Microcalorimetry in the screening of discovery compounds and in the investigation of novel drug delivery systems

Calorimetry has for some time been proposed as a rapid method for determination of bioactivity. This paper describes the background to this application and describes how it has been extended to the study of bioassay techniques via microcalorimetry in the development of structure activity relationships (SARs). That SARs can be developed indicates that it is possible to guide drug synthetic strategy through the results of microcalorimetric investigations, and this approach is explored here. In an extension of this approach it is argued that microcalorimetry is well suited to the examination of novel drug delivery systems, allowing investigation of the capacity of drug delivery molecules to release the drug in the presence of a target organism.     

Experimental and ab initio study of the HO2.CH3OH complex: thermodynamics and kinetics of formation

Near-infrared spectroscopy was used to monitor HO2 formed by pulsed laser photolysis of Cl2-O2-CH3OH-N2 mixtures. On the microsecond time scale, [HO2] exhibited a time dependence consistent with a mechanism in which [HO2] approached equilibrium via HO2 + HO2.CH3OH (3, -3). The equilibrium constant for reaction 3, K(p), was measured between 231 and 261 K at 50 and 100 Torr, leading to standard reaction enthalpy and entropy values (1 sigma) of delta(r) = -37.4 +/- 4.8 kJ mol(-1) and delta(r) = -100 +/- 19 J mol(-1) K(-1). The effective bimolecular rate constant, k3, for formation of the HO2.CH3OH complex is .10(-15).exp[(1800 +/- 500)/T] cm3 molecule(-1) s(-1) at 100 Torr (1 sigma). Ab initio calculations of the optimized structure and energetics of the HO2.CH3OH complex were performed at the CCSD(T)/6-311++G(3df,3pd)//MP2(full)/6-311++G(2df,2pd) level. The complex was found to have a strong hydrogen bond (D(e) = 43.9 kJ mol(-1)) with the hydrogen in HO2 binding to the oxygen in CH3OH. The calculated enthalpy for association is delta(r) = -36.8 kJ mol(-1). The potentials for the torsion about the O2-H bond and for the hydrogen-bond stretch were computed and 1D vibrational levels determined. After explicitly accounting for these degrees of freedom, the calculated Third Law entropy of association is delta(r) = -106 J mol(-1) K(-1). Both the calculated enthalpy and entropy of association are in reasonably good agreement with experiment. When combined with results from our previous study (Christensen et al. Geophys. Res. Lett. 2002, 29; doi:10.1029/2001GL014525), the rate coefficient for the reaction of HO2 with the complex, HO2 + HO2.CH3OH, is determined to be (2.1 +/- 0.7) x 10(-11) cm3 molecule(-1) s(-1). The results of the present work argue for a reinterpretation of the recent measurement of the HO2 self-reaction rate constant by Stone and Rowley (Phys. Chem. Chem. Phys. 2005, 7, 2156). Significant complex concentrations are present at the high methanol concentrations used in that work and lead to a nonlinear methanol dependence of the apparent rate constant. This nonlinearity introduces substantial uncertainty in the extrapolation to zero methanol.     

Angular dependence of tunneling magnetoresistance in La0.7Sr0.3MnO3 step-edge junctions

La_0.7Sr_0.3MnO₃ (LSMO) tunneling magnetoresistance (TMR) junctions have been fabricated on step-edge (0 0 1) SrTiO₃ substrates with a high step-edge angle. In the measurement of magnetoresistance (MR) ratio versus external magnetic field H, butterfly-like MR curves are clearly observed. The MR(H  ) curves vary with θ$\theta$, the angle between the applied magnetic field and the current direction in the substrate plane, showing anisotropic MR properties. A much broader MR(H) response is observed for the configuration of H perpendicular to the substrate plane. Additionally, the maxima-MR field H_p almost coincides with the coercive field H_c for θ<60°$\theta <60°$ but obeys a different form from _Hc(θ)$H_{\mathrm{c}}(\theta )$. The high-field junction resistance shows an intrinsic sin²θ${\sin }^2\theta$ angular dependence, while the low-field resistance shows an extrinsic cos(4θ)$\cos (4\theta )$ angular dependence. The distinctive features are mainly due to the induced magnetization anisotropy in the artificial steps of grain boundaries.     

Variation of parameters and solutions of composite products of linear differential equations

Given a basis of solutions to k ordinary linear differential equations ?j[y]=0(j=1,2,…,k), we show how Green's functions can be used to construct a basis of solutions to the homogeneous differential equation ?[y]=0, where ? is the composite product ?=?₁?₂…?k. The construction of these solutions is elementary and classical. In particular, we consider the special case when . Remarkably, in this case, if {y₁,y₂,…,yn} is a basis of ?₁[y]=0, then our method produces a basis of for any k∈N. We illustrate our results with several classical differential equations and their special function solutions.     

On Birman's sequence of Hardy–Rellich-type inequalities

In 1961, Birman proved a sequence of inequalities $\{I_n\}$, for $n\in \mathbb{N}$, valid for functions in $C_0^n((0,\infty ))?L^2((0,\infty ))$. In particular, $I_1$ is the classical (integral) Hardy inequality and $I_2$ is the well-known Rellich inequality. In this paper, we give a proof of this sequence of inequalities valid on a certain Hilbert space $H_n([0,\infty ))$ of functions defined on $[0,\infty )$. Moreover, $f\in H_n([0,\infty ))$ implies $f^{\prime }\in H_{n?1}([0,\infty ))$; as a consequence of this inclusion, we see that the classical Hardy inequality implies each of the inequalities in Birman's sequence. We also show that for any finite $b>0$, these inequalities hold on the standard Sobolev space $H_0^n((0,b))$. Furthermore, in all cases, the Birman constants ${[(2n?1)!!]}^2/2^{2n}$ in these inequalities are sharp and the only function that gives equality in any of these inequalities is the trivial function in $L^2((0,\infty ))$ (resp., $L^2((0,b))$). We also show that these Birman constants are related to the norm of a generalized continuous Cesàro averaging operator whose spectral properties we determine in detail.