Molecular mechanisms of projection neuron production and maturation in the developing cerebral cortex

The cerebral cortex is a brain structure unique to mammals and highly adapted to process complex information. Through multiple developmental steps, the cerebral cortex is assembled as a huge diversity of neurons comprising a complex laminar structure, and with both local and long-distance connectivity within the nervous system. Key processes must take place during its construction, including: (i) regulation of the correct number of neurons produced by progenitor cells, (ii) temporal and spatial generation of neuronal diversity, and (iii) control of neuron migration and laminar positioning as well as terminal differentiation within the mature cortex. Here, we seek to highlight recent cellular and molecular findings underlying these sequential steps of neurogenesis, cell fate specification and migration during cortical development, with particular emphasis on cortical projection neurons.     

Calibration plot for proteomics: A graphical tool to visually check the assumptions underlying FDR control in quantitative experiments

In MS‐based quantitative proteomics, the FDR control (i.e. the limitation of the number of proteins that are wrongly claimed as differentially abundant between several conditions) is a major postanalysis step. It is classically achieved thanks to a specific statistical procedure that computes the adjusted p‐values of the putative differentially abundant proteins. Unfortunately, such adjustment is conservative only if the p‐values are well‐calibrated; the false discovery control being spuriously underestimated otherwise. However, well‐calibration is a property that can be violated in some practical cases. To overcome this limitation, we propose a graphical method to straightforwardly and visually assess the p‐value well‐calibration, as well as the R codes to embed it in any pipeline. All MS data have been deposited in the ProteomeXchange with identifier PXD002370 ( http://proteomecentral.proteomexchange.org/dataset/PXD002370 ).     

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.     

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

Background  

Two 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.     

A Langmuir film approach to elucidating interactions in lipid membranes: 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine/cholesterol/metal cation systems

The interactions between two membrane lipids, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) and cholesterol (CHOL), were studied in Langmuir films using surface pressure isotherms and Brewster angle microscopy. The DPPE/CHOL interactions were probed for chosen monolayer and subphase (Na(+), Ca(2+)) composition at 20, 25, and 30 degrees C. The results obtained show that DPPE and CHOL are miscible for the cholesterol mol fractions x(CHOL)=0.3-0.5. Cholesterol induces condensation of the DPPE monolayers. The most significant condensation of the DPPE/CHOL monolayers was observed in the presence of Ca(2+) ions in the subphase at x(CHOL)=0.4. The negative deviation of the molecular surface area (MMA) additivity from the ideal behavior together with negative values of excess free enthalpy of mixing in the monolayers were interpreted in terms of attractive interactions between lipid molecules.     

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.     

Contribution of Genome-Wide Association Studies to Scientific Research: A Bibliometric Survey of the Citation Impacts of GWAS and Candidate Gene Studies Published during the Same Period and in the Same Journals

In genetic epidemiology, genome-wide association studies (GWAS) are used to rapidly scan a large set of genetic variants and thus to identify associations with a particular trait or disease. The GWAS philosophy is different to that of conventional candidate-gene-based approaches, which directly test the effects of genetic variants of potentially contributory genes in an association study. One controversial question is whether GWAS provide relevant scientific outcomes by comparison with candidate-gene studies. We thus performed a bibliometric study using two citation metrics to assess whether the GWAS have contributed a capital gain in knowledge discovery by comparison with candidate-gene approaches. We selected GWAS published between 2005 and 2009 and matched them with candidate-gene studies on the same topic and published in the same period of time. We observed that the GWAS papers have received, on average, 30±55 citations more than the candidate gene papers, 1 year after their publication date, and 39±58 citations more 2 years after their publication date. The GWAS papers were, on average, 2.8±2.4 and 2.9±2.4 times more cited than expected, 1 and 2 years after their publication date; whereas the candidate gene papers were 1.5±1.2 and 1.5±1.4 times more cited than expected. While the evaluation of the contribution to scientific research through citation metrics may be challenged, it cannot be denied that GWAS are great hypothesis generators, and are a powerful complement to candidate gene studies.