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The Near-Infrared Spectrograph (NIRSpec) is one of the four focal plane instruments on the James Webb Space Telescope. In this paper, we summarize the in-orbit performance of NIRSpec, as derived from data collected during its commissioning campaign and the first few months of nominal science operations. More specifically, we discuss the performance of some critical hardware components such as the two NIRSpec Hawaii-2RG detectors, wheel mechanisms, and the microshutter array. We also summarize the accuracy of the two target acquisition procedures used to accurately place science targets into the slit apertures, discuss the current status of the spectrophotometric and wavelength calibration of NIRSpec spectra, and provide the “as measured” sensitivity in all NIRSpec science modes. Finally, we point out a few important considerations for the preparation of NIRSpec science programs.

It is twenty years since the seminal works by Magorrian and co-authors and by Silk and Rees, which, along with other related work, ignited an explosion of publications connecting active galactic nucleus (AGN)-driven outflows to galaxy evolution. With a surge in observations of AGN outflows, studies are attempting to test AGN feedback models directly using the outflow properties. With a focus on outflows traced by optical and CO emission lines, we discuss significant challenges that greatly complicate this task, from both an observational and theoretical perspective. We highlight the observational uncertainties involved and the assumptions required when deriving kinetic coupling efficiencies (that is, outflow kinetic power as a fraction of AGN luminosity) from typical observations. Based on recent models we demonstrate that extreme caution should be taken when comparing observationally derived kinetic coupling efficiencies to coupling efficiencies from fiducial feedback models.

This study provides insights into the tectonic evolution of the normal Mt Morrone Fault System (MMFS) in Central Italy and highlights the utility of multidisciplinary approaches in reconstructing the seismic history of dormant fault systems. The MMFS comprises two parallel normal faults that traverse the western slope of Mt. Morrone, and although the system can produce M > 6 earthquakes, it has been aseismic in post Roman times. Here, we combine geochemical analysis of carbonate fault‐scarp samples with new structural fault data and Lidar‐based topographic analysis to provide new constraints on fault geometries and kinematics, the paleo‐earthquake history of MMFS since the Last Glacial Maximum and its slip rates. Structural analysis reveals kinematic similarities between the two parallel strands, reflecting their response to the same stress regime. Rare Earth Elements analyses on 53 limestone samples reveal a minimum of eight concentration fluctuations upscarp, here interpreted as tectonic exhumation of the fault scarp due to post LGM earthquakes. Slip per event ranges from 30 to 110 cm typical of earthquakes with 6.3 ≤ M ≤ 6.8. Lidar analysis reveals triangular slip profiles on both fault strands. We estimate that an earthquake with an average M = 6.5–6.6 would have a recurrence interval of ∼2,125 ± 125 years. Slip rates were calculated to be 0.5–0.65 mm/yr on the lower and 0.65–0.7 mm/yr on the upper fault strand, with the combined system having slip rates of 0.62–0.69 mm/yr. Our findings indicate that both strands of the MMFS are active and accumulate slip interdependently, a finding that is critical for seismic hazard assessment. Plain Language Summary This study focuses on Mount Morrone in central Italy, which is affected by faults that haven't caused significant earthquakes in post Roman times but have the potential for strong earthquakes (magnitude >6). We combined different techniques to study the fault's characteristics, history, and how it has moved over time. Techniques include: (a) geochemical analysis on rock samples from a carbonate fault scarp, which records past movements caused by earthquakes through changes in the content of chemical elements; (b) structural‐geological data collected from faults exposed in the area; (c) displacement measurements using high‐resolution terrain models. By analyzing carbonate samples, we found at least eight past earthquakes, each causing the fault to move between 30 and 110 cm, equivalent to earthquakes 6.3 ≤ M ≤ 6.8. Structural analysis shows that the mount is affected by two faults responding to the same stress in the Earth's crust. We estimate that a significant earthquake (around magnitude 6.5) could occur approximately every 2,125 years. The fault moves at a rate of ∼0.62–0.69 mm per year. These insights are crucial for assessing the seismic risk in the densely populated Sulmona Basin, as understanding the behavior of the MMFS can improve safety measures in the region. Key Points The Mt Morrone fault ruptured at the surface 8 times in the past 17 ky with M6.3–6.8 earthquakes with an average return time of 2,125 ± 125 years Post‐17 ky slip rates are 0.5–0.65 and 0.65–0.7 mm/yr for the lower and upper fault strands, respectively, and 0.62–0.69 mm/yr when combined The two parallel fault strands of Mt Morrone have similar post‐17ky slip patterns associated with triangular and/or asymmetric slip profiles

Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra , contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product ‘de-orphaning’. Natural products provide a rich source of leads for drug discovery. Now, a computational method is available that can be used to identify the macromolecular targets of these compounds. Much like medicinal chemists' reasoning, the software infers target information by comparing the substructures with those of drugs and other natural products with known targets.

An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer’s disease (AD) treatment. Building upon these findings, we have now designed and completed the whole synthesis of PZ1 in the so-called deep eutectic solvents (DESs), which have emerged as an unconventional class of bio-renewable reaction media in green synthesis. Under optimized reaction conditions, the preparation of a series of 2-hydroxyphenylbenzimidazole-based nuclei has also been perfected in DESs, and comparison with other routes which employ toxic and volatile organic solvents (VOCs) provided. The functionalization of the aromatic ring can have implications on some important biological properties of the described derivatives and will be the subject of future studies of structure-activity relationships (SARs).

The cell adhesion protein and tumour suppressor E-cadherin exhibits important functions in the prevention of gastric cancer. As a class-I carcinogen, Helicobacter pylori ( H. pylori ) has developed a unique strategy to interfere with E-cadherin functions. In previous studies, we have demonstrated that H. pylori secretes the protease high temperature requirement A (HtrA) which cleaves off the E-cadherin ectodomain (NTF) on epithelial cells. This opens cell-to-cell junctions, allowing bacterial transmigration across the polarised epithelium. Here, we investigated the molecular mechanism of the HtrA-E-cadherin interaction and identified E-cadherin cleavage sites for HtrA. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern, which were preferentially cleaved by HtrA. Based on these sites, we developed a substrate-derived peptide inhibitor that selectively bound and inhibited HtrA, thereby blocking transmigration of H. pylori. The discovery of HtrA-targeted signature sites might further explain why we detected a stable 90 kDa NTF fragment during H. pylori infection, but also additional E-cadherin fragments ranging from 105 kDa to 48 kDa in in vitro cleavage experiments. In conclusion, HtrA targets E-cadherin signature sites that are accessible in in vitro reactions, but might be partially masked on epithelial cells through functional homophilic E-cadherin interactions.

The sensitivity of lymph node core-needle biopsy under imaging guidance requires validation. We employed power Doppler ultrasonography (PDUS) to select the lymph node most suspected of malignancy and to histologically characterize it through the use of large cutting needle. Institutional review board approval and informed consent were obtained for this randomized clinical trial. In a single center between 1 January 2009 and 31 December 2015, patients with lymph node enlargement suspected for lymphoma were randomly assigned (1:1) to biopsy with either standard surgery or PDUS-guided 16-gauge modified Menghini needle. The primary endpoint was the superiority of sensitivity for the diagnosis of malignancy for core-needle cutting biopsy (CNCB). Secondary endpoints were times to biopsy, complications, and costs. A total of 376 patients were randomized into the two arms and received allocated biopsy. However, four patients undergoing CNCB were excluded for inadequate samples; thus, 372 patients were analyzed. Sensitivity for the detection of malignancy was significantly better for PDUS-guided CNCB [98.8%; 95% confidence interval (CI), 95.9–99.9] than standard biopsy (88.7%; 95% CI, 82.9–93; P  < 0.001). For all secondary endpoints, the comparison was significantly disadvantageous for conventional approach. In particular, estimated cost per biopsy performed with standard surgery was 24-fold higher compared with that performed with CNCB. The presence of satellite enlarged reactive and/or necrotic lymph nodes may impair the success of an open surgical biopsy (OSB). PDUS and CNCB with adequate gauge are diagnostic tools that enable effective, safe, fast, and low-cost routine biopsy for patients with suspected lymphoma, avoiding psychological and physical pain of an unnecessary surgical intervention.

We report that phenacyl azides are key compounds for a regiodivergent synthesis of valuable, functionalized imidazole (32–98% yield) and pyrimidine derivatives (45–88% yield), with a broad substrate scope, when using deep eutectic solvents [choline chloride (ChCl)/glycerol (1:2 mol/mol) and ChCl/urea (1:2 mol/mol)] as environmentally benign and non-innocent reaction media, by modulating the temperature (25 or 80 °C) in the presence or absence of bases (Et 3 N).

The current study characterizes associations between physical and social contexts of self-reported primary episodes of eating/drinking and sociodemographic and obesity-related variables in US adults. Multinomial logistic regression was used to analyse a nationally representative sample of adults from the 2006-2008 American Time Use Survey. Models identifying physical (where) and social (whom) contexts of primary eating/drinking episodes at the population level, controlling for demographic characteristics, weight status and time of eating, were conducted. A nationally representative sample of US adults (n 21 315). Eating/drinking with immediate family was positively associated with age (OR = 1·15 (95 % CI 1·04, 1·27) to 1·23 (95 % CI 1·09, 1·39)), education level (OR = 1·16 (95 % CI 1·03, 1·30) to 1·36 (95 % CI 1·21, 1·54)), obesity (OR = 1·13 (95 % CI 1·04, 1·22)), children in the household (OR = 3·39 (95 % CI 3·14, 3·66)) and time of day (OR = 1·70 (95 % CI 1·39, 2·07) to 5·73 (95 % CI 4·70, 6·99)). Eating in the workplace was negatively associated with female gender (OR = 0·65 (95 % CI 0·60, 0·70)) and children in the household (OR = 0·90 (95 % CI 0·83, 0·98)), while positively associated with non-white status (OR = 1·14 (95 % CI 1·01, 1·29) to 1·47 (95 % CI 1·32, 1·65)) and time of day (OR = 0·25 (95 % CI 0·28, 0·30) to 5·65 (95 % CI 4·66, 6·85)). Women (OR = 0·80 (95 % CI 0·74, 0·86)), those aged >34 years (OR = 0·48 (95 % CI 0·43, 0·54) to 0·83 (95 % CI 0·74, 0·93)) and respondents with children (OR = 0·69 (95 % CI 0·63, 0·75)) were less likely to eat in a restaurant/bar/retail than at home. Overweight and obese respondents had a greater odds of reporting an episode of eating in social situations v. alone (e.g. immediate family and extended family; OR = 1·13 (95 % CI 1·04, 1·22)) and episodes occurring in restaurant/bar/retail locations (OR = 1·12 (95 % CI 1·03, 1·23) to 1·14 (95 % CI 1·05, 1·24)). Findings underscore the multidimensional nature of describing eating/drinking episodes. Social and physical contexts for eating/drinking and their demographic correlates suggest opportunities for tailoring interventions related to diet and may inform intervention targeting and scope.

Background Sunburn is the strongest risk factor for melanoma and non-melanoma skin cancers. Adolescent sunburns are related to higher risk of developing melanoma later in life. Little is known about the association of sunburns and shade, particularly tree cover, around adolescent homes and schools. This linkage study assessed associations of adolescent self-reported sunburns with ambient ultraviolet radiation (UV) and tree cover. Methods We analyzed a U.S. national sample of parent–child dyads (n = 1333) from the 2014 Family Life, Activity, Sun, Health, and Eating (FLASHE) study conducted by the National Cancer Institute. The outcome was adolescent sunburns reported for the previous 12 months. GIS buffers around geocoded home and school addresses were used to summarize UV and tree cover. A sensitivity analysis assessed different UV measures and tree cover buffer distances. Logistic regression models estimated the adjusted odds of any sunburns for five models: (1) no environmental variables; (2) spatial variables of latitude and longitude; (3) UV; (4) tree cover; and, (5) a combined model with UV and tree cover. Covariates included common sunburn-related items such as sun protective behaviors, socio-demographics, and latitude. Model residuals were assessed for spatial dependency and clustering. Results Overall, 44% of adolescents reported any sunburns in the previous 12 months. For the bivariate associations, lower categories of UV were associated with any reported sunburns ( p-trend  = 0.002). Home tree cover was not associated with any reported sunburns ( p-trend  = 0.08), whereas schools with lower categories of tree cover were associated with sunburns ( p-trend  = 0.008). The adjusted odds of any sunburns by UV tertiles, as a linear tread, was 0.89 (0.76–1.05) ( p  = 0.17); school tree cover was: 0.91 (0.78–1.07) ( p  = 0.25). Neither UV nor tree cover, in a combined model, were significant. Sensitivity analyses resulted in the optimal buffer size of 200 m for summarizing tree cover. Spatial dependence of residuals was not significant and clustering was significant for about 6% or less of the sample in each model. Conclusions We did not find significant relationships between UV or tree cover and adolescent sunburns, when adjusted by sunburn-related covariates. Better contextual data about where sunburns occurred is needed to identify environmental correlates of sunburn.