A global horizon scan of the future impacts of robotics and autonomous systems on urban ecosystems.

Technology is transforming societies worldwide. A major innovation is the emergence of robotics and autonomous systems (RAS), which have the potential to revolutionize cities for both people and nature. Nonetheless, the opportunities and challenges associated with RAS for urban ecosystems have yet to be considered systematically. Here, we report the findings of an online horizon scan involving 170 expert participants from 35 countries. We conclude that RAS are likely to transform land use, transport systems and human-nature interactions. The prioritized opportunities were primarily centred on the deployment of RAS for the monitoring and management of biodiversity and ecosystems. Fewer challenges were prioritized. Those that were emphasized concerns surrounding waste from unrecovered RAS, and the quality and interpretation of RAS-collected data. Although the future impacts of RAS for urban ecosystems are difficult to predict, examining potentially important developments early is essential if we are to avoid detrimental consequences but fully realize the benefits.

A Novel Bioelectronic Reporter System in Living Cells Tested with a Synthetic Biological Comparator.

As the fields of biotechnology and synthetic biology expand, cheap and sensitive tools are needed to measure increasingly complicated genetic circuits. In order to bypass some drawbacks of optical fluorescent reporting systems, we have designed and created a co-culture microbial fuel cell (MFC) system for electronic reporting. This system leverages the syntrophic growth of Escheriachia. coli (E. coli) and an electrogenic bacterium Shewanella oneidensis MR-1 (S. oneidensis). The fermentative products of E. coli provide a carbon and electron source for S. oneidensis MR-1, which then reports on such activity electrically at the anode of the MFC. To further test the capability of electrical reporting of complicated synthetic circuits, a novel synthetic biological comparator was designed and tested with both fluorescent and electrical reporting systems. The results suggest that the electrical reporting system is a good alternative to commonly used optical fluorescent reporter systems since it is a non-toxic reporting system with a much wider dynamic range.

GPs' knowledge, use, and confidence in national physical activity and health guidelines and tools: a questionnaire-based survey of general practice in England.

BACKGROUND: Physical activity (PA) brief advice in health care is effective at getting individuals active. It has been suggested that one in four people would be more active if advised by a GP or nurse, but as many as 72% of GPs do not discuss the benefits of physical activity with patients. AIM: To assess the knowledge, use, and confidence in national PA and Chief Medical Officer (CMO) health guidelines and tools among GPs in England. DESIGN AND SETTING: Online questionnaire-based survey of self-selecting GPs in England that took place over a 10-day period in March 2016. METHOD: The questionnaire consisted of six multiple-choice questions and was available on the Doctors.net.uk (DNUK) homepage. Quotas were used to ensure good regional representation. RESULTS: The final analysis included 1013 responses. Only 20% of responders were broadly or very familiar with the national PA guidelines. In all, 70% of GPs were aware of the General Practice Physical Activity Questionnaire (GPPAQ), but 26% were not familiar with any PA assessment tools, and 55% reported that they had not undertaken any training with respect to encouraging PA. CONCLUSION: The majority of GPs in England (80%) are unfamiliar with the national PA guidelines. Awareness of the recommended tool for assessment, GPPAQ, is higher than use by GPs. This may be because it is used by other clinical staff, for example, as part of the NHS Health Check programme. Although brief advice in isolation by GPs on PA will only be a part of the behaviour change journey, it is an important prompt, especially if repeated as part of routine practice. This study highlights the need for significant improvement in knowledge, skills, and confidence to maximise the potential for PA advice in GP consultations.

Inhibition of the ERCC1-XPF structure-specific endonuclease to overcome cancer chemoresistance.

ERCC1-XPF is a structure-specific endonuclease that is required for the repair of DNA lesions, generated by the widely used platinum-containing cancer chemotherapeutics such as cisplatin, through the Nucleotide Excision Repair and Interstrand Crosslink Repair pathways. Based on mouse xenograft experiments, where ERCC1-deficient melanomas were cured by cisplatin therapy, we proposed that inhibition of ERCC1-XPF could enhance the effectiveness of platinum-based chemotherapy. Here we report the identification and properties of inhibitors against two key targets on ERCC1-XPF. By targeting the ERCC1-XPF interaction domain we proposed that inhibition would disrupt the ERCC1-XPF heterodimer resulting in destabilisation of both proteins. Using in silico screening, we identified an inhibitor that bound to ERCC1-XPF in a biophysical assay, reduced the level of ERCC1-XPF complexes in ovarian cancer cells, inhibited Nucleotide Excision Repair and sensitised melanoma cells to cisplatin. We also utilised high throughput and in silico screening to identify the first reported inhibitors of the other key target, the XPF endonuclease domain. We demonstrate that two of these compounds display specificity in vitro for ERCC1-XPF over two other endonucleases, bind to ERCC1-XPF, inhibit Nucleotide Excision Repair in two independent assays and specifically sensitise Nucleotide Excision Repair-proficient, but not Nucleotide Excision Repair-deficient human and mouse cells to cisplatin.

Fragment-based hit identification: thinking in 3D.

The identification of high-quality hits during the early phases of drug discovery is essential if projects are to have a realistic chance of progressing into clinical development and delivering marketed drugs. As the pharmaceutical industry goes through unprecedented change, there are increasing opportunities to collaborate via pre-competitive networks to marshal multifunctional resources and knowledge to drive impactful, innovative science. The 3D Fragment Consortium is developing fragment-screening libraries with enhanced 3D characteristics and evaluating their effect on the quality of fragment-based hit identification (FBHI) projects.

Interleukin-4 and interleukin-13 cause barrier dysfunction in human airway epithelial cells.

Emerging evidence indicates that airway epithelial barrier function is compromised in asthma, a disease characterized by Th2-skewed immune response against inhaled allergens, but the mechanisms involved are not well understood. The purpose of this study was to investigate the effects of Th2-type cytokines on airway epithelial barrier function. 16HBE14o- human bronchial epithelial cells monolayers were grown on collagen coated Transwell inserts. The basolateral or apical surfaces of airway epithelia were exposed to human interleukin-4 (IL-4), IL-13, IL-25, IL-33, thymic stromal lymphopoietin (TSLP) alone or in combination at various concentrations and time points. We analyzed epithelial apical junctional complex (AJC) function by measuring transepithelial electrical resistance (TEER) and permeability to FITC-conjugated dextran over time. We analyzed AJC structure using immunofluorescence with antibodies directed against key junctional components including occludin, ZO-1, ß-catenin and E-cadherin. Transepithelial resistance was significantly decreased after both basolateral and apical exposure to IL-4. Permeability to 3 kDa dextran was also increased in IL-4-exposed cells. Similar results were obtained with IL-13, but none of the innate type 2 cytokines examined (TSLP, IL-25 or IL-33) significantly affected barrier function. IL-4 and IL-13-induced barrier dysfunction was accompanied by reduced expression of membrane AJC components but not by induction of claudin- 2. Enhanced permeability caused by IL-4 was not affected by wortmannin, an inhibitor of PI3 kinase signaling, but was attenuated by a broad spectrum inhibitor of janus associated kinases. Our study indicates that IL-4 and IL-13 have disruptive effect on airway epithelial barrier function. Th2-cytokine induced epithelial barrier dysfunction may contribute to airway inflammation in allergic asthma.

Effective inhibitors of the essential kinase PknB and their potential as anti-mycobacterial agents.

PknB is an essential serine/threonine kinase of Mycobacterium tuberculosis with possible roles in a number of signalling pathways involved in cell division and metabolism. We screened a library of >50,000 compounds for inhibitors of the in vitro phosphorylation of GarA (Rv1827) by PknB and identified a number of inhibitors. A program of synthetic medicinal chemistry was subsequently conducted around one class of inhibitors and was successful in generating ATP competitive inhibitors with potency in the nanomolar range. Compounds in this class showed cross-reactivity with the related M. tuberculosis kinase, PknF, but not with PknG in an in vitro autophosphorylation assay. These synthesised inhibitors were able to prevent the growth of M. tuberculosis in an Alamar blue assay and in an intracellular model of infection, but only in the micromolar range. We attempted to determine if cell wall permeability was an explanation for the discrepancy between the potent in vitro compared with relatively poor in vivo activity, but found no evidence that the activity of the inhibitors could be improved by weakening the cell wall. Despite a number of drug discovery efforts attempting to develop inhibitors against PknB, it is yet to be reported that any such inhibitors prevent mycobacterial growth at submicromolar concentrations.

Attitudes and interests toward research among students at two colleges of acupuncture and Oriental medicine.

BACKGROUND: Collaborative input from clinicians of acupuncture and Oriental medicine (AOM) is required for sound AOM research, and AOM training institutions have begun to include research education into their curriculum. However, few attempts have been made to systematically evaluate AOM practitioners' perspectives on the value of research to their profession. METHODS: We conducted surveys of AOM students at two institutions that have begun to integrate research training into their curriculum, the New England School of Acupuncture and the Oregon College of Oriental Medicine. Surveys were conducted to assess current attitudes regarding the value of research and to serve as a reference point for documenting the impact of ongoing research training programs on these attitudes. Surveys at both institutions were independently developed and administered but shared seven questions that were phrased very similarly. This paper summarizes responses to these questions. RESULTS: Surveys at both institutions suggest interest in research among AOM students is high in first-year students; students in later years showed a lower level of interest, but the cross-sectional design of this survey does not allow any temporal effects to be inferred. Results also indicate that AOM students believe research is highly relevant to how both the public and the health insurance industry view their system of healthcare but not highly relevant to their own clinical practice of AOM. The belief that research is of limited relevance to clinical practice was associated with widespread belief that scientific methods may not be consistent with the principles of AOM. CONCLUSIONS: Results of these surveys provide important preliminary information about attitudes of AOM students toward research, and thus the value and future specific needs of research training programs targeting this population. Repeated implementation of validated versions of our surveys are needed to confirm the trends we report and to evaluate the impact of research training programs already in place on AOM students' attitudes toward research.

Alcohol use disorders in relatives of patients with panic disorder.

OBJECTIVE: The aim of this study was to use data from a family study of anxiety disorders to examine the familial association between alcohol use disorders and panic disorder (PD), controlling for alcohol use disorders in the proband. METHOD: Data from a family study of anxiety disorders were used to compare rates of alcohol use disorders in the relatives of 3 proband groups (PD with lifetime alcohol use disorders, PD without lifetime alcohol use disorders, and not-ill controls). RESULTS: There was a significantly higher rate (12%) of alcohol use disorders among the relatives of PD probands compared with relatives of controls (5%), even in the absence of alcohol use disorders in the proband and after adjusting for differences in sociodemographic characteristics and lifetime drug use disorders (chi2 = 5.4; df = 1; P = .02). Anxiety symptoms were more frequent among the male relatives of panic probands who received an alcohol diagnosis, compared with those who did not have alcohol use disorders (10/25 vs 22/111; chi2 = 4.6; df = 1; P = .03). A similar pattern was found in women (8/11 vs 63/156; chi2 = 4.4; df = 1; P = .036). CONCLUSIONS: These findings suggest a familial association between PD and alcohol use disorders. Future studies with more refined alcohol diagnoses are needed to replicate and investigate the mechanism of this association.