Cardiovascular Disease in Women—Challenges Deserving a Comprehensive Translational Approach

Heart disease in women is associated with high levels of morbidity and mortality. Although many of the underlying causes are similar for both genders, cardiovascular disease among women has some unique features, including higher coronary heart disease mortality, higher frequency of sudden cardiac death without previous symptoms, and increased mortality among older women compared to men following a myocardial infarction. During recent years, increasing efforts have been placed on identifying preventive measures, but translation of knowledge from epidemiological studies and clinical trials remain incomplete, particularly in women. The recent launch of the National Institutes of Health’s Clinical and Translational Science Award program offers opportunities to address these gaps and represent a unique opportunity to foster a new generation of researchers familiar with important issues regarding women’s cardiovascular health

Boron-Rich Nanoscale Delivery Agents for the Boron Neutron Capture Therapy of Cancer

Nanoscience Poster SessionThe translational research effort in boron neutron capture therapy (BNCT) described below and recently initiated at the University of Missouri International Institute of Nano and Molecular Medicine and the University of Missouri Research Reactor would benefit from collaboration with a research group knowledgeable in modeling human tumors using small animal hosts and cellular biology as it relates to therapeutic results and the treatment of experimental data. The boron-10 (10B) isotope is unique among light elements for its high neutron cross-section and low inherent toxicity. When subjected to relatively benign thermal neutrons, the 10B nucleus undergoes a neutron capture reaction forming an excited 11B species. This unstable nucleus subsequently undergoes essentially instantaneous fission to release 2.4 MeV of kinetic energy in the form of a pair of 7Li3+ and 4He2+ ions, which are confined to the volume of about one cell. Therefore, preferential accumulation of 10B-containing structures within cancerous cells can lead to selective destruction of these cells. This process is more commonly known as Boron Neutron Capture Therapy (BNCT) for cancer. The key to the implementation of this potentially powerful and selective therapy is the delivery of at least 30 parts per million (ppm) of 10B within the tumor tissue while minimizing superfluous 10B within the surrounding healthy tissue. This difference in 10B concentration is often denoted through the boron concentration in tumor to boron concentration in blood ratio, with a higher ratio being preferable. Herein we describe the synthesis and results of biodistribution experiments with two nano-scale boron delivery agents: liposomes and oligomeric phosphate diesters (OPDs). Liposomes, containing both amphiphilic (KC2B9H11(CH2)15CH3, MAC) and hydrophilic (Na3B20H17NH3, TAC) components and ranging in diameter from 30 to 100 nm, showed tumor boron accumulations as high as 50 ppm and tumor to blood ratios over 8. OPDs, ranging in size from 1 to 5 nm in diameter, also exhibited preferential tumor accumulations of 30 ppm at tumor to blood ratios as high as 35 to 1. In both cases, liposomes and OPDs greatly outperformed currently available small boron-containing pharmaceuticals at the same injected dose of 10B. Studies in which OPDs were fluorescently labeled proved their localization within the cellular nucleus, increasing the relative efficacy of these species due to their proximity to the DNA target. In conclusion, both liposomes and OPDs show great promise as nano-sized delivery vehicles for BNCT

Phylogenomic Analysis Reveals Dynamic Evolutionary History of the Drosophila Heterochromatin Protein 1 (HP1) Gene Family

Heterochromatin is the gene-poor, satellite-rich eukaryotic genome compartment that supports many essential cellular processes. The functional diversity of proteins that bind and often epigenetically define heterochromatic DNA sequence reflects the diverse functions supported by this enigmatic genome compartment. Moreover, heterogeneous signatures of selection at chromosomal proteins often mirror the heterogeneity of evolutionary forces that act on heterochromatic DNA. To identify new such surrogates for dissecting heterochromatin function and evolution, we conducted a comprehensive phylogenomic analysis of the Heterochromatin Protein 1 gene family across 40 million years of Drosophila evolution. Our study expands this gene family from 5 genes to at least 26 genes, including several uncharacterized genes in Drosophila melanogaster. The 21 newly defined HP1s introduce unprecedented structural diversity, lineage-restriction, and germline-biased expression patterns into the HP1 family. We find little evidence of positive selection at these HP1 genes in both population genetic and molecular evolution analyses. Instead, we find that dynamic evolution occurs via prolific gene gains and losses. Despite this dynamic gene turnover, the number of HP1 genes is relatively constant across species. We propose that karyotype evolution drives at least some HP1 gene turnover. For example, the loss of the male germline-restricted HP1E in the obscura group coincides with one episode of dramatic karyotypic evolution, including the gain of a neo-Y in this lineage. This expanded compendium of ovary- and testis-restricted HP1 genes revealed by our study, together with correlated gain/loss dynamics and chromosome fission/fusion events, will guide functional analyses of novel roles supported by germline chromatin

Heterosubtype Neutralizing Responses to Influenza A (H5N1) Viruses Are Mediated by Antibodies to Virus Haemagglutinin

Background: It is increasingly clear that influenza A infection induces cross-subtype neutralizing antibodies that may potentially confer protection against zoonotic infections. It is unclear whether this is mediated by antibodies to the neuraminidase (NA) or haemagglutinin (HA). We use pseudoviral particles (H5pp) coated with H5 haemagglutinin but not N1 neuraminidase to address this question. In this study, we investigate whether cross-neutralizing antibodies in persons unexposed to H5N1 is reactive to the H5 haemagglutinin. Methodology/Principal Findings: We measured H5-neutralization antibody titers pre- and post-vaccination using the H5N1 micro-neutralization test (MN) and H5pp tests in subjects given seasonal vaccines and in selected sera from European elderly volunteers in a H5N1 vaccine trial who had detectable pre-vaccination H5N1 MN antibody titers. We found detectable (titer ≥20) H5N1 neutralizing antibodies in a minority of pre-seasonal vaccine sera and evidence of a serological response to H5N1 in others after seasonal influenza vaccination. There was excellent correlation in the antibody titers between the H5N1 MN and H5pp tests. Similar correlations were found between MN and H5pp in the pre-vaccine sera from the cohort of H5N1 vaccine trial recipients. Conclusions/Significance: Heterosubtype neutralizing antibody to H5N1 in healthy volunteers unexposed to H5N1 is mediated by cross-reaction to the H5 haemagglutinin. Copyright: © 2009 Garcia et al.published_or_final_versio

Microstructure and pinning properties of hexagonal-disc shaped single crystalline MgB2

We synthesized hexagonal-disc-shaped MgB2 single crystals under high-pressure conditions and analyzed the microstructure and pinning properties. The lattice constants and the Laue pattern of the crystals from X-ray micro-diffraction showed the crystal symmetry of MgB2. A thorough crystallographic mapping within a single crystal showed that the edge and c-axis of hexagonal-disc shape exactly matched the (10-10) and the (0001) directions of the MgB2 phase. Thus, these well-shaped single crystals may be the best candidates for studying the direction dependences of the physical properties. The magnetization curve and the magnetic hysteresis for these single crystals showed the existence of a wide reversible region and weak pinning properties, which supported our single crystals being very clean.Comment: 5 pages, 3 figures. submitted to Phys. Rev.

Perspective of mesenchymal transformation in glioblastoma.

Despite aggressive multimodal treatment, glioblastoma (GBM), a grade IV primary brain tumor, still portends a poor prognosis with a median overall survival of 12-16 months. The complexity of GBM treatment mainly lies in the inter- and intra-tumoral heterogeneity, which largely contributes to the treatment-refractory and recurrent nature of GBM. By paving the road towards the development of personalized medicine for GBM patients, the cancer genome atlas classification scheme of GBM into distinct transcriptional subtypes has been considered an invaluable approach to overcoming this heterogeneity. Among the identified transcriptional subtypes, the mesenchymal subtype has been found associated with more aggressive, invasive, angiogenic, hypoxic, necrotic, inflammatory, and multitherapy-resistant features than other transcriptional subtypes. Accordingly, mesenchymal GBM patients were found to exhibit worse prognosis than other subtypes when patients with high transcriptional heterogeneity were excluded. Furthermore, identification of the master mesenchymal regulators and their downstream signaling pathways has not only increased our understanding of the complex regulatory transcriptional networks of mesenchymal GBM, but also has generated a list of potent inhibitors for clinical trials. Importantly, the mesenchymal transition of GBM has been found to be tightly associated with treatment-induced phenotypic changes in recurrence. Together, these findings indicate that elucidating the governing and plastic transcriptomic natures of mesenchymal GBM is critical in order to develop novel and selective therapeutic strategies that can improve both patient care and clinical outcomes. Thus, the focus of our review will be on the recent advances in the understanding of the transcriptome of mesenchymal GBM and discuss microenvironmental, metabolic, and treatment-related factors as critical components through which the mesenchymal signature may be acquired. We also take into consideration the transcriptomic plasticity of GBM to discuss the future perspectives in employing selective therapeutic strategies against mesenchymal GBM

CCR5 Is Essential for NK Cell Trafficking and Host Survival following Toxoplasma gondii Infection

The host response to intracellular pathogens requires the coordinated action of both the innate and acquired immune systems. Chemokines play a critical role in the trafficking of immune cells and transitioning an innate immune response into an acquired response. We analyzed the host response of mice deficient in the chemokine receptor CCR5 following infection with the intracellular protozoan parasite Toxoplasma gondii. We found that CCR5 controls recruitment of natural killer (NK) cells into infected tissues. Without this influx of NK cells, tissues from CCR5-deficient (CCR5(−/−)) mice were less able to generate an inflammatory response, had decreased chemokine and interferon γ production, and had higher parasite burden. As a result, CCR5(−/−) mice were more susceptible to infection with T. gondii but were less susceptible to the immune-mediated tissue injury seen in certain inbred strains. Adoptive transfer of CCR5(+/+) NK cells into CCR5(−/−) mice restored their ability to survive lethal T. gondii infection and demonstrated that CCR5 is required for NK cell homing into infected liver and spleen. This study establishes CCR5 as a critical receptor guiding NK cell trafficking in host defense

The Distance To The Hyades Cluster Based On Hubble Space Telescope Fine Guidance Sensor Parallaxes

Trigonometric parallax observations made with the Hubble Space Telescope (HST) Fine Guidance Sensor (FGS) 3 of seven Hyades members in six fields of view have been analyzed along with their proper motions to determine the distance to the cluster. Knowledge of the convergent point and mean proper motion of the Hyades is critical to the derivation of the distance to the center of the cluster. Depending on the choice of the proper-motion system, the derived cluster center distance varies by 9%. Adopting a reference distance of 46.1 pc or m - M = 3.32, which is derived from the ground-based parallaxes in the General Catalogue of Trigonometric Stellar Parallaxes (1995 edition), the FK5/PPM proper-motion system yields a distance 4% larger, while the Hanson system yields a distance 2% smaller. The HST FGS parallaxes reported here yield either a 14% or 5% larger distance, depending on the choice of the proper-motion system. Orbital parallaxes (Torres et al.) yield an average distance 4% larger than the reference distance. The variation in the distance derived from the HST data illustrates the importance of the proper-motion system and the individual proper motions to the derivation of the distance to the Hyades center; therefore, a full utilization of the HST FGS parallaxes awaits the establishment of an accurate and consistent proper-motion system.NASA HST GTO, HF-1042.01-93A, HF-1046.01-93A, NAS526555Astronom

Low-noise stimulated Brillouin lasing in a microrod resonator

We demonstrate a Brillouin microcavity laser based on a microrod resonator exhibiting a frequency noise of 140 HZ/√Hz at 10 Hz offset. The corresponding laser linewidth is measured to be below 400 Hz

Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

<p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>Design, Setting, and Participants: Men aged 40–79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>Results: A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt