Endothelial membrane reorganization during leukocyte extravasation

Leukocyte trafficking from the bloodstream to inflamed tissues across the endothelial barrier is an essential response in innate immunity. Leukocyte adhesion, locomotion, and diapedesis induce signaling in endothelial cells and this is accompanied by a profound reorganization of the endothelial cell surfaces that is only starting to be unveiled. Here we review the current knowledge on the leukocyte-mediated alterations of endothelial membrane dynamics and their role in promoting leukocyte extravasation. The formation of protein- and lipid-mediated cell adhesion nanodomains at the endothelial apical surface, the extension of micrometric apical membrane docking structures, which are derived from microvilli and embrace adhered leukocytes, as well as the vesicle-trafficking pathways that are required for efficient leukocyte diapedesis, are discussed. The coordination between these different endothelial membrane-remodeling events probably provides the road map for transmigrating leukocytes to find exit points in the vessel wall, in a context of severe mechanical and inflammatory stress. A better understanding of how vascular endothelial cells respond to immune cell adhesion should enable new therapeutic strategies to be developed that can abrogate uncontrolled leukocyte extravasation in inflammatory diseases.     

Recent insights into the role of integrins in cancer metastasis

Integrins have been repeatedly found involved in cancer metastasis. The past two years have seen considerable evolution in our knowledge on the role of these integrins in tumour cells. This includes the elucidation of different signalling pathways by which integrins dictate the anchorage-independent growth, survival and motility of tumour cells. Moreover, integrins may have a more complex role in cancer metastasis as they cooperate with serine proteases and metalloproteases to promote tumour cell invasion and angiogenesis. Finally, integrins favour tumor cell extravasation.     

Recent insights into the biology and biomedical applications of Flock House virus

Flock House virus (FHV) is a nonenveloped, icosahedral insect virus whose genome consists of two molecules of single-stranded, positive-sense RNA. FHV is a highly tractable system for studies on a variety of basic aspects of RNA virology. In this review, recent studies on the replication of FHV genomic and subgenomic RNA are discussed, including a landmark study on the ultrastructure and molecular organization of FHV replication complexes. In addition, we show how research on FHV B2, a potent suppressor of RNA silencing, resulted in significant insights into antiviral immunity in insects. We also explain how the specific packaging of the bipartite genome of this virus is not only controlled by specific RNA-protein interactions but also by coupling between RNA replication and genome recognition. Finally, applications for FHV as an epitopepresenting system are described with particular reference to its recent use for the development of a novel anthrax antitoxin and vaccine.     

Novel insights into the biology of interleukin-32

Interleukin (IL)-32 is known as a proinflammatory cytokine that is likely involved in several diseases, including infections, chronic inflammation, and cancer. Since the first report in 2005, IL-32 has been the subject of numerous studies to unravel the biological function of this molecule. For example, silencing of endogenous IL-32 in primary or cell lines of human origin consistently suppressed responses to Toll-like receptors. The protein folding structure of the six isoforms of IL-32 does not resemble that of any classical cytokine and as of this writing, a specific IL-32 receptor has not been identified. Instead, we propose a mechanism by which exposure to extracellular IL-32 or overexpression of the molecule results in binding to intracellular partners that influences functions such as gene expression, cell death, or survival. As such, this review offers insights into the role of IL-32 in several diseases, host defense, inflammation, immune function, and cancer. Finally, possibilities to target IL-32 in several diseases are proposed.     

Molecular insights into the novel aspects of diatom biology

Diatoms are unicellular photosynthetic eukaryotes that are thought to contribute as much as 25% of global primary productivity. In spite of their ecological importance in the worlds oceans, very little information is available at the molecular level about the novel aspects of their biology. Recent advances, such as the development of gene transfer protocols, are now allowing the genetic dissection of diatom biology. Notable examples are advances in understanding the genetic basis for the silica-based bioinorganic pattern formation of their cell walls and for elucidating key aspects of diatom ecophysiology. The potentiation of current research will allow an evaluation of the use of diatoms to construct submicrometre-scale silicon structures for the nanotechnology industry and will reveal the molecular secrets underlying their ecological success. Received 29 March 2001; received after revision 31 May 2001; accepted 31 May 2001     

New insights into the molecular mechanisms of sperm-egg interaction

At the moment of insemination millions of mammalian sperm cells are released into the female reproductive tract in order to find a single cell – the oocyte. The spermatozoa subsequently ignore the thousands of cells they make contact with during their journey to the site of fertilisation, until they reach the surface of the oocyte. At this point, they bind tenaciously to the acellular coat, known as the zona pellucida, that surrounds the oocyte and initiate the chain of cellular interactions that will culminate in fertilization. These exquisitely cell- and species-specific recognition events are among the most strategically important cellular interactions in biology. Understanding the cellular and molecular mechanisms that underpin them has implications for diagnosis of the aetiology of human infertility and the development of novel targets for fertility regulation. Herein, we describe two models indicating the plethora of highly orchestrated molecular interactions underlying successful sperm zona binding and sperm oocyte fusion. Received 17 December 2006; received after revision 31 January 2007; accepted 16 March 2007     

Structural insights into the multiple functions of protein C inhibitor

Protein C inhibitor (PCI) is a widely distributed, multifunctional member of the serpin family of protease inhibitors, and has been implicated in several physiological processes and disease states. Its inhibitory activity and specificity are regulated by binding to cofactors such as heparin, thrombomodulin and phospholipids, and it also appears to have non-inhibitory functions related to hormone and lipid binding. Just how the highly conserved serpin architecture can support the multiple diverse functions of PCI is a riddle best addressed by protein crystallography. Over the last few years we have solved the structure of PCI in its native, cleaved and protein-complexed states. They reveal a conserved serpin fold and general mechanism of protease inhibition, but with some unique features relating to inhibitory specificity/promiscuity, cofactor binding and hydrophobic ligand transport. Received 1 July 2008; received after revision 16 August 2008; accepted 22 August 2008     

The human selenoproteome: recent insights into functions and regulation

Selenium (Se) is a nutritional trace mineral essential for various aspects of human health that exerts its effects mainly through its incorporation into selenoproteins as the amino acid, selenocysteine. Twenty-five selenoprotein genes have been identified in humans and several selenoproteins are broadly classified as antioxidant enzymes. As progress is made on characterizing the individual members of this protein family, however, it is becoming clear that their properties and functions are quite diverse. This review summarizes recent insights into properties of individual selenoproteins such as tissue distribution, subcellular localization, and regulation of expression. Also discussed are potential roles the different selenoproteins play in human health and disease.     

Studies of bone matrix molecules give us insights into bone remodelling

Bone is one of the most dynamic tissues, with constant remodelling and repair of minor defects during the whole life cycle. These processes have key roles in replacing fatigued, non-functional tissue with fresh tissue which has the proper mechanical properties. In this process, a balance between breakdown of less functional tissue and new tissue production is a prerequisite for tissue integrity and function. One of the major health problems in the elderly, i.e. osteoporosis and ensuing bone fracture, is caused by an imbalance between breakdown and synthesis in this continuous bone remodelling. Thus the study of cellular and molecular events governing the relevant processes is a prerequisite for understanding mechanisms and for future efficient therapeutical intervention.     

Mechanistic insights into the efficacy of cell penetrating peptide-based cancer vaccines

Immunotherapies are increasingly used to treat cancer, with some outstanding results. Immunotherapy modalities include therapeutic vaccination to eliminate cancer cells through the activation of patient’s immune system against tumor-derived antigens. Nevertheless, the full potential of therapeutic vaccination has yet to be demonstrated clinically because many early generation vaccines elicited low-level immune responses targeting only few tumor antigens. Cell penetrating peptides (CPPs) are highly promising tools to advance the field towards clinical success. CPPs efficiently penetrate cell membranes, even when linked to antigenic cargos, which can induce both CD8 and CD4 T-cell responses. Pre-clinical studies demonstrated that targeting multiple tumor antigens, even those considered to be poorly immunogenic, led to tumor regression. Therefore, CPP-based cancer vaccines represent a flexible and powerful means to extend therapeutic vaccination to many cancer indications. Here, we review recent findings in CPP development and discuss their use in next generation immunotherapies.     

New insights into the metabolic and molecular basis for diabetic neuropathy

Diabetic polyneuropathy is the most common complication of diabetes mellitus. Several interactive pathogenetic mechanisms have been identified mainly in streptozotocin-induced diabetes in rats and have been ascribed to hyperglycemia. Over the last number of years it is becoming increasingly clear that diabetic neuropathy differs in type 1 and type 2 diabetes in humans and in murine models that more accurately mimic the human disorders. Beside hyperglycemia, attention is increasingly being paid to the pathogenetic roles of insulin and C-peptide deficiencies, particularly in type 1 diabetic neuropathy. There is now evidence to suggest that insulin and C-peptide deficiencies are mainly responsible for perturbations of neurotrophic factors and contribute to oxidative stress in diabetic nerve. This may also be true for apoptotic phenomena afflicting both the peripheral and central nervous systems in diabetes. The new data have lead to re-evaluations of pathogenetic components in this complex disorder, and their further exploration is likely to form a more refined basis for future therapeutic and preventive measures.Received 25 February 2003; received after revision 12 May 2003; accepted 19 May 2003