Glucose Sensing in \u3ci\u3eTrypanosoma brucei\u3c/i\u3e

Trypanosoma brucei is the protozoan parasite that causes human African trypanosomiasis (HAT, also known as sleeping sickness) and nagana disease in livestock. During its life cycle, trypanosomes occupy niches with very different nutrient contents and immune features. They use glucose solely for ATP production in the mammalian bloodstream while switching to amino acid metabolism in the midgut of the tsetse fly vector. A fast and accurate coordination of gene expression with environment alteration is critical for the successful parasitization of the two hosts. My study focuses on the signaling role of glucose in the development and adaptation of T. brucei. I have found that depletion of glucose triggers very distinct responses in parasites at different life stages. The lack of glucose is lethal to the proliferating long slender bloodstream form, while the absence of the hexose serves as a differentiation cue for the quiescent stumpy bloodstream form. Finally, environments without glucose are favorable for culture of the procyclic form insect stage. My data also suggests the existence of glycolysis independent glucose signaling pathways in T. brucei that may guide the development of parasites by regulating major metabolic pathways. Blood stage parasites have been found to colonize various mammalian tissues besides blood. The consequences of the dynamic glucose concentrations in these tissues on parasite behavior are unresolved. Here, we describe how bloodstream parasites regulate gene expression at the post-transcriptional level in response to the near-absence of glucose. This regulation only occurs when the environmental glucose concentration reaches an extremely low level (\u3c10 μM). We also describe a novel stem-loop structure in the 3’ untranslated region the cytochrome c oxidase subunit VI that is responsible for glucose-depletion-induced translational upregulation

Probing the effects of TbHK2 on Trypanosoma brucei growth, social behavior, and inhibitor response

In sub-Saharan Africa the protozoan parasite, Trypanosoma brucei, continues to be of major concern for the health and economic development of the region. This parasite is known to cause human African trypanosomiasis (HAT or African sleeping sickness) and nagana in livestock such as cattle. Social behaviors, such as colonization and migration, are important in the study of T. brucei because of the way the parasite infects its mammalian host. During the fly bloodmeal, the parasite first passes into the gut but then eventually migrates to the fly salivary glands where it will continue to develop before transmission as a parasitic form able to infect and cause disease in humans and livestock. Past research has shown that the social motility, the ability of the multitude of parasites in an infection to move in a coordinated fashion, is affected by the removal of the T. brucei hexokinase 2 (TbHK2) gene or expression of excess copies of the TbHK2 protein. In exploring social motility phenotypes of TbHK2-deficient insect stage (procylic form, PF)T. brucei parasites and parental forms complemented with excess TbHK2 gene, this project aims to understand more about the role of TbHK2 in social motility of T. brucei. Additionally, in order to understand how hexokinase 2 could be targeted by enzyme inhibitors, known hexokinase 1 inhibitors are explored for their effects on TbHK2 complemented cells compared to the parental strain parasites

Recent advances in the repair of degenerative intervertebral disc for preclinical applications

The intervertebral disc (IVD) is a load-bearing, avascular tissue that cushions pressure and increases flexibility in the spine. Under the influence of obesity, injury, and reduced nutrient supply, it develops pathological changes such as fibular annulus (AF) injury, disc herniation, and inflammation, eventually leading to intervertebral disc degeneration (IDD). Lower back pain (LBP) caused by IDD is a severe chronic disorder that severely affects patients’ quality of life and has a substantial socioeconomic impact. Patients may consider surgical treatment after conservative treatment has failed. However, the broken AF cannot be repaired after surgery, and the incidence of re-protrusion and reoccurring pain is high, possibly leading to a degeneration of the adjacent vertebrae. Therefore, effective treatment strategies must be explored to repair and prevent IDD. This paper systematically reviews recent advances in repairing IVD, describes its advantages and shortcomings, and explores the future direction of repair technology

Comparative transcriptome profiling provides insights into plant salt tolerance in seashore paspalum (\u3ci\u3ePaspalum vaginatum\u3c/i\u3e)

Background Seashore paspalum (Paspalum vaginatum), a halophytic warm-seasoned perennial grass, is tolerant of many environmental stresses, especially salt stress. To investigate molecular mechanisms underlying salinity tolerance in seashore paspalum, physiological characteristics and global transcription profiles of highly (Supreme) and moderately (Parish) salinity-tolerant cultivars under normal and salt stressed conditions were analyzed. Results Physiological characterization comparing highly (Supreme) and moderately (Parish) salinity-tolerant cultivars revealed that Supreme’s higher salinity tolerance is associated with higher Na+ and Ca2+ accumulation under normal conditions and further increase of Na+ under salt-treated conditions (400 mM NaCl), possibly by vacuolar sequestration. Moreover, K+ retention under salt treatment occurs in both cultivars, suggesting that it may be a conserved mechanism for prevention of Na+ toxicity. We sequenced the transcriptome of the two cultivars under both normal and salt-treated conditions (400 mM NaCl) using RNA-seq. De novo assembly of about 153 million high-quality reads and identification of Open Reading Frames (ORFs) uncovered a total of 82,608 non-redundant unigenes, of which 3250 genes were identified as transcription factors (TFs). Gene Ontology (GO) annotation revealed the presence of genes involved in diverse cellular processes in seashore paspalum’s transcriptome. Differential expression analysis identified a total of 828 and 2222 genes that are responsive to high salinity for Supreme and Parish, respectively. “Oxidation-reduction process” and “nucleic acid binding” are significantly enriched GOs among differentially expressed genes in both cultivars under salt treatment. Interestingly, compared to Parish, a number of salt stress induced transcription factors are enriched and show higher abundance in Supreme under normal conditions, possibly due to enhanced Ca2+ signaling transduction out of Na+ accumulation, which may be another contributor to Supreme’s higher salinity tolerance. Conclusion Physiological and transcriptome analyses of seashore paspalum reveal major molecular underpinnings contributing to plant response to salt stress in this halophytic warm-seasoned perennial grass. The data obtained provide valuable molecular resources for functional studies and developing strategies to engineer plant salinity tolerance

Probing the Effects of TbHK2 on Trypanosoma brucei Growth, Social Growth, and Inhibitor Response

In sub-Saharan Africa the protozoan parasite, Trypanosoma brucei, continues to be of major concern for the health and economic development of the region. This parasite is known to cause human African trypanosomiasis (HAT or African sleeping sickness) and nagana in livestock such as cattle. Social behaviors, such as colonization and migration, are important in the study of T. brucei because of the way the parasite infects its mammalian host. During the fly bloodmeal, the parasite first passes into the gut but then eventually migrates to the fly salivary glands where it will continue to develop before transmission as a parasitic form able to infect and cause disease in humans and livestock. Past research has shown that the social motility, the ability of the multitude of parasites in an infection to move in a coordinated fashion, is affected by the removal of the T. brucei hexokinase 2 (TbHK2) gene or expression of excess copies of the TbHK2 protein. In exploring social motility phenotypes of TbHK2-deficient insect stage (procylic form, PF)T. brucei parasites and parental forms complemented with excess TbHK2 gene, this project aims to understand more about the role of TbHK2 in social motility of T. brucei. Additionally, in order to understand how hexokinase 2 could be targeted by enzyme inhibitors, known hexokinase 1 inhibitors are explored for their effects on TbHK2 complemented cells compared to the parental strain parasites

Nonlinear photoluminescence of ZnO/ZnS nanotetrapods

In this work, two-photon-excited photoluminescence dynamics in ZnS functionalized ZnO nanotetrapods were investigated. Comparing to the bare ZnO nanotetrapods, the emission peaks of the ZnO/ZnS nanotetrapods red-shifted by 5-10 nm, and the photoluminescence intensity and lifetime of the ultraviolet exciton radiative transition increased more than 20 times due to the passivation effect of the core/shell structure. (C) 2008 Elsevier B.V. All rights reserved

Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy.

Glutamine metabolism is reprogrammed during tumorigenesis and has been investigated as a promising target for cancer therapy. However, efforts to drug this process are confounded by the intrinsic metabolic heterogeneity and flexibility of tumors, as well as the risk of adverse effects on the anticancer immune response. Recent research has yielded important insights into the mechanisms that determine the tumor and the host immune responses to pharmacological perturbation of glutamine metabolism. Here, we discuss these findings and suggest that, collectively, they point toward patient stratification and drug combination strategies to maximize the efficacy of glutamine metabolism inhibitors as cancer therapeutics

Glucose Signaling Is Important for Nutrient Adaptation during Differentiation of Pleomorphic African Trypanosomes

The African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its life cycle. During transition from mammalian blood to insect vector gut, parasites experience a rapid reduction in environmental glucose. Here we describe how pleomorphic parasites respond to glucose depletion with a focus on parasite changes in energy metabolism and growth. Long slender bloodstream form parasites were rapidly killed as glucose concentrations fell, while short stumpy bloodstream form parasites persisted to differentiate into the insect-stage procyclic form parasite. The rate of differentiation was lower than that triggered by other cues but reached physiological rates when combined with cold shock. Both differentiation and growth of resulting procyclic form parasites were inhibited by glucose and nonmetabolizable glucose analogs, and these parasites were found to have upregulated amino acid metabolic pathway component gene expression. In summary, glucose transitions from the primary metabolite of the blood-stage infection to a negative regulator of cell development and growth in the insect vector, suggesting that the hexose is not only a key metabolic agent but also an important signaling molecule