A number of inherited (constitutional/genetic) disorders are characterized by BM (Bone Marrow) failure usually in association with one or more somatic abnormality. The BM failure may involve all or a single lineage; in some cases it may be initially associated with a single peripheral cytopenia and then progress to pancytopenia. Scientifically, they constitute an exciting group of disorders and the two syndromes that are frequently associated with generalized BM failure? are FA (Fanconi’sAnemia, named for Swiss pediatrician, Guido Fanconi) and DC (DyskeratosisCongenita) (Ref.1). FA is a rare autosomal recessive chromosome instability disorder clinically characterized by developmental defects, progressive BM failure, progressive AA (Aplastic Anemia), diverse[..]

The G12 subfamily of heterotrimeric G proteins, comprised of the Alpha-subunits G-Alpha12 and G-Alpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. Activated G-Alpha12 and G-Alpha13 have a molecular weight of 43,000 kDa and they show more than 66% amino acid identity. They stimulate mitogenic signaling pathways leading to the oncogenic transformation of fibroblast cell lines. Recent analyses have indicated that G-Alpha12 and G-Alpha13 regulate cytoplasmic as well as nuclear signaling events through downstream targets such as Ras-, Rac-, Rho-, and CDC42 (Cell Division Cycle-42) dependent pathways, leading to cytoskeletal reorganization and to the activation of MAPK[..]

In mammals, the circadian system is comprised of three major components: the lateral eyes, the hypothalamic SCN (Suprachiasmatic Nucleus) and the pineal gland. The SCN harbours the endogenous oscillator that is entrained everyday to the ambient lighting conditions via retinal input. Among the many circadian rhythms in the body that are driven by SCN output, the synthesis of Melatonin (N-Acetyl-5 Methoxy-Tryptamine) in the pineal gland functions as a hormonal message encoding for the duration of darkness. Melatonin  is a hormone secreted mainly by the pineal gland or epiphysis; it is also produced, but in much smaller quantities, by the retina. Melatonin is produced nocturnally, and is a neurochemical representation of time. Dissemination of this circadian[..]

T-Cells are a subset of lymphocytes that play a large role in the immune response. The TCR (T-Cell Receptor) is a complex of integral membrane proteins that participates in the activation of T-Cells in response to the presentation of antigen. Stimulation of TCR is triggered by MHC (Major Histocompatibility Complex) molecules on Antigen Presenting Cells that present antigen peptides to TCR complexes and induce a series of intracellular signaling cascades. Engagement of the TCR initiates positive (signal-enhancing) and negative (signal-attenuating) cascades that ultimately result in cellular proliferation, differentiation, cytokine production, and/or activation-induced cell death. These signaling cascades regulate T-Cell development, homeostasis, activation, acquisition[..]

MAPKs (Mitogen-Activated Protein Kinases) are Serine-threonine protein Kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. MAPKs are expressed in multiple cell types including Cardiomyocytes, Vascular Endothelial cells, and Vascular Smooth Muscle Cells. Three major MAPKs include ERKs (Extracellular signal-Regulated Kinases), JNKs (c-Jun NH(2)-terminal protein Kinases), and p38 Kinases. Members of the JNK/SAPK (Stress-Activated Protein Kinase) family of MAPKs are strongly stimulated by numerous Environmental Stresses, but also more modestly stimulated by Mitogens, Inflammatory Cytokines, Oncogenes, and inducers of Cell differentiation and morphogenesis. Ten mammalian JNK[..]

In response to a variety of extracellular stimuli, actin filament assembly at the leading edge of motile cells causes protrusion during cell crawling and chemotaxis, nerve growth and cell spreading. The actin filament network immediately under the plasma membrane in regions of rapid cellular protrusion consists of short, branched filaments while those deeper in the cortex, as well as at focal adhesions, stress fibers and in microvilli, are much longer and rarely branched (Ref.1). The dynamic organization of the actin cytoskeleton provides the force for cell motility and is regulated by small GTPases of the Rho family, in particular Rac1, RhoA and CDC42. The microtubule cytoskeleton is also polarized in a migrating cell, and in addition to organizing the actin[..]

Complement is a system of circulating enzymes that is part of the body's response to illness or injury. The complement system plays an essential role in host defence against infectious agents and in the inflammatory process. It consists of about thirty plasma proteins that function either as enzymes or as binding proteins. In addition to these plasma proteins, the complement system includes multiple distinct cell-surface receptors that exhibit specificity for the physiological fragments of complement proteins and that occur on inflammatory cells and cells of the immune system. There are also several regulatory membrane proteins that function to prevent autologous complement activation and protect host cells from accidental complement attack. The complement system can[..]

The TNFR (Tumor Necrosis Factor Receptor) superfamily comprises a growing family of type I membrane bound glycoproteins, which interact with the TNF family of soluble mediators and type II transmembrane proteins. At least 23 TNFR superfamily members and 17 known ligands have been identified in mammals. These receptors trigger pleiotropic responses, ranging from apoptosis and differentiation to proliferation, and have been implicated in immune regulation, host defense and lymphoid organ development. Members of the TNFR family are characterized by the presence of varying numbers (two to six) of cysteine-rich repeats in their cytoplasmic domains. Among these molecules, a novel subgroup has been defined, termed DR (Death Receptors), as one of their most prominent functions[..]

GITR (Glucocorticoid-Induced TNFR Family-Related) also termed AITR (Activation-Inducible TNFR Family Receptor) is a member of the TNFRSF18 (TNF Receptor Superfamily 18). It is a 228-amino acids type I transmembrane protein that is suggested to be a close relative of 4-1BB and CD27. Inducible during T-Cell activation, the molecule has a 19 amino acid residue signal sequence, a 134 amino acid residue extracellular region, a 23 amino acid residue transmembrane segment and a 52 amino acid residue cytoplasmic domain. It has three cysteine-rich motifs in its extracellular region. Its ligand is GITRL (AITRL). GITR expression is upregulated on T-Cells. A high level of GITR is constitutively expressed on CD4+ CD25+ regulatory T-Cells. CD4+ GITR+ T-Cells are equivalent to CD4+[..]

The Tubby protein is the founding member of a multigene protein family that plays an important role in maintenance and function of neuronal cells during development and post-differentiation. Currently, four Tubby gene family members (TUB, TULP1, TULP2 and TULP3) have been identified, which are conserved among different species of mammals (Ref.1). Besides, Tubby-like proteins are also found in other multicellular organisms including plants. These proteins feature a characteristic "Tubby domain" of approximately 260 amino acids at the C-terminus that forms a unique helix-filled barrel structure; this C-terminal domain binds avidly to double-stranded DNA. Most Tubby proteins include NH2-terminal regions that, in general, are not closely related to one another.[..]

Development of a functional cardiovascular system is dependent on the regulated proliferation, migration, and differentiation of endothelial cells in two discrete processes known as vasculogenesis and angiogenesis. Angiogenesis is the formation of new capillaries from pre-existing vessels, whereas vasculogenesis is de-novo capillary formation from EPCs (Endothelial Precursor Cells). New capillaries arise from preexisting larger vessels to give rise to a more complex vascular network with a hierarchy of both large and small vessels (Ref.1). These sequential vascular developments are tightly regulated by a range of pro- and antiangiogenic factors, including VEGF (Vascular Endothelial Growth Factor ), bFGF(basic Fibroblast Growth Factor ), Thrombospondin, Angiopoietins,[..]

Actin Nucleation By ARP-WASP Complex For many cell types, the ability to move across a solid surface is fundamental to their biological function. Certain aspects of cell locomotion, such as the protrusion of the plasma membrane in lamellipodia and filopodia, are driven by the polymerization of actin cytoskeleton. The actin cytoskeleton is a dynamic filament network that is essential for cell movement during embryo development, polarization, morphogenesis, cell division, and immune system function and in the metastasis of cancer cells. To engage in these complex behaviors, cells must direct actin assembly with a high degree of spatial and temporal resolution in response to extracellular signals (Ref.1). To coordinate these behaviors, tight spatial and temporal control[..]