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体积 8, 问题 3 (2014)

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The Emerging Role of the Hematopoietic Stem Cell Niche in Myeloproliferative Neoplasms

Biquan Luo

Myeloproliferative neoplasms (MPN) are chronic hematological neoplasms arising from the accumulation of genetic mutations in hematopoietic stem cells (HSCs). This notion is supported by genomic studies on MPN patients, in which recurrent mutations on genes such as JAK2, CALR, and MPL have been identified. Interestingly, recent studies using MPN mouse models have demonstrated that the HSC niche, where HSCs are located and maintained in the bone marrow (BM), plays an important role in MPN initiation and progression. Changes in the BM microenvironment alone can serve as a driver for altered hematopoiesis and hematological malignancies. Additionally, during MPN progression mutant HSCs remodel the HSC niche into a hospitable microenvironment for themselves that accelerates disease progression, creating a positive feedback loop where mutant HSCs thrive, and continue to alter the BM microenvironment to their advantage. In an attempt to provide a fresh perspective in understanding MPN pathogenesis, this review highlights the studies conducted that explore the role of the HSC niche in MPN pathogenesis and progression.

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Genetic Susceptibility: A Forgotten Aspect of Poliomyelitis

Wyatt HV

There was evidence of genetic susceptibility to poliomyelitis, but in the mid 1930's that evidence and the idea of genetic susceptibility disappeared from the literature and the collective research psyche. Alternative hypotheses, not amenable to test, were adopted but seldom formulated. Subsequent evidence for genetic susceptibility was ignored. I suggest that the ill-fated vaccine trials in 1935 presented a psychological watershed for researchers. The later vaccines owed their success to unwritten and untested hypotheses: genetic susceptibility might have been an insuperable barrier to testing vaccines in children. Now that eradication is probable, new research suggests that many people may be susceptible to paralysis and that plans must be made for possible reappearance of the disease.

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The Paralogous Group HOX 13 Discriminates between Normal Colon Tissue and Colon Cancer

Procino Alfredo

Colon diseases are more common in the world with an increasing trend. Despite the different etiology and physiology, the epithelial-mesenchymal transition (EMT), is crucial during transformation, migration and invasive ability of colon cancer cells. Several genes are implicated in the control of EMT (Wnt, Notch, Src, Ras, etc.). The homeobox genes are a transcription factor family, they are arranged in several classes. Class I homeobox genes (Hox in mice and HOX in humans), are 39 transcription factors, mainly involved in the regulation of embryonic development program. In the present study, we have analyzed the expression of HOX genes, during tumor cell lines differentiation (CaCo2) and compared with the expression of HOX gene network, in the normal intestinal mucosa

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Human iPSC Models: A Platform for Investigating Neurodevelopmental Diseases

Cindy E McKinney and Stephan L Brown

Many human diseases arise as the result of DNA mutations in the patient’s genome. The neurodevelopmental diseases of early childhood have proven difficult to model due to lack of access to embryonic tissue and ethical concerns. Federal restrictions on the use of embryonic material also preclude studying some stages of neurodevelopmental disease. The onset of illness in utero or early childhood is frequently preceded by normal development of critical milestones. Recent work has led to methodologies to transform somatic cells to embryoniclike stem cells using four exogenous transcription factors. With this approach, it is now possible to validate the use of human induced pluripotent stem cells (hiPSCs) to model aspects of neurodevelopmental diseases using a patient’s donated cells or genome editing of hiPSC cells to contain known disease mutations. The reprogramming of somatic cells to hiPSC requires dedifferentiation and resetting of epigenetic signatures in the genome. The newest approaches are evaluating propagating the cells in three dimensions on artificial matrices to recapitulate regional neural cyto-architecture within the brain. Newer genome editing techniques that rely on site-specific sequence recognition by synthetic enzymes can be used to generate hiPSC neurodevelopmental disease models. A hiPSC disease model has several advantages, the patient’s own cells may be transduced to provide the investigative cell model and compared to other patient’s cells with the same disease. Additionally, a hiPSC model addresses some of the concerns about gene engineered animal models accurately recapitulating human disease since the model context is a patient-specific human cell line. Here we review the emerging use of hiPSC to model neurodevelopmental diseases.

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Prospective Tuberculosis Treatment: Peptides, Immunity and Autophagy

Jonathan Gabriel Rodriguez Plaza, Bruno Rivas-Santiago, Rogelio Hernandez-Pando and Gabriel Del Rio

Tuberculosis (TB) is a world-leading infectious disease caused by Mycobacterium tuberculosis (Mtb). The current treatment lasts 6 months and has contributed to the development of multidrug resistant (MDR) strains that nowadays cause almost half a million deaths around the globe. Forty years of research have rendered only 1 new drug to treat the new MDR strains. In the current review we present emerging trends to treat TB particularly focused on natural and synthetic peptides. The ability of some of these peptides to display multifunctional roles in TB treatment, particularly immune system modulation through autophagy and direct antimicrobial activity against Mtb, may present advantages to control the impact of this disease. We review the mechanisms of action relevant in the development of multifunctional peptides that may lead to evaluate new ways to treat TB, a disease that has accompanied human society for centuries

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Elastin Insufficiency Predisposes Mice to Impaired Glucose Metabolism

Antea J DeMarsilis, Tezin A Walji, Justine A Maedeker, Kellie V Stoka, Beth A Kozel, Robert P Mecham, Jessica E Wagenseil and Clarissa S Craft

Williams-Beuren syndrome is the consequence of a large contiguous-gene deletion on the seventh human chromosome that includes the elastin gene. Elastin is an extracellular matrix protein responsible for the cardiovascular abnormalities associated with Williams’s syndrome, including hypertension and aortic stenosis. A high percentage of individuals with Williams’s syndrome also have impaired glucose tolerance, independent of traditional risk factors for diabetes. Here, we show that murine adipose tissue does assemble elastic fibers; however, isolated elastin insufficiency (Eln+/-) in mice does not independently influence glucose metabolism or tissue lipid accumulation. Similarly, isolated ApoE deficiency (ApoE-/-), a model of hyperlipidemia and atherosclerosis, does not impair insulin sensitivity. However, Eln+/-; ApoE-/- double mutant mice exhibit notable hyperglycemia, adipocyte hypertrophy, inflammation of adipose tissue, and ectopic lipid accumulation in liver tissue. Further, Eln+/-; ApoE-/- mutants have significant impairment of insulin sensitivity by insulin tolerance testing, independent of body weight or diet, suggesting that elastin insufficiency predisposes to metabolic disease in susceptible individuals.

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Update on Genetic Determinants of Type1 Diabetes

Philippe A Lysy

Type 1 diabetes (T1D) results from a progressive destruction of insulin-secreting β cells with consecutive life-long dependence to exogenous insulin. Avoidance of end-stage β-cell mass destruction through primary and secondary prevention strategies requires understanding of initial molecular events leading to insulinopenia. Although autoimmune dysregulation is predominant in T1D, environmental and genetic predisposing factors have been identified and partly account for the heterogeneity of the disease. The use of patient databases and the development of new technologies for genetic screening will help to identify at-risk individuals in the general population or in families with affected siblings. Here we discuss the latest developments in the identification of genetic determinants of T1D and their use for evaluation of disease risk.

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Current Methods for the Prevention of Transmission of Mitochondrial DNA Diseases

Kelly A Turner and Francis YM Choy

It is estimated that mitochondrial diseases affect 1 in 5,000-10,000 live births. At present, there is no cure for a mitochondrial disease and current treatments are limited to reducing symptoms and slowing disease progression. The prevention of transmission of mitochondrial diseases is of vital importance to parents with a mitochondrial disease who wish to make informed reproductive decisions. This paper provides a critical evaluation of the various established and experimental techniques involved in the prevention and treatment of mtDNA disease at the germline level, including fertilization using donor oocytes, pre-implantation genetic diagnosis, chorionic villus sampling, amniocentesis, cytoplasmic transfer, germinal vesicle transfer, pronuclear transfer, and spindle-chromosomal complex transfer; the latter two of which have been publicly endorsed by the Human Fertilisation and Embryology Authority in the UK in 2014 as being potentially useful and safe methods for the prevention of transmission of severe mtDNA diseases.

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Chemical Antagonists of Plasminogen Activator Inhibitor-1: Mechanisms of Action and Therapeutic Potential in Vascular Disease

Tessa M Simone, Stephen P Higgins, Craig E Higgins, Michelle R Lennartz and Paul J Higgins

Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) is a member of the serine protease inhibitor (SERPIN) superfamily and the predominant physiologic inhibitor of urokinase (uPA) and tissue-type (tPA) plasmingen activators. This system effectively restricts, both spatially and temporally, the conversion of plasminogen to plasmin, thereby regulating physiologic and pathophysiologic stromal remodeling. Dysregulation of this cascade frequently results in anomalies of the tissue repair response. Elevated PAI-1 levels are a causative factor in various forms of vascular disease and tissue fibrotic syndromes. Independent of its role in proteolysis, PAI-1 stimulates cell motility via interacting with low-density lipoprotein receptor-related protein-1 (LRP1) activating several cellular signaling pathwaays. PAI-1 also regulates the availability of cell-surface integrins by promoting their endocytosis in an LRP-1- dependent manner via PAI-1/uPA/uPAR (uPA receptor)/LRPI/integrin complexes. This process fine tunes the special control of pericellular proteolysis and the overall cadence of cell detachment/re-adhesion required for efficient cell migration. These data suggest that PAI-1 modulates cell motility under several contexts, both via by its established anti-proteolytic properties and as a signaling initiator.

研究文章

An In vitro Assay to Quantify Nitrosative Component of Oxidative Stress

S Balaiya and KV Chalam

Oxidative stress is a major contributing factor in a variety of neurodegenerative and vascular diseases. In vitro assessment of a major oxidant reactive nitrogen oxide species (RNOS) using dihydrorhodamine 123 (DHR 123) is a useful assay to quantify the reactive oxygen species in a cell. DHR 123, non-fluorescent laser dye freely penetrates the cell membrane and stains the mitochondria. Density of staining varies with the level of peroxynitrite (O=NOO-); as a result of interaction of superoxide anion (O2-) and nitric oxide (NO). The fluorescence is read using a spectrophotometer. Cells are seeded in 24 or 96- well plate and DHR 123 working solution is added after appropriate treatment. The fluorescence is read after 60 minutes of incubation at 485/528 nm with spectrophotometer. This assay is more sensitive and forms a stable end product than comparable assays and takes 90 minutes to complete.

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