Mathematical and computational models of the retina in health, development and disease

The retina confers upon us the gift of vision, enabling us to perceive the world in a manner unparalleled by any other tissue. Experimental and clinical studies have provided great insight into the physiology and biochemistry of the retina; however, there are questions which cannot be answered using these methods alone. Mathematical and computational techniques can provide complementary insight into this inherently complex and nonlinear system. They allow us to characterise and predict the behaviour of the retina, as well as to test hypotheses which are experimentally intractable. In this review, we survey some of the key theoretical models of the retina in the healthy, developmental and diseased states. The main insights derived from each of these modelling studies are highlighted, as are model predictions which have yet to be tested, and data which need to be gathered to inform future modelling work. Possible directions for future research are also discussed. Whilst the present modelling studies have achieved great success in unravelling the workings of the retina, they have yet to achieve their full potential. For this to happen, greater involvement with the modelling community is required, and stronger collaborations forged between experimentalists, clinicians and theoreticians. It is hoped that, in addition to bringing the fruits of current modelling studies to the attention of the ophthalmological community, this review will encourage many such future collaborations

Molecular and functional variation in iPSC-derived sensory neurons

Induced pluripotent stem cells (iPSCs), and cells derived from them, have become key tools for modeling biological processes, particularly in cell types that are difficult to obtain from living donors. Here we present a map of regulatory variants in iPSC-derived neurons, based on 123 differentiations of iPSCs to a sensory neuronal fate. Gene expression was more variable across cultures than in primary dorsal root ganglion, particularly for genes related to nervous system development. Using single-cell RNA-sequencing, we found that the number of neuronal versus contaminating cells was influenced by iPSC culture conditions before differentiation. Despite high differentiation-induced variability, our allele-specific method detected thousands of quantitative trait loci (QTLs) that influenced gene expression, chromatin accessibility, and RNA splicing. On the basis of these detected QTLs, we estimate that recall-by-genotype studies that use iPSC-derived cells will require cells from at least 20-80 individuals to detect the effects of regulatory variants with moderately large effect sizes

Optimizing Combination Therapies with Existing and Future CML Drugs

Small-molecule inhibitors imatinib, dasatinib and nilotinib have been developed to treat Chromic Myeloid Leukemia (CML). The existence of a triple-cross-resistant mutation, T315I, has been a challenging problem, which can be overcome by finding new inhibitors. Many new compounds active against T315I mutants are now at different stages of development. In this paper we develop an algorithm which can weigh different combination treatment protocols according to their cross-resistance properties, and find the protocols with the highest probability of treatment success. This algorithm also takes into account drug toxicity by minimizing the number of drugs used, and their concentration. Although our methodology is based on a stochastic model of CML microevolution, the algorithm itself does not require measurements of any parameters (such as mutation rates, or division/death rates of cells), and can be used by medical professionals without a mathematical background. For illustration, we apply this algorithm to the mutation data obtained in [1], [2]

CD44(+)/CD24(- )breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis

INTRODUCTION: A subpopulation (CD44(+)/CD24(-)) of breast cancer cells has been reported to have stem/progenitor cell properties. The aim of this study was to investigate whether this subpopulation of cancer cells has the unique ability to invade, home, and proliferate at sites of metastasis. METHODS: CD44 and CD24 expression was determined by flow cytometry. Northern blotting was used to determine the expression of proinvasive and 'bone and lung metastasis signature' genes. A matrigel invasion assay and intracardiac inoculation into nude mice were used to evaluate invasion, and homing and proliferation at sites of metastasis, respectively. RESULTS: Five among 13 breast cancer cell lines examined (MDA-MB-231, MDA-MB-436, Hs578T, SUM1315, and HBL-100) contained a higher percentage (>30%) of CD44(+)/CD24(- )cells. Cell lines with high CD44(+)/CD24(- )cell numbers express basal/mesenchymal or myoepithelial but not luminal markers. Expression levels of proinvasive genes (IL-1α, IL-6, IL-8, and urokinase plasminogen activator [UPA]) were higher in cell lines with a significant CD44(+)/CD24(- )population than in other cell lines. Among the CD44(+)/CD24(-)-positive cell lines, MDA-MB-231 has the unique property of expressing a broad range of genes that favor bone and lung metastasis. Consistent with previous studies in nude mice, cell lines with CD44(+)/CD24(- )subpopulation were more invasive than other cell lines. However, only a subset of CD44(+)/CD24(-)-positive cell lines was able to home and proliferate in lungs. CONCLUSION: Breast cancer cells with CD44(+)/CD24(- )subpopulation express higher levels of proinvasive genes and have highly invasive properties. However, this phenotype is not sufficient to predict capacity for pulmonary metastasis

NPR3 and NPR4 are receptors for the immune signal salicylic acid in plants

Salicylic acid (SA) is a plant immune signal produced upon pathogen challenge to induce systemic acquired resistance (SAR). It is the only major plant hormone for which the receptor has not been firmly identified. SAR in Arabidopsis requires the transcription cofactor NPR1 (nonexpresser of PR genes 1), whose degradation serves as a molecular switch for SAR. Here we show that NPR1 paralogues, NPR3 and NPR4, are SA receptors that bind SA with different affinities and function as adaptors of the Cullin 3 ubiquitin E3 ligase to mediate NPR1 degradation in an SA-regulated manner. Accordingly, the npr3 npr4 mutant accumulates higher levels of NPR1 and is insensitive to SAR induction. Moreover, this mutant is defective in pathogen effector-triggered programmed cell death and immunity. Our study reveals the mechanism of SA perception in determining cell death and survival in response to pathogen challenge

Contextual adaptation of the Personnel Evaluation Standards for assessing faculty evaluation systems in developing countries: the case of Iran

<p>Abstract</p> <p>Background</p> <p>Faculty evaluations can identify needs to be addressed in effective development programs. Generic evaluation models exist, but these require adaptation to a particular context of interest. We report on one approach to such adaptation in the context of medical education in Iran, which is integrated into the delivery and management of healthcare services nationwide.</p> <p>Methods</p> <p>Using a triangulation design, interviews with senior faculty leaders were conducted to identify relevant areas for faculty evaluation. We then adapted the published checklist of the Personnel Evaluation Standards to fit the Iranian medical universities' context by considering faculty members' diverse roles. Then the adapted instrument was administered to faculty at twelve medical schools in Iran.</p> <p>Results</p> <p>The interviews revealed poor linkages between existing forms of development and evaluation, imbalance between the faculty work components and evaluated areas, inappropriate feedback and use of information in decision making. The principles of Personnel Evaluation Standards addressed almost all of these concerns and were used to assess the existing faculty evaluation system and also adapted to evaluate the core faculty roles. The survey response rate was 74%. Responses showed that the four principles in all faculty members' roles were met <it>occasionally </it>to <it>frequently</it>. Evaluation of teaching and research had the highest mean scores, while clinical and healthcare services, institutional administration, and self-development had the lowest mean scores. There were statistically significant differences between small medium and large medical schools (p < 0.000).</p> <p>Conclusion</p> <p>The adapted Personnel Evaluation Standards appears to be valid and applicable for monitoring and continuous improvement of a faculty evaluation system in the context of medical universities in Iran. The approach developed here provides a more balanced assessment of multiple faculty roles, including educational, clinical and healthcare services. In order to address identified deficiencies, the evaluation system should recognize, document, and uniformly reward those activities that are vital to the academic mission. Inclusion of personal developmental concerns in the evaluation discussion is essential for evaluation systems.</p

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up. © 2012 Nature America, Inc. All rights reserved