1,721,072 research outputs found
From computational genomics to systems metabolomics for precision cancer medicine and drug discovery
No full textNotwithstanding decades of scientific and clinical investigation, cancer remains a disease that endangers many lives and brings deep sorrow to many families. So far, the war on cancer has been technology-driven. First, recombinant DNA technologies have led to the identification of oncogenes and tumour suppressor genes. Next, genomic sequencing and transcriptome analysis have allowed the characterization of both the set of mutated oncogenes and the very complex and variable transcriptome expression profiles, which appear to characterize each different cancer cell, both in human cell lines and in clinical samples. Enormous amounts of omics data of various kinds have been collected and analyzed using refined analytical technologies, and stored and made available for retrieval in specialized databases. By connecting such data with information on which drugs have been used for each patient, characterized by the specific signature of the driver mutation and the omics profile, and on the treatment outcome, the scientific community is now generating the so-called Cancer Big Data. On these bases, genomic Big Data and their analysis by computer sciences are predicted to be the field in which the war on cancer will finally be wo
Astrogliosis as a therapeutic target for neurodegenerative diseases
No full textChronic neurodegenerative diseases represent major unmet needs for therapeutic interventions. Recently, the neurocentric view of brain function and disease has been challenged by a great number of evidence supporting the physiopathological potential of neuroglia. Astrocytes, in particular, play a pivotal role in brain homeostasis as they actively participate in neuronal metabolism, synaptic plasticity and neuroprotection. Furthermore, they are intrinsic components of brain responses to toxic and traumatic insults through complex processes involving several molecular and functional alterations that may lead to disruption of brain homeostasis and connectivity. This review provides a brief overview of current knowledge of astrocyte functions in the brain, and focuses on some glial-specific pathways involved in astrocytic dysfunction that might be effective therapeutic targets for clinical management of neurodegenerative disorder
Inhibition of human immunodeficiency virus reactivation from latency by a tat transdominant negative mutant.
No full textA BK virus (BKV) expression vector, specific for human cells, was engineered to express antisense human immunodeficiency virus type 1 (HIV-1) tat cDNA (tat-AS) or a tat mutant in cysteine 22 (tat22). Cysteine residues in the cysteine-rich domain of tat are necessary for tat transactivation of the HIV-1 long terminal repeat (LTR). Both the AS tat and the tat mutant significantly inhibited transactivation by tat when assayed in cells cotransfected with an expression vector where the reporter gene for chloramphenicol acetyl transferase was driven by the HIV-1 LTR. Infection of Jurkat cell clones stably expressing tat22 (Jurkat/tat22) or tat-AS (Jurkat/tat-AS) with HIV-1 did not show differences in virus titer in comparison to HIV-1-infected control cells. However, in two Jurkat/tat22 cell clones, entrance of HIV-1 into latency was accelerated significantly and reactivation of HIV-1 from latency induced by tumor necrosis factor-alpha (TNF-alpha) or tat was blocked. These results suggest that, in a combined and integrated approach to the treatment of acquired immunodeficiency syndrome (AIDS), anti-tat genetic therapy could be successfully applied to maintain virus in latency, thereby extending the duration of the asymptomatic phase preceding full-blown AIDS
Analysis of the Secondary Structure of the Catalytic Domain of Mouse Ras Exchange Factor CDC25Mm
Full text linkThe minimal active domain GEF domain. of the mouse Ras exchange factor CDC25Mm was purified to homogeneity
from recombinant Escherichia coli culture. The 256 amino acids polypeptide shows high activity in vitro and forms a stable
complex with H-ras p21 in absence of guanine nucleotides. Circular dichroism CD. spectra in the far UV region indicate
that this domain is highly structured with a high content of a-helix 42%.. Near UV CD spectra evidenced good signal due
to phenylalanine and tyrosine while a poor contribution was elicited by the three tryptophan residues contained in this
domain. The tryptophan fluorescence signal was scarcely affected by denaturation of the protein or by formation of the
binary complex with H-ras p21, suggesting that the Trp residues, which are well conserved in the GEF domain of several
Ras-exchange factors, were exposed to the surface of the protein and they are not most probably directly involved in the
interaction with Ras proteins. q1998 Elsevier Science B.
Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System.
Full text linkCoagulation and the immune system interact in several physiological and pathological conditions, including tissue repair, host defense, and homeostatic maintenance. This network plays a key role in diseases of the central nervous system (CNS) by involving several cells (CNS resident cells, platelets, endothelium, and leukocytes) and molecular pathways (protease activity, complement factors, platelet granule content). Endothelial damage prompts platelet activation and the coagulation cascade as the first physiological step to support the rescue of damaged tissues, a flawed rescuing system ultimately producing neuroinflammation. Leukocytes, platelets, and endothelial cells are sensitive to the damage and indeed can release or respond to chemokines and cytokines (platelet factor 4, CXCL4, TNF, interleukins), and growth factors (including platelet-derived growth factor, vascular endothelial growth factor, and brain-derived neurotrophic factor) with platelet activation, change in capillary permeability, migration or differentiation of leukocytes. Thrombin, plasmin, activated complement factors and matrix metalloproteinase-1 (MMP-1), furthermore, activate intracellular transduction through complement or protease-activated receptors. Impairment of the neuro-immune hemostasis network induces acute or chronic CNS pathologies related to the neurovascular unit, either directly or by the systemic activation of its main steps. Neurons, glial cells (astrocytes and microglia) and the extracellular matrix play a crucial function in a "tetrapartite" synaptic model. Taking into account the neurovascular unit, in this review we thoroughly analyzed the influence of neuro-immune hemostasis on these five elements acting as a functional unit ("pentapartite" synapse) in the adaptive and maladaptive plasticity and discuss the relevance of these events in inflammatory, cerebrovascular, Alzheimer, neoplastic and psychiatric diseases. Finally, based on the solid reviewed data, we hypothesize a model of neuro-immune hemostatic network based on protein-protein interactions. In addition, we propose that, to better understand and favor the maintenance of adaptive plasticity, it would be useful to construct predictive molecular models, able to enlighten the regulating logic of the complex molecular network, which belongs to different cellular domains. A modeling approach would help to define how nodes of the network interact with basic cellular functions, such as mitochondrial metabolism, autophagy or apoptosis. It is expected that dynamic systems biology models might help to elucidate the fine structure of molecular events generated by blood coagulation and neuro-immune responses in several CNS diseases, thereby opening the way to more effective treatments
Targeting reactive astrogliosis by novel biotechnological strategies
No full textNeuroglial cells are fundamental for control of brain homeostasis and synaptic plasticity. Decades of pathological and physiological studies have focused on neurons in neurodegenerative disorders, but it is becoming increasingly evident that glial cells play an irreplaceable part in brain homeostasis and synaptic plasticity. Animal models of brain injury and neurodegenerative diseases have largely contributed to current understanding of astrocyte-specific mechanisms participating in brain function and neurodegeneration. Specifically, gliotransmission (presence of glial neurotransmitters, and their receptors and active transporters), trophic support (release, maturation and degradation of neurotrophins) and metabolism (production of lactate and GSH components) are relevant aspects of astrocyte function in neuronal metabolism, synaptic plasticity and neuroprotection. Morpho-functional changes of astrocytes and microglial cells after traumatic or toxic insults to the central nervous system (namely, reactive gliosis) disrupt the complex neuro-glial networks underlying homeostasis and connectivity within brain circuits. Thus, neurodegenerative diseases might be primarily regarded as gliodegenerative processes, in which profound alterations of glial activation have a clear impact on progression and outcomes of neuropathological processes. This review provides an overview of current knowledge of astrocyte functions in the brain and how targeting glial-specific pathways might ultimately impact the development of therapies for clinical management of neurodegenerative disorders
Molecular cloning and regulation of the expression of the MET2 gene of Saccharomyces cerevisiae
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