Plausible function of Golgi cells in the cerebellar cortex

The function of Golgi cells in the cerebellar cortex is quantitatively examined in consideration of the nonlinear input-output characteristics and convergence and divergence numbers of cells. It is strongly suggested that the two signal paths to Golgi cells have different function. The feed-forward path will have the same function as assumed in the previous theories of the cerebellar cortex, that is, to keep the firing rate of granule cells approximately constant over considerable variation in the firing rate of mossy fibers. The feedback path will, on the other hand, have a new function which has not been assumed in the previous theories. The function is to cause oscillation of the firing rate of granule cells for stationary mossy fiber inputs. The assumption of the new function enables us to explain cerebellar function to keep stationary posture.     

Establishing the mental health baseline

This paper introduces a new organization, cognitive-web.org, whose goal is to make cognitive tests available on the internet, and thereby to provide users with a "mental health baseline" against which to assess their cognitive function over time. These tests will provide information about changes in cognitive function during normal aging and in dementia.     

miRNA的研究进展

微小RNAs(microRNAs,miRNAs)是一类长度在22nt左右、能调节mRNAs表达的非编码RNA基因产物。miRNAs最初在线虫体内被发现,广泛存在于真核生物体内,对于生物体的发育等诸多方面有调节作用,并在进化中保守。miRNAs作用机制尚不完全清楚,但已知其能通过与mRNAs的3′非翻译区结合而影响翻译水平。部分miRNAs可以行使类似siRNAs的作用。本文就miRNAs的生物发生、作用机制、应用方向等研究进展作一综述。相信对miRNAs的深入认识将为基因功能研究提供新思路,同时也将为基因操作技术提供新的手段。     

The jewels of our genome: the search for the genomic changes underlying the evolutionarily unique capacities of the human brain

The recent publication of the initial sequence and analysis of the chimp genome allows us, for the first time, to compare our genome with that of our closest living evolutionary relative. With more primate genome sequences being pursued, and with other genome-wide, cross-species comparative techniques emerging, we are entering an era in which we will be able to carry out genomic comparisons of unprecedented scope and detail. These studies should yield a bounty of new insights about the genes and genomic features that are unique to our species as well as those that are unique to other primate lineages, and may begin to causally link some of these to lineage-specific phenotypic characteristics. The most intriguing potential of these new approaches will be in the area of evolutionary neurogenomics and in the possibility that the key human lineage–specific (HLS) genomic changes that underlie the evolution of the human brain will be identified. Such new knowledge should provide fresh insights into neuronal development and higher cognitive function and dysfunction, and may possibly uncover biological mechanisms for information storage, analysis, and retrieval never previously seen.     

New paradigms of signaling in the vasculature: ephrins and metalloproteases

As our understanding of the control of vasculogenesis and angiogenesis continues to grow, we will be confronted with an increasing number of interacting and intersecting receptor-mediated signaling pathways. If we are to be successful in developing new and novel effective therapeutic reagents that can function as stimulators or inhibitors of these critically important processes, we will have to develop a sophisticated, full understanding of the complex interactions associated with ephrin-based and metalloprotease-based signaling pathways.     

Chemical strategies for the global analysis of protein function

As the human genome project nears completion, biological research is entering a new era in which experimental focus will shift from identifying novel genes to determining the function of gene products. Rising to this challenge, several technologies have emerged that aim to characterise genes and/or proteins collectively rather than individually. Of particular interest is a new breed of strategies that employs synthetic chemistry to enrich our understanding of protein function on a global scale.     

Approach of the functional evolution of duplicated genes in Saccharomyces cerevisiae using a new classification method based on protein-protein interaction data

The concept of protein function is widely used and manipulated by biologists. However, the means of the concept and its understanding may vary depending on the level of functionality one considers (molecular, cellular, physiological, etc.). Genomic studies and new high-throughput methods of the post-genomic era provide the opportunity to shed a new light on the concept of protein function: protein-protein interactions can now be considered as pieces of incomplete but still gigantic networks and the analysis of these networks will permit the emergence of a more integrated view of protein function. In this context, we propose a new functional classification method, which, unlike usual methods based on sequence homology, allows the definition of functional classes of protein based on the identity of their interacting partners. An example of such classification will be shown and discussed for a subset of Saccharomyces cerevisiae proteins, accounting for 7% of the yeast proteome. The genome of the budding yeast contains 50% of protein-coding genes that are paralogs, including 457 pairs of duplicated genes coming probably from an ancient whole genome duplication. We will comment on the functional classification of the duplicated genes when using our method and discuss the contribution of these results to the understanding of function evolution for the duplicated genes.     

Dissecting the molecular function of reggie/flotillin proteins

Reggie-1/flotillin-2 and reggie-2/flotillin-1 are ubiquitously expressed, well-conserved proteins that are associated with membrane microdomains known as rafts. Studies from us and others have suggested a role in various cellular processes such as insulin signaling, T cell activation, membrane trafficking, phagocytosis, and epidermal growth factor receptor signaling. Recent findings also demonstrate that reggie-1 is associated with cell motility and transformation. However, the exact function of reggie proteins remains to be clarified. In this review, we will focus on some recent findings that have shed new light on the elusive molecular function of these highly interesting proteins. We will especially discuss the emerging role of reggie proteins in membrane receptor signaling and membrane trafficking, with emphasis on the regulation of the molecular function of reggies by post-translational modifications such as phosphorylation and lipid modifications.     

Re-defining the chromatin loop domain

It is commonly accepted that the loop domain represents the basic structural unit of eukaryotic chromatin associated with DNA replication, gene expression and higher order packaging. However, molecular-cytological information defining the loop domain is lacking. There are gaps in our knowledge of the loop structure and how it regulates gene expression. The combination of new data/reagents from the Human Genome Project plus the use of novel molecular cytological technology will provide answers. Here we briefly review the status of chromatin loop research and pose questions that need to be addressed. New experimental systems are also presented to target some long-standing issues regarding the structure and function of the chromatin loop domain and its relationship with the nuclear matrix. This new knowledge will have a profound impact for modern genetics and molecular medicine.     

The Billion Cell Construct: Will Three-Dimensional Printing Get Us There?

How structure relates to function—across spatial scales, from the single molecule to the whole organism—is a central theme in biology. Bioengineers, however, wrestle with the converse question: will function follow form? That is, we struggle to approximate the architecture of living tissues experimentally, hoping that the structure we create will lead to the function we desire. A new means to explore the relationship between form and function in living tissue has arrived with three-dimensional printing, but the technology is not without limitations.     

Functional analysis of the yeast genome

The release of the complete genome sequence of the yeast Saccharomyces cerevisiae has ushered in a new phase of genome research in which sequence function will be assigned. The goal is to determine the biological function of each of the >6,000 open reading frames in the yeast genome. Innovative approaches have been developed that exploit the sequence data and yield information about gene expression levels, protein levels, subcellular localization and gene function for the entire genome.     

Protein engineering strategies with potential applications for altering clinically relevant cellular pathways at the protein level

All diseases can be fundamentally viewed as the result of malfunctioning cellular pathways. Protein engineering offers the potential to develop new tools that will allow these dysfunctional pathways to be better understood, in addition to potentially providing new routes to restore proper function. Here we discuss different approaches that can be used to change the intracellular activity of a protein by intervening at the protein level: targeted protein sequestration, protein recruitment, protein degradation, and selective inhibition of binding interfaces. The potential of each of these tools to be developed into effective therapeutic treatments will also be discussed, along with any major barriers that currently block their translation into the clinic.     

Will genetics really revolutionize the drug discovery process?

Genetics has played only a modest role in drug discovery, but new technologies will radically change this. Whole genome sequencing will identify new drug discovery targets, and emerging methods for the determination of gene function will increase the ability to select robust targets. Detection of single nucleotide polymorphisms and common polymorphisms will enhance the investigation of polygenic diseases and the use of genetics in drug development. Oligonucleotide arraying technologies will allow analysis of gene expression patterns in novel ways.     

Illuminating the genome-wide activity of genome editors for safe and effective therapeutics

Genome editing holds remarkable promise to transform human medicine as new therapies that can directly address the genetic causes of disease. However, concerns remain about possible undesired biological consequences of genome editors, particularly the introduction of unintended ‘off-target’ mutations. Here, we discuss both important considerations for therapeutic genome editing and our understanding of the functional impact of undesired off-target mutations. An important challenge for the future will be the development of new approaches for predicting and defining the probable function of unintended genome-editing mutations, which will inspire confidence in the next generation of promising genome-editing therapies.     

Applications of the polymerase chain reaction to genome analysis

The objectives of the Human Genome Project are to create high-resolution genetic and physical maps, and ultimately to determine the complete nucleotide sequence of the human genome. The result of this initiative will be to localize the estimated 50,000-100,000 human genes, and acquire information that will enable development of a better understanding of the relationship between genome structure and function. To achieve these goals, new methodologies that provide more rapid, efficient, and cost effective means of genomic analysis will be required. From both conceptual and practical perspectives, the polymerase chain reaction (PCR) represents a fundamental technology for genome mapping and sequencing. The availability of PCR has allowed definition of a technically credible form that the final composite map of the human genome will take, as described in the sequence-tagged site proposal. Moreover, applications of PCR have provided efficient approaches for identifying, isolating, mapping, and sequencing DNA, many of which are amenable to automation. The versatility and power provided by PCR have encouraged its involvement in almost every aspect of human genome research, with new applications of PCR being developed on a continual basis.     

Assessment of putative protein targets derived from the SARS genome

The ability to rapidly and reliably develop hypotheses on the function of newly discovered protein sequences requires systematic and comprehensive analysis. Such an analysis, embodied within the DS GeneAtlas pipeline, has been used to critically evaluate the severe acute respiratory syndrome (SARS) genome with the goal of identifying new potential targets for viral therapeutic intervention. This paper discusses several new functional hypotheses on the roles played by the constituent gene products of SARS, and will serve as an example of how such assignments can be developed or extended on other systems of interest.     

The Rise of Pathogens: Predation as a Factor Driving the Evolution of Human Pathogens in the Environment

Bacteria in the environment must survive predation from bacteriophage, heterotrophic protists, and predatory bacteria. This selective pressure has resulted in the evolution of a variety of defense mechanisms, which can also function as virulence factors. Here we discuss the potential dual function of some of the mechanisms, which protect against heterotrophic protists, and how predation pressure leads to the evolution of pathogenicity. This is in accordance with the coincidental evolution hypothesis, which suggests that virulence factors arose as a response to other selective pressures, for example, predation rather than for virulence per se. In this review we discuss some of those environmental factors that may be associated with the rise of pathogens in the marine environment. In particular, we will discuss the role of heterotrophic protists in the evolution of virulence factors in marine bacteria. Finally, we will discuss the implications for expansion of current pathogens and emergence of new pathogens.     

Exploring the structure and function paradigm

Advances in protein structure determination, led by the structural genomics initiatives have increased the proportion of novel folds deposited in the Protein Data Bank. However, these structures are often not accompanied by functional annotations with experimental confirmation. In this review, we reassess the meaning of structural novelty and examine its relevance to the complexity of the structure-function paradigm. Recent advances in the prediction of protein function from structure are discussed, as well as new sequence-based methods for partitioning large, diverse superfamilies into biologically meaningful clusters. Obtaining structural data for these functionally coherent groups of proteins will allow us to better understand the relationship between structure and function.