Synthetic phospholipid vesicles containing a purified viral antigen and cell membrane proteins stimulate the development of cytotoxic T lymphocytes

Synthetic phospholipid vesicles (liposomes) containing the purified glycoprotein (G) of vesicular stomatitis virus (VSV) and solubilized membrane proteins from cells of the appropriate H-2 haplotype elicited H-2-restricted cytotoxic T lymphocytes (CTL) that lysed VSV-infected target cells. The CTL were elicited by intact liposomes, not by released components. Thus, when spleen cells from VSV-primed H-2d X H- 2b hybrid mice were stimulated with liposomes having G protein + membrane proteins from cells with one of the parental H-2 haplotypes, the resulting CTL lysed only VSV-infected target cells with that parent's H-2 type. This result argues against the view that T cells in general recognize only processed antigenic fragments on macrophages. Moreover, liposomes were only effective when G protein and cell membrane proteins were included in the same vesicles. This result suggests that for effective interaction with CTL precursors the antigen (G protein) and products of the H-2 complex must be closer to each other than 600-1,000 angstrom, the diameter of the lipid vesicles used in this study

Sexual Dysfunction among Latino men and women with poorly controlled diabetes

Latinos are the largest minority population in the United States and are diagnosed with diabetes at nearly twice the rate of non-Hispanic whites. Latinos not only suffer disproportionately from diabetes but also from diabetes related complications, including sexual dysfunction. Much of the existing literature on sexual dysfunction among Latinos with diabetes has focused on erectile dysfunction (ED). There is a dearth of information on sexual functioning among Latina women with diabetes or information on both genders in other sexual domains. Our study examined the prevalence of sexual dysfunction among a cohort of 106 poorly controlled Latino diabetics in South Florida who participated in the Miami Healthy Heart Initiative, an NIH/NLBI sponsored clinical trial addressing diabetes management among Latinos. We explored gender differences in various domains of sexual health and examined the role of poor glycemic control and depression on sexual dysfunction. A large proportion of both genders in our sample met the criteria for sexual dysfunction though females exhibited a greater prevalence than males. Depression affected more than one third of our sample, but we did not find any significant associations between sexual dysfunction and depression. We also did not find a linear correlation between glycemic control and sexual dysfunction. We concluded that interventions are needed to address high rates of sexual dysfunction among Latinos with diabetes with particular emphasis on Latina women, who were much more likely than men to report problems with desire and other areas of sexual functioning. Until effective pharmacologic agents to improve desire among women with diabetes become available, clinicians caring for this population should consider behavioral approaches that may limit the impact of sexual dysfunction

Autonomous Rover Traverse and Precise Arm Placement on Remotely Designated Targets

This software controls a rover platform to traverse rocky terrain autonomously, plan paths, and avoid obstacles using its stereo hazard and navigation cameras. It does so while continuously tracking a target of interest selected from 10 20 m away. The rover drives and tracks the target until it reaches the vicinity of the target. The rover then positions itself to approach the target, deploys its robotic arm, and places the end effector instrument on the designated target to within 2-3-cm accuracy of the originally selected target. This software features continuous navigation in a fairly rocky field in an outdoor environment and the ability to enable the rover to avoid large rocks and traverse over smaller ones. Using point-and-click mouse commands, a scientist designates targets in the initial imagery acquired from the rover s mast cameras. The navigation software uses stereo imaging, traversability analysis, path planning, trajectory generation, and trajectory execution. It also includes visual target tracking of a designated target selected from 10 m away while continuously navigating the rocky terrain. Improvements in this design include steering while driving, which uses continuous curvature paths. There are also several improvements to the traversability analyzer, including improved data fusion of traversability maps that result from pose estimation uncertainties, dealing with boundary effects to enable tighter maneuvers, and handling a wider range of obstacles. This work advances what has been previously developed and integrated on the Mars Exploration Rovers by using algorithms that are capable of traversing more rock-dense terrains, enabling tight, thread-the-needle maneuvers. These algorithms were integrated on the newly refurbished Athena Mars research rover, and were fielded in the JPL Mars Yard. Forty-three runs were conducted with targets at distances ranging from 5 to 15 m, and a success rate of 93% was achieved for placement of the instrument within 2-3 cm of the target

Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth

The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multi- forme (GBM) cell lines and primary culture models are reported. Dose–response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repop- ulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR func- tions. DP68-induced interstrand DNA cross-links were dem- onstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell–cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced anti- glioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collec- tively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DN

Multimodal quantitative imaging of brain cancer in cultured cells

Fluorescence emission, polarization and subcellular localization of methylene blue (MB) were studied in four cancerous and two normal human brain cell lines. Fluorescence emission and polarization images were acquired and analyzed. The co-localization of MB with mitochondria, lysosomes and nuclei of the cells was evaluated. Glioblastoma cells exhibited significantly higher MB fluorescence polarization compared to normal astrocytes. Preferential accumulation of MB in mitochondria of glioblastoma cells may explain higher fluorescence polarization values in cancer cells as compared to normal. These findings may lead to the development of a quantitative method for the detection of brain cancer in single cells

TrkA expression decreases the in vivo aggressiveness of C6 glioma cells

We stably expressed the nerve growth factor receptor trkA or a truncated trkA lacking the kinase domain (trkA delta) in a highly tumorigenic rat glioma cell line, C6. Survival of rats with large intrastriatal inocula of C6trkA cells was significantly longer than for rats bearing C6 or C6trkA delta cells. Histological studies revealed that C6trkA cells were much less invasive than C6 or C6trkA delta cells and had a greater rate of apoptosis. There was no apparent induction of differentiation of C6 cells by trkA. Therefore, unlike what is observed in neuroblastomas, trkA decreases tumorigenicity by modulating invasiveness and tumor cell death independent of inducing differentiation. This novel mechanism suggests a new therapeutic strategy for malignant gliomas

Barriers to HIV Testing Within a Sample of Spanish-speaking Latinx Gay, Bisexual, and Other Men Who Have Sex with Men: Implications for HIV Prevention and Care

Gay, bisexual, and other men who have sex with men (GBMSM) have higher rates of HIV infection compared to the general population in the United States, and the infection rate is growing among Latinx GBMSM, compared to a decline in most other demographic subgroups. Uptake of pre-exposure prophylaxis (PrEP), a biomedical strategy designed to reduce HIV transmission, is very low among Latinx GBMSM. HIV testing is a critical first step in the HIV prevention and care continua. We analyzed data from a community-based sample of Latinx GBMSM in the southeastern United States to identify the most common HIV testing barriers and the factors associated with barriers. The five most commonly reported HIV testing barriers included not knowing where to get tested, not having health insurance, fear of being HIV positive, practicing safer sex and perceiving not needing to be tested, and not being recommended to get tested. Using multivariable logistic regression modeling, speaking only Spanish, being unemployed, and adhering to traditional notions of masculinity were associated with increased barriers to HIV testing. We recommend that interventions to increase HIV testing among Latinx GBMSM be provided in Spanish and use culturally congruent messaging, be accessible to those who are unemployed, and incorporate positive risk-reducing aspects of masculinity

Comparison of Upper Tropospheric Carbon Monoxide from MOPITT, ACE-FTS, and HIPPO-QCLS

Products from the Measurements Of Pollution In The Troposphere (MOPITT) instrument are regularly validated using in situ airborne measurements. However, few of these measurements reach into the upper troposphere, thus hindering MOPITT validation in that region. Here we evaluate upper tropospheric (~500 hPa to the tropopause) MOPITT CO profiles by comparing them to satellite Atmospheric Chemistry Experiment Fourier Transform Spectrometer (ACE-FTS) retrievals and to measurements from the High-performance Instrumented Airborne Platform for Environmental Research Pole to Pole Observations (HIPPO) Quantum Cascade Laser Spectrometer (QCLS). Direct comparison of colocated v5 MOPITT thermal infrared-only retrievals, v3.0 ACE-FTS retrievals, and HIPPO-QCLS measurements shows a slight positive MOPITT CO bias within its 10% accuracy requirement with respect to the other two data sets. Direct comparison of colocated ACE-FTS and HIPPO-QCLS measurements results in a small number of samples due to the large disparity in sampling pattern and density of these data sets. Thus, two additional indirect techniques for comparison of noncoincident data sets have been applied: tracer-tracer (CO-O3) correlation analysis and analysis of profiles in tropopause coordinates. These techniques suggest a negative bias of ACE-FTS with respect to HIPPO-QCLS; this could be caused by differences in resolution (horizontal, vertical) or by deficiencies in the ACE-FTS CO retrievals below ~20 km of altitude, among others. We also investigate the temporal stability of MOPITT and ACE-FTS data, which provide unique global CO records and are thus important in climate analysis. Our results indicate that the relative bias between the two data sets has remained generally stable during the 2004–2010 period. © 2014. American Geophysical Union

Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo

Despite great efforts taken to advance therapeutic measures for patients with glioblastoma, the clinical prognosis remains grim. The antiapoptotic Bcl-2 family protein Mcl-1 is overexpressed in glioblastoma and represents an important resistance factor to the BH-3 mimetic ABT263. In this study, we show that combined treatment with ABT263 and GX15-070 overcomes apoptotic resistance in established glioblastoma cell lines, glioma stem-like cells and primary cultures. Moreover, this treatment regimen also proves to be advantageous in vivo. On the molecular level, GX15-070 enhanced apoptosis by posttranslational down-regulation of the deubiquitinase, Usp9X, and the chaperone Bag3, leading to a sustained depletion of Mcl-1 protein levels. Moreover, knock-down of Usp9X or Bag3 depleted endogenous Mcl-1 protein levels and in turn enhanced apoptosis induced through Bcl-2/Bcl-xL inhibition. In conclusion, combined treatment with ABT263 and GX15-070 results in a significantly enhanced anti-cancer activity in vitro as well as in vivo in the setting of glioblastoma. Both drugs, ABT263 and GX15-070 have been evaluated in clinical studies which facilitates the translational aspect of taking this combinatorial approach to the clinical setting. Furthermore we present a novel mechanism by which GX15-070 counteracts Mcl-1 expression which may lay a foundation for a novel target in cancer therapy

Joining the conspiracy? Negotiating ethics and emotions in researching (around) AIDS in southern Africa

AIDS is an emotive subject, particularly in southern Africa. Among those who have been directly affected by the disease, or who perceive themselves to be personally at risk, talking about AIDS inevitably arouses strong emotions - amongst them fear, distress, loss and anger. Conventionally, human geography research has avoided engagement with such emotions. Although the ideal of the detached observer has been roundly critiqued, the emphasis in methodological literature on 'doing no harm' has led even qualitative researchers to avoid difficult emotional encounters. Nonetheless, research is inevitably shaped by emotions, not least those of the researchers themselves. In this paper, we examine the role of emotions in the research process through our experiences of researching the lives of 'Young AIDS migrants' in Malawi and Lesotho. We explore how the context of the research gave rise to the production of particular emotions, and how, in response, we shaped the research, presenting a research agenda focused more on migration than AIDS. This example reveals a tension between universalised ethics expressed through ethical research guidelines that demand informed consent, and ethics of care, sensitive to emotional context. It also demonstrates how dualistic distinctions between reason and emotion, justice and care, global and local are unhelpful in interpreting the ethics of research practice