GABA action in immature neocortical neurons directly depends on the availability of ketone bodies

In the early postnatal period, energy metabolism in the suckling rodent brain relies to a large extent on metabolic pathways alternate to glucose such as the utilization of ketone bodies (KBs). However, how KBs affect neuronal excitability is not known. Using recordings of single NMDA and GABA-activated channels in neocortical pyramidal cells we studied the effects of KBs on the resting membrane potential ( E _m) and reversal potential of GABA-induced anionic currents ( E _GABA), respectively. We show that during postnatal development (P3–P19) if neocortical brain slices are adequately supplied with KBs, E _m and E _GABA are both maintained at negative levels of about −83 and −80 mV, respectively. Conversely, a KB deficiency causes a significant depolarization of both E _m (>5 mV) and E _GABA (>15 mV). The KB-mediated shift in E _GABA is largely determined by the interaction of the NKCC1 cotransporter and Cl⁻/HCO₃ transporter(s). Therefore, by inducing a hyperpolarizing shift in E _m and modulating GABA signaling mode, KBs can efficiently control the excitability of neonatal cortical neurons.     

Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.     

The evolutionary epidemiology of multilocus drug resistance

The evolution of resistance to drugs is a major public health concern as it erodes the efficacy of our therapeutic arsenal against bacterial, viral, and fungal pathogens. Increasingly, it is recognized that the evolution of resistance involves genetic changes at more than one locus, both in cases where multiple changes are required to obtain high-level resistance, and where compensatory changes at secondary loci ameliorate the costs of resistance. Similarly, multiple loci are often involved in the evolution of multidrug resistance. There has been widespread interest recently in understanding the evolutionary consequences of multilocus resistance, with many empirical studies documenting extensive patterns of genetic interactions (i.e., epistasis) among the loci involved. Currently, however, there are few general theoretical results available that bridge the gap between classical multilocus population genetics and mathematical epidemiology. Here, such theory is developed to shed new light on these previous studies, and to provide further guidance on the type of data required to predict the evolution of pathogens in response to drug pressure. Our results reveal the importance of feedbacks between the epidemiological and evolutionary dynamics, and illustrate how these feedbacks can be exploited to control resistance. In particular, we show how interventions such as social distancing and isolation can influence rates of recombination, and how this then can slow the spread of multilocus resistance and increase the likelihood of reversion to drug sensitivity once drug therapy has ceased.     

FLU, a negative feedback regulator of tetrapyrrole biosynthesis, is physically linked to the final steps of the Mg(++)-branch of this pathway

Regulation of tetrapyrrole biosynthesis in higher plants has been attributed to negative feedback control. Two effectors of feedback inhibition have been identified, heme and the FLU protein. Inhibition by heme implicates the Fe-branch via regulation of the initial step of tetrapyrrole synthesis. In the present work a FLU-containing chloroplast membrane complex was identified, that besides FLU comprises the four enzymes catalyzing the final steps of chlorophyll synthesis. The results support the notion that FLU links chlorophyll synthesis and the target of feedback control, glutamyl-tRNA reductase, thereby allowing also the Mg-branch to control the initial step of tetrapyrrole synthesis.     

A non-Mendelian MAPK-generated hereditary unit controlled by a second MAPK pathway in Podospora anserina

The Podospora anserina PaMpk1 MAP kinase (MAPK) signaling pathway can generate a cytoplasmic and infectious element resembling prions. When present in the cells, this C element causes the crippled growth (CG) cell degeneration. CG results from the inappropriate autocatalytic activation of the PaMpk1 MAPK pathway during growth, whereas this cascade normally signals stationary phase. Little is known about the control of such prion-like hereditary units involved in regulatory inheritance. Here, we show that another MAPK pathway, PaMpk2, is crucial at every stage of the fungus life cycle, in particular those controlled by PaMpk1 during stationary phase, which includes the generation of C. Inactivation of the third P. anserina MAPK pathway, PaMpk3, has no effect on the development of the fungus. Mutants of MAPK, MAPK kinase, and MAPK kinase kinase of the PaMpk2 pathway are unable to present CG. This inability likely relies upon an incorrect activation of PaMpk1, although this MAPK is normally phosphorylated in the mutants. In PaMpk2 null mutants, hyphae are abnormal and PaMpk1 is mislocalized. Correspondingly, stationary phase differentiations controlled by PaMpk1 are defective in the mutants of the PaMpk2 cascade. Constitutive activation of the PaMpk2 pathway mimics in many ways its inactivation, including an effect on PaMpk1 localization. Analysis of double and triple mutants inactivated for two or all three MAPK genes undercover new growth and differentiation phenotypes, suggesting overlapping roles. Our data underscore the complex regulation of a prion-like element in a model organism.     

2-D Structure of the A Region of Xist RNA and Its Implication for PRC2 Association

In placental mammals, inactivation of one of the X chromosomes in female cells ensures sex chromosome dosage compensation. The 17 kb non-coding Xist RNA is crucial to this process and accumulates on the future inactive X chromosome. The most conserved Xist RNA region, the A region, contains eight or nine repeats separated by U-rich spacers. It is implicated in the recruitment of late inactivated X genes to the silencing compartment and likely in the recruitment of complex PRC2. Little is known about the structure of the A region and more generally about Xist RNA structure. Knowledge of its structure is restricted to an NMR study of a single A repeat element. Our study is the first experimental analysis of the structure of the entire A region in solution. By the use of chemical and enzymatic probes and FRET experiments, using oligonucleotides carrying fluorescent dyes, we resolved problems linked to sequence redundancies and established a 2-D structure for the A region that contains two long stem-loop structures each including four repeats. Interactions formed between repeats and between repeats and spacers stabilize these structures. Conservation of the spacer terminal sequences allows formation of such structures in all sequenced Xist RNAs. By combination of RNP affinity chromatography, immunoprecipitation assays, mass spectrometry, and Western blot analysis, we demonstrate that the A region can associate with components of the PRC2 complex in mouse ES cell nuclear extracts. Whilst a single four-repeat motif is able to associate with components of this complex, recruitment of Suz12 is clearly more efficient when the entire A region is present. Our data with their emphasis on the importance of inter-repeat pairing change fundamentally our conception of the 2-D structure of the A region of Xist RNA and support its possible implication in recruitment of the PRC2 complex.     

Interaction of climate,demography and genetics: a ten-year study of <Emphasis Type="Italic">Brassica insularis</Emphasis>, a narrow endemic Mediterranean species

Long-term demographic surveys, needed to obtain accurate information on population dynamics and efficiently manage rare species, are still very scarce. Matrix population models are useful tools to identify key demographic transitions and thus help setting up conservation actions. Furthermore, the combination of ecological, demographic and genetic data is likely to improve the identification of the threats acting upon populations and help conservation decisions. In this paper we illustrate the power of this approach on Brassica insularis, a Mediterranean endemic plant species, rare and endangered in Corsica (France). In four populations of this species, a long-term demographic survey (2000–2009), genetic analyses (in 2000 and 2009) and survey of ecological variables (climatic variables, competition and herbivory) were performed. By using both deterministic and stochastic matrix model analyses, we assessed the viability of each population and tested for both spatial and temporal variations in demographic vital rates. Populations exhibited differing demographic behaviours and environmental stochasticity occurred in populations. Significant correlations between climatic variables and vital rates were detected. Stochastic simulations suggested that three out of the four populations studied might present a high risk of extinction on the short-term and should actively be managed, or at least surveyed. It could be, however, that two of these populations are experiencing density-dependent regulation, rather than being declining. Microsatellite diversity was slightly reduced in a single population and similar in the three others, consistently with expectations based on population census size and geographic area, as well as with diversity at the S-locus observed in 2000. The combination of all data led to specific recommendations for managing each population. We discuss the implications for conservation of such a general approach.     

Attraction Basins as Gauges of Robustness against Boundary Conditions in Biological Complex Systems

One fundamental concept in the context of biological systems on which researches have flourished in the past decade is that of the apparent robustness of these systems, i.e., their ability to resist to perturbations or constraints induced by external or boundary elements such as electromagnetic fields acting on neural networks, micro-RNAs acting on genetic networks and even hormone flows acting both on neural and genetic networks. Recent studies have shown the importance of addressing the question of the environmental robustness of biological networks such as neural and genetic networks. In some cases, external regulatory elements can be given a relevant formal representation by assimilating them to or modeling them by boundary conditions. This article presents a generic mathematical approach to understand the influence of boundary elements on the dynamics of regulation networks, considering their attraction basins as gauges of their robustness. The application of this method on a real genetic regulation network will point out a mathematical explanation of a biological phenomenon which has only been observed experimentally until now, namely the necessity of the presence of gibberellin for the flower of the plant Arabidopsis thaliana to develop normally.