth, ethnic background (cultural context);belongingness (community context) and social networks (social context). Results showed that onlysome immigrant groups are significantly lonelier than older adults born in Canada. Immigrants withsimilar language and culture are not lonelier; while those from countries that differ in nativelanguage/culture are significantly higher on loneliness. Multivariate analyses showed the importanceof cultural background, of composition of the network of relatives and friends, and of localparticipation and feelings of belonging to the Canadian society in explaining loneliness of olderimmigrants

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis

BACKGROUND:Cesarean birth rates continue to rise worldwide with recent (2016) reported rates of 24.5% in Western Europe, 32% in North America, and 41% in South America. The objective of this systematic review is to describe the long-term risks and benefits of cesarean delivery for mother, baby, and subsequent pregnancies. The primary maternal outcome was pelvic floor dysfunction, the primary baby outcome was asthma, and the primary subsequent pregnancy outcome was perinatal death. METHODS AND FINDINGS:Medline, Embase, Cochrane, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were systematically searched for published studies in human subjects (last search 25 May 2017), supplemented by manual searches. Included studies were randomized controlled trials (RCTs) and large (more than 1,000 participants) prospective cohort studies with greater than or equal to one-year follow-up comparing outcomes of women delivering by cesarean delivery and by vaginal delivery. Two assessors screened 30,327 abstracts. Studies were graded for risk of bias by two assessors using the Scottish Intercollegiate Guideline Network (SIGN) Methodology Checklist and the Risk of Bias Assessment tool for Non-Randomized Studies. Results were pooled in fixed effects meta-analyses or in random effects models when significant heterogeneity was present (I2 ≥ 40%). One RCT and 79 cohort studies (all from high income countries) were included, involving 29,928,274 participants. Compared to vaginal delivery, cesarean delivery was associated with decreased risk of urinary incontinence, odds ratio (OR) 0.56 (95% CI 0.47 to 0.66; n = 58,900; 8 studies) and pelvic organ prolapse (OR 0.29, 0.17 to 0.51; n = 39,208; 2 studies). Children delivered by cesarean delivery had increased risk of asthma up to the age of 12 years (OR 1.21, 1.11 to 1.32; n = 887,960; 13 studies) and obesity up to the age of 5 years (OR 1.59, 1.33 to 1.90; n = 64,113; 6 studies). Pregnancy after cesarean delivery was associated with increased risk of miscarriage (OR 1.17, 1.03 to 1.32; n = 151,412; 4 studies) and stillbirth (OR 1.27, 1.15 to 1.40; n = 703,562; 8 studies), but not perinatal mortality (OR 1.11, 0.89 to 1.39; n = 91,429; 2 studies). Pregnancy following cesarean delivery was associated with increased risk of placenta previa (OR 1.74, 1.62 to 1.87; n = 7,101,692; 10 studies), placenta accreta (OR 2.95, 1.32 to 6.60; n = 705,108; 3 studies), and placental abruption (OR 1.38, 1.27 to 1.49; n = 5,667,160; 6 studies). This is a comprehensive review adhering to a registered protocol, and guidelines for the Meta-analysis of Observational Studies in Epidemiology were followed, but it is based on predominantly observational data, and in some meta-analyses, between-study heterogeneity is high; therefore, causation cannot be inferred and the results should be interpreted with caution. CONCLUSIONS:When compared with vaginal delivery, cesarean delivery is associated with a reduced rate of urinary incontinence and pelvic organ prolapse, but this should be weighed against the association with increased risks for fertility, future pregnancy, and long-term childhood outcomes. This information could be valuable in counselling women on mode of delivery

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

Anti-inflammatory activity of diindolylmethane alleviates Riemerella anatipestifer infection in ducks.

3,3'-Diindolylmethane (DIM) is found in cruciferous vegetables and is used to treat various inflammatory diseases because of its potential anti-inflammatory effects. To investigate effects of DIM in Riemerella anatipestifer-infected ducks which induce upregulation of inflammatory cytokines, ducks were treated orally with DIM at dose of 200 mg/kg/day and infected the following day with R. anatipestifer. Infected and DIM-treated ducks exhibited 14% increased survival rate and significantly decreased bacterial burden compared to infected untreated ducks. Next, the effect on the expression level of inflammatory cytokines (interleukin [IL]-17A, IL-17F, IL-6, IL-1β) of both in vitro and in vivo DIM-treated groups was monitored by quantitative reverse-transcription PCR (qRT-PCR). Generally, the expression levels of the cytokines were significantly reduced in DIM-treated splenic lymphocytes stimulated with killed R. anatipestifer compared to stimulated untreated splenic lymphocytes. Similarly, the expression levels of the cytokines were significantly reduced in the spleens and livers of DIM-treated R. anatipestifer-infected ducks compared to infected untreated ducks. This study demonstrated the ameliorative effects of DIM in ducks infected with R. anatipestifer. Thus, DIM can potentially be used to prevent and/or treat R. anatipestifer infection via inhibition of inflammatory cytokine expression

High occurrence of viruses in the mucus layer of scleractinian corals

Viruses attract increasing interest from environmental microbiologists seeking to understand their function and role in coral health. However, little is known about their main ecological traits within the coral holobiont. In this study, a quantitative and qualitative characterization of viral and bacterial communities was conducted on the mucus of seven different coral species of the Van Phong Bay (Vietnam). On average, the concentrations of viruses and bacteria were, respectively, 17- and twofold higher in the mucus than in the surrounding water. The examination of bacterial community composition also showed remarkable differences between mucus and water samples. The percentage of active respiring cells was nearly threefold higher in mucus (m=24.8%) than in water (m=8.6%). Interestingly, a positive and highly significant correlation was observed between the proportion of active cells and viral abundance in the mucus, suggesting that the metabolism of the bacterial associates is probably a strong determinant of the distribution of viruses within the coral holobiont. Overall, coral mucus, given its unique physicochemical characteristics and sticking properties, can be regarded as a highly selective biotope for abundant, diversified and specialized symbiotic microbial and viral organisms