Inflammatory diseases: is ubiquitinated NEMO at the hub?

Many patients with Crohn's disease carry mutations in NOD2, a molecule that can both activate and attenuate the pro-inflammatory effects of NF-kappa B. Recent studies implicate NOD2-induced ubiquitination of the NF-kappa B regulator NEMO as a potential means of manipulating the NF-kappa B signal.     

Deciphering translocations from relicts in Baranof Island mountain goats: is an endemic genetic lineage at risk?

Human-mediated movement of wildlife is a common practice in North America. Some translocations have occurred where local populations were thought to be extinct or simply not present. In Alaska’s Alexander Archipelago, mountain goats (Oreamnos americanus) were not considered indigenous and were introduced to Baranof Island in 1923. However, a range-wide survey using microsatellites and mitochondrial DNA revealed a distinct genetic subpopulation endemic to the island. In this study, we attempted to clarify the evolutionary history of the mountain goats on Baranof Island by examining sequence variation in the Y chromosome. We first screened five regions of the Y chromosome in a subset of mountain goats from across their native range. We detected a single polymorphic site in the SRY promoter, and subsequently sequenced this gene in 100 mountain goats. A unique Y chromosome polymorphism was restricted to Baranof Island and an area near Haines, Alaska, and not detected in the presumed source population. An island-to-mainland dispersal scenario from a cryptic refugial population during the retreat of the Cordilleran ice-sheet would account for this distribution. Overall, these data support the hypothesis that a glacial relict population of mountain goats was present on the island prior to introduction. Based on a combination of mitochondrial, microsatellite, and Y chromosome data, we recommend recognizing Baranof Island mountain goats as an evolutionary significant unit.     

Life at low temperatures: is disorder the driving force?

The thermodynamic characterization of various biological systems from psychrophiles points to a larger entropic contribution when compared to the corresponding mesophilic or (hyper) thermophilic counterparts, either at the level of the macromolecules (thermodynamic and kinetic stabilities) or of their function (ligand binding, catalytic activity). It is suggested here that in an environment characterized by a low heat content (enthalpy) and at temperatures that strongly slowdown molecular motions, the cold-adapted biological systems rely on a larger disorder to maintain macromolecular dynamics and function. Such pre-eminent involvement of entropy is observed in the experimental results and, from a macroscopic point of view, is also reflected for instance by the steric hindrances introduced by cis-unsaturated and branched lipids to maintain membrane fluidity, by the loose conformation of psychrophilic proteins or by the local destabilization of tRNA by dihydrouridine in psychrophilic bacteria.     

Mutation processes at the protein level: is Lamarck back?

The experimental evidence accumulated for the last half of the century clearly suggests that inherited variation is not restricted to the changes in genomic sequences. The prion model, originally based on unusual transmission of certain neurodegenerative diseases in mammals, provides a molecular mechanism for the template-like reproduction of alternative protein conformations. Recent data extend this model to protein-based genetic elements in yeast and other fungi. Reproduction and transmission of yeast protein-based genetic elements is controlled by the "prion replication" machinery of the cell, composed of the protein helpers responsible for the processes of assembly and disassembly of protein structures and multiprotein complexes. Among these, the stress-related chaperones of Hsp100 and Hsp70 groups play an important role. Alterations of levels or activity of these proteins result in "mutator" or "antimutator" affects in regard to protein-based genetic elements. "Protein mutagens" have also been identified that affect formation and/or propagation of the alternative protein conformations. Prion-forming abilities appear to be conserved in evolution, despite the divergence of the corresponding amino acid sequences. Moreover, a wide variety of proteins of different origins appear to possess the ability to form amyloid-like aggregates, that in certain conditions might potentially result in prion-like switches. This suggests a possible mechanism for the inheritance of acquired traits, postulated in the Lamarckian theory of evolution. The prion model also puts in doubt the notion that cloned animals are genetically identical to their genome donors, and suggests that genome sequence would not provide a complete information about the genetic makeup of an organism.     

Human adult olfactory bulb neurogenesis? Novelty is the best policy

There is ongoing controversy as to whether the understanding of adult mammalian neurogenesis gained from rodent studies is applicable to humans. In this issue of Neuron, Bergmann et al. (2012) propose that adult human olfactory bulb neurogenesis with long-term neuronal survival is extremely limited.     

Human nucleolus organizers: the satellites or the stalks?

A silver-staining technique specific for demonstrating nucleolus organizer regions (NOR) showed that the achromatic stalks of the 10 acrocentric autosomes of the human complement represent the NORs. Some variability in number of stained stalks is observed from cell-to-cell and from individual-to-individual. The silver-stained masses may extend beyond the stalks and cover the satellites, especially in chromosomes with short stalks or minute satellites.     

Reciprocal translocations: a trap for cytogenetists?

We report four cases of subjects with phenotypic abnormalities and mental retardation associated with apparently balanced translocations, two inherited and two de novo, which showed, by molecular analysis, a hidden complexity. All the cases have been analyzed with different molecular techniques, including array-CGH, and in two of them the translocation breakpoints have been defined at the level of base pairs via studies in somatic hybrids containing single derivative chromosomes. We demonstrated that all the translocations were in fact complex rearrangements and that an imbalance was present in three of them, thus accounting for the phenotypic abnormalities. In one case, a Prader–Willi subject, we were not able to determine the molecular cause of his phenotype. This study, while confirming previous data showing unexpected complexity in translocations, further underscores the need for molecular investigations before taking for granted an apparently simple cytogenetic interpretation.R. Ciccone and R. Giorda contributed equally to this work     

What is the best approach to reducing birth defects associated with isotretinoin?

BACKGROUND TO THE DEBATE: Isotretinoin is an effective treatment for severe acne, a condition which can be physically, emotionally, and socially disabling. Because the drug is teratogenic, causing severe birth defects, women taking the drug are directed to avoid pregnancy. In the United States, a series of risk reduction programs have been implemented that aim to prevent pregnant women from taking the drug and to prevent women taking it from getting pregnant. The most recent, and most stringent, is an Internet-based, performance-linked system called iPLEDGE, which tries to ensure that the drug is dispensed only when there is documentary proof that the patient is not pregnant and is using two forms of birth control. Is iPLEDGE the best way to reduce isotretinoin birth defects, or is it an unproven and overly burdensome system?     

The structures at the termini of chromosomes: what is there hidden under the cap ?

The telomeres are the nucleoproteic structures present at the ends of eukaryotic chromosomes. One can compare them to the protective ends of a shoelace; when the ends get eroded, the shoelace disintegrates and we dispose of it. The same thus applies to the chromosomes; when telomeres reach a critical threshold for function, the genome becomes unstable and the cell senesces. Therefore, telomeres, and particularly their terminal DNA structures, are critical for the integrity of the genome.     

Growth and survivorship in juvenile woodlice: is birth mass important?

Growth and survivorship of individually reared offspring of the woodlice (Isopoda Oniscidae) Porcellionides pruinosus (Brandt) and Aphiloscia vilis (Budde-Lund) were measured under laboratory conditions These measures of offspring fitness were compared to birth mass, which is a realistic measure of parental investment in offspring for these species, to test a key assumption of life history theory that an increase in resource allocation to offspring will increase offspring fitness In both species birth mass had no significant effect on survivorship to 60 days and in P pruinosus birth mass did not correlate with mass at 15, 30 or 45 days after birth In A vilis larger young at birth had a slight growth advantage to 15 days but not thereafter There appears to be little effect of birth mass on offspring fitness despite a considerable range in birth mass within broods In these species high variance in juvenile growth may spread subsequent reproductive effort and avoid risks of total reproductive failure     

Cardiac adrenoceptors at low temperature: what is the experimental evidence for the adrenoceptor interconversion hypothesis?

Isolated heart preparations of frog and rat were used to test the validity of the adrenoceptor interconversion hypothesis. This hypothesis claims that low temperature converts the inotropic beta-adrenoceptors in isolated frog and rat heart to alpha-adrenoceptors. The present results do not support the adrenoceptor interconversion hypothesis. In the isolated frog ventricle, lowering the temperature from 24 C to 14 C did not significantly alter the inotropic potency of the sympathomimetic drugs isoprenaline, epinephrine, and phenylephrine and did not reduce the potency of the beta-adrenoceptor blocking drug propranolol as an epinephrine antagonist. In the isolated rat left atrium, lowering the temperature from 31 C to 17-19 C did not significantly change the inotropic potency of isoprenaline, norepinephrine and phenylephrine, did not diminish the potency of propranolol, and did not increase the potency of the alpha-adrenoceptor blocking drug phentolamine.--Benfey, B. G. Cardiac adrenoceptors at low temperature; what is the experimental evidence for the adrenoceptor interconversion hypothesis?     

What is the shape of the distribution of protein conformations at equilibrium?

According to the thermodynamic hypothesis, the native state of proteins is that in which the free energy of the system is at its lowest, so that at normal temperature and pressure, proteins evolve to that state. We selected four proteins representative of each of the four classes, and for each protein make four simulations, one starting from the native structure and the other three starting from the structure obtained by threading the sequence of one protein onto the native backbone fold of the other three proteins. Because of their large conformational distances with respect to the native structure, the three alternative initial structures cannot be considered as local minima within the native ensemble of the corresponding protein. As expected, the initial native states are preserved in the .5?μs simulations performed here and validate the simulations. On the other hand, when the initial state is not native, an analysis of the trajectories does not reveal any evolution towards the native state, during that time. These results indicate that the distribution of protein conformations is multipeak shaped, so that apart from the peak corresponding to the native state, there are other peaks associated with average structures that are very different from the native and that can last as long as the native state.     

How is bursting mode maintained under the action of exo- and endogenous factors?

The investigation is concerned with slow oscillations of the intracellular calcium concentration, fast oscillations of the membrane potential, and their interactions during bursting generation. The question associated with functioning of the bursting mode is considered: how is the condition of simultaneous existence of the slow and fast membrane potential oscillations (necessary for the bursting mode) realized under exo- and endogenous actions that result in changes in the neuron membrane parameters? To answer the question the regions of existence of fast, slow and bursting oscillations have been constructed on different parameter planes. The study has revealed that in spite of the fact the regions of the existence of the slow and fast oscillations are sensitive to parameter variations, the condition of the bursting mode existence remains due to invariance of the spatial vicinity of these regions. Furthermore, it has been demonstrated that there exists the possibility to enhance the maximal conductances of the calcium-dependent currents simultaneously such that even strong variations of their values do not induce changes of the oscillations mode (i.e. it remains bursting).