Leveraging GWAS data to identify metabolic pathways and networks involved in maize lipid biosynthesis

Maize (Zea mays mays) oil is a rich source of polyunsaturated fatty acids (FAs) and energy, making it a valuable resource for human food, animal feed, and bio‐energy. Although this trait has been studied via conventional genome‐wide association study (GWAS), the single nucleotide polymorphism (SNP)‐trait associations generated by GWAS may miss the underlying associations when traits are based on many genes, each with small effects that can be overshadowed by genetic background and environmental variation. Detecting these SNPs statistically is also limited by the levels set for false discovery rate. A complementary pathways analysis that emphasizes the cumulative aspects of SNP‐trait associations, rather than just the significance of single SNPs, was performed to understand the balance of lipid metabolism, conversion, and catabolism in this study. This pathway analysis indicated that acyl‐lipid pathways, including biosynthesis of wax esters, sphingolipids, phospholipids and flavonoids, along with FA and triacylglycerol (TAG) biosynthesis, were important for increasing oil and FA content. The allelic variation found among the genes involved in many degradation pathways, and many biosynthesis pathways leading from FAs and carbon partitioning pathways, was critical for determining final FA content, changing FA ratios and, ultimately, to final oil content. The pathways and pathway networks identified in this study, and especially the acyl‐lipid associated pathways identified beyond what had been found with GWAS alone, provide a real opportunity to precisely and efficiently manipulate high‐oil maize genetic improvement.     

Inhibition of lysine biosynthesis: an evolving antibiotic strategy

Bacterial biosynthesis of lysine has come under increased scrutiny as a target for novel antibacterial agents as it provides lysine for protein synthesis and both lysine and meso-diaminopimelate for construction of the bacterial peptidoglycan cell wall. In this Highlight article we review recent advances in the validation of antibiotic targets, studies of the enzymes of the lysine biosynthetic pathway and development of inhibitors of these enzymes.     

Visualising health risks with medical imaging for changing recipients’ health behaviours and risk factors: Systematic review with meta-analysis

BackgroundThere is ongoing clinical and research interest in determining whether providing personalised risk information could motivate risk-reducing health behaviours. We aimed to assess the impact on behaviours and risk factors of feeding back to individuals’ images of their bodies generated via medical imaging technologies in assessing their current disease status or risk.Methods and findingsA systematic review with meta-analysis was conducted using Cochrane methods. MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to July 28, 2021, with backward and forward citation searches up to July 29, 2021. Eligible studies were randomised controlled trials including adults who underwent medical imaging procedures assessing current health status or risk of disease, for which personal risk may be reduced by modifying behaviour. Trials included an intervention group that received the imaging procedure plus feedback of visualised results and assessed subsequent risk-reducing health behaviour. We examined 12,620 abstracts and included 21 studies, involving 9,248 randomised participants. Studies reported on 10 risk-reducing behaviours, with most data for smoking (8 studies; n = 4,308), medication use (6 studies; n = 4,539), and physical activity (4 studies; n = 1,877). Meta-analysis revealed beneficial effects of feedback of visualised medical imaging results on reduced smoking (risk ratio 1.11, 95% confidence interval [CI] 1.01 to 1.23, p = 0.04), healthier diet (standardised mean difference [SMD] 0.30, 95% CI 0.11 to 0.50, p = 0.003), increased physical activity (SMD 0.11, 95% CI 0.003 to 0.21, p = 0.04), and increased oral hygiene behaviours (SMD 0.35, 95% CI 0.13 to 0.57, p = 0.002). In addition, single studies reported increased skin self-examination and increased foot care. For other behavioural outcomes (medication use, sun protection, tanning booth use, and blood glucose testing) estimates favoured the intervention but were not statistically significant. Regarding secondary risk factor outcomes, there was clear evidence for reduced systolic blood pressure, waist circumference, and improved oral health, and some indication of reduced Framingham risk score. There was no evidence of any adverse effects, including anxiety, depression, or stress, although these were rarely assessed. A key limitation is that there were some concerns about risk of bias for all studies, with evidence for most outcomes being of low certainty. In particular, valid and precise measures of behaviour were rarely used, and there were few instances of preregistered protocols and analysis plans, increasing the likelihood of selective outcome reporting.ConclusionsIn this study, we observed that feedback of medical images to individuals has the potential to motivate risk-reducing behaviours and reduce risk factors. Should this promise be corroborated through further adequately powered trials that better mitigate against risk of bias, such interventions could usefully capitalise upon the widespread and growing use of medical imaging technologies in healthcare.

In a systematic review and meta-analysis, Gareth Hollands and colleagues study the relationship between receipt of visual feedback of results following medical imaging procedures and risk-reducing health-related behaviors.     

Cytokinin production by plant growth promoting rhizobacteria and selected mutants

One of the proposed mechanisms by which rhizobacteria enhance plant growth is through the production of plant growth regulators. Five plant growth promoting rhizobacterial (PGPR) strains produced the cytokinin dihydrozeatin riboside (DHZR) in pure culture. Cytokinin production by Pseudomonas fluorescens G20-18, a rifampicin-resistant mutant (RIF), and two TnphoA-derived mutants (CNT1, CNT2), with reduced capacity to synthesize cytokinins, was further characterized in pure culture using immunoassay and thin layer chromatography. G20-18 produced higher amounts of three cytokinins, isopentenyl adenosine (IPA), trans-zeatin ribose (ZR), and DHZR than the three mutants during stationary phase. IPA was the major metabolite produced, but the proportion of ZR and DHZR accumulated by CNT1 and CNT2 increased with time. No differences were observed between strain G20-18 and the mutants in the amounts of indole acetic acid synthesized, nor were gibberellins detected in supernatants of any of the strains. Addition of 10(-5) M adenine increased cytokinin production in 96- and 168-h cultures of strain G20-18 by approximately 67%. G20-18 and the mutants CNT1 and CNT2 may be useful for determination of the role of cytokinin production in plant growth promotion by PGPR.     

Hydrocortisone increases the rate of differentiation of cultured human osteoblasts

Reduced bone formation is the main finding in glucocorticoid-induced osteoporosis. The aim of this study was to determine whether differentiation of cultured human osteoblasts is inhibited by high concentrations of hydrocortisone. We measured the levels of mRNAs for three markers of cellular differentiation, type 1 collagen (COL1), alkaline phosphatase (ALP), and osteocalcin (OC), in four lines of human osteoblasts from female donors cultured with doses of hydrocortisone from 0 microM to 4 microM. The change in ALP/COL1 mRNA ratio over a given time was used to determine the average rate of differentiation of the cells in a culture. Although basal expression profiles and their changes with time were different for the different cell lines, all cell lines showed a dose-dependent rise in the rate of increase of ALP mRNA relative to COL1 mRNA. However, increase in OC mRNA with time, seen here only in young donor hOBs, was significantly inhibited by 4 microM hydrocortisone, indicating that hydrocortisone can inhibit OC expression while promoting cellular differentiation. The data suggest that increasing concentrations of glucocorticoid, including concentrations similar to plasma levels in patients receiving oral glucocorticoid therapy, increase the rate of cellular differentiation.     

Fitness reduction and potential extinction of wild populations of Atlantic salmon, Salmo salar, as a result of interactions with escaped farm salmon

The high level of escapes from Atlantic salmon farms, up to two million fishes per year in the North Atlantic, has raised concern about the potential impact on wild populations. We report on a two-generation experiment examining the estimated lifetime successes, relative to wild natives, of farm, F(1) and F(2) hybrids and BC(1) backcrosses to wild and farm salmon. Offspring of farm and "hybrids" (i.e. all F(1), F(2) and BC(1) groups) showed reduced survival compared with wild salmon but grew faster as juveniles and displaced wild parr, which as a group were significantly smaller. Where suitable habitat for these emigrant parr is absent, this competition would result in reduced wild smolt production. In the experimental conditions, where emigrants survived downstream, the relative estimated lifetime success ranged from 2% (farm) to 89% (BC(1) wild) of that of wild salmon, indicating additive genetic variation for survival. Wild salmon primarily returned to fresh water after one sea winter (1SW) but farm and 'hybrids' produced proportionately more 2SW salmon. However, lower overall survival means that this would result in reduced recruitment despite increased 2SW fecundity. We thus demonstrate that interaction of farm with wild salmon results in lowered fitness, with repeated escapes causing cumulative fitness depression and potentially an extinction vortex in vulnerable populations.     

Plant introductions,hybridization and gene flow

Many regional floras contain a high proportion of recently introduced plant species. Occasionally, hybridization between an introduced species and another species (introduced or native) can result in interspecific gene flow. This may occur even in instances where the F(1) hybrid shows very high sterility, but occasionally produces a few viable gametes. We provide examples of gene flow occurring between some rhododendrons recently introduced to the British flora, and between an introduced and native Senecio species. Neutral molecular markers have normally been employed to obtain evidence of interspecific gene flow, but the challenge now is to isolate and characterize functional introgressed genes and to determine how they affect the fitness of introgressants and whether they improve adaptation to novel habitats allowing introgressants to expand the range of a species. We outline a candidate gene approach for isolating and characterizing an allele of the RAY gene in Senecio vulgaris, which is believed to have introgressed from S. squalidus, and which causes the production of ray florets in flower heads. We discuss the effects of this introgressed allele on individual fitness, including those that originate directly from the production of ray florets plus those that may arise from pleiotropy and/or linkage.     

Potentiating effect of distant sites in non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain

Without the presence of a phosphotyrosyl group, a phage library derived non-phosphorylated cyclic peptide ligand of Grb2-SH2 domain attributed its high affinity and specificity to well-defined and highly favored interactions of its structural elements with the binding pocket of the protein. We have disclosed a significant compensatory role of the Glu(2-) sidechain for the absence of the phosphate functionality on Tyr(0) in the peptide ligand, cyclo(CH(2)CO-Glu(2-)-Leu-Tyr(0)-Glu-Asn-Val-Gly-Met(5+)-Tyr-Cys)-amide (termed G1TE). In this study, we report the importance of hydrophobic residue at the Tyr+5 site in G1TE. Both acidic and basic amino acid substitutes are disfavored at this position, and replacement of Met with beta-tert-butyl-Ala was found to improve the antagonist properties. Besides, the polarity of the cyclization linkage was implicated as important in stabilizing the favored binding conformation. Oxidation of the thioether linkage into sulfoxide facilitated the binding to Grb2-SH2 markedly. Simultaneous modification of the three distant sites within G1TE provided the best agent with an IC(50) of 220 nM, which is among the most potent non-phosphorous- and non-phosphotyrosine-mimic containing Grb2-SH2 domain inhibitors yet reported. This potent peptidomimetic provides a novel template for the development of chemotherapeutic agents for the treatment of erbB2-related cancer. Biological assays on G1TE(Gla(2-)) in which the original residue of Glu(2-) was substituted by gamma-carboxyglutamic acid (Gla) indicated that it could inhibit the interaction between activated GF receptor and Grb2 protein in cell homogenates of MDA-MB-453 breast cancer cells at the 2 microM level. More significantly, both G1TE(Gla(2-)) alone and the conjugate of G1TE(Gla(2-)) with a peptide carrier can effectively inhibit intracellular association of erbB2 and Grb2 in the same cell lines with IC(50) of 50 and 2 microM, respectively.