Pluripotency and Cellular Reprogramming: Facts, Hypotheses, Unresolved Issues

Direct reprogramming of somatic cells to induced pluripotent stem cells by ectopic expression of defined transcription factors has raised fundamental questions regarding the epigenetic stability of the differentiated cell state. In addition, evidence has accumulated that distinct states of pluripotency can interconvert through the modulation of both cell-intrinsic and exogenous factors. To fully realize the potential of in vitro reprogrammed cells, we need to understand the molecular and epigenetic determinants that convert one cell type into another. Here we review recent advances in this rapidly moving field and emphasize unresolved and controversial questions.Genzyme Corporation (Fellowship)Helen Hay Whitney Foundation (Fellowship)Swiss Federal Institute of Technology Zurich (Society in Science: Branco-Weiss fellowship

Surface air temperature fluctuations and lapse rates on Olivares Gamma Glacier, Rio Olivares basin, central Chile, from a novel meteorological sensor network

Empirically based studies of glacier meteorology, especially for the Southern Hemisphere, are relatively sparse in the literature. Here, we use an innovative network of highly-portable, low-cost thermometers to report on high-frequency (1-min time resolution) surface air temperature fluctuations and lapse rates (LR) in a ~800-m elevational range (from 3,675 to 4,492 m a.s.l.) across the glacier Olivares Gamma in the central Andes, Chile. Temperatures were measured during an intense field campaign in late Southern summer, 19–27 March 2015, under varying weather conditions. We found a complex dependence of high-frequency LR on time of day, topography and wider meteorological conditions, with hourly temperature variations during this week that were probably mainly associated with short- and long-wave radiation changes and not with wind speed/direction changes. Using various pairs of sites within our station network, we also analyze spatial variations in LR. Uniquely in this study, we compare temperatures measured at heights of 1-m and 2-m above the glacier surface for the network of five sites, and found that temperatures at these two heights occasionally differed by more than ±4°C during the early afternoons, although the mean temperature difference is much smaller (~0.3°C). An implication of our results is that daily, hourly, or even monthly-averaged LR may be insufficient for feeding into accurate melt models of glacier change, with the adoption of sub-hourly (ideally 1–10-min) resolution LR likely to prove fruitful in developing new innovative high-time-resolution melt modelling. Our results are useful potentially as input LR for local glacier melt models, and for improving the understanding of lapse-rate fluctuations and glacier response to climate change

Central Corneal Thickness: A Retrospective Comparison of Handheld Ultrasound Pachymetry and Optical Biometric Analysis Measurements

Purpose To determine if the measure of central cornea thickness among suspected and confirmed glaucomatous patients is significantly influenced by instrument device. Methods We retrospectively examined the charts of all patients having a central corneal thickness (CCT) measured with both ultrasound pachymetry and IOL Master 700 at the Kresge Eye Institute within the past year. Intraocular pressure and demographic data including age and race, were also collected. Significant corneal disease such as Fuchs corneal dystrophy, other corneal dystrophies, corneal transplant, and corneal edema were excluded. Statistical analysis of the paired CCT measurements were performed with a paired t-test and regression analysis. Results The total number of patients having a CCT measured with both ultrasound pachymetry and IOLMaster700 was 59. Mean CCT measured with ultrasound pachymetry was 539.38 ± 49.56 µm (n=118). Mean CCT measured with IOLMaster700 was 536.83 ± 42.52 µm (n=112). The intraparticipant mean of differences between the ultrasound pachymetry and the IOLMaster700 was 3.16 ± 25 µm. Analysis with a paired t-test did not find a significant difference between the two groups (p=0.19). A regression analysis of the paired CCTs yielded an R2 value of 0.74. Conclusion There is no significant difference between CCT measurements taken with handheld ultrasound pachymetry compared to the IOL Master 700. More data is warranted to confirm, but the IOL Master 700 may yield lower variability and a lower mean CCT, possibly due to greater instrument precision and increased likelihood of a central measurement. In practice, the IOL Master 700 may provide a more reliable measure of central cornea thickness when compared with ultrasound pachymetry

Immunoglobulin variable-region gene mutational lineage tree analysis: application to autoimmune diseases

Lineage trees have frequently been drawn to illustrate diversification, via somatic hypermutation (SHM), of immunoglobulin variable-region (IGV) genes. In order to extract more information from IGV sequences, we developed a novel mathematical method for analyzing the graphical properties of IgV gene lineage trees, allowing quantification of the differences between the dynamics of SHM and antigen-driven selection in different lymphoid tissues, species, and disease situations. Here, we investigated trees generated from published IGV sequence data from B cell clones participating in autoimmune responses in patients with Myasthenia Gravis (MG), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). At present, as no standards exist for cell sampling and sequence extraction methods, data obtained by different research groups from two studies of the same disease often vary considerably. Nevertheless, based on comparisons of data groups within individual studies, we show here that lineage trees from different individual patients are often similar and can be grouped together, as can trees from two different tissues in the same patient, and even from IgG- and IgA-expressing B cell clones. Additionally, lineage trees from most studies reflect the chronic character of autoimmune diseases

Harnessing Soluble NK Cell Killer Receptors for the Generation of Novel Cancer Immune Therapy

The natural cytotoxic receptors (NCRs) are a unique set of activating proteins expressed mainly on the surface of natural killer (NK) cells. The NCRs, which include three members; NKp46, NKp44 and NKp30, are critically involved in NK cytotoxicity against different targets, including a wide range of tumor cells derived from various origins. Even though the tumor ligands of the NCRs have not been identified yet, the selective manner by which these receptors target tumor cells may provide an excellent basis for the development of novel anti-tumor therapies. To test the potential use of the NCRs as anti-tumor agents, we generated soluble NCR-Ig fusion proteins in which the constant region of human IgG1 was fused to the extracellular portion of the receptor. We demonstrate, using two different human prostate cancer cell lines, that treatment with NKp30-Ig, dramatically inhibits tumor growth in vivo. Activated macrophages were shown to mediate an ADCC response against the NKp30-Ig coated prostate cell lines. Finally, the Ig fusion proteins were also demonstrated to discriminate between benign prostate hyperplasia and prostate cancer. This may provide a novel diagnostic modality in the difficult task of differentiating between these highly common pathological conditions

Blackstone Canal District Alliance (BCDA) and Fairfax Films: Worcester’s Role in the American Industrial Revolution

The problem this project assesses is the lack of knowledge on Worcester’s rich history among the local community. With the aid of the Blackstone Canal District Alliance and Fairfax Films, the project aims to evoke how the Blackstone Canal helped industrialize Worcester with a focus on the Blackstone Canal District. The goals of the project are met through the production of a promotional documentary film