HIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in Caenorhabditis elegans

Dietary restriction (DR) extends lifespan in various species and also slows the onset of age-related diseases. Previous studies from flies and yeast have demonstrated that the target of rapamycin (TOR) pathway is essential for longevity phenotypes resulting from DR. TOR is a conserved protein kinase that regulates growth and metabolism in response to nutrients and growth factors. While some of the downstream targets of TOR have been implicated in regulating lifespan, it is still unclear whether additional targets of this pathway also modulate lifespan. It has been shown that the hypoxia inducible factor-1 (HIF-1) is one of the targets of the TOR pathway in mammalian cells. HIF-1 is a transcription factor complex that plays key roles in oxygen homeostasis, tumor formation, glucose metabolism, cell survival, and inflammatory response. Here, we describe a novel role for HIF-1 in modulating lifespan extension by DR in Caenorhabditis elegans. We find that HIF-1 deficiency results in extended lifespan, which overlaps with that by inhibition of the RSKS-1/S6 kinase, a key component of the TOR pathway. Using a modified DR method based on variation of bacterial food concentrations on solid agar plates, we find that HIF-1 modulates longevity in a nutrient-dependent manner. The hif-1 loss-of-function mutant extends lifespan under rich nutrient conditions but fails to show lifespan extension under DR. Conversely, a mutation in egl-9, which increases HIF-1 activity, diminishes the lifespan extension under DR. This deficiency is rescued by tissue-specific expression of egl-9 in specific neurons and muscles. Increased lifespan by hif-1 or DR is dependent on the endoplasmic reticulum (ER) stress regulator inositol-requiring protein-1 (IRE-1) and is associated with lower levels of ER stress. Therefore, our results demonstrate a tissue-specific role for HIF-1 in the lifespan extension by DR involving the IRE-1 ER stress pathway

Alanine Zipper-Like Coiled-Coil Domains Are Necessary for Homotypic Dimerization of Plant GAGA-Factors in the Nucleus and Nucleolus

GAGA-motif binding proteins control transcriptional activation or repression of homeotic genes. Interestingly, there are no sequence similarities between animal and plant proteins. Plant BBR/BPC-proteins can be classified into two distinct groups: Previous studies have elaborated on group I members only and so little is known about group II proteins. Here, we focused on the initial characterization of AtBPC6, a group II protein from Arabidopsis thaliana. Comparison of orthologous BBR/BPC sequences disclosed two conserved signatures besides the DNA binding domain. A first peptide signature is essential and sufficient to target AtBPC6-GFP to the nucleus and nucleolus. A second domain is predicted to form a zipper-like coiled-coil structure. This novel type of domain is similar to Leucine zippers, but contains invariant alanine residues with a heptad spacing of 7 amino acids. By yeast-2-hybrid and BiFC-assays we could show that this Alanine zipper domain is essential for homotypic dimerization of group II proteins in vivo. Interhelical salt bridges and charge-stabilized hydrogen bonds between acidic and basic residues of the two monomers are predicted to form an interaction domain, which does not follow the classical knobs-into-holes zipper model. FRET-FLIM analysis of GFP/RFP-hybrid fusion proteins validates the formation of parallel dimers in planta. Sequence comparison uncovered that this type of domain is not restricted to BBR/BPC proteins, but is found in all kingdoms

Drug discovery: Insights from the invertebrate Caenorhabditis elegans

Therapeutic drug development is a long, expensive, and complex process that usually takes 12–15 years. In the early phases of drug discovery, in particular, there is a growing need for animal models that ensure the reduction in both cost and time. Caenorhabditis elegans has been traditionally used to address fundamental aspects of key biological processes, such as apoptosis, aging, and gene expression regulation. During the last decade, with the advent of large-scale platforms for screenings, this invertebrate has also emerged as an essential tool in the pharmaceutical research industry to identify novel drugs and drug targets. In this review, we discuss the reasons why C. elegans has been positioned as an outstanding cost-effective option for drug discovery, highlighting both the advantages and drawbacks of this model. Particular attention is paid to the suitability of this nematode in large-scale genetic and pharmacological screenings. High-throughput screenings in C. elegans have indeed contributed to the breakthrough of a wide variety of candidate compounds involved in extensive fields including neurodegeneration, pathogen infections and metabolic disorders. The versatility of this nematode, which enables its instrumentation as a model of human diseases, is another attribute also herein underscored. As illustrative examples, we discuss the utility of C. elegans models of both human neurodegenerative diseases and parasitic nematodes in the drug discovery industry. Summing up, this review aims to demonstrate the impact of C. elegans models on the drug discovery pipeline.Fil: Giunti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Andersen, Natalia Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentin

Landslide initiation and runout susceptibility modeling in the context of hill cutting and rapid urbanization: a combined approach of weights of evidence and spatial multi-criteria

Rainfall induced landslides are a common threat to the communities living on dangerous hill-slopes in Chittagong Metropolitan Area, Bangladesh. Extreme population pressure, indiscriminate hill cutting, increased precipitation events due to global warming and associated unplanned urbanization in the hills are exaggerating landslide events. The aim of this article is to prepare a scientifically accurate landslide susceptibility map by combining landslide initiation and runout maps. Land cover, slope, soil permeability, surface geology, precipitation, aspect, and distance to hill cut, road cut, drainage and stream network factor maps were selected by conditional independence test. The locations of 56 landslides were collected by field surveying. A weight of evidence (WoE) method was applied to calculate the positive (presence of landslides) and negative (absence of landslides) factor weights. A combination of analytical hierarchical process (AHP) and fuzzy membership standardization (weighs from 0 to 1) was applied for performing a spatial multi-criteria evaluation. Expert opinion guided the decision rule for AHP. The Flow-R tool that allows modeling landslide runout from the initiation sources was applied. The flow direction was calculated using the modified Holmgren’s algorithm. The AHP landslide initiation and runout susceptibility maps were used to prepare a combined landslide susceptibility map. The relative operating characteristic curve was used for model validation purpose. The accuracy of WoE, AHP, and combined susceptibility map was calculated 96%, 97%, and 98%, respectively

Zur Geologie Der Chromfuhrenden Ophiolite Der Osttorkei

Der osttürkische Chromerzbezirk, ein Teil der grossen anatolisch-balkanischen Ophiolith-Chromprovinz, liegt im Kettenzug der Iraniden und erstreckt sich von der Tigrisquelle ostwarts bis zum Vansee. Der geologische Bau des Gebietes ist auf Grund von einer Übersichtskartierung durch İHSAN KETİN (1950) geklart worden. Er ist gekennzeichnet durch die Randüberschiebung der Iraniden auf die Arabische Tafel. Das berühmte Chrombergbauzentrum ist Guleman. Die Lagerstatten des Guleman-Gebietes haben ihre erste wissenschaftliche Bearbeitung schon 1938 durch A. HELKE erfahren. Die Erkenntnis der tektonischen Überschiebung des erzfuhrenden Serpentins von Guleman gewan G. ROSIER 1939. Spater haben sich V. KOVENKO (1943), P. de WIJKERSLOOTH (1947) und neuerdings H. BORCHERT (unveroffentlichter Bericht 1953) mit den Chromerzlagerstatten eingehend befasst. Dem Verfasser wurde durch einen grosszügigen Forschungsauftrag durch das M. T. A. Ankara im Sommer 1956 die Möglichkeit geboten, einige grundsatzliche Fragen der Ophiolithe und Chromerze der Osttürkei zu bearbeiten. Die praktischen Folgerungen aus dieser Bearbeitung fur die Aufschlussarbeiten sind in einem Bericht fur das M. T. A. prazisiert, wahrend die ailgemein-geologischen und lagerstattenkundlichen Ergebnisse in den folgenden Zeilen bekannt gemacht werden sollerk Dankbar gederike ich dabei der haufigen Führung und befruchtenden Aussprache im Gelande mit Herrn Dipl. Ing. ROMBERG und Herrn Dr. A. HELKE