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Notch proteins are ligand-activated transmembrane receptors involved in cell-fate selection throughout development 1 , 2 , 3 . No known enzymatic activity is contained within Notch and the molecular mechanism by which it transduces signals across the cell membrane is poorly understood. In many instances, Notch activation results in transcriptional changes in the nucleus through an association with members of the CSL family of DNA-binding proteins (where CSL stands for CBF1, Su(H), Lag-1) 1 , 2 , 3 , 4 . As Notch is located in the plasma membrane and CSL is a nuclear protein, two models have been proposed to explain how they interact ( Fig. 1 ) . The first suggests that the two interact transiently at the membrane 1 , 5 , 6 , 7 . The second postulates that Notch is cleaved by a protease, enabling the cleaved fragment to enter the nucleus 6 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . Here we show that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL. Very small amounts of NICD are active, explaining why it is hard to detect in the nucleus in vivo . We also show that it is ligand binding that induces release of NICD. Figure 1 Different predictions are made by two models of Notch signalling. a , Models not invoking processing propose that interactions between Notch and CSL at the membrane may be sufficient to transduce a signal. Thus, ligand-regulated NICD release is not expected to be necessary for signalling. b , The processing model suggests that Notch signalling requires the release of NICD, which is capable of direct interaction with CSL in the nucleus, to turn on transcription of target genes. This model predicts that NICD release is regulated by ligand binding and that blocking proteolysis interferes with signalling. Notch-1 domain symbols as in Fig. 2 .

Nowadays, Quality Management tools such as failure mode and effect analysis (FMEA) are widely used throughout the aeronautical, automotive, software, food services, health care and many other industries to sustain and improve quality and safety. The increasing complexity of scientific research makes it more difficult to maintain all activities under control, in order to guarantee validity and reproducibility of results. Even in non-regulated research, scientists need to be supported with management tools that maximize study performance and outcomes, while facilitating the research process. Frequently, steps that involve human intervention are the weak links in the process. Risk analysis therefore gives considerable benefit to analytical validation, assessing and avoiding failures due to human error, potential imprecision in applying protocols, uncertainty in equipment function and imperfect control of materials. This paper describes in detail how FMEA methodology can be applied as a performance improvement tool in the field of non-regulated research, specifically on a basic Life Sciences research process. We chose as “pilot process” the selection of oligonucleotide aptamers for therapeutic purposes, as an example of a complex and multi-step process, suitable for technology transfer. We applied FMEA methodology, seeking every opportunity for error and its impact on process output, and then, a set of improvement actions was generated covering most aspects of laboratory practice, such as equipment management and staff training. We also propose a useful tool supporting the risk assessment of research processes and its outputs and that we named “FMEA strip worksheet.” These tools can help scientists working in non-regulated research to approach Quality Management and to perform risk evaluation of key scientific procedures and processes with the final aim to increase and better control efficiency and efficacy of their research.

This work reports the isolation and characterization of a line of human, nontransformed and differentiated prostate epithelial cells (EPN) in continuous culture. Primary cultures of epithelial prostate cells were set up using normal tissue isolated from a prostate sample collected after radical prostatectomy for cancer. After 70 passages, EPN cells did not undergo “Hayflikc crisis” and were free of fibroblast contamination and were thus subcloned and characterized. EPN cells in culture, as prostate epithelial cells in vivo, express high–molecular weight cytokeratin and Pyk2, whereas they do not express desmin. EPN cells are nontransformed because they do not form colonies in semisolid medium and do not form tumors once injected into nude mice. EPN cells express the functional androgen receptor, which can mediate the mitogenic activity of testosterone. Finally, clonal production of the prostate-specific antigen could be detected in EPN cells. The availability of a line of epithelial nontransformed prostate cell in culture will be useful in investigating the complex process regulating normal prostate physiology as well as the development and progression of prostate tumors.

This work reports the isolation and characterization of a line of human, nontransformed and differentiated prostate epithelial cells (EPN) in continuous culture. Primary cultures of epithelial prostate cells were set up using normal tissue isolated from a prostate sample collected after radical prostatectomy for cancer. After 70 passages, EPN cells did not undergo 'Hayflikc crisis' and were free of fibroblast contamination and were thus subcloned and characterized. EPN cells in culture, as prostate epithelial cells in vivo, express high-molecular weight cytokeratin and Pyk2, whereas they do not express desmin. EPN cells are nontransformed because they do not form colonies in semisolid medium and do not form tumors once injected into nude mice. EPN cells express the functional androgen receptor, which can mediate the mitogenic activity of testosterone. Finally, clonal production of the prostate-specific antigen could be detected in EPN cells. The availability of a line of epithelial nontransformed prostate cell in culture will be useful in investigating the complex process regulating normal prostate physiology as well as the development and progression of prostate tumors.

This study used a 125-item mailed survey to investigate clergy burnout. The survey, which consisted of a modified version of the Maslach Burnout Inventory (MBI, 1996), the Big Five Inventory, and additional original scales, collected data concerning the prevalence, vulnerability, and resistance to professional burnout among active Presbyterian clergy (PCUSA) members of six Presbyteries in Southwestern Pennsylvania. The study asked whether personal characteristics of ministers (e.g., personality type, age, gender, religious attitudes, social support, coping habits), or specific types of ministry situations, or a combination of the two, best predict which ministers score high on burnout and other \"unhappiness\" measures such as depression and desire to leave the ministry. The study also tested the hypothesis that role dysfunction concerning or inadequate preparation for pastoral care and counseling explain a significant portion of variability in ministers' burnout levels. Of 320 survey packets mailed out, 114 usable responses were returned. Burnout prevalence among survey respondents was found to be significantly lower than among a national sample of over 11,000 respondents from a variety of different occupations across the United States reported in the MBI manual. Hierarchical regression analysis showed that in comparison to situational factors, ministers' personality factors explained more variability in a composite burnout variable and in additional measures of burnout dimensions. However certain situational factors (congregation size, congregation growth, congregation age, congregation trouble history), and the way certain ministers' personalities fit certain situations, were also significant. Factors related to pastoral care also significantly predicted variance in ministerial burnout scores. In particular, ambiguity in and mismatched expectations of the pastoral role, including boundary issues and overall pastoral workload, were important predictors of burnout variability. This study indicates that further research into personality measures and pastoral role \"fit\" indicators may help clergy, congregations, denominational officials, and mental health professionals find tools to prevent, screen for, and alleviate burnout in professional clergy and clergy candidates.

The high volatility of the price of cobalt and the geopolitical limitations of cobalt mining have made the elimination of Co a pressing need for the automotive industry 1 . Owing to their high energy density and low-cost advantages, high-Ni and low-Co or Co-free (zero-Co) layered cathodes have become the most promising cathodes for next-generation lithium-ion batteries 2 , 3 . However, current high-Ni cathode materials, without exception, suffer severely from their intrinsic thermal and chemo-mechanical instabilities and insufficient cycle life. Here, by using a new compositionally complex (high-entropy) doping strategy, we successfully fabricate a high-Ni, zero-Co layered cathode that has extremely high thermal and cycling stability. Combining X-ray diffraction, transmission electron microscopy and nanotomography, we find that the cathode exhibits nearly zero volumetric change over a wide electrochemical window, resulting in greatly reduced lattice defects and local strain-induced cracks. In-situ heating experiments reveal that the thermal stability of the new cathode is significantly improved, reaching the level of the ultra-stable NMC-532. Owing to the considerably increased thermal stability and the zero volumetric change, it exhibits greatly improved capacity retention. This work, by resolving the long-standing safety and stability concerns for high-Ni, zero-Co cathode materials, offers a commercially viable cathode for safe, long-life lithium-ion batteries and a universal strategy for suppressing strain and phase transformation in intercalation electrodes. A compositionally complex (high-entropy) doping strategy is proposed to fabricate zero-strain high-Ni and Co-free layered cathodes with superior structural and mechanical stabilities and long cycle life.

The performance of superconducting quantum circuits for quantum computing has advanced tremendously in recent decades; however, a comprehensive understanding of relaxation mechanisms does not yet exist. In this work, we utilize a multimode approach to characterizing energy losses in superconducting quantum circuits, with the goals of predicting device performance and improving coherence through materials, process, and circuit design optimization. Using this approach, we measure significant reductions in surface and bulk dielectric losses by employing a tantalum-based materials platform and annealed sapphire substrates. With this knowledge we predict the relaxation times of aluminum- and tantalum-based transmon qubits, and find that they are consistent with experimental results. We additionally optimize device geometry to maximize coherence within a coaxial tunnel architecture, and realize on-chip quantum memories with single-photon Ramsey times of 2.0 − 2.7 ms, limited by their energy relaxation times of 1.0 − 1.4 ms. These results demonstrate an advancement towards a more modular and compact coaxial circuit architecture for bosonic qubits with reproducibly high coherence. Understanding loss mechanisms in superconducting circuits is crucial for improving qubit coherence. Here the authors use a multimode resonator to study loss mechanisms in thin-film superconducting circuits and demonstrate on-chip quantum memories with lifetimes exceeding 1ms, using Ta thin-films and high-temperature substrate annealing

High-Ni-content layered materials are promising cathodes for next-generation lithium-ion batteries. However, investigating the atomic configurations of the delithiation-induced complex phase boundaries and their transitions remains challenging. Here, by using deep-learning-aided super-resolution electron microscopy, we resolve the intralayer transition motifs at complex phase boundaries in high-Ni cathodes. We reveal that an O3 → O1 transformation driven by delithiation leads to the formation of two types of O1–O3 interface, the continuous- and abrupt-transition interfaces. The interfacial misfit is accommodated by a continuous shear-transition zone and an abrupt structural unit, respectively. Atomic-scale simulations show that uneven in-plane Li+ distribution contributes to the formation of both types of interface, and the abrupt transition is energetically more favourable in a delithiated state where O1 is dominant, or when there is an uneven in-plane Li+ distribution in a delithiated O3 lattice. Moreover, a twin-like motif that introduces structural units analogous to the abrupt-type O1–O3 interface is also uncovered. The structural transition motifs resolved in this study provide further understanding of shear-induced phase transformations and phase boundaries in high-Ni layered cathodes.High-Ni-content layered cathodes are promising for lithium-ion batteries, but investigating their delithiation-induced phase boundaries is challenging. Intralayer transition motifs at complex phase boundaries in these high-Ni electrodes are now resolved using deep-learning-aided super-resolution electron microscopy.

There is an urgent need to develop technologies that use renewable energy to convert waste products such as carbon dioxide into hydrocarbon fuels. Carbon dioxide can be electrochemically reduced to hydrocarbons over copper catalysts, although higher efficiency is required. We have developed oxidized copper catalysts displaying lower overpotentials for carbon dioxide electroreduction and record selectivity towards ethylene (60%) through facile and tunable plasma treatments. Herein we provide insight into the improved performance of these catalysts by combining electrochemical measurements with microscopic and spectroscopic characterization techniques. Operando X-ray absorption spectroscopy and cross-sectional scanning transmission electron microscopy show that copper oxides are surprisingly resistant to reduction and copper + species remain on the surface during the reaction. Our results demonstrate that the roughness of oxide-derived copper catalysts plays only a partial role in determining the catalytic performance, while the presence of copper + is key for lowering the onset potential and enhancing ethylene selectivity. Carbon dioxide electroreduction is a promising route to hydrocarbon synthesis, but more efficient and selective catalysts are needed. Here the authors show that plasma-activated copper can catalyse the reduction of carbon dioxide to ethylene with high efficiency and reveal cationic copper as the active site.

High-nickel content cathode materials offer high energy density. However, the structural and surface instability may cause poor capacity retention and thermal stability of them. To circumvent this problem, nickel concentration-gradient materials have been developed to enhance high-nickel content cathode materials’ thermal and cycling stability. Even though promising, the fundamental mechanism of the nickel concentration gradient’s stabilization effect remains elusive because it is inseparable from nickel’s valence gradient effect. To isolate nickel’s valence gradient effect and understand its fundamental stabilization mechanism, we design and synthesize a LiNi 0.8 Mn 0.1 Co 0.1 O 2 material that is compositionally uniform and has a hierarchical valence gradient. The nickel valence gradient material shows superior cycling and thermal stability than the conventional one. The result suggests creating an oxidation state gradient that hides the more capacitive but less stable Ni 3+ away from the secondary particle surfaces is a viable principle towards the optimization of high-nickel content cathode materials. High-nickel content cathode materials suffer issues of structural and surface instability. Herewith authors show that introduction of a nickel valence gradient enhances the thermal and cycle stability of high-nickel content cathode materials.