Operating in the space plasma environment: A spacecraft charging study of the Solar X-ray Imager

This study presents the results of a spacecraft charging effects protection study conducted on the Solar X-ray Imager (SXI). The SXI is being developed by NASA Marshall Space Flight Center for NOAA's Space Environment Laboratory, and will be used to aid in forecasting energetic particle events and geomagnetic storms. Images will provide information on the intensity and location of solar flares, coronal mass ejections, and high speed solar streams. The SXI will be flown on a next-generation GOES sometime in the mid to late 1990's. Charging due to the encounter with a worst-case magnetic substorm environment is modeled using the NASCAP/GEO computer code. Charging levels of exterior surfaces and the floating potential of the spacecraft relative to plasma are determined as a function of spacecraft design, operational configuration, and orbital conditions. Areas where large surface voltage gradients exist on or near the SXI are identified as possible arc-discharge sites. Results of the charging analysis are then used to develop design recommendations that will limit the effects of spacecraft charging on the SXI operation

Validation of a Multivariate Serum Profile for Epithelial Ovarian Cancer Using a Prospective Multi-Site Collection

In previous studies we described the use of a retrospective collection of ovarian cancer and benign disease samples, in combination with a large set of multiplexed immunoassays and a multivariate pattern recognition algorithm, to develop an 11-biomarker classification profile that is predictive for the presence of epithelial ovarian cancer. In this study, customized, Luminex-based multiplexed immunoassay kits were GMP-manufactured and the classification profile was refined from 11 to 8 biomarkers (CA-125, epidermal growth factor receptor, CA 19-9, C-reactive protein, tenascin C, apolipoprotein AI, apolipoprotein CIII, and myoglobin). The customized kits and the 8-biomarker profile were then validated in a double-blinded manner using prospective samples collected from women scheduled for surgery, with a gynecologic oncologist, for suspicion of having ovarian cancer. The performance observed in model development held in validation, demonstrating 81.1% sensitivity (95% CI 72.6 – 87.9%) for invasive epithelial ovarian cancer and 85.4% specificity (95% CI 81.1 – 88.9%) for benign ovarian conditions. The specificity for normal healthy women was 95.6% (95% CI 83.6 – 99.2%). These results have encouraged us to undertake a second validation study arm, currently in progress, to examine the performance of the 8-biomarker profile on the population of women not under the surgical care of a gynecologic oncologist

Effects of sorghum wet distillers grains plus solubles in steam-flaked corn–based finishing diets on steer performance, carcass characteristics, and digestibility characteristics

Two studies were conducted to evaluate the effects of sorghum wet distillers grains (SWDGS) in finishing diets on steer performance, carcass characteristics, and nutrient digestibility. In Exp. 1, 240 steers (initial BW = 379 ± 1 kg) were fed steam-flaked corn–based diets with or without 25% SWDGS and 7.5, 10.0, or 12.5% alfalfa hay. There were no effects of alfalfa hay concentration on BW, DMI, ADG, or G:F (P ≥ 0.16). Including SWDGS reduced (P ≤ 0.05) ADG and G:F. Fat thickness decreased (P = 0.03) and DP tended to decrease (P = 0.09) linearly as level of alfalfa hay increased. Final BW of steers consuming diets containing 25% SWDGS were 12 kg lighter (P = 0.05) than those of steers fed diets without SWDGS. Hot carcass weight tended (P = 0.09) to be lighter for steers fed SWDGS. In Exp. 2, effects of corn processing method (steam-flaked corn and dry-rolled corn) and 20% corn wet distillers grains with solubles (CWDGS) or SWDGS inclusion on ruminal pH and in situ digestibility were evaluated. Cattle consuming diets containing SWDGS had a greater (P ≤ 0.05) ruminal pH than steers consuming diets with CWDGS or no wet distillers grains with solubles. Including wet distillers grains with solubles did not affect (P ≥ 0.37) steam-flaked corn or dry-rolled corn in situ DM digestibility. In situ digestibility of DM and NDF differed between CWDGS and SWDGS (P \u3c 0.0001). Differences in performance and nutrient digestibility between CWDGS and SWDGS are the result of differences in the product rather than an interaction with corn processing method

Pharmacologic and Genetic Manipulation of MMP-2 and -9 Affects Retinal Neovascularization in Rodent Models of OIR

PURPOSE. The efficacy of three matrix metalloproteinase (MMP) inhibitors with various selectivities (Ro-31-9790, AG3340, and DPC-A37668) was investigated in a rat model of retinopathy of prematurity, to examine the roles of MMP-2 and -9 in retinal neovascularization. The susceptibilities of MMP-2 Ϫ/Ϫ and -9 Ϫ/Ϫ mice to preretinal neovascularization were investigated in a mouse model of oxygen-induced retinopathy. METHODS. Sprague-Dawley newborn rats were exposed to alternating episodes of 50% and 10% oxygen (variable oxygen exposure) to induce retinal neovascularization. Three MMP inhibitors with various selectivity profiles were administered to variable oxygen-exposed rats via local or systemic routes. Antineovascular efficacy was determined in drug-treated versus vehicle-treated rat pups by computerized imaging of adenosine diphosphatase (ADPase)-stained retinal flatmounts. Wild-type C57BL/6J and isogenic MMP-2 Ϫ/Ϫ and -9 Ϫ/Ϫ mice were exposed to 75% oxygen followed by normoxia. The mice were killed immediately before or after the normoxic exposure, and eyes were either harvested for retinal dissection and flatmounting or were paraffin embedded and sectioned. Retinal vascular area and retinal neovascularization were assessed by adenosine diphosphatase staining of retinal flatmounts and by counting preretinal nuclei of hematoxylin and eosin-stained retinal sections, respectively. RESULTS. Ro-31-9790, AG3340, and DPC-A37668 had no effect on normal development of the rat retinal vasculature, regardless of dose or route of administration. Intravitreal injection of Ro-31-9790 (broad-spectrum) immediately after variable-oxygen exposure and 2 days after exposure resulted in 78% and 82% inhibition of retinal neovascularization, respectively. AG3340 (MMP-2-and -9-selective inhibitor) and DPC-A37668 (MMP-2-selective inhibitor) resulted in 65% and 52% inhibition, respectively, when administered by intravitreal injection immediately after variable-oxygen exposure. Intraperitoneal injection of 5, 15, and 50 mg/mL AG3340 or DPC-A37668 for 6 days after variable oxygen exposure resulted in 22% to 39% and 0% to 31% inhibition of neovascularization, respectively. AG3340 and DPC-A37668 administered by oral gavage at doses of 3, 10, or 30 mg/mL provided up to 42% and 86% inhibition of neovascularization, respectively. The average vascular areas of retinas from MMP-2 Ϫ/Ϫ or -9 Ϫ/Ϫ mice at postnatal day 12 were not significantly different from the wild-type control. There was a 75% (P Ͻ 0.001) and 44% (P Ͻ 0.01) reduction in preretinal neovascularization in oxygen-exposed MMP-2 Ϫ/Ϫ and -9 Ϫ/Ϫ mice at postnatal day 19, respectively, compared with wild-type control mice. CONCLUSIONS. The results of this study suggest that MMP-2 plays a predominant role in retinal angiogenesis in both the mouse and rat models of oxygen-induced retinopathy. Furthermore, MMP-2 inhibition may be a viable therapeutic approach for ocular diseases characterized by retinal neovascularization. (Invest Ophthalmol Vis Sci. 2007;48:907-915) DOI:10.1167/ iovs.06-0082 T he term angiogenesis refers to the growth of new capillaries from preexisting blood vessels. The initial events of angiogenesis involve proteolytic basement membrane degradation; extracellular matrix remodeling; and endothelial cell (EC) proliferation, migration, and differentiation. The integration of these events in physiologic angiogenesis involves complex interactions among cells, growth factors, cytokines, and extracellular matrix components. 1 Matrix metalloproteinases (MMPs) comprise a family of proteolytic enzymes of more than 20 members that are zinc and calcium dependent. Most MMPs are secreted in the inactive proenzyme form, some of them by endothelial cells of the angiogenic phenotype. 2 MMP proenzymes are activated, in part, by the plasminogen activator (PA) system, giving rise to active forms that digest and remodel the basement membrane and extracellular matrix. 6 Although tPA is secreted by established vessels, 7 studies in a guinea pig corneal neovascularization (NV) model demonstrated that endothelial cells in new vessel sprouts secrete uPA exclusively (Jerdan JA et al. IOVS 1988;29:ARVO Abstract 109). uPA and tPA activities are rigidly controlled by plasminogen activator inhibitor (PAI)-1. MMP-2 and -9 degrade gelatin; elastin; and collagens IV (a major basement membrane component), V, VII, and X. 2 MMP-2 and -9 are most likely involved in tumor angiogenesis, 9 -11 and recent studies indicate that MMP-2 and -9 are critical for NV in the posterior segment of the eye. For example, experiments From th

Phase I Evaluation of STA-1474, a Prodrug of the Novel HSP90 Inhibitor Ganetespib, in Dogs with Spontaneous Cancer

The novel water soluble compound STA-1474 is metabolized to ganetespib (formerly STA-9090), a potent HSP90 inhibitor previously shown to kill canine tumor cell lines in vitro and inhibit tumor growth in the setting of murine xenografts. The purpose of the following study was to extend these observations and investigate the safety and efficacy of STA-1474 in dogs with spontaneous tumors.This was a Phase 1 trial in which dogs with spontaneous tumors received STA-1474 under one of three different dosing schemes. Pharmacokinetics, toxicities, biomarker changes, and tumor responses were assessed. Twenty-five dogs with a variety of cancers were enrolled. Toxicities were primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Upregulation of HSP70 protein expression was noted in both tumor specimens and PBMCs within 7 hours following drug administration. Measurable objective responses were observed in dogs with malignant mast cell disease (n = 3), osteosarcoma (n = 1), melanoma (n = 1) and thyroid carcinoma (n = 1), for a response rate of 24% (6/25). Stable disease (>10 weeks) was seen in 3 dogs, for a resultant overall biological activity of 36% (9/25).This study provides evidence that STA-1474 exhibits biologic activity in a relevant large animal model of cancer. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 activation, it is likely that STA-1474 and ganetespib will demonstrate comparable anti-cancer activity in human patients

Protecting children in low-income and middle-income countries from COVID-19

CITATION: Ahmed, S. et al. 2020. Protecting children in low-income and middle-income countries from COVID-19. BMJ Global Health, 5:e002844. doi:10.1136/bmjgh-2020-002844.The original publication is available at https://gh.bmj.comA saving grace of the COVID-19 pandemic in high-income and upper middle-income countries has been the relative sparing of children. As the disease spreads across low-income and middle-income countries (LMICs), long-standing system vulnerabilities may tragically manifest, and we worry that children will be increasingly impacted, both directly and indirectly. Drawing on our shared child pneumonia experience globally, we highlight these potential impacts on children in LMICs and propose actions for a collective response.https://gh.bmj.com/content/5/5/e002844.abstractPublisher's versio

Exact Hybrid Particle/Population Simulation of Rule-Based Models of Biochemical Systems

Detailed modeling and simulation of biochemical systems is complicated by the problem of combinatorial complexity, an explosion in the number of species and reactions due to myriad protein-protein interactions and post-translational modifications. Rule-based modeling overcomes this problem by representing molecules as structured objects and encoding their interactions as pattern-based rules. This greatly simplifies the process of model specification, avoiding the tedious and error prone task of manually enumerating all species and reactions that can potentially exist in a system. From a simulation perspective, rule-based models can be expanded algorithmically into fully-enumerated reaction networks and simulated using a variety of network-based simulation methods, such as ordinary differential equations or Gillespie's algorithm, provided that the network is not exceedingly large. Alternatively, rule-based models can be simulated directly using particle-based kinetic Monte Carlo methods. This "network-free" approach produces exact stochastic trajectories with a computational cost that is independent of network size. However, memory and run time costs increase with the number of particles, limiting the size of system that can be feasibly simulated. Here, we present a hybrid particle/population simulation method that combines the best attributes of both the network-based and network-free approaches. The method takes as input a rule-based model and a user-specified subset of species to treat as population variables rather than as particles. The model is then transformed by a process of "partial network expansion" into a dynamically equivalent form that can be simulated using a population-adapted network-free simulator. The transformation method has been implemented within the open-source rule-based modeling platform BioNetGen, and resulting hybrid models can be simulated using the particle-based simulator NFsim. Performance tests show that significant memory savings can be achieved using the new approach and a monetary cost analysis provides a practical measure of its utility. © 2014 Hogg et al

Perspectives on utilization of edible coatings and nano-laminate coatings for extension of postharvest storage of fruits and vegetables

It is known that in developing countries, a large quantity of fruit and vegetable losses results at postharvest and processing stages due to poor or scarce storage technology and mishandling during harvest. The use of new and innovative technologies for reducing postharvest losses is a requirement that has not been fully covered. The use of edible coatings (mainly based on biopolymers) as a postharvest technique for agricultural commodities has offered biodegradable alternatives in order to solve problems (e.g., microbiological growth) during produce storage. However, biopolymer-based coatings can present some disadvantages such as: poor mechanical properties (e.g., lipids) or poor water vapor barrier properties (e.g., polysaccharides), thus requiring the development of new alternatives to solve these drawbacks. Recently, nanotechnology has emerged as a promising tool in the food processing industry, providing new insights about postharvest technologies on produce storage. Nanotechnological approaches can contribute through the design of functional packing materials with lower amounts of bioactive ingredients, better gas and mechanical properties and with reduced impact on the sensorial qualities of the fruits and vegetables. This work reviews some of the main factors involved in postharvest losses and new technologies for extension of postharvest storage of fruits and vegetables, focused on perspective uses of edible coatings and nano-laminate coatings.María L. Flores-López thanks Mexican Science and Technology Council (CONACYT, Mexico) for PhD fellowship support (CONACYT Grant Number: 215499/310847). Miguel A. Cerqueira (SFRH/BPD/72753/2010) is recipient of a fellowship from the Fundação para a Ciência e Tecnologia (FCT, POPH-QREN and FSE Portugal). The authors also thank the FCT Strategic Project of UID/ BIO/04469/2013 unit, the project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and the project ‘‘BioInd Biotechnology and Bioengineering for improved Industrial and AgroFood processes,’’ REF. NORTE-07-0124-FEDER-000028 Co-funded by the Programa Operacional Regional do Norte (ON.2 – O Novo Norte), QREN, FEDER. Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico – FUNCAP, CE Brazil (CI10080-00055.01.00/13)

Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme