Microengineering The Neural Tube

Early embryonic development is a complex and highly regulated orchestra of instructive cues that collectively guide naïve stem cells towards progressively more specialized fates. In the neural tube, the precursor structure to the brain and spinal cord, these signals emanate from ‘organizing centers’ surrounding the neural tube. These organizing centers send out soluble cues or morphogens that diffuse tens to hundreds of microns to recipient cells residing in the neural tube. Re-creating this dynamic landscape of cues in vitro is impossible using standard cell culture tools and techniques. However, microfluidics is perfectly suited to fill this gap, allowing precise control over the microenvironment on the same length scale as the developing embryo. A microfluidic device is presented that is able to re-create some of the spatial patterning events that occur during the early development of the neural tube. This platform enables developmental biologists to reverse engineer development from the ground up, enabling researchers to pose radically new experiments to help answer some of the most relevant questions regarding fate specification in the developing neural tube. Here the device is used to guide mouse embryonic stem cells into motor neurons. Importantly, these motor neurons are able to be directed to differentiate in a defined region of the microdevice, a spatial patterning event that is the hallmark of the developing neural tube. For the first time it is now possible to study the effect of development cues on live populations of stem cells. The characterization of these fundamental developmental processes will prove invaluable in understanding how humans acquire both form and function. One day, it may allow researchers to harness these developmental techniques, which have been refined over thousands of years of evolution, to guide patient derived cells into any user defined cell fate

USE OF INHALANT ANESTHETICS IN THREE SNAKE SPECIES

Different snake species respond differently to various anesthetic agents. Hence, an anesthetic procedure developed for one species cannot necessarily be safely transferred to another species. The goal of this paper is to summarize our experience using inhalant anesthetics on three snake species, including both procedures that were successful and those we found to be less satisfactory. We found isoflurane delivered with a precision vaporizer to be the best agent to anesthetize black rat snakes (Elaphe o. obsoleta). Sex and mass did not seem to affect induction times in black rat snakes, but larger female rat snakes recovered faster from anesthesia than smaller females. Halothane delivered in the open method provided consistent anesthesia in northern water snakes (Nerodia s. sipedon), although it caused some mortality and should not be used on debilitated patients. Halothane delivered with a precision vaporizer may be used to anesthetize eastern massasauga rattlesnakes (Sistrurus c. catenatus). However, care must be taken to prevent mortality resulting from anesthetic overdose. Sex and mass had no effect on induction and recovery times in the rattlesnakes, but stressed animals require longer induction and recovery times

High Efficiency Coolant Nozzle Design for Abrasive Wire Wafer Slicing

Sufficient coolant systems are vital when utilizing diamond wire slicing in the production of silicon wafers. Based on provided design parameters, multiple nozzles have been designed for Saint Gobain to use in their new abrasive diamond wire wafer-slicing machine. Each design has been analyzed using three-dimensional CFD simulation in order to obtain flow characteristics and determine the most effective design. This final design was fabricated at WPI as well as tested in the Saint Gobain testing laboratory

Heart failure and cognitive impairment: Challenges and opportunities

As populations age, heart failure (HF) is becoming increasingly common, and in addition to a high burden of morbidity and mortality, HF has an enormous financial impact. Though disproportionately affected by HF, the elderly are less likely to receive recommended therapies, in part because clinical trials of HF therapy have ignored outcomes of importance to this population, including impaired cognitive function (ICF). HF is associated with ICF, manifested primarily as delirium in hospitalized patients, or as mild cognitive impairment or dementia in otherwise stable outpatients. This association is likely the result of shared risk factors, as well as perfusion and rheological abnormalities that occur in patients with HF. Evidence suggests that these abnormalities may be partially reversible with standard HF therapy. The clinical consequences of ICF in HF patients are significant. Clinicians should consider becoming familiar with screening instruments for ICF, including delirium and dementia, in order to identify patients at risk of nonadherence to HF therapy and related adverse consequences. Preliminary evidence suggests that optimal HF therapy in elderly patients may preserve or even improve cognitive function, though the impact on related outcomes remains to be determined

Exploring Halo Substructure with Giant Stars IV: The Extended Structure of the Ursa Minor Dwarf Spheroidal

We present a large area photometric survey of the Ursa Minor dSph. We identify UMi giant star candidates extending to ~3 deg from the center of the dSph. Comparison to previous catalogues of stars within the tidal radius of UMi suggests that our photometric luminosity classification is 100% accurate. Over a large fraction of the survey area, blue horizontal branch stars associated with UMi can also be identified. The spatial distribution of both the UMi giant stars and the BHB stars are remarkably similar, and a large fraction of both samples of stars are found outside the tidal radius of UMi. An isodensity contour map of the stars within the tidal radius of UMi reveals two morphological peculiarities: (1) The highest density of dSph stars is offset from the center of symmetry of the outer isodensity contours. (2) The overall shape of the outer contours appear S-shaped. We find that previously determined King profiles with ~50' tidal radii do not fit well the distribution of our UMi stars. A King profile with a larger tidal radius produces a reasonable fit, however a power law with index -3 provides a better fit for radii > 20'. The existence of UMi stars at large distances from the core of the galaxy, the peculiar morphology of the dSph within its tidal radius, and the shape of its surface density profile all suggest that UMi is evolving significantly due to the tidal influence of the Milky Way. However, the photometric data on UMi stars alone does not allow us to determine if the candidate extratidal stars are now unbound or if they remain bound to the dSph within an extended dark matter halo. (Abridged)Comment: accepted by AJ, 32 pages, 15 figures, emulateapj5 styl

Predictive Modeling Techniques in Prostate Cancer

A number of new predictive modeling techniques have emerged in the past several years. These methods can be used independently or in combination with traditional modeling techniques to produce useful tools for the management of prostate cancer. Investigators should be aware of these techniques and avail themselves of their potentially useful properties. This review outlines selected predictive methods that can be used to develop models that may be useful to patients and clinicians for prostate cancer management.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63147/1/10915360152745812.pd

Proper Motions of Dwarf Spheroidal Galaxies from Hubble Space Telescope Imaging. III: Measurement for Ursa Minor

This article presents a measurement of the proper motion of the Ursa Minor dwarf spheroidal galaxy determined from images taken with the Hubble Space Telescope in two distinct fields.Comment: AJ, accepted; 23 pages, 17 figures (Fig. 1 abridged), 5 table

Rational mutagenesis to support structure-based drug design: MAPKAP kinase 2 as a case study

<p>Abstract</p> <p>Background</p> <p>Structure-based drug design (SBDD) can provide valuable guidance to drug discovery programs. Robust construct design and expression, protein purification and characterization, protein crystallization, and high-resolution diffraction are all needed for rapid, iterative inhibitor design. We describe here robust methods to support SBDD on an oral anti-cytokine drug target, human MAPKAP kinase 2 (MK2). Our goal was to obtain useful diffraction data with a large number of chemically diverse lead compounds. Although MK2 structures and structural methods have been reported previously, reproducibility was low and improved methods were needed.</p> <p>Results</p> <p>Our construct design strategy had four tactics: <it>N</it>- and <it>C</it>-terminal variations; entropy-reducing surface mutations; activation loop deletions; and pseudoactivation mutations. Generic, high-throughput methods for cloning and expression were coupled with automated liquid dispensing for the rapid testing of crystallization conditions with minimal sample requirements. Initial results led to development of a novel, customized robotic crystallization screen that yielded MK2/inhibitor complex crystals under many conditions in seven crystal forms. In all, 44 MK2 constructs were generated, ~500 crystals were tested for diffraction, and ~30 structures were determined, delivering high-impact structural data to support our MK2 drug design effort.</p> <p>Conclusion</p> <p>Key lessons included setting reasonable criteria for construct performance and prioritization, a willingness to design and use customized crystallization screens, and, crucially, initiation of high-throughput construct exploration very early in the drug discovery process.</p