Yohann Grondin

Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice

BACKGROUND Short-term dietary restriction (DR) without malnutrition preconditions against surgical stress in rodents; however, the nutritional basis and underlying nutrient/energy-sensing pathways remain poorly understood. OBJECTIVES We investigated the relative contribution of protein restriction (PR) vs. calorie restriction (CR) to protection from renal ischemia reperfusion injury (IRI) and changes in organ-autonomous nutrient/energy-sensing pathways and hormones underlying beneficial effects. METHODS Mice were preconditioned on experimental diets lacking total calories (0-50% CR) or protein/essential amino acids (EAAs) vs. complete diets consumed ad libitum (AL) for 1 wk before IRI. Renal outcome was assessed by serum markers and histology and integrated over a 2-dimensional protein/energy landscape by geometric framework analysis. Changes in renal nutrient/energy-sensing signal transduction and systemic hormones leptin and adiponectin were also measured. The genetic requirement for amino acid sensing via general control non-derepressible 2 (GCN2) was tested with knockout vs. control mice. The involvement of the hormone leptin was tested by injection of recombinant protein vs. vehicle during the preconditioning period. RESULTS CR-mediated protection was dose dependent up to 50% with maximal 2-fold effect sizes. PR benefits were abrogated by EAA re-addition and additive with CR, with maximal benefits at any given amount of CR occurring with a protein-free diet. GCN2 was not required for functional benefits of PR. Activation and repression of nutrient/energy-sensing kinases, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1), respectively, on PR reflected a state of negative energy balance, paralleled by 13% weight loss and an 87% decrease in leptin, independent of calorie intake. Recombinant leptin administration partially abrogated benefits of dietary preconditioning against renal IRI. CONCLUSIONS In male mice, PR and CR both contributed to the benefits of short-term DR against renal IRI independent of GCN2 but partially dependent on reduced circulating leptin and coincident with AMPK activation and mTORC1 repression.

Computing with bacterial constituents, cells and populations: from bioputing to bactoputing

The relevance of biological materials and processes to computing—aliasbioputing—has been explored for decades. These materials include DNA, RNA and proteins, while the processes include transcription, translation, signal transduction and regulation. Recently, the use of bacteria themselves as living computers has been explored but this use generally falls within the classical paradigm of computing. Computer scientists, however, have a variety of problems to which they seek solutions, while microbiologists are having new insights into the problems bacteria are solving and how they are solving them. Here, we envisage that bacteria might be used for new sorts of computing. These could be based on the capacity of bacteria to grow, move and adapt to a myriad different fickle environments both as individuals and as populations of bacteria plus bacteriophage. New principles might be based on the way that bacteria explore phenotype space via hyperstructure dynamics and the fundamental nature of the cell cycle. This computing might even extend to developing a high level language appropriate to using populations of bacteria and bacteriophage. Here, we offer a speculative tour of what we term bactoputing, namely the use of the natural behaviour of bacteria for calculating.

Genetic Polymorphisms Associated with Hearing Threshold Shift in Subjects during First Encounter with Occupational Impulse Noise

Noise-induced hearing loss (NIHL) is the most significant occupational health issue worldwide. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with hearing threshold shift in young males undergoing their first encounter with occupational impulse noise. We report a significant association of SNP rs7598759 (p < 5 x 10-7; p = 0.01 after permutation and correction; Odds Ratio = 12.75) in the gene coding for nucleolin, a multifunctional phosphoprotein involved in the control of senescence and protection against apoptosis. Interestingly, nucleolin has been shown to mediate the anti-apoptotic effect of HSP70, a protein found to prevent ototoxicity and whose polymorphisms have been associated with susceptibility to NIHL. Increase in nucleolin expression has also been associated with the prevention of apoptosis in cells undergoing oxidative stress, a well-known metabolic sequela of noise exposure. To assess the potential role of nucleolin in hearing loss, we tested down-regulation of nucleolin in cochlear sensory cells HEI-OC1 under oxidative stress conditions and report increased sensitivity to cisplatin, a chemotherapeutic drug with ototoxic side effects. Additional SNPs were found with suggestive association (p < 5 x 10-4), of which 7 SNPs were located in genes previously reported to be related to NIHL and 43 of them were observed in 36 other genes previously not reported to be associated with NIHL. Taken together, our GWAS data and in vitro studies reported herein suggest that nucleolin is a potential candidate associated with NIHL in this population.

Pulmonary delivery of d-methionine is associated with an increase in ALCAR and glutathione in cochlear fluids

In animals, hearing loss resulting from cochlear mechanosensory cell damage can be mitigated by antioxidants such as d-methionine (d-met) and acetyl-l-carnitine (ALCAR). The systemic routes of administration of these compounds, that must of necessity transit trough the cochlear fluids, may affect the antioxidant levels in the cochlea and the resulting oto-protective effect. In this study, we analyzed the pharmacokinetics of [(14)C]d-met in the cochlea and four other tissues after intratracheal (IT), intranasal (IN), and oral by gavage (OG) administration and compared it to intravenous administration (IV). We then analyzed the effect of these four routes on the antioxidant content of the cochlear fluids after d-met or ALCAR administration, by liquid chromatography/mass spectrometry. Our results showed that the concentration of methionine and ALCAR in cochlear fluids significantly increased after their respective systemic administration. Interestingly, d-met administration also contributed to an increase of ALCAR. Our results also showed that the delivery routes differently affected the bioavailability of administered [(14)C]d-met as well as the concentrations of methionine, ALCAR and the ratio of oxidized to reduced glutathione. Overall, pulmonary delivery via IT administration achieved high concentrations of methionine, ALCAR, and oxidative-related metabolites in cochlear fluids, in some cases surpassing IV administration, while IN route appeared to be the least efficacious. To our knowledge, this is the first report of the direct measurements of antioxidant levels in cochlear fluids after their systemic administration. This report also demonstrates the validity of the pulmonary administration of antioxidants and highlights the different contributions of d-met and ALCAR allowing to further investigate their impact on oxidative stress in the cochlear microenvironment.

The correlation between architecture and mRNA abundance in the genetic regulatory network of Escherichia coli.

BackgroundTwo aspects of genetic regulatory networks are the static architecture that describes the overall connectivity between the genes and the dynamics that describes the sequence of genes active at any one time as deduced from mRNA abundances. The nature of the relationship between these two aspects of these networks is a fundamental question. To address it, we have used the static architecture of the connectivity of the regulatory proteins of Escherichia coli to analyse their relationship to the abundance of the mRNAs encoding these proteins. In this we build on previous work which uses Boolean network models, but impose biological constraints that cannot be deduced from the mRNA abundances alone.ResultsFor a cell population of E. coli, we find that there is a strong and statistically significant linear dependence between the abundance of mRNA encoding a regulatory protein and the number of genes regulated by this protein. We use this result, together with the ratio of regulatory repressors to promoters, to simulate numerically a genetic regulatory network of a single cell. The resulting model exhibits similar correlations to that of E. coli.ConclusionThis analysis clarifies the relationship between the static architecture of a regulatory network and the consequences for the dynamics of its pattern of mRNA abundances. It also provides the constraints on the architecture required to construct a model network to simulate mRNA production.

Complex 9p Rearrangement in an XY Patient With Ambiguous Genitalia and Features of Both 9p Duplication and Deletion

Complex 9p Rearrangement in an XY Patient With Ambiguous Genitalia and Features of Both 9p Duplication and Deletion Vivian Alejandra Neira, Carlos C ordova-Fletes,* Yohann Grondin, Azubel Ramirez-Velazco, Luis E. Figuera, Roc io Ort iz-L opez, and Michela Barbaro Divisi on de Gen etica, Centro de Investigaci on Biom edica de Occidente, CMNO-IMSS, Guadalajara, M exico Doctorado en Gen etica Humana, Universidad de Guadalajara, Guadalajara, Jalisco, M exico Unidad de Biolog ia Molecular, Gen omica y Secuenciaci on, Centro de Investigaci on y Desarrollo en Ciencias de la Salud, Universidad Aut onoma de Nuevo Le on, Monterrey, Nuevo Le on, M exico Facultad deMedicina, DepartamentodeBioqu imicayMedicinaMolecular, UniversidadAut onomadeNuevoLe on,Monterrey, NuevoLe on,M exico Facultad de Ciencias Biol ogicas, Universidad Aut onoma de Nuevo Le on, Monterrey, Nuevo Le on, M exico Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

Networks as constrained thermodynamic systems

We show how a network of interconnections between nodes can be constructed to have a specified distribution of nodal degrees. This is achieved by treating the network as a thermodynamic system subject to constraints and then rewiring the system to maintain the constraints while increasing the entropy. The general construction is given and illustrated by the simple example of an exponential network. By considering the constraints as a cost function analogous to an internal energy, we obtain a characterisation of the correspondence between the intensive and extensive variables of the network. Applied to networks in living organisms, this approach may lead to macroscopic variables useful in characterising living systems.

DNA Movies and Panspermia

There are several ways that our species might try to send a message to another species separated from us by space and/or time. Synthetic biology might be used to write an epitaph to our species, or simply “Kilroy was here”, in the genome of a bacterium via the patterns of either (1) the codons to exploit Lifes non-equilibrium character or (2) the bases themselves to exploit Lifes quasi-equilibrium character. We suggest here how DNA movies might be designed using such patterns. We also suggest that a search for mechanisms to create and preserve such patterns might lead to a better understanding of modern cells. Finally, we argue that the cutting-edge microbiology and synthetic biology needed for the Kilroy project would put origin-of-life studies in the vanguard of research.

Life at the “edge of chaos” in a genetic model

Genetic regulatory networks are often represented as Boolean networks and characterised by average parameters such as internal homogeneity (the probability that a node outputs a 1). Here we present a different formalism in which the nodes interact through positive and negative links with the state of the nodes determined by a single, general logical function. The main parameter of the system is in this case the proportion of negative links. At a critical value of the proportion of negative links the networks display a phase transition from a periodic to a chaotic regime The proportion of negative links in the bacterium Escherichia coli corresponds in our model to a range where the network behaves at the edge of chaos.