Tracking in the Wlds--the hunting of the SIRT and the luring of the Draper

Wallerian degeneration of distal axons after nerve injury is significantly delayed in the Wlds mutant mouse. The Wlds protein is a fusion of nicotinamide mononucleotide adenyltransferase-1 (Nmnat1), an essential enzyme in the biosynthesis pathway of nicotinamide adenine dinucleotide (NAD), with the N-terminal 70 amino acids of the Ube4b ubiquitination assembly factor. The mechanism of Wlds action is still enigmatic, although recent efforts suggest that it is indirect and requires sequences flanking or linking the two fused open reading frames. Three papers in this issue of Neuron now show that Wlds action is conserved in Drosophila and that a critical role of Wlds may be the suppression of axonal self-destruct signals that induce Draper-mediated clearance of damaged axons by glial cells.     

The variances of the distributions of the combinations of the sexes within mammalian litters: Notes to mark the centenary of the problem

It is 100 years since Gini noted that in some samples of litters of mice and rabbits, the variances of the distributions of the combinations of the sexes are sub-binomial. In other words, in contrast with binomial expectation, there are too many litters in which the sexes are equally balanced, and there are too few unisexual litters. In the intervening years, this finding has been replicated in a number of further species, but no explanation has become established. Potential explanations are reviewed here, and it is suggested that the most likely cause is that, at the time of formation of the zygotes, p, the probability that a zygote will be male, varies from one zygote to another within litters, thus constituting an example of Poisson variation. And it is a standard result in probability theory that such variation causes sub-binomial variance.     

On the origin of the genetic code and the stability of the translation apparatus

An “error theory” is developed which can be applied to determine the stability of a macromolecular translation machinery which reproduces itself. It is shown that the overall effects of a multitude of possible error versions of macromolecules can be treated statistically, and that such a statistical approach is of considerable usefulness in the theoretical treatment of complex macromolecular systems. The theory is developed within the context of a detailed treatment of the “frozen accident” hypothesis for the origin of the genetic code. A model is described which permits some thermodynamic characterization of the components involved in the code nucleation. The model also proves useful in resolving a stability “paradox” described by Orgel, which relates to the translation stability in present-day organisms and mechanisms of ageing. It indicates that any experimentally found decrease in translation accuracy with age is probably not due to an inherent instability in the translation apparatus. Relevant experiments are suggested.     

On the nature of the tumor-initiating cell

Certain aspects of tumors that may influence areas of basic biology and medicine are reviewed. The hypothesis that malignant stem cells evolve from normal stem cells, is considered. Information is being accumulated on the possibility that certain cell populations that can be propagated as cell lines in vitro can produce cells with features of differentiated cells in addition to others that maintain the line and, in some cases may also initiate tumor formation in vivo. Up to the present time, there is evidence to show that cancer stem cells persist in many cell lines. Tyrosine kinase inhibition produces combinations of autophagy and apoptosis in the human erythroleukemia cell line TF-1 hinting at a heterotypic aggregation of cells containing cancer stem cells. Finally, the mechanisms of cancer development, invasion and metastasis are operatively defined. The purpose of this paper is to review some of the salient features of cancer stem cells in support of the proposal that research in neoplasia be increased. Rather than presenting details of various studies, we have attempted to indicate general areas in which work has been done or is in progress. It is hoped that this survey of the subject will demonstrate a variety of opportunities for additional research in human neoplasia.     

Glycosylation of the Escherichia coli TibA Self-Associating Autotransporter Influences the Conformation and the Functionality of the Protein

The self-associating autotransporters (SAATs) are multifunctional secreted proteins of Escherichia coli, comprising the AIDA-I, TibA and Ag43 proteins. One of their characteristics is that they can be glycosylated. Glycosylation of AIDA-I and Ag43 have been investigated, but not that of TibA. It is still not clear whether glycosylation of the SAATs affect their structure or their functionality. Therefore, we have looked at the effects of glycosylation on the TibA adhesin/invasin. TibA is glycosylated by TibC, a specific glycosyltransferase, and the two genes are encoded in an operon. In this study, we have found that the glycosylation of TibA is not limited to the extracellular functional domain, as previously observed with AIDA-I and Ag43. We have determined that unglycosylated TibA is not able to promote the adhesion of bacteria on cultured epithelial cell, even though it is still able to promote invasion, biofilm formation and autoaggregation of bacteria. We have purified the glycosylated and unglycosylated forms of TibA, and determined that TibA is less stable when not glycosylated. We finally observed that glycosylation affects the oligomerisation of TibA and that unglycosylated TibA is locked in a conformation that is not suited for adhesion. Our results suggest that the effect of glycosylation on the functionality of TibA is indirect.     

On the existence of a gradient of sensitivity to the lack of sodium in the spinal roots of the bullfrog

The Et class of fibers includes fibers of Gasser's d.r. C group. The fibers of the dorsal root are more sensitive to the effect of lack of sodium than are the fibers of the ventral root. In the two roots there is a gradient of sensitivity to the lack of sodium, which is such that in all the root fibers the sensitivity decreases with increasing distance from the spinal cord. The gradient continues in the trunk up to about 10 to 12 mm. peripheral to the trunk-roots margin. No comparable gradient of sensitivity to the lack of sodium has been observed in the rest of the nerve trunk. The gradient of sensitivity to the lack of sodium has no relationship to the anatomical distribution of the epineurium. As a working hypothesis it is suggested that the gradient of sensitivity to the lack of sodium is one aspect of a transitional gradient that serves to establish a gradual change between the properties that the axons have inside the spinal cord and the properties that they have inside the nerve trunks. Details are given of the temporal course of the loss of excitability by root fibers deprived of sodium. It is suggested that sodium is present in the nerve fibers, in 2 forms, loosely and tightly bound sodium and that loss of loosely bound sodium is sufficient to render the nerve fibers unable to conduct impulses. If the rate of loss of loosely bound sodium is decreased, conversion of tightly bound into loosely bound sodium may temporarily restore the excitability of the nerve fibers.     

Calorimetric study of the mechanism of uncoiling the collagen molecule in the presence of ions

Calorimetric and polarimetric studies of partially denaturated collagen in the presence and absence of one and two valence ions were performed. It is shown that in the presence of salt in partial denaturation of renaturated collagen the denaturation enthalpy is changed upon two steps. Both stages are followed by the conformational alteration. The denaturation enthalpy of the renaturated collagen is less than that of the native one, but in the presence of salts it is rather higher than in its absence. The study made possible to indicate that two-stage alteration of denaturation enthalpy is occurrence of denaturation products with partially reconstructed structure in which the salts take an active part.     

Observations on the structure of kefir grains and the distribution of the microflora

The mixed flora of yeasts and lactobacilli of kefir is held together in non-dispersible structures which build up into large grains. The fibrillar extracellular material of the matrix in which the microflora is embedded was stained by ruthenium red and periodic acid-thiosemicarbazide silver proteinate, indicating that it was largely composed of carbohydrate. It is suggested that the carbohydrate is of bacterial origin and that this is produced by a population of lactobacilli which resides within the matrix and which separates non-carbohydrate-producing populations of lactobacilli and yeasts so that sheet-like structures are formed which show asymmetry, with yeasts predominating on one side and lactobacilli on the other.     

Analysis of the spatial-temporal EEG organization as the way to the knowledge of neurophysiological mechanisms of the integrative brain activity

Short results' review of investigations of Laboratory of Neurophysiology of Child of Sechenov Institute is presented in the article. Investigations are based on concept of academic M.N. Livanov about special role of spatial-temporal relations of brain potentials oscillations of various brain areas in providing of functional connection between them. It is shown, that in rest condition the structure of interregional relations of cortex biopotentials in all healthy people is characterized by high spatial orderliness that obviously assists to optimal realization of informational processes during various functional conditions from rest to complex cognitive functions. Special attention is given for the problem of functional signigicance of phase shifts of EEG waves. Data, that allows concluding that brainstem and thalamocartical integrative systems are characterized with relatively small inherited and phenotypic variability whereas fiber systems of both hemispheres that provide processes of intercortical integration are characterized by more expressed inter-individual variability, is presented. Intensive development of long associative and commissural tracks of telencephalon that joined even the most distanced cortical regions of hemispheres in united formation apparently results in formation of morpho-functional "skeleton" of neocortex, that occurred to be the basis for origin of qualitatively new (in comparison to animals) principals of formation of system organization of integral activity of the brain. Existence of long mono- and oligo-synaptic connections provides conditions for correlative develoment in ontogenesis of new function that is not conditioned by phylogenetic development.     

Digitoxose and the existence of a glucoreceptor in the beta cells of the islets of langerhans of the rat

On the basis that digitoxin is the only drug reported up to now that stimulating insulin release per se, partially inhibits glucose stimulated insulin release, in this work the idea that the competition glucose-digitoxin may be at the level of a hypothetical glucoreceptor in the beta cells (binding of the glycoside sugar molecule) has been investigated. Our findings indicate that the integrity of the chemical structure of digitoxin is needed to exert its pharmacological action on insulin release. We also demonstrate that digitoxose inhibits glucose stimulated insulin release without inhibiting the glucose oxidation rates of the islets. The discovery of a sugar (digitoxose) that inhibitis the insulin secretory response to glucose without inhibiting glucose metabolism is a strong evidence that the action of glucose itself is blocked at the level of glucoreceptors located in the cell membrane, which appear to be the regulator sites of insulin release.     

Meiofauna and the origins of the Metazoa*

Possible alternative habitats and life-styles of the original metazoan are considered. It is argued from the dominance of the benthic habitat in present-day groups that the original metazoan habitat was benthic rather than planktonic. Similarly, plesiomorphic metazoan taxa tend to be holobenthic rather than pelago-benthic. It is therefore probable that the early Metazoa were holobenthic. The concept of plesiohabitats and apohabitats in the evolution of taxa is presented. This leads to the proposition that the early metazoans were interstitial bionts of fine sand. Finally, the controversy concerning the aerobic or anaerobic origin of the Metazoa is considered. It is shown that competition theory predicts that plesiomorphic taxa are likely to remain in plesiohabitats. Diagrams showing the possible evolution of major taxa in relation to available habitats are presented. It is concluded that the earliest Metazoa could have evolved in anaerobic marine sand and that the early Plathelminthomorpha and Aschelminthes did so.     

Localization of the gene of the glyceraldehyde 3 phosphate dehydrogenase on the distal segment of the short arm of the chromosome 12]

The enzymatic activity of G3PD and LDH-B in erythrocytes has been assayed in three patients carrying a rearrangement of the short arm of chromosome 12. The first patient is trisomic for the whole short arm. The second is trisomic only for the distal part and the third is monosomic for the proximal part. G3PD: Activity increased in patients 1 and 2 and normal in patient 3. LDH-B: Activity increased in patients 1 and 2 and decreased in patient 3. From these observations it is concluded that the erythrocytic G3PD locus is localized on the distal part of 12p, between 12p12.2 and 12 pter, and that LDH-B locus is on the middle third between 12p12.1 and 12p12.2     

Sites of Origin of the Peripheral Microtubule System of the Vegetative Cell of the Angiosperm Pollen Tube

From earlier published work it is known that microtubules inthe vegetative cell of angiosperm pollen tubes mainly occurin the form of longitudinally disposed strands closely associatedwith the plasmalemma. This peripheral cytoskeleton is extendedapically at a speed matching the growth rate of the tube. Immunofluorescencelocalization shows that in the actively elongating tube it originatesin the sub-apical zone in bands or ribbons up to 2 µmwide, interpreted here as comprising aggregates of apposed,axially oriented microtubules. These appear first in the corticalcytoplasm in close association with the wall in the part ofthe tube where the callose inner lining can first be detected.The bands do not extend apically into the region of the pecticsheath of the extreme tip. In the course of normal growth, theperipheral microtubule investment remains in the older partsof the tube from which the bulk of the cytoplasm has been withdrawn,indicating that tubulin is probably not recycled. If the growth of the tube is retarded, the inner callosic layerextends apically. The acropetal movement of callose is accompaniedby a migration of the limit of detectable tubulin towards theextreme tip, and the axially oriented bands are replaced bya confused mass of granules and short spicules. It is suggested that the bands represent nucleation zones associatedwith the stabilizing plasmalemma in the sub-apical stretch ofthe tube where the insertion of wall-precursor material is diminishing,and that it is from these zones that the microtubule cytoskeletonof the pollen tube originates. Since during growth the nucleationzones progress rapidly forward into association with new membrane,it is considered unlikely that their sites are determined bylocal differentiations of the plasmalemma. An alternative possibilityis that the distribution of the zones is related to the calciumion gradient known to be present in the apical stretch of theextending pollen tube. Microtubules, pollen tube growth, Lilium auratum     

Analysis of the Role of the C-Terminal Tail in the Regulation of the Epidermal Growth Factor Receptor

The ∼230-residue C-terminal tail of the epidermal growth factor receptor (EGFR) is phosphorylated upon activation. We examined whether this phosphorylation is affected by deletions within the tail and whether the two tails in the asymmetric active EGFR dimer are phosphorylated differently. We monitored autophosphorylation in cells using flow cytometry and found that the first ∼80 residues of the tail are inhibitory, as demonstrated previously. The entire ∼80-residue span is important for autoinhibition and needs to be released from both kinases that form the dimer. These results are interpreted in terms of crystal structures of the inactive kinase domain, including two new ones presented here. Deletions in the remaining portion of the tail do not affect autophosphorylation, except for a six-residue segment spanning Tyr 1086 that is critical for activation loop phosphorylation. Phosphorylation of the two tails in the dimer is asymmetric, with the activator tail being phosphorylated somewhat more strongly. Unexpectedly, we found that reconstitution of the transmembrane and cytoplasmic domains of EGFR in vesicles leads to a peculiar phenomenon in which kinase domains appear to be trapped between stacks of lipid bilayers. This artifactual trapping of kinases between membranes enhances an intrinsic functional asymmetry in the two tails in a dimer.     

Interoception: the sense of the physiological condition of the body

Converging evidence indicates that primates have a distinct cortical image of homeostatic afferent activity that reflects all aspects of the physiological condition of all tissues of the body. This interoceptive system, associated with autonomic motor control, is distinct from the exteroceptive system (cutaneous mechanoreception and proprioception) that guides somatic motor activity. The primary interoceptive representation in the dorsal posterior insula engenders distinct highly resolved feelings from the body that include pain, temperature, itch, sensual touch, muscular and visceral sensations, vasomotor activity, hunger, thirst, and 'air hunger'. In humans, a meta-representation of the primary interoceptive activity is engendered in the right anterior insula, which seems to provide the basis for the subjective image of the material self as a feeling (sentient) entity, that is, emotional awareness.     

Natural foci of diseases: the development of the concept at the close of the century

E. N. Pavlovski?'s concept of natural focality of diseases and the development of general knowledge about natural foci and their structural (components), functional (mechanisms of pathogen maintenance), and ecosystem-related organization (assortment and interrelations of ecosystems) are reviewed from principal (in authors' opinion) aspects. The 60-year history of this theory includes three stages at which its scope and contents differed. At the first stage, it concerned transmissible zoonoses. It had been assumed that structurally, natural foci necessarily include the pathogen-vector-host triad, and the functioning of the focus is provided for by only pathogen circulation in terrestrial ecosystems. At the second stage, it became clear that vector is not a necessary structural component of any focus (an example of nontransmissible diseases), although the functioning of foci remained to be unequivocally attributed to the continuous pathogen circulation among animals of terrestrial ecosystems. The third stage is characterized by an understanding that, in general, the presence of a warm-blooded host in the focus is also unnecessary for pathogen survival, and natural foci can be represented by soil and aquatic ecosystems. The only necessary and specific component of any natural focus is the pathogen population. In this context, modern views on natural focality of diseases are reviewed, and the essence of the terms "natural focus" and "epizootic process" is defined. It is proposed to distinguish the phases of pathogen reservation and epizootic spread (circulation) in ecosystems of any type. The current state of this concept provides evidence that, in general biological terms, studies on natural focality of diseases belong to one of the fields of symbiotology.     

The functions of the proprioceptors of the eye muscles

This article sets out to present a fairly comprehensive review of our knowledge about the functions of the receptors that have been found in the extraocular muscles--the six muscles that move each eye of vertebrates in its orbit--of all the animals in which they have been sought, including Man. Since their discovery at the beginning of the 20th century these receptors have, at various times, been credited with important roles in the control of eye movement and the construction of extrapersonal space and have also been denied any function whatsoever. Experiments intended to study the actions of eye muscle receptors and, even more so, opinions (and indeed polemic) derived from these observations have been influenced by the changing fashions and beliefs about the more general question of how limb position and movement is detected by the brain and which signals contribute to those aspects of this that are perceived (kinaesthesis). But the conclusions drawn from studies on the eye have also influenced beliefs about the mechanisms of kinaesthesis and, arguably, this influence has been even larger than that in the converse direction. Experimental evidence accumulated over rather more than a century is set out and discussed. It supports the view that, at the beginning of the 21st century, there are excellent grounds for believing that the receptors in the extraocular muscles are indeed proprioceptors, that is to say that the signals that they send into the brain are used to provide information about the position and movement of the eye in the orbit. It seems that this information is important in the control of eye movements of at least some types, and in the determination by the brain of the direction of gaze and the relationship of the organism to its environment. In addition, signals from these receptors in the eye muscles are seen to be necessary for the development of normal mechanisms of visual analysis in the mammalian visual cortex and for both the development and maintenance of normal visuomotor behaviour. Man is among those vertebrates to whose brains eye muscle proprioceptive signals provide information apparently used in normal sensorimotor functions; these include various aspects of perception, and of the control of eye movement. It is possible that abnormalities of the eye muscle proprioceptors and their signals may play a part in the genesis of some types of human squint (strabismus); conversely studies of patients with squint in the course of their surgical or pharmacological treatment have yielded much interesting evidence about the central actions of the proprioceptive signals from the extraocular muscles. The results of experiments on the eye have played a large part in the historical controversy, now in at least its third century, about the origin of signals that inform the brain about movement of parts of the body. Some of these results, and more of the interpretations of them, now need to be critically re-examined. The re-examination in the light of recent experiments that is presented here does not support many of the conclusions confidently drawn in the past and leads to both new insights and fresh questions about the roles of information from motor signals flowing out of the brain and that from signals from the peripheral receptors flowing into it. There remain many lacunae in our knowledge and filling some of these will, it is contended, be essential to advance our understanding further. It is argued that such understanding of eye muscle proprioception is a necessary part of the understanding of the physiology and pathophysiology of eye movement control and that it is also essential to an account of how organisms, including Man, build and maintain knowledge of their relationship to the external visual world. The eye would seem to provide a uniquely favourable system in which to study the way in which information derived within the brain about motor actions may interact with signals flowing in from peripheral receptors. The review is constructed in relatively independent sections that deal with particular topics. It ends with a fairly brief piece in which the author sets out some personal views about what has been achieved recently and what most immediately needs to be done. It also suggests some lines of study that appear to the author to be important for the future.     

Characterization of the structure and the amyloidogenic properties of the Josephin domain of the polyglutamine-containing protein ataxin-3

Expansion of the polyglutamine (polyQ) region in the protein ataxin-3 is associated with spinocerebellar ataxia type 3, an inherited neurodegenerative disorder that belongs to the family of polyQ diseases. Increasing evidence indicates that protein aggregation and fibre formation play an important role in these pathologies. In a previous study, we determined the domain architecture of ataxin-3, suggesting that it comprises a globular domain, named Josephin, and a more flexible C-terminal region, that includes the polyQ tract. Here, we have characterised for the first time the biophysical properties of the isolated Josephin motif, showing that it is an autonomously folded unit and that it has no significant interactions with the C-terminal region. Study of its thermodynamic stability indicates that Josephin has an intrinsic tendency to aggregate and forms temperature-induced fibrils similar to those described for expanded ataxin-3. We show that, under destabilising conditions, the behaviours of the isolated Josephin domain and ataxin-3 are extremely similar. Our data therefore strongly suggest that the stability and aggregation properties of non-expanded ataxin-3 are determined by those of the Josephin domain, which is sufficient to reproduce the behaviour of the full-length protein. Our data support a mechanism in which the thermodynamic stability of ataxin-3 is governed by the properties of the Josephin domain, but the presence of an expanded polyQ tract increases dramatically the protein's tendency to aggregate.     

Mechanism of the development of functional hyperemia in the palatal salivary glands of the rat

At various regimens of the secretory activity in the palatile salivary glands, changes occurring in the transversal profiles of the postcapillary venules, but not of the blood capillaries, are most noticeable. Under food stimulation of secretion, the former dilate essentially, that can demonstrate certain functional hyperemia developing in the palatine salivary glands. Some previous experiments concerning interpretation of principles on the microcirculatory bed spatial organization give a good reason to suggest that dilatation of the postcapillary venules is connected with an increased blood perfusion in the canals of the preferrable blood stream. The postcapillary dilatation is possible because blood from the precapillaries gets into the capacitance blood microvessels and its volume at that moment is greater than the capacity of the venous microvessels. A suggestion is made that filtrative function of the palatile salivary glands depends on development of the functional hyperemia. It is possible, that this mechanism is universal, since owing to it, reflectory reactions of the salivary glands directed to the immediate secure of the oral cavity with a necessary amount of liquor become possible.