The metabolism of glucose and glutamine, primary carbon sources utilized by mitochondria to generate energy and macromolecules for cell growth, is directly regulated by mTORC1. We show that glucose ...and glutamine, by supplying carbons to the TCA cycle to produce ATP, positively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTORC1 assembly and its lysosomal localization. We discovered that the ATP-dependent TTT-RUVBL1/2 complex was disassembled and repressed by energy depletion, resulting in its decreased interaction with mTOR. The TTT-RUVBL complex was necessary for the interaction between mTORC1 and Rag and formation of mTORC1 obligate dimers. In cancer tissues, TTT-RUVBL complex mRNAs were elevated and positively correlated with transcripts encoding proteins of anabolic metabolism and mitochondrial function—all mTORC1-regulated processes. Thus, the TTT-RUVBL1/2 complex responds to the cell’s metabolic state, directly regulating the functional assembly of mTORC1 and indirectly controlling the nutrient signal from Rags to mTORC1.
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► Glucose and glutamine feed back to promote mTORC1 signaling through ATP production ► Energetic stress prevents mTOR lysosomal localization independently of AMPK and Rag ► ATP-dependent TTT-RUVBL complex is disassembled and repressed by energetic stress ► TTT-RUVBL is required for mTORC1 functional assembly and lysosomal localization
Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian ...target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach.
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•mTORC1 regulates glutamine anaplerosis (catabolism)•mTORC1 represses SIRT4 transcription to regulate glutamate dehydrogenase activity•SIRT4 represses cell proliferation and is downregulated in human cancer•Combined glutamine and glucose metabolism inhibition results in death of cancer cells
mTORC1 regulates glutamine catabolism by controlling the levels of SIRT4, thus contributing to the metabolic reprogramming that drives tumor cell growth and proliferation.
Switchgrass is a leading dedicated bioenergy feedstock in the United States because it is a native, high-yielding, perennial prairie grass with a broad cultivation range and low agronomic input ...requirements. Biomass conversion research has developed processes for production of ethanol and other biofuels, but they remain costly primarily because of the intrinsic recalcitrance of biomass. We show here that genetic modification of switchgrass can produce phenotypically normal plants that have reduced thermal-chemical (less-than or equal to180 °C), enzymatic, and microbial recalcitrance. Down-regulation of the switchgrass caffeic acid O-methyltransferase gene decreases lignin content modestly, reduces the syringyl:guaiacyl lignin monomer ratio, improves forage quality, and, most importantly, increases the ethanol yield by up to 38% using conventional biomass fermentation processes. The down-regulated lines require less severe pretreatment and 300-400% lower cellulase dosages for equivalent product yields using simultaneous saccharification and fermentation with yeast. Furthermore, fermentation of diluted acid-pretreated transgenic switchgrass using Clostridium thermocellum with no added enzymes showed better product yields than obtained with unmodified switchgrass. Therefore, this apparent reduction in the recalcitrance of transgenic switchgrass has the potential to lower processing costs for biomass fermentation-derived fuels and chemicals significantly. Alternatively, such modified transgenic switchgrass lines should yield significantly more fermentation chemicals per hectare under identical process conditions.
The mammalian translational initiation machinery is a tightly controlled system that is composed of eukaryotic initiation factors, and which controls the recruitment of ribosomes to mediate ...cap-dependent translation. Accordingly, the mTORC1 complex functionally controls this cap-dependent translation machinery through the phosphorylation of its downstream substrates 4E-BPs and S6Ks. It is generally accepted that rapamycin, a specific inhibitor of mTORC1, is a potent translational repressor. Here we report the unexpected discovery that rapamycin's ability to regulate cap-dependent translation varies significantly among cell types. We show that this effect is mechanistically caused by rapamycin's differential effect on 4E-BP1 versus S6Ks. While rapamycin potently inhibits S6K activity throughout the duration of treatment, 4E-BP1 recovers in phosphorylation within 6 h despite initial inhibition (1-3 h). This reemerged 4E-BP1 phosphorylation is rapamycin-resistant but still requires mTOR, Raptor, and mTORC1's activity. Therefore, these results explain how cap-dependent translation can be maintained in the presence of rapamycin. In addition, we have also defined the condition by which rapamycin can control cap-dependent translation in various cell types. Finally, we show that mTOR catalytic inhibitors are effective inhibitors of the rapamycin-resistant phenotype.
The mTORC1 signaling pathway is a critical regulator of cell growth and is hyper activated in many different cancers. Rapamycin, an allosteric inhibitor of mTORC1, has been approved for treatment ...against renal cell carcinomas and is being evaluated for other cancers. Mechanistically, mTORC1 controls cell growth in part through its two well-characterized substrates S6K1 and 4E-BP1. In this review, we discuss the implications of a recent finding that showed differential inhibition of S6K1 and 4E-BP1 by rapamycin, leading to cell-type-specific repression of cap-dependent translation. We discuss potential mechanisms for this effect, and propose that mTOR-specific kinase inhibitors, instead of rapamycin, should be considered for mTOR-targeted cancer therapy.
Summary
From the perspective of Malaysian health care providers, denosumab was cost-effective in the treatment of postmenopausal osteoporosis, with an optimal outcome starting at age 60 years. Our ...results provide important insights into the value for money of anti-osteoporotic agents that can serve as a reference for other countries with comparable epidemiological data.
Introduction
The study aimed to compare the cost-effectiveness of denosumab with alendronate and no treatment in the management of postmenopausal osteoporosis among the Malaysian population.
Methods
A well-validated Markov model was used to estimate the cost-effectiveness of denosumab in a hypothetical cohort of postmenopausal osteoporotic women between 50 and 80 years old who had no history of fractures. A 10-year time horizon from the perspective of Malaysian health care providers was used in this analysis. The model parameters, including transition probabilities and costs, were based on Malaysian sources. Treatment efficacy data were obtained from a network meta-analysis. The study outcomes were presented as incremental cost per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed to ensure the robustness of the results. A cost-effectiveness threshold was set at MYR 21,438 (USD 5175) per QALY.
Results
Denosumab was found to be a cost-effective option for postmenopausal osteoporotic women aged 60 and older. The incremental cost-effectiveness ratios (ICERs) for denosumab versus alendronate ranged from MYR 16,955 (USD 4093) per QALY at age 60 to MYR 4380 (USD 1057) per QALY at age 80. The cost-effectiveness of denosumab improved monotonically with increasing age. Denosumab was 72.8–92.7% likely to be cost-effective at the cost-effectiveness threshold. Sensitivity analyses demonstrated that the results were robust across all parameter variations, with the annual cost of denosumab being the most sensitive.
Conclusions
From the perspective of the Malaysian health care provider, denosumab appears to be a cost-effective treatment choice for postmenopausal osteoporotic women over 60 years of age.
Huntington's disease (HD) is initiated by an abnormally expanded polyglutamine stretch in the huntingtin protein, conferring a novel property on the protein that leads to the loss of striatal ...neurons. Defects in mitochondrial function have been implicated in the pathogenesis of HD. Here, we have examined the hypothesis that the mutant huntingtin protein may directly interact with the mitochondrion and affect its function. In human neuroblastoma cells and clonal striatal cells established from HdhQ7 (wild-type) and HdhQ111 (mutant) homozygote mouse knock-in embryos, huntingtin was present in a purified mitochondrial fraction. Subfractionation of the mitochondria and limited trypsin digestion of the organelle demonstrated that huntingtin was associated with the outer mitochondrial membrane. We further demonstrated that a recombinant truncated mutant huntingtin protein, but not a wild-type, directly induced mitochondrial permeability transition (MPT) pore opening in isolated mouse liver mitochondria, an effect that was prevented completely by cyclosporin A (CSA) and ATP. Importantly, the mutant huntingtin protein significantly decreased the Ca2+ threshold necessary to trigger MPT pore opening. We found a similar increased susceptibility to the calcium-induced MPT in liver mitochondria isolated from a knock-in HD mouse model. The mutant huntingtin protein-induced MPT pore opening was accompanied by a significant release of cytochrome c, an effect completely inhibited by CSA. These findings suggest that the development of specific MPT inhibitors may be an interesting therapeutic avenue to delay the onset of HD.
The paper investigates the interaction effects due to diffraction by a large volume substructure and an installation barge, during the operation of setting the deck onto the substructure. Linear ...theory is adopted. The barge motions are constrained by attachments to the fixed substructure, and the effects of the constraints are modeled here by a two-stage hydrodynamic/dynamic analysis. The multi-body diffraction problem is first solved without any constraints between the bodies, and in the second stage the constrained equations of motion are solved. The analysis is validated through comparisons with published results for five interconnected barges. Three configurations of substructure are then investigated for an installation configuration: a non-diffracting steel space framed structure (as a reference case); an array of four large diameter vertical columns mounted on the seabed and a Gravity Based Structure consisting of the same four columns with a subsurface caisson.
► The two-stage approach is efficient in the analysis of constrained multi-body systems. ► Results of MOB are validated by comparing with published paper. ► In analysis of float-over installations, some useful insight has been revealed.
Giant clams live in nutrient-poor reef waters of the Indo-Pacific and rely on symbiotic dinoflagellates (
spp., also known as zooxanthellae) for nutrients. As the symbionts are nitrogen deficient, ...the host clam has to absorb exogenous nitrogen and supply it to them. This study aimed to demonstrate light-enhanced urea absorption in the fluted giant clam,
, and to clone and characterize the urea active transporter DUR3-like from its ctenidium (gill). The results indicate that
absorbs exogenous urea, and the rate of urea uptake in the light was significantly higher than that in darkness. The
coding sequence obtained from its ctenidium comprised 2346 bp, encoding a protein of 782 amino acids and 87.0 kDa.
was expressed strongly in the ctenidium, outer mantle and kidney. Twelve hours of exposure to light had no significant effect on the transcript level of ctenidial
However, between 3 and 12 h of light exposure, DUR3-like protein abundance increased progressively in the ctenidium, and became significantly greater than that in the control at 12 h. DUR3-like had an apical localization in the epithelia of the ctenidial filaments and tertiary water channels. Taken together, these results indicate that DUR3-like might participate in light-enhanced urea absorption in the ctenidium of
When made available to the symbiotic zooxanthellae that are known to possess urease, the absorbed urea can be metabolized to NH
and CO
to support amino acid synthesis and photosynthesis, respectively, during insolation.
Of the many types of catalysis involving two or more catalysts, synergistic catalysis is of great interest because novel reactions or reaction pathways may be discovered when there is synergy between ...the catalysts. Herein, we describe a synergistic cascade catalysis, in which immobilized Au/Pd bimetallic nanoparticles and Lewis acids work in tandem to achieve the
-alkylation of primary amides to secondary amides with alcohols
hydrogen autotransfer. When Au/Pd nanoparticles were used with metal triflates, a significant rate acceleration was observed, and the desired secondary amides were obtained in excellent yields. The metal triflate is thought to not only facilitate the addition of primary amides to aldehydes generated
, but also enhance the returning of hydrogen from nanoparticles to hydrogen-accepting intermediates. This resulted in a more rapid turnover of the nanoparticle catalyst, and ultimately translated into an increase in the overall rate of the reaction. The two catalysts in this co-catalytic system work in a synergistic and cascade fashion, resulting in an efficient hydrogen autotransfer process.
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