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The high street is in crisis. How did we get here and what's next? This is the story of our towns and cities, and how they can adapt to change.

Bacterial infections have been traditionally controlled by antibiotics and vaccines, and these approaches have greatly improved health and longevity. However, multiple stakeholders are declaring that the lack of new interventions is putting our ability to prevent and treat bacterial infections at risk. Vaccine and antibiotic approaches still have the potential to address this threat. Innovative vaccine technologies, such as reverse vaccinology, novel adjuvants, and rationally designed bacterial outer membrane vesicles, together with progress in polysaccharide conjugation and antigen design, have the potential to boost the development of vaccines targeting several classes of multidrug-resistant bacteria. Furthermore, new approaches to deliver small-molecule antibacterials into bacteria, such as hijacking active uptake pathways and potentiator approaches, along with a focus on alternative modalities, such as targeting host factors, blocking bacterial virulence factors, monoclonal antibodies, and microbiome interventions, all have potential. Both vaccines and antibacterial approaches are needed to tackle the global challenge of antimicrobial resistance (AMR), and both areas have the underpinning science to address this need. However, a concerted research agenda and rethinking of the value society puts on interventions that save lives, by preventing or treating life-threatening bacterial infections, are needed to bring these ideas to fruition.

The brightness, robustness, and flexibility of high-power fiber laser sources provide an enabling technology for science and industry. Lasers are used in a wide range of applications that benefit from the pinsharp (spatially coherent) beam and immense pulse peak power they can provide. In many cases, notably manufacturing, high average power is essential for cutting, welding, and drilling. The low-power optical fiber amplifier ( 1 ), acclaimed as the mainstay of the fiber-based Internet, can be massively scaled to emerge as an industrial laser frontrunner, reaching an output power of >1 kW ( 2 ) and, more recently, an astounding 10 kW ( 3 ). These results were obtained with (nearly) diffraction-limited beam quality, which determines the ability to focus to a tight spot. Together with the power and wavelength, it determines the spatial brightness, or radiance. The brightness is exceptionally high for these fiber lasers, and this, rather than the power itself, determines the power density achievable on a target.

Bimetallic catalysts combining precious and earth-abundant metals in well designed nanoparticle architectures can enable cost efficient and stable heterogeneous catalysis. Here, we present an interaction-driven in-situ approach to engineer finely dispersed Ni decorated Pt nanoparticles (1-6 nm) on perovskite nanofibres via reduction at high temperatures (600-800 o C). Deposition of Pt (0.5 wt%) enhances the reducibility of the perovskite support and promotes the nucleation of Ni cations via metal-support interaction, thereafter the Ni species react with Pt forming alloy nanoparticles, with the combined processes yielding smaller nanoparticles that either of the contributing processes. Tuneable uniform Pt-Ni nanoparticles are produced on the perovskite surface, yielding reactivity and stability surpassing 1 wt.% Pt/γ-Al 2 O 3 catalysts for CO oxidation. This approach heralds the possibility of in-situ fabrication of supported bimetallic nanoparticles with engineered compositional distributions and performance. Utilizing “Chemistry at a point”, Ni is exsolved from a perovskite lattice under deposited Pt nanoparticles. This yields even smaller Ni Pt alloy nanoparticles on a perovskite nanofiber structure, exhibiting high catalytic activity.

\"Remotely piloted aircraft (RPA) and the personnel that operate them are well understood to be crucial to mission success in today's Air Force, and demand for skilled pilots continues to grow rapidly. However, recent studies suggest that personnel in the RPA pilot career field are dissatisfied with aspects of the job and are experiencing stress as a result. Although a variety of workplace factors lead to the stress and dissatisfaction, a large portion of them relate to issues associated with career field planning. These career field planning issues exist, in part, because of the newness and rapid growth of the RPA enterprise. The 18X RPA pilot force (those whose first and only rated job is as an RPA pilot) is only six years old, and plans for the future of the career field are still evolving. Moreover, as the rapid growth in demand for 18X pilots has outpaced the Air Force's ability to produce them, the Air Force is now struggling to train and retain enough personnel to meet the demand. Recognizing that a more thoughtful and stable plan for managing the career field is needed to ensure the future health of the force, Air Force leadership asked RAND to assist in building a long-term career field planning model that addresses those force health issues and the timeline required to build a healthy, sustainable career field. This report documents RAND's efforts to develop that model; explains its main features, underlying content, and data inputs; and describes its key technical aspects.\"--Publisher's description.

Background MicroRNA 398 (miR398), one of the conserved miRNAs, is known to target multiple genes encoding Cu 2+ -containing proteins such as the conserved two Cu/Zn Superoxide dismutases (CSD1 and CSD2) and a Cu 2+ -chaperone for CSDs (CCS) as primary targets. Additionally, miR398 is known to target transcripts of Cu 2+ -containing proteins such as cytochrome C-oxidase, Cupredoxin, and blue copper binding protein (BCBP) that are poorly conserved among plants. Results Our recently generated rice degradomes have validated Selenium Binding Protein (SBP), yet another Cu 2+ -containing protein, as a genuine target of miR398. Because SBP was largely underappreciated target of miR398, we sought to uncover potential conservation of miR398-SBP regulatory module in plants. This analysis revealed that miR398 is targeting SBP transcripts in several monocot clades. Though this regulation was also obvious but less prominent in dicots. Publicly available degradome analysis provided evidence for miR398-induced cleavage on SBP mRNAs in six monocots and four dicots. Conclusions These findings suggest that miR398 has picked up SBP as a secondary target in several clades of monocots, but less frequently in dicots. At the biochemical level, SBP proteins, like CSDs, are Cu 2+ -containing proteins that are thought to function in oxidative stress responses. Thus, miR398 regulates diverse families of Cu 2+ -containing proteins (CSDs and SBPs) that are part of the same biochemical pathway.

Key Points Despite the well-recognized medical need for new antibiotics, there has been a marked decrease in antibacterial drug discovery, with many companies leaving the area. In addition to the regulatory requirements and competitive commercial environment, which pose significant barriers to investment, there are scientific hurdles to making novel antibacterials that are underappreciated. Bacterial genome sequencing and analysis has greatly enhanced our understanding of evolution and bacterial physiology. In the mid-1990s, many in the scientific community and pharmaceutical industry believed that this knowledge was going to translate into a new generation of antibacterial drugs that acted by novel mechanisms. GlaxoSmithKline (GSK) embraced this 'genomics' approach to antibacterial discovery, using bioinformatic analysis of genomic information to identify target genes, testing the importance of these genes to bacterial viability by genetic means and finally screening compound collections against the target gene product for inhibitor compounds. GSK scientists validated hundreds of candidate genes and ran more than 70 high-throughput screening (HTS) campaigns between 1995–2001. Blind spots in target validation and an inability to find lead compounds from HTS together with the larger problem of making a single compound that has broad-spectrum activity and is safe at the high serum concentrations needed to cover the least susceptible organisms have left an empty industrial antibacterial portfolio. Eleven years after the first bacterial genome was sequenced, there is still not a single agent in the industrial pipeline that can be construed as being derived from genomic efforts. GSK has found that optimizing novel chemical structures that inhibit highly validated targets for drug-like properties is a more promising, if less trendy, route. Since 2002, our strategy has been to invest heavily in a select number of programmes, with large teams of chemists synthesizing drug-like compounds and with biologists focused on accelerating the critical path pharmacology and microbiological efficacy studies for each new compound synthesized. This approach has produced more novel mechanism antibacterial development candidates at GSK in the past 4 years than in the previous 20. However, high attrition rates in clinical development demand a broader industrial involvement and more aggressive research efforts to assure novel mechanism agents for the future. Genomics promised to revitalize the search for new antibiotics but still no new drug class against a novel target has materialized. Payne and colleagues describe the frustrations of their genomics efforts at GlaxoSmithKline and how this changed their approach to antibacterial R&D. The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.