Developing kinase inhibitors for malaria: an opportunity or liability?

Highly druggable and essential to almost all aspects of cellular life, the protein and phosphoinositide kinase gene families offer a wealth of potential targets for pharmacological modulation for both noncommunicable and infectious diseases. Despite the success of kinase inhibitors in oncology and other disease indications, targeting kinases comes with significant challenges. Key hurdles for kinase drug discovery include selectivity and acquired resistance. The phosphatidylinositol 4-kinase beta inhibitor MMV390048 showed good efficacy in Phase 2a clinical trials, demonstrating the potential of kinase inhibitors for malaria treatment. Here we argue that the potential benefits of Plasmodium kinase inhibitors outweigh the risks, and we highlight the opportunity for designed polypharmacology to reduce the risk of resistance.     

microRNA deregulation in keloids: an opportunity for clinical intervention?

Keloids are defined as benign dermal scars invading adjacent healthy tissue, characterized by aberrant fibroblast dynamics and overproduction of extracellular matrix. However, the aetiology and molecular mechanism of keloid production remain poorly understood. Recent discoveries have shed new light on the involvement of a class of non‐coding RNAs known as microRNAs (miRNA), in keloid formation. A number of miRNAs have differential expression in keloid tissues and keloid‐derived fibroblasts. These miRNAs have been characterized as novel regulators of cellular processes pertinent to wound healing, including extracellular matrix deposition and fibroblast proliferation. Delineating the functional significance of miRNA deregulation may help us better understand pathogenesis of keloids, and promote development of miRNA‐directed therapeutics against this condition.     

The impact of protein-conjugate polysaccharide vaccines: an endgame for meningitis?

The development and implementation of conjugate polysaccharide vaccines against invasive bacterial diseases, specifically those caused by the encapsulated bacteria Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae, has been one of the most effective public health innovations of the last 25 years. These vaccines have resulted in significant reductions in childhood morbidity and mortality worldwide, with their effectiveness due in large part to their ability to induce long-lasting immunity in a range of age groups. At the population level this immunity reduces carriage and interrupts transmission resulting in herd immunity; however, these beneficial effects can be counterbalanced by the selection pressures that immunity against carriage can impose, potentially promoting the emergence and spread of virulent vaccine escape variants. Studies following the implementation of meningococcal serogroup C vaccines improved our understanding of these effects in relation to the biology of accidental pathogens such as the meningococcus. This understanding has enabled the refinement of the implementation of conjugate polysaccharide vaccines against meningitis-associated bacteria, and will be crucial in maintaining and improving vaccine control of these infections. To date there is little evidence for the spread of virulent vaccine escape variants of the meningococcus and H. influenzae, although this has been reported in pneumococci.     

The mast cell: an active participant or an innocent bystander?

Mast cells (MC) are phylogenetically old cells which are distributed throughout the human organism and, on the whole, occupy roughly the volume of the spleen. MC have long been recognized as key cells of type I hypersensitivity reactions. Several lines of evidence, however, indicate that they not only express critical effector functions in classic IgE-associated allergic disorders, but also play important roles in host defence against parasites, bacteria and perhaps even viruses. Indeed, it is now clear that MC can contribute to host defence in the context of either acquired or innate immune responses through the release of a myriad of pro-inflammatory and immunoregulatory molecules and the expression of a wide spectrum of surface receptors for cytokines and chemokines. Moreover, there is growing evidence that MC exert distinct non-immunological functions, playing a relevant role in tissue homeostasis, remodeling and fibrosis as well as in the processes of tissue angiogenesis. In this review, we provide a small insight into the biology of human MC and their potential implications in clinical pathology.     

Metabolic pathway compartmentalization: an underappreciated opportunity?

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Production of ethanol,organic acids and hydrogen: an opportunity for mixed culture biotechnology?

Anaerobic fermentation of biodegradable organic materials is usually carried out to obtain the final product, methane, a valuable energy source. However, it is also well known that various intermediates are produced in this process, e.g. ethanol, volatile organic acids and hydrogen. All these species have applications and value as fuels or chemicals. This paper shows a critical analysis of the potential of using anaerobic fermentation by mixed cultures to produce intermediates, e.g. ethanol, acetic, lactic and butyric acid and hydrogen, rather than methane. This paper discusses the current processes to produce these chemicals and compares them with the alternative approach of using open mixed cultures to produce them simultaneously via fermentation from renewable resources. None of these chemicals is currently produced via mixed culture fermentation: ethanol and lactic acid are usually produced in pure culture fermentation using food crops, e.g. corn or sugar cane, as starting materials; hydrogen, acetic and butyric acids are mainly produced via chemical synthesis from fossil fuel derived starting materials. A possible flow-sheet for the production of these chemicals from organic waste using mixed culture fermentation is proposed and the advantages and disadvantages of this process compared to current processes are critically discussed. The paper also discusses the research challenges which need to be addressed to make this process feasible.     

Genome evolution: extinction,continuation or explosion?

Darwin recognised the processes of speciation and the frequent extinction of species. We now understand many of the genome-scale processes occurring during evolution involving mutations, amplification, loss or homogenisation of DNA sequences; rearrangement, fusion and fission of chromosomes; and horizontal transfer of genes or genomes, including processes involving hybridisation and polyploidy. DNA sequence information, combined with appropriate informatic tools and experimental approaches such as generation of synthetic hybrids, comparison of genotypes across environments, and modelling of genomic responses, is now letting us link genome behaviour with its consequences. The understanding of genome evolution will be of critical value both for conservation of the biodiversity of the plant kingdom and addressing the challenges of breeding new and more sustainable crops to feed the human population.     

The risk of extinction—the mutational meltdown or the overpopulation

The phase diagrams survival-extinction for the Penna model with parameters: (mutations rate)-(birth rate), (mutation rate)-(harmful mutations threshold), (harmful mutation threshold)-(minimal reproduction age) are presented. The extinction phase may be caused by either mutational meltdown or overpopulation. When the Verhulst factor is responsible for removing only newly born babies and does not act on adults the overpopulation is avoided and only genetic factors may lead to species extinction.     

The Arabidopsis clock: time for an about-face?

Three recent studies have altered thinking on the role of TIMING OF CAB EXPRESSION 1 (TOC1), a core element in the plant circadian oscillator.     

Gene-based modelling for rice: an opportunity to enhance the simulation of rice growth and development?

Process-based crop simulation models require employment of new knowledge for continuous improvement. To simulate growth and development of different genotypes of a given crop, most models use empirical relationships or parameters defined as genetic coefficients to represent the various cultivar characteristics. Such a loose introduction of different cultivar characteristics can result in bias within a simulation, which could potentially integrate to a high simulation error at the end of the growing season when final yield at maturity is predicted. Recent advances in genetics and biomolecular analysis provide important opportunities for incorporating genetic information into process-based models to improve the accuracy of the simulation of growth and development and ultimately the final yield. This improvement is especially important for complex applications of models. For instance, the effect of the climate change on the crop growth processes in the context of natural climatic and soil variability and a large range of crop management options (e.g., N management) make it difficult to predict the potential impact of the climate change on the crop production. Quantification of the interaction of the environmental variables with the management factors requires fine tuning of the crop models to consider differences among different genotypes. In this paper we present this concept by reviewing the available knowledge of major genes and quantitative trait loci (QTLs) for important traits of rice for improvement of rice growth modelling and further requirements. It is our aim to review the assumption of the adequacy of the available knowledge of rice genes and QTL information to be introduced into the models. Although the rice genome sequence has been completed, the development of gene-based rice models still requires additional information than is currently unavailable. We conclude that a multidiscipline research project would be able to introduce this concept for practical applications.     

Plantation forests and biodiversity: oxymoron or opportunity?

Losses of natural and semi-natural forests, mostly to agriculture, are a significant concern for biodiversity. Against this trend, the area of intensively managed plantation forests increases, and there is much debate about the implications for biodiversity. We provide a comprehensive review of the function of plantation forests as habitat compared with other land cover, examine the effects on biodiversity at the landscape scale, and synthesise context-specific effects of plantation forestry on biodiversity. Natural forests are usually more suitable as habitat for a wider range of native forest species than plantation forests but there is abundant evidence that plantation forests can provide valuable habitat, even for some threatened and endangered species, and may contribute to the conservation of biodiversity by various mechanisms. In landscapes where forest is the natural land cover, plantation forests may represent a low-contrast matrix, and afforestation of agricultural land can assist conservation by providing complementary forest habitat, buffering edge effects, and increasing connectivity. In contrast, conversion of natural forests and afforestation of natural non-forest land is detrimental. However, regional deforestation pressure for agricultural development may render plantation forestry a ‘lesser evil’ if forest managers protect indigenous vegetation remnants. We provide numerous context-specific examples and case studies to assist impact assessments of plantation forestry, and we offer a range of management recommendations. This paper also serves as an introduction and background paper to this special issue on the effects of plantation forests on biodiversity.

Non-canonical autophagy: an exception or an underestimated form of autophagy?

Macroautophagy (hereafter called autophagy) is a dynamic and evolutionarily conserved process used to sequester and degrade cytoplasm and entire organelles in a sequestering vesicle with a double membrane, known as the autophagosome, which ultimately fuses with a lysosome to degrade its autophagic cargo. Recently, we have unraveled two distinct forms of autophagy in cancer cells, which we term canonical and non-canonical autophagy. In contrast to classical or canonical autophagy, non-canonical autophagy is a process that does not require the entire set of autophagy-related (Atg) proteins in particular Beclin 1, to form the autophagosome. Non-canonical autophagy is therefore not blocked by the knockdown of Beclin 1 or of its binding partner hVps34. Moreover overexpression of Bcl-2, which is known to block canonical starvation-induced autophagy by binding to Beclin 1, is unable to reverse the non-canonical autophagy triggered by the polyphenol resveratrol in the breast cancer MCF-7 cell line. In MCF-7 cells, at least, non-canonical autophagy is involved in the caspase-independent cell death induced by resveratrol.     

Photosynthesis in the fleeting shadows: an overlooked opportunity for increasing crop productivity?

Photosynthesis measurements are traditionally taken under steady‐state conditions; however, leaves in crop fields experience frequent fluctuations in light and take time to respond. This slow response reduces the efficiency of carbon assimilation. Transitions from low to high light require photosynthetic induction, including the activation of Rubisco and the opening of stomata, whereas transitions from high to low light require the relaxation of dissipative energy processes, collectively known as non‐photochemical quenching (NPQ). Previous attempts to assess the impact of these delays on net carbon assimilation have used simplified models of crop canopies, limiting the accuracy of predictions. Here, we use ray tracing to predict the spatial and temporal dynamics of lighting for a rendered mature Glycine max (soybean) canopy to review the relative importance of these delays on net cumulative assimilation over the course of both a sunny and a cloudy summer day. Combined limitations result in a 13% reduction in crop carbon assimilation on both sunny and cloudy days, with induction being more important on cloudy than on sunny days. Genetic variation in NPQ relaxation rates and photosynthetic induction in parental lines of a soybean nested association mapping (NAM) population was assessed. Short‐term NPQ relaxation (<30 min) showed little variation across the NAM lines, but substantial variation was found in the speeds of photosynthetic induction, attributable to Rubisco activation. Over the course of a sunny and an intermittently cloudy day these would translate to substantial differences in total crop carbon assimilation. These findings suggest an unexplored potential for breeding improved photosynthetic potential in our major crops.