Formulation and Optimization of Aliskiren Loaded Poly(Lactide-Co-Glycolide) Nanoparticles

Aliskiren is a non-peptide, orally active renin inhibitor with poor absorption and low bioavailability (~2.6%). In order to improve the current drug delivery system, a commercially available, biodegradable copolymer, poly(lactide-co-glycolide) (PLGA), was employed for a nanoparticle (NP) reformulation of aliskiren. An emulsion-diffusion-evaporation technique was implemented where aliskiren and PLGA were dissolved in dichloromethane, ethyl acetate, or ethyl acetate/acetone. To an aqueous phase containing 0.25% w/v didodecyldimethylammonium bromide (DMAB) as stabilizer, the previously prepared organic phase was added drop-wise. Following sonication, NP diffusion was expedited with the addition of water, and the organic phase was evaporated to form a suspension. Centrifugation was performed at 10,000 rpm, and the supernatant was analyzed for drug entrapment efficiency via ultraviolet-visible spectroscopy as well as particle morphology with the use of a transmission electron microscope (TEM). Having the highest entrapment efficiency (82.68 ± 1.18 %), ethyl acetate was used as the organic solvent in further testing, such as examining the effects of variation in DMAB stabilizer concentration (0.10, 0.25, 0.50, or 1.00% w/v) and centrifugation speed (10,000 or 12,000 rpm). The optimum formulation was ascertained through observing certain NP characteristics, such as entrapment efficiency particle size, zeta potential, and polydispersity index (PDI). A NICOMP Particle Sizer was used to measure particle size, zeta potential, and PDI. The smallest NP size (67.27 ± 0.87 nm) was accomplished with 0.50% w/v DMAB concentration using a centrifugation speed of 12,000 rpm, while the highest zeta potential (18.73 ± 0.03 mV) was detected with the 1.00% w/v DMAB concentration and a 10,000 rpm centrifugation speed. Further, the best entrapment efficiency and PDI (82.68 ± 1.18 % and 0.15 ± 0.03, respectively) were accomplished with 0.25% w/v DMAB and centrifugation at 10,000 rpm. The most favorable formulation yielding the highest zeta potential (18.73 ± 0.03 mV) was observed when DMAB stabilizer was 1.00% w/v and centrifuged at 10,000 rpm. Particle size and entrapment efficiency for this formulation were 75.67 ± 0.89 nm and 71.62 ± 0.11 %, respectively

A fixed-target platform for serial femtosecond crystallography in a hydrated environment.

For serial femtosecond crystallography at X-ray free-electron lasers, which entails collection of single-pulse diffraction patterns from a constantly refreshed supply of microcrystalline sample, delivery of the sample into the X-ray beam path while maintaining low background remains a technical challenge for some experiments, especially where this methodology is applied to relatively low-ordered samples or those difficult to purify and crystallize in large quantities. This work demonstrates a scheme to encapsulate biological samples using polymer thin films and graphene to maintain sample hydration in vacuum conditions. The encapsulated sample is delivered into the X-ray beam on fixed targets for rapid scanning using the Roadrunner fixed-target system towards a long-term goal of low-background measurements on weakly diffracting samples. As a proof of principle, we used microcrystals of the 24 kDa rapid encystment protein (REP24) to provide a benchmark for polymer/graphene sandwich performance. The REP24 microcrystal unit cell obtained from our sandwiched in-vacuum sample was consistent with previously established unit-cell parameters and with those measured by us without encapsulation in humidified helium, indicating that the platform is robust against evaporative losses. While significant scattering from water was observed because of the sample-deposition method, the polymer/graphene sandwich itself was shown to contribute minimally to background scattering

Understanding the dispersion and assembly of bacterial cellulose in organic solvents

The constituent nanofibrils of bacterial cellulose are of interest to many researchers because of their purity and excellent mechanical properties. Mechanisms to disrupt the network structure of bacterial cellulose (BC) to isolate bacterial cellulose nanofibrils (BCN) are limited. This work focuses on liquid-phase dispersions of BCN in a range of organic solvents. It builds on work to disperse similarly intractable nanomaterials, such as single-walled carbon nanotubes, where optimum dispersion is seen for solvents whose surface energies are close to the surface energy of the nanomaterial; bacterial cellulose is shown to disperse in a similar fashion. Inverse gas chromatography was used to determine the surface energy of bacterial cellulose, under relevant conditions, by quantifying the surface heterogeneity of the material as a function of coverage. Films of pure BCN were prepared from dispersions in a range of solvents; the extent of BCN exfoliation is shown to have a strong effect on the mechanical properties of BC films and to fit models based on the volumetric density of nanofibril junctions. Such control offers new routes to producing robust cellulose films of bacterial cellulose nanofibrils

Mitigating agency risk between investors and ventures’ managers

The general management literature has long focused on the agency risks involved in the relationship between general managers and shareholders. Shareholders can deploy contractual and non-contractual mechanisms to reduce these inefficiencies. This study examines - based on a broad international sample of investment contracts - how the use of contractual and non-contractual mechanisms is related to the degree of risks associated with the venture’s development stage as well as how these practices differ across countries. Hypotheses are tested using a proprietary dataset of 265 hand-collected investment contracts associated with ventures in the U.S., Israel and nine European countries. Findings suggest that the use of mitigating contractual and non-contractual mechanisms is related to the degree of agency risks, and that these practices vary across countries. This study draws implications for how investors can best deploy their capital in different institutional settings whilst nurturing their relationships with managers and entrepreneurs

On the effect of resonances in composite Higgs phenomenology

We consider a generic composite Higgs model based on the coset SO(5)/SO(4) and study its phenomenology beyond the leading low-energy effective lagrangian approximation. Our basic goal is to introduce in a controllable and simple way the lowest-lying, possibly narrow, resonances that may exist is such models. We do so by proposing a criterion that we call partial UV completion. We characterize the simplest cases, corresponding respectively to a scalar in either singlet or tensor representation of SO(4) and to vectors in the adjoint of SO(4). We study the impact of these resonances on the signals associated to high-energy vector boson scattering, pointing out for each resonance the characteristic patterns of depletion and enhancement with respect to the leading-order chiral lagrangian. En route we derive the O(p^4) general chiral lagrangian and discuss its peculiar accidental and approximate symmetries.Comment: v3: a few typos corrected. Conclusions unchange

Theoretical Constraints on the Higgs Effective Couplings

We derive constraints on the sign of couplings in an effective Higgs Lagrangian using prime principles such as the naturalness principle, global symmetries, and unitarity. Specifically, we study four dimension-six operators, O_H, O_y, O_g, and O_gamma, which contribute to the production and decay of the Higgs boson at the Large Hadron Collider (LHC), among other things. Assuming the Higgs is a fundamental scalar, we find: 1) the coefficient of O_H is positive except when there are triplet scalars, resulting in a reduction in the Higgs on-shell coupling from their standard model (SM) expectations if no other operators contribute, 2) the linear combination of O_H and O_y controlling the overall Higgs coupling to fermion is always reduced, 3) the sign of O_g induced by a new colored fermion is such that it interferes destructively with the SM top contribution in the gluon fusion production of the Higgs, if the new fermion cancels the top quadratic divergence in the Higgs mass, and 4) the correlation between naturalness and the sign of O_gamma is similar to that of O_g, when there is a new set of heavy electroweak gauge bosons. Next considering a composite scalar for the Higgs, we find the reduction in the on-shell Higgs couplings persists. If further assuming a collective breaking mechanism as in little Higgs theories, the coefficient of O_H remains positive even in the presence of triplet scalars. In the end, we conclude that the gluon fusion production of the Higgs boson is reduced from the SM rate in all composite Higgs models. Our study suggests a wealth of information could be revealed by precise measurements of the Higgs couplings, providing strong motivations for both improving on measurements at the LHC and building a precision machine such as the linear collider.Comment: 37 pages, one figure; v2: improved discussion on dispersion relation and other minor modifications; version accepted for publication

Radiative Electroweak Symmetry Breaking in a Little Higgs Model

We present a new Little Higgs model, motivated by the deconstruction of a five-dimensional gauge-Higgs model. The approximate global symmetry is $SO(5)_0\times SO(5)_1$, breaking to $SO(5)$, with a gauged subgroup of $[SU(2)_{0L}\times U(1)_{0R}]\times O(4)_1$, breaking to $SU(2)_L \times U(1)_Y$. Radiative corrections produce an additional small vacuum misalignment, breaking the electroweak symmetry down to $U(1)_{EM}$. Novel features of this model are: the only un-eaten pseudo-Goldstone boson in the effective theory is the Higgs boson; the model contains a custodial symmetry, which ensures that $\hat{T}=0$ at tree-level; and the potential for the Higgs boson is generated entirely through one-loop radiative corrections. A small negative mass-squared in the Higgs potential is obtained by a cancellation between the contribution of two heavy partners of the top quark, which is readily achieved over much of the parameter space. We can then obtain both a vacuum expectation value of $v=246$ GeV and a light Higgs boson mass, which is strongly correlated with the masses of the two heavy top quark partners. For a scale of the global symmetry breaking of $f=1$ TeV and using a single cutoff for the fermion loops, the Higgs boson mass satisfies 120 GeV $\lesssim M_H\lesssim150$ GeV over much of the range of parameter space. For $f$ raised to 10 TeV, these values increase by about 40 GeV. Effects at the ultraviolet cutoff scale may also raise the predicted values of the Higgs boson mass, but the model still favors $M_H\lesssim 200$ GeV.Comment: 32 pages, 10 figures, JHEP style. Version accepted for publication in JHEP. Includes additional discussion of sensitivity to UV effects and fine-tuning, revised Fig. 9, added appendix and additional references

Alcohol Use and Periodic Limb Movements of Sleep

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65771/1/j.1530-0277.1993.tb00747.x.pd

Risk measures for direct real estate investments with non-normal or unknown return distributions

The volatility of returns is probably the most widely used risk measure for real estate. This is rather surprising since a number of studies have cast doubts on the view that volatility can capture the manifold risks attached to properties and corresponds to the risk attitude of investors. A central issue in this discussion is the statistical properties of real estate returns—in contrast to neoclassical capital market theory they are mostly non-normal and often unknown, which render many statistical measures useless. Based on a literature review and an analysis of data from Germany we provide evidence that volatility alone is inappropriate for measuring the risk of direct real estate. We use a unique data sample by IPD, which includes the total returns of 939 properties across different usage types (56% office, 20% retail, 8% others and 16% residential properties) from 1996 to 2009, the German IPD Index, and the German Property Index. The analysis of the distributional characteristics shows that German real estate returns in this period were not normally distributed and that a logistic distribution would have been a better fit. This is in line with most of the current literature on this subject and leads to the question which indicators are more appropriate to measure real estate risks. We suggest that a combination of quantitative and qualitative risk measures more adequately captures real estate risks and conforms better with investor attitudes to risk. Furthermore, we present criteria for the purpose of risk classification