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Follow the curve Cell membranes are far more than mere outer envelopes: remodelling of their topology is linked to vital tasks such as endocytosis, vesicle formation and protein sorting. Specialized proteins can sense and create membrane curvature, and direct membrane remodelling. Several proteins need to act together to accomplish this task, so a more generic, universal effect is thought to be at work as well. For years physicists, mathematicians, materials scientists and cell biologists have studied a possible universal effect — attraction between proteins that is induced solely by membrane curvature. But the nature of membrane-curvature-induced interactions between proteins, and even the question of whether they are attractive or repulsive, remained obscure. Now computer simulations reveal that curvature-induced interactions can indeed be attractive, strong, and robust. Well up to the task of effecting membrane remodelling. On the cover, a virtual membrane covered with capsids during cooperative budding. Specialized proteins can sense and create membrane curvature, and direct membrane remodelling, linked to important cellular tasks such as endocytosis and protein sorting; but whether such proteins might be assisted by more generic, universal effects has been unclear. One of the most sophisticated simulation tools available for the task has now been used to confirm that that is indeed the case; membrane curvature caused by simple protein adsorption can drive clustering of proteins lacking any specific interactions, and even induce local membrane transformation into vesicles. Membrane remodelling 1 , 2 , 3 , 4 , 5 plays an important role in cellular tasks such as endocytosis, vesiculation and protein sorting, and in the biogenesis of organelles such as the endoplasmic reticulum or the Golgi apparatus. It is well established that the remodelling process is aided by specialized proteins that can sense 4 as well as create 6 membrane curvature, and trigger tubulation 7 , 8 , 9 when added to synthetic liposomes. Because the energy needed for such large-scale changes in membrane geometry significantly exceeds the binding energy between individual proteins and between protein and membrane, cooperative action is essential. It has recently been suggested 10 , 11 that curvature-mediated attractive interactions could aid cooperation and complement the effects of specific binding events on membrane remodelling. But it is difficult to experimentally isolate curvature-mediated interactions from direct attractions between proteins. Moreover, approximate theories predict repulsion between isotropically curving proteins 12 , 13 , 14 , 15 . Here we use coarse-grained membrane simulations to show that curvature-inducing model proteins adsorbed on lipid bilayer membranes can experience attractive interactions that arise purely as a result of membrane curvature. We find that once a minimal local bending is realized, the effect robustly drives protein cluster formation and subsequent transformation into vesicles with radii that correlate with the local curvature imprint. Owing to its universal nature, curvature-mediated attraction can operate even between proteins lacking any specific interactions, such as newly synthesized and still immature membrane proteins in the endoplasmic reticulum.

Spatial navigation research in humans increasingly relies on experiments using virtual reality (VR) tools, which allow for the creation of highly flexible, and immersive study environments, that can react to participant interaction in real time. Despite the popularity of VR, tools simplifying the creation and data management of such experiments are rare and often restricted to a specific scope—limiting usability and comparability. To overcome those limitations, we introduce the Virtual Navigation Toolbox (VNT), a collection of interchangeable and independent tools for the development of spatial navigation VR experiments using the popular Unity game engine. The VNT’s features are packaged in loosely coupled and reusable modules, facilitating convenient implementation of diverse experimental designs. Here, we depict how the VNT fulfils feature requirements of different VR environments and experiments, guiding through the implementation and execution of a showcase study using the toolbox. The presented showcase study reveals that homing performance in a classic triangle completion task is invariant to translation velocity of the participant’s avatar, but highly sensitive to the number of landmarks. The VNT is freely available under a creative commons license, and we invite researchers to contribute, extending and improving tools using the provided repository.

The two licensed bivalent and quadrivalent human papillomavirus (HPV) L1 (the major papillomavirus virion protein) virus-like particle (VLP) vaccines are regarded as safe, effective, and well established prophylactic vaccines. However, they have some inherent limitations, including a fairly high production and delivery cost, virus-type restricted protection, and no reported therapeutic activity, which might be addressed with the development of alternative dosing schedules and vaccine products. A change from a three-dose to a two-dose protocol for the licensed HPV vaccines, especially in younger adolescents (aged 9–13 years), is underway in several countries and is likely to become the future norm. Preliminary evidence suggests that recipients of HPV vaccines might derive prophylactic benefits from one dose of the bivalent vaccine. Substantial interest exists in both the academic and industrial sectors in the development of second-generation L1 VLP vaccines in terms of cost reduction—eg, by production in Escherichia coli or alternative types of yeast. However, Merck's nonavalent vaccine, produced via the Saccharomyces cerevisiae production system that is also used for their quadrivalent vaccine, is the first second-generation HPV VLP vaccine to be available on the market. By contrast, other pharmaceutical companies are developing microbial vectors that deliver L1 genes. These two approaches would add an HPV component to existing live attenuated vaccines for measles and typhoid fever. Prophylactic vaccines that are based on induction of broadly cross-neutralising antibodies to L2, the minor HPV capsid protein, are also being developed both as simple monomeric fusion proteins and as virus-like display vaccines. The strong interest in developing the next generation of vaccines, particularly by manufacturers in middle-to-high income countries, increases the likelihood that vaccine production will become decentralised with the hope that effective HPV vaccines will be made increasingly available in low-resource settings where they are most needed.

The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.

The deposition and nanostructure of polyelectrolyte (PEL) multilayers (PEMs) of branched poly(ethyleneimine)/poly(acrylic acid) (PEI/PAA) onto silicon substrates was studied in terms of the dependence of pH and the PEL concentration (cPEL) in the individual adsorption steps z. Both a commercial automatic dipping device and a homebuilt automatic stream coating device (flow cell) were used. Gravimetry, SFM, transmission (TRANS) and in situ attenuated total reflection (ATR) FTIR spectroscopy were used for the quantitative determination of the adsorbed amount, thickness, chemical composition and morphology of deposited PEMs, respectively. Firstly, the combination of pH = 10 for PEI and pH = 4 for PAA, where both PEL were predominantly in the neutral state, resulted in an extraordinarily high PEM deposition, while pH combinations, where one PEL component was charged, resulted in a significantly lower PEM deposition. This was attributed to both PEL conformation effects and acid/base interactions between basic PEI and acidic PAA. Secondly, for that pH combination an exponential relationship between PEM thickness and adsorption step z was found. Thirdly, based on the results of three independent methods, the course of the deposited amount of a PEM-10 (z = 10) versus cPEL in the range 0.001 to 0.015 M at pH = 10/4 was non-monotonous showing a pronounced maximum at cPEL = 0.005 M. Analogously, for cPEL = 0.005 M a maximum of roughness and structure size was found. Fourthly, related to that finding, in situ ATR-FTIR measurements gave evidence for the release of outermost located PEI upon PAA immersion (even step) and of outermost PAA upon PEI immersion (odd step) under formation of PEL complexes in solution. These studies help us to prepare PEL-based films with a defined thickness and morphology for interaction with biofluids in the biomedical and food fields.

ObjectivesCommunication breakdown is one of the main causes of adverse events in clinical routine, particularly in handover situations. The communication tool SBAR (situation, background, assessment and recommendation) was developed to increase handover quality and is widely assumed to increase patient safety. The objective of this review is to summarise the impact of the implementation of SBAR on patient safety.DesignA systematic review of articles published on SBAR was performed in PUBMED, EMBASE, CINAHL, Cochrane Library and PsycINFO in January 2017. All original research articles on SBAR fulfilling the following eligibility criteria were included: (1) SBAR was implemented into clinical routine, (2) the investigation of SBAR was the primary objective and (3) at least one patient outcome was reported.SettingA wide range of settings within primary and secondary care and nursing homes.ParticipantsA variety of heath professionals including nurses and physicians.Primary and secondary outcome measuresAspects of patient safety (patient outcomes) defined as the occurrence or incidence of adverse events.ResultsEight studies with a before–after design and three controlled clinical trials performed in different clinical settings met the inclusion criteria. The objectives of the studies were to improve team communication, patient hand-offs and communication in telephone calls from nurses to physicians. The studies were heterogeneous with regard to study characteristics, especially patient outcomes. In total, 26 different patient outcomes were measured, of which eight were reported to be significantly improved. Eleven were described as improved but no further statistical tests were reported, and six outcomes did not change significantly. Only one study reported a descriptive reduction in patient outcomes.ConclusionsThis review found moderate evidence for improved patient safety through SBAR implementation, especially when used to structure communication over the phone. However, there is a lack of high-quality research on this widely used communication tool.Trial registrationnone

Very‐low‐carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno‐nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T‐cell responses. CD4 + , CD8 + , and regulatory T‐cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very‐low‐carbohydrate diet as a clinical tool to improve human T‐cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required. SYNOPSIS Ketogenic diet (KD) is characterized by a very limited uptake of carbohydrates, resulting in endogenous production of ketone bodies. This study identifies KD as a potent nutritional immunometabolic intervention to reprogram human T cell immunometabolism, favouring mitochondrial oxidative phosphorylation, thus enhancing both effector and regulatory T cell immune capacity and priming human T cells towards memory cell formation. KD augmented human CD4 + and CD8 + T cell cytokine production and cell lysis capacity in vitro and in vivo . Additionally, KD also enhanced regulatory T cell abundance and function, and primed human T cells to memory cell formation. In response to KD, increased mitochondrial mass, ETC complex formation, aerobic oxidative phosphorylation capacity and ‐tightly controlled‐ ROS production was identified in human T cells. Transcriptomic analysis revealed fundamental immunometabolic reprogramming of human CD4 + and CD8 + T cells after 3 weeks of KD. Both, elevated bioenergetic capacity and ROS ‐serving as T‐cell second messenger molecules‐ provide the immunometabolic basis for enhanced T cell immunity on a KD. Graphical Abstract Ketogenic diet (KD) is characterized by a very limited uptake of carbohydrates, resulting in endogenous production of ketone bodies. This study identifies KD as a potent nutritional immunometabolic intervention to reprogram human T cell immunometabolism, favouring mitochondrial oxidative phosphorylation, thus enhancing both effector and regulatory T cell immune capacity and priming human T cells towards memory cell formation.

Automated, reliable, and objective microstructure inference from micrographs is essential for a comprehensive understanding of process-microstructure-property relations and tailored materials development. However, such inference, with the increasing complexity of microstructures, requires advanced segmentation methodologies. While deep learning offers new opportunities, an intuition about the required data quality/quantity and a methodological guideline for microstructure quantification is still missing. This, along with deep learning’s seemingly intransparent decision-making process, hampers its breakthrough in this field. We apply a multidisciplinary deep learning approach, devoting equal attention to specimen preparation and imaging, and train distinct U-Net architectures with 30–50 micrographs of different imaging modalities and electron backscatter diffraction-informed annotations. On the challenging task of lath-bainite segmentation in complex-phase steel, we achieve accuracies of 90% rivaling expert segmentations. Further, we discuss the impact of image context, pre-training with domain-extrinsic data, and data augmentation. Network visualization techniques demonstrate plausible model decisions based on grain boundary morphology. Segmentation and classification of microstructures are required by quality control and materials development. The authors apply deep learning for the segmentation of complex phase steel microstructures, providing a bridge between experimental and computational methods for materials analysis.

Museums, theaters, and other cultural organizations can be important actors in the sustainability transition, enjoying high visibility and public trust. Yet, we know little about their performance with respect to key sustainability indicators. This study develops a sector-specific sustainability benchmark and applies it in a survey of 206 leading cultural institutions worldwide and 21 semi-structured interviews. The results show that, for the majority of organizations, sustainability did not appear as a management issue until approximately five years ago. Moreover, sustainability commitments do not translate consistently into action. More than half of the organizations obtain poor sustainability scores of below 30 (out of 100) on both the environmental and the social dimension. The presence of a green team and government regulation are associated with higher sustainability scores. Our findings suggest the need for a concerted approach to sustainability in the cultural sector, including a common standard, regular monitoring (for example using this benchmark), and incentivized funding.

Plants adjust their energy metabolism to continuous environmental fluctuations, resulting in a tremendous plasticity in their architecture. The regulatory circuits involved, however, remain largely unresolved. In Arabidopsis, moderate perturbations in photosynthetic activity, administered by short-term low light exposure or unexpected darkness, lead to increased lateral root (LR) initiation. Consistent with expression of low-energy markers, these treatments alter energy homeostasis and reduce sugar availability in roots. Here, we demonstrate that the LR response requires the metabolic stress sensor kinase Snf1-RELATED-KINASE1 (SnRK1), which phosphorylates the transcription factor BASIC LEUCINE ZIPPER63 (bZIP63) that directly binds and activates the promoter of AUXIN RESPONSE FACTOR19 (ARF19), a key regulator of LR initiation. Consistently, starvation-induced ARF19 transcription is impaired in bzip63 mutants. This study highlights a positive developmental function of SnRK1. During energy limitation, LRs are initiated and primed for outgrowth upon recovery. Hence, this study provides mechanistic insights into how energy shapes the agronomically important root system.