Flight Measurements of Flying Qualities of a P-47D-30 Airplane (AAF No. 43-3441) to Determine Longitudinal Stability and Control and Stalling Characteristics

Flight tests have been made to determine the longitudinal stability and control and stalling characteristics of the P-47.E-30 airplane. The teat results show the airplane to be unstable stick free in any power-on condition even at the most forward center-of-gravity position tested. At the rearward center-of-gravity position tested the airplane also had neutral to negative stick-fixed stability with power on. The characteristics in accelerated flight were acceptable at the forward center-of-gravity position at low and high altitudes except at high speed where the control-force variations with acceleration were high. At the rearward center-of-gravity position, elevator-force reversals were experienced in turns at low speeds, and the force per g was low at all the other speeds. Ample stall warning was afforded in all the conditions tested and the stalling characteristics were very satisfactory except in the approach and wave-off conditions

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients.

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. Results: All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8+ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4+ T cells are eliminated by self-tolerance, while CD8+ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. Conclusions: Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8+, but not autoimmune CD4+, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. TRIAL REGISTRATION: This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737

The molecular basis for apolipoprotein E4 as the major risk factor for late onset Alzheimer's disease

Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an -helical, 299-amino acid protein. Homozygosity for the ε4 allele is the major risk factor for developing late onset Alzheimer’s disease (AD). ApoE2, ApoE3 and ApoE4 differ at amino acid positions 112 and 158 and these sequence variations may confer conformational differences that underlie their participation in the risk of developing AD. Here, we compared the shape, oligomerisation state, conformation and stability of ApoE isoforms using a range of complementary biophysical methods including small angle X-ray scattering, analytical ultracentrifugation, circular dichroism, X-ray fibre diffraction and transmission electron microscopy We provide an in-depth and definitive study demonstrating that all three proteins are similar in stability and conformation. However, we show that ApoE4 has a propensity to polymerise to form wavy filaments which do not share the characteristics of cross- amyloid fibrils. Moreover, we provide evidence for the inhibition of ApoE4 fibril formation by ApoE3. This study shows that recombinant ApoE isoforms show no significant differences at the structural or conformational level. However, self-assembly of the ApoE4 isoform may play a role in pathogenesis and these results open opportunities for uncovering new triggers for AD onset

Empirically Derived Integrated Stellar Yields of Fe-Peak Elements

We present here the initial results of a new study of massive star yields of Fe-peak elements. We have compiled from the literature a database of carefully determined solar neighborhood stellar abundances of seven iron-peak elements, Ti, V, Cr, Mn, Fe, Co, and Ni and then plotted [X/Fe] versus [Fe/H] to study the trends as functions of metallicity. Chemical evolution models were then employed to force a fit to the observed trends by adjusting the input massive star metallicity-sensitive yields of Kobayashi et al. Our results suggest that yields of Ti, V, and Co are generally larger as well as anticorrelated with metallicity, in contrast to the Kobayashi et al. predictions. We also find the yields of Cr and Mn to be generally smaller and directly correlated with metallicity compared to the theoretical results. Our results for Ni are consistent with theory, although our model suggests that all Ni yields should be scaled up slightly. The outcome of this exercise is the computation of a set of integrated yields, i.e., stellar yields weighted by a slightly flattened time-independent Salpeter initial mass function and integrated over stellar mass, for each of the above elements at several metallicity points spanned by the broad range of observations. These results are designed to be used as empirical constraints on future iron-peak yield predictions by stellar evolution modelers. Special attention is paid to the interesting behavior of [Cr/Co] with metallicity -- these two elements have opposite slopes -- as well as the indirect correlation of [Ti/Fe] with [Fe/H]. These particular trends, as well as those exhibited by the inferred integrated yields of all iron-peak elements with metallicity, are discussed in terms of both supernova nucleosynthesis and atomic physics.Comment: 27 pages, 6 figures; Accepted for Publication in the Astrophysical Journa

MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

AbstractThe emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.</jats:p

Subdermal Ultrasound Contrast Agent Injection for Sentinel Lymph Node Identification: An Analysis of Safety and Contrast Agent Dose in Healthy Volunteers.

Objectives—Mapping of the lymphatic chain for identification of the sentinel lymph node (SLN) is an important aspect of predicting outcomes for breast cancer patients, and it is usually performed as an intraoperative procedure using blue dye and/or radiopharmaceuticals agents. Recently the use of contrast-enhanced ultrasound (CEUS) has been proposed as an alternative imaging technique for this mapping. The objective of this study was to evaluate the use of subdermal administration of the ultrasound contrast agent Sonazoid (GE Healthcare) in terms of patient safety and to select the dose to be used for lymphatic applications in humans. Methods—This study was performed in 12 female volunteers that received bilateral subdermal injections of Sonazoid (1 or 2 ml doses) in the mid-upper outer quadrant of their breasts at two different time-points. CEUS was performed 0, 0.25, 0.5, 1, 2, 4, 6 and 24 hours post-injection to identify SLNs. Results—SLNs were identified within the first hour post-injection as enhanced structures and there was no significant difference by dose in the number of SLNs identified (p=0.74). Volunteers only experienced minor adverse experiences (AEs) that resolved completely without intervention by study completion. Conclusion—The subdermal use of Sonazoid in this study showed only minor local and non-significant AEs that were completely resolved without any intervention. Two different doses were compared with no significant differences observed between them. Hence, the lower dose studied (1 ml) was selected for use in future clinical studies

Predictions for the X-ray circumgalactic medium of edge-on discs and spheroids

We investigate how the X-ray circumgalactic medium (CGM) of present-day galaxies depends on galaxy morphology and azimuthal angle using mock observations generated from the EAGLE cosmological hydrodynamic simulation. By creating mock stacks of {\it eROSITA}-observed galaxies oriented to be edge-on, we make several observationally-testable predictions for galaxies in the stellar mass range $M_\star=10^{10.7-11.2}\;$M$_{\odot}$. The soft X-ray CGM of disc galaxies is between 60 and 100\% brighter along the semi-major axis compared to the semi-minor axis, between 10-30 kpc. This azimuthal dependence is a consequence of the hot ($T>10^6$ K) CGM being non-spherical: specifically it is flattened along the minor axis such that denser and more luminous gas resides in the disc plane and co-rotates with the galaxy. Outflows enrich and heat the CGM preferentially perpendicular to the disc, but we do not find an observationally-detectable signature along the semi-minor axis. Spheroidal galaxies have hotter CGMs than disc galaxies related to spheroids residing at higher halos masses, which may be measurable through hardness ratios spanning the $0.2-1.5$ keV band. While spheroids appear to have brighter CGMs than discs for the selected fixed $M_\star$ bin, this owes to spheroids having higher stellar and halo masses within that $M_\star$ bin, and obscures the fact that both simulated populations have similar total CGM luminosities at the exact same $M_\star$. Discs have brighter emission inside 20 kpc and more steeply declining profiles with radius than spheroids. We predict that the {\it eROSITA} 4-year all-sky survey should detect many of the signatures we predict here, although targeted follow-up observations of highly inclined nearby discs after the survey may be necessary to observe some of our azimuthally-dependent predictions.Comment: 12 pages, 11 figures, 1 table. Submitted to MNRAS. Comments welcom

Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330

Lithium, which is still the gold standard in the treatment of bipolar disorder, has been proposed to inhibit inositol monophosphatase (IMPase) and is hypothesized to exert its therapeutic effects by attenuating phosphatidylinositol (PI) cell signalling. Drug-discovery efforts have focused on small-molecule lithium mimetics that would specifically inhibit IMPase without exhibiting the undesired side effects of lithium. L-690,330 is a potent bisphosphonate substrate-based inhibitor developed by Merck Sharp & Dohme. To aid future structure-based inhibitor design, determination of the exact binding mechanism of L-690,330 to IMPase was of interest. Here, the high-resolution X-ray structure of human IMPase in complex with L690,330 and manganese ions determined at 1.39 Å resolution is reported