Training spatial knowledge acquisition using virtual environments

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1997.Includes bibliographical references (leaves 104-105).by Glenn Koh.M.Eng

Ultrastructure of pedal muscle as a function of temperature in nacellid limpets

Temperature and mitochondrial plasticity are well studied in fishes, but little is known about this relationship in invertebrates. The effects of habitat temperature on mitochondrial ultrastructure were examined in three con-familial limpets from the Antarctic (Nacella concinna), New Zealand (Cellana ornata), and Singapore (Cellana radiata). The effects of seasonal changes in temperature were also examined in winter and summer C. ornata. Stereological methods showed that limpet pedal myocytes were 1-2 orders of magnitude smaller in diameter (≈3.5μm) than in vertebrates, and that the diameter did not vary as a function of temperature. Mitochondrial volume density (Vv(mt,f)) was approximately 2-4 times higher in N. concinna (0.024) than in the other species (0.01 and 0.006), which were not significantly different from each other. Mitochondrial cristae surface density (Sv(im,mt)) was significantly lower in summer C. ornata (24.1±0.50μm2μm−3) than both winter C. ornata (32.3±0.95μm2μm−3) and N. concinna (34.3±4.43μm2μm−3). The surface area of mitochondrial cristae per unit fibre volume was significantly higher in N. concinna, due largely to the greater mitochondrial volume density. These results and previous studies indicate that mitochondrial proliferation in the cold is a common, but not universal response by different species from different thermal habitats. Seasonal temperature decreases on the other hand, leading preferentially to an increase in cristae surface density. Stereological measures also showed that energetic reserves, i.e. lipid droplets and glycogen in the pedal muscle changed greatly with season and species. This was most likely related to gametogenesis and spawnin

Distinct histological patterns in chronic hepatitis D with nucleos(t)ide analogue therapy

BackgroundChronic hepatitis delta virus (HDV) infection leads to a more severe hepatitis than hepatitis B virus (HBV) infection alone. Specific histological staining patterns have been described in HBV mono-infection, however this has not been extensively investigated in HDV co-infection. This study evaluated whether the use of nucleos(t)ide analogs (NAs) for concurrent HBV infection has an impact on the histological appearance of chronic HDV.MethodsLiver biopsies of all patients referred for management of HDV infection were reviewed and hepatitis-specific stains for HBV antigens were evaluated. Clinical and histological characteristics were compared between patients on and off-NA therapy.Results50 patients were included in our analysis, of which 26 (52%) were on NA therapy at the time of the biopsy. Overall, 8% stained for HBV core antigen and 86% stained for HBV surface antigen. On and off-NA groups had similar degrees of fibrosis and inflammation, however NA patients had an odds ratio of 7.15 for membranous staining and 0.13 for scattered granular staining (p = 0.001). No association was found with markers of disease severity or viral activity, with nonetheless a lower score of total inflammation noted in biopsies with a positive membranous stain (8.5 vs. 10.3 p = 0.04).ConclusionIn chronic HDV infection, patients treated with nucleos(t)ide analogs demonstrate a unique membranous staining pattern for hepatitis B surface antigen, which is not associated with HBV or HDV replicative activity. These findings may help improve the understanding of the role of HBV directed therapy in HDV pathophysiology.HighlightsHistological staining is associated with viral activity in chronic HBV, however this has been infrequently explored in HDV. In HDV, staining patterns differ based on HBV treatment status and do not appear to be associated with markers of viral activity

Transcription factors NRF2 and HSF1 have opposing functions in autophagy

Abstract Autophagy plays a critical role in the maintenance of cellular homeostasis by degrading proteins, lipids and organelles. Autophagy is activated in response to stress, but its regulation in the context of other stress response pathways, such as those mediated by heat shock factor 1 (HSF1) and nuclear factor-erythroid 2 p45-related factor 2 (NRF2), is not well understood. We found that the Michael acceptor bis(2-hydoxybenzylidene)acetone (HBB2), a dual activator of NRF2 and HSF1, protects against the development of UV irradiation-mediated cutaneous squamous cell carcinoma in mice. We further show that HBB2 is an inducer of autophagy. In cells, HBB2 increases the levels of the autophagy-cargo protein p62/sequestosome 1, and the lipidated form of microtubule-associated protein light chain 3 isoform B. Activation of autophagy by HBB2 is impaired in NRF2-deficient cells, which have reduced autophagic flux and low basal and induced levels of p62. Conversely, HSF1-deficient cells have increased autophagic flux under both basal as well as HBB2-induced conditions, accompanied by increased p62 levels. Our findings suggest that NRF2 and HSF1 have opposing roles during autophagy, and illustrate the existence of tight mechanistic links between the cellular stress responses

Identifying and confirming quantitative trait loci associated with heat tolerance at flowering stage in different rice populations

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background Climate change is affecting rice production in many countries. Developing new rice varieties with heat tolerance is an essential way to sustain rice production in future global warming. We have previously reported four quantitative trait loci (QTLs) responsible for rice spikelet fertility under high temperature at flowering stage from an IR64/N22 population. To further explore additional QTL from other varieties, two bi-parental F2 populations and one three-way F2 population derived from heat tolerant variety Giza178 were used for indentifying and confirming QTLs for heat tolerance at flowering stage. Results Four QTLs (qHTSF1.2, qHTSF2.1, qHTSF3.1 and qHTSF4.1) were identified in the IR64/Giza178 population, and two other QTLs (qHTSF6.1 and qHTSF11.2) were identified in the Milyang23/Giza178 population. To confirm the identified QTLs, another three-way-cross population derived from IR64//Milyang23/Giza178 was genotyped using 6K SNP chips. Five QTLs were identified in the three-way-cross population, and three of those QTLs (qHTSF1.2, qHTSF4.1 and qHTSF6.1) were overlapped with the QTLs identified in the bi-parental populations. The tolerance alleles of these QTLs were from the tolerant parent Giza178 except for qHTSF3.1. The QTL on chromosome 4 (qHTSF4.1) is the same QTL previously identified in the IR64/N22 population. Conclusion The results from different populations suggest that heat tolerance in rice at flowering stage is controlled by several QTLs with small effects and stronger heat tolerance could be attained through pyramiding validated heat tolerance QTLs. QTL qHTSF4.1 was consistently detected across different genetic backgrounds and could be an important source for enhancing heat tolerance in rice at flowering stage. Polymorphic SNP markers in these QTL regions can be used for future fine mapping and developing SNP chips for marker-assisted breeding

A comprehensive platform for highly multiplexed mammalian functional genetic screens

<p>Abstract</p> <p>Background</p> <p>Genome-wide screening in human and mouse cells using RNA interference and open reading frame over-expression libraries is rapidly becoming a viable experimental approach for many research labs. There are a variety of gene expression modulation libraries commercially available, however, detailed and validated protocols as well as the reagents necessary for deconvolving genome-scale gene screens using these libraries are lacking. As a solution, we designed a comprehensive platform for highly multiplexed functional genetic screens in human, mouse and yeast cells using popular, commercially available gene modulation libraries. The Gene Modulation Array Platform (GMAP) is a single microarray-based detection solution for deconvolution of loss and gain-of-function pooled screens.</p> <p>Results</p> <p>Experiments with specially constructed lentiviral-based plasmid pools containing ~78,000 shRNAs demonstrated that the GMAP is capable of deconvolving genome-wide shRNA "dropout" screens. Further experiments with a larger, ~90,000 shRNA pool demonstrate that equivalent results are obtained from plasmid pools and from genomic DNA derived from lentivirus infected cells. Parallel testing of large shRNA pools using GMAP and next-generation sequencing methods revealed that the two methods provide valid and complementary approaches to deconvolution of genome-wide shRNA screens. Additional experiments demonstrated that GMAP is equivalent to similar microarray-based products when used for deconvolution of open reading frame over-expression screens.</p> <p>Conclusion</p> <p>Herein, we demonstrate four major applications for the GMAP resource, including deconvolution of pooled RNAi screens in cells with at least 90,000 distinct shRNAs. We also provide detailed methodologies for pooled shRNA screen readout using GMAP and compare next-generation sequencing to GMAP (i.e. microarray) based deconvolution methods.</p

Stochastic Binding of Ca2+ Ions in the Dyadic Cleft; Continuous versus Random Walk Description of Diffusion

Ca2+ signaling in the dyadic cleft in ventricular myocytes is fundamentally discrete and stochastic. We study the stochastic binding of single Ca2+ ions to receptors in the cleft using two different models of diffusion: a stochastic and discrete Random Walk (RW) model, and a deterministic continuous model. We investigate whether the latter model, together with a stochastic receptor model, can reproduce binding events registered in fully stochastic RW simulations. By evaluating the continuous model goodness-of-fit for a large range of parameters, we present evidence that it can. Further, we show that the large fluctuations in binding rate observed at the level of single time-steps are integrated and smoothed at the larger timescale of binding events, which explains the continuous model goodness-of-fit. With these results we demonstrate that the stochasticity and discreteness of the Ca2+ signaling in the dyadic cleft, determined by single binding events, can be described using a deterministic model of Ca2+ diffusion together with a stochastic model of the binding events, for a specific range of physiological relevant parameters. Time-consuming RW simulations can thus be avoided. We also present a new analytical model of bimolecular binding probabilities, which we use in the RW simulations and the statistical analysis

Adalimumab in Active and Inactive, Non-Infectious Uveitis:Global Results from the VISUAL I and VISUAL II Trials

Purpose: Report global adalimumab safety and efficacy outcomes in patients with non-infectious uveitis. Methods: Adults with non-infectious intermediate, posterior, or panuveitis were randomized 1:1 to receive placebo or adalimumab in the VISUAL I (active uveitis) or VISUAL II (inactive uveitis) trials. Integrated global and Japan substudy results are reported. The primary endpoint was time to treatment failure (TF). Results: In the integrated studies, TF risk was significantly reduced (hazard ratio [95% CI]) with adalimumab versus placebo (VISUAL I: HR = 0.56 [0.40-0.76], p < 0.001; VISUAL II: HR = 0.52 [0.37-0.74], p < 0.001). In Japan substudies, no consistent trends were observed between groups (VISUAL I: HR = 1.20 [0.41-3.54]; VISUAL II: HR = 0.45 [0.20-1.03]). Adverse event rates were similar between treatment groups in both studies (854 to 1063 events/100 participant-years). Conclusions: Adalimumab lowered time to TF versus placebo in the integrated population; no consistent trends were observed in Japan substudies. Safety results were consistent between studies

Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases