Inexact Solves in Interpolatory Model Reduction

We investigate the use of inexact solves for interpolatory model reduction and consider associated perturbation effects on the underlying model reduction problem. We give bounds on system perturbations induced by inexact solves and relate this to termination criteria for iterative solution methods. We show that when a Petrov-Galerkin framework is employed for the inexact solves, the associated reduced order model is an exact interpolatory model for a nearby full-order system; thus demonstrating backward stability. We also give evidence that for \h2-optimal interpolation points, interpolatory model reduction is robust with respect to perturbations due to inexact solves. Finally, we demonstrate the effecitveness of direct use of inexact solves in optimal ${\mathcal H}_2$ approximation. The result is an effective model reduction strategy that is applicable in realistically large-scale settings.Comment: 42 pages, 5 figure

Ectopic PDX-1 Expression Directly Reprograms Human Keratinocytes along Pancreatic Insulin-Producing Cells Fate

BACKGROUND: Cellular differentiation and lineage commitment have previously been considered irreversible processes. However, recent studies have indicated that differentiated adult cells can be reprogrammed to pluripotency and, in some cases, directly into alternate committed lineages. However, although pluripotent cells can be induced in numerous somatic cell sources, it was thought that inducing alternate committed lineages is primarily only possible in cells of developmentally related tissues. Here, we challenge this view and analyze whether direct adult cell reprogramming to alternate committed lineages can cross the boundaries of distinct developmental germ layers. METHODOLOGY/PRINCIPAL FINDINGS: We ectopically expressed non-integrating pancreatic differentiation factors in ectoderm-derived human keratinocytes to determine whether these factors could directly induce endoderm-derived pancreatic lineage and β-cell-like function. We found that PDX-1 and to a lesser extent other pancreatic transcription factors, could rapidly and specifically activate pancreatic lineage and β-cell-like functional characteristics in ectoderm-derived human keratinocytes. Human keratinocytes transdifferentiated along the β cell lineage produced processed and secreted insulin in response to elevated glucose concentrations. Using irreversible lineage tracing for KRT-5 promoter activity, we present supporting evidence that insulin-positive cells induced by ectopic PDX-1 expression are generated in ectoderm derived keratinocytes. CONCLUSIONS/SIGNIFICANCE: These findings constitute the first demonstration of human ectoderm cells to endoderm derived pancreatic cells transdifferentiation. The study represents a proof of concept which suggests that transcription factors induced reprogramming is wider and more general developmental process than initially considered. These results expanded the arsenal of adult cells that can be used as a cell source for generating functional endocrine pancreatic cells. Directly reprogramming somatic cells into alternate desired tissues has important implications in developing patient-specific, regenerative medicine approaches

Conservation within the RIC-3 gene family: Effectors of mammalian nicotinic acetylcholine receptor expression

In Caenorhabditis elegans, the ric-3 gene is required for the maturation of multiple nicotinic acetylcholine receptors (nAChRs), whereas other neurotransmittergated channels expressed within the same cells are unaffected by the presence of RIC-3. Here we show that RIC-3 is a member of a conserved gene family with representatives in both vertebrates and invertebrates. All members of this family have two transmembrane domains followed by a coiled-coil domain. Expression of the human ric-3 homolog, hric3, like the C. elegans ric-3, enhances C. elegans DEG-3/DES-2, rat α7, and human α7 nAChR-dependent whole-cell current amplitudes in Xenopus leavis oocytes, thus demonstrating functional conservation. However, hric3 also reduces human α4β2 and α3β4 nAChR-dependent whole-cell current amplitudes. Thus, hric3 shows differential effects on human nAChRs unlike the observed uniform effect of ric-3 on C. elegans nAChRs. Moreover, hric3 totally abolished currents evoked by 5-HT3 serotonin receptors, whereas it barely modified α1 glycine receptor currents. With this caveat, RIC-3 belongs to a conserved family of genes likely to regulate nAChR-mediated transmission throughout evolution. Analysis of transcripts encoded by the hric3 locus shows that it encodes for multiple transcripts, likely to produce multiple hric3 isoforms, and that hric3 is expressed in neurons and muscles, thus enabling its interactions with nAChRs in vivo.This work was supported by a U. S.-Israel Binational Science Foundation Grant 1999-074-01 and grants from the Ministry of Education of Spain (Grants PM98-0097 and PM98-0104) and Generalitat Valenciana (Grant CTIDIB/2002/138).Peer reviewe

The C.elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors

Mutations in ric-3 (resistant to inhibitors of cholinesterase) suppress the neuronal degenerations caused by a gain of function mutation in the Caenorhabditis elegans DEG-3 acetylcholine receptor. RIC-3 is a novel protein with two transmembrane domains and extensive coiled-coil domains. It is expressed in both muscles and neurons, and the protein is concentrated within the cell bodies. We demonstrate that RIC-3 is required for the function of at least four nicotinic acetylcholine receptors. However, GABA and glutamate receptors expressed in the same cells are unaffected. In ric-3 mutants, the DEG-3 receptor accumulates in the cell body instead of in the cell processes. Moreover, co-expression of ric-3 in Xenopus laevis oocytes enhances the activity of the C.elegans DEG-3/DES-2 and of the rat α-7 acetylcholine receptors. Together, these data suggest that RIC-3 is specifically required for the maturation of acetylcholine receptors

Evaluation of a course to prepare international students for the United States Medical Licensing Examination step 2 clinical skills exam

Purpose United States (US) and Canadian citizens attending medical school abroad often desire to return to the US for residency, and therefore must pass US licensing exams. We describe a 2-day United States Medical Licensing Examination (USMLE) step 2 clinical skills (CS) preparation course for students in the Technion American Medical School program (Haifa, Israel) between 2012 and 2016. Methods Students completed pre- and post-course questionnaires. The paired t-test was used to measure students’ perceptions of knowledge, preparation, confidence, and competence in CS pre- and post-course. To test for differences by gender or country of birth, analysis of variance was used. We compared USMLE step 2 CS pass rates between the 5 years prior to the course and the 5 years during which the course was offered. Results Ninety students took the course between 2012 and 2016. Course evaluations began in 2013. Seventy-three students agreed to participate in the evaluation, and 64 completed the pre- and post-course surveys. Of the 64 students, 58% were US-born and 53% were male. Students reported statistically significant improvements in confidence and competence in all areas. No differences were found by gender or country of origin. The average pass rate for the 5 years prior to the course was 82%, and the average pass rate for the 5 years of the course was 89%. Conclusion A CS course delivered at an international medical school may help to close the gap between the pass rates of US and international medical graduates on a high-stakes licensing exam. More experience is needed to determine if this model is replicable

Evaluation of a course to prepare international students for the United States Medical Licensing Examination Step 2 Clinical Skills Exam

Ninety students participated since 2012 with 76 during the evaluation period between 2013 and 2016. Students completed pre- and post- course questionnaires of knowledge, preparation, confidence, and competence in clinical skills. The survey included Likert scale and open ended responses