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The article cites key findings from various research papers presented during the international "Mechanisms of Exocytosis 2008" meeting at the Slovenian Academy of Sciences and Arts in Ljubljana, Slovenia from May 22 to 25, 2008. It includes an in-depth analysis of various issues relevant to the physiological process of exocytosis that are discussed by the research papers including intracellular messengers and exocytosis, molecular mechanisms of exocytosis and vesicle dynamics and cell types. Also cited are various leading scientists in the field who presented their research studies during the event.

Vitamin D seems to be implicated in the pathophysiology of autoimmune disorders as a natural immune modulator. Beneficial effects of vitamin D have been associated with different cells of the immune system; however, thus far, B cells seem to be somewhat neglected. In this paper, we describe the possible direct effects of vitamin D on B cells, with a focus on antibody production and the more recently identified regulatory B (Breg) cells. B cells upregulate the vitamin D receptor (VDR) upon activation. Furthermore, due to regulated expression of the metabolizing enzymes CYP27B1 and CYP24A1, B cells have the potential to control the local availability of active vitamin D. B cells, therefore, may participate in vitamin D-mediated immune homeostasis, including plasma cell generation. Whether or not other B cell subsets, such as Breg cells, are equally responsive to vitamin D remains to be established. [ABSTRACT FROM AUTHOR]

Programmed death-1 (PD-1) is a surface receptor critical for the regulation of T cell function during immunity and tolerance. PD-1 interactions with its ligands PD-L1 and PD-L2 inhibit T cell effector functions in an antigen-specific manner. This paper examines the role of PD-1 in limiting autoreactivity and establishing self-tolerance and discusses the hypothesis that PD-1 ligand (PD-L) expression both spatially and temporally dictates the fate of self-reactive T cells during the breakdown of peripheral tolerance and development of autoimmunity. We focus our discussion on the role of PD-1/PD-L interactions during peripheral tolerance, the differential role for PD-L1 and PD-L2 in response to environmental or self-antigens, and the impact of PD-1 signaling on dynamic T cell motility and the T cell receptor (TCR) stop signal. Finally, we discuss the potential to selectively target the PD-1 pathway therapeutically to alter T cell function during autoimmunity. [ABSTRACT FROM AUTHOR]

Occludin, tricellulin, and marvelD3 belong to the tight junction (TJ)‐associated MARVEL protein family. Occludin and tricellulin jointly contribute to TJ strand branching point formation and epithelial barrier maintenance. However, whether marvelD3 has the same function remains unclear. Furthermore, the roles of the carboxy‐terminal cytoplasmic tail, which is conserved in occludin and tricellulin, on the regulation of TJ strand morphology have not yet been explored in epithelial cells. We established tricellulin/occludin/marveld3 triple‐gene knockout (tKO) MDCK II cells and evaluated the roles of marvelD3 in the TJ strand structure and barrier function using MDCK II cells and a mathematical model. The complexity of TJ strand networks and paracellular barrier did not change in tKO cells compared to that in tricellulin/occludin double‐gene knockout (dKO) cells. Exogenous marvelD3 expression in dKO cells did not increase the complexity of TJ strand networks and epithelial barrier tightness. The expression of the carboxy‐terminal truncation mutant of tricellulin restored the barrier function in the dKO cells, whereas occludin lacking the carboxy‐terminal cytoplasmic tail was not expressed on the plasma membrane. These data suggest that marvelD3 does not affect the morphology of TJ strands and barrier function in MDCK II cells and that the carboxy‐terminal cytoplasmic tail of tricellulin is dispensable for barrier improvement. [ABSTRACT FROM AUTHOR]

The effects of NCX knockout were determined in a variety of cardiac cell models. Those of the mouse and rat ventricles, and of atrial cells in other species behave similarly to the experiments on mouse ventricle showing only small effects, and considerable tolerance of NCX knockout. Models of ventricular cells with high action potential plateaus, however, are more sensitive and require compensatory mechanisms to adjust other conductance parameters to enable the cells to resist NCX knockout. The effects can therefore be expected to be species-specific, and it is not possible to extrapolate the mouse results to those that may occur in the Guinea pig or human. [ABSTRACT FROM AUTHOR]

Esophageal diseases are highly prevalent and carry significant socioeconomic burden. Despite the apparently simple function of the esophagus, we still struggle to better understand its physiology and pathophysiology. The assessment of large data sets and application of multiscale mathematical organ models have gained attention as part of the Physiome Project. This has long been recognized in cardiology but has only recently gained attention for the gastrointestinal(GI) tract. The term "esophagiome" implies a holistic assessment of esophageal function, from cellular and muscle physiology to the mechanical responses that transport and mix fluid contents. These anatomical, mechanical, and physiological models underlie the development of a "virtual esophagus" modeling framework to characterize and analyze function and disease. Functional models incorporate anatomical details with sensory–motor responses, especially related to biomechanical functions such as bolus transport. Our review builds on previous reviews and focuses on assessment of detailed anatomical and geometric data using advanced imaging technology for evaluation of gastro‐esophageal reflux disease (GERD), and on esophageal mechanophysiology assessed using technologies that distend the esophagus. Integration of mechanics‐ and physiology‐based analysis is a useful characteristic of the esophagiome. Experimental data on pressures and geometric characteristics are useful for the validation of mathematical and computer models of the esophagus that may provide predictions of novel endoscopic, surgical, and pharmaceutical treatment options. The physiology and pathophysiology of the esophagus is still not completely understood. This has led to the esophagiome project, a holistic assessment of esophageal function, from cellular and muscle physiology to the mechanical responses that transport and mix fluid contents. The focus of this review on the esophagiome is on the assessment of detailed anatomical and geometric data using advanced imaging technology for evaluation of gastro‐esophageal reflux disease, and on esophageal mechanophysiology assessed using technologies that distend the esophagus. [ABSTRACT FROM AUTHOR]

A foreword to the "Annals of the New York Academy of Sciences" is presented.

The article presents the history of the discovery of the sodium-calcium (Na/Ca) exchanger and the plasma membrane Ca2+-ATPase. Na/Ca exchange was discovered simultaneously and independently by Harald Reuter in Mainz, Germany and Peter F. Baker and Mordecai P. Blaustein in Plymouth, England in 1966.

Cord blood (CB) transplantation has been used over the last 24 years to treat patients with malignant and nonmalignant disorders. CB has its advantages and disadvantages compared with other sources of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) for transplantation. More knowledge of the cytokines and intracellular signaling molecules regulating HSCs and HPCs could be used to modulate these regulators for clinical benefit. This review provides information about the general field of CB transplantation and about studies from the author's laboratory that focus on regulation of HSCs and HPCs by CD26/DPPIV, SDF-1/CXCL12, the Rheb2-mTOR pathway, SIRT1, DEK, cyclin-dependent kinase inhibitors, and cytokines/growth factors. Cryopreservation of CB HSCs and HPCs is also briefly discussed. [ABSTRACT FROM AUTHOR]

The hypothalamic-pituitary-adrenocortical (HPA) axis is a major neuroendocrine system involved in the regulation of numerous physiological processes and in adaptation to stress. A wide range of variability can be observed in all the components of the system, and the contribution of genetic factors has been shown in the central regulation of the axis, the production of glucocorticoid hormones by the adrenal cortex, their bioavailability, and the efficiency of their action at the level of receptor and postreceptor mechanisms. Numerous molecular polymorphisms have been described that contribute to physiological variation as well as to HPA axis-related pathological conditions. Although most studies focus on single gene polymorphisms, future studies should aim to integrate the different sources of variation into a systems genetic model to take into account the strong interdependence of the different components of the axis. [ABSTRACT FROM AUTHOR]

A short historical review from the early days of neuroendocrinology is presented recognizing hormones secreted by the pituitary gland; control of its functions by nuclei of the hypothalamus through the release of unknown substances in special capillary vessels; characterization of these releasing factors as peptides; studies of their mode of action; their use in clinical medicine; new and still ongoing demonstration of their ubiquity though not random in the brain and peripheral organs; and recent implications in control of behavior in animals and humans. [ABSTRACT FROM AUTHOR]

The mechanism by which neurons and neurosecretory cells govern the expression and the exocytic discharge of their clear and dense-core vesicles had remained unclear until recently when studies in the neurosecretory cell model PC12 revealed these processes to be orchestrated by the transcriptional repressor neuron restrictive silencer factor (NRSF)/repressor element-1 silencing transcription factor (REST). In wild-type PC12 fully competent for neurosecretion, NRSF/REST is low. The genes of the proteins involved in neurosecretion [from the secretory to vesicle membrane and plasma membrane proteins, including the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) of exocytosis] were all repressed by increases of NRSF/REST expression to various extents when the increase was only a fewfold but were completely or almost completely repressed when the increase was large, as in spontaneously defective PC12 clones. In the first case the dense-core vesicles were still competent for exocytosis but were smaller and less dense than in wild-type cells; in the second they were no longer visible but did reappear when the repression was attenuated by transfection of a dominant-negative construct of NRSF/REST combined with a secretory chromogranin or strengthened by treatment with a blocker of NRSF/REST-associated enzymes, the histone deacetylases. [ABSTRACT FROM AUTHOR]

Type 1 Diabetes TrialNet is an international consortium of clinical research centers aimed at the prevention or delay of type 1 diabetes (T1D). The fundamental goal of TrialNet is to counter the T1D disease process by immune modulation and/or enhancement of β cell proliferation and regeneration. To achieve this goal, TrialNet researchers are working to better understand the natural history of the disease, to identify persons at risk, and to clinically evaluate novel therapies that balance potential risks and benefits. The particular focus is on studies of preventive measures. In addition, TrialNet evaluates therapies in individuals with newly diagnosed T1D with preserved β cell function to help determine the risk/benefit profile and gain an initial assessment of potential efficacy in preservation of β cell function, so that promising agents can be studied in prevention trials. In addition, TrialNet evaluates methodologies that enhance the conduct of its clinical trials, which includes tests of outcome assessment methodology, the evaluation of surrogate markers, and mechanistic studies laying the foundation for future clinical trials. [ABSTRACT FROM AUTHOR]

During the past few decades, sleep curtailment has become a very common in industrialized countries. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity and diabetes. Evidence is rapidly accumulating to indicate that chronic partial sleep loss may increase the risk of obesity and diabetes. Laboratory studies in healthy volunteers have shown that experimental sleep restriction is associated with an adverse impact on glucose homeostasis. Insulin sensitivity decreases rapidly and markedly without adequate compensation in beta cell function, resulting in an elevated risk of diabetes. Prospective epidemiologic studies in both children and adults are consistent with a causative role of short sleep in the increased risk of diabetes. Sleep curtailment is also associated with a dysregulation of the neuroendocrine control of appetite, with a reduction of the satiety factor, leptin, and an increase in the hunger-promoting hormone, ghrelin. Thus, sleep loss may alter the ability of leptin and ghrelin to accurately signal caloric need, acting in concert to produce an internal misperception of insufficient energy availability. The adverse impact of sleep deprivation on appetite regulation is likely to be driven by increased activity in neuronal populations expressing the excitatory peptides orexins that promote both waking and feeding. Consistent with the laboratory evidence, multiple epidemiologic studies have shown an association between short sleep and higher body mass index after controlling for a variety of possible confounders. [ABSTRACT FROM AUTHOR]

In pathological conditions, the exchanger may generate deleterious calcium entry. A drug that inhibited calcium entry, while still allowing transport of calcium out of the cell would then seem attractive. In fact, this is impossible for thermodynamic reasons. Inhibitors may appear to be more effective when the exchanger is operating in net calcium entry mode than in calcium exit mode. This is, however, always attributable to differences in conditions because there is strong internal sodium dependence of drug action on the exchanger. When the exchanger is operating near equilibrium, drug action is found to be equally effective in both directions. [ABSTRACT FROM AUTHOR]

Many studies suggest that endoplasmic reticulum (ER) Ca2+ pool rather than cytosolic Ca2+ may play a crucial role in triggering apoptosis. In this study, we performed an image analysis of cells loaded with the fluorescent dye chlortetracycline (CTC) to in situ analyze Ca2+ changes within the ER in apoptosing promonocytic U937 cells. The results, validated through the use of thapsigargin (THG) as ER Ca2+ depletor, confirm the findings that apoptotic cells have a Ca2+-depleted ER, in contrast with treated but still viable cells. [ABSTRACT FROM AUTHOR]