An initial assessment of the environmental impact of grocery products

This report presents a series of analyses with the common purpose of establishing which grocery products are likely to contribute most to the environmental impacts (carbon footprint or embodied carbon, embodied energy, water, materials use and waste) associated with UK household consumption. Understanding and prioritising these has enabled reduction actions, interventions and further research to be directed more effectively at those products with the greatest potential to influence overall consumption impacts.The report includes a systematic review of 1,900 grocery carbon footprint data points for 191 products; believed to be the largest assessment of its kind at the time of publication

Development of an occupational airborne chemical exposure matrix

Background Population-based studies of the occupational contribution to chronic obstructive pulmonary disease generally rely on self-reported exposures to vapours, gases, dusts and fumes (VGDF), which are susceptible to misclassification. Aims To develop an airborne chemical job exposure matrix (ACE JEM) for use with the UK Standard Occupational Classification (SOC 2000) system. Methods We developed the ACE JEM in stages: (i) agreement of definitions, (ii) a binary assignation of exposed/not exposed to VGDF, fibres or mists (VGDFFiM), for each of the individual 353 SOC codes and (iii) assignation of levels of exposure (L; low, medium and high) and (iv) the proportion of workers (P) likely to be exposed in each code. We then expanded the estimated exposures to include biological dusts, mineral dusts, metals, diesel fumes and asthmagens. \ud Results We assigned 186 (53%) of all SOC codes as exposed to at least one category of VGDFFiM, with 23% assigned as having medium or high exposure. We assigned over 68% of all codes as not being exposed to fibres, gases or mists. The most common exposure was to dusts (22% of codes with >50% exposed); 12% of codes were assigned exposure to fibres. We assigned higher percentages of the codes as exposed to diesel fumes (14%) compared with metals (8%). Conclusions We developed an expert-derived JEM, using a strict set of a priori defined rules. The ACE JEM could also be applied to studies to assess risks of diseases where the main route of occupational exposure is via inhalation

ILF-3 is a regulator of the neural plate border marker Zic1 in chick embryos

Background: The neural crest is a multipotent cell type unique to the vertebrate lineage and capable of differentiating into a large number of varied cell types, including ganglia of the peripheral nervous system, cartilage, and glia. An early step in neural crest specification occurs at the neural plate border, a region defined by the overlap of transcription factors of the Zic, Msx, and Pax families. Results: Here we identify a novel chick gene with close homology to double-stranded RNA-binding protein Interleukin enhancer binding factor 3 (ILF-3) in other species. Our results show that chick Ilf-3 is required for proper expression of the transcription factor, Zic-1, at the neural plate border. Conclusion: We have identified a novel chick gene and show it has a role in the correct specification of Zic-1 at the neural plate border

Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells : a randomised, double-blind placebo-controlled feasibility trial

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury. Here, we evaluated the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, determined the impact on endometrial decidualization, and assessed the feasibility of a full-scale clinical trial. Methods: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more miscarriages, regular menstrual cycles, and no contraindications to sitagliptin. Thirty-eight subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. Colony forming unit (CFU) assays were used to quantify eMSC in midluteal endometrial biopsies. The primary outcome measure was CFU counts. Secondary outcome measures were endometrial thickness, study acceptability, and first pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations. Findings: CFU counts following sitagliptin were higher compared to placebo only when adjusted for baseline CFU counts and age (RR: 1.52, 95% CI: 1.32–1.75, P<0.01). The change in CFU count was 1.68 in the sitagliptin group and 1.08 in the placebo group. Trial recruitment, acceptability, and drug compliance were high. There were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells. Interpretation: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted. Funding: Tommy's Baby Charity. Clinical trial registration: EU Clinical Trials Register no. 2016-001120-54

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition

Reducing isocyanate exposure and asthma risk in motor vehicle repair

Purpose – Exposure to isocyanates was the leading cause of occupational asthma in the UK. Motor vehicle repair (MVR) bodyshop paint sprayers were at greatest risk, despite widespread use of air-fed breathing apparatus and ventilated booths. Most paint sprayers work in small and medium enterprises (SMEs). The purpose of the Health and Safety Executive (HSE) project, described in this paper, is to improve exposure control measures in at least 20 per cent of MVR bodyshops, and reduce the risk of occupational asthma. The paper aims to discuss this issue. Design/methodology/approach – A three-stranded plan consisted of: Safety and Health Awareness Days (SHADs); workplace inspections; and third-party stakeholder communications. The impact of various parts of the project were evaluated. Findings – Approximately 18 per cent of bodyshops in the UK attended one of 32 SHADs, following which over 90 per cent of delegates expressed an “intention to act” to improve exposure control measures. A local assessment showed that at least 50 per cent of bodyshops improved exposure control measures. An evaluation of 109 inspections found that enforcement action was taken at 40 per cent of visits. Third-party engagement produced a joint HSE-industry designed poster, new agreed guidance on spray booths and dissemination of SHAD material. Knowledge of booth clearance time has become widespread, and 85 per cent of booths now have pressure gauges. Biological monitoring data show that, post-SHAD, exposures were lower. Originality/value – A sustained national project using clear, relevant, tested messages delivered via different routes, had a sector-wide impact in bodyshops. It is probable that the project has improved isocyanate exposure control in at least 20 per cent of bodyshops. The generic lessons could be applied to other widespread SME businesses. </jats:sec

12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets

Context: The 12-lipoxygenase (12-LO) pathway produces proinflammatory metabolites, and its activation is implicated in islet inflammation associated with type 1 and type 2 diabetes (T2D). Objectives: We aimed to test the efficacy of ML355, a highly selective, small molecule inhibitor of 12-LO, for the preservation of islet function. Design: Human islets from nondiabetic donors were incubated with a mixture of tumor necrosis factor α , interluekin-1β, and interferon-γ to model islet inflammation. Cytokine-treated islets and human islets from T2D donors were incubated in the presence and absence of ML355. Setting: In vitro study. Participants: Human islets from organ donors aged >20 years of both sexes and any race were used. T2D status was defined from either medical history or most recent hemoglobin A1c value >6.5%. Intervention: Glucose stimulation. Main Outcome Measures: Static and dynamic insulin secretion and oxygen consumption rate (OCR). Results: ML355 prevented the reduction of insulin secretion and OCR in cytokine-treated human islets and improved both parameters in human islets from T2D donors. Conclusions: ML355 was efficacious in improving human islet function after cytokine treatment and in T2D islets in vitro. The study suggests that the blockade of the 12-LO pathway may serve as a target for both form of diabetes and provides the basis for further study of this small molecule inhibitor in vivo

EndoTime: non-categorical timing estimates for luteal endometrium

STUDY QUESTION Can the accuracy of timing of luteal phase endometrial biopsies based on urinary ovulation testing be improved by measuring the expression of a small number of genes and a continuous, non-categorical modelling approach? SUMMARY ANSWER Measuring the expression levels of six genes (IL2RB, IGFBP1, CXCL14, DPP4, GPX3 and SLC15A2) is sufficient to obtain substantially more accurate timing estimates and to assess the reliability of timing estimates for each sample. WHAT IS KNOWN ALREADY Commercially available endometrial timing approaches based on gene expression require large gene sets and use a categorical approach that classifies samples as pre-receptive, receptive or post-receptive. STUDY DESIGN, SIZE, DURATION Gene expression was measured by RTq-PCR in different sample sets, comprising a total of 664 endometrial biopsies obtained 4–12 days after a self-reported positive home ovulation test. A further 36 endometrial samples were profiled by RTq-PCR as well as RNA-sequencing. PARTICIPANTS/MATERIALS, SETTING, METHODS A computational procedure, named ‘EndoTime’, was established that models the temporal profile of each gene and estimates the timing of each sample. Iterating these steps, temporal profiles are gradually refined as sample timings are being updated, and confidence in timing estimates is increased. After convergence, the method reports updated timing estimates for each sample while preserving the overall distribution of time points. MAIN RESULTS AND THE ROLE OF CHANCE The Wilcoxon rank-sum test was used to confirm that ordering samples by EndoTime estimates yields sharper temporal expression profiles for held-out genes (not used when determining sample timings) than ordering the same expression values by patient-reported times (GPX3: P  0.05). LARGE SCALE DATA The RTq-PCR data files are available via the GitHub repository for the EndoTime software at https://github.com/AE-Mitchell/EndoTime, as is the code used for pre-processing of RTq-PCR data. The RNA-sequencing data are available on GEO (accession GSE180485). LIMITATIONS, REASONS FOR CAUTION Timing estimates are informed by glandular gene expression and will only represent the temporal state of other endometrial cell types if in synchrony with the epithelium. Methods that estimate the day of ovulation are still required as these data are essential inputs in our method. Our approach, in its current iteration, performs batch correction such that larger sample batches impart greater accuracy to timing estimations. In theory, our method requires endometrial samples obtained at different days in the luteal phase. In practice, however, this is not a concern as timings based on urinary ovulation testing are associated with a sufficient level of noise to ensure that a variety of time points will be sampled. WIDER IMPLICATIONS OF THE FINDINGS Our method is the first to assay the temporal state of luteal-phase endometrial samples on a continuous domain. It is freely available with fully shared data and open-source software. EndoTime enables accurate temporal profiling of any gene in luteal endometrial samples for a wide range of research applications and, potentially, clinical use

Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria