మాలిక్యులర్ మరియు జెనెటిక్ మెడిసిన్

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.

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.

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

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.

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

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.

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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