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.

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.

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.

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.

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.

Growth factors, cytokines, chemokines and neuropeptides in the modeling of T-cells.

The T lymphocyte lineage, from initial stem cells to peripheral mature T-cells, are members of a highly reactive cell system engaged in the control of internal homoeostasis and body intactness. It fulfills its commitments in close communication with the cellular and non-cellular microenvironment and with neuroendocrine regulatory mechanisms. Tools of such communication are various substances and compounds identified as cytokines, chemokines, hormones, growth factors and neuropeptides.

A computational analysis of Canale-Smith syndrome: chronic lymphadenopathy simulating malignant lymphoma.

Objective: The objective of this study was to simulate changes in the human T cell system representing Canale-Smith syndrome using a dynamic computer model of T cell development and comparing with available human data.

Study Design: Physiological stepwise maturation and function of T lymphocytes in the computer model is altered by introducing functional disturbances following lymphotropic virus infection. In the present model, acute and chronic persistent infection with the human herpesvirus-6 (HHV-6) was simulated, and ensuing changes in T cell populations were compared with those measured in human patients.

Dynamics of HTLV-1 leukemogenesis: data acquisition for computer modeling.

A literature search for HTLV-1-induced adult T-cell leukemia (ATL) at the National Library of Medicine resulted in 1003 publications which were evaluated with regard to HTLV-1 virus load, apoptosis and peripheral blood leukocyte changes during the latent period and leukemia development following virus infection. The data are presented in a comparable way to previous publications of infections with HHV-6 and HIV (which target the same CD4+ cell for infection) to be used for computer validation studies. After initial infection, HTLV-1 remains clinically latent for many years at low provirus copy numbers in CD4 cells.