Development of a Scalable Synthesis of HP-β-CD Pluronic Polyrotaxanes

Polyrotaxanes are polymers that have macrocycles threaded onto them, analogous to beads threaded onto a string. These materials are used for a variety of different biomedical applications.1-3 The Thompson group has been developing 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) polyrotaxanes as therapeutics for the treatment of Niemann-Pick Type C (NPC) disease. NPC is a debilitating genetic disorder where cholesterol accumulates in the lysosomes of cells.4 Developing a scalable process is crucial for the advancement of these materials as NPC therapeutics. The goal of this project is to optimize the only protocol for the synthesis of HP-β-CD/Pluronic polyrotaxanes in order to develop a synthetic method that can be operated on the multi-gram scale to support preclinical studies.5 Each component of the protocol was screened to determine which combination lead to the formation of polyrotaxanes with the highest yields and threading efficiencies in the shortest amount of time. Threading efficiency is a measure of how many HP-β-CD molecules are threaded onto each polymer. In addition to optimizing the current protocol, we have also explored flowing the reaction mixture through a bath sonicator and using a hydraulic press as alternative syntheses. It was found that probe sonication and bath sonication are both necessary components of the protocol. This indicates that sufficient agitation of the reaction mixture is required to promote the non-covalent threading reaction. Furthermore, bath sonication for one hour, followed by stirring for two days gave the highest threading efficiency. The results of these studies have simplified the existing protocol, but additional studies are needed to reveal whether this protocol is robust enough for efficient preparation of other HP-β-CD/Pluronic polyrotaxane derivatives

A SCUBA survey of the NGC 2068/2071 protoclusters

We report the results of a submillimeter dust continuum survey of the protoclusters NGC 2068 and NGC 2071 in Orion B carried out at 850 microns and 450 microns with SCUBA on JCMT. The mapped region is ~ 32' x 18' in size (~ 4 pc x 2 pc) and consists of filamentary dense cores which break up into small-scale (~ 5000 AU) fragments, including 70 starless condensations and 5 circumstellar envelopes/disks. The starless condensations, seen on the same spatial scales as protostellar envelopes, are likely to be gravitationally bound and pre-stellar in nature. Their mass spectrum, ranging from ~ 0.3 Msun to ~ 5 Msun, is reminiscent of the stellar initial mass function (IMF). Their mass-size relation suggests that they originate from gravitationally-driven fragmentation. We thus argue that pre-collapse cloud fragmentation plays a major role in shaping the IMF.Comment: 6 pages, 4 figures, 1 table. Letter accepted by Astronomy & Astrophysic

The initial conditions of isolated star formation - X. A suggested evolutionary diagram for prestellar cores

We propose an evolutionary path for prestellar cores on the radius-mass diagram, which is analogous to stellar evolutionary paths on the Hertzsprung-Russell Diagram. Using James Clerk Maxwell Telescope (JCMT) observations of L1688 in the Ophiuchus star-forming complex, we analyse the HCO+ (J=4\rightarrow3) spectral line profiles of prestellar cores. We find that of the 58 cores observed, 14 show signs of infall in the form of a blue-asymmetric double-peaked line profile. These 14 cores all lie beyond the Jeans mass line for the region on a radius-mass plot. Furthermore another 10 cores showing tentative signs of infall, in their spectral line profile shapes, appear on or just over the Jeans mass line. We therefore propose the manner in which a prestellar core evolves across this diagram. We hypothesise that a core is formed in the low-mass, low-radius region of the plot. It then accretes quasistatically, increasing in both mass and radius. When it crosses the limit of gravitational instability it begins to collapse, decreasing in radius, towards the region of the diagram where protostellar cores are seen.Comment: 42 pages, 11 figures (+58 in appendix), Accepted for publication in MNRA

Calcium influx and vascular reactivity in systemic hypertension

Numerous studies have focused on functional vascular changes that characterize the hypertensive state. Recent evidence that suggests that increased vascular reactivity in hypertension is due to changes in the delivery of activator Ca++ through channels in the cell membrane will be reviewed. The primary evidence supporting this hypothesis comes from studies that characterize the effects of Ca++-free solution and calcium channel blockers on contractile properties of isolated vascular smooth muscle. In the present study, experiments were performed to investigate the role of Ca++ influx in vascular contractions produced by interventions that cause membrane depolarization. Isometric tension development in helical strips of carotid arteries from stroke-prone spontaneously hypertensive rats in response to elevated K+ and tetraethylammonium chloride was greater than that in carotid arteries from Wistar-Kyoto normotensive rats. The rate of tension development to K+-free solution in carotid arteries from stroke-prone spontaneously hypertensive rats was faster than in Wistar-Kyoto normotensive rat arteries. Contractile responses to all 3 depolarizing interventions were reduced in arterial strips incubated in Ca++-free solution containing the chelator ethylene glycol bis-([beta]-aminoethyl ether) N,N,N',N'-tetraacetic acid and in arterial strips treated with the Ca++ channel blocker verapamil. These results are consistent with the hypothesis that constrictor stimuli that produce membrane depolarization cause an opening of Ca++ channels in the plasma membrane that are sensitive to the organic channel blockers. Further, a change in Ca++ permeability or membrane depolarizing mechanisms contributes to increased contractile responsiveness in carotid arteries of stroke-prone spontaneously hypertensive rats.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26837/1/0000397.pd

H2O line mapping at high spatial and spectral resolution - Herschel observations of the VLA1623 outflow

Apart from being an important coolant, H2O is known to be a tracer of high-velocity molecular gas. Recent models predict relatively high abundances behind interstellar shockwaves. The dynamical and physical conditions of the H2O emitting gas, however, are not fully understood yet. We aim to determine the abundance and distribution of H2O, its kinematics and the physical conditions of the gas responsible for the H2O emission. The observed line profile shapes help us understand the dynamics in molecular outflows. We mapped the VLA1623 outflow, in the ground-state transitions of o-H2O, with the HIFI and PACS instruments. We also present observations of higher energy transitions of o-H2O and p-H2O obtained with HIFI and PACS towards selected outflow positions. From comparison with non-LTE radiative transfer calculations, we estimate the physical parameters of the water emitting regions. The observed water emission line profiles vary over the mapped area. Spectral features and components, tracing gas in different excitation conditions, allow us to constrain the density and temperature of the gas. The H2O emission originates in a region where temperatures are comparable to that of the warm H2 gas (T\gtrsim200K). Thus, the H2O emission traces a gas component significantly warmer than the gas responsible for the low-J CO emission. The H2O column densities at the CO peak positions are low, i.e. N(H2O) \simeq (0.03-10)x10e14 cm-2. The H2O abundance with respect to H2 in the extended outflow is estimated at X(H2O)<1x10e-6, significantly lower than what would be expected from most recent shock models. The H2O emission traces a gas component moving at relatively high velocity compared to the low-J CO emitting gas. However, other dynamical quantities such as the momentum rate, energy and mechanical luminosity are estimated to be the same, independent of the molecular tracer used, CO or H2O.Comment: 14 pages, 13 figures, 4 table

Deuterated formaldehyde in rho Ophiuchi A

From mapping observations of H2CO, HDCO, and D2CO, we have determined how the degree of deuterium fractionation changes over the central 3'x3' region of rho Oph A. The multi-transition data of the various H2CO isotopologues, as well as from other molecules (e.g., CH3OH and N2D+) present in the observed bands, were analysed using both the standard type rotation diagram analysis and, in selected cases, a more elaborate method of solving the radiative transfer for optically thick emission. In addition to molecular column densities, the analysis also estimates the kinetic temperature and H2 density. Toward the SM1 core in rho Oph A, the H2CO deuterium fractionation is very high. In fact, the observed D2CO/HDCO ratio is 1.34+/-0.19, while the HDCO/H2CO ratio is 0.107+/-0.015. This is the first time, to our knowledge, that the D2CO/HDCO abundance ratio is observed to be greater than 1. The kinetic temperature is in the range 20-30 K in the cores of rho Oph A, and the H2 density is (6-10)x10^5 cm-3. We estimate that the total H2 column density toward the deuterium peak is (1-4)x10^23 cm-2. As depleted gas-phase chemistry is not adequate, we suggest that grain chemistry, possibly due to abstraction and exchange reactions along the reaction chain H2CO -> HDCO -> D2CO, is at work to produce the very high deuterium levels observed.Comment: 17 pages, 11 figures, accepted for publication in Astronomy & Astrophysic

Far-infrared observations of a massive cluster forming in the Monoceros R2 filament hub

We present far-infrared observations of Monoceros R2 (a giant molecular cloud at approximately 830 pc distance, containing several sites of active star formation), as observed at 70 μm, 160 μm, 250 μm, 350 μm, and 500 μm by the Photodetector Array Camera and Spectrometer (PACS) and Spectral and Photometric Imaging Receiver (SPIRE) instruments on the Herschel Space Observatory as part of the Herschel imaging survey of OB young stellar objects (HOBYS) Key programme. The Herschel data are complemented by SCUBA-2 data in the submillimetre range, and WISE and Spitzer data in the mid-infrared. In addition, C18O data from the IRAM 30-m Telescope are presented, and used for kinematic information. Sources were extracted from the maps with getsources, and from the fluxes measured, spectral energy distributions were constructed, allowing measurements of source mass and dust temperature. Of 177 Herschel sources robustly detected in the region (a detection with high signal-to-noise and low axis ratio at multiple wavelengths), including protostars and starless cores, 29 are found in a filamentary hub at the centre of the region (a little over 1% of the observed area). These objects are on average smaller, more massive, and more luminous than those in the surrounding regions (which together suggest that they are at a later stage of evolution), a result that cannot be explained entirely by selection effects. These results suggest a picture in which the hub may have begun star formation at a point significantly earlier than the outer regions, possibly forming as a result of feedback from earlier star formation. Furthermore, the hub may be sustaining its star formation by accreting material from the surrounding filaments

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual\u27s risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig\u27s potential to enhance clinical therapeutic innovation to improve human health. (Figure presented.)

Control of star formation by supersonic turbulence

Understanding the formation of stars in galaxies is central to much of modern astrophysics. For several decades it has been thought that stellar birth is primarily controlled by the interplay between gravity and magnetostatic support, modulated by ambipolar diffusion. Recently, however, both observational and numerical work has begun to suggest that support by supersonic turbulence rather than magnetic fields controls star formation. In this review we outline a new theory of star formation relying on the control by turbulence. We demonstrate that although supersonic turbulence can provide global support, it nevertheless produces density enhancements that allow local collapse. Inefficient, isolated star formation is a hallmark of turbulent support, while efficient, clustered star formation occurs in its absence. The consequences of this theory are then explored for both local star formation and galactic scale star formation. (ABSTRACT ABBREVIATED)Comment: Invited review for "Reviews of Modern Physics", 87 pages including 28 figures, in pres

Multi-line detection of O2 toward rho Oph A

Models of pure gas-phase chemistry in well-shielded regions of molecular clouds predict relatively high levels of molecular oxygen, O2, and water, H2O. Contrary to expectation, the space missions SWAS and Odin found only very small amounts of water vapour and essentially no O2 in the dense star-forming interstellar medium. Only toward rho Oph A did Odin detect a weak line of O2 at 119 GHz in a beam size of 10 arcmin. A larger telescope aperture such as that of the Herschel Space Observatory is required to resolve the O2 emission and to pinpoint its origin. We use the Heterodyne Instrument for the Far Infrared aboard Herschel to obtain high resolution O2 spectra toward selected positions in rho Oph A. These data are analysed using standard techniques for O2 excitation and compared to recent PDR-like chemical cloud models. The 487.2GHz line was clearly detected toward all three observed positions in rho Oph A. In addition, an oversampled map of the 773.8GHz transition revealed the detection of the line in only half of the observed area. Based on their ratios, the temperature of the O2 emitting gas appears to vary quite substantially, with warm gas (> 50 K) adjacent to a much colder region, where temperatures are below 30 K. The exploited models predict O2 column densities to be sensitive to the prevailing dust temperatures, but rather insensitive to the temperatures of the gas. In agreement with these model, the observationally determined O2 column densities seem not to depend strongly on the derived gas temperatures, but fall into the range N(O2) = (3 to >6)e15/cm^2. Beam averaged O2 abundances are about 5e-8 relative to H2. Combining the HIFI data with earlier Odin observations yields a source size at 119 GHz of about 4 - 5 arcmin, encompassing the entire rho Oph A core.Comment: 10 pages, 8 figures intended for publication in A&