Role of copper in tumour angiogenesis--clinical implications.

The formation of new blood vessels is the initial step in progressive tumour development and metastasis. The first stage in tumour angiogenesis is the activation of endothelial cells. Copper ions stimulate proliferation and migration of endothelial cells. It has been shown that serum copper concentration increases as the cancer disease progresses and correlates with tumour incidence and burden. Copper ions also activate several proangiogenic factors, e.g., vascular endothelial growth factor, basic fibroblast growth factor, tumour necrosis factor alpha and interleukin 1. This review concerns a brief introduction into the basics of tumour blood vessel development as well as the regulatory mechanisms of this process. The role of copper ions in tumour angiogenesis is discussed. The new antiangiogenic therapies based on a reduction of copper levels in tumour microenvironment are reviewed.     

Catenins: playing both sides of the synapse

Synapses of the central nervous system (CNS) are specialized cell-cell junctions that mediate intercellular signal transmission from one neuron to another. The directional nature of signal relay requires synaptic contacts to be morphologically asymmetric with distinct protein components, while changes in synaptic communication during neural network formation require synapses to be plastic. Synapse morphology and plasticity require a dynamic actin cytoskeleton. Classical cadherins, which are junctional proteins associated with the actin cytoskeleton, localize to synapses and regulate synaptic adhesion, stability and remodeling. The major intracellular components of cadherin junctions are the catenin proteins, and increasing evidence suggests that cadherin-catenin complexes modulate an array of synaptic processes. Here we review the role of catenins in regulating the development of pre- and postsynaptic compartments and function in synaptic plasticity, with particular focus on their role in regulating the actin cytoskeleton.     

The retinoic acid metabolising gene, CYP26B1, patterns the cartilaginous cranial neural crest in zebrafish

We have investigated the function of the retinoic acid metabolising enzyme, CYP26B1, by administering an antisense morpholino oligonucleotide to zebrafish embryos. The result was an alteration in the morphology of the embryo in those regions which express the gene, namely an embryo with a smaller head, correspondingly smaller hindbrain rhombomeres and severely reduced numbers of vagal brachiomotor neurons. Most strikingly, these embryos had defective or absent jaw cartilages implying a role for this enzyme in patterning or migration of the neural crest cells which give rise to this tissue type. In order to determine whether this phenotype resembles that of excess retinoic acid or a deficiency of retinoic acid, we compared the jaw defects following retinoic acid treatment or DEAB treatment, the latter being an inhibitor of retinoic acid synthesis. The effects of the inhibitor rather than excess retinoic acid most closely phenocopied the jaw defects seen with the Cyp26B1 morpholino which suggests that, at least in the zebrafish embryo, the action of CYP26B1 in the neural crest may not be simply to catabolise all-trans-RA.     

A protein arginine N-methyltransferase 1 (PRMT1) and 2 heteromeric interaction increases PRMT1 enzymatic activity

Protein arginine N-methyltransferases (PRMTs) act in signaling pathways and gene expression by methylating arginine residues within target proteins. PRMT1 is responsible for most cellular arginine methylation activity and can work independently or in collaboration with other PRMTs. In this study, we demonstrate a direct interaction between PRMT1 and PRMT2 using co-immunoprecipitation, bimolecular fluorescence complementation, and enzymatic assays. As a result of this interaction, PRMT2 stimulated PRMT1 activity, affecting its apparent V(max) and K(M) values in vitro and increasing the production of methylarginines in cells. Active site mutations and regional deletions from PRMT1 and -2 were also investigated, which demonstrated that complex formation required full-length, active PRMT1. Although the inhibition of methylation by adenosine dialdehyde prevented the interaction between PRMT1 and -2, it did not prevent the interaction between PRMT1 and a truncation mutant of PRMT2 lacking its Src homology 3 (SH3) domain. This result suggests that the SH3 domain may mediate an interaction between PRMT1 and -2 in a methylation-dependent fashion. On the basis of our findings, we propose that PRMT1 serves as the major methyltransferase in cells by forming higher-order oligomers with itself, PRMT2, and possibly other PRMTs.     

DDESC: Dragon database for exploration of sodium channels in human

Background

Hepcidin/LEAP-1 is an iron regulatory hormone originally identified as an antimicrobial peptide. As part of a systematic analysis of the evolution of host defense peptides in primates, we have sequenced the orthologous gene from 14 species of non-human primates.

Results

The sequence of the mature peptide is highly conserved amongst all the analyzed species, being identical to the human one in great apes and gibbons, with a single residue conservative variation in Old-World monkeys and with few substitutions in New-World monkeys.

Conclusion

Our analysis indicates that hepcidin's role as a regulatory hormone, which involves interaction with a conserved receptor (ferroportin), may result in conservation over most of its sequence, with the exception of the stretch between residues 15 and 18, which in New-World monkeys (as well as in other mammals) shows a significant variation, possibly indicating that this structural region is involved in other functions.     

Glucomannan-mediated attachment of Rhizobium leguminosarum to pea root hairs is required for competitive nodule infection

The Rhizobium leguminosarum biovar viciae genome contains several genes predicted to determine surface polysaccharides. Mutants predicted to affect the initial steps of polysaccharide synthesis were identified and characterized. In addition to the known cellulose (cel) and acidic exopolysaccharide (EPS) (pss) genes, we mutated three other loci; one of these loci (gmsA) determines glucomannan synthesis and one (gelA) determines a gel-forming polysaccharide, but the role of the other locus (an exoY-like gene) was not identified. Mutants were tested for attachment and biofilm formation in vitro and on root hairs; the mutant lacking the EPS was defective for both of these characteristics, but mutation of gelA or the exoY-like gene had no effect on either type of attachment. The cellulose (celA) mutant attached and formed normal biofilms in vitro, but it did not form a biofilm on root hairs, although attachment did occur. The cellulose-dependent biofilm on root hairs appears not to be critical for nodulation, because the celA mutant competed with the wild-type for nodule infection. The glucomannan (gmsA) mutant attached and formed normal biofilms in vitro, but it was defective for attachment and biofilm formation on root hairs. Although this mutant formed nodules on peas, it was very strongly outcompeted by the wild type in mixed inoculations, showing that glucomannan is critical for competitive nodulation. The polysaccharide synthesis genes around gmsA are highly conserved among other rhizobia and agrobacteria but are absent from closely related bacteria (such as Brucella spp.) that are not normally plant associated, suggesting that these genes may play a wide role in bacterium-plant interactions.     

Downregulation of protein 4.1R, a mature centriole protein, disrupts centrosomes, alters cell cycle progression, and perturbs mitotic spindles and anaphase

Centrosomes nucleate and organize interphase microtubules and are instrumental in mitotic bipolar spindle assembly, ensuring orderly cell cycle progression with accurate chromosome segregation. We report that the multifunctional structural protein 4.1R localizes at centrosomes to distal/subdistal regions of mature centrioles in a cell cycle-dependent pattern. Significantly, 4.1R-specific depletion mediated by RNA interference perturbs subdistal appendage proteins ninein and outer dense fiber 2/cenexin at mature centrosomes and concomitantly reduces interphase microtubule anchoring and organization. 4.1R depletion causes G(1) accumulation in p53-proficient cells, similar to depletion of many other proteins that compromise centrosome integrity. In p53-deficient cells, 4.1R depletion delays S phase, but aberrant ninein distribution is not dependent on the S-phase delay. In 4.1R-depleted mitotic cells, efficient centrosome separation is reduced, resulting in monopolar spindle formation. Multipolar spindles and bipolar spindles with misaligned chromatin are also induced by 4.1R depletion. Notably, all types of defective spindles have mislocalized NuMA (nuclear mitotic apparatus protein), a 4.1R binding partner essential for spindle pole focusing. These disruptions contribute to lagging chromosomes and aberrant microtubule bridges during anaphase/telophase. Our data provide functional evidence that 4.1R makes crucial contributions to the structural integrity of centrosomes and mitotic spindles which normally enable mitosis and anaphase to proceed with the coordinated precision required to avoid pathological events.     

Autonomy,Equality, and Teaching among Aka Foragers and Ngandu Farmers of the Congo Basin

The significance of teaching to the evolution of human culture is under debate. We contribute to the discussion by using a quantitative, cross-cultural comparative approach to investigate the role of teaching in the lives of children in two small-scale societies: Aka foragers and Ngandu farmers of the Central African Republic. Focal follows with behavior coding were used to record social learning experiences of children aged 4 to 16 during daily life. “Teaching” was coded based on a functional definition from evolutionary biology. Frequencies, contexts, and subtypes of teaching as well as the identity of teachers were analyzed. Teaching was rare compared to observational learning, although both forms of social learning were negatively correlated with age. Children received teaching from a variety of individuals, and they also engaged in teaching. Several teaching types were observed, including instruction, negative feedback, and commands. Statistical differences in the distribution of teaching types and the identity of teachers corresponded with contrasting forager vs. farmer foundational cultural schema. For example, Aka children received less instruction, which empirically limits autonomous learning, and were as likely to receive instruction and negative feedback from other children as they were from adults. Commands, however, exhibited a different pattern suggesting a more complex role for this teaching type. Although consistent with claims that teaching is relatively rare in small-scale societies, this evidence supports the conclusion that teaching is a universal, early emerging cognitive ability in humans. However, culture (e.g., values for autonomy and egalitarianism) structures the nature of teaching.     

Environmental cues and extended estuarine residence in seaward migrating eels (Anguilla australis)

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Modeling daily flowering probabilities: expected impact of climate change on Japanese cherry phenology

Understanding the drivers of phenological events is vital for forecasting species’ responses to climate change. We developed flexible Bayesian survival regression models to assess a 29‐year, individual‐level time series of flowering phenology from four taxa of Japanese cherry trees (Prunus spachiana, Prunus × yedoensis, Prunus jamasakura, and Prunus lannesiana), from the Tama Forest Cherry Preservation Garden in Hachioji, Japan. Our modeling framework used time‐varying (chill and heat units) and time‐invariant (slope, aspect, and elevation) factors. We found limited differences among taxa in sensitivity to chill, but earlier flowering taxa, such as P. spachiana, were more sensitive to heat than later flowering taxa, such as P. lannesiana. Using an ensemble of three downscaled regional climate models under the A1B emissions scenario, we projected shifts in flowering timing by 2100. Projections suggest that each taxa will flower about 30 days earlier on average by 2100 with 2–6 days greater uncertainty around the species mean flowering date. Dramatic shifts in the flowering times of cherry trees may have implications for economically important cultural festivals in Japan and East Asia. The survival models used here provide a mechanistic modeling approach and are broadly applicable to any time‐to‐event phenological data, such as plant leafing, bird arrival time, and insect emergence. The ability to explicitly quantify uncertainty, examine phenological responses on a fine time scale, and incorporate conditions leading up to an event may provide future insight into phenologically driven changes in carbon balance and ecological mismatches of plants and pollinators in natural populations and horticultural crops.