Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) allows a fast and reliable bacterial identification from culture plates. Direct analysis of clinical ...samples may increase its usefulness in samples in which a fast identification of microorganisms can guide empirical treatment, such as blood cultures (BC). Three hundred and thirty BC, reported as positive by the automated BC incubation device, were processed by conventional methods for BC processing, and by a fast method based on direct MALDI-TOF MS. Three hundred and eighteen of them yield growth on culture plates, and 12 were false positive. The MALDI-TOF MS-based method reported that no peaks were found, or the absence of a reliable identification profile, in all these false positive BC. No mixed cultures were found. Among these 318 BC, we isolated 61 Gram-negatives (GN), 239 Gram-positives (GP) and 18 fungi. Microorganism identifications in GN were coincident with conventional identification, at the species level, in 83.3% of BC and, at the genus level, in 96.6%. In GP, identifications were coincident with conventional identification in 31.8% of BC at the species level, and in 64.8% at the genus level. Fungaemia was not reliably detected by MALDI-TOF. In 18 BC positive for Candida species (eight C. albicans, nine C. parapsilosis and one C. tropicalis), no microorganisms were identified at the species level, and only one (5.6%) was detected at the genus level. The results of the present study show that this fast, MALDI-TOF MS-based method allows bacterial identification directly from presumptively positive BC in a short time (<30 min), with a high accuracy, especially when GN bacteria are involved.
Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to ...several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO.
We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO.
Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval CI = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77).
In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.
Summary
A systematic review and meta‐analyses were conducted to evaluate the effects of interventions to reduce sugar‐sweetened beverages (SSB) or increase water intakes and to examine the impact of ...behaviour change techniques (BCTs) in consumption patterns. Randomized and nonrandomized controlled trials published after January 1990 and until December 2016 reporting daily changes in intakes of SSB or water in volumetric measurements (mL d−1) were included. References were retrieved through searches of electronic databases and quality appraisal followed Cochrane principles. We calculated mean differences (MD) and synthesized data with random‐effects models. Forty studies with 16 505 participants were meta‐analysed. Interventions significantly decreased consumption of SSB in children by 76 mL d−1 (95% confidence interval CI −105 to −46; 23 studies, P < 0.01), and in adolescents (−66 mL d−1, 95% CI −130 to −2; 5 studies, P = 0.04) but not in adults (−13 mL d−1, 95% CI −44 to 18; 12 studies, P = 0.16). Pooled estimates of water intakes were only possible for interventions in children, and results were indicative of increases in water intake (MD +67 mL d−1, 95% CI 6 to 128; 7 studies, P = 0.04). For children, there was evidence to suggest that modelling/demonstrating the behaviour helped to reduce SSB intake and that interventions within the home environment had greater effects than school‐based interventions. In conclusion, public health interventions – mainly via nutritional education/counselling – are moderately successful at reducing intakes of SSB and increasing water intakes in children. However, on average, only small reductions in SSBs have been achieved by interventions targeting adolescents and adults. Complementary measures may be needed to achieve greater improvements in both dietary behaviours across all age groups.
It has been recognized that a number of mechanisms mediating the health benefits of beneficial bacterial cells do require viability. However, new terms such as paraprobiotic or postbiotic have ...emerged to denote that non-viable microbial cells, microbial fractions, or cell lysates might also offer physiological benefits to the host by providing additional bioactivity.
This review provides an overview of the postbiotic concept, evidence of their health benefits and possible signaling pathways involved in their protective effects, as well as perspectives for applications in foods and pharmaceuticals.
Postbiotics refers to soluble factors (products or metabolic byproducts), secreted by live bacteria, or released after bacterial lysis, such as enzymes, peptides, teichoic acids, peptidoglycan-derived muropeptides, polysaccharides, cell surface proteins, and organic acids. These postbiotics have drawn attention because of their clear chemical structure, safety dose parameters, long shelf life and the content of various signaling molecules which may have anti-inflammatory, immunomodulatory, anti-obesogenic, antihypertensive, hypocholesterolemic, anti-proliferative, and antioxidant activities. These properties suggest that postbiotics may contribute, to the improvement of host health by improving specific physiological functions, even though the exact mechanisms have not been entirely elucidated.
•Postbiotics comprise metabolites and/or cell-wall components released by probiotics.•Postbiotics may, together with probiotics, improve host health.•The exact mechanisms of postbiotic bioactivities have not been fully elucidated.
Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, and implicates specific metabolic factors in neural functions that drive behaviour
. In neurons, acetylation of ...histones relies on the metabolite acetyl-CoA, which is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2)
. Notably, the breakdown of alcohol in the liver leads to a rapid increase in levels of blood acetate
, and alcohol is therefore a major source of acetate in the body. Histone acetylation in neurons may thus be under the influence of acetate that is derived from alcohol
, with potential effects on alcohol-induced gene expression in the brain, and on behaviour
. Here, using in vivo stable-isotope labelling in mice, we show that the metabolism of alcohol contributes to rapid acetylation of histones in the brain, and that this occurs in part through the direct deposition of acetyl groups that are derived from alcohol onto histones in an ACSS2-dependent manner. A similar direct deposition was observed when mice were injected with heavy-labelled acetate in vivo. In a pregnant mouse, exposure to labelled alcohol resulted in the incorporation of labelled acetyl groups into gestating fetal brains. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced transcriptional programs related to learning and memory, which were sensitive to ACSS2 inhibition. We show that alcohol-related associative learning requires ACSS2 in vivo. These findings suggest that there is a direct link between alcohol metabolism and gene regulation, through the ACSS2-dependent acetylation of histones in the brain.
The Community Earth System Model Version 2 (CESM2) Danabasoglu, G.; Lamarque, J.‐F.; Bacmeister, J. ...
Journal of advances in modeling earth systems,
February 2020, Letnik:
12, Številka:
2
Journal Article
Recenzirano
Odprti dostop
An overview of the Community Earth System Model Version 2 (CESM2) is provided, including a discussion of the challenges encountered during its development and how they were addressed. In addition, an ...evaluation of a pair of CESM2 long preindustrial control and historical ensemble simulations is presented. These simulations were performed using the nominal 1° horizontal resolution configuration of the coupled model with both the “low‐top” (40 km, with limited chemistry) and “high‐top” (130 km, with comprehensive chemistry) versions of the atmospheric component. CESM2 contains many substantial science and infrastructure improvements and new capabilities since its previous major release, CESM1, resulting in improved historical simulations in comparison to CESM1 and available observations. These include major reductions in low‐latitude precipitation and shortwave cloud forcing biases; better representation of the Madden‐Julian Oscillation; better El Niño‐Southern Oscillation‐related teleconnections; and a global land carbon accumulation trend that agrees well with observationally based estimates. Most tropospheric and surface features of the low‐ and high‐top simulations are very similar to each other, so these improvements are present in both configurations. CESM2 has an equilibrium climate sensitivity of 5.1–5.3 °C, larger than in CESM1, primarily due to a combination of relatively small changes to cloud microphysics and boundary layer parameters. In contrast, CESM2's transient climate response of 1.9–2.0 °C is comparable to that of CESM1. The model outputs from these and many other simulations are available to the research community, and they represent CESM2's contributions to the Coupled Model Intercomparison Project Phase 6.
Plain Language Summary
The Community Earth System Model (CESM) is an open‐source, comprehensive model used in simulations of the Earth's past, present, and future climates. The newest version, CESM2, has many new technical and scientific capabilities ranging from a more realistic representation of Greenland's evolving ice sheet, to the ability to model in detail how crops interact with the larger Earth system, to improved representation of clouds and rain, and to the addition of wind‐driven waves on the model's ocean surface. The data sets from a large set of simulations that include integrations for the preindustrial conditions (1850s) and for the 1850‐2014 historical period are available to the community, representing CESM2's contributions to the Coupled Model Intercomparison Project Phase 6 (CMIP6).
Key Points
Community Earth System Model Version 2 includes many substantial science and infrastructure improvements since its previous version
Preindustrial control and historical simulations were performed with low‐top and high‐top with comprehensive chemistry atmospheric models
Comparisons to observations are improved relative to previous versions, including major reductions in radiation and precipitation biases
Regulation of circulating free fatty acid (FFA) levels and delivery is crucial to maintain tissue homeostasis. Exosomes are nanomembranous vesicles that are released from diverse cell types and ...mediate intercellular communication by delivering bioactive molecules. Here, we sought to investigate the uptake of FFAs by circulating exosomes, the delivery of FFA-loaded exosomes to cardiac cells and the possible role of the FFA transporter CD36 in these processes. Circulating exosomes were purified from the serum of healthy donors after an overnight fast (F) or 20 minutes after a high caloric breakfast (postprandial, PP). Western blotting, Immunogold Electron Microscopy and FACS analysis of circulating exosomes showed that CD36 was expressed under both states, but was higher in postprandial-derived exosomes. Flow cytometry analysis showed that circulating exosomes were able to take-up FFA directly from serum. Importantly, preincubation of exosomes with a blocking CD36 antibody significantly impeded uptake of the FFA analogue BODIPY, pointing to the role of CD36 in FFA exosomal uptake. Finally, we found that circulating exosomes could delivery FFA analogue BODIPY into cardiac cells ex vivo and in vivo in a mice model. Overall, our results suggest a novel mechanism in which circulating exosomes can delivery FFAs from the bloodstream to cardiac tissue. Further studies will be necessary to understand this mechanism and, in particular, its potential involvement in metabolic pathologies such as obesity, diabetes and atherosclerosis.
The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A ...secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.
Balanced fishing across a range of species, stocks, and sizes could mitigate adverse effects and address food security better than increased selectivity.
Concern about the impact of fishing on ...ecosystems and fisheries production is increasing (
1
,
2
). Strategies to reduce these impacts while addressing the growing need for food security (
3
) include increasing selectivity (
1
,
2
): capturing species, sexes, and sizes in proportions that differ from their occurrence in the ecosystem. Increasing evidence suggests that more selective fishing neither maximizes production nor minimizes impacts (
4
–
7
). Balanced harvesting would more effectively mitigate adverse ecological effects of fishing while supporting sustainable fisheries. This strategy, which challenges present management paradigms, distributes a moderate mortality from fishing across the widest possible range of species, stocks, and sizes in an ecosystem, in proportion to their natural productivity (
8
), so that the relative size and species composition is maintained.
Aims/hypothesis
We report a genome-wide association study of type 2 diabetes in an admixed sample from Mexico City and describe the results of a meta-analysis of this study and another genome-wide ...scan in a Mexican-American sample from Starr County, TX, USA. The top signals observed in this meta-analysis were followed up in the Diabetes Genetics Replication and Meta-analysis Consortium (DIAGRAM) and DIAGRAM+ datasets.
Methods
We analysed 967 cases and 343 normoglycaemic controls. The samples were genotyped with the Affymetrix Genome-wide Human SNP array 5.0. Associations of genotyped and imputed markers with type 2 diabetes were tested using a missing data likelihood score test. A fixed-effects meta-analysis including 1,804 cases and 780 normoglycaemic controls was carried out by weighting the effect estimates by their inverse variances.
Results
In the meta-analysis of the two Hispanic studies, markers showing suggestive associations (
p
< 10
−5
) were identified in two known diabetes genes,
HNF1A
and
KCNQ1
, as well as in several additional regions. Meta-analysis of the two Hispanic studies and the recent DIAGRAM+ dataset identified genome-wide significant signals (
p
< 5 × 10
−8
) within or near the genes
HNF1A
and
CDKN2A/CDKN2B
, as well as suggestive associations in three additional regions,
IGF2BP2, KCNQ1
and the previously unreported
C14orf70.
Conclusions/interpretation
We observed numerous regions with suggestive associations with type 2 diabetes. Some of these signals correspond to regions described in previous studies. However, many of these regions could not be replicated in the DIAGRAM datasets. It is critical to carry out additional studies in Hispanic and American Indian populations, which have a high prevalence of type 2 diabetes.
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