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 June May April March February January 2006 2005 2004 2003 2002 2001

Jul 31, 2007 TGFβ signalling in control of T-cell-mediated self-reactivity
  In the immune system, transforming growth factor-beta (TGFbeta) affects multiple cell lineages by either promoting or opposing their differentiation, survival and proliferation. Understanding the cellular mechanisms of TGFbeta-mediated regulation is complicated due to a broad distribution of TGFbeta receptors on the surface of different immune-cell types. Recent studies using in vivo genetic approaches revealed a critical role for TGFbeta signalling in T cells in restraining fatal autoimmune lesions. Here, we review recent advances in our understanding of a role for TGFbeta signalling in the regulation of T-cell differentiation in the thymus and in the periphery, with a particular emphasis on TGFbeta-mediated control of self-reactive T cells.
Jul 30, 2007 Neuronal subtype specification in the cerebral cortex
  In recent years, tremendous progress has been made in understanding the mechanisms underlying the specification of projection neurons within the mammalian neocortex. New experimental approaches have made it possible to identify progenitors and study the lineage relationships of different neocortical projection neurons. An expanding set of genes with layer and neuronal subtype specificity have been identified within the neocortex, and their function during projection neuron development is starting to be elucidated. Here, we assess recent data regarding the nature of neocortical progenitors, review the roles of individual genes in projection neuron specification and discuss the implications for progenitor plasticity.
Jul 29, 2007 Microenvironmental regulation of biomacromolecular therapies
  There is currently great interest in molecular therapies to treat various diseases, and this has prompted extensive efforts to achieve target-specific and controlled delivery of bioactive macromolecules (for example, proteins, antibodies, DNA and small interfering RNA) through the design of smart drug carriers. By contrast, the influence of the microenvironment in which the target cell resides and the effect it might have on the success of biomacromolecular therapies has been under-appreciated. The extracellular matrix (ECM) component of the cellular niche may be particularly important, as many diseases and injury disrupt the normal ECM architecture, the cell adhesion to ECM, and the subsequent cellular activities. This Review will discuss the importance of the ECM and the ECM-cell interactions on the cell response to bioactive macromolecules, and suggest how this information could lead to new criteria for the design of novel drug delivery systems.
Jul 28, 2007 CDC25 phosphatases in cancer cells: key players? Good targets?
  Cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell cycle phases during normal cell division, and in the event of DNA damage they are key targets of the checkpoint machinery that ensures genetic stability. Taking only this into consideration, it is not surprising that CDC25 overexpression has been reported in a significant number of human cancers. However, in light of the significant body of evidence detailing the stringent complexity with which CDC25 activities are regulated, the significance of CDC25 overexpression in a subset of cancers and its association with poor prognosis are proving difficult to assess. We will focus on the roles of CDC25 phosphatases in both normal and abnormal cell proliferation, provide a critical assessment of the current data on CDC25 overexpression in cancer, and discuss both current and future therapeutic strategies for targeting CDC25 activity in cancer treatment.
Jul 27, 2007 TH1 cells control themselves by producing interleukin-10
  Inflammatory T helper 1 (T(H)1)-cell responses successfully eradicate pathogens, but often also cause immunopathology. To minimize this deleterious side-effect the anti-inflammatory cytokine interleukin-10 (IL-10) is produced. Although IL-10 was originally isolated from T(H)2 cells it is now known to be produced by many cell types. Here, we discuss the recent evidence that shows that T(H)1 cells are the main source of IL-10 that controls the immune response against Leishmania major and Toxoplasma gondii infection.
Jul 26, 2007 TRP channels in mechanosensation: direct or indirect activation?
  Ion channels of the transient receptor potential (TRP) superfamily are involved in a wide variety of neural signalling processes, most prominently in sensory receptor cells. They are essential for mechanosensation in systems ranging from fruitfly hearing, to nematode touch, to mouse mechanical pain. However, it is unclear in many instances whether a TRP channel directly transduces the mechanical stimulus or is part of a downstream signalling pathway. Here, we propose criteria for establishing direct mechanical activation of ion channels and review these criteria in a number of mechanosensory systems in which TRP channels are involved.
Jul 25, 2007 Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases
  Matrix metalloproteinases (MMPs) have outgrown the field of extracellular-matrix biology and have progressed towards being important regulatory molecules in cancer and inflammation. This rise in status was accompanied by the development of various classes of inhibitors. Although clinical trials with synthetic inhibitors for the treatment of cancer were disappointing, recent data indicate that the use of selective inhibitors might lead to new therapies for acute and chronic inflammatory and vascular diseases. In this Review, we compare the major classes of MMP inhibitors and advocate that future drug discovery should be based on crucial insights into the differential roles of specific MMPs in pathophysiology obtained with animal models, including knockout studies.
Jul 24, 2007 Space and time in visual context
  No sensory stimulus is an island unto itself; rather, it can only properly be interpreted in light of the stimuli that surround it in space and time. This can result in entertaining illusions and puzzling results in psychological and neurophysiological experiments. We concentrate on perhaps the best studied test case, namely orientation or tilt, which gives rise to the notorious tilt illusion and the adaptation tilt after-effect. We review the empirical literature and discuss the computational and statistical ideas that are battling to explain these conundrums, and thereby gain favour as more general accounts of cortical processing.
Jul 23, 2007 Calcium and cancer: targeting Ca2+ transport
  Ca(2+) is a ubiquitous cellular signal. Altered expression of specific Ca(2+) channels and pumps are characterizing features of some cancers. The ability of Ca(2+) to regulate both cell death and proliferation, combined with the potential for pharmacological modulation, offers the opportunity for a set of new drug targets in cancer. However, the ubiquity of the Ca(2+) signal is often mistakenly presumed to thwart the specific therapeutic targeting of proteins that transport Ca(2+). This Review presents evidence to the contrary and addresses the question: which Ca(2+) channels and pumps should be targeted?
Jul 22, 2007 Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases
  Aggregation of hyperphosphorylated tau is one of the characteristic neuropathological lesions of Alzheimer's disease and other neurodegenerative disorders. Pharmacological modulation of tau hyperphosphorylation might represent a valid and feasible therapeutic strategy for such disorders. Here, we consider recent evidence supporting the validity of the three most relevant kinases affecting tau hyperphosphorylation - GSK3beta, CDK5 and ERK2 - as drug targets and describe progress in the design of inhibitors for these kinases.
Jul 21, 2007 Signal integration in the endoplasmic reticulum unfolded protein response
  The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways - cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.
Jul 20, 2007 SOCS proteins, cytokine signalling and immune regulation
  Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Studies have shown that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. Evidence is also emerging of the involvement of SOCS proteins in diseases of the immune system. In this Review we bring together data from recent studies on SOCS proteins and their role in immunity, and propose a cohesive model of how cytokine signalling regulates immune-cell function.
Jul 19, 2007 The nuclear envelope and transcriptional control
  Cells have evolved sophisticated multi-protein complexes that can regulate gene activity at various steps of the transcription process. Recent advances highlight the role of nuclear positioning in the control of gene expression and have put nuclear envelope components at centre stage. On the inner face of the nuclear envelope, active genes localize to nuclear-pore structures whereas silent chromatin localizes to non-pore sites. Nuclear-pore components seem to not only recruit the RNA-processing and RNA-export machinery, but contribute a level of regulation that might enhance gene expression in a heritable manner.
Jul 18, 2007 Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets
  The involvement of the RAS superfamily of monomeric GTPases in carcinogenesis is increasingly being appreciated. A complex array of post-translational modifications and a highly sophisticated protein network regulate the spatio-temporal activation of these GTPases. Previous attempts to pharmacologically target this family have focused on the development of farnesyltransferase inhibitors, but the performance of such agents in cancer clinical trials has not been as good as hoped. Here, we review emerging druggable targets and novel therapeutic approaches targeting prenylation and post-prenylation modifications and the functional regulation of GDP/GTP exchange as exciting alternatives for anticancer therapy.
Jul 17, 2007 Intracellular amyloid-β in Alzheimer’s disease
  The primal role that the amyloid-beta (Abeta) peptide has in the development of Alzheimer's disease is now almost universally accepted. It is also well recognized that Abeta exists in multiple assembly states, which have different physiological or pathophysiological effects. Although the classical view is that Abeta is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.
Jul 16, 2007 The cofilin pathway in breast cancer invasion and metastasis
  Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.
Jul 15, 2007 The role of junctional adhesion molecules in vascular inflammation
  Junctional adhesion molecules (JAMs) of the immunoglobulin superfamily are important in the control of vascular permeability and leukocyte transmigration across endothelial-cell surfaces, by engaging in homophilic, heterophilic and lateral interactions. Through their localization on the endothelial-cell surface and expression by platelets, JAMs contribute to adhesive interactions with circulating leukocytes and platelets. Antibody-blocking studies and studies using genetically modified mice have implicated these functions of JAMs in the regulation of leukocyte recruitment to sites of inflammation and ischaemia-reperfusion injury, in growth-factor-mediated angiogenesis, atherogenesis and neointima formation. The comparison of different JAM-family members and animal models, however, shows that the picture remains rather complex. This Review summarizes recent progress and future directions in understanding the role of JAMs as 'gate keepers' in inflammation and vascular pathology.
Jul 14, 2007 RNA regulons: coordination of post-transcriptional events
  Recent findings demonstrate that multiple mRNAs are co-regulated by one or more sequence-specific RNA-binding proteins that orchestrate their splicing, export, stability, localization and translation. These and other observations have given rise to a model in which mRNAs that encode functionally related proteins are coordinately regulated during cell growth and differentiation as post-transcriptional RNA operons or regulons, through a ribonucleoprotein-driven mechanism. Here I describe several recently discovered examples of RNA operons in budding yeast, fruitfly and mammalian cells, and their potential importance in processes such as immune response, oxidative metabolism, stress response, circadian rhythms and disease. I close by considering the evolutionary wiring and rewiring of these combinatorial post-transcriptional gene-expression networks.
Jul 13, 2007 Utilizing RNA interference to enhance cancer drug discovery
  With the development of RNA interference (RNAi) libraries, systematic and cost-effective genome-wide loss-of-function screens can now be carried out with the aim of assessing the role of specific genes in neoplastic phenotypes, and the rapid identification of novel drug targets. Here, we discuss the existing applications of RNAi in cancer drug discovery and highlight areas in this process that may benefit from this technology in the future.
Jul 12, 2007 Neural mechanisms of aggression
  Unchecked aggression and violence exact a significant toll on human societies. Aggression is an umbrella term for behaviours that are intended to inflict harm. These behaviours evolved as adaptations to deal with competition, but when expressed out of context, they can have destructive consequences. Uncontrolled aggression has several components, such as impaired recognition of social cues and enhanced impulsivity. Molecular approaches to the study of aggression have revealed biological signals that mediate the components of aggressive behaviour. These signals may provide targets for therapeutic intervention for individuals with extreme aggressive outbursts. This Review summarizes the complex interactions between genes, biological signals, neural circuits and the environment that influence the development and expression of aggressive behaviour.
Jul 11, 2007 Life and death in peripheral T cells
  During the course of an immune response, antigen-reactive T cells clonally expand and then are removed by apoptosis to maintain immune homeostasis. Life and death of T cells is determined by multiple factors, such as T-cell receptor triggering, co-stimulation or cytokine signalling, and by molecules, such as caspase-8 (FLICE)-like inhibitory protein (FLIP) and haematopoietic progenitor kinase 1 (HPK1), which regulate the nuclear factor-kappaB (NF-kappaB) pathway. Here, we discuss the concepts of activation-induced cell death (AICD) and activated cell-autonomous death (ACAD) in the regulation of life and death in T cells.
Jul 10, 2007 Chromatin crosstalk in development and disease: lessons from REST
  Protein complexes that contain chromatin-modifying enzymes have an important role in regulating gene expression. Recent studies have shown that a single transcription factor, the repressor element 1-silencing transcription factor (REST), can act as a hub for the recruitment of multiple chromatin-modifying enzymes, uncovering interdependencies among individual enzymes that affect gene regulation. Research into the function of REST and its corepressors has provided novel insight into how chromatin-modifying proteins cooperate, and how alterations in this function cause disease. These mechanisms will be relevant to the combinatorial functioning of modular transcriptional regulators that work together to regulate a common promoter; they should also identify targets for potential therapies for a range of human diseases.
Jul 9, 2007 Morphogens, morphostats, microarchitecture and malignancy
  Morphogenetic fields organize tissue morphology in the embryo. By analogy, morphostatic fields maintain normal cell behaviour and normal tissue microarchitecture in the adult. The most prominent feature of cancer is the disruption of tissue microarchitecture. Cancer occurs much more frequently when morphostatic influences fail (metaplasia) or at the junction of two different morphostatic fields. This Review will describe what we know about morphostats and morphostasis, discuss the evidence for the role of disruption of morphostasis in malignancy, and address some testable hypotheses.
Jul 8, 2007 The perfect mix: recent progress in adjuvant research
  Developing efficient and safe adjuvants for use in human vaccines remains both a challenge and a necessity. Past approaches have been largely empirical and generally used a single type of adjuvant, such as aluminium salts or emulsions. However, new vaccine targets often require the induction of well-defined cell-mediated responses in addition to antibodies, and thus new immunostimulants are required. Recent advances in basic immunology have elucidated how early innate immune signals can shape subsequent adaptive responses and this, coupled with improvements in biochemical techniques, has led to the design and development of more specific and focused adjuvants. In this Review, I discuss the research that has made it possible for vaccinologists to now be able to choose between a large panel of adjuvants, which potentially can act synergistically, and combine them in formulations that are specifically adapted to each target and to the relevant correlate(s) of protection.
Jul 7, 2007 Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies
  The enteric nervous system (ENS) has been explored by developmental neurobiologists and medical researchers for decades. Whereas developmental biologists have been unravelling the molecular mechanisms underlying the migration, proliferation and differentiation of the neural crest derivatives that give rise to the ENS, human geneticists have been uncovering the genetic basis for diseases of the ENS, notably Hirschsprung's disease. Here we discuss the exciting recent advances, including novel transgenic and genetic tools, a broadening range of model organisms, and the pursuit of ENS stem cells as a therapeutic tool, that are bringing these fields closer together.
Jul 6, 2007 Control points in NKT-cell development
  CD1d-dependent natural killer T (NKT) cells are a unique T-cell subset with the ability to regulate the immune system in response to a broad range of diseases. That low NKT-cell numbers are associated with many different disease states in mice and humans, combined with the fact that NKT-cell numbers vary widely between individuals, makes it crucial to understand how these cells develop and how their numbers are maintained. Here, we review the current state of knowledge of NKT-cell development and attempt to highlight the most important questions in this field.
Jul 5, 2007 CDC25 phosphatases in cancer cells: key players? Good targets?
  Cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell cycle phases during normal cell division, and in the event of DNA damage they are key targets of the checkpoint machinery that ensures genetic stability. Taking only this into consideration, it is not surprising that CDC25 overexpression has been reported in a significant number of human cancers. However, in light of the significant body of evidence detailing the stringent complexity with which CDC25 activities are regulated, the significance of CDC25 overexpression in a subset of cancers and its association with poor prognosis are proving difficult to assess. We will focus on the roles of CDC25 phosphatases in both normal and abnormal cell proliferation, provide a critical assessment of the current data on CDC25 overexpression in cancer, and discuss both current and future therapeutic strategies for targeting CDC25 activity in cancer treatment.
Jul 4, 2007 Transposable elements and the epigenetic regulation of the genome
  Overlapping epigenetic mechanisms have evolved in eukaryotic cells to silence the expression and mobility of transposable elements (TEs). Owing to their ability to recruit the silencing machinery, TEs have served as building blocks for epigenetic phenomena, both at the level of single genes and across larger chromosomal regions. Important progress has been made recently in understanding these silencing mechanisms. In addition, new insights have been gained into how this silencing has been co-opted to serve essential functions in 'host' cells, highlighting the importance of TEs in the epigenetic regulation of the genome.
Jul 3, 2007 Xenotransplantation: current status and a perspective on the future
  Xenotransplantation using pigs as the transplant source has the potential to resolve the severe shortage of human organ donors. Although the development of relatively non-toxic immunosuppressive or tolerance-inducing regimens will be required to justify clinical trials using pig organs, recent advances in our understanding of the biology of xenograft rejection and zoonotic infections, and the generation of alpha1,3-galactosyltransferase-deficient pigs have moved this approach closer to clinical application. This Review highlights the major obstacles impeding the translation of xenotransplantation into clinical therapies and the potential solutions, providing a perspective on the future of clinical xenotransplantation.
Jul 2, 2007 Universal strategies in research and drug discovery based on protein-fragment complementation assays
  Changes in the interactions among proteins that participate in a biochemical pathway can reflect the immediate regulatory responses to intrinsic or extrinsic perturbations of the pathway. Thus, methods that allow for the direct detection of the dynamics of protein-protein interactions can be used to probe the effects of any perturbation on any pathway of interest. Here we describe experimental strategies - based on protein-fragment complementation assays (PCAs) - that can achieve this. PCA-based strategies can be used with or instead of traditional target-based drug discovery strategies to identify novel pathway-component proteins of therapeutic interest, to increase the quantity and quality of information about the actions of potential drugs, and to gain insight into the intricate networks that make up the molecular machinery of living cells.
Jul 1, 2007 Cell-cycle control and cortical development
  The spatio-temporal timing of the last round of mitosis, followed by the migration of neuroblasts to the cortical plate leads to the formation of the six-layered cortex that is subdivided into functionally defined cortical areas. Whereas many of the cellular and molecular mechanisms have been established in rodents, there are a number of unique features that require further elucidation in primates. Recent findings both in rodents and in primates indicate that regulation of the cell cycle, specifically of the G1 phase has a crucial role in controlling area-specific rates of neuron production and the generation of cytoarchitectonic maps.

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