Flavonoids from engineered tomatoes inhibit gut barrier pro-inflammatory cytokines and chemokines, via SAPK/JNK and p38 MAPK pathways

Flavonoids are a diverse group of plant secondary metabolites, known to reduce inflammatory bowel disease symptoms. How they achieve this is largely unknown. Our study focuses on the gut epithelium as it receives high topological doses of dietary constituents, maintains gut homeostasis, and orchestrates gut immunity. Dysregulation leads to chronic gut inflammation, via dendritic cell (DC)-driven immune responses. Tomatoes engineered for enriched sets of flavonoids (anthocyanins or flavonols) provided a unique and complex naturally consumed food matrix to study the effect of diet on chronic inflammation. Primary murine colonic epithelial cell-based inflammation assays consist of chemokine induction, apoptosis and proliferation, and effects on kinase pathways. Primary murine leukocytes and DCs were used to assay effects on transmigration. A murine intestinal cell line was used to assay wound healing. Engineered tomato extracts (enriched in anthocyanins or flavonols) showed strong and specific inhibitory effects on a set of key epithelial pro-inflammatory cytokines and chemokines. Chemotaxis assays showed a resulting reduction in the migration of primary leukocytes and DCs. Activation of epithelial cell SAPK/JNK and p38 MAPK signaling pathways were specifically inhibited. The epithelial wound healing-associated STAT3 pathway was unaffected. Cellular migration, proliferation, and apoptosis assays confirmed that wound healing processes were not affected by flavonoids. We show flavonoids target epithelial pro-inflammatory kinase pathways, inhibiting chemotactic signals resulting in reduced leukocyte and DC chemotaxis. Thus, both anthocyanins and flavonols modulate epithelial cells to become hyporesponsive to bacterial stimulation. Our results identify a viable mechanism to explain the in vivo anti-inflammatory effects of flavonoids

Mathematical modelling of tissue-engineering angiogenesis

We present a mathematical model for the vascularisation of a porous scaffold following implantation in vivo. The model is given as a set of coupled non-linear ordinary differential equations (ODEs) which describe the evolution in time of the amounts of the different tissue constituents inside the scaffold. Bifurcation analyses reveal how the extent of scaffold vascularisation changes as a function of the parameter values. For example, it is shown how the loss of seeded cells arising from slow infiltration of vascular tissue can be overcome using a prevascularisation strategy consisting of seeding the scaffold with vascular cells. Using certain assumptions it is shown how the system can be simplified to one which is partially tractable and for which some analysis is given. Limited comparison is also given of the model solutions with experimental data from the chick chorioallantoic membrane (CAM) assay

No evidence for tephra in Greenland from the historic eruption of Vesuvius in 79 CE: implications for geochronology and paleoclimatology

Volcanic fallout in polar ice sheets provide important opportunities to date and correlate ice-core records as well as to investigate the environmental impacts of eruptions. Only the geochemical characterization of volcanic ash (tephra) embedded in the ice strata can confirm the source of the eruption, however, and is a requisite if historical eruption ages are to be used as valid chronological checks on annual ice layer counting. Here we report the investigation of ash particles in a Greenland ice core that are associated with a volcanic sulfuric acid layer previously attributed to the 79 CE eruption of Vesuvius. Major and trace element composition of the particles indicates that the tephra does not derive from Vesuvius but most likely originates from an unidentified eruption in the Aleutian arc. Using ash dispersal modelling, we find that only an eruption large enough to include stratospheric injection is likely to account for the sizeable (24–85 μm) ash particles observed in the Greenland ice at this time. Despite its likely explosivity, this event does not appear to have triggered significant climate perturbations, unlike some other large extra-tropical eruptions. In light of a recent re-evaluation of the Greenland ice-core chronologies, our findings further challenge the previous assignation of this volcanic event to 79 CE. We highlight the need for the revised Common Era ice-core chronology to be formally accepted by the wider ice-core and climate modelling communities in order to ensure robust age linkages to precisely dated historical and paleoclimate proxy records

The positive transcriptional elongation factor (P-TEFb) is required for neural crest specification

Regulation of gene expression at the level of transcriptional elongation has been shown to be important in stem cells and tumour cells, but its role in the whole animal is only now being fully explored. Neural crest cells (NCCs) are a multipotent population of cells that migrate during early development from the dorsal neural tube throughout the embryo where they differentiate into a variety of cell types including pigment cells, cranio-facial skeleton and sensory neurons. Specification of NCCs is both spatially and temporally regulated during embryonic development. Here we show that components of the transcriptional elongation regulatory machinery, CDK9 and CYCLINT1 of the P-TEFb complex, are required to regulate neural crest specification. In particular, we show that expression of the proto-oncogene c-Myc and c-Myc responsive genes are affected. Our data suggest that P-TEFb is crucial to drive expression of c-Myc, which acts as a ‘gate-keeper’ for the correct temporal and spatial development of the neural crest

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis

Background & AimsInsulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.MethodsFourteen patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.ResultsLiraglutide reduced BMI (−1.9 vs. +0.04kg/m2; p<0.001), HbA1c (−0.3 vs. +0.3%; p<0.01), cholesterol-LDL (−0.7 vs. +0.05mmol/L; p<0.01), ALT (−54 vs. −4.0IU/L; p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (−9.36 vs. −2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (−24.9 vs. +54.8pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (−1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).ConclusionsLiraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH

Can We Calculate Mean Arterial Pressure in Humans?

Mean arterial pressure (MAP) is either measured with an oscillometric cuff and then systolic (SBP) and diastolic (DBP) blood pressures are estimated from an unknown algorithm; or SBP and DBP are measured via auscultation and MAP calculated using measures of systolic pressure (SBP), diastolic pressure (DBP), and a form-factor (FF; equation: [(SBP-DBP)*FF]+DBP). The typical FF used is 0.33 though others (0.4) have been proposed. Recent work indicates that estimation of aortic MAP via a FF leads to inaccurate values and should therefore be interpreted with caution, whether this is the case for local MAP is unknown. While the implications for hypertension (HTN) diagnosis are minimal, the calculation of local MAP is essential to the study of blood pressure regulation and exercise hemodynamics in patient populations (e.g. heart failure). PURPOSE: To compare the calculation of local MAP using catheter waveforms and a FF, against MAP derived from the pressure-time integral (PTI; i.e. average pressure across the cardiac cycle) measured via radial arterial catheterization. METHODS: We analyzed radial arterial catheter waveforms from 39 patients (Age: 71±7 years; BMI: 38.4±6.7; Female: 66%; HTN prevalence: 97%) with heart failure with preserved ejection fraction (HFpEF) at rest and during cycling exercise at 20 Watts. We compared the PTI (from the catheter waveform) with the calculation of MAP from the peak and nadir of the same waveforms (5-beat averages) using the 0.33 and 0.4 FF’s in the FF equation. RESULTS: Compared to the PTI (91±13 mmHg), resting MAP was not significantly different when calculated using the 0.33 FF (91±11 mmHg, P\u3e0.999) but was higher when using the 0.4 FF (96±12 mmHg, PCONCLUSION:While the 0.33 FF provides an accurate assessment of MAP on average during rest and exercise in the radial artery in patients with HFpEF, the limits of agreement are large reflecting a lack of precision in measurement at an individual level. Indirect calculations of MAP via a FF may lead to inaccurate conclusions regarding the mechanisms of blood pressure regulation both at rest and during exercise testing in this population

Combining natural language processing and metabarcoding to reveal pathogen-environment associations.

Cryptococcus neoformans is responsible for life-threatening infections that primarily affect immunocompromised individuals and has an estimated worldwide burden of 220,000 new cases each year-with 180,000 resulting deaths-mostly in sub-Saharan Africa. Surprisingly, little is known about the ecological niches occupied by C. neoformans in nature. To expand our understanding of the distribution and ecological associations of this pathogen we implement a Natural Language Processing approach to better describe the niche of C. neoformans. We use a Latent Dirichlet Allocation model to de novo topic model sets of metagenetic research articles written about varied subjects which either explicitly mention, inadvertently find, or fail to find C. neoformans. These articles are all linked to NCBI Sequence Read Archive datasets of 18S ribosomal RNA and/or Internal Transcribed Spacer gene-regions. The number of topics was determined based on the model coherence score, and articles were assigned to the created topics via a Machine Learning approach with a Random Forest algorithm. Our analysis provides support for a previously suggested linkage between C. neoformans and soils associated with decomposing wood. Our approach, using a search of single-locus metagenetic data, gathering papers connected to the datasets, de novo determination of topics, the number of topics, and assignment of articles to the topics, illustrates how such an analysis pipeline can harness large-scale datasets that are published/available but not necessarily fully analyzed, or whose metadata is not harmonized with other studies. Our approach can be applied to a variety of systems to assert potential evidence of environmental associations

Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

Pathogenesis and treatment of chronic pulmonary disease

Attitude towards and factors affecting uptake of population based BRCA testing in the Ashkenazi Jewish population: a cohort study

Objective To evaluate factors affecting unselected‐population‐based‐BRCA‐testing in Ashkenazi‐Jews (AJ). Design Cohort‐study set within recruitment to the GCaPPS‐trial (ISRCTN73338115). Setting North‐London AJ‐population. Population or Sample AJ women/men >18‐years, recruited through self‐referral. Methods AJ‐women/men underwent pre‐test counselling for BRCA‐testing through recruitment clinics (clusters). Consenting individuals provided blood‐sample for BRCA‐testing. Socio‐demographic/family‐history/knowledge/psychological well‐being data along‐with benefits/risks/cultural‐influences (18‐item‐questionnaire measuring ‘attitude’) were collected. 4‐item likert‐scales analysed initial ‘interest’ and ‘intention‐to‐test’ pre‐counselling. Uni‐&‐multivariable logistic‐regression‐models evaluated factors affecting uptake/interest/intention‐to undergo BRCA‐testing. Statistical inference was based on cluster robust standard‐errors and joint Wald‐tests for significance. Item‐Response‐Theory and graded‐response‐models modelled responses to 18‐item questionnaire. Main Outcome Measures Interest, intention, uptake, attitude towards BRCA‐testing. Results 935 (women=67%/men=33%; mean‐age=53.8(S.D=15.02) years) individuals underwent pre‐test genetic‐counselling. Pre‐counselling 96% expressed interest but 60% indicated clear intention‐to undergo BRCA‐testing. Subsequently 88% opted for BRCA‐testing. BRCA‐related knowledge (p=0.013) and degree‐level education(p=0.01) were positively and negatively (respectively) associated with intention‐to‐test. Being married/cohabiting had four‐fold higher‐odds for BRCA‐testing uptake (p=0.009). Perceived benefits were associated with higher pre‐counselling odds for interest and intention‐to undergo BRCA‐testing. Reduced uncertainty/reassurance were the most important factors contributing to decision‐making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional‐impact/inability to prevent cancer/marriage‐ability/ethnic‐focus/stigmatization) were significantly associated with lower‐odds of uptake‐of BRCA‐testing, and discriminated between acceptors and decliners. Male‐gender/degree‐level‐education (p=0.001) had weaker, while having children had stronger (p=0.005) attitudes towards BRCA‐testing. Conclusions BRCA‐testing in the AJ‐population has high acceptability. Pre‐test counselling increases awareness of disadvantages/limitations of BRCA‐testing, influencing final cost‐benefit perception and decision‐making on undergoing testing. This article is protected by copyright. All rights reserved