The effects of benfotiamine in attenuating hyperglycemia-induced cardiac pathology

Type 2 diabetes is a major global health problem. It is also a risk factor for the onset of cardiovascular diseases, the current leading cause of global mortality. The first part of this mini-review describes hyperglycemia-induced cellular alterations and its effects on cardiac function. In particular, we emphasize the role of hyperglycemia-induced oxidative stress in the activation of non-oxidative glucose pathways (NOGPs), that may contribute to cardiac pathology. For the second part, we evaluate the utility of benfotiamine (a vitamin B1 derivative) in treating diabetes-related cardiac pathology. The focus is on its role in activating the pentose phosphate pathway, which may reduce flux though the NOGPs. A possible role for benfotiamine in activating pro-survival signaling and reducing cell death in the heart is also described. We also discuss benfotiamine’s potential cardioprotective role in preventing the diabetic cardiomyopathy, treating myocardial infarction and maintaining the viability of cardiac progenitor cells. These findings warrant further investigation into the therapeutic potential of benfotiamine in treating diabetes-related cardiac complications.Keywords: Diabetes; cardiovascular disease; hyperglycemia; oxidative stress; non-oxidative glucose pathways; benfotiamin

Species matter when considering landscape effects on carabid distributions

Increasing the abundance and diversity of carabid beetles is a common objective of farm habitat management to deliver sustainable pest control. Carabid spatial distributions in relation to crop areas are important to the delivery of this ecosystem service. We used pitfall count data at distances from edge habitats into crop centres, from farm sites across the UK, to determine the effects of in-field and adjacent environmental features on carabid abundance and diversity. Overall carabid abundance increased towards the crop centre, whilst species richness and diversity decreased. The analyses of carabid abundance based on all the species pooled together strongly reflected the behaviour of the most abundant species. Species preferences varied by crop, soil type, and environmental features. For instance, some species were positively associated with habitats such as margins, while others responded negatively. This contrast in individual species models highlights the limitations on pooled models in elucidating responses. Studies informing farm-habitat design should consider individual species’ preferences for effective enhancement of pest control services. Diverse cropping and landscape heterogeneity at the farm scale can benefit the varied preferences of individual species, help build diverse communities and, potentially increase service resilience and stability over time

Facilitating the elicitation of beliefs for use in Bayesian Belief modelling

Expert opinion is increasingly being used to inform Bayesian Belief Networks, in particular to define the conditional dependencies modelled by the graphical structure. The elicitation of such expert opinion remains a major challenge due to both the quantity of information required and the ability of experts to quantify subjective beliefs effectively. In this work, we introduce a method designed to initialise conditional probability tables based on a small number of simple questions that capture the overall shape of a conditional probability distribution before enabling the expert to refine their results in an efficient way. These methods have been incorporated into a software Application for Conditional probability Elicitation (ACE), freely available at https://github.com/KirstyLHassall/ACE Hassall (2019

The democratic role of campaign journalism: partisan representation and public participation

Campaign journalism is a distinctive but under-researched form of editorialised news reporting that aims to influence politicians rather than inform voters. In this it diverges from liberal norms of social responsibility, but instead campaigning newspapers make claims to represent the interests or opinions of publics such as their readers or groups affected by the issue. This could be understood as democratically valid in relation to alternative models such as participatory or corporatist democracy. This essay examines journalists’ understanding of the identity and views of these publics, and how their professional norms are operationalised in their journalistic practice in relation to five case studies in the Scottish press. The campaigns are analysed in terms of four normative criteria associated with corporatist and participatory democracy: firstly, the extent to which subjective advocacy is combined with objectivity and accuracy; secondly, the extent to which civic society organisations are accorded access; thirdly, whether the disadvantage of resource-poor groups in society is compensated for; and finally, to what extent the mobilisation of public support for the campaigns aims to encourage an active citizenry

Azathioprine Has a Deleterious Effect on the Bone Health of Mice with DSS-Induced Inflammatory Bowel Disease

Patients with inflammatory bowel disease (IBD) often present poor bone health and are 40% more at risk of bone fracture. Studies have implicated autophagy in IBD pathology and drugs used to treat IBD stimulate autophagy in varying degrees, however, their effect on the skeleton is currently unknown. Here, we have utilised the dextran sulphate sodium (DSS) model of colitis in mice to examine the effects of the thiopurine drug azathioprine on the skeleton. 10-week-old male mice (n=6/group) received 3.0% DSS in their drinking water for 4 days, followed by a 14-day recovery period. Mice were treated with 10mg/kg/day azathioprine or vehicle control. Histopathological analysis of the colon from DSS mice revealed significant increases in scores for inflammation severity, extent and crypt damage (

Hepcidin is regulated by promoter-associated histone acetylation and HDAC3.

Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency and increased erythropoiesis but is pathologic in thalassemia and hemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and iron deficiency suppress hepcidin via erythroferrone-dependent and -independent mechanisms, respectively, in vivo, but both involve reversible loss of H3K9ac and H3K4me3 at the hepcidin locus. In vitro, pan-histone deacetylase inhibition elevates hepcidin expression, and in vivo maintains H3K9ac at hepcidin-associated chromatin and abrogates hepcidin suppression by erythropoietin, iron deficiency, thalassemia, and hemochromatosis. Histone deacetylase 3 and its cofactor NCOR1 regulate hepcidin; histone deacetylase 3 binds chromatin at the hepcidin locus, and histone deacetylase 3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting bone morphogenetic protein signaling. In iron deficient mice, the histone deacetylase 3 inhibitor RGFP966 increases hepcidin, and RNA sequencing confirms hepcidin is one of the genes most differentially regulated by this drug in vivo. We conclude that suppression of hepcidin expression involves epigenetic regulation by histone deacetylase 3.Hepcidin controls systemic iron levels by inhibiting intestinal iron absorption and iron recycling. Here, Pasricha et al. demonstrate that the hepcidin-chromatin locus displays HDAC3-mediated reversible epigenetic modifications during both erythropoiesis and iron deficiency

Strong Carbon Features and a Red Early Color in the Underluminous Type Ia SN 2022xkq

We present optical, infrared, ultraviolet, and radio observations of SN 2022xkq, an underluminous fast-declining type Ia supernova (SN Ia) in NGC 1784 ($\mathrm{D}\approx31$ Mpc), from $<1$ to 180 days after explosion. The high-cadence observations of SN 2022xkq, a photometrically transitional and spectroscopically 91bg-like SN Ia, cover the first days and weeks following explosion which are critical to distinguishing between explosion scenarios. The early light curve of SN 2022xkq has a red early color and exhibits a flux excess which is more prominent in redder bands; this is the first time such a feature has been seen in a transitional/91bg-like SN Ia. We also present 92 optical and 19 near-infrared (NIR) spectra, beginning 0.4 days after explosion in the optical and 2.6 days after explosion in the NIR. SN 2022xkq exhibits a long-lived C I 1.0693 $\mu$m feature which persists until 5 days post-maximum. We also detect C II $\lambda$6580 in the pre-maximum optical spectra. These lines are evidence for unburnt carbon that is difficult to reconcile with the double detonation of a sub-Chandrasekhar mass white dwarf. No existing explosion model can fully explain the photometric and spectroscopic dataset of SN 2022xkq, but the considerable breadth of the observations is ideal for furthering our understanding of the processes which produce faint SNe Ia.Comment: 38 pages, 16 figures, accepted for publication in ApJ, the figure 15 input models and synthetic spectra are now available at https://zenodo.org/record/837925

Hepcidin is regulated by promoter-associated histone acetylation and HDAC3

Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency and increased erythropoiesis but is pathologic in thalassemia and hemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and iron deficiency suppress hepcidin via erythroferrone-dependent and -independent mechanisms, respectively, in vivo, but both involve reversible loss of H3K9ac and H3K4me3 at the hepcidin locus. In vitro, pan-histone deacetylase inhibition elevates hepcidin expression, and in vivo maintains H3K9ac at hepcidin-associated chromatin and abrogates hepcidin suppression by erythropoietin, iron deficiency, thalassemia, and hemochromatosis. Histone deacetylase 3 and its cofactor NCOR1 regulate hepcidin; histone deacetylase 3 binds chromatin at the hepcidin locus, and histone deacetylase 3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting bone morphogenetic protein signaling. In iron deficient mice, the histone deacetylase 3 inhibitor RGFP966 increases hepcidin, and RNA sequencing confirms hepcidin is one of the genes most differentially regulated by this drug in vivo. We conclude that suppression of hepcidin expression involves epigenetic regulation by histone deacetylase 3.Hepcidin controls systemic iron levels by inhibiting intestinal iron absorption and iron recycling. Here, Pasricha et al. demonstrate that the hepcidin-chromatin locus displays HDAC3-mediated reversible epigenetic modifications during both erythropoiesis and iron deficiency

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme