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1.
Metabolic engineering to increase crop yield: From concept to execution.
Skraly, FA, Ambavaram, MMR, Peoples, O, Snell, KD
Plant science : an international journal of experimental plant biology. 2018;:23-32
Abstract
Although the return on investment over the last 20 years for mass screening of individual plant genes to improve crop performance has been low, the investment in these activities was essential to establish the infrastructure and tools of modern plant genomics. Complex traits such as crop yield are likely multigenic, and the exhaustive screening of random gene combinations to achieve yield gains is not realistic. Clearly, smart approaches must be developed. In silico analyses of plant metabolism and gene networks can move a trait discovery program beyond trial-and-error approaches and towards rational design strategies. Metabolic models employing flux-balance analysis are useful to determine the contribution of individual genes to a trait, or to compare, optimize, or even design metabolic pathways. Regulatory association networks provide a transcriptome-based view of the plant and can lead to the identification of transcription factors that control expression of multiple genes affecting a trait. In this review, the use of these models from the perspective of an Ag innovation company's trait discovery and development program will be discussed. Important decisions that can have significant impacts on the cost and timeline to develop a commercial trait will also be presented.
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2.
Understanding the Genetic Basis of C4 Kranz Anatomy with a View to Engineering C3 Crops.
Sedelnikova, OV, Hughes, TE, Langdale, JA
Annual review of genetics. 2018;:249-270
Abstract
One of the most remarkable examples of convergent evolution is the transition from C3 to C4 photosynthesis, an event that occurred on over 60 independent occasions. The evolution of C4 is particularly noteworthy because of the complexity of the developmental and metabolic changes that took place. In most cases, compartmentalized metabolic reactions were facilitated by the development of a distinct leaf anatomy known as Kranz. C4 Kranz anatomy differs from ancestral C3 anatomy with respect to vein spacing patterns across the leaf, cell-type specification around veins, and cell-specific organelle function. Here we review our current understanding of how Kranz anatomy evolved and how it develops, with a focus on studies that are dissecting the underlying genetic mechanisms. This research field has gained prominence in recent years because understanding the genetic regulation of Kranz may enable the C3-to-C4 transition to be engineered, an endeavor that would significantly enhance crop productivity.
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3.
Regulation of carbohydrate degradation pathways in Pseudomonas involves a versatile set of transcriptional regulators.
Udaondo, Z, Ramos, JL, Segura, A, Krell, T, Daddaoua, A
Microbial biotechnology. 2018;(3):442-454
Abstract
Bacteria of the genus Pseudomonas are widespread in nature. In the last decades, members of this genus, especially Pseudomonas aeruginosa and Pseudomonas putida, have acquired great interest because of their interactions with higher organisms. Pseudomonas aeruginosa is an opportunistic pathogen that colonizes the lung of cystic fibrosis patients, while P. putida is a soil bacterium able to establish a positive interaction with the plant rhizosphere. Members of Pseudomonas genus have a robust metabolism for amino acids and organic acids as well as aromatic compounds; however, these microbes metabolize a very limited number of sugars. Interestingly, they have three-pronged metabolic system to generate 6-phosphogluconate from glucose suggesting an adaptation to efficiently consume this sugar. This review focuses on the description of the regulatory network of glucose utilization in Pseudomonas, highlighting the differences between P. putida and P. aeruginosa. Most interestingly, It is highlighted a functional link between glucose assimilation and exotoxin A production in P. aeruginosa. The physiological relevance of this connection remains unclear, and it needs to be established whether a similar relationship is also found in other bacteria.
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4.
Acute sleep loss results in tissue-specific alterations in genome-wide DNA methylation state and metabolic fuel utilization in humans.
Cedernaes, J, Schönke, M, Westholm, JO, Mi, J, Chibalin, A, Voisin, S, Osler, M, Vogel, H, Hörnaeus, K, Dickson, SL, et al
Science advances. 2018;(8):eaar8590
Abstract
Curtailed sleep promotes weight gain and loss of lean mass in humans, although the underlying molecular mechanisms are poorly understood. We investigated the genomic and physiological impact of acute sleep loss in peripheral tissues by obtaining adipose tissue and skeletal muscle after one night of sleep loss and after one full night of sleep. We find that acute sleep loss alters genome-wide DNA methylation in adipose tissue, and unbiased transcriptome-, protein-, and metabolite-level analyses also reveal highly tissue-specific changes that are partially reflected by altered metabolite levels in blood. We observe transcriptomic signatures of inflammation in both tissues following acute sleep loss, but changes involving the circadian clock are evident only in skeletal muscle, and we uncover molecular signatures suggestive of muscle breakdown that contrast with an anabolic adipose tissue signature. Our findings provide insight into how disruption of sleep and circadian rhythms may promote weight gain and sarcopenia.
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5.
Is the secret for a successful aging to keep track of cancer pathways?
Tramontano, D, De Amicis, F
Journal of cellular physiology. 2018;(11):8467-8476
Abstract
A successful aging could be gained by life satisfaction, social functioning, or psychological resources and, definitely, by increasing resistance to diverse age-related pathologies. Nowadays, cancer can be considered an age-related disease since the incidence of most cancers increases with age, rising more rapidly beginning in midlife. Although adults with extended longevity are less likely to develop cancer, it is now emerging that aging and cancer share common molecular links, and thus targeting these mechanisms may be suitable to treat multiple disorders, for the prolonging of healthy aging. At present, one of the cornerstones of antiaging is hormone-replacement therapy to treat diseases associated with a state of age-related sex-hormone deficiency in women and men; however, many studies question the relationship of hormone replacement to cancer recurrence. Here, we discuss signaling and metabolic molecular crossroad linking aging and cancer. This is useful to argue about the current knowledge of prolongevity and druggable targets and to motivate specific intervention strategies that could modify practices of the aging population, activating multiple longevity pathways but keeping track of cancer pathways, thereby potentially preserving health status.
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6.
From plant metabolic engineering to plant synthetic biology: The evolution of the design/build/test/learn cycle.
Pouvreau, B, Vanhercke, T, Singh, S
Plant science : an international journal of experimental plant biology. 2018;:3-12
Abstract
Genetic improvement of crops started since the dawn of agriculture and has continuously evolved in parallel with emerging technological innovations. The use of genome engineering in crop improvement has already revolutionised modern agriculture in less than thirty years. Plant metabolic engineering is still at a development stage and faces several challenges, in particular with the time necessary to develop plant based solutions to bio-industrial demands. However the recent success of several metabolic engineering approaches applied to major crops are encouraging and the emerging field of plant synthetic biology offers new opportunities. Some pioneering studies have demonstrated that synthetic genetic circuits or orthogonal metabolic pathways can be introduced into plants to achieve a desired function. The combination of metabolic engineering and synthetic biology is expected to significantly accelerate crop improvement. A defining aspect of both fields is the design/build/test/learn cycle, or the use of iterative rounds of testing modifications to refine hypotheses and develop best solutions. Several technological and technical improvements are now available to make a better use of each design, build, test, and learn components of the cycle. All these advances should facilitate the rapid development of a wide variety of bio-products for a world in need of sustainable solutions.
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7.
Genome-scale metabolic reconstructions of multiple Salmonella strains reveal serovar-specific metabolic traits.
Seif, Y, Kavvas, E, Lachance, JC, Yurkovich, JT, Nuccio, SP, Fang, X, Catoiu, E, Raffatellu, M, Palsson, BO, Monk, JM
Nature communications. 2018;(1):3771
Abstract
Salmonella strains are traditionally classified into serovars based on their surface antigens. While increasing availability of whole-genome sequences has allowed for more detailed subtyping of strains, links between genotype, serovar, and host remain elusive. Here we reconstruct genome-scale metabolic models for 410 Salmonella strains spanning 64 serovars. Model-predicted growth capabilities in over 530 different environments demonstrate that: (1) the Salmonella accessory metabolic network includes alternative carbon metabolism, and cell wall biosynthesis; (2) metabolic capabilities correspond to each strain's serovar and isolation host; (3) growth predictions agree with 83.1% of experimental outcomes for 12 strains (690 out of 858); (4) 27 strains are auxotrophic for at least one compound, including L-tryptophan, niacin, L-histidine, L-cysteine, and p-aminobenzoate; and (5) the catabolic pathways that are important for fitness in the gastrointestinal environment are lost amongst extraintestinal serovars. Our results reveal growth differences that may reflect adaptation to particular colonization sites.
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8.
Current strategies for the treatment of inborn errors of metabolism.
Gambello, MJ, Li, H
Journal of genetics and genomics = Yi chuan xue bao. 2018;(2):61-70
Abstract
Inborn errors of metabolism (IEMs) are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed.
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9.
Soluble Leptin Receptor Predicts Insulin Sensitivity and Correlates With Upregulation of Metabolic Pathways in Men.
Sommer, C, Lee, S, Gulseth, HL, Jensen, J, Drevon, CA, Birkeland, KI
The Journal of clinical endocrinology and metabolism. 2018;(3):1024-1032
Abstract
CONTEXT Plasma soluble leptin receptor (sOb-R) seems protective of gestational and type 2 diabetes in observational studies, but the mechanisms are unknown. sOb-R is formed by ectodomain shedding of membrane-bound leptin receptors (Ob-Rs), but its associations with messenger RNA (mRNA) expression are scarcely explored. OBJECTIVE To explore associations between plasma levels of sOb-R and (1) insulin sensitivity, (2) mRNA pathways in adipose tissue and skeletal muscle, and (3) mRNA of candidate genes for sOb-R generation in adipose tissue and skeletal muscle. DESIGN AND PARTICIPANTS The MyoGlu study included 26 sedentary, middle-aged men who underwent a 12-week intensive exercise intervention. We measured plasma sOb-R with enzyme-linked immunosorbent assay, insulin sensitivity with a hyperinsulinemic euglycemic clamp, and mRNA in skeletal muscle and adipose tissue with high-throughput sequencing. RESULTS Baseline plasma sOb-R was strongly associated with baseline glucose infusion rate (GIR) [β (95% confidence interval), 1.19 (0.57 to 1.82) mg/kg/min, P = 0.0006] and GIR improvement after the exercise intervention [0.58 (0.03 to 1.12) mg/kg/min, P = 0.039], also independently of covariates, including plasma leptin. In pathway analyses, high plasma sOb-R correlated with upregulation of metabolic pathways and downregulation of inflammatory pathways in both adipose tissue and skeletal muscle. In skeletal muscle, mRNA of LEPROT and LEPROTL1 (involved in Ob-R cell surface expression) and ADAM10 and ADAM17 (involved sOb-R-shedding) increased after the exercise intervention. CONCLUSIONS Higher plasma sOb-R was associated with improved GIR, upregulation of metabolic pathways, and downregulation of inflammatory pathways, which may be possible mechanisms for the seemingly protective effect of plasma sOb-R on subsequent risk of gestational and type 2 diabetes found in observational studies.
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10.
On the Evolution of Specificity in Members of the Yeast Amino Acid Transporter Family as Parts of Specific Metabolic Pathways.
Gournas, C, Athanasopoulos, A, Sophianopoulou, V
International journal of molecular sciences. 2018;(5)
Abstract
In the recent years, molecular modeling and substrate docking, coupled with biochemical and genetic analyses have identified the substrate-binding residues of several amino acid transporters of the yeast amino acid transporter (YAT) family. These consist of (a) residues conserved across YATs that interact with the invariable part of amino acid substrates and (b) variable residues that interact with the side chain of the amino acid substrate and thus define specificity. Secondary structure sequence alignments showed that the positions of these residues are conserved across YATs and could thus be used to predict the specificity of YATs. Here, we discuss the potential of combining molecular modeling and structural alignments with intra-species phylogenetic comparisons of transporters, in order to predict the function of uncharacterized members of the family. We additionally define some orphan branches which include transporters with potentially novel, and to be characterized specificities. In addition, we discuss the particular case of the highly specific l-proline transporter, PrnB, of Aspergillus nidulans, whose gene is part of a cluster of genes required for the utilization of proline as a carbon and/or nitrogen source. This clustering correlates with transcriptional regulation of these genes, potentially leading to the efficient coordination of the uptake of externally provided l-Pro via PrnB and its enzymatic degradation in the cell.