Multiple roles for Src in a PDGF-stimulated cell

The observation that platelet-derived growth factor (PDGF) increases the catalytic activity of Src family members (Src) suggests that they contribute to PDGF-dependent responses. The role of Src in PDGF-dependent cell cycle progression, phosphorylation of proteins, and chemotaxis has been tested by investigators using a variety of cell types and approaches, and it appears that the contribution of Src is highly variable. This idea is perhaps best illustrated by the finding that Src plays radically different roles downstream of the PDGF alpha- and beta-receptor subunits. Hence, Src is a versatile signal relay enzyme, whose contribution to a signaling cascade depends on variables such as the nature of the receptor via which the cell is activated, as well as the cell type itself.     

For debate . . . Individual contributions to multiauthor papers.

The curricula vitae of four candidates for a professorial appointment at Athens University were examined to estimate the actual contribution of each candidate to the papers of which he was a coauthor. A total of 879 research papers by the four candidates were analysed in terms of the number of authors, the sequence of names, and the year of publication. The four authors presented 364, 349, 96, and 70 papers. If an equal contribution of all coauthors is assumed, the actual number of papers (all papers divided by the number of authors), is about 106, 83, 28, and 26, respectively, so that the rank of the four candidates did not change. On the assumption that the contribution was related to the candidate''s position in the order of the coauthors'' names, the numbers of papers were corrected to 84, 95, 26, 33 using one statistical method and to 88, 94, 28, 31 using another. These assumptions may not be valid, however, especially as the last author may be more important than the intermediate ones. It is suggested that the journals require authors to state their specific contribution to a paper, such as original idea, planning, collecting data, writing up, etc.     

On Darwin's 'metaphysical notebooks'. I: teleology and the project of a theory.

Huxley's essay On the Reception of the 'Origin of Species' brings us close to the issue of cause and of why- and how-questions in the understanding of the living world. The present contribution, which is divided into two parts, reviews the problem of Teleology as conceived by Huxley and re-examines Darwin as the author who revealed the existence of a 'foundations problem' in the explanation of an entire realm of nature, i.e., the problem of explaining such realm in terms of its own, specific legality, or iuxta sua propria principia. In the first part the enquiry is mainly focused on the secularization of natural history after Paley; in the second part it is mainly focused on the desubjectivization of the inquiry into natural history after Erasmus Darwin and Lamarck. The second part will be published in the next issue of Rivista di Biologia/Biology Forum. In the first part below an analysis is made of Notebooks M and N. The author disputes the correctness of conceiving them only as the works where Darwin envisages the 'metaphysical' themes later to become the subject of The Expression of the Emotions. He suggests to conceive of them also as the works where Darwin defines the terms of the general project of his own, peculiar evolutionary theory. The author then outlines the intellectual progress of Darwin from the inosculation to the transmutation hypotheses. Darwin's reading of Malthus appears to be analytically decisive, because it offers him the vintage point to attack the metaphysical and theological citadels on the morphological side. Darwin is thus able to re-consider Erasmus' comprehensive zoonomic project, by displacing it, however, from the old idea of the scala naturae to the new one of the "coral of life", and by emphasising the distinction between "the fittest" and "the best" vs. the tradition of Natural Theology.     

The multifaceted role of TMEM16A in cancer

The calcium-activated chloride channel TMEM16A is intimately linked to cancers. Over decades, TMEM16A over-expression and contribution to prognosis have been widely studied for multiple cancers strengthening the idea that TMEM16A could be a valuable biomarker and a promising therapeutic target. Surprisingly, from the survey of the literature, it appears that TMEM16A has been involved in multiple cancer-related functions and a large number of molecular targets of TMEM16A have been proposed. Thus, TMEM16A appears to be an ion channel with a multifaceted role in cancers.In this review, we summarize the latest development regarding TMEM16A contribution to cancers. We will survey TMEM16A contribution in cancer prognosis, the origins of its over-expression in cancer cells, the multiple biological functions and molecular pathways regulated by TMEM16A. Then, we will consider the question regarding the molecular mechanism of TMEM16A in cancers and the possible basis for the multifaceted role of TMEM16A in cancers.     

Anion-channel blockers interfere with auxin responses in dark-grown Arabidopsis hypocotyls.

Anion channels are thought to participate in signal transduction and turgor regulation in higher plant cells. The regulation of hypocotyl cell elongation is a situation in which these channels could play important roles because it involves ionic fluxes that are implicated in turgor control and orchestrated by various signals. We have used a pharmacological approach to reveal the contribution of anion channels in the regulation of the development of hypocotyls by auxins. Auxins induce an inhibition of elongation, a disintegration of the cortical cell layers, and the formation of adventitious roots on Arabidopsis thaliana hypocotyls grown in the dark. Anion-channel blockers such as anthracene-9-carboxylic acid, 4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid, 4-acetamido-4'-isothiocyanato-stilbene-2-2'-disulfonic acid, and R(+)-methylindazone; indanyloxyacteic acid-94, which produce little or no stimulation of hypocotyl elongation by themselves, are able to counteract the inhibition and the disintegration induced by auxins with various efficiencies. This interference appears to be specific for auxins and does not occur when hypocotyl elongation is inhibited by other growth regulators such as ethylene or cytokinins. The putative involvement of anion channels in auxin signal transduction is discussed.     

The role of stem cells in skeletal and cardiac muscle repair.

In postnatal muscle, skeletal muscle precursors (myoblasts) can be derived from satellite cells (reserve cells located on the surface of mature myofibers) or from cells lying beyond the myofiber, e.g., interstitial connective tissue or bone marrow. Both of these classes of cells may have stem cell properties. In addition, the heretical idea that post-mitotic myonuclei lying within mature myofibers might be able to re-form myoblasts or stem cells is examined and related to recent observations for similar post-mitotic cardiomyocytes. In adult hearts (which previously were not considered capable of repair), the role of replicating endogenous cardiomyocytes and the recruitment of other (stem) cells into cardiomyocytes for new cardiac muscle formation has recently attracted much attention. The relative contribution of these various sources of precursor cells in postnatal muscles and the factors that may enhance stem cell participation in the formation of new skeletal and cardiac muscle in vivo are the focus of this review. We concluded that, although many endogenous cell types can be converted to skeletal muscle, the contribution of non-myogenic cells to the formation of new postnatal skeletal muscle in vivo appears to be negligible. Whether the recruitment of such cells to the myogenic lineage can be significantly enhanced by specific inducers and the appropriate microenvironment is a current topic of intense interest. However, dermal fibroblasts appear promising as a realistic alternative source of exogenous myoblasts for transplantation purposes. For heart muscle, experiments showing the participation of bone marrow-derived stem cells and endothelial cells in the repair of damaged cardiac muscle are encouraging.     

Thermodynamical studies of oxygen equilibrium of hemoglobin. Nonuniform heats and entropy changes for the individual oxygenation steps and enthalpy-entropy compensation.

Precise oxygen equilibrium curves of human adult hemoglobin were determined by the automatic recording method at several temperatures in the presence and absence of 2,3-diphosphoglycerate (DPG) or inositol hexaphosphate (IHP) with 0.05 M 2,2-bis(hydroxymethyl)-2,2',2'-nitrolotriethanol (bis-tris) buffers (pH 7.4) containing 0.1 M Cl-. The equilibrium data were analyzed according to the Adair scheme, and the heats, deltaHi (i = 1,2,3,4) and the entropy changes, deltaSi (i = 1,2,3,4), for the individual oxygenation steps were obtained. The shape of the equilibrium curve varies on temperature changes whether DPG or IHP is present or absent. In consequence, the deltaHi value depends on i and on the presence of DPG and IHP. Behavior of deltaSi is similar to that of deltaHi. The similar behavior of deltaHi and deltaSi resulted in a compensation phenomenon. The contribution of T cdeltaSi to the free energy change is compensated by the contribution of deltaHi at the first three oxygenation steps but not at the fourth step, and for i = 1,2, and 3 changes of T cdeltaSi value upon the addition of DPG and IHP are compensated by accompanied changes of deltaHi value, where T c (= 260 K) is the compensation temperature. A major part of both the enthalpy-entropy compensation and nonuniformity of deltaHi and deltaSi appears to be attributable to contributions of the oxygen-linked binding of Cl-, DPG and IHP, by hemoglobin. The present results do not necessarily support the earlier idea of Wyman that the cooperative oxygenbinding is essentially an entropy effect.     

The binding of aromatic derivatives of β-d-galactopyranosides to the fab' of immunoglobulin J539. Observation on the nature of ligand-antibody interactions

A number of d-galactopyranosides bearing aromatic substituents have been prepared, and their binding to immunoglobulin J539 (Fab') has been studied. It appears that the main contribution of the 6-O-aromatic moiety to binding arises from the fact that it imparts an increased hydrophobicity to the ligand, causing a decrease in its hydration (solubility) that results in a greater free-energy of binding. In the d-galactosides having an aromatic aglycon, the phenyl group appears to partake in actual interactions with the protein.     

Predation and the evolution of gregariousness. I. Models for concealment and evasion

The contribution of predation to the evolution of gregariousness is examined, and it is suggested that the needs of both predator and prey to conceal themselves and to detect the other may have been a major factor directing the development of social behaviour. This implies that it is important to consider the sensory capacities and the strategies open to both sides. Some relevant features of sensory detection are discussed and illustrated by an experiment on visual summation. These features are taken into account in devising two models for the interaction between predator and prey which allow the relative advantages of different dispersion patterns to be assessed. The first model assumes that the prey's main resource is concealment: it then appears that when detection will result in only one kill group formation is usually of advantage, but when the predator may destroy all or a proportion of a discovered group, it may be better to be solitary. A second model assumes that the prey have resources for evasion and defence. The occurrence of a kill will then be determined by priority of detection and under this constraint kill rate is lowered by group formation and falls with increasing group size.     

Sodium pump hyperpolarization-relaxation in rat caudal artery

Electrogenic ion transport contributes vitally to the Em in vascular muscle and thus is an important influence on contraction and relaxation. Agents that act on membrane ion transport will cause depolarization or hyperpolarization of sufficient magnitude to cause contraction or relaxation, respectively. In the caudal artery of the rat, the principal ion involved appears to be Na+. The transport process appears to be the Na+, K+-ATPase, which is ouabain sensitive, rather than other possible candidates such as the Na+-Ca2+ countertransport mechanism. The hyperpolarization and parallel relaxation found in caudal artery on return to K+ provide unequivocal evidence for an electrogenic Na+ pump. In contrast, the lack of a contraction on transition to O Na+ suggests that the caudal artery does not show an Na+-K+ countertransport system. Although other ion transport systems might be established later for caudal artery and other kinds of vascular muscle, it now appears that the electrogenic Na+ pump is the main ion transport system controlling contraction through a continuous contribution to Em.     

Dominant role of local dipoles in stabilizing uncompensated charges on a sulfate sequestered in a periplasmic active transport protein.

Electrostatic interactions are among the key factors determining the structure and function of proteins. Here we report experimental results that illuminate the functional importance of local dipoles to these interactions. The refined 1.7-A X-ray structure of the liganded form of the sulfate-binding protein, a primary sulfate active transport receptor of Salmonella typhimurium, shows that the sulfate dianion is completely buried and bound by hydrogen bonds (mostly main-chain peptide NH groups) and van der Waals forces. The sulfate is also closely linked, via one of these peptide units, to a His residue. It is also adjacent to the N-termini of three alpha-helices, of which the two shortest have their C-termini "capped" by Arg residues. Site-directed mutagenesis of the recombinant Escherichia coli sulfate receptor had no effect on sulfate-binding activity when an Asn residue was substituted for the positively charged His and the two Arg (changed singly and together) residues. These results, combined with other observations, further solidify the idea that stabilization of uncompensated charges in a protein is a highly localized process that involves a collection of local dipoles, including those of peptide units confined to the first turns of helices. The contribution of helix macrodipoles appears insignificant.     

A major gene for primary hypoalphalipoproteinemia.

Sixteen kindreds were ascertained through probands clinically determined to have primary hypoalphalipoproteinemia, characterized by bottom decile high-density lipoprotein cholesterol (HDL-c), but otherwise normolipidemic. Age- and sex-adjusted, standardized HDL-c levels on 64 individuals in 14 nuclear families in which the proband was a parent were analyzed using the unified mixed model of segregation analysis as implemented in the computer program POINTER. The analysis proceeded by using the likelihood of offspring conditional on the parental phenotypes (conditional likelihood), which appears to overcome the limitation of possible heterogeneity in the selection criteria and provides an appropriate correction for the ascertainment. In these families, the multifactorial contribution to the phenotype appears to be small and significant only in the offspring generation. Although it was not possible to resolve the dominance pattern at the major locus since none of a recessive, additive, or dominant hypothesis could be firmly rejected, these families provided clear evidence for a major gene. Genetic heterogeneity is still a possibility, even within "primary" hypoalphalipoproteinemia.     

Complex bird clocks.

The circadian pacemaking system of birds comprises three major components: (i) the pineal gland, which rhythmically synthesizes and secretes melatonin; (ii) a hypothalamic region, possibly equivalent to the mammalian suprachiasmatic nuclei; and (iii) the retinae of the eyes. These components jointly interact, stabilize and amplify each other to produce a highly self-sustained circadian output. Their relative contribution to overt rhythmicity appears to differ between species and the system may change its properties even within an individual depending, for example, on its state in the annual cycle or its photic environment. Changes in pacemaker properties are partly mediated by changes in certain features of the pineal melatonin rhythm. It is proposed that this variability is functionally important, for instance, for enabling high-Arctic birds to retain synchronized circadian rhythms during the low-amplitude zeitgeber conditions in midsummer or for allowing birds to adjust quickly their circadian system to changing environmental conditions during migratory seasons. The pineal melatonin rhythm, apart from being involved in generating the avian pacemaking oscillation, is also capable of retaining day length information after isolation from the animal. Hence, it appears to participate in photoperiodic after-effects. Our results suggest that complex circadian clocks have evolved to help birds cope with complex environments.     

Potential DNA slippage structures acquired during evolutionary divergence of Acinetobacter calcoaceticus chromosomal benABC and Pseudomonas putida TOL pWW0 plasmid xylXYZ, genes encoding benzoate dioxygenases.

The xylXYZ DNA region is carried on the TOL pWW0 plasmid in Pseudomonas putida and encodes a benzoate dioxygenase with broad substrate specificity. The DNA sequence of the region is presented and compared with benABC, the chromosomal region encoding the benzoate dioxygenase of Acinetobacter calcoaceticus. Corresponding genes from the two biological sources share common ancestry: comparison of aligned XylX-BenA, XylY-BenB, and XylZ-BenC amino acid sequences revealed respective identities of 58.3, 61.3, and 53%. The aligned genes have diverged to assume G+C contents that differ by 14.0 to 14.9%. Usage of the unusual arginine codons AGA and AGG appears to have been selected in the P. putida xylX gene as it diverged from the ancestor it shared with A. calcoaceticus benA. Homologous A. calcoaceticus and P. putida genes exhibit different patterns of DNA sequence repetition, and analysis of one such pattern suggests that mutations creating different DNA slippage structures made a significant contribution to the evolutionary divergence of xylX.     

Recording and manipulating the in vivo correlational structure of neuronal activity during visual cortical development.

Many aspects of visual cortical functional architecture, such as orientation and ocular dominance columns, are present before animals have had any visual experience, indicating that the initial formation of cortical circuitry takes place without the influence of environmental cues. For this reason, it has been proposed that spontaneous activity within the developing visual pathway carries instructive information to guide the early establishment of cortical circuits. Recently developed recording and stimulation techniques are revealing new information about the in vivo organization of this spontaneous activity and its contribution to cortical development. Multielectrode recordings in the developing lateral geniculate nucleus (LGN) of ferrets demonstrate that retinal spontaneous activity is not simply relayed to the visual cortex, but is reshaped and transformed by a variety of mechanisms including cortical feedback and endogenous oscillatory activity. The resulting patterns are consistent with many of the predictions of correlation-based models of cortical development. In addition, the introduction of artificially correlated activity into the visual pathway disrupts some but not all aspects of orientation tuning development. Thus, while these results support an instructive role of spontaneous activity in shaping cortical development, there still appears to be a number of aspects of this process that cannot be accounted for by activity alone.     

Polycyclic aromatic hydrocarbons in the diet.

Polycyclic aromatic hydrocarbons (PAHs), of which benzo[a]pyrene is the most commonly studied and measured, are formed by the incomplete combustion of organic matter. They are widely distributed in the environment and human exposure to them is unavoidable. A number of them, such as benzo[a]pyrene, are carcinogenic and mutagenic, and they are widely believed to make a substantial contribution to the overall burden of cancer in humans. Their presence in the environment is reflected in their presence at detectable levels in many types of uncooked food. In addition, cooking processes can generate PAHs in food. PAHs can also be formed during the curing and processing of raw food prior to cooking. Several studies have been carried out to determine the levels of exposure to PAHs from representative human diets, and the proportion of the overall burden of environmental exposure to PAHs that is attributable to the diet. In most cases, it is concluded that diet is the major source of human exposure to PAHs. The major dietary sources of PAHs are cereals and vegetables, rather than meat, except where there is high consumption of meat cooked over an open flame. More recently, biomonitoring procedures have been developed to assess human exposure to PAHs and these have also indicated that diet is a major source of exposure. Exposure to nitro-PAHs through food consumption appears to be very low.