The practices of synthetic biology are being integrated into 'multiscale' designs enabling two-way communication across organic and inorganic information substrates in biological, digital and ...cyber-physical system integrations. Novel applications of 'bio-informational' engineering will arise in environmental monitoring, precision agriculture, precision medicine and next-generation biomanufacturing. Potential developments include sentinel plants for environmental monitoring and autonomous bioreactors that respond to biosensor signaling. As bio-informational understanding progresses, both natural and engineered biological systems will need to be reimagined as cyber-physical architectures. We propose that a multiple length scale taxonomy will assist in rationalizing and enabling this transformative development in engineering biology.
The global burden of sickle cell anaemia (SCA) is set to rise as a consequence of improved survival in high-prevalence low- and middle-income countries and population migration to higher-income ...countries. The host of quantitative evidence documenting these changes has not been assembled at the global level. The purpose of this study is to estimate trends in the future number of newborns with SCA and the number of lives that could be saved in under-five children with SCA by the implementation of different levels of health interventions.
First, we calculated projected numbers of newborns with SCA for each 5-y interval between 2010 and 2050 by combining estimates of national SCA frequencies with projected demographic data. We then accounted for under-five mortality (U5m) projections and tested different levels of excess mortality for children with SCA, reflecting the benefits of implementing specific health interventions for under-five patients in 2015, to assess the number of lives that could be saved with appropriate health care services. The estimated number of newborns with SCA globally will increase from 305,800 (confidence interval CI: 238,400-398,800) in 2010 to 404,200 (CI: 242,500-657,600) in 2050. It is likely that Nigeria (2010: 91,000 newborns with SCA CI: 77,900-106,100; 2050: 140,800 CI: 95,500-200,600) and the Democratic Republic of the Congo (2010: 39,700 CI: 32,600-48,800; 2050: 44,700 CI: 27,100-70,500) will remain the countries most in need of policies for the prevention and management of SCA. We predict a decrease in the annual number of newborns with SCA in India (2010: 44,400 CI: 33,700-59,100; 2050: 33,900 CI: 15,900-64,700). The implementation of basic health interventions (e.g., prenatal diagnosis, penicillin prophylaxis, and vaccination) for SCA in 2015, leading to significant reductions in excess mortality among under-five children with SCA, could, by 2050, prolong the lives of 5,302,900 CI: 3,174,800-6,699,100 newborns with SCA. Similarly, large-scale universal screening could save the lives of up to 9,806,000 (CI: 6,745,800-14,232,700) newborns with SCA globally, 85% (CI: 81%-88%) of whom will be born in sub-Saharan Africa. The study findings are limited by the uncertainty in the estimates and the assumptions around mortality reductions associated with interventions.
Our quantitative approach confirms that the global burden of SCA is increasing, and highlights the need to develop specific national policies for appropriate public health planning, particularly in low- and middle-income countries. Further empirical collaborative epidemiological studies are vital to assess current and future health care needs, especially in Nigeria, the Democratic Republic of the Congo, and India.
•Isoprenoids are industrially important natural products.•Yeast are key industrial production vehicles.•New synthetic biology approaches in recent years are reviewed.•Future requirements and ...prospects are discussed.
Isoprenoids (terpenes/terpenoids) have many useful industrial applications, but are often not produced at industrially viable level in their natural sources. Synthetic biology approaches have been used extensively to reconstruct metabolic pathways in tractable microbial hosts such as yeast and re-engineer pathways and networks to increase yields. Here we review recent advances in this field, focusing on central carbon metabolism engineering to increase precursor supply, re-directing carbon flux for production of C10, C15, or C20 isoprenoids, and chemical decoration of high value diterpenoids (C20). We also overview other novel synthetic biology strategies that have potential utility in yeast isoprenoid pathway engineering. Finally, we address the question of what is required in the future to move the field forwards.
Sickle Cell Anemia and Its Phenotypes Williams, Thomas N; Thein, Swee Lay
Annual review of genomics and human genetics,
08/2018, Volume:
19, Issue:
1
Journal Article
Peer reviewed
Open access
In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. ...By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. Recent years, however, have seen major advances on several fronts. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as
BCL11A
provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA. Meanwhile, an unprecedented number of new drugs aimed at both the treatment and prevention of end-organ damage are now in the pipeline, outcomes from potentially curative treatments such as allogeneic hematopoietic stem cell transplantation are improving, and great strides are being made in gene therapy, where methods employing both antisickling β-globin lentiviral vectors and gene editing are now entering clinical trials. Encouragingly, after a century of neglect, the profile of the vast majority of those with SCA in Africa and India is also finally improving.
Flux balance models of metabolism generally utilize synthesis of biomass as the main determinant of intracellular fluxes. However, the biomass constraint alone is not sufficient to predict realistic ...fluxes in central heterotrophic metabolism of plant cells because of the major demand on the energy budget due to transport costs and cell maintenance. This major limitation can be addressed by incorporating transport steps into the metabolic model and by implementing a procedure that uses Pareto optimality analysis to explore the trade‐off between ATP and NADPH production for maintenance. This leads to a method for predicting cell maintenance costs on the basis of the measured flux ratio between the oxidative steps of the oxidative pentose phosphate pathway and glycolysis. We show that accounting for transport and maintenance costs substantially improves the accuracy of fluxes predicted from a flux balance model of heterotrophic Arabidopsis cells in culture, irrespective of the objective function used in the analysis. Moreover, when the new method was applied to cells under control, elevated temperature and hyper‐osmotic conditions, only elevated temperature led to a substantial increase in cell maintenance costs. It is concluded that the hyper‐osmotic conditions tested did not impose a metabolic stress, in as much as the metabolic network is not forced to devote more resources to cell maintenance.
Malaria has been the pre-eminent cause of early mortality in many parts of the world throughout much of the last five thousand years and, as a result, it is the strongest force for selective pressure ...on the human genome yet described. Around one third of the variability in the risk of severe and complicated malaria is now explained by additive host genetic effects. Many individual variants have been identified that are associated with malaria protection, but the most important all relate to the structure or function of red blood cells. They include the classical polymorphisms that cause sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. More recently however, with improving technology and experimental design, others have been identified that include the Dantu blood group variant, polymorphisms in the red cell membrane protein
ATP2B4
, and several variants related to the immune response. Characterising how these genes confer their effects could eventually inform novel therapeutic approaches to combat malaria. Nevertheless, all together, only a small proportion of the heritable component of malaria resistance can be explained by the variants described so far, underscoring its complex genetic architecture and the need for continued research.
Sickle cell disease (SCD) is a single gene disorder causing a debilitating systemic syndrome characterised by chronic anaemia, acute painful episodes, organ infarction and chronic organ damage and by ...a significant reduction in life expectancy. The origin of SCD lies in the malarial regions of the tropics where carriers are protected against death from malaria and hence enjoy an evolutionary advantage. More recently, population migration has meant that SCD now has a worldwide distribution and that a substantial number of children are born with the condition in higher-income areas, including large parts of Europe and North and South America. Newborn screening, systematic clinical follow-up and prevention of sepsis and organ damage have led to an increased life expectancy among people with SCD in many such countries; however, in resource-limited settings where the majority continue to be born, most affected children continue to die in early childhood, usually undiagnosed, due to the lack of effective programmes for its early detection and treatment. As new therapies emerge, potentially leading to disease amelioration or cure, it is of paramount importance that the significant burden of SCD in resource-poor countries is properly recognised.
Flux is a key measure of the metabolic phenotype. Recently, complete (genome-scale) metabolic network models have been established for Arabidopsis (Arabidopsis thaliana), and flux distributions have ...been predicted using constraints-based modeling and optimization algorithms such as linear programming. While these models are useful for investigating possible flux states under different metabolic scenarios, it is not clear how close the predicted flux distributions are to those occurring in vivo. To address this, fluxes were predicted for heterotrophic Arabidopsis cells and compared with fluxes estimated in parallel by ¹³C-metabolic flux analysis (MFA). Reactions of the central carbon metabolic network (glycolysis, the oxidative pentose phosphate pathway, and the tricarboxylic acid TCA cycle) were independently analyzed by the two approaches. Net fluxes in glycolysis and the TCA cycle were predicted accurately from the genome-scale model, whereas the oxidative pentose phosphate pathway was poorly predicted. MFA showed that increased temperature and hyperosmotic stress, which altered cell growth, also affected the intracellular flux distribution. Under both conditions, the genome-scale model was able to predict both the direction and magnitude of the changes in flux: namely, increased TCA cycle and decreased phosphoenolpyruvate carboxylase flux at high temperature and a general decrease in fluxes under hyperosmotic stress. MFA also revealed a 3-fold reduction in carbon-use efficiency at the higher temperature. It is concluded that constraints-based genome-scale modeling can be used to predict flux changes in central carbon metabolism under stress conditions.
Cell stresses occur in a wide variety of settings: in disease, during industrial processes, and as part of normal day-to-day rhythms. Adaptation to these stresses requires cells to alter their ...proteome. Cells modify the proteins they synthesize to aid proteome adaptation. Changes in both mRNA transcription and translation contribute to altered protein synthesis. Here, we discuss the changes in translational mechanisms that occur following the onset of stress, and the impact these have on stress adaptation.
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