Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes

Centrosomes associate with spindle poles; thus, the presence of two centrosomes promotes bipolar spindle assembly in normal cells. Cancer cells often contain supernumerary centrosomes, and to avoid multipolar mitosis and cell death, these are clustered into two poles by the microtubule motor protein HSET. We report the discovery of an allosteric inhibitor of HSET, CW069, which we designed using a methodology on an interface of chemistry and biology. Using this approach, we explored millions of compounds in silico and utilized convergent syntheses. Only compound CW069 showed marked activity against HSET in vitro. The inhibitor induced multipolar mitoses only in cells containing supernumerary centrosomes. CW069 therefore constitutes a valuable tool for probing HSET function and, by reducing the growth of cells containing supernumerary centrosomes, paves the way for new cancer therapeutics

Setting Priorities for Space Research: Opportunities and Imperatives

This report represents the first phase of a study by a task group convened by the Space Studies Board to ascertain whether it should attempt to develop a methodology for recommending priorities among the various initiatives in space research (that is, scientific activities concerned with phenomena in space or utilizing observations from space). The report argues that such priority statements by the space research community are both necessary and desirable and would contribute to the formulation and implementation of public policy. The report advocates the establishment of priorities to enhance effective management of the nation's scientific research program in space. It argues that scientific objectives and purposes should determine how and under what circumstances scientific research should be done. The report does not take a position on the controversy between advocates of manned space exploration and those who favor the exclusive use of unmanned space vehicles. Nor does the report address questions about the value or appropriateness of Space Station Freedom or proposals to establish a permanent manned Moon base or to undertake a manned mission to Mars. These issues lie beyond the charge to the task group

Concern About Petrochemical Health Risk Before and After a Refinery Explosion

On March 23, 2005, a large explosion at an oil refinery in Texas City, Texas caused 15 deaths and approximately 170 injuries. Little is known about how such an industrial accident influences concern about environmental health risks. We used measures of environmental health concern about nearby petrochemical production with a sample of Texas City residents to understand patterns of concern and change in concern after an industrial accident, as well as individual and contextual factors associated with those patterns. Survey interviews with residents of Texas City, Texas (N =315) both pre- and postexplosion using a brief Concern About Petrochemical Health Risk Scale (CAPHRS) and other questions were used to collect pertinent predictor information. CAPHRS baseline, postexplosion, and change scores were compared and modeled using ordinary least squares (OLS) regression and a mixed model. Higher preexplosion CAPHRS scores were predicted by younger adults, foreign-born Hispanics, non-Hispanic blacks, lower- and middle-income groups, and those who live with someone who has worked at the petrochemical plants. Higher CAPHRS change scores are predicted by the same variables (except income), as well as proximity to, or perception of, the explosion, and reports of neighborhood damage. Findings suggest these groups’ concern scores could indicate a greater vulnerability to psychological and physical harm generated by concern and stress arising from local petrochemical activities. A clearer understanding of concern about actual environmental health risks in exposed populations may enhance the evolving theory of stress and coping and eventually enable public health professionals to develop appropriate mitigation strategies

Maximal Spontaneous Photon Emission and Energy Loss from Free Electrons

Free electron radiation such as Cerenkov, Smith--Purcell, and transition radiation can be greatly affected by structured optical environments, as has been demonstrated in a variety of polaritonic, photonic-crystal, and metamaterial systems. However, the amount of radiation that can ultimately be extracted from free electrons near an arbitrary material structure has remained elusive. Here we derive a fundamental upper limit to the spontaneous photon emission and energy loss of free electrons, regardless of geometry, which illuminates the effects of material properties and electron velocities. We obtain experimental evidence for our theory with quantitative measurements of Smith--Purcell radiation. Our framework allows us to make two predictions. One is a new regime of radiation operation---at subwavelength separations, slower (nonrelativistic) electrons can achieve stronger radiation than fast (relativistic) electrons. The second is a divergence of the emission probability in the limit of lossless materials. We further reveal that such divergences can be approached by coupling free electrons to photonic bound states in the continuum (BICs). Our findings suggest that compact and efficient free-electron radiation sources from microwaves to the soft X-ray regime may be achievable without requiring ultrahigh accelerating voltages.Comment: 7 pages, 4 figure

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

Draft Genome of the Filarial Nematode Parasite \u3ci\u3eBrugia malayi\u3c/i\u3e

Parasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the ∼90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict ∼11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during ∼350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design

Listening In on the Past: What Can Otolith δ18O Values Really Tell Us about the Environmental History of Fishes?

Oxygen isotope ratios from fish otoliths are used to discriminate marine stocks and reconstruct past climate, assuming that variations in otolith δ18O values closely reflect differences in temperature history of fish when accounting for salinity induced variability in water δ18O. To investigate this, we exploited the environmental and migratory data gathered from a decade using archival tags to study the behaviour of adult plaice (Pleuronectes platessa L.) in the North Sea. Based on the tag-derived monthly distributions of the fish and corresponding temperature and salinity estimates modelled across three consecutive years, we first predicted annual otolith δ18O values for three geographically discrete offshore sub-stocks, using three alternative plausible scenarios for otolith growth. Comparison of predicted vs. measured annual δ18O values demonstrated >96% correct prediction of sub-stock membership, irrespective of the otolith growth scenario. Pronounced inter-stock differences in δ18O values, notably in summer, provide a robust marker for reconstructing broad-scale plaice distribution in the North Sea. However, although largely congruent, measured and predicted annual δ18O values of did not fully match. Small, but consistent, offsets were also observed between individual high-resolution otolith δ18O values measured during tag recording time and corresponding δ18O predictions using concomitant tag-recorded temperatures and location-specific salinity estimates. The nature of the shifts differed among sub-stocks, suggesting specific vital effects linked to variation in physiological response to temperature. Therefore, although otolith δ18O in free-ranging fish largely reflects environmental temperature and salinity, we counsel prudence when interpreting otolith δ18O data for stock discrimination or temperature reconstruction until the mechanisms underpinning otolith δ18O signature acquisition, and associated variation, are clarified

Investigating the Atmospheric Mass Loss of the Kepler-105 Planets Straddling the Radius Gap

An intriguing pattern among exoplanets is the lack of detected planets between approximately $1.5$ R$_\oplus$ and $2.0$ R$_\oplus$. One proposed explanation for this "radius gap" is the photoevaporation of planetary atmospheres, a theory that can be tested by studying individual planetary systems. Kepler-105 is an ideal system for such testing due to the ordering and sizes of its planets. Kepler-105 is a sun-like star that hosts two planets straddling the radius gap in a rare architecture with the larger planet closer to the host star ($R_b = 2.53\pm0.07$ R$_\oplus$, $P_b = 5.41$ days, $R_c = 1.44\pm0.04$ R$_\oplus$, $P_c = 7.13$ days). If photoevaporation sculpted the atmospheres of these planets, then Kepler-105b would need to be much more massive than Kepler-105c to retain its atmosphere, given its closer proximity to the host star. To test this hypothesis, we simultaneously analyzed radial velocities (RVs) and transit timing variations (TTVs) of the Kepler-105 system, measuring disparate masses of $M_b = 10.8\pm2.3$ M$_\oplus$ ($\rho_b = 0.97\pm0.22$ g cm$^{-3}$) and $M_c = 5.6\pm1.2$ M$_\oplus$ ($\rho_c = 2.64\pm0.61$ g cm$^{-3}$). Based on these masses, the difference in gas envelope content of the Kepler-105 planets could be entirely due to photoevaporation (in 76\% of scenarios), although other mechanisms like core-powered mass loss could have played a role for some planet albedos.Comment: 14 pages, 3 figures, 2 table

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200