Actions of Camptothecin Derivatives on Larvae and Adults of the Arboviral Vector Aedes aegypti

Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and Onchocerca volvulus endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of Aedes aegypti were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced A. aegypti larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC_{50} of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to A. aegypti adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries

Food insecurity in adults with severe mental illness living in Northern England: A co-produced cross-sectional study

\ua9 2024 The Authors. Nutrition & Dietetics published by John Wiley & Sons Australia, Ltd on behalf of Dietitians Australia.Aim: This study aimed to explore food insecurity prevalence and experiences of adults with severe mental illness living in Northern England. Methods: This mixed-methods cross-sectional study took place between March and October 2022. Participants were adults with self-reported severe mental illness living in Northern England. The survey included demographic, health, and financial questions. Food insecurity was measured using the US Department of Agriculture Adult Food Security measure. Quantitative data were analysed using descriptive statistics and binary logistic regression; and qualitative data using content analysis. Results: In total, 135 participants completed the survey, with a mean age of 44.7 years (SD: 14.1, range: 18–75 years). Participants were predominantly male (53.3%), white (88%) and from Yorkshire (50.4%). The food insecurity prevalence was 50.4% (n = 68). There was statistical significance in food insecurity status by region (p = 0.001); impacts of severe mental illness on activities of daily living (p = 0.02); and the Covid pandemic on food access (p < 0.001). The North West had the highest prevalence of food insecurity (73.3%); followed by the Humber and North East regions (66.7%); and Yorkshire (33.8%). In multivariable binary logistic regression, severe mental illness\u27 impact on daily living was the only predictive variable for food insecurity (odds ratio = 4.618, 95% confidence interval: 1.071–19.924, p = 0.04). Conclusion: The prevalence of food insecurity in this study is higher than is reported in similar studies (41%). Mental health practitioners should routinely assess and monitor food insecurity in people living with severe mental illness. Further research should focus on food insecurity interventions in this population

A Rice Plastidial Nucleotide Sugar Epimerase Is Involved in Galactolipid Biosynthesis and Improves Photosynthetic Efficiency

Photosynthesis is the final determinator for crop yield. To gain insight into genes controlling photosynthetic capacity, we selected from our large T-DNA mutant population a rice stunted growth mutant with decreased carbon assimilate and yield production named photoassimilate defective1 (phd1). Molecular and biochemical analyses revealed that PHD1 encodes a novel chloroplast-localized UDP-glucose epimerase (UGE), which is conserved in the plant kingdom. The chloroplast localization of PHD1 was confirmed by immunoblots, immunocytochemistry, and UGE activity in isolated chloroplasts, which was approximately 50% lower in the phd1-1 mutant than in the wild type. In addition, the amounts of UDP-glucose and UDP-galactose substrates in chloroplasts were significantly higher and lower, respectively, indicating that PHD1 was responsible for a major part of UGE activity in plastids. The relative amount of monogalactosyldiacylglycerol (MGDG), a major chloroplast membrane galactolipid, was decreased in the mutant, while the digalactosyldiacylglycerol (DGDG) amount was not significantly altered, suggesting that PHD1 participates mainly in UDP-galactose supply for MGDG biosynthesis in chloroplasts. The phd1 mutant showed decreased chlorophyll content, photosynthetic activity, and altered chloroplast ultrastructure, suggesting that a correct amount of galactoglycerolipids and the ratio of glycolipids versus phospholipids are necessary for proper chloroplast function. Downregulated expression of starch biosynthesis genes and upregulated expression of sucrose cleavage genes might be a result of reduced photosynthetic activity and account for the decreased starch and sucrose levels seen in phd1 leaves. PHD1 overexpression increased photosynthetic efficiency, biomass, and grain production, suggesting that PHD1 plays an important role in supplying sufficient galactolipids to thylakoid membranes for proper chloroplast biogenesis and photosynthetic activity. These findings will be useful for improving crop yields and for bioenergy crop engineering

The Minimal Domain of Adipose Triglyceride Lipase (ATGL) Ranges until Leucine 254 and Can Be Activated and Inhibited by CGI-58 and G0S2, Respectively

Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme of lipolysis. ATGL specifically hydrolyzes triacylglycerols (TGs), thereby generating diacylglycerols and free fatty acids. ATGL's enzymatic activity is co-activated by the protein comparative gene identification-58 (CGI-58) and inhibited by the protein G0/G1 switch gene 2 (G0S2). The enzyme is predicted to act through a catalytic dyad (Ser47, Asp166) located within the conserved patatin domain (Ile10-Leu178). Yet, neither an experimentally determined 3D structure nor a model of ATGL is currently available, which would help to understand how CGI-58 and G0S2 modulate ATGL's activity. In this study we determined the minimal active domain of ATGL. This minimal fragment of ATGL could still be activated and inhibited by CGI-58 and G0S2, respectively. Furthermore, we show that this minimal domain is sufficient for protein-protein interaction of ATGL with its regulatory proteins. Based on these data, we generated a 3D homology model for the minimal domain. It strengthens our experimental finding that amino acids between Leu178 and Leu254 are essential for the formation of a stable protein domain related to the patatin fold. Our data provide insights into the structure-function relationship of ATGL and indicate higher structural similarities in the N-terminal halves of mammalian patatin-like phospholipase domain containing proteins, (PNPLA1, -2,- 3 and -5) than originally anticipated

Growth Inhibition and Apoptosis Induced by Osthole, A Natural Coumarin, in Hepatocellular Carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Osthole, a natural coumarin derivative, has been shown to have anti-tumor activity. However, the effects of osthole on HCC have not yet been reported. METHODS AND FINDINGS: HCC cell lines were treated with osthole at various concentrations for 24, 48 and 72 hours. The proliferations of the HCC cells were measured by MTT assays. Cell cycle distribution and apoptosis were determined by flow cytometry. HCC tumor models were established in mice by subcutaneously injection of SMMC-7721 or Hepa1-6 cells and the effect of osthole on tumor growths in vivo and the drug toxicity were studied. NF-κB activity after osthole treatment was determined by electrophoretic mobility shift assays and the expression of caspase-3 was measured by western blotting. The expression levels of other apoptosis-related genes were also determined by real-time PCR (PCR array) assays. Osthole displayed a dose- and time-dependent inhibition of the HCC cell proliferations in vitro. It also induced apoptosis and caused cell accumulation in G2 phase. Osthole could significantly suppress HCC tumor growth in vivo with no toxicity at the dose we used. NF-κB activity was significantly suppressed by osthole at the dose- and time-dependent manner. The cleaved caspase-3 was also increased by osthole treatment. The expression levels of some apoptosis-related genes that belong to TNF ligand family, TNF receptor family, Bcl-2 family, caspase family, TRAF family, death domain family, CIDE domain and death effector domain family and CARD family were all increased with osthole treatment. CONCLUSION: Osthole could significantly inhibit HCC growth in vitro and in vivo through cell cycle arrest and inducing apoptosis by suppressing NF-κB activity and promoting the expressions of apoptosis-related genes

Trading between healthy food, alcohol and physical activity behaviours

BACKGROUND: While recent lifestyle studies have explored the role that food, alcohol or physical activity have on health and wellbeing, few have explored the interplay between these behaviours and the impact this has on a healthy lifestyle. Given the long term health advantages associated with leading healthier lifestyles, this study seeks to: 1) explore the interplay between the food, alcohol and physical activity behaviours of young adults (aged 19–26 years) in the North East of England; 2) explore the trade-offs young adults make between their food, alcohol and physical activity behaviours; and 3) recognise the positive and negative associations between the three behaviours. METHODS: Qualitative self-reported lifestyle diaries and in-depth interviews were conducted with 50 young adults from the North East of England between February and June 2008. Qualitative thematic analysis was undertaken using Nvivo QSR software, and diary coding using Windiets software. RESULTS: Young adults who attempt to achieve a ‘healthy lifestyle’ make trade-offs between the food and alcohol they consume, and the amounts of physical activity they undertake. There are negative reasons and positive consequences associated with these trade-offs. Young adults recognise the consequences of their behaviours and as a result are prepared to undertake healthy behaviours to compensate for unhealthy behaviours. They prefer certain strategies to promote healthier behaviours over others, in particular those that relate to personalised advice and support, more affordable ways to be healthier and easily-accessed advice from a range of media sources. CONCLUSIONS: Young adults seek to compensate unhealthy behaviours (e.g. binge drinking) with healthy behaviours (e.g. physical activity). Creative solutions may be required to tackle these trade-offs and promote a balance across the food, alcohol and physical activity behaviours of this age group. Solutions that may be effective with this age group include environmental changes (e.g. green spaces and increasing the price of alcohol) designed to encourage and facilitate young people making healthier choices and improving their access to, and lowering the price of, healthy food products. Solutions must recognise these trade-offs and in particular, the strong reluctance of young adults to alter their higher-than-recommended levels of alcohol consumption

Dietary behaviors related to cancer prevention among pre-adolescents and adolescents: the gap between recommendations and reality

<p>Abstract</p> <p>Background</p> <p>Diet is thought to play an important role in cancer risk. This paper summarizes dietary recommendations for cancer prevention and compares these recommendations to the dietary behaviors of U.S. youth ages 8-18.</p> <p>Methods</p> <p>We identified cancer prevention-related dietary recommendations from key health organizations and assessed dietary consumption patterns among youth using published statistics from the National Health and Nutrition Examination Survey, the national Youth Risk Behavior Survey, and other supplemental sources.</p> <p>Results</p> <p>Cancer prevention guidelines recommend a diet rich in fruits, vegetables, and whole grains, recommend limiting sugary foods and beverages, red and processed meats, sodium, and alcohol, and recommend avoiding foods contaminated with carcinogens. However, youth typically do not meet the daily recommendations for fruit, vegetable, or whole grain consumption and are over-consuming energy-dense, sugary and salty foods.</p> <p>Conclusions</p> <p>A large discrepancy exists between expert recommendations about diet and cancer and actual dietary practices among young people and points to the need for more research to better promote the translation of science into practice. Future research should focus on developing and evaluating policies and interventions at the community, state and national levels for aligning the diets of youth with the evolving scientific evidence regarding cancer prevention.</p

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

Observations of Lyα\alpha Emitters at High Redshift

In this series of lectures, I review our observational understanding of high-$z$ Ly$\alpha$ emitters (LAEs) and relevant scientific topics. Since the discovery of LAEs in the late 1990s, more than ten (one) thousand(s) of LAEs have been identified photometrically (spectroscopically) at $z\sim 0$ to $z\sim 10$. These large samples of LAEs are useful to address two major astrophysical issues, galaxy formation and cosmic reionization. Statistical studies have revealed the general picture of LAEs' physical properties: young stellar populations, remarkable luminosity function evolutions, compact morphologies, highly ionized inter-stellar media (ISM) with low metal/dust contents, low masses of dark-matter halos. Typical LAEs represent low-mass high-$z$ galaxies, high-$z$ analogs of dwarf galaxies, some of which are thought to be candidates of population III galaxies. These observational studies have also pinpointed rare bright Ly$\alpha$ sources extended over $\sim 10-100$ kpc, dubbed Ly$\alpha$ blobs, whose physical origins are under debate. LAEs are used as probes of cosmic reionization history through the Ly$\alpha$ damping wing absorption given by the neutral hydrogen of the inter-galactic medium (IGM), which complement the cosmic microwave background radiation and 21cm observations. The low-mass and highly-ionized population of LAEs can be major sources of cosmic reionization. The budget of ionizing photons for cosmic reionization has been constrained, although there remain large observational uncertainties in the parameters. Beyond galaxy formation and cosmic reionization, several new usages of LAEs for science frontiers have been suggested such as the distribution of {\sc Hi} gas in the circum-galactic medium and filaments of large-scale structures. On-going programs and future telescope projects, such as JWST, ELTs, and SKA, will push the horizons of the science frontiers.Comment: Lecture notes for `Lyman-alpha as an Astrophysical and Cosmological Tool', Saas-Fee Advanced Course 46. Verhamme, A., North, P., Cantalupo, S., & Atek, H. (eds.) --- 147 pages, 103 figures. Abstract abridged. Link to the lecture program including the video recording and ppt files : https://obswww.unige.ch/Courses/saas-fee-2016/program.cg