Epigenetic silencing of SOCS3 expression contributes to fibrosis in Crohn’s disease

Identified risk polymorphisms affecting the Jak-STAT3 pathway in patients with Crohn’s disease could affect TGF-β1 and collagen I expression and in the pathway’s negative regulator, SOCS3. Genetic factors, however, account for only ~25% of disease. Epigenetic events also shape gene expression. Recent experiments showed that autocrine IL-6 production in mesenchymal cells, subepithelial myofibroblasts (SEMF) and muscle cells, of patients with fibrostenotic Crohn’s disease causes sustained Jak-STAT3 activity, excess TGF-β1 and Collagen I production and fibrosis. SOCS3 paradoxically decreased in these cells. We now identify epigenetic mechanisms that silence SOCS3 expression in SEMF of patients with fibrostenotic Crohn’s disease. In a previous experiment, using isolated SEMF of normal ileum and affected ileum from patients with each Crohn’s phenotype, inflammatory (Montreal B1), fibrostenotic (B2) and penetrating (B3), we confirmed decreased SOCS3 protein levels were unique to B2 patients. Expression of miR-19b increased in SEMF of affected ileum. SOCS3 transcriptional activity decreased after transfection of miR-19b mimic and increased when antagomiR-19b was expressed. Epigenetic silencing of SOCS3 in ileal SEMF of patients with fibrostenotic Crohn’s disease occurs by increased miR-19b mediated inhibition of SOCS3

Students' approach to user needs analysis

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2008.Includes bibliographical references (leaf 18).Various methods exist to help engineers and designers determine user needs as part of the user-oriented design process. Many of these methods are taught in engineering design classes throughout the country. By following the progress of 18 groups of student teams in a product design project-based class at MIT, it is found that students' awareness of these user-needs methods is critical, as students are more likely to use a method based on their familiarity with the method than their opinion of the method. While many student teams choose methods that are easy-to-use, such as interviews, those teams that choose methods based on their appropriateness found more insightful user-needs information. In addition, through several case studies, it is shown that the teams that choose the more appropriate methods are then more likely to use the gathered user needs and incorporate them into well-designed products. Thus it is important in engineering design education to familiarize students with the breadth of tools and methods available to them through every stage of the process, and reinforce the importance of using the appropriate methods in design.by Emily Y. Li.S.B

Midbrain dopaminergic neuron fate specification: Of mice and embryonic stem cells

The midbrain dopaminergic (mDA) neurons of the substantia nigra and the ventral tegmental area play a fundamental role in the control of voluntary movement and the regulation of emotion, and are severely affected in Parkinson's disease. Recent advances in mouse genetics and vertebrate development have provided us with insight into the genetic cascades involved in the development of mDA neurons, including the induction of mDA neuron progenitors in the ventral mesencephalon, the specification of the mDA neuronal fate and the maintenance of postmitotic mDA neurons. In parallel, rapid progress has been made in the generation of DA neurons from pluripotent stem cells and the development of stem cell-based therapies for Parkinson's disease. Here, we summarize the new findings via the developmental progression of mDA neurons and outline how this knowledge has been exploited to develop novel paradigms for the in vitro generation of these neurons from embryonic stem cells

Opinions of Mississippi Pharmacists on the Prescription to OTC Switch, and the OTC Status of Ibuprofen

[No abstract provided.

Constraints of FL Motif on the Targeting and Function of Sodium-Bicarbonate Cotransporter 1

A C-terminal dihydrophobic FL motif plays a vital role in the basolateral targeting of sodium bicarbonate cotransporter 1. To further characterize the role of dihydrophobic FL motif, 1). the FL motif in wild type (PFLS) was reversed to LF (PLFS), 2). the FL motif (PFLS) was shifted upstream (FLPS), and 3). the FL motif (PFLS) was shifted downstream (PSFL). The wild type (PFLS) and its mutant (PLFS) were exclusively expressed on the basolateral membrane by con-focal microscopy, however, the mutant (FLPS) and (PSFL) were predominantly mistargeted to the apical membrane and the cytoplasm, respectively. Functional studies showed that the mutant (PSFL) displayed a remarkably reduced current (p value<0.05 vs wild type). The mutant (PSFL) displayed a more reduced membrane surface expression than the wild type and was co-localized with ER marker. The protein sequence spanning FL motif in kNBC1 C-terminal cytoplasmic tail shows a helical structure, mutants (PLFS) and (PSFL) reduce a-helical contents by circular dichroism study. Reversed FL isn't a constraint for basolateral targeting, but shifting it upstream and downstream are ones