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 September August July June May April March February January 2003 2002 2001

October 31,2004 Drug delivery of oligonucleotides by peptides
  Oligonucleotides are promising tools for in vitro studies where specific downregulation of proteins is required. In addition, antisense oligonucleotides have been studied in vivo and have entered clinical trials as new chemical entities with various therapeutic targets such as antiviral drugs or for tumour treatments. The formulation of these substances were widely studied in the past. With this review we will focus on peptides used as drug delivery vehicles for oligonucleotides. Different strategies are summarised. Cationically charged peptides from different origins were used e.g. as cellular penetration enhancers or nuclear localisation tool. Examples are given for Poly-L-lysine alone or in combination with receptor specific targeting ligands such as asialoglycoprotein, galactose, growth factors or transferrin.
October 30,2004 Oxidative DNA damage and disease
  The generation of reactive oxygen species may be both beneficial to cells, performing a function in inter- and intracellular signalling, and detrimental, modifying cellular biomolecules, accumulation of which has been associated with numerous diseases. Of the molecules subject to oxidative modification, DNA has received the greatest attention, with biomarkers of exposure and effect closest to validation. Despite nearly a quarter of a century of study, and a large number of base- and sugar-derived DNA lesions having been identified, the majority of studies have focussed upon the guanine modification, 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-OH-dG).For the most part, the biological significance of other lesions has not, as yet, been investigated.
October 29,2004 Pathophysiology of Vascular Calcification in Chronic Kidney Disease
  Patients with chronic kidney disease (CKD) on dialysis have 2- to 5-fold more coronary artery calcification than age-matched individuals with angiographically proven coronary artery disease. In addition to increased traditional risk factors, CKD patients also have a number of nontraditional cardiovascular risk factors that may play a prominent role in the pathogenesis of arterial calcification, including duration of dialysis and disorders of mineral metabolism. In histological specimens from the inferior epigastric artery of dialysis patients, we have found expression of the osteoblast differentiation factor core binding factor α-1 (Cbfa1) and several bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen) in both the intima and medial layers when calcification was present.
October 28,2004 Interactions of viruses with the cellular DNA repair machinery
  Mammalian cells are equipped with complex machinery to monitor and repair damaged DNA. In addition to responding to breaks in cellular DNA, recent studies have revealed that the DNA repair machinery also recognizes viral genetic material. We review some examples that highlight the different strategies that viruses have developed to interact with the host DNA repair apparatus. While adenovirus (Ad) inactivates the host machinery to prevent signaling and concatemerization of the viral genome, other viruses may utilize DNA repair to their own advantage. Viral interactions with the repair machinery can also have detrimental consequences for the host cells and their ability to maintain the integrity of the host genome.
October 27,2004 Telomere dysfunction in genome instability syndromes
  Telomeres are nucleoprotein complexes located at the end of eukaryotic chromosomes. They have essential roles in preventing terminal fusions, protecting chromosome ends from degradation, and in chromosome positioning in the nucleus. These terminal structures consist of a tandemly repeated DNA sequence (TTAGGG in vertebrates) that varies in length from 5 to 15 kb in humans. Several proteins are attached to this telomeric DNA, some of which are also involved in different DNA damage response pathways, including Ku80, Mre11, NBS and BLM, among others. Mutations in the genes encoding these proteins cause a number of rare genetic syndromes characterized by chromosome and/or genetic instability and cancer predisposition.
October 26,2004 signaling cells in the immune continuum
  Platelets have intricate signaling mechanisms and participate in a breadth of cellular interactions. This diversity is frequently unrecognized. In addition to being the chief cellular effectors of haemostasis, platelets are innate inflammatory cells that have previously unrecog-nized molecular pathways and synthetic capacities, which can link innate and adaptive responses in the immune continuum. Characterization of these features and parallel in vivo observations identify new sentinel, surveillance and information-transfer functions. Recent observations indicate that platelets have key roles in adaptive responses to microbial and antigen challenge, in addition to their well known acute defensive activities in tissue injury, and suggest that these mechanisms can be dysregulated in disease.
October 25,2004 The p53 response to DNA damage
  The p53 tumour suppressor protein is a highly potent transcription factor which, under normal circumstances, is maintained at low levels through the action of MDM2, an E3 ubiquitin ligase which directs p53 ubiquitylation and degradation. Expression of the mdm2 gene is stimulated by p53 and this reciprocal relationship forms the basis of a negative feedback loop. Both genotoxic and non-genotoxic stresses that induce p53 focus principally on interruption of the p53-MDM2 loop with the consequence that p53 becomes stabilised, leading to changes in the expression of p53-responsive genes. The biological outcome of inducing this pathway can be either growth arrest or apoptosis: factors affecting the functioning of the loop, the biochemical activity of p53 itself and the cellular environment govern the choice between these outcomes in a cell type- and stress-specific manner.
October 24,2004 Risk factors for low birth weight: a review
  Low birth weight (LBW) is one of the main predictors of infant mortality. The global incidence of LBWis around 17%, although estimates vary from 19% in the developing countries (countries where it is an important public health problem) to 5–7% in the developed countries. The incidence in Spain in the decade 1980–1989 was about 5.7%. LBW is generally associated with situations in which uterine malnutrition is produced due to alterations in placental circulation. There are many known risk factors, the most important of which are socio-economic factors, medical risks before or during gestation and maternal lifestyles. However, although interventions exist to prevent many of these factors before and during pregnancy, the incidence of LBW has not decreased.
October 23,2004 The role of platelet inhibition in the drug-eluting stent era
  The use of antiplatelet agents in the management of patients undergoing percutaneous coronary interventions involves the administration of aspirin, thienopyridines, and in high-risk patients, GPIIb-IIIa antagonists. Drug-eluting stents now account for greater than 50% of stenting procedures. This review focuses on the limited available data describing the use of antiplatelet agents in patients undergoing drug-eluting stent implantation.
October 22,2004 Genetic mutant screening by direct metabolite analysis
  The elucidation of metabolic pathways in bacteria and eukaryotes would have been considerably more diffcult if it had not been for the availability of genetic mutants impaired in specific aspects of metabolism.The traditional approach has been to isolate metabolic mutants of bacterial or unicellular eukaryotic genetic model organisms,which require the supply of an essen- tial metabolite for growth on a defined minimal medium (auxotrophy).The analysis of auxotrophic mutants has led to a deep understanding of the essential pathways of central metabolism in model organisms,and broad aspects of animal and plant metabolism could be inferred from these studies.
October 21,2004 The genomics of gene expression
  The study of gene regulation on a genomic scale has been constrained by the modest pace with which new trans-regulatory factors have been identified and by the fact that cis-regulatory sequences have to date been described even in part for only a small fraction of vertebrate genes. An indirect approach for assessing the significance of cis- and trans-regulatory mechanisms on a global scale is to utilize gene expression as a surrogate for transcriptional regulation and to combine genome-scale transcriptional profiling with studies of genetic variation, classical genetic techniques such as linkage analysis, and examination of allelic expression patterns that reveal cis-regulatory variability.
October 20,2004 INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS AS SIGNAL INTEGRATORS
  The inositol 1,4,5 trisphosphate (IP3 ) receptor (IP3 R) is a Ca 2+ release channel that responds to the second messenger IP3 . Exquisite modulation of intracellular Ca 2+ release via IP3 Rs is achieved by the ability of IP3 R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only ~5% of the IP3 R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP3 R modulates diverse cellular functions, which include, but are not limited to, contrac-tion/ excitation, secretion, gene expression, and cellular growth.
October 19,2004 PATHWAYS OF APOPTOTIC AND NON-APOPTOTIC DEATH IN TUMOUR CELLS
  Defects in cell-death pathways are hallmarks of cancer. Although resistance to apoptosis is closely linked to tumorigenesis, tumour cells can still be induced to die by non-apoptotic mechanisms, such as necrosis, senescence, autophagy and mitotic catastrophe. The molecular pathways that underlie these non-apoptotic responses remain unclear. Several apoptotic and non-apoptotic pathways of cell death have been defined in normal physiology and during tumorigenesis, and these could potentially be manipulated to develop new cancer therapies. The mitotic-checkpoint molecule survivin — the inactivation of which induces the death of p53-deficient cells by mitotic catastrophe — is of particular interest.
October 18,2004 ANALYZING CELLULAR BIOCHEMISTRY IN TERMS OF MOLECULAR NETWORKS
  One way to understand cells and circumscribe the function of proteins is through molecular networks. These networks take a variety of forms including webs of protein-protein interactions, regulatory circuits linking transcription factors and targets, and complex pathways of metabolic reactions. We first survey experi-mental techniques for mapping networks . We then turn our attention to computational approaches for predicting networks from individual protein features, such as correlating gene expression levels or analyzing sequence coevolution. All the experimental techniques and individual predictions suffer from noise and systematic biases.
October 17,2004 AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS
  The present reviewfocuses on the concept that cellular and humoral im-munity to the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is the initiating mechanism in the earliest stages of atherosclerosis. Subjecting arte-rial endothelial cells to classical atherosclerosis risk factors leads to the expression of HSP60 that then may serve as a target for pre-existent cross-reactive antimicro-bial HSP60 immunity or bona fide autoimmune reactions induced by biochemically altered autologous HSP60. Endothelial cells can also bind microbial or autologous HSP60 via Toll-like receptors, providing another possibility for targetting adaptive or innate immunological effector mechanisms.
October 16,2004 CHEMOTAXIS: SIGNALLING THE WAY FORWARD
  During random locomotion, human neutrophils and Dictyostelium discoideum amoebae repeatedly extend and retract cytoplasmic processes. During directed cell migration — chemotaxis — these pseudopodia form predominantly at the leading edge in response to the local accumulation of certain signalling molecules. Concurrent changes in actin and myosin enable the cell to move towards the stimulus. Recent studies are beginning to identify an intricate network of signalling molecules that mediate these processes, and how these molecules become localized in the cell is now becoming clear.
October 15,2004 THE ROLE OF WATER IN PROTEIN-DNA RECOGNITION
  Is it by design or by default that water molecules are observed at the interfaces of some protein-DNA complexes? Both experimental and theoretical studies on the thermodynamics of protein-DNA binding overwhelmingly support the extended hydrophobic view that water release from interfaces favors binding. Structural and en-ergy analyses indicate that the waters that remain at the interfaces of protein-DNA complexes ensure liquid-state packing densities, screen the electrostatic repulsions be-tween like charges (which seems to be by design), and in a few cases act as linkers between complementary charges on the biomolecules (which may well be by default).
October 14,2004 Cardiac ion channel expression and regulation
  The expression and function of numerous cardiac ion channels change with development and disease. Whereas multiple regulatory processes and molecular mechanisms are certainly involved, one factor, sympathetic innervation, contributes to many of the developmental changes and is suggested to play a role in pathology. The onset of cardiac sympathetic innervation of the mammalian ventricle during early post-natal life has been associated with functional alterations in several ionic currents, including Na + , L-type Ca 2+ , pacemaker, inward rectifier and transient outward K + currents.
October 13,2004 MOLECULAR MACHINES
  Molecular machines are tiny energy conversion devices on the mole-cular- size scale. Whether naturally occurring or synthetic, these machines are generally more efficient than their macroscale counterparts. They have their own mechanochem-istry, dynamics, workspace, and usability and are composed of nature’s building blocks: namely proteins, DNA, and other compounds, built atom by atom. With modern sci-entific capabilities it has become possible to create synthetic molecular devices and interface them with each other.
October 12,2004 Model systems in stem cell biology
  Stem cell scientists and ethicists have focused intently on questions relevant to the developmental stage and developmental capacities of stem cells. Comparably less attention has been paid to an equally important set of questions about the nature of stem cells, their common characteristics, their non-negligible differences and their possible developmental species specificity. Answers to these questions are essential to the project of justly inferring anything about human stem cell biology from studies in non-human model systems—and so to the possibility of eventually developing human therapies based on stem cell biology. After introducing and discussing these questions, I conclude with a brief discussion of the creation of novel model systems in stem cell biology: human-to-animal embryonic chimeras.
October 11,2004 MAPPING AND SEQUENCING COMPLEX GENOMES
  Physical maps provide an essential framework for ordering and joining sequence data, genetically mapped markers and large-insert clones in eukaryotic genome projects. A good physical map is also an important resource for cloning specific genes of interest, comparing genomes, and understanding the size and complexity of a genome. Although physical maps are usually taken at face value, a good deal of technology, molecular biology and statistics goes into their making. Understanding the science behind map building is important if users are to critically assess, use and build physical maps.
October 10,2004 A Firm Link to Endothelial Cell Dysfunction
  The advanced glycation end products (AGEs) are a heterogeneous class of molecules, including the following main subgroups: bis(lysyl)imidazolium cross-links, hydroimidazolones, 3-deoxyglucosone derivatives, and monolysyl adducts. AGEs are increased in diabetes, renal failure, and aging. Microvascular lesions correlate with the accumulation of AGEs, as demonstrated in diabetic retinopathy or renal glomerulosclerosis. On endothelial cells, ligation of receptor for AGE (RAGE) by AGEs induces the expression of cell adhesion molecules, tissue factor, cytokines such as interleukin-6, and monocyte chemoattractant protein-1.
October 9,2004 Mining our ABCs
  The association of transporter proteins and cancer drug resistance has been known for approximately 25 years, with recent discoveries pointing to an ever-increasing number of ATP binding cassette (ABC) transporter proteins involved with the response of cancer cells to pharmacotherapy. As reported in this issue of Cancer Cell, Szakács et al. couple quantitative, real-time PCR assays for all 48 human ABC transporters with chemosensitivity information mined from the NCI-60 cancer cell line database. Predictions of transporter involvement in drug effect were validated in selected cases, and furthermore produced novel leads relating ABC transporter expression and chemoresistance or chemosensitivity.
October 8,2004 THE EXCITEMENT OF DISCOVERY
  I had the good luck to start research at the dawn of molecular biology when it was possible to ask fundamental questions about the nature of the nucleic acids and how information is transferred in living systems. The search for answers led me into many different areas, often with the question of how molecular structure leads to biological function. Early work in this period provided some of the roots supporting the current explosive developments in life sciences. Here I give a brief account of my development, describe some contributions, and provide a hint of the exhilaration in discovering new things. Most of all, I had the good fortune to have inspiring teachers, stimulating colleagues, and excellent students.
October 7,2004 Prospects for an AIDS vaccine
  The unremitting devastation created by the AIDS pandemic will probably only be controlled when a vaccine is developed that is safe, effective, affordable, and simple enough to permit implementation in developing countries where the impact of AIDS is most severe. Although formidable practical, political, economic, social, and ethical challenges face the AIDS vaccine development effort, the most fundamental challenges now reside at the level of the basic biology of HIV-1 infection and pathogenesis. Of these biological considerations, three questions loom especially large.
October 6,2004 T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS
  Human vascular endothelial cells (EC) basally display class I and II MHC-peptide complexes on their surface and come in regular contact with circulating T cells. We propose that EC present microbial antigens to memory T cells as a mechanism of immune surveillance. Activated T cells, in turn, provide both soluble and contact-dependant signals to modulate normal EC functions, including formation and remodeling of blood vessels, regulation of blood flow, regulation of blood fluidity, maintenance of permselectivity, recruitment of inflammatory leukocytes, and antigen presentation leading to activation of T cells.
October 5,2004 Vaccine and antibody-directed T cell tumour immunotherapy
  Clearer evidence for immune surveillance in malignancy and the identification of many new tumour-associated antigens (TAAs) have driven novel vaccine and antibody-targeted responses for therapy in cancer. The exploitation of active immunisation may be particularly favourable for TAAwhere tolerance is incomplete but passive immunisation may offer an additional strategy where the immune repertoire is affected by either tolerance or immune suppression. This review will consider how to utilise both active and passive types of therapy delivered by T cells in the context of the failure of tumour-specific immunity by presenting cancer patients.
October 4,2004 PHOSPHOINOSITIDE 3-KINASE
  Cells of the immune system carry out diverse functions that are controlled by surface receptors for antigen, costimulatory molecules, cytokines, chemokines, and other ligands. A shared feature of signal transduction downstream of most receptors on immune cells, as in nonhematopoietic cell types, is the activation of phosphoinositide 3-kinase (PI3K). The mechanism by which this common signaling event is elicited by distinct receptors and contributes to unique functional outcomes is an intriguing puzzle. Understanding how specificity is achieved in PI3K signaling is of particular significance because altered regulation of this pathway is observed in many disease states, including leukemia and lymphoma.
October 3,2004 Update on Statins
  The number of significant developments in the years since the first version of this review has made necessary an update about the evolving role of 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, in the management and prevention of cardiovascular disease.1 Two contrasting events have dominated the statin field in the last 3 years. First, the withdrawal of cerivastatin in 2001 reignited the issue of statin safety. Second, the efficacy and safety of statins in both the primary and secondary prevention of cardiovascular disease in diverse patient populations have helped shape the most recent set of guidelines from the National Cholesterol Education Program (NCEP).2 The NCEP’s Third Adult Treatment Panel (ATP III) forms the basis for contemporary lipid management.
October 2,2004 LYSOPHOSPHOLIPID RECEPTORS
  Lysophospholipids (LPs), such as lysophosphatidic acid and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators. LPs can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis. In recent years, identification of multiple cognate G protein-coupled receptors has provided a mechanistic framework for understanding how LPs play such diverse roles.
October 1,2004 Serial analysis of gene expression (SAGE)
  Serial analysis of gene expression (SAGE) is a powerful technique that can be used for global analysis of gene expression. Its chief advantage over other methodsis that it does not require prior knowledge of the genes of interest and provides qualitative and quantitative data of potentially every transcribed sequence in a particular cell or tissue type. This is a technique of expression profiling, which permits simultaneous, comparative and quantitative analysis of gene-specific, 9- to 13-basepair sequences. These short sequences, called SAGE tags, are linked together for efficient sequencing. The sequencing data are then analyzed to identify each gene expressed in the cell and the levels at which each gene is expressed.

September August July June May April March February January 2003 2002 2001