Triterpene based compounds with potent anti-maturation activity against HIV-1

Efforts towards developing orally bioavailable HIV-1 maturation inhibitors starting from betulinic acid 1 are described. SAR resulted in improved potency, physicochemical properties, and enhanced oral absorption in rats.     

Reduction of Abeta accumulation in the Tg2576 animal model of Alzheimer's disease after oral administration of the phosphatidyl-inositol kinase inhibitor wortmannin.

The abnormal accumulation of the amyloid beta protein (Abeta) has been implicated as an early and critical event in the etiology and pathogenesis of Alzheimer's disease (AD). Compounds that reduce Abeta accumulation may therefore be useful therapeutically. In cell-based screens we detected a significant reduction in Abeta concentration after treatment with the phosphatidylinositol kinase inhibitors wortmannin and LY294002. To determine the effect of this class of compounds on in vivo Abeta accumulation, we administered wortmannin to the Tg2576 mouse model of AD. Oral administration of wortmannin over four months resulted in a significant, non-overlapping 40%-50% reduction in the number of senile plaques, one of the pathological hallmarks of AD. Sandwich ELISA analysis of formic acid extractable Abeta in the brain of treated animals indicates that both Abeta40 and the longer, more amyloidogenic form of the peptide, Abeta42, were significantly reduced. These data provide the first direct evidence that compounds identified by their ability to reduce Abeta concentration in vitro can reduce Abeta accumulation and deposition in the brain, thus establishing a basic paradigm for the identification and evaluation of additional compounds that lower Abeta accumulation.     

Theoretical analysis of molecular diffusion in pressure-driven laminar flow in microfluidic channels

The T-sensor is a microfluidic analytical device that operates at low Reynolds numbers to ensure entirely laminar flow. Diffusion of molecules between streams flowing side by side may be observed directly. The pressure-driven velocity profile in the duct-shaped device influences diffusive transport in ways that affect the use of the T-sensor to measure molecular properties. The primary effect is a position-dependent variation in the extent of diffusion that occurs due to the distribution of residence time among different fluid laminae. A more detailed characterization reveals that resultant secondary concentration gradients yield variations in the scaling behavior between diffusive displacement and elapsed time in different regions of the channel. In this study, the time-dependent evolution of analyte distribution has been quantified using a combination of one- and two-dimensional models. The results include an accurate portrayal of the shape of the interdiffusion region in a representative T-sensor assay, calculation of the diffusive scaling law across the width of the channel, and quantification of artifacts that occur when making diffusion coefficient measurements in the T-sensor.     

The relationship between the structure of the headgroup of sphingolipids and their ability to form complex high axial ratio microstructures

Ceramides with chemically modified polar headgroups were prepared and examined for their ability to form complex high axial ratio microstructures (CHARMS), potential drug delivery vehicles. In general, if the modified ceramide had either a hydrogen bond donor or acceptor at C-1 and C-3, including hydrophobic or hydrophilic groups attached to C-1 microstructures formed. Tolerated groups include amides, esters, sulfonates, and ethers. If modification at C-3 added significant bulk (greater than four carbons regardless of hydrophilicity), then amorphous aggregates formed. Ceramides with C-1 and C-3 bridged through a cyclic structure also made microstructures. By using a sphingolipid with an amine headgroup, CHARMs may be modified covalently after formation.     

Compact, high performance surface plasmon resonance imaging system

We report the construction and characterization of a new compact surface plasmon resonance imaging instrument. Surface plasmon resonance imaging is a versatile technique for detection, quantification and visualization of biomolecular binding events which have spatial structure. The imager uses a folded light path, wide-field optics and a tilted detector to implement a high performance optical system in a volume 7 in. x 4 in. x 2 in. A bright diode light source and an image detector with fast frame rate and integrated digital signal processor enable real-time averaging of multiple images for improved signal-to-noise ratio. Operating angle of the imager is adjusted by linear translation of the light source. Imager performance is illustrated using resolution test targets, refractive index test solutions, and competition assays for the antiepileptic drug phenytoin. Microfluidic flowcells are used to enable simultaneous assay of three sample streams. Noise level of refractive index measurements was found to decrease proportional to the square root of the number of pixels averaged, reaching approximately 5 x 10(-7) refractive index units root-mean-square for 160 x 120 pixels image regions imaged for 1s. The simple, compact construction and high performance of the imager will allow the device to be readily applied to a wide range of applications.     

Studies on the mechanism of inhibition of 2-acetylaminofluorene toxicity by butylated hydroxytoluene.

Male rats were placed on a diet containing 0.05% (w/w) of the hepatic carcinogen 2-acetylaminofluorene (AAF). They ceased to gain weight. However, when the carcinogenic diet was supplemented with butylated hydroxytoluene (BHT) (0.5% w/w), an antioxidant, the animals gained weight at approximately one-half of the normal rate. This observation led to a series of experiments aimed at elucidating the mechanism(s) by which BHT reduced the toxicity of AAF. These initial studies were directed towards the effect of BHT on the extent and duration of the covalent binding of AAF with DNA. BHT feeding was shown to reduce the binding of carcinogen to hepatic DNA. Studies employing cells in culture demonstrated that BHT does not influence either excision repair or post-replication repair of DNA. These data indicate that a potential mechanism of action of BHT is at the anti-initiation level of carcinogen-induced DNA damage.     

Loss of Potential Aquatic-Terrestrial Subsidies Along the Missouri River Floodplain

Ecosystems - The floodplains of large rivers have been heavily modified due to riparian development and channel modifications, both of which can eliminate shallow off-channel habitats. The...     

De novo infection of B cells during murine gammaherpesvirus 68 latency

The mechanisms by which gammaherpesviruses maintain latency are unclear. Here we used a murine gammaherpesvirus model to show that previously uninfected B cells in immunocompetent mice can acquire virus during latency. In vivo depletion of T cells allowed viral reactivation, as measured by increased viral loads, but not enhanced transfer of virus to new cells. In the absence of both immune T cells and antibody following the transfer of latently infected cells into naïve animals, there was robust infection of new B cells. These data confirm that both T cells and antibody contribute to the control of gammaherpesvirus latency, reactivation, and spread.     

HIV/AIDS,Food Supplementation and Livelihood Programs in Uganda: A Way Forward?

Background

Over the last decade, health, nutrition and policy experts have become increasingly aware of the many ways in which food insecurity and HIV infection negatively impact and reinforce one another. In response, many organizations providing HIV care began supplying food aid to clients in need. Food supplementation, however, was quickly recognized as an unsustainable and incomplete intervention. Many HIV care organizations therefore developed integrated HIV and livelihood programs (IHLPs) to target the root causes of food insecurity.

Methods and Findings

We conducted a qualitative study using in-depth interviews with 21 key informants who worked at seven organizations providing HIV care, food aid, or IHLPs in Kampala, Uganda in 2007-2008 to better understand the impact of IHLPs on the well-being of people living with HIV and AIDS (PLWHAs) and the challenges in transitioning clients from food aid to IHLPs. There was strong consensus among those interviewed that IHLPs are an important intervention in addressing food insecurity and its adverse health consequences among PLWHAs. Key informants identified three main challenges in transitioning PLWHAs from food supplementation programs to IHLPs: (1) lack of resources (2) timing of the transition and (3) logistical considerations including geography and weather. Factors seen as contributing to the success of programs included: (1) close involvement of community leaders (2) close ties with local and national government (3) diversification of IHLP activities and (4) close integration with food supplementation programs, all linked through a central program of HIV care.

Conclusion

Health, policy and development experts should continue to strengthen IHLPs for participants in need. Further research is needed to determine when and how participants should be transitioned from food supplementation to IHLPs, and to determine how to better correlate measures of food insecurity with objective clinical outcomes so as to better evaluate program results.