With the revelation that Facebook handed over personally identifiable information of more than 87 million users to Cambridge Analytica, it is now imperative that comprehensive privacy policy laws be ...developed. Technologists, researchers, and innovators should meaningfully contribute to the development of these policies.
How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly ...upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.
•GDH1 predominantly controls intracellular α-KG and subsequent fumarate levels•GDH1 contributes to redox homeostasis by activating GPx1•Fumarate binds to and activates GPx1•GDH1 is a promising anticancer target
Jin et al. show that mitochondrial glutaminolysis contributes to redox homeostasis through glutamate dehydrogenase 1 (GDH1) regulation of α-ketoglutarate, fumarate, and GPx1. GDH1 is upregulated in human cancers, and its inhibition perturbs redox homeostasis and attenuates cancer cell proliferation and tumor growth.
The combination of relative nutrient deprivation and dysregulation of protein synthesis make malignant cells especially prone to protein misfolding. Endoplasmic reticulum stress, which results from ...protein misfolding within the secretory pathway, has a profound effect on cancer cell proliferation and survival. In this review, we examine the evidence implicating endoplasmic reticulum dysfunction in the pathology of cancer and discuss how recent findings may help to identify novel therapeutic targets.
Abstract Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact ...pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune-mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune-modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation.
Microgels are commonly synthesized in batch experiments, yielding quantities sufficient to perform characterization experiments for physical property studies. With increasing attention on the ...application potential of microgels, little attention is yet paid to the questions (a) whether they can be produced continuously on a larger scale, (b) whether synthesis routes can be easily transferred from batch to continuous synthesis, and (c) whether their properties can be precisely controlled as a function of synthesis parameters under continuous flow reaction conditions. We present a new continuous synthesis process of two typical but different microgel systems. Their size, size distribution, and temperature-responsive behavior are compared in depth to those of microgels synthesized using batch processes, and the influence of premixing and surfactant is also investigated. For the surfactant-free poly(N-vinylcaprolactam) and poly(N-isopropylacrylamide) systems, microgels are systematically smaller, while the actual size is depending on the premixing of the reaction solutions. However, by the use of a surfactant, the size difference between batch and continuous preparation diminishes, resulting in equal-sized microgels. Temperature-induced swelling–deswelling of microgels synthesized under continuous flow conditions was similar to that of their analogues synthesized using the batch polymerization process. Additionally, investigation of the internal microgel structure using static light scattering showed no significant changes between microgels prepared under batch and continuous conditions. The work encourages synthesis concepts of sequential chemical conditions in continuous flow reactors to prepare precisely tuned new microgel systems.
The relationship between methane emissions and salinity is not well understood in tidal marshes, leading to uncertainty about the net effect of marsh conservation and restoration on greenhouse gas ...balance. We used published and unpublished field data to investigate the relationships between tidal marsh methane emissions, salinity, and porewater concentrations of methane and sulfate, then used these relationships to consider the balance between methane emissions and soil carbon sequestration. Polyhaline tidal marshes (salinity >18) had significantly lower methane emissions (mean ± sd = 1 ± 2 g m
−2
yr
−1
) than other marshes, and can be expected to decrease radiative forcing when created or restored. There was no significant difference in methane emissions from fresh (salinity = 0–0.5) and mesohaline (5–18) marshes (42 ± 76 and 16 ± 11 g m
−2
yr
−1
, respectively), while oligohaline (0.5–5) marshes had the highest and most variable methane emissions (150 ± 221 g m
−2
yr
−1
). Annual methane emissions were modeled using a linear fit of salinity against log-transformed methane flux (
; r
2
= 0.52;
p
< 0.0001). Managers interested in using marshes as greenhouse gas sinks can assume negligible methane emissions in polyhaline systems, but need to estimate or monitor methane emissions in lower-salinity marshes.
Nitrogen fertilization is critical to optimize short-term crop yield, but its long-term effect on soil organic C (SOC) is uncertain. Here, we clarify the impact of N fertilization on SOC in typical ...maize-based (Zea mays L.) Midwest U.S. cropping systems by accounting for site-to-site variability in maize yield response to N fertilization. Within continuous maize and maize-soybean Glycine max (L.) Merr. systems at four Iowa locations, we evaluated changes in surface SOC over 14 to 16 years across a range of N fertilizer rates empirically determined to be insufficient, optimum, or excessive for maximum maize yield. Soil organic C balances were negative where no N was applied but neutral (maize-soybean) or positive (continuous maize) at the agronomic optimum N rate (AONR). For continuous maize, the rate of SOC storage increased with increasing N rate, reaching a maximum at the AONR and decreasing above the AONR. Greater SOC storage in the optimally fertilized continuous maize system than in the optimally fertilized maize-soybean system was attributed to greater crop residue production and greater SOC storage efficiency in the continuous maize system. Mean annual crop residue production at the AONR was 22% greater in the continuous maize system than in the maize-soybean system and the rate of SOC storage per unit residue C input was 58% greater in the monocrop system. Our results demonstrate that agronomic optimum N fertilization is critical to maintain or increase SOC of Midwest U.S. cropland.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Given a dynamical system with m independent conserved quantities, we construct a multiparameter family of new systems in which these quantities evolve monotonically and proportionally, and are ...replaced by m−1 conserved linear combinations of themselves, with any of the original quantities as limiting cases. The modification of the dynamics employs an exterior product of gradients of the original quantities, and often evolves the system toward asymptotic linear dependence of these gradients in a nontrivial state. The process both generalizes and provides additional structure to existing techniques for selective dissipation in the literature on fluids and plasmas, nonequilibrium thermodynamics, and nonlinear controls. It may be iterated or adapted to obtain any reduction in the degree of integrability. It may enable discovery of extremal states, limit cycles, or solitons, and the construction of new integrable systems from superintegrable systems. We briefly illustrate the approach by its application to the cyclic three-body Toda lattice, driven from an aperiodic orbit toward a limit cycle.
It is unclear how cancer cells coordinate glycolysis and biosynthesis to support rapidly growing tumors. We found that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), commonly upregulated in ...human cancers due to loss of TP53, contributes to biosynthesis regulation in part by controlling intracellular levels of its substrate, 3-phosphoglycerate (3-PG), and product, 2-phosphoglycerate (2-PG). 3-PG binds to and inhibits 6-phosphogluconate dehydrogenase in the oxidative pentose phosphate pathway (PPP), while 2-PG activates 3-phosphoglycerate dehydrogenase to provide feedback control of 3-PG levels. Inhibition of PGAM1 by shRNA or a small molecule inhibitor PGMI-004A results in increased 3-PG and decreased 2-PG levels in cancer cells, leading to significantly decreased glycolysis, PPP flux and biosynthesis, as well as attenuated cell proliferation and tumor growth.
► PGAM1 controls 3-PG and 2-PG levels to coordinate glycolysis and biosynthesis ► 3-PG binds to and inhibits 6PGD in the oxidative PPP ► 2-PG potentiates PHGDH to provide feedback control of 3-PG levels ► PGAM1 is a promising anticancer target
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