The evolution of the neocortex in mammals: how is phenotypic diversity generated?

Evolution of the mammalian neocortex is difficult to examine directly. For this reason, comparative studies and developmental studies are the best way of gaining insight into the evolutionary process. Comparative studies indicate that neocortical evolution is constrained, and that the types of systems-level modifications made to the neocortex are limited. Developmental studies of gene expression suggest that genetic contingencies set up aspects of cortical organization and connectivity, and that the complex spatial and temporal interactions of genes constrain development and evolution. Although genes obviously contribute to phenotypic variability, variability can also be achieved through alterations in the sensory receptor arrays, or changes in sensory driven activity. The intracellular mechanisms that enable phenotypic variability might evolve, but often the phenotypic characteristic in question is context-dependent.     

Mitochondrial uncoupling proteins--what is their physiological role?

The physiological functions of the mitochondrial uncoupling proteins (UCP2 and UCP3) are still under debate. There is, however, ample evidence to indicate that, in contrast to UCP1, they are not crucial for nonshivering thermogenesis and do not catalyze the basal proton conductance of mitochondria. Rather, there is good evidence that they increase mitochondrial proton conductance when activated by superoxide, reactive oxygen species derivatives such as hydroxynonenal, and other alkenals or their analogues. This review critically examines the evidence of the different proposed mechanisms for UCPs functions, namely (a) to export fatty acid anions from mitochondria, (b) to regulate insulin secretion in pancreatic beta-cells, and (c) to cause mild uncoupling and so diminish mitochondrial superoxide production, hence protecting against oxidative damage. Beside, available scientific data on UCP4 and UCP5/BMCP1 will be reviewed. However, their physiological function has not yet been established.     

The Mastodon in the room: how Darwinian is neo-Darwinism?

Failing to acknowledge substantial differences between Darwinism and neo-Darwinism impedes evolutionary biology. Darwin described evolution as the outcome of interactions between the nature of the organism and the nature of the conditions, each relatively autonomous but both historically and spatially intertwined. Furthermore, he postulated that the nature of the organism was more important than the nature of the conditions, leading to natural selection as an inevitable emergent product of biological systems. The neo-Darwinian tradition assumed a creative rather than selective view of natural selection, with the nature of the organism determined by the nature of the conditions, rendering the nature of the organism and temporal contingency unnecessary. Contemporary advances in biology, specifically the phylogenetics revolution and evo-devo, underscore the significance of history and the nature of the organism in biology. Darwinism explains more biology better, and better resolves apparent anomalies between living systems and more general natural laws, than does neo-Darwinism. The "extended" or "expanded" synthesis currently called for by neo-Darwinians is Darwinism.     

The shape of life: how much is written in stone?

Considering the enormous diversity of living organisms, representing mostly untapped resources for studying ecological, ontogenetic and phylogenetic patterns and processes, why should evolutionary biologists concern themselves with the remains of animals and plants that died out tens or even hundreds of millions of years ago? The reason is that important new insights into some of the most vexing evolutionary questions are being revealed at the interfaces of palaeontology, developmental biology and molecular biology. Attempts to synthesise information from these disciplines, however, often encounter their greatest hurdles in considerations of the radiation of the Metazoa. Ongoing challenges relate to the origins of body plans, the relationships of the metazoan phyla and the timing of major evolutionary radiations. Palaeontology not only has its own unique contributions to the study of evolutionary processes, but provides a lynchpin for many of the emerging techniques.     

Microtubules and cellulose microfibrils: how intimate is their relationship?

The recent visualization of the motion of fluorescently labeled cellulose synthase complexes by Alexander Paredez and colleagues heralds the start of a new era in the science of the plant cell wall. Upon drug-induced complete depolymerization, the movement of the complexes does not become disordered but instead establishes an apparently self-organized novel pattern. The ability to label complexes in vivo has provided us with the ideal tool for tackling the intriguing question of the underlying default mechanisms at play.     

How widespread is adult neurogenesis in mammals?

It is now widely accepted that neurogenesis occurs in two regions of the adult mammalian brain--the hippocampus and the olfactory bulb. There is evidence for adult neurogenesis in several additional areas, including the neocortex, striatum, amygdala and substantia nigra, but this has been difficult to replicate consistently other than in the damaged brain. The discrepancies may be due to variations in the sensitivity of the methods used to detect new neurons.     

The war of tools: how can NMR spectroscopists detect errors in their structures?

Protein structure determination by NMR methods has started in the mid-eighties and has been growing steadily since then. Ca. 14% of the protein structures deposited in the PDB have been solved by NMR. The evaluation of the quality of NMR structures however is still lacking a well-established practice. In this work, we examined various tools for the assessment of structural quality to ascertain the extent to which these tools could be applied to detect flaws in NMR structures. In particular, we investigated the variation in the scores assigned by these programs as a function of the deviation of the structures induced by errors in assignments or in the upper distance limits used. These perturbations did not distort radically the protein fold, but resulted in backbone RMS deviations up to 3 Å, which is in line with errors highlighted in the available literature. We found that it is quite difficult to discriminate the structures perturbed because of misassignments from the original ones, also because the spread in score over the conformers of the original bundle is relatively large. ?–ψ distributions and normality scores related to the backbone conformation and to the distribution of side-chain dihedral angles are the most sensitive indicators of flaws.     

Proline-rich domain in dynamin-2 has a low microtubule-binding activity: how is this activity controlled during mitosis in HeLa cells?

The large GTPase dynamin is strongly accumulated in the constricted area including midzonal microtubules of dividing cells. The proline-rich domain (PRD) of dynamin has been considered as a microtubule-binding domain. However, it remains unclear how PRD controls dynamin-microtubule interaction in mitotic cells. Here, we found that the microtubule-binding activity of PRD is low in dynamin-2. One of the mitosis-specific kinase activities to PRD in HeLa cells was identified as cyclin B-Cdc2 kinase. The kinase phosphorylated PRD at Ser(764) and/or Thr(766) and reduced the microtubule-binding activity of PRD. These results suggest that phosphorylation of PRD by cyclin B-Cdc2 kinase plays an important role to control dynamin-2-microtubule interaction in mitotic HeLa cells.     

The CFTR and ENaC debate: how important is ENaC in CF lung disease?

Cystic fibrosis (CF) is caused by the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) function and results in a respiratory phenotype that is characterized by dehydrated mucus and bacterial infections that affect CF patients throughout their lives. Much of the morbidity and mortality in CF results from a failure to clear bacteria from the lungs. What causes the defect in the bacterial clearance in the CF lung has been the subject of an ongoing debate. Here we discuss the arguments for and against the role of the epithelial sodium channel, ENaC, in the development of CF lung disease.     

The origins of axial patterning in the metazoa: how old is bilateral symmetry?

Bilateral symmetry is a hallmark of the Bilateria. It is achieved by the intersection of two orthogonal axes of polarity: the anterior-posterior (A-P) axis and the dorsal-ventral (D-V) axis. It is widely thought that bilateral symmetry evolved in the common ancestor of the Bilateria. However, it has long been known that members of the phylum Cnidaria, an outgroup to the Bilateria, also exhibit bilateral symmetry. Recent studies have examined the developmental expression of axial patterning genes in members of the phylum Cnidaria. Hox genes play a conserved role in patterning the A-P axis of bilaterians. Hox genes are expressed in staggered axial domains along the oral-aboral axis of cnidarians, suggesting that Hox patterning of the primary body axis was already present in the cnidarian-bilaterian ancestor. Dpp plays a conserved role patterning the D-V axis of bilaterians. Asymmetric expression of dpp about the directive axis of cnidarians implies that this patterning system is similarly ancient. Taken together, these result imply that bilateral symmetry had already evolved before the Cnidaria diverged from the Bilateria.     

Collagen-induced arthritis and related animal models: how much of their pathogenesis is auto-immune, how much is auto-inflammatory?

In this review, we discuss our studies on the pathogenesis of collagen-induced arthritis (CIA) and related mouse models for rheumatoid arthritis. Of note, these models invariably rely on the use of complete Freund's adjuvant (CFA). Our analysis has focused on explaining the dichotomous - either protective or disease-promoting - role of endogenous IFN-γ. Induction of a myelopoietic burst by CFA was identified as an important and underestimated factor in mediating the role of IFN-γ and other cytokines (IL-6, IL-17, GCP-2, RANK-L). Myelopoiesis provides an excess in precursors for joint-infiltrating neutrophils and osteoclasts. We postulate that classical CIA is primarily an auto-inflammatory disease, in part because of a strong innate immune response to the adjuvant. Superimposed on this, collagen-specific auto-immunity reinforces inflammatory reactivity in joints.     

How strong is the mutagenicity of recombination in mammals?

It is commonly believed that a high recombination rate such as that in a pseudoautosomal region (PAR) greatly increases the mutation rate because a 170-fold increase was estimated for the mouse PAR region. However, sequencing PAR and non-PAR introns of the Fxy gene in four Mus taxa, we found an increase of only twofold to fivefold. Furthermore, analyses of sequence data from human and orangutan PAR and X-linked regions and from autosomal regions showed a weak effect of recombination on mutation rate (a slope of less than 0.2% per cM/Mb), although a much stronger effect on GC content (1% to 2% per cM/Mb). Because typical recombination rates in mammals are much lower than those in PARs, the mutagenicity of recombination is weak or, at best, moderate, although its effect on GC% is much stronger. In addition, contrary to a previous study, we found no Fxy duplicate in Mus spretus.     

The posttranslational concept of protein folding: how valid is it?

Two concepts of protein folding are known. One of them, the cotranslational concept, states that a protein folds during the synthesis of the polypeptide chain on the ribosome. According to the other, the posttranslational concept, the protein starts to fold just after the synthesis of its polypeptide chain. This article attempts to show that the posttranslational concept is hardly suited to solve the problem of protein folding. In our opinion, polypeptide chains cannot be represented as random coils. They are stiff chain-like macromolecules rather than flexible ones: the single bond rotational barriers of a polypeptide substantially exceed the accepted standard values; even in strong denaturing conditions, a protein possesses a considerable amount of residual folded structures. We believe that the popular "hierarchical" models for the protein folding mechanism are not realistic because the formation of secondary and tertiary structures of proteins occurs simultaneously and cooperatively. The time for the elongation of a polypeptide chain by one amino acid residue during biosynthesis exceeds considerably the time of the formation of alpha-helices and beta-sheets in proteins as well as the time supposed for the spatial structure formation of a native protein during renaturation. Thus, we believe that the mechanism of protein folding in vivo cannot be clarified by denaturation-renaturation experiments. In our opinion, the phenomenon of protein renaturation is no more than the restoration of native protein conformation (which initially forms cotranslationally) disrupted during denaturation, and thus denaturation-renaturation experiments cannot serve as a model to clarify the mechanism of protein folding.     

Local translation in neuronal compartments: how local is local?

Efficient neuronal function depends on the continued modulation of the local neuronal proteome. Local protein synthesis plays a central role in tuning the neuronal proteome at specific neuronal regions. Various aspects of translation such as the localization of translational machinery, spatial spread of the newly translated proteins, and their site of action are carried out in specialized neuronal subcompartments to result in a localized functional outcome. In this review, we focus on the various aspects of these local translation compartments such as size, biochemical and organelle composition, structural boundaries, and temporal dynamics. We also discuss the apparent absence of definitive components of translation in these local compartments and the emerging state‐of‐the‐art tools that could help dissecting these conundrums in greater detail in the future.