Therapeutic targets in cardiovascular disorders

The feasibility of gene therapy for cardiovascular diseases related to atherosclerosis is a topic that needs to be addressed. Most recent papers have dealt with technical aspects and feasibility and most of the genes transferred were reporter genes like those for β-galactosidase or luciferase. This may mean that the ideal vector, one that is not pathogenic or immunotolerant but is still efficient, is still not available. The results of these studies are ambiguous and it has been doubted whether the genes targeted really affect the disease. Further efforts are therefore needed to elucidate the underlying pathophysiology.     

Comparative maps: adding pieces to the mammalian jigsaw puzzle

Comparative maps display the chromosomal location of homologous genes in different species and highlight genetic segments that are conserved in evolution. These maps are used to study chromosomal changes that occurred during the divergence of mammalian lineages, to identify candidates for hereditary disease genes, and to facilitate mapping in other species. Recently, physical mapping in regions of known conserved linkage has revealed previously undetected chromosomal changes that may provide clues to understanding chromosomal structure and function and evolutionary processes. The availability of these data in electronically accessible formats is critical to the growth and analysis of comparative maps.     

Strategies to alter the progression of Alzheimer's disease

Recent advances in the genetics of familial Alzheimer's disease provide direction for therapeutic strategies to alter the progressive neurodegeneration. The rationale is particularly strong for targeting the deposition of amyloid into neuritic plaques, but attention has also turned to abnormalities in apoptosis and signal-transduction processes.     

Coordinate control of secondary metabolite production and asexual sporulation in Aspergillus nidulans

Microbial secondary metabolite production is frequently associated with developmental processes such as sporulation, but there are few cases where this correlation is understood. Recent work with the filamentous fungus Aspergillus nidulans has provided new insights into the mechanisms coordinating production of the toxic secondary metabolite sterigmatocystin with asexual sporulation. These processes have been shown to be linked through a common need to inactivate a heterotrimeric G protein dependent signaling pathway that, when active, serves to stimulate growth while blocking both sporulation and sterigmatocystin biosynthesis.     

Gen(om)e duplications in the evolution of early vertebrates

Phylogenetic analyses and sequence surveys of developmental regulator gene families indicate that two large-scale gene duplications, most likely genome duplications, occurred in ancestors of vertebrates. Relaxed constraints allowed duplicated and thus redundant genes to diverge in a two stage mechanism. Neutral changes dominated at first but then positively selected regulatory changes evolved the novel and increasingly complex vertebrate developmental program.     

Pax genes and their roles in cell differentiation and development

Members of the Pax gene family are expressed in various tissues during ontogenesis. Evidence for their crucial role in morphogenesis, organogenesis, cell differentiation and oncogenesis is provided by rodent mutants and human diseases. Additionally, recent experimental in vivo and in vitro approaches have led to the identification of molecules that interact with Pax proteins.     

GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins

Cell biology depends on the interactions of macromolecules, such as protein—DNA, protein—protein or protein—nucleotide interactions. GTP-binding proteins are no exception to the rule. They regulate cellular processes as diverse as protein biosynthesis and intracellular membrane trafficking. Recently, a large number of genes encoding GTP-binding proteins and the proteins that interact witht these molecular switches have been cloned and expressed. The 3D structures of some of these have also been elucidated     

Role of cytokines and extracellular matrix in the regulation of haemopoietic stem cells

The understanding of molecular mechanisms regulating the formation, growth and differentiation of haemopoietic stem cells has advanced considerably recently. Particular progress has been made in defining the cytokines, chemokines and extracellular matrix components which retain and maintain primitive haemopoietic cell populations in bone marrow. Furthermore, signal transduction pathways that are critical for haemopoiesis, both in vivo and in vitro, and that are activated by cytokines have also been identified and further characterised. The importance of these processes has, this year, been exemplified by the phenotypes of mice deficient in key signal transduction proteins and the discovery that mutations in the component proteins of some signalling pathways are linked to human diseases. Significant advances in understanding the molecular mechanisms for mobilisation of stem cells from bone marrow have also been made this year; this has potential importance for bone marrow transplantation.     

Chemistry and physics of giant vesicles as biomembrane models

The giant vesicle is becoming an object of intense scrutiny by chemists, biologists, and physicists who are interested in membrane behavior. Recent advances include new models to explain morphological changes, new experimental methods for studying vesicle adhesion, layering and adsorption, and new cataloging of ‘cytomimetic’ processes.     

Sister chromatid cohesion in mitosis

Sister chromatid cohesion is essential for accurate chromosome segregation during the cell cycle. Newly identified structural proteins are required for sister chromatid cohesion and there may be a link in some organisms between the processes of cohesion and condensation. Proteins that induce and regulate the separation of sister chromatids have also been recently identified.     

Epidermal growth factor receptors: function modulation by phosphorylation and glycosylation interplay

Post-translational modifications (PTMs) of proteins induce structural and functional changes that are most often transitory and difficult to follow and investigate in vivo. In silico prediction procedures for PTMs are very valuable to foresee and define such transitory changes responsible for the multifunctionality of proteins. Epidermal growth factor receptor (EGFR) is such a multifunctional transmembrane protein with intrinsic tyrosine kinase activity that is regulated primarily by ligand-stimulated transphosphorylation of dimerized receptors. In human EGFR, potential phosphorylation sites on Ser, Thr and Tyr residues including five autophosphorylation sites on Tyr were investigated using in silico procedures. In addition to phosphorylation, O-GlcNAc modifications and interplay between these two modifications was also predicted. The interplay of phosphorylation and O-GlcNAc modification on same or neighboring Ser/Thr residues is termed as Yin Yang hypothesis and the interplay sites are named as Yin Yang sites. Amongst these modification sites, one residue is localized in the juxtamembrane (Thr 654) and two are found in the catalytic domain (Ser 1046/1047) of the EGFR. We propose that, when EGFR is O-GlcNAc modified on Thr 654, EGFR may be transferred from early to late endosomes, whereas when EGFR is O-GlcNAc modified on Ser 1046/1047 desensitization of the receptor may be prevented. These findings suggest a complex interplay between phosphorylation and O-GlcNAc modification resulting in modulation of EGFR's functionality.     

Everything in moderation: Archaea as ‘non-extremophiles’

Well characterized and cultivated archaea are prokaryotic specialists that thrive in habitats of elevated temperature, low pH, high salinity, or strict anoxia. Recently, however, new groups of abundant, uncultivated archaea have been found to be widespread in more pedestrian biotopes, including marine plankton, terrestrial soils, lakes, marine and freshwater sediments, and in association with metazoa. Research efforts are presently focused on characterizing the physiology, biochemistry and genetics of these abundant and cosmopolitan but poorly understood archaea.     

Medical implications of understanding complex disease traits

The application of genetic mapping to human disease gene identification has led to the definition of many linkages and a few disease genes in complex traits over the past two years. Its application has also increased to include aspects of pharmacogenetics relating to pharmacokinetics and pharmacodynamics.     

Recent work on Alzheimer''s disease transgenics

The most significant feature of the current transgenic models of Alzheimer's disease continues to be the amyloid phenotype. In the past year, mice have been more extensively characterized in terms of the effect of amyloid accumulation on downstream events, such as neurodegeneration and behavioral changes, but the results have been complex. Genetic crosses have shown that apolipoprotein E and TGF-β1 influence the deposition event and that the presenilins act synergistically with the amyloid precursor protein in pathology development. The mice have great utility in amyloid modulation studies but are still not complete models of Alzheimer's disease.     

The evolution of the Hox cluster: insights from outgroups

Two burgeoning research trends are helping to reconstruct the evolution of the Hox cluster with greater detail and clarity. First, Hox genes are being studied in a broader phylogenetic sampling of taxa: the past year has witnessed important new data from teleost fishes, onychophorans, myriapods, polychaetes, glossiphoniid leeches, ribbon worms, and sea anemones. Second, commonly accepted notions of animal relationships are being challenged by alternative phylogenetic hypotheses that are causing us to rethink the evolutionary relationships of important metazoan lineages, especially arthropods, annelids, nematodes, and platyhelminthes.     

Connections between growth and the cell cycle

To maintain a constant size during cellular proliferation, a cell's growth rate must match its rate of division. Factors that govern proliferation must therefore coordinately regulate two distinct processes: the cellular biosynthesis that drives accumulation of mass, and progression through the cell division cycle. Recent work has identified several mechanisms which couple cell division to growth. Different mechanisms are used at different times during development to coordinate growth, cell division, and patterning.     

Cellular and biochemical mechanisms underlying circadian rhythms in vertebrates

Circadian clocks organize neural processes, such as motor activities, into near 24-hour oscillations and adaptively synchronize these rhythms to the solar cycle. Recently, the first mammalian clock genes have been found. Unpredicted diversity in signaling pathways and clock-controlled gating of signals that modulate timekeeping has been discovered. A diffusible clock output has been found to control some behavioral rhythms. Consensus is emerging that circadian mechanisms are conserved across phylogeny, but that mammals have developed a great complexity of controls.     

Cortical control of reaching movements

Recent studies provide further support for the hypothesis that spatial representations of limb position, target locations, and potential motor actions are expressed in the neuronal activity in parietal cortex. In contrast, precentral cortical activity more strongly expresses processes involved in the selection and execution of motor actions. As a general conceptual framework, these processes may be interpreted in terms of such formalisms as sensorimotor transformation and ‘internal models’.