Application of Calspan pitch rate control system to the Space Shuttle for approach and landing

A pitch rate control system designed for use in the shuttle during approach and landing was analyzed and compared with a revised control system developed by NASA and the existing OFT control system. The design concept control system uses filtered pitch rate feedback with proportional plus integral paths in the forward loop. Control system parameters were designed as a function of flight configuration. Analysis included time and frequency domain techniques. Results indicate that both the Calspan and NASA systems significantly improve the flying qualities of the shuttle over the OFT. Better attitude and flight path control and less time delay are the primary reasons. The Calspan system is preferred because of reduced time delay and simpler mechanization. Further testing of the improved flight control systems in an in-flight simulator is recommended

Reducing delays in the diagnosis and treatment of muscle-invasive bladder cancer using simulation modelling

This is the author accepted manuscript. The final version is available from SAGE Publications via the DOI in this record Objective: To develop a simulation model to identify key bottlenecks in the bladder cancer pathway at Royal Cornwall Hospital and predict the impact of potential changes to reduce these delays. Materials and methods: The diagnosis and treatment of muscle-invasive bladder cancer can suffer numerous delays, which can significantly affect patient outcomes. We developed a discrete event computer simulation model of the flow of patients through the bladder cancer pathway at the hospital, using anonymised patient records from 2014 and 2015. The changes tested in the model were for patients suspected to have muscle-invasive disease on flexible cystoscopy. Those patients were ‘fast-tracked’ to receive their transurethral resection of bladder tumour (TURBT) treatment using operating slots kept free for these patients. A staging computed tomography scan was booked in the haematuria clinic. Pathology requests were marked as 48 hour turnaround. The nurse specialist would then speak to the patient whilst they were on the ward following their TURBT to give information about their ongoing treatment and provide support. Results: The model predicted that if the changes were implemented, delays in the system could be reduced by around 5 weeks. The changes were implemented, and analysis of 3 months of the data post-implementation shows that the average time in the system was reduced by 5 weeks. The environment created by the changes in the pathway improved referral to treatment times in both muscle-invasive and non-muscle-invasive groups. Conclusion: The simulation model proved an invaluable tool for facilitating the implementation of changes. Simple changes to the pathway led to significant reductions in delays for bladder cancer patients at Royal Cornwall Hospital. Level of evidence: Not applicable for this cohort study.National Institute for Health Research (NIHR

Insensitivity of alkenone carbon isotopes to atmospheric CO₂ at low to moderate CO₂ levels

Atmospheric pCO2 is a critical component of the global carbon system and is considered to be the major control of Earth’s past, present and future climate. Accurate and precise reconstructions of its concentration through geological time are, therefore, crucial to our understanding of the Earth system. Ice core records document pCO2 for the past 800 kyrs, but at no point during this interval were CO2 levels higher than today. Interpretation of older pCO2 has been hampered by discrepancies during some time intervals between two of the main ocean-based proxy methods used to reconstruct pCO2: the carbon isotope fractionation that occurs during photosynthesis as recorded by haptophyte biomarkers (alkenones) and the boron isotope composition (δ11B) of foraminifer shells. Here we present alkenone and δ11B-based pCO2 reconstructions generated from the same samples from the Plio-Pleistocene at ODP Site 999 across a glacial-interglacial cycle. We find a muted response to pCO2 in the alkenone record compared to contemporaneous ice core and δ11B records, suggesting caution in the interpretation of alkenone-based records at low pCO2 levels. This is possibly caused by the physiology of CO2 uptake in the haptophytes. Our new understanding resolves some of the inconsistencies between the proxies and highlights that caution may be required when interpreting alkenone-based reconstructions of pCO2

Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

History of malaria treatment as a predictor of subsequent subclinical parasitaemia: A cross-sectional survey and malaria case records from three villages in Pailin, western Cambodia

Background: Treatment of the sub-clinical reservoir of malaria, which may maintain transmission, could be an important component of elimination strategies. The reliable detection of asymptomatic infections with low levels of parasitaemia requires high-volume quantitative polymerase chain reaction (uPCR), which is impractical to conduct on a large scale. It is unknown to what extent sub-clinical parasitaemias originate from recent or older clinical episodes. This study explored the association between clinical history of malaria and subsequent sub-clinical parasitaemia. Methods: In June 2013 a cross-sectional survey was conducted in three villages in Pailin, western Cambodia. Demographic and epidemiological data and blood samples were collected. Blood was tested for malaria by high-volume qP

Binding MOAD, a high-quality protein–ligand database

Binding MOAD (Mother of All Databases) is a database of 9836 protein–ligand crystal structures. All biologically relevant ligands are annotated, and experimental binding-affinity data is reported when available. Binding MOAD has almost doubled in size since it was originally introduced in 2004, demonstrating steady growth with each annual update. Several technologies, such as natural language processing, help drive this constant expansion. Along with increasing data, Binding MOAD has improved usability. The website now showcases a faster, more featured viewer to examine the protein–ligand structures. Ligands have additional chemical data, allowing for cheminformatics mining. Lastly, logins are no longer necessary, and Binding MOAD is freely available to all at http://www.BindingMOAD.org

BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells

Osteosarcoma (OS) survival rates have plateaued in part due to a lack of new therapeutic options. Here we demonstrate that bromodomain inhibitors (BETi), JQ1, I-BET151, I-BET762, exert potent anti-tumour activity against primary and established OS cell lines, mediated by inhibition of BRD4. Strikingly, unlike previous observations in long-term established human OS cell lines, the antiproliferative activity of JQ1 in primary OS cells was driven by the induction of apoptosis, not cell cycle arrest. In further contrast, JQ1 activity in OS was mediated independently of MYC downregulation. We identified that JQ1 suppresses the transcription factor FOSL1 by displacement of BRD4 from its locus. Loss of FOSL1 phenocopied the antiproliferative effects of JQ1, identifying FOSL1 suppression as a potential novel therapeutic approach for OS. As a monotherapy JQ1 demonstrated significant anti-tumour activity in vivo in an OS graft model. Further, combinatorial treatment approaches showed that JQ1 increased the sensitivity of OS cells to doxorubicin and induced potent synergistic activity when rationally combined with CDK inhibitors. The greater level of activity achieved with the combination of BETi with CDK inhibitors demonstrates the efficacy of this combination therapy. Taken together, our studies show that BET inhibitors are a promising new therapeutic for OS.Emma K Baker, Scott Taylor, Ankita Gupte, Phillip P Sharp, Mannu Walia, Nicole C Walsh, Andrew CW Zannettino, Alistair M Chalk, Christopher J Burns, Carl R Walkle

Minimal Size of Cell Assemblies Coordinated by Gamma Oscillations

In networks of excitatory and inhibitory neurons with mutual synaptic coupling, specific drive to sub-ensembles of cells often leads to gamma-frequency (25–100 Hz) oscillations. When the number of driven cells is too small, however, the synaptic interactions may not be strong or homogeneous enough to support the mechanism underlying the rhythm. Using a combination of computational simulation and mathematical analysis, we study the breakdown of gamma rhythms as the driven ensembles become too small, or the synaptic interactions become too weak and heterogeneous. Heterogeneities in drives or synaptic strengths play an important role in the breakdown of the rhythms; nonetheless, we find that the analysis of homogeneous networks yields insight into the breakdown of rhythms in heterogeneous networks. In particular, if parameter values are such that in a homogeneous network, it takes several gamma cycles to converge to synchrony, then in a similar, but realistically heterogeneous network, synchrony breaks down altogether. This leads to the surprising conclusion that in a network with realistic heterogeneity, gamma rhythms based on the interaction of excitatory and inhibitory cell populations must arise either rapidly, or not at all. For given synaptic strengths and heterogeneities, there is a (soft) lower bound on the possible number of cells in an ensemble oscillating at gamma frequency, based simply on the requirement that synaptic interactions between the two cell populations be strong enough. This observation suggests explanations for recent experimental results concerning the modulation of gamma oscillations in macaque primary visual cortex by varying spatial stimulus size or attention level, and for our own experimental results, reported here, concerning the optogenetic modulation of gamma oscillations in kainate-activated hippocampal slices. We make specific predictions about the behavior of pyramidal cells and fast-spiking interneurons in these experiments.Collaborative Research in Computational NeuroscienceNational Institutes of Health (U.S.) (grant 1R01 NS067199)National Institutes of Health (U.S.) (grant DMS 0717670)National Institutes of Health (U.S.) (grant 1R01 DA029639)National Institutes of Health (U.S.) (grant 1RC1 MH088182)National Institutes of Health (U.S.) (grant DP2OD002002)Paul G. Allen Family FoundationnGoogle (Firm

siDirect 2.0: updated software for designing functional siRNA with reduced seed-dependent off-target effect

<p>Abstract</p> <p>Background</p> <p>RNA interference (RNAi), mediated by 21-nucleotide (nt)-length small interfering RNAs (siRNAs), is a powerful tool not only for studying gene function but also for therapeutic applications. RNAi, requiring perfect complementarity between the siRNA guide strand and the target mRNA, was believed to be extremely specific. However, a recent growing body of evidence has suggested that siRNA could down-regulate unintended genes whose transcripts possess complementarity to the 7-nt siRNA seed region. This off-target gene silencing may often provide incongruous results obtained from knockdown experiments, leading to misinterpretation. Thus, an efficient algorithm for designing functional siRNAs with minimal off-target effect based on the mechanistic features is considered of value.</p> <p>Results</p> <p>We present siDirect 2.0, an update of our web-based software siDirect, which provides functional and off-target minimized siRNA design for mammalian RNAi. The previous version of our software designed functional siRNAs by considering the relationship between siRNA sequence and RNAi activity, and provided them along with the enumeration of potential off-target gene candidates by using a fast and sensitive homology search algorithm. In the new version, the siRNA design algorithm is extensively updated to eliminate off-target effects by reflecting our recent finding that the capability of siRNA to induce off-target effect is highly correlated to the thermodynamic stability, or the melting temperature (Tm), of the seed-target duplex, which is formed between the nucleotides positioned at 2-8 from the 5' end of the siRNA guide strand and its target mRNA. Selection of siRNAs with lower seed-target duplex stabilities (benchmark Tm < 21.5°C) followed by the elimination of unrelated transcripts with nearly perfect match should minimize the off-target effects.</p> <p>Conclusion</p> <p>siDirect 2.0 provides functional, target-specific siRNA design with the updated algorithm which significantly reduces off-target silencing. When the candidate functional siRNAs could form seed-target duplexes with Tm values below 21.5°C, and their 19-nt regions spanning positions 2-20 of both strands have at least two mismatches to any other non-targeted transcripts, siDirect 2.0 can design at least one qualified siRNA for >94% of human mRNA sequences in RefSeq. siDirect 2.0 is available at <url>http://siDirect2.RNAi.jp/</url>.</p