Free Space Laser Communication Experiments from Earth to the Lunar Reconnaissance Orbiter in Lunar Orbit

Laser communication and ranging experiments were successfully conducted from the satellite laser ranging (SLR) station at NASA Goddard Space Flight Center (GSFC) to the Lunar Reconnaissance Orbiter (LRO) in lunar orbit. The experiments used 4096-ary pulse position modulation (PPM) for the laser pulses during one-way LRO Laser Ranging (LR) operations. Reed-Solomon forward error correction codes were used to correct the PPM symbol errors due to atmosphere turbulence and pointing jitter. The signal fading was measured and the results were compared to the model

Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase

Objectives To evaluate the efficacy of two novel compounds against mycobacteria and determine the molecular basis of their action on DNA gyrase using structural and mechanistic approaches. Methods Redx03863 and Redx04739 were tested in antibacterial assays, and also against their target, DNA gyrase, using DNA supercoiling and ATPase assays. X-ray crystallography was used to determine the structure of the gyrase B protein ATPase sub-domain from Mycobacterium smegmatis complexed with the aminocoumarin drug novobiocin, and structures of the same domain from Mycobacterium thermoresistibile complexed with novobiocin, and also with Redx03863. Results Both compounds, Redx03863 and Redx04739, were active against selected Gram-positive and Gram-negative species, with Redx03863 being the more potent, and Redx04739 showing selectivity against M. smegmatis. Both compounds were potent inhibitors of the supercoiling and ATPase reactions of DNA gyrase, but did not appreciably affect the ATP-independent relaxation reaction. The structure of Redx03863 bound to the gyrase B protein ATPase sub-domain from M. thermoresistibile shows that it binds at a site adjacent to the ATP- and novobiocin-binding sites. We found that most of the mutations that we made in the Redx03863-binding pocket, based on the structure, rendered gyrase inactive. Conclusions Redx03863 and Redx04739 inhibit gyrase by preventing the binding of ATP. The fact that the Redx03863-binding pocket is distinct from that of novobiocin, coupled with the lack of activity of resistant mutants, suggests that such compounds could have potential to be further exploited as antibiotics

GPs' use of problem solving therapy for depression: a qualitative study of barriers to and enablers of evidence based care

BACKGROUND: Depression is a major health concern, predominantly treated by general practitioners (GPs). Problem solving therapy (PST) is recognised as an effective treatment for depression that is not widely used by GPs. This research aims to explore barriers and enablers that may influence GPs use of this treatment. METHOD: Qualitative methodology was used including individual and focus group interviews of GPs, PST experts and consumers. Analysis was undertaken using the Theory of Planned Behaviour (TPB) as a framework. RESULTS: A spectrum of potential influences, on GPs' use of PST emerged. Both barriers and enablers were identified. PST was perceived as being close to current practice approaches and potentially beneficial to both doctor and patient. In addition to a broadly positive attitude to PST, expressed by those with previous experience of its use, potential solutions to perceived barriers emerged. By contrast some GPs expressed fear that the use of PST would result in loss of doctor control of consultations and associated potential adverse patient outcomes. Patient expectations, which emerged as not always coinciding with GPs' perception of those expectations, were identified as a potential influence on GPs' decision concerning adoption of PST. In addition specific factors, including GP skill and confidence, consultation time constraints and technical issues related to PST were noted as potential concerns. CONCLUSION: This research contributes to our knowledge of the factors that may influence GPs' decisions regarding use of PST as a treatment for depression. It recognises both barriers and enablers. It suggests that for many GPs, PST is viewed in a positive light, providing encouragement to those seeking to increase the provision of PST by GPs. In identifying a number of potential barriers, along with associated options to address many of these barriers, it provides insights which may assist in the planning of GP training in PST

Economic outcomes of percutaneous coronary intervention with drug-eluting stents versus bypass surgery for patients with left main or three-vessel coronary artery disease: One-year results from the SYNTAX trial

Objectives: To evaluate the cost-effectiveness of alternative approaches to revascularization for patients with three-vessel or left main coronary artery disease (CAD). Background: Previous studies have demonstrated that, despite higher initial costs, long-term costs with bypass surgery (CABG) in multivessel CAD are similar to those for percutaneous coronary intervention (PCI). The impact of drug-eluting stents (DES) on these results is unknown. Methods: The SYNTAX trial randomized 1,800 patients with left main or three-vessel CAD to either CABG (n = 897) or PCI using paclitaxel-eluting stents (n = 903). Resource utilization data were collected prospectively for all patients, and cumulative 1-year costs were assessed from the perspective of the U.S. healthcare system. Results: Total costs for the initial hospitalization were $5,693/patient higher with CABG, whereas follow-up costs were$2,282/patient higher with PCI due mainly to more frequent revascularization procedures and higher outpatient medication costs. Total 1-year costs were thus $3,590/patient higher with CABG, while quality-adjusted life expectancy was slightly higher with PCI. Although PCI was an economically dominant strategy for the overall population, cost-effectiveness varied considerably according to angiographic complexity. For patients with high angiographic complexity (SYNTAX score > 32), total 1-year costs were similar for CABG and PCI, and the incremental cost-effectiveness ratio for CABG was$43,486 per quality-adjusted life-year gained. Conclusions: Among patients with three-vessel or left main CAD, PCI is an economically attractive strategy over the first year for patients with low and moderate angiographic complexity, while CABG is favored among patients with high angiographic complexity

Remote climate forcing of decadal-scale regime shifts in Northwest Atlantic shelf ecosystems

Author Posting. © Association for the Sciences of Limnology and Oceanography, 2013. This article is posted here by permission of Association for the Sciences of Limnology and Oceanography for personal use, not for redistribution. The definitive version was published in Association for the Sciences of Limnology and Oceanography, doi:10.4319/lo.2013.58.3.0803.Decadal-scale regime shifts in Northwest Atlantic shelf ecosystems can be remotely forced by climate-associated atmosphere–ocean interactions in the North Atlantic and Arctic Ocean Basins. This remote climate forcing is mediated primarily by basin- and hemispheric-scale changes in ocean circulation. We review and synthesize results from process-oriented field studies and retrospective analyses of time-series data to document the linkages between climate, ocean circulation, and ecosystem dynamics. Bottom-up forcing associated with climate plays a prominent role in the dynamics of these ecosystems, comparable in importance to that of top-down forcing associated with commercial fishing. A broad perspective, one encompassing the effects of basin- and hemispheric-scale climate processes on marine ecosystems, will be critical to the sustainable management of marine living resources in the Northwest Atlantic.Funding for this research was provided by the National Science Foundation as part of the Regional and Pan-Regional Synthesis Phases of the U.S. Global Ocean Ecosystem (GLOBEC) Program

Recent Arctic climate change and its remote forcing of Northwest Atlantic shelf ecosystems

Author Posting. © The Oceanography Society, 2012. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 25, no. 3 (2012): 208-213, doi:10.5670/oceanog.2012.64.During recent decades, historically unprecedented changes have been observed in the Arctic as climate warming has increased precipitation, river discharge, and glacial as well as sea-ice melting. Additionally, shifts in the Arctic's atmospheric pressure field have altered surface winds, ocean circulation, and freshwater storage in the Beaufort Gyre. These processes have resulted in variable patterns of freshwater export from the Arctic Ocean, including the emergence of great salinity anomalies propagating throughout the North Atlantic. Here, we link these variable patterns of freshwater export from the Arctic Ocean to the regime shifts observed in Northwest Atlantic shelf ecosystems. Specifically, we hypothesize that the corresponding salinity anomalies, both negative and positive, alter the timing and extent of water-column stratification, thereby impacting the production and seasonal cycles of phytoplankton, zooplankton, and higher-trophic-level consumers. Should this hypothesis hold up to critical evaluation, it has the potential to fundamentally alter our current understanding of the processes forcing the dynamics of Northwest Atlantic shelf ecosystems.Funding for this research was provided by the National Science Foundation as part of the Regional and Pan-Regional Synthesis Phases of the US Global Ocean Ecosystem (GLOBEC) Program

Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase

According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates

Removable partial dentures: The clinical need for innovation

Statement of problem: The number of partially dentate adults is increasing, and many patients will require replacement of missing teeth. Although current treatment options also include fixed partial dentures and implants, removable partial dentures (RPDs) can have advantages and are widely used in clinical practice. However, a significant need exists to advance materials and fabrication technologies because of the unwanted health consequences associated with current RPDs. Purpose: The purpose of this review was to assess the current state of and future need for prosthetics such as RPDs for patients with partial edentulism, highlight areas of weakness, and outline possible solutions to issues that affect patient satisfaction and the use of RPDs. Material and methods: The data on treatment for partial edentulism were reviewed and summarized with a focus on currently available and future RPD designs, materials, means of production, and impact on oral health. Data on patient satisfaction and compliance with RPD treatment were also reviewed to assess patient-centered care. Results: Design, materials, ease of repair, patient education, and follow-up for RPD treatment all had a significant impact on treatment success. Almost 40% of patients no longer use their RPD within 5 years because of factors such as sociodemographics, pain, and esthetics. Research on RPD-based treatment for partial edentulism for both disease-oriented and patient-centered outcomes is lacking. Conclusions: Future trials should evaluate new RPD materials and design technologies and include both long-term follow-up and health-related and patient-reported outcomes. Advances in materials and digital design/production along with patient education promise to further the application of RPDs and improve the quality of life for patients requiring RPDs

A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.</p

In-Vitro Helix Opening of M. tuberculosis oriC by DnaA Occurs at Precise Location and Is Inhibited by IciA Like Protein

BACKGROUND: Mycobacterium tuberculosis (M.tb), the pathogen that causes tuberculosis, is capable of staying asymptomatically in a latent form, persisting for years in very low replicating state, before getting reactivated to cause active infection. It is therefore important to study M.tb chromosome replication, specifically its initiation and regulation. While the region between dnaA and dnaN gene is capable of autonomous replication, little is known about the interaction between DnaA initiator protein, oriC origin of replication sequences and their negative effectors of replication. METHODOLOGY/PRINCIPAL FINDINGS: By KMnO(4) mapping assays the sequences involved in open complex formation within oriC, mediated by M.tb DnaA protein, were mapped to position -500 to -518 with respect to the dnaN gene. Contrary to E. coli, the M.tb DnaA in the presence of non-hydrolysable analogue of ATP (ATPgammaS) was unable to participate in helix opening thereby pointing to the importance of ATP hydrolysis. Interestingly, ATPase activity in the presence of supercoiled template was higher than that observed for DnaA box alone. M.tb rRv1985c, a homologue of E.coli IciA (Inhibitor of chromosomal initiation) protein, could inhibit DnaA-mediated in-vitro helix opening by specifically binding to A+T rich region of oriC, provided the open complex formation had not initiated. rIciA could also inhibit in-vitro replication of plasmid carrying the M.tb origin of replication. CONCLUSIONS/SIGNIFICANCE: These results have a bearing on the functional role of the important regulator of M.tb chromosomal replication belonging to the LysR family of bacterial regulatory proteins in the context of latency