Explore the vast range of titles available.

Electrochemical synthesis can provide more sustainable routes to industrial chemicals 1 – 3 . Electrosynthetic oxidations may often be performed ‘reagent-free’, generating hydrogen (H 2 ) derived from the substrate as the sole by-product at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications 4 , but more sustainable options are needed at larger scale. Anodic water oxidation is an especially appealing option 1 , 5 , 6 , but many reductions require anhydrous, air-free reaction conditions. In such cases, H 2 represents an ideal alternative, motivating the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions 7 – 12 . Here we report a mediated H 2 anode that achieves indirect electrochemical oxidation of H 2 by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H 2 anode is used to support nickel-catalysed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption in the pharmaceutical industry 13 – 15 . Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H 2 anode technology disclosed here offers a general strategy to support H 2 -driven electrosynthetic reductions. A quinone-mediated hydrogen anode design shows that hydrogen can be used as the electron source in non-aqueous reductive electrosynthesis, for a more sustainable way to make molecules at larger scale.

The outer membrane of Gram-negative bacteria has an external leaflet that is largely composed of lipopolysaccharide, which provides a selective permeation barrier, particularly against antimicrobials 1 . The final and crucial step in the biosynthesis of lipopolysaccharide is the addition of a species-dependent O-antigen to the lipid A core oligosaccharide, which is catalysed by the O-antigen ligase WaaL 2 . Here we present structures of WaaL from Cupriavidus metallidurans , both in the apo state and in complex with its lipid carrier undecaprenyl pyrophosphate, determined by single-particle cryo-electron microscopy. The structures reveal that WaaL comprises 12 transmembrane helices and a predominantly α-helical periplasmic region, which we show contains many of the conserved residues that are required for catalysis. We observe a conserved fold within the GT-C family of glycosyltransferases and hypothesize that they have a common mechanism for shuttling the undecaprenyl-based carrier to and from the active site. The structures, combined with genetic, biochemical, bioinformatics and molecular dynamics simulation experiments, offer molecular details on how the ligands come in apposition, and allows us to propose a mechanistic model for catalysis. Together, our work provides a structural basis for lipopolysaccharide maturation in a member of the GT-C superfamily of glycosyltransferases. Cryo-electron microscopy structures of the bacterial O-antigen ligase WaaL, combined with genetics, biochemistry and molecular dynamics simulations, provide insight into the mechanism by which WaaL catalyses the biosynthesis of lipopolysaccharide.

Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively. Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.).

Preoperative (neoadjuvant) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer. In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m2, l-folinic acid 175 mg, fluorouracil 400 mg/m2 bolus, then 2400 mg/m2 by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the first 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratification variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no significant differences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in significant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate. Cancer Research UK.

1. Horizon scanning is an essential tool for environmental scientists if they are to contribute to the evidence base for Government, its agencies and other decision makers to devise and implement environmental policies. The implication of not foreseeing issues that are foreseeable is illustrated by the contentious responses to genetically modified herbicide-tolerant crops in the UK, and by challenges surrounding biofuels, foot and mouth disease, avian influenza and climate change. 2. A total of 35 representatives from organizations involved in environmental policy, academia, scientific journalism and horizon scanning were asked to use wide consultation to identify the future novel or step changes in threats to, and opportunities for, biodiversity that might arise in the UK up to 2050, but that had not been important in the recent past. At least 452 people were consulted. 3. Cases for 195 submitted issues were distributed to all participants for comments and additions. All issues were scored (probability, hazard, novelty and overall score) prior to a 2-day workshop. Shortlisting to 41 issues and then the final 25 issues, together with refinement of these issues, took place at the workshop during another two rounds of discussion and scoring. 4. We provide summaries of the 25 shortlisted issues and outline the research needs. 5. We suggest that horizon scanning incorporating wide consultation with providers and users of environmental science is used by environmental policy makers and researchers. This can be used to identify gaps in knowledge and policy, and to identify future key issues for biodiversity, including those arising from outside the domains of ecology and biodiversity. 6. Synthesis and applications. Horizon scanning can be used by environmental policy makers and researchers to identify gaps in knowledge and policy. Drawing on the experience, expertise and research of policy advisors, academics and journalists, this exercise helps set the agenda for policy, practice and research.

This research examines media richness by modeling face-to-face, telephone, and electronic media as one construct and testing its performance implications. The context is the third-party logistics industry, in which a customer firm allows a service provider to assume responsibility for all or part of a critical business process. This business-to-business service environment is characterized by high levels of complexity (uncertainty, variability, equivocality) and network interdependence, key contextual attributes that enhance media richness' impact. We found a direct effect of media richness on relational performance and through it, indirect effects on satisfaction and loyalty . Furthermore, we found a direct effect of media richness on loyalty, which suggests that service firms in networked relationships provide loyalty-inducing benefits the genesis of which is not in the satisfaction created by the service itself. While past studies have examined the relationship of richness-related constructs and performance, no significant link was found. Our study is the first to demonstrate that media richness can affect firm performance when businesses interact in a complex environment.

Breeding synchrony with the lunar cycle has been reported for many marine organisms but is essentially unknown for birds. Most organisms shown to breed synchronously with the lunar cycle provide no parental care to young, and such explosive breeding assemblages are usually promiscuous. Saltmarsh Sharp-tailed Sparrows (Ammodramus caudacutus caudacutus) nest exclusively on salt marshes and are subjected to predictable, catastrophic flooding caused during flood tides every 28 days. Here, we show that Saltmarsh Sharp-tailed Sparrow males were nonterritorial and promiscuous and provided no parental care to young. Breeding behaviors of both sexes were synchronized with the lunar cycle. By contrast, males of a sympatric sister species, Nelson's Sharp-tailed Sparrow (A. nelsoni subvirgatus), consistently mate-guarded females, and breeding was not synchronized with the lunar cycle, yielding 21% lower reproductive success compared with Saltmarsh Sharp-tailed Sparrows. Saltmarsh and Nelson's sharp-tailed sparrows renested 2.9 ± 0.6 (SE) days and 10.3 ± 1.7 days after nest flooding, respectively. Patterns of vicariance between Nelson's and Saltmarsh sharp-tailed sparrows may explain the differences in social behavior and nesting ecology. Ancestral sharp-tailed sparrows diverged from Seaside Sparrows (A. maritimus) in tidal wetlands, and Nelson's Sharp-tailed Sparrows then diverged from Saltmarsh Sharp-tailed Sparrows in nontidal freshwater wetlands of interior North America. Nelson's Sharp-tailed Sparrows' range recently expanded into coastal salt marshes, where Saltmarsh Sharp-tailed Sparrows are better adapted to tidally influenced inundations. Adaptation to tidal flooding partially explains the evolution of the unique Saltmarsh Sharp-tailed Sparrow mating system. Las Inundaciones Mareales Afectan la Ecología Reproductiva de Dos Especies Simpátricas de Ammodramus

The research examines the relationships among three dimensions of logistics service performance (operational, relational, and cost performance), customer satisfaction, customer loyalty, and market share. Perceptions of customers of third party logistics (3PL) providers are used to assess 3PL performance constructs. Of the three dimensions of service performance, relational performance is the single most important factor in engendering customer satisfaction. The research supports the strong relationship between customer satisfaction and loyalty identified in previous studies. It also establishes an empirical link between customer loyalty and a measure of market share that is anchored by objective, secondary data.

Nelson's (Ammodramus nelsoni) and Saltmarsh (A. caudacutus) sparrows are sympatric breeders in tidal marshes of the southern Gulf of Maine. These sparrows hybridize, have different mating strategies, and males do not defend territories or provide parental care. We estimated and compared core area sizes, home range sizes, and habitat use between species and between males and females. We radio-marked 140 sparrows (63 Nelson's and 77 Saltmarsh sparrows) during three breeding seasons (1999–2001) at Scarborough Marsh, Maine, USA. Home ranges of male A. nelsoni were 2.3 times larger (± SE) (119.68 ± 19.43 ha) than those of male A. caudacutus (52.85 ± 8.68 ha). Home range sizes of female Nelson's and female Saltmarsh sparrows did not differ from each other (female Nelson's home range  =  43.58 ± 13.10 ha; female Saltmarsh home range  =  27.81 ± 6.3 ha). More than 40% of male and 18% of female home ranges had two discrete core areas and, in most instances, each core area corresponded to a separate lunar cycle. We suggest that differences in mating strategies, densities, and adaptation to nesting in tidal marshes explain the larger home range estimates for male Nelson's Sparrows. Female and male Nelson's Sparrows' home ranges had more Spartina alterniflora cover and female Saltmarsh Sparrows' home ranges had greater Juncus gerardii cover than random locations. Home ranges of female Saltmarsh Sparrows had less Spartina alterniflora cover and more Juncus gerardii cover than female Nelson's Sparrows. We did not detect any differences in vegetation variables between male Saltmarsh and male Nelson's sparrow home ranges.

IntroductionObesity is a risk factor for the development of colorectal cancer (CRC).1 Colonoscopy in obese patients has been suggested to be more technically difficult,2 3 but variation in indication and age of patients, and operator technical ability may be confounding factors. The Bowel Cancer Screening Programme (BCSP) has a single indication for colonoscopy in a narrow age band (60–70 years) and the colonoscopists are of a proven standard, therefore studying data from this group of patients may avoid confounding factors and give a truer assessment of technical difficulty.MethodsWe compared measures of technical difficulty (quality of preparation; caecal intubation rate and time; sedation/analgesia dose; and patient tolerance) and findings (polyp and cancer detection) in the Taunton Faecal Occult Blood positive (FOB+ve) BCSP colonoscopy patients in 2008/9 (N=359, males 209, females 150) in relation to their BMI.ResultsBMI was known in 348, and was 15.7–58.3 (median 28.0). One hundred and eleven patients (31.8%) had BMI >30. Bowel preparation scores were not affected by BMI (Fisher's Exact Test, p=0.62), nor were sedation and analgesia requirements (all comparisons obese vs non-obese, Fisher's Exact Test or regression analysis). Comfort scores were similar (minimal or no discomfort 63% vs 68%, p=0.33). Overall caecal intubation rates were 96.3%, vs 97.4% (p=0.73). Caecal intubation time was not effected by BMI (r=0.022, p=0.68). Polyps were found in 210 (58.4%) patients and cancer in 43 (11.9%) in total. BMI did not affect the number of polyps found (p=0.33). There was no significant difference in the number of cancers identified in patients with a BMI>30 (14 of 97) compared to the others (29 of 208) (p=1.0).ConclusionObesity does not impair the technical performance of colonoscopy in this population. There is a high rate of obesity in the FOB +ve BCSP population, but the effect of obesity on findings cannot be assessed by this study, since the proportion of obese patients in the overall population from which this group is drawn was not available. Nether-the-less this study suggests that obesity should not be a factor in deciding whether colonoscopy is an appropriate investigation to exclude CRC.