Dual control of NAD + synthesis by purine metabolites in yeast

International audienceMetabolism is a highly integrated process resulting in energy and biomass production. While individual metabolic routes are well characterized, the mechanisms ensuring crosstalk between pathways are poorly described, although they are crucial for homeostasis. Here, we establish a co-regulation of purine and pyridine metabolism in response to external adenine through two separable mechanisms. First, adenine depletion promotes transcriptional upregulation of the de novo NAD + biosynthesis genes by a mechanism requiring the key-purine intermediates ZMP/SZMP and the Bas1/Pho2 transcription factors. Second, adenine supplementation favors the pyridine salvage route resulting in an ATP-dependent increase of intracellular NAD +. This control operates at the level of the nicotinic acid mononucleotide adenylyl-transferase Nma1 and can be bypassed by overexpressing this enzyme. Therefore, in yeast, pyridine metabolism is under the dual control of ZMP/SZMP and ATP, revealing a much wider regulatory role for these intermediate metabolites in an integrated biosynthesis network

Proposal for the implementation of sustainable urban drainage systems (SUDS) in the city of Tunja Boyacá

En la ciudad de Tunja capital del departamento de Boyacá más, conocida como la ciudad de los tesoros escondidos, los fenómenos de amenazas hidrometeorológico tienes un alto impacto, como se han presentado inundaciones en zonas pobladas de la ciudad desde hace varios años, estas se deben a diferentes factores, como: la permeabilización de los suelos por la construcción de vías y viviendas en la periferias de los ríos, afectando la recarga de los acuíferos que se encuentran en la zona, por lo que se ve alterado el ciclo hidrológico, por ende mediante el presente artículo se plantean una propuesta de alternativas de aplicación de Sistemas Urbano de Drenaje Sostenible (SUDS) con el fin de disminuir las inundación en las zonas bajas de la ciudad de Tunja y contribuir con los objetivos de desarrollo sostenible, y cambio climático, La metodología se basa en la recopilación de datos históricos de precipitaciones en la ciudad, artículos, norma técnica NS-166, 2018, entre otras fuentes, confiables, para realizar el análisis de la información y posteriormente se define la tipología adecuada de SUDS en zonas urbanas, de acuerdo a las particularidades de cada tipología y de la zona.In the city of Tunja, capital of the department of Boyacá, known as the city of hidden treasures, hydrometeorological hazard phenomena have a high impact, as floods have occurred in populated areas of the city for several years, these are due to to different factors, such as: the permeabilization of the soil due to the construction of roads and houses on the peripheries of the rivers, highlighting the recharge of the aquifers found in the area, which is why the hydrological cycle is altered, therefore Through this article, a proposal for alternatives for the application of Sustainable Urban Drainage Systems (SUDS) is proposed in order to reduce flooding in the low-lying areas of the city of Tunja and contribute to the objectives of sustainable development and climate change. The methodology is based on the collection of historical data on rainfall in the city, articles, technical standard NS-166, 2018, among other sources, confi iabl es, to analyze the information and subsequently define the appropriate type of SUDS in urban areas, according to the particularities of each type and the areaEspecializació

Les effets d’un risque démographique sur l’épargne.

Cet article étudie les effets sur l'épargne d'une incertitude sur le taux de croissance de la population dans un modèle à générations imbriquées. Nous montrons que les hypothèses nécessaires à la formation d'une épargne individuelle de précaution ne suffisent pas dans un cadre d'équilibre général. Le motif de précaution ne permet plus à lui seul ainsi de déterminer l'influence d'un accroissement du risque sur l'épargne d'équilibre.

Multiple chemo-genetic interactions between a toxic metabolite and the ubiquitin pathway in yeast

International audienc

Identification of Yeast and Human 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAr) Transporters

International audienc

Disruption of Nucleotide Homeostasis by the Antiproliferative Drug 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside Monophosphate (AICAR)

International audienceBackground: AICAR is a potent anti-proliferative compound, but the basis of its cytotoxicity is poorly understood. Results: AICAR affects NTP homeostasis in a carbon source-dependent way, in both yeast and human cells. Conclusion: AICAR balance with nucleotides triphosphate is critical for its in vivo effects. Significance: AICAR is significantly more cytotoxic on glucose and thus potentially targets cells prone to Warburg effect

Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model

Increasing evidence involves sustained pro-inflammatory microglia activation in the pathogenesis of different neurodegenerative diseases, particularly Parkinson's disease (PD). We recently uncovered a completely novel and unexpected role for caspase-8 and its downstream substrates caspase-3/7 in the control of microglia activation and associated neurotoxicity to dopaminergic cells. To demonstrate the genetic evidence, mice bearing a floxed allele of CASP8 were crossed onto a transgenic line expressing Cre under the control of Lysozyme 2 gene. Analysis of caspase-8 gene deletion in brain microglia demonstrated a high efficiency in activated but not in resident microglia. Mice were challenged with lipopolysaccharide, a potent inducer of microglia activation, or with MPTP, which promotes specific dopaminergic cell damage and consequent reactive microgliosis. In neither of these models, CASP8 deletion appeared to affect the overall number of microglia expressing the pan specific microglia marker, Iba1. In contrast, CD16/CD32 expression, a microglial pro-inflammatory marker, was found to be negatively affected upon CASP8 deletion. Expression of additional proinflammatory markers were also found to be reduced in response to lipopolysaccharide. Of importance, reduced pro-inflammatory microglia activation was accompanied by a significant protection of the nigro-striatal dopaminergic system in the MPTP mouse model of PD.España Ministerio de Economía y Competitividad SAF2012-39029España Andalucía Junta de Andalucia P10-CTS-649

Caspase-8 inhibition represses initial human monocyte activation in septic shock model

In septic patients, the onset of septic shock occurs due to the over-activation of monocytes. We tested the therapeutic potential of directly targeting innate immune cell activation to limit the cytokine storm and downstream phases. We initially investigated whether caspase-8 could be an appropriate target given it has recently been shown to be involved in microglial activation. We found that LPS caused a mild increase in caspase-8 activity and that the caspase-8 inhibitor IETD-fmk partially decreased monocyte activation. Furthermore, caspase-8 inhibition induced necroptotic cell death of activated monocytes. Despite inducing necroptosis, caspase-8 inhibition reduced LPS-induced expression and release of IL-1β and IL-10. Thus, blocking monocyte activation has positive effects on both the pro and anti-inflammatory phases of septic shock. We also found that in primary mouse monocytes, caspase-8 inhibition did not reduce LPS-induced activation or induce necroptosis. On the other hand, broad caspase inhibitors, which have already been shown to improve survival in mouse models of sepsis, achieved both. Thus, given that monocyte activation can be regulated in humans via the inhibition of a single caspase, we propose that the therapeutic use of caspase-8 inhibitors could represent a more selective alternative that blocks both phases of septic shock at the source.Unión Europea, Ministerio de Economía y Competitividad SAF2012-39029Unión Europea, Ministerio de Economía y Competitividad SAF2015-64171REspaña,Junta de Andalucía P10-CTS-649

Consequences of Atlantification on a Zooplanktivorous Arctic Seabird

Global warming, combined with an increasing influence of Atlantic Waters in the European Arctic, are causing a so-called Atlantification of the Arctic. This phenomenon is affecting the plankton biomass and communities with potential consequences for the upper trophic levels. Using long-term data (2005-2020) from a high Arctic zooplanktivorous seabird, the little auk (Alle alle), we tested the hypothesis that the Atlantification affects its diet, body condition and demography. We based our study on data collected in three fjords in West Spitsbergen, Svalbard, characterized by distinct oceanographic conditions. In all three fjords, we found a positive relationship between the inflow of Atlantic Waters and the proportion of Atlantic prey, notably of the copepod Calanus finmarchicus, in the little auk chick diet. A high proportion of Atlantic prey was negatively associated with adult body mass (though the effect size was small) and with chick survival (only in one fjord where chick survival until 21 days was available). We also found a negative and marginally significant effect of the average proportion of Atlantic prey in the chick diet on chick growth rate (data were available for one fjord only). Our results suggest that there are fitness costs for the little auk associated with the Atlantification of West Spitsbergen fjords. These costs seem especially pronounced during the late phase of the chick rearing period, when the energetic needs of the chicks are the highest. Consequently, even if little auks can partly adapt their foraging behaviour to changing environmental conditions, they are negatively affected by the ongoing changes in the Arctic marine ecosystems. These results stress the importance of long-term monitoring data in the Arctic to improve our understanding of the ongoing Atlantification and highlight the relevance of using seabirds as indicators of environmental change.publishedVersio