Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes.

BackgroundMyriad challenges to the proper folding and structural maturation of secretory pathway client proteins in the endoplasmic reticulum (ER) - a condition referred to as "ER stress" - activate intracellular signaling pathways termed the unfolded protein response (UPR).Scope of reviewThrough executing transcriptional and translational programs the UPR restores homeostasis in those cells experiencing manageable levels of ER stress. But the UPR also actively triggers cell degeneration and apoptosis in those cells that are encountering ER stress levels that exceed irremediable thresholds. Thus, UPR outputs are "double-edged". In pancreatic islet β-cells, numerous genetic mutations affecting the balance between these opposing UPR functions cause diabetes mellitus in both rodents and humans, amply demonstrating the principle that the UPR is critical for the proper functioning and survival of the cell.Major conclusionsSpecifically, we have found that the UPR master regulator IRE1α kinase/endoribonuclease (RNase) triggers apoptosis, β-cell degeneration, and diabetes, when ER stress reaches critical levels. Based on these mechanistic findings, we find that novel small molecule compounds that inhibit IRE1α during such "terminal" UPR signaling can spare ER stressed β-cells from death, perhaps affording future opportunities to test new drug candidates for disease modification in patients suffering from diabetes

Persistent reduced ecosystem respiration after insect disturbance in high elevation forests

Amid a worldwide increase in tree mortality, mountain pine beetles (Dendroctonus ponderosae Hopkins) have led to the death of billions of trees from Mexico to Alaska since 2000. This is predicted to have important carbon, water and energy balance feedbacks on the Earth system. Counter to current projections, we show that on a decadal scale, tree mortality causes no increase in ecosystem respiration from scales of several square metres up to an 84 km2 valley. Rather, we found comparable declines in both gross primary productivity and respiration suggesting little change in net flux, with a transitory recovery of respiration 6–7 years after mortality associated with increased incorporation of leaf litter C into soil organic matter, followed by further decline in years 8–10. The mechanism of the impact of tree mortality caused by these biotic disturbances is consistent with reduced input rather than increased output of carbon

Stability of Pyruvic Acid Adsorbed Onto Clays and Exposed to Ionizing Radiation: Relevance in Chemical Evolution

Chemical evolution studies focus on the synthesis and stability of organic molecules during various transformative physicochemical processes. Gaining insight into the possible mechanisms behind these processes requires the use of various energy sources and catalysts that can produce such transformations. In this work, ionizing radiation (60Co) was used as a source of energy, and two clays with different exchangeable cations-sodium and iron (III)-were combined with pyruvic acid, a key alpha keto acid in metabolism. The samples of pyruvic acid were prepared at a concentration of 0.01 M; then, adsorption experiments were carried out by combining sodium or iron montmorillonite at different times. The amount that adsorbed onto iron montmorillonite was greater than the amount that adsorbed onto sodium montmorillonite. Samples of alpha keto acid at the same concentration were irradiated-in the absence of clay-at 0 to 146.1 kGy and at two pHs (6.7 and 2.0). The suspended samples with sodium and iron clay were then irradiated at the same doses. The results show that keto acid decomposes more quickly at more acidic pHs. The main reaction to irradiation without clay involves the dimerization of pyruvic acid, and 2,3-dimethyltartaric acid is the majority product. When irradiated in the presence of clay, the main reaction is decarboxylation, and acetic acid is the majority product. The exchangeable cation type modifies the interactions between the organic molecule and the solid phase. The percentage of recovered pyruvic acid is higher for iron montmorillonite than for sodium montmorillonite

High proportion of cactus species threatened with extinction

This is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record.Consejo Nacional de Ciencia y Tecnologí

Ionizing Radiation, an Instrument in Chemical Evolution Studies: Scope and Perspectives

The study of synthesis and stability of molecules in different environments it’s been part of chemistry evolution and origin of life studies for more than 70 years. Various kinds of ionizing radiation have been analyzed as possible sources of energy for the transformations undergone by the first organic molecules. Now experimental and computational simulation approaches continue with different groups of organic molecules, in search for more information that help us to understand and reconstruct somehow the mechanisms that toke place on early Earth and space. In that line, this paper presents first approach of keto acids stability to ionizing radiation, an interesting group of molecules involved in the Krebs cycle and glycolysis. Preliminary results obtained by HPLC/UV analysis of irradiating aqueous solutions of 5 keto acids ranging from 3 to 6 carbons with a 60Co gamma ray source, using doses up to 53 kGy, show different stabilities and a general tendency of shifting the keto-enol equilibrium to the enol tautomer before decomposition

Analysis of the proposed relocation of the neutron criticality clusters in the process buildings for the Portsmouth Gaseous Diffusion Plant

Radiation levels in Buildings X-326, X-330 and X-333 have been determined for the ANSI minimum accident of concern at both the current and the proposed locations of the criticality alum system neutron detectors. This was performed in order to evaluate whether or not the detectors could be lowered from their current positions and still respond to the minimum accident of concern. Relocating the detectors could reduce the potential for worker in injury when the approximately 90-pound alarms need to be removed for periodic maintenance. It could also decrease the incidence of battery failure from elevated temperatures which can exceed 160 degrees F. At the proposed 1-meter elevation the detectors would be surrounded by the cells containing the cascade equipment; therefore, the detectors would be less responsive to a criticality event. The results of this analysis indicate that the detectors could be lowered from their current height of 5 meters to a height of 1 meter and still respond to the minimum accident of concern. This analysis was performed using the MCNP monte carlo code with a source corresponding to a critical system of uranyl fluoride solutions of 1.2, 3.0, and 4.95 weight percent U-235 enrichment. The neutron dose rates were evaluated at positions of 69 meters and 100 meters radially outward from the source at 5 meter and 1 meter heights. All neutron detectors located in the three process buildings are located within 100 meters from any potential criticality. This report details the methodology used for this study, background on the data employed, and a comparison to a similar analysis performed in 1983

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals