Nanoparticle-based drug delivery: case studies for cancer and cardiovascular applications

Nanoparticles (NPs) comprised of nanoengineered complexes are providing new opportunities for enabling targeted delivery of a range of therapeutics and combinations. A range of functionalities can be included within a nanoparticle complex, including surface chemistry that allows attachment of cell-specific ligands for targeted delivery, surface coatings to increase circulation times for enhanced bioavailability, specific materials on the surface or in the nanoparticle core that enable storage of a therapeutic cargo until the target site is reached, and materials sensitive to local or remote actuation cues that allow controlled delivery of therapeutics to the target cells. However, despite the potential benefits of NPs as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of NP materials, as well as their size and shape. The need to validate each NP for safety and efficacy with each therapeutic compound or combination of therapeutics is an enormous challenge, which forces industry to focus mainly on those nanoparticle materials where data on safety and efficacy already exists, i.e., predominantly polymer NPs. However, the enhanced functionality affordable by inclusion of metallic materials as part of nanoengineered particles provides a wealth of new opportunity for innovation and new, more effective, and safer therapeutics for applications such as cancer and cardiovascular diseases, which require selective targeting of the therapeutic to maximize effectiveness while avoiding adverse effects on non-target tissues.     

Effects of long-term livestock grazing and habitat on understory vegetation

The herbaceous understory stratum contains most of the plant diversity in ponderosa pine ( Pinus ponderosa P. & C. Lawson var. scopulorum Engelm.) forests of the American Southwest and provides critical food and habitat for many wildlife species. During the last century, this stratum has been affected by livestock grazing and by increased dominance of overstory trees. We sampled a unique grazing exclosure to examine the relative importance of long-term livestock grazing (grazed or ungrazed) and habitat (park or tree) on the understory community. We sampled 3 plots of 192 contiguous quadrats (each quadrat 0.5 m 2 ) in each of the 4 treatment combinations, for a total of 2304 quadrats. Species-area curves were generated by aggregating quadrats into nonoverlapping areas at grain sizes of 0.5 to 576 m 2 . The effects of habitat and grazing on species density were evident at very different scales. Species density was higher in park than tree plots at scales ≤32 m 2 but did not differ between habitats at larger scales. Species density differed minimally between grazed and ungrazed treatments at small grains, but grazed plots contained more species than ungrazed plots at larger grains. Grazing treatments differed at smaller grains (to 4–8 m 2 ) than did habitats (to 32 m 2 ), with respect to density of native species and graminoids. Grazed plots had more exotic species than ungrazed plots at all grain sizes, though few exotics were present. Twenty-two species were identified as indicator species associated with habitats and/or grazing treatments. Evaluations of plant community response to treatments would be improved by accounting for the grain at which data have been collected and analyzed and by identifying indicator species associated with various treatments. These data would enable more-informed conservation and management decisions.     

Soil properties associated with vegetation patches in a Pinus ponderosa —bunchgrass mosaic

Since Euro-American settlement, fire exclusion and other factors have dramatically altered interior western coniferous forests. Once open and parklike, present-day structure in many southwestern Pinus ponderosa forests consists of dense stands of young, small-diameter trees, with small patches of larger, old trees, and relict open bunchgrass areas. Our objectives were to assess differences in soil properties associated with these different vegetation patches. We examined soil morphological characteristics, pH, organic C concentration, total N concentration, C:N ratio, and phytolith concentration from profiles within 6 transects (18 soil pedons) crossing patches of dense stands of small diameter trees, patches of old-growth trees, and open grassy areas. Results indicate that old-growth plots had significantly lower A horizon pH and thicker O horizons than grass plots. In general, we found vegetation patches had statistically similar C and N concentrations and C:N ratios for A and B horizons; however, C in the A horizon was positively correlated with O horizon accumulation ( r 2 = 0.79). Greater accumulation of organic C in the A horizon of forested areas contrasts with commonly reported results from mesic, mid-continental prairie-forest ecosystems but is typical for many arid, semiarid, and humid savanna ecosystems. Phytolith concentration was similar among old-growth pine, dense younger pine, and open grassy plots; the lack of a spatial pattern in phytolith distribution could indicate that grass cover was more spatially continuous in the past. Additionally, this interpretation is consistent with current theories regarding historical vegetation change in these forests.     

Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination(4), showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases.     

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.     

The detection of structural deformation errors in attitude determination

In the determination of the attitude parameters from a multi-antenna GPS array, one of the major assumptions is that the body frame is rigid at all times. If this assumption is not true then the derived attitude parameters will be in error. It is well known that in airborne platforms the wings often experience some displacement during flight, especially during periods of initializing maneouvres, such as taking off, landing,and banking. Often it is at these points in time that it is most critical to have the most precise attitude parameters.There are a number of techniques available for the detection of modeling errors.The CUSUM algorithm has successfully been implemented in the past to detect small persistent changes. In this paper the authors investigate different methods of generating the residuals, to be tested by the CUSUM algorithm, in an effort to determine which technique is best suited for the detection of structural deformation of an airborne platform. The methods investigated include monitoring the mean of the residuals generated from the difference between the known body frame coordinates, and those calculated from the derived attitude parameters. The generated residuals are then passed to a CUSUM algorithm to detect any small persistent changes. An alternative method involves transforming the generated residuals into the frequency domain through the use of the Fast Fourier Transform. The CUSUM algorithm is then used to detect any frequency changes. The final technique investigated involves transforming the generated residuals using the Haar wavelet. The wavelet coefficients are then monitored by the CUSUM algorithm in order to detect any significant change to the rigidity of the body frame.Detecting structural deformation, and quantifying the degree of deformation, during flight will ensure that these effects can be removed from the system, thus ensuring the most precise and reliable attitude parameter solutions. This paper, through a series ofsimulations, will assess the effectiveness of the above mentioned techniques for detecting structural deformation effects on a GPS multi-antenna array. These principles are then tested with experimental data.     

Tetramerization of an RNA oligonucleotide containing a GGGG sequence.

Poly rG can form four-stranded helices. The Hoogsteen-paired quartets of G residues on which such structures depend are so stable that they will form in 5'-GMP solutions, provided that Na+ or K+ are present (see for example, refs 2-4). Telomeric DNA sequences, which are G-rich, adopt four-stranded antiparallel G-quartet conformations in vitro, and parallel tetramerization of G-rich sequences may be involved in meiosis. Here we show that RNAs containing short runs of Gs can also tetramerize. A 19-base oligonucleotide derived from the 5S RNA of Escherichia coli (strand III), 5'GCCGAUGGUAGUGUGGGGU3', forms a K(+)-stabilized tetrameric aggregate that depends on the G residues at its 3' end. This complex is so stable that it would be surprising if similar structures do not occur in nature.