A novel RNA aptamer identifies plasma membrane ATP synthase beta subunit as an early marker and therapeutic target in aggressive cancer

PURPOSE: Primary breast and prostate cancers can be cured, but metastatic disease cannot. Identifying cell factors that predict metastatic potential could guide both prognosis and treatment. METHODS: We used Cell-SELEX to screen an RNA aptamer library for differential binding to prostate cancer cell lines with high vs. low metastatic potential. Mass spectroscopy, immunoblot, and immunohistochemistry were used to identify and validate aptamer targets. Aptamer properties were tested in vitro, in xenograft models, and in clinical biopsies. Gene expression datasets were queried for target associations in cancer. RESULTS: We identified a novel aptamer (Apt63) that binds to the beta subunit of F1Fo ATP synthase (ATP5B), present on the plasma membrane of certain normal and cancer cells. Apt63 bound to plasma membranes of multiple aggressive breast and prostate cell lines, but not to normal breast and prostate epithelial cells, and weakly or not at all to non-metastasizing cancer cells; binding led to rapid cell death. A single intravenous injection of Apt63 induced rapid, tumor cell-selective binding and cytotoxicity in MDA-MB-231 xenograft tumors, associated with endonuclease G nuclear translocation and DNA fragmentation. Apt63 was not toxic to non-transformed epithelial cells in vitro or adjacent normal tissue in vivo. In breast cancer tissue arrays, plasma membrane staining with Apt63 correlated with tumor stage (p < 0.0001, n = 416) and was independent of other cancer markers. Across multiple datasets, ATP5B expression was significantly increased relative to normal tissue, and negatively correlated with metastasis-free (p = 0.0063, 0.00039, respectively) and overall (p = 0.050, 0.0198) survival. CONCLUSION: Ecto-ATP5B binding by Apt63 may disrupt an essential survival mechanism in a subset of tumors with high metastatic potential, and defines a novel category of cancers with potential vulnerability to ATP5B-targeted therapy. Apt63 is a unique tool for elucidating the function of surface ATP synthase, and potentially for predicting and treating metastatic breast and prostate cancer

The evolution of inflorescence diversity in the nightshades and heterochrony during meristem maturation

One of the most remarkable manifestations of plant evolution is the diversity for floral branching systems. These "inflorescences" arise from stem cell populations in shoot meristems that mature gradually to reproductive states in response to environmental and endogenous signals. The morphology of the shoot meristem maturation process is conserved across distantly related plants, raising the question of how diverse inflorescence architectures arise from seemingly common maturation programs. In tomato and related nightshades (Solanaceae), inflorescences range from solitary flowers to highly branched structures bearing hundreds of flowers. Since reproductive barriers between even closely related Solanaceae have precluded a genetic dissection, we captured and compared meristem maturation transcriptomes from five domesticated and wild species reflecting the evolutionary continuum of inflorescence complexity. We find these divergent species share hundreds of dynamically expressed genes, enriched for transcription factors. Meristem stages are defined by distinct molecular states and point to modified maturation schedules underlying architectural variation. These modified schedules are marked by a peak of transcriptome expression divergence during the reproductive transition, driven by heterochronic shifts of dynamic genes, including transcriptional regulators with known roles in flowering. Thus, evolutionary diversity in Solanaceae inflorescence complexity is determined by subtle modifications of transcriptional programs during a critical transitional window of meristem maturation, which we propose underlies similar cases of plant architectural variation. More broadly, our findings parallel the recently described transcriptome "inverse hourglass" model for animal embryogenesis, suggesting both plant and animal morphological variation is guided by a mid-development period of transcriptome divergence

Magnetoresistance of UPt3

We have performed measurements of the temperature dependence of the magnetoresistance up to 9 T in bulk single crystals of UPt3 with the magnetic field along the b axis, the easy magnetization axis. We have confirmed previous results for transverse magnetoresistance with the current along the c axis, and report measurements of the longitudinal magnetoresistance with the current along the b axis. The presence of a linear term in both cases indicates broken orientational symmetry associated with magnetic order. With the current along the c axis the linear term appears near 5 K, increasing rapidly with decreasing temperature. For current along the b axis the linear contribution is negative.Comment: 6 pages, 3 figures, submitted to Quantum Fluids and Solids Conference (QFS 2006

Anisotropic Aerogels for Studying Superfluid 3^3He

It may be possible to stabilize new superfluid phases of $^{3}$He with anisotropic silica aerogels. We discuss two methods that introduce anisotropy in the aerogel on length scales relevant to superfluid $^{3}$He. First, anisotropy can be induced with uniaxial strain. A second method generates anisotropy during the growth and drying stages. We have grown cylindrical $\sim$98% aerogels with anisotropy indicated by preferential radial shrinkage after supercritical drying and find that this shrinkage correlates with small angle x-ray scattering (SAXS). The growth-induced anisotropy was found to be $\sim90^\circ$ out of phase relative to that induced by strain. This has implications for the possible stabilization of superfluid phases with specific symmetry.Comment: 6 pages, 4 figures, submitted to Quantum Fluids and Solids (QFS) conference 200

Compressed Silica Aerogels for the Study of Superfluid 3He

We have performed Small Angle X-ray Scattering (SAXS) on uniaxially strained aerogels and measured the strain-induced structural anisotropy. We use a model to connect our SAXS results to anisotropy of the 3He quasiparticle mean free path in aerogel.Comment: 2 pages, 2 figures, accepted for publication in the proceedings of the 24th Low Temperature Physics Conferenc

Space-Time Approach to Scattering from Many Body Systems

We present scattering from many body systems in a new light. In place of the usual van Hove treatment, (applicable to a wide range of scattering processes using both photons and massive particles) based on plane waves, we calculate the scattering amplitude as a space-time integral over the scattering sample for an incident wave characterized by its correlation function which results from the shaping of the wave field by the apparatus. Instrument resolution effects - seen as due to the loss of correlation caused by the path differences in the different arms of the instrument are automatically included and analytic forms of the resolution function for different instruments are obtained. The intersection of the moving correlation volumes (those regions where the correlation functions are significant) associated with the different elements of the apparatus determines the maximum correlation lengths (times) that can be observed in a sample, and hence, the momentum (energy) resolution of the measurement. This geometrical picture of moving correlation volumes derived by our technique shows how the interaction of the scatterer with the wave field shaped by the apparatus proceeds in space and time. Matching of the correlation volumes so as to maximize the intersection region yields a transparent, graphical method of instrument design. PACS: 03.65.Nk, 3.80 +r, 03.75, 61.12.BComment: Latex document with 6 fig

Globally Anisotropic High Porosity Silica Aerogels

We discuss two methods by which high porosity silica aerogels can be engineered to exhibit global anisotropy. First, anisotropy can be introduced with axial strain. In addition, intrinsic anisotropy can result during growth and drying stages and, suitably controlled, it can be correlated with preferential radial shrinkage in cylindrical samples. We have performed small angle X-ray scattering (SAXS) to characterize these two types of anisotropy. We show that global anisotropy originating from either strain or shrinkage leads to optical birefringence and that optical cross-polarization studies are a useful characterization of the uniformity of the imposed global anisotropy.Comment: 18 pages, 14 figures, submitted to Journal of Non-Crystalline Solid

HIV selfscreening distribution preferences and experiences among men who have sex with men in Mpumalanga Province: Informing policy for South Africa

Current research suggests that HIV self-screening (HIVSS) is a feasible and acceptable approach to increase HIV testing among men who have sex with men (MSM). However, few data are available to shape policy around dissemination and implementation. Gaps in knowledge include preferences for distribution of HIVSS kits, potential social harms and benefits of their use, and how much test users would be willing to pay for the kits. The aim was to inform policy recommendations to optimise distribution of HIVSS kits to MSM in South Africa (SA), where there is a high HIV incidence and unmet testing needs. MSM in the high-HIV-prevalence Gert Sibande and Ehlanzeni districts of Mpumalanga Province, SA, were enrolled between October 2015 and May 2017. Participants were provided with their choice of blood or oral fluid HIVSS test kits, receiving 5 kits at enrolment and 4 additional kits at the 3-month follow-up visit. Questionnaires were administered at enrolment, 3 months and 6 months. We analysed participants’ reported social benefits and harms, and their preferences for kit distribution and pricing. Among 127 MSM screened and enrolled, 114 responded to follow-up questionnaires regarding distribution preferences, 49.3% preferred to acquire HIVSS kits at a community-based organisation (CBO) and 42.7% at a clinic, with 8% preferring a pharmacy. Participants with higher education preferred CBO sites for distribution; in other respects preferences were similar by demographic characteristics. Reported social benefits were common, including knowing one’s status, prevention knowledge gained and improved communication with partners. Despite ubiquitous interest in using the kits, the majority of MSM could not afford to purchase test kits. SA guidelines have integrated HIVSS into HIV and testing policy, but little has been published regarding distribution channels of the kits for MSM and other key populations. There is a partnership between the National Department of Health and CBOs that specialise in key population programming to ensure MSM and other populations with unmet testing needs can access affordable test kits. We observed no social harms, and there were multiple social benefits. Consequently, we recommend immediate free or low-cost distribution of HIVSS kits to MSM through community-based initiatives. Future research should continue to assess optimised linkage to care

Interplay between magnetism and superconductivity and appearance of a second superconducting transition in alpha-FeSe at high pressure

We synthesized tetragonal alpha-FeSe by melting a powder mixture of iron and selenium at high pressure. Subsequent annealing at normal pressure results in removing traces of hexagonal beta- FeSe, formation of a rather sharp transition to superconducting state at Tc ~ 7 K, and the appearance of a magnetic transition near Tm = 120 K. Resistivity and ac-susceptibility were measured on the annealed sample at hydrostatic pressure up to 4.5 GPa. A magnetic transition visible in ac-susceptibility shifts down under pressure and the resistive anomaly typical for a spin density wave (SDW) antiferromagnetic transition develops near the susceptibility anomaly. Tc determined by the appearance of a diamagnetic response in susceptibility, increases linearly under pressure at a rate dTc/dP = 3.5 K/GPa. Below 1.5 GPa, the resistive superconducting transition is sharp; the width of transition does not change with pressure; and, Tc determined by a peak in drho/dT increases at a rate ~ 3.5 K/GPa. At higher pressure, a giant broadening of the resistive transition develops. This effect cannot be explained by possible pressure gradients in the sample and is inherent to alpha-FeSe. The dependences drho(T)/dT show a signature for a second peak above 3 GPa which is indicative of the appearance of another superconducting state in alpha-FeSe at high pressure. We argue that this second superconducting phase coexists with SDW antiferromagnetism in a partial volume fraction and originates from pairing of charge carriers from other sheets of the Fermi surface

HIV self-screening distribution preferences and experiences among men who have sex with men in Mpumalanga Province: Informing policy for South Africa

Current research suggests that HIV self-screening (HIVSS) is a feasible and acceptable approach to increase HIV testing among men who have sex with men (MSM). However, few data are available to shape policy around dissemination and implementation. Gaps in knowledge include preferences for distribution of HIVSS kits, potential social harms and benefits of their use, and how much test users would be willing to pay for the kits. The aim was to inform policy recommendations to optimise distribution of HIVSS kits to MSM in South Africa (SA), where there is a high HIV incidence and unmet testing needs. MSM in the high-HIV-prevalence Gert Sibande and Ehlanzeni districts of Mpumalanga Province, SA, were enrolled between October 2015 and May 2017. Participants were provided with their choice of blood or oral fluid HIVSS test kits, receiving 5 kits at enrolment and 4 additional kits at the 3-month follow-up visit. Questionnaires were administered at enrolment, 3 months and 6 months. We analysed participants’ reported social benefits and harms, and their preferences for kit distribution and pricing. Among 127 MSM screened and enrolled, 114 responded to follow-up questionnaires regarding distribution preferences, 49.3% preferred to acquire HIVSS kits at a community-based organisation (CBO) and 42.7% at a clinic, with 8% preferring a pharmacy. Participants with higher education preferred CBO sites for distribution; in other respects preferences were similar by demographic characteristics. Reported social benefits were common, including knowing one’s status, prevention knowledge gained and improved communication with partners. Despite ubiquitous interest in using the kits, the majority of MSM could not afford to purchase test kits. SA guidelines have integrated HIVSS into HIV and testing policy, but little has been published regarding distribution channels of the kits for MSM and other key populations. There is a partnership between the National Department of Health and CBOs that specialise in key population programming to ensure MSM and other populations with unmet testing needs can access affordable test kits. We observed no social harms, and there were multiple social benefits. Consequently, we recommend immediate free or low-cost distribution of HIVSS kits to MSM through community-based initiatives. Future research should continue to assess optimised linkage to care