The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Sleep Disorders Reduce Health-Related Quality of Life in Multiple Sclerosis (Nottingham Health Profile Data in Patients with Multiple Sclerosis)

Quality of Life (QoL) is decreased in multiple sclerosis (MS), but studies about the impact of sleep disorders (SD) on health-related quality of Life (HRQoL) are lacking. From our original cohort, a cross-sectional polysomnographic (PSG) study in consecutive MS patients, we retrospectively analysed the previously unpublished data of the Nottingham Health Profile (NHP). Those MS patients suffering from sleep disorders (n = 49) showed significantly lower HRQoL compared to MS patients without sleep disorders (n = 17). Subsequently, we classified the patients into four subgroups: insomnia (n = 17), restless-legs syndrome, periodic limb movement disorder and SD due to leg pain (n = 24), obstructive sleep apnea (n = 8) and patients without sleep disorder (n = 17). OSA and insomnia patients showed significantly higher NHP values and decreased HRQoL not only for the sleep subscale but also for the “energy” and “emotional” area of the NHP. In addition, OSA patients also showed increased NHP values in the “physical abilities” area. Interestingly, we did not find a correlation between the objective PSG parameters and the subjective sleep items of the NHP. However, this study demonstrates that sleep disorders can reduce HRQoL in MS patients and should be considered as an important confounder in all studies investigating HRQoL in MS.     

Monolithically-integrated BiVO4/p+-n GaAs1-xPx tandem photoanodes capable of unassisted solar water splitting

Monolithically-integrated tandem photoanodes were fabricated on substrates consisting of epitaxial n-GaAs_1-xP_x (x ? 0.32) grown on n⁺-GaAs wafers. A p⁺-n junction photovoltaic (PV) cell was first formed by zinc diffusion into the n-GaAs_0.68P_0.32 from a deposited ZnO coating. After diffusion the ZnO serves as a transparent electrical contact to the resulting p⁺-GaAs_0.68P_0.32 surface layer. Transparent, conducting SnO₂:F provides chemical and mechanical protection for the ZnO and the underlying PV cell, and it electrically connects this cell to a top BiVO₄ photocatalyst layer. In some photoanodes, a WO₃ thin film was interposed between the SnO₂:F and BiVO₄. All oxide coatings were produced by ultrasonic spray pyrolysis except WO₃, which was spin coated. Unassisted (unbiased) solar water splitting was achieved, with a solar-to-hydrogen efficiency approaching 2%, without addition of any co-catalyst to the BiVO₄ surface. This work can provide insights to other researchers regarding scalable, low cost approaches for the planar monolithic integration of oxide photoanode materials with PV cells to create new tandem devices.     

Single chamber Solid Oxide Fuel Cells selective electrodes: A real chance with brownmillerite-based nanocomposites

In this contribution brownmillerite-based nanocomposite cathode for Single-Chamber Solid Oxide Fuel Cells is developed. These cells can be very attractive especially for small and cheap devices because of the absence of seals. The efficiency of SC-SOFCs is strictly connected to the selectivity of anode and cathode, the bottleneck for this technology. The development of a cathode inert in fuel oxidation is particularly challenging. Our strategy is to start from a catalytically un-active support (CFA = Ca₂FeAl_0.95Mg_0.05O₅) and induce the formation of iron oxide based nanoparticles, expected to activate oxygen. Symmetric (CFA + FeO_x/CGO/CFA + FeO_x) and complete cells (CFA + FeO_x/CGO/Ni-CGO) are studied in air and methane/oxygen 2:1 mixture. The Area Specific Resistance of CFA + FeO_x is less than 1/3 that of CFA. The high selectivity allows to reach an efficiency of 25%; power still needs to be increased but we demonstrated the possibility to develop selective low cost electrodes. The effect of air, methane/oxygen exposure and the heat treatments were carefully investigated.     

Dissociating uncertainty responses and reinforcement signals in the comparative study of uncertainty monitoring.

Although researchers are exploring animals' capacity for monitoring their states of uncertainty, the use of some paradigms allows the criticism that animals map avoidance responses to error-causing stimuli not because of uncertainty monitored but because of feedback signals and stimulus aversion. The authors addressed this criticism with an uncertainty-monitoring task in which participants completed blocks of trials with feedback deferred so that they could not associate reinforcement signals to particular stimuli or stimulus-response pairs. Humans and 1 of 2 monkeys were able to make cognitive, decisional uncertainty responses that were independent of feedback or reinforcement history within a task. This finding unifies the comparative literature on uncertainty monitoring. The dissociation of performance from reinforcement has theoretical implications, and the deferred-feedback technique has many applications. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Scalable and Structured Scheduling

Scheduling a program (i.e. constructing a timetable for the execution of its operations) is one of the most powerful methods for automatic parallelization. A schedule gives a blueprint for constructing a synchronous program, suitable for an ASIC or VLIW processor. However, constructing a schedule entails solving a large linear program. Even if one accepts the (experimental) fact that the Simplex is almost always polynomial, the scheduling time is of the order of a large power of the program size. Hence, the method does not scale well. The present paper proposes two methods for improving the situation. First, a large program can be divided into smaller units (processes), which can be scheduled separately. This is structured scheduling. Second, one can use projection methods for solving linear programs incrementally. This is specially efficient if the dependence graph is sparse.     

Measurements of small-scale fading and path loss for long range RF tags

RF modulated backscatter (RFMB), also known as modulated radar cross section or sigma modulation, is a RF transmission technique useful for short-range, low-data-rate applications, such as nonstop toll collection, electronic shelf tags, freight container identification and chassis identification in automobile manufacturing, that are constrained to have extremely low power requirements. The small-scale fading observed on the backscattered signal has deeper fades than the signal from a traditional one-way link of the same range in the same environment because the fading on the backscattered signal is the product of the fading on the off-board-generated carrier times the fading on the reflected signal. This paper considers the continuous wave (CW) type of RFMB, in which the interrogator transmitter and receiver antennas are different. This two-way link also doubles the path loss exponent of the one-way link. This paper presents the cumulative distribution functions for the measured small-scale fading and the measured path loss for short ranges in an indoor environment at 2.4 GHz over this type of link.     

1/f noise in large-area Hg<Subscript>1−x</Subscript>Cd<Subscript>x</Subscript>Te photodiodes

The 1/f noise in photovoltaic (PV) molecular-beam epitaxy (MBE)-grown Hg_1−xCd_xTe double-layer planar heterostructure (DLPH) large-area detectors is a critical noise component with the potential to limit sensitivity of the cross-track infrared sounder (CrIS) instrument. Therefore, an understanding of the origins and mechanisms of noise currents in these PV detectors is of great importance. Excess low-frequency noise has been measured on a number of 1000-μm-diameter active-area detectors of varying “quality” (i.e., having a wide range of I-V characteristics at 78 K). The 1/f noise was measured as a function of cut-off wavelength under illuminated conditions. For short-wave infrared (SWIR) detectors at 98 K, minimal 1/f noise was measured when the total current was dominated by diffusion with white noise spectral density in the mid-10⁻¹⁵A/Hz^1/2 range. For SWIR detectors dominated by other than diffusion current, the ratio, α, of the noise current in unit bandwidth i_n(f = 1 Hz, V_d = −60 mV, and Δf = 1 Hz) to dark current I_d(V_d = −60 mV) was α_SW-d = i_n/I_d ∼ 1 × 10⁻³. The SWIR detectors measured at 0 mV under illuminated conditions had median α_SW-P = i_n/I_ph ∼ 7 × 10⁻⁶. For mid-wave infrared (MWIR) detectors, α_MW-d = i_n/I_d ∼ 2 × 10⁻⁴, due to tunneling current contributions to the 1/f noise. Measurements on forty-nine 1000-μm-diameter MWIR detectors under illuminated conditions at 98 K and −60 mV bias resulted in α_MW-P = i_n/I_ph = 4.16 ± 1.69 × 10⁻⁶. A significant point to note is that the photo-induced noise spectra are nearly identical at 0 mV and 100 mV reverse bias, with a noise-current-to-photocurrent ratio, α_MW-P, in the mid 10⁻⁶ range. For long-wave infrared (LWIR) detectors measured at 78 K, the ratio, α_LW-d = i_n/I_d ∼ 6 × 10⁻⁶, for the best performers. The majority of the LWIR detectors exhibited α_LW-d on the order of 2 × 10⁻⁵. The photo-induced 1/f noise had α_LW-P = i_n/I_ph ∼ 5 × 10⁻⁶. The value of the noise-current-to-dark-current ratio, α appears to increase with increasing bandgap. It is not clear if this is due to different current mechanisms impacting 1/f noise performance. Measurements on detectors of different bandgaps are needed at temperatures where diffusion current is the dominant current. Excess low-frequency noise measurements made as a function of detector reverse bias indicate 1/f noise may result primarily from the dominant current mechanism at each particular bias. The 1/f noise was not a direct function of the applied bias.     

Securing Mobile Ad hoc Networks — A Motivational Approach

Mobile ad hoc networks rely on the co-operation of devices that route for each other. This immediately presents security problems. Each device's data passes through the not so friendly hands of other devices. Forwarding devices must use their processing power and battery power to route packets for others. When bandwidth is limited they must also use bandwidth that they might want to use for themselves. These are not great issues with the first incarnations of ad hoc networks — military systems or others where all the devices are owned by a single organisation. However, if ad hoc networks are to be generally deployed and become an alternative or adjunct to future cellular systems, then ways to encourage co-operation are required. This revised version was published online in July 2006 with corrections to the Cover Date.