Seeking mTORC1 Inhibitors Through Molecular Dynamics Simulation of Arginine Analogs Inhibiting CASTOR1.

Background: Hyperactivity of the mechanistic target of rapamycin complex 1 (mTORC1) is implicated in a variety of diseases such as cancer and diabetes. Treatment may benefit from effective mTORC1 inhibition, which can be achieved by preventing arginine from disrupting the cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1)-GTPase-activating proteins toward RAGS subcomplex 2 (GATOR2) complex through binding with CASTOR1. An attractive idea is to determine analogues of arginine that are as competent as arginine in binding with CASTOR1, but without disrupting the CASTOR1-GATOR2 interaction.

The Importance of the Autopsy in Medicine: Perspectives of Pathology Colleagues.

This article presents a perspective on the importance of the autopsy in medical practice and science based on experiences of the authors as physician-scientists involved in autopsy practice. Our perspectives are presented on the seminal contributions of the autopsy in the areas of cardiovascular disease, including congenital heart disease, atherosclerosis, coronary artery disease, and myocardial infarction, and infectious disease, including tuberculosis and viral infections. On the positive side of the future of the autopsy, we discuss the tremendous opportunities for important research to be done by application of advanced molecular biological techniques to formalin-fixed, paraffin-embedded tissue blocks obtained at autopsy.

Human Herpesvirus 6 and Malignancy: A Review.

In order to determine the role of human herpesvirus 6 (HHV-6) in human disease, several confounding factors, including methods of detection, types of controls, and the ubiquitous nature of the virus, must be considered. This is particularly problematic in the case of cancer, in which rates of detection vary greatly among studies. To determine what part, if any, HHV-6 plays in oncogenesis, a review of the literature was performed.

Active HHV-6 Infection of Cerebellar Purkinje Cells in Mood Disorders.

Early-life infections and associated neuroinflammation is incriminated in the pathogenesis of various mood disorders. Infection with human roseoloviruses, HHV-6A and HHV-6B, allows viral latency in the central nervous system and other tissues, which can later be activated causing cognitive and behavioral disturbances. Hence, this study was designed to evaluate possible association of HHV-6A and HHV-6B activation with three different groups of psychiatric patients.

Lymphoproliferative Syndromes Associated with Human Herpesvirus-6A and Human Herpesvirus-6B.

Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) have been noted since their discovery for their T-lymphotropism. Although it has proven difficult to determine the extent to which HHV-6A and HHV-6B are involved in the pathogenesis of many diseases, evidence suggests that primary infection and reactivation of both viruses may induce or contribute to the progression of several lymphoproliferative disorders, ranging from benign to malignant and including infectious mononucleosis-like illness, drug induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), and nodular sclerosis Hodgkin's lymphoma. Herein, we discuss the conditions associated with the lymphoproliferative capacity of HHV-6, as well as the potential mechanisms behind them.

Copy Number Heterogeneity, Large Origin Tandem Repeats, and Interspecies Recombination in Human Herpesvirus 6A (HHV-6A) and HHV-6B Reference Strains.

Quantitative PCR is a diagnostic pillar for clinical virology testing, and reference materials are necessary for accurate, comparable quantitation between clinical laboratories. Accurate quantitation of human herpesvirus 6A/B (HHV-6A/B) is important for detection of viral reactivation and inherited chromosomally integrated HHV-6A/B in immunocompromised patients. Reference materials in clinical virology commonly consist of laboratory-adapted viral strains that may be affected by the culture process.

Human herpesvirus 6-induced inflammatory cardiomyopathy in immunocompetent children.

Over the last decade, human herpesvirus 6 (HHV-6) has been implicated in the etiology of pediatric myocarditis and subsequent dilated cardiomyopathy (DCM). This review provides an overview of recent literature investigating the pathophysiological relevance of HHV-6 in inflammatory cardiomyopathy. We examined 11 cases of previously published pediatric myocarditis and/or DCM associated with HHV-6 and also our experience of detection of virus particles in vascular endothelium of HHV-6 positive endomyocardial biopsy tissue by electron microscopy.

Anti-herpesviral effects of a novel broad range anti-microbial quaternary ammonium silane, K21.

We have created a novel quaternary ammonium silane, K21 through sol-gel chemistry, using an ethoxylated version of an organosilane quaternary ammonium compound and TetraEthyl Ortho Silicate (TEOS) as precursors. Previous studies using the precursor molecule quaternary ammonium compounds (QACs) and a methacryloxy version of K21, primarily designed for use in dental healthcare, have shown inhibited growth properties against several types of gram-positive and gram-negative bacteria including Escherichia coli, Streptococcus mutans, Actinomyces naeslundii and Candida albicans etc. Here we tested the effect of K21 on HSV-1, HHV-6A and HHV-7 in in vitro cell culture infection models.

Altered Micro-RNA Degradation Promotes Tumor Heterogeneity: A Result from Boolean Network Modeling.

Cancer heterogeneity may reflect differential dynamical outcomes of the regulatory network encompassing biomolecules at both transcriptional and post-transcriptional levels. In other words, differential gene-expression profiles may correspond to different stable steady states of a mathematical model for simulation of biomolecular networks. To test this hypothesis, we simplified a regulatory network that is important for soft-tissue sarcoma metastasis and heterogeneity, comprising of transcription factors, micro-RNAs, and signaling components of the NOTCH pathway.

Chromosomally integrated human herpesvirus 6 in heart failure: prevalence and treatment.

Aims: Human herpesvirus 6 (HHV-6) A and B are two betaherpesviruses that are associated with many conditions including roseola, drug-induced hypersensitivity syndrome, limbic encephalitis, and myocarditis. HHV-6 is integrated in the germline [chromosomically integrated HHV-6 (ciHHV-6)] in ∼0.8% of the human population.

Certain surfactants show promise in the therapy of pulmonary tuberculosis.

Background/aim: The aim of the present study was to develop the basis for the use of surfactants in the treatment of pulmonary tuberculosis (TB). Bacteria are surrounded by a thick lipid coat primarily consisting of trehalose dimycolate (TDM) and, consequently, are well shielded from the immune system's response and antibiotics. This protective barrier was removed by exposing the bacteria to certain surfactants.

Computational analysis of mTOR signaling pathway: bifurcation, carcinogenesis, and drug discovery.

Molecularly targeted therapeutics provides potentially more reliable performance while significantly reducing toxicity in comparison with chemotherapy. For cancer signaling networks which are usually complex, multiple molecules should be simultaneously targeted in order to stay in tune with the control mechanisms of the network and to achieve the maximum synergistic effects. Mathematical modeling and computer simulation are important in reproducing the dynamics of the network, some of which may correspond to healthy or cancer phenotypes.

The impact of declining clinical autopsy: need for revised healthcare policy.

In Western countries, autopsy rates for patients deceased in hospitals have dropped to record lows, while the average frequency of major errors in clinical diagnoses has more than doubled during the same time period. Meanwhile, the Institute of Medicine and the U.S.

Complement C2 receptor inhibitor trispanning: a novel human complement inhibitory receptor.

The complement system presents a powerful defense against infection and is tightly regulated to prevent damage to self by functionally equivalent soluble and membrane regulators. We describe complement C2 receptor inhibitor trispanning (CRIT), a novel human complement regulatory receptor, expressed on hemopoietic cells and a wide range of tissues throughout the body. CRIT is present in human parasites through horizontal transmission.

Immunologic aspects of chronic fatigue syndrome. Report on a Research Symposium convened by The CFIDS Association of America and co-sponsored by the US Centers for Disease Control and Prevention and the National Institutes of Health.

Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800,000 Americans of all ages, races, socioeconomic groups and genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the immune system. A symposium was organized in October 2001 to explore the possibility of an association between immune dysfunction and CFS, with special emphasis on the interactions between immune dysfunction and other abnormalities noted in the neuroendocrine and autonomic nervous systems of individuals with CFS.

Feed-forward and feedback mechanisms in a dynamic model of human T cell development and regulation.

We describe a computational model of human T cell regulatory dynamics. We used this model to simulate changes in T cell pool numbers and for studying feedback and feed-forward responses in and among these pools. The pools identified were the bone marrow stem cell compartment, early and late thymocyte compartments and the peripheral compartment of mature T lymphocytes.

A general mathematical method for investigating the thymic microenvironment, thymocyte development, and immunopathogenesis.

T-lymphocyte (T-cell) development constitutes one of the basic and most vital processes in immunology. The process is profoundly affected by the thymic microenvironment, the dysregulation of which may be the pathogenesis or the etiology of some diseases. On the basis of a general conceptual framework, we have designed the first biophysical model to describe thymocyte development.

A continuous model studying T cell differentiation and lymphomagenesis and its distinction with discrete models.

The development of T-lymphocytes (T cells) constitute one of the basic and most vital processes in immunology. Conventional mathematical models, being based on the systems theory, fail to sufficiently distinguish the constituents of thymocytes and are thus of limited significance. On the basis of some well thought-out definitions and concepts, a continuous model was designed to describe T cell maturation in the thymus.

A simple model to simulate cellular changes in the T cell system following HIV-1 infection.

A new mathematical model is presented to simulate various changes of cell pools in the T cell immune system with validation procedures imitating viral infections. The present paper focuses on changes during the course of an acute progressive HIV-1 infection. Parameters are optimized by a direct search method and the stability of the model is studied.

Mathematical model to simulate the cellular dynamics of infection with human herpesvirus-6 in EBV-negative infectious mononucleosis.

Acute infection with human herpesvirus-6 induces physiological cell proliferation in persons without major immune deficiency. It thus can serve as a parameter to validate a mathematical model designed to simulate cell proliferation under physiological and pathological conditions. Such a mathematical model is presented to simulate various cell changes of the T-cell immune system during the course of HHV-6 infection.

Human herpesvirus-6: a short review of its biological behavior.

HHV-6 shows a widespread distribution with life-long persistence. The virus is frequently reactivated, yet remains clinically inapparent unless the patient is immunodeficient in some way. Even then, HHV-6 reactivation may simply enhance the pathogenicity of other viruses or existing autoimmune disorders rather than becoming a pathogen itself.

A simplified and comprehensive computational model to study the behavior of T cell populations in the thymus during normal maturation and in infection with mouse moloney leukemiavirus.

Based on a previously developed theory of dysregulative lymphoma pathogenesis, an advanced mathematical model was developed for simulation of thymic T cell populations and their differentiation stages. The model subsequently was tested in comparison to thymic changes in mice with Moloneyvirus infection and leukemia development. Numerical examples are given, which suggest that the model is useful to study T cell proliferation, differentiation, and may probably also be useful to simulate T cell changes in various lymphoproliferative diseases.

Growth factors, cytokines, chemokines and neuropeptides in the modeling of T cells. Part II: Data tables of normal values in man.

Members of the T lymphocyte lineage belong to a highly reactive cell system engaged in the control of internal homoeostasis and bodily intactness. It fulfills its commitments in close communication with the cellular and non-cellular microenvironment and with neuroendocrine regulatory mechanisms. The tools of such communication are various substances and compounds identified as cytokines, chemokines, hormones, growth factors, neuropeptides and components of the extracellular matrix.

TCM-1: a nonlinear dynamical computational model to simulate cellular changes in the T cell system; conceptional design and validation.

Based upon a previously developed theory of dysregulative lymphoma pathogenesis, a computer model is designed in order to simulate cell changes occurring in disturbances of the T cell immune system and in lymphoproliferative diseases. The model is based upon the concept that factors identified as proliferation factors, differentiation factors and inhibition factors exert a network regulation upon development and function of the T cell system, and that selective disturbances of these factors may lead to hyperplastic, aplastic or neoplastic diseases. The resulting computer model (TCM-1) was validated by comparing it with data from human diseases such as acute HHV-6 (viral) infection, chronic persistent HHV-6 infection, progressive HIV1 infection and HTLV-1 infection, and comparing the simulation results with the actual cell data in the human patients.

Human herpesvirus-6 has no apparent influence on course of HCV hepatitis, but may complicate HBV hepatitis and alcoholic liver disease. A pilot study.

Human herpesvirus-6 (HHV-6) is a widespread virus with occasional reactivation and a potential hepatotropism. The present study was undertaken to investigate the frequency of HHV-6 reactivation in viral (HCV, HBV) and alcoholic liver diseases and its implication for the course of the primary disease. Serological and immunohistochemical tests were done to document viral activity, hepatocellular apoptosis or proliferation, and autoantibody formation.