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Ultrafast stimuli can stabilize metastable states of matter inaccessible by equilibrium means. Establishing the spatiotemporal link between ultrafast excitation and metastability is crucial to understand these phenomena. Here we utilize single-shot optical pump–X-ray probe measurements to capture snapshots of the emergence of a persistent polar vortex supercrystal in a heterostructure that hosts a fine balance between built-in electrostatic and elastic frustrations by design. By perturbing this balance with photoinduced charges, an initially heterogeneous mixture of polar phase disorders within a few picoseconds, leading to a state composed of disordered ferroelectric and suppressed vortex orders. On the picosecond–nanosecond timescales, transient labyrinthine fluctuations develop, accompanied by the recovery of the vortex order. On longer timescales, these fluctuations are progressively quenched by dynamical strain modulations, which drive the collective emergence of a single vortex supercrystal phase. Our results, corroborated by dynamical phase-field modelling, reveal non-equilibrium pathways following the ultrafast excitation of designer systems to persistent metastability.

Manipulating the polarization of light at the nanoscale is key to the development of next-generation optoelectronic devices. This is typically done via waveplates using optically anisotropic crystals, with thicknesses on the order of the wavelength. Here, using a novel ultrafast electron-beam-based technique sensitive to transient near fields at THz frequencies, we observe a giant anisotropy in the linear optical response in the semimetal WTe2and demonstrate that one can tune the THz polarization using a 50 nm thick film, acting as a broadband wave plate with thickness 3 orders of magnitude smaller than the wavelength. The observed circular deflections of the electron beam are consistent with simulations tracking the trajectory of the electron beam in the near field of the THz pulse. This finding offers a promising approach to enable atomically thin THz polarization control using anisotropic semimetals and defines new approaches for characterizing THz near-field optical response at far-subwavelength length scales.

Identifying multiple rival reaction products and transient species formed during ultrafast photochemical reactions and determining their time-evolving relative populations are key steps toward understanding and predicting photochemical outcomes. Yet, most contemporary ultrafast studies struggle with clearly identifying and quantifying competing molecular structures/species among the emerging reaction products. Here, we show that mega-electronvolt ultrafast electron diffraction in combination with ab initiomolecular dynamics calculations offer a powerful route to determining time-resolvedpopulations of the various isomeric products formed after UV (266 nm) excitation of the five-membered heterocyclic molecule 2(5H)-thiophenone. This strategy provides experimental validation of the predicted high (∼50%) yield of an episulfide isomer containing a strained three-membered ring within ∼1 ps of photoexcitation and highlights the rapidity of interconversion between the rival highly vibrationally excited photoproducts in their ground electronic state.

Predicting practical rates of transport in condensed phases enables the rational design of materials, devices and processes. This is especially critical to developing low-carbon energy technologies such as rechargeable batteries1–3. For ionic conduction, the collective mechanisms4,5, variation of conductivity with timescales6–8and confinement9,10, and ambiguity in the phononic origin of translation11,12, call for a direct probe of the fundamental steps of ionic diffusion: ion hops. However, such hops are rare-event large-amplitude translations, and are challenging to excite and detect. Here we use single-cycle terahertz pumps to impulsively trigger ionic hopping in battery solid electrolytes. This is visualized by an induced transient birefringence, enabling direct probing of anisotropy in ionic hopping on the picosecond timescale. The relaxation of the transient signal measures the decay of orientational memory, and the production of entropy in diffusion. We extend experimental results using in silico transient birefringence to identify vibrational attempt frequencies for ion hopping. Using nonlinear optical methods, we probe ion transport at its fastest limit, distinguish correlated conduction mechanisms from a true random walk at the atomic scale, and demonstrate the connection between activated transport and the thermodynamics of information.

Intense attosecond X-ray pulses are key for ultrafast nonlinear spectroscopy and diffractive imaging. Here we demonstrate the generation of terawatt-scale isolated attosecond pulses with a two-stage cascaded X-ray free-electron laser. These pulses have a median energy in excess of 100 μJ in the soft X-ray region. The temporal profile is characterized with an angular streaking measurement, revealing a maximum peak power of 1.1 TW. Our data show an increase in the average peak power of attosecond X-ray pulses by one order of magnitude over previous reported results and provide strong evidence of soliton-like superradiant behaviour in the X-ray regime.

We present a toolchain for solving path planning problems for concentric tube robots through obstacle fields. First, ellipsoidal sets representing the target area and obstacles are constructed from labelled point clouds. Then, the nonlinear and highly nonconvex optimal control problem is solved by introducing a homotopy on the obstacle positions where at one extreme of the parameter the obstacles are removed from the operating space, and at the other extreme they are located at their intended positions. We present a detailed example (with more than a thousand obstacles) from stereotactic neurosurgery with real-world data obtained from labelled MRI scans.

This contribution deals with multi-objective model-predictive control (MPC) of a wave energy converter (WEC) device concept, which can harvest energy from sea waves using a dielectric elastomer generator (DEG) power take-off system. We aim to maximise the extracted energy through control while minimising the accumulated damage to the DEG. With reference to system operation in stochastic waves, we first generate ground truth solutions by solving an optimal control problem, comparing it to the performance of MPC to determine a prediction horizon that trades off accuracy and efficiency for computation. Fixed weights in the MPC scheme can produce unpredictable costs for variable sea conditions, meaning the average rate of cost accumulation can vary vastly. To steer this cost growth, we propose a heuristic to adapt the algorithm by changing the weighting of the cost functions for fulfilling the long-time goal of accumulating a small enough damage in a fixed time. A simulated case-study is presented in order to evaluate the performance of the proposed MPC framework and the weight-adaptation algorithm. The proposed heuristic proves to be able to limit the amount of accumulated damage while improving the energy yield obtained with a comparable fixed-weight MPC.

To develop tools to investigate the biological functions of butyrylcholinesterase (BChE) and the mechanisms by which BChE affects Alzheimer’s disease (AD), we synthesized several selective, nanomolar active, pseudoirreversible photoswitchable BChE inhibitors. The compounds were able to specifically influence different kinetic parameters of the inhibition process by light. For one compound, a 10-fold difference in the IC50-values (44.6 nM cis, 424 nM trans) in vitrowas translated to an “all or nothing” response with complete recovery in a murine cognition-deficit AD model at dosages as low as 0.3 mg/kg.

In this paper, we model the multi-objective optimisation problem for maximising the energetic performance while minimising the damage accumulation in ocean wave energy converters based on dielectric elastomer generators (DEGs). DEGs are electrostatic smart-material-based transducers that are cheaper, lighter, and more adaptable to the marine environment than conventional power take-off systems. Because DEGs are prone to electrical breakdown upon cyclic loading, identifying trade-offs between achievable performance and lifetime is currently a crucial research question. Based on some assumptions on the system layout and material properties, and using the methods of Pareto optimisation, we prove that a suitably chosen control strategy can potentially achievez a dramatic reduction in the accumulated damage at the expense of a small reduction in the harvested energy. We further compare the Pareto optimal control solutions with commonly used control heuristics for DEGs, showing that optimal control can provide a reduction in the accumulated damage while preserving (or even improving) the energy performance.

In this paper, we propose a path-planning problem for stereotactic neurosurgery using concentric tube robots. The main goal is to reach a given region of interest inside the brain, e.g. a tumor, starting from a feasible point on the skull with an ideally short path avoiding certain sensitive brain areas. To describe the shape of the entire cannula from an entry point to the point of interest we use an existing mechanical model for continuum robots. We show numerically that our approach enables the surgeon to reach areas within the brain that would be impossible with a straight cannula as it is currently state of the art.

The application of Pareto optimization in control engineering requires decision-making as a downstream step since one solution has to be selected from the set of computed Pareto optimal points. Economic Model Predictive Control (MPC) requires repeated optimization and, in multi-objective optimization problems, selection of Pareto optimal points at every time step. Thus, designing an automated selection strategy is favorable. However, it is challenging to come up with a measure – possibly based on a Pareto front analysis – that characterizes preferred Pareto optimal points uniformly across different Pareto fronts. In this work, we first discuss these difficulties for application within MPC and then suggest a solution based on unsupervised machine learning methods. The approach is based on categorizing Pareto fronts as an intermediate step. This allows generating an individual set of rules for every category. Thereby, the human decision-maker's preferences can be modeled more accurately and the selection of a Pareto optimal solution becomes less time-consuming while breaking down the decision-making process into a selection solely based on the Pareto front's shape. Here, the measures act as anchor points for the decision rules. Lastly, a novel knee point measure, i.e. an approximation of the Pareto front's curvature, is presented and used for a knee point-focused categorization. The proposed algorithm is successfully applied to a case study for an energy management system. Moreover, we compare our method to using singular measures for decision-making in order to show its higher flexibility leading to better performance of the controller.

Neurodegenerative disorders are among the most common diseases in modern society. However, the molecular bases of diseases such as multiple sclerosis or Charcot–Marie–Tooth disease remain far from being fully understood. Research in this field is limited by the complex nature of native myelin and by difficulties in obtaining good in vitro model systems of myelin. Here, we introduce an easy-to-use model system of the myelin sheath that can be used to study myelin proteins in a native-like yet well-controlled environment. To this end, we present myelin-mimicking nanodiscs prepared through one of the amphiphilic copolymers styrene/maleic acid (SMA), diisobutylene/maleic acid (DIBMA), and styrene/maleimide sulfobetaine (SMA-SB). These nanodiscs were tested for their lipid composition using chromatographic (HPLC) and mass spectrometric (MS) methods and, utilizing spin probes within the nanodisc, their comparability with liposomes was studied. In addition, their binding behavior with bovine myelin basic protein (MBP) was scrutinized to ensure that the nanodiscs represent a suitable model system of myelin. Our results suggest that both SMA and SMA-SB are able to solubilize the myelin-like (cytoplasmic) liposomes without preferences for specific lipid headgroups or fatty acyl chains. In nanodiscs of both SMA and SMA-SB (called SMA(-SB)-lipid particles, short SMALPs or SMA-SBLPs, respectively), the polymers restrict the lipids’ motion in the hydrophobic center of the bilayer. The headgroups of the lipids, however, are sterically less hindered in nanodiscs when compared with liposomes. Myelin-like SMALPs are able to bind bovine MBP, which can stack the lipid bilayers like in native myelin, showing the usability of these simple, well-controlled systems in further studies of protein–lipid interactions of native myelin.

The collective dynamics of topological structures1–6are of interest from both fundamental and applied perspectives. For example, studies of dynamical properties of magnetic vortices and skyrmions3,4have not only deepened our understanding of many-body physics but also offered potential applications in data processing and storage7. Topological structures constructed from electrical polarization, rather than electron spin, have recently been realized in ferroelectric superlattices5,6, and these are promising for ultrafast electric-field control of topological orders. However, little is known about the dynamics underlying the functionality of such complex extended nanostructures. Here, using terahertz-field excitation and femtosecond X-ray diffraction measurements, we observe ultrafast collective polarization dynamics that are unique to polar vortices, with orders-of-magnitude higher frequencies and smaller lateral size than those of experimentally realized magnetic vortices3. A previously unseen tunable mode, hereafter referred to as a vortexon, emerges in the form of transient arrays of nanoscale circular patterns of atomic displacements, which reverse their vorticity on picosecond timescales. Its frequency is considerably reduced (softened) at a critical strain, indicating a condensation (freezing) of structural dynamics. We use first-principles-based atomistic calculations and phase-field modelling to reveal the microscopic atomic arrangements and corroborate the frequencies of the vortex modes. The discovery of subterahertz collective dynamics in polar vortices opens opportunities for electric-field-driven data processing in topological structures with ultrahigh speed and density.

The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10bas a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu2+chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aβ25−35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.

In this study, we characterized monolayers of an azide-modified lipid at the air–water interface, pure and in its mixtures with the model lipid DPPC, with the aim of proving its potential to be applied for photo-cross-linking with other molecules. We chose a phospholipid bearing a terminal azide group in one of its hydrophobic tails to study its monolayer characteristics with the Langmuir film balance technique. Furthermore, we performed infrared reflection absorption spectroscopy (IRRAS) to get detailed insights into the organization of those monolayers as well as high-resolution mass spectrometry (HRMS) to see the effects of UV-irradiation on the lipids’ chemical structure and organization. Our results suggest that in expanded monolayers of pure azide-modified membrane lipids, the azido-terminated chain folds back toward the air–water interface. Above the LE/LC (liquid-expanded/liquid-condensed) phase transition, the chains stretched, and thus, the azide group detaches from the interface. From temperature-dependent monolayer compressions, we evaluated all relevant thermodynamic parameters of the monolayers, such as the phase transition pressure, the critical temperature, and the triple point, and compare them to those of model lipids. For future applications, we studied the miscibility of the azide-modified lipid with DPPC in monolayers and found at least a certain miscibility over all investigated mixing ratios ranging from 10 to 75% of the azidolipid. Finally, we irradiated the azidolipid monolayer with UV light at 305 nm and measured photodissociation of the azide, leading to chemical cross-linking with other lipids, which shows the potential to be used as a cross-linking agent within self-assembled lipid or lipid/protein layers.

The European XFEL is a hard X-ray free-electron laser (FEL) based on a high-electron-energy superconducting linear accelerator. The superconducting technology allows for the acceleration of many electron bunches within one radio-frequency pulse of the accelerating voltage and, in turn, for the generation of a large number of hard X-ray pulses. We report on the performance of the European XFEL accelerator with up to 5,000 electron bunches per second and demonstrating a full energy of 17.5 GeV. Feedback mechanisms enable stabilization of the electron beam delivery at the FEL undulator in space and time. The measured FEL gain curve at 9.3 keV is in good agreement with predictions for saturated FEL radiation. Hard X-ray lasing was achieved between 7 keV and 14 keV with pulse energies of up to 2.0 mJ. Using the high repetition rate, an FEL beam with 6 W average power was created.

Circular DNA is ubiquitous in nature in the form of plasmids, circular DNA viruses, and extrachromosomal circular DNA (eccDNA) in eukaryotes. Sequencing of such molecules is essential to profiling virus distributions, discovering new viruses and understanding the roles of eccDNAs in eukaryotic cells. Circular DNA enrichment sequencing (CIDER-Seq) is a technique to enrich and accurately sequence circular DNA without the need for polymerase chain reaction amplification, cloning, and computational sequence assembly. The approach is based on randomly primed circular DNA amplification, which is followed by several enzymatic DNA repair steps and then by long-read sequencing. CIDER-Seq includes a custom data analysis package (CIDER-Seq Data Analysis Software 2) that implements the DeConcat algorithm to deconcatenate the long sequencing products of random circular DNA amplification into the intact sequences of the input circular DNA. The CIDER-Seq data analysis package can generate full-length annotated virus genomes, as well as circular DNA sequences of novel viruses. Applications of CIDER-Seq also include profiling of eccDNA molecules such as transposable elements (TEs) from biological samples. The method takes ~2 weeks to complete, depending on the computational resources available. Owing to the present constraints of long-read single-molecule sequencing, the accuracy of circular virus and eccDNA sequences generated by the CIDER-Seq method scales with sequence length, and the greatest accuracy is obtained for molecules <10 kb long.

To investigate the evolutionary diversification and morphological evolution of grass supertribe Poodae (subfam. Pooideae, Poaceae) we conducted a comprehensive molecular phylogenetic analysis including representatives from most of its accepted genera. We focused on generating a DNA sequence dataset of plastid matKgene–3′trnKexon and trnL‐trnFregions and nuclear ribosomal (nr) ITS1–5.8S gene–ITS2 and ETS that was taxonomically overlapping as completely as possible (altogether 257 species). The idea was to infer whether phylogenetic trees or certain clades based on plastid and nrDNA data correspond with each other or discord, revealing signatures of past hybridization. The datasets were analysed separately, in combination, by excluding taxa with discordant placements in the individual gene trees and with duplication of these taxa in a way that each duplicate has only one data partition (plastid or nrDNA). We used maximum likelihood, maximum parsimony and Bayesian approaches. Instances of severe conflicts between the phylogenetic trees derived from both datasets, some of which have been noted earlier, point to hybrid origin of several lineages such as the ABCV clade encompassing several subtribes and subordinate clades, subtribes Airinae, Anthoxanthinae, Antinoriinae, subtr. nov., Aristaveninae, Avenulinae, subtr. nov., Helictochloinae, subtr. nov., Holcinae, Phalaridinae, Scolochloinae, Sesleriinae, Torreyochloinae and genera Arctopoa, Castellia, Graphephorum, Hyalopodium, Lagurus, Macrobriza, Puccinelliaplus Sclerochloa, Sesleria, Tricholemma, Tzveleviochloa, etc. ‘Calamagrostis’ flavensappears to be an intergeneric hybrid between Agrostisand Calamagrostis. Analyses excluding all lineages with demonstrably cytonuclear discordance revealed three supported main clades within Poodae that were present in both the plastid and nrDNA trees. They fully corresponded in their delineation but were phylogenetically differently arranged, pointing to hybrid origin of one of them. We propose to consider these main clades in classification as separate tribes Aveneae, Poeae s.str. and Festuceae with a phylogenetic arrangement of Aveneae(Poeae,Festuceae) in plastid versus Festuceae(Aveneae,Poeae) in nrDNA trees. Phylogenetic incongruence of the plastid and nuclear markers extends across all hierarchical taxonomic levels of Poodae, ranging from species (not studied here) to genera, subtribes and tribes, therefore the deepest taxonomic levels, emphasizing the enormous significance of reticulate evolution in this large group of grasses. A partly revised classification is presented, including the introduction of a new tribe Festuceae and a re‐instatement of tribe Aveneae. Following a comparatively narrow delineation of preferably monophyletic subtribes, Antinoriinae, Avenulinae, Brizochloinae, Helictochloinae and Hypseochloinae are described as new. New genera are Arctohyalopoaand Hyalopodium. New combinations are Anthoxanthum glabrumsubsp. sibiricum, A. nitenssubsp. kolymense, Arctohyalopoa ivanovae, A. jurtzevii, A. lanatiflora, A. momica, Colpodium biebersteinianum, C. kochii, C. pisidicum, C. trichopodum, C. verticillatum, Dupontia fulva, Festuca masafuerana, F. robinsoniana, Graphephorum canescens, G. cernuum, Hyalopodium araraticum, Paracolpodium baltistanicum, Parapholis cylindrica, P. ×pauneroi. Festuca dolichatheraand F. masatierraeare new names.

Geminiviruses cause damaging diseases in several important crop species. However, limited progress has been made in developing crop varieties resistant to these highly diverse DNA viruses. Recently, the bacterial CRISPR/Cas9 system has been transferred to plants to target and confer immunity to geminiviruses. In this study, we use CRISPR-Cas9 interference in the staple food crop cassava with the aim of engineering resistance to African cassava mosaic virus, a member of a widespread and important family (Geminiviridae) of plant-pathogenic DNA viruses. Our results show that the CRISPR system fails to confer effective resistance to the virus during glasshouse inoculations. Further, we find that between 33 and 48% of edited virus genomes evolve a conserved single-nucleotide mutation that confers resistance to CRISPR-Cas9 cleavage. We also find that in the model plant Nicotiana benthamianathe replication of the novel, mutant virus is dependent on the presence of the wild-type virus. Our study highlights the risks associated with CRISPR-Cas9 virus immunity in eukaryotes given that the mutagenic nature of the system generates viral escapes in a short time period. Our in-depth analysis of virus populations also represents a template for future studies analyzing virus escape from anti-viral CRISPR transgenics. This is especially important for informing regulation of such actively mutagenic applications of CRISPR-Cas9 technology in agriculture.

In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for hBChE over human acetycholinesterase (hAChE), yielding short-, medium-, and long-acting nanomolar hBChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer’s disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.

We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of β-amyloid (Aβ), and Aβ self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB1R and hCB2R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer’s mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).

Two-dimensional transition metal dichalcogenides (TMDs) draw strong interest in materials science, with applications in optoelectronics and many other fields. Good performance requires high carrier concentrations and long lifetimes. However, high concentrations accelerate energy exchange between charged particles by Auger-type processes, especially in TMDs where many-body interactions are strong, thus facilitating carrier trapping. We report time-resolved optical pump-THz probe measurements of carrier lifetimes as a function of carrier density. Surprisingly, the lifetime reduction with increased density is very weak. It decreases only by 20% when we increase the pump fluence 100 times. This unexpected feature of the Auger process is rationalized by our time-domain ab initio simulations. The simulations show that phonon-driven trapping competes successfully with the Auger process. On the one hand, trap states are relatively close to band edges, and phonons accommodate efficiently the electronic energy during the trapping. On the other hand, trap states localize around defects, and the overlap of trapped and free carriers is small, decreasing carrier-carrier interactions. At low carrier densities, phonons provide the main charge trapping mechanism, decreasing carrier lifetimes compared to defect-free samples. At high carrier densities, phonons suppress Auger processes and lower the dependence of the trapping rate on carrier density. Our results provide theoretical insights into the diverse roles played by phonons and Auger processes in TMDs, and generate guidelines for defect engineering to improve device performance at high carrier densities.

The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promising targets for pharmacotherapy in the later stages of Alzheimer’s disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted μ-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.

Topological quantum materials exhibit fascinating properties1–3, with important applications for dissipationless electronics and fault-tolerant quantum computers4,5. Manipulating the topological invariants in these materials would allow the development of topological switching applications analogous to switching of transistors6. Lattice strain provides the most natural means of tuning these topological invariants because it directly modifies the electron–ion interactions and potentially alters the underlying crystalline symmetry on which the topological properties depend7–9. However, conventional means of applying strain through heteroepitaxial lattice mismatch10and dislocations11are not extendable to controllable time-varying protocols, which are required in transistors. Integration into a functional device requires the ability to go beyond the robust, topologically protected properties of materials and to manipulate the topology at high speeds. Here we use crystallographic measurements by relativistic electron diffraction to demonstrate that terahertz light pulses can be used to induce terahertz-frequency interlayer shear strain with large strain amplitude in the Weyl semimetal WTe2, leading to a topologically distinct metastable phase. Separate nonlinear optical measurements indicate that this transition is associated with a symmetry change to a centrosymmetric, topologically trivial phase. We further show that such shear strain provides an ultrafast, energy-efficient way of inducing robust, well separated Weyl points or of annihilating all Weyl points of opposite chirality. This work demonstrates possibilities for ultrafast manipulation of the topological properties of solids and for the development of a topological switch operating at terahertz frequencies.

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Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.

Understanding pathways that promote HIV-1 broadly neutralizing antibody (bnAb) induction is crucial to advance bnAb-based vaccines. We recently demarcated host, viral, and disease parameters associated with bnAb development in a large HIV-1 cohort screen. By establishing comprehensive antibody signatures based on IgG1, IgG2, and IgG3 activity to 13 HIV-1 antigens in 4,281 individuals in the same cohort, we now show that the same four parameters that are significantly linked with neutralization breadth, namely viral load, infection length, viral diversity, and ethnicity, also strongly influence HIV-1–binding antibody responses. However, the effects proved selective, shaping binding antibody responses in an antigen and IgG subclass–dependent manner. IgG response landscapes in bnAb inducers indicated a differentially regulated, IgG1-driven HIV-1 antigen response, and IgG1 binding of the BG505 SOSIP trimer proved the best predictor of HIV-1 neutralization breadth in plasma. Our findings emphasize the need to unravel immune modulators that underlie the differentially regulated IgG response in bnAb inducers to guide vaccine development.

Cleavage and (re)formation of oxymethylene moieties are essential steps during the build-up of polyoxymethylene (POM), a technically relevant high-performance polymer. To reveal how the catalyst accomplishes the cleavage of oxymethylene moieties, the kinetics of the ring-opening of trioxane was studied. Thereby insights into the initial phase of the growth of oxymethylene chains were obtained. The chain length of short oligomers was controlled with acetic anhydride as transfer agent. With a high ratio of acetic anhydride to trioxane, the first homologues of the series, trioxymethylene diacetate, dioxymethylene diacetate and monooxymethylene diacetate were obtained in excellent yield. The homologues show distinct features in the NMR and IR spectra that were related to their reactivity during chain propagation. Formation of intermediate hemi-acetal oxonium moieties is suggested to be a key step in the reaction pathway. Such molecular level insight may be a crucial factor for further tailoring production and properties of polyoxymethylene as well as introducing oligomeric oxymethylene diacetates to new application fields.

Broadly neutralizing antibodies (bnAbs) develop in a minority of HIV-infected individuals. Analyzing data from more than 4,000 infected individuals, Alexandra Trkola and colleagues identify viral, host and disease factors associated with the development of bNAbs that may inform future vaccine design.

BI 1002494 [(R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6]napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one] is a novel, potent, and selective spleen tyrosine kinase (SYK) inhibitor with sustained plasma exposure after oral administration in rats, which qualifies this molecule as a good in vitro and in vivo tool compound. BI 1002494 exhibits higher potency in inhibiting high-affinity IgE receptor–mediated mast cell and basophil degranulation (IC50= 115 nM) compared with B-cell receptor–mediated activation of B cells (IC50= 810 nM). This may be explained by lower kinase potency when the physiologic ligand B-cell linker was used, suggesting that SYK inhibitors may exhibit differential potency depending on the cell type and the respective signal transduction ligand. A 3-fold decrease in potency was observed in rat basophils (IC50= 323 nM) compared with human basophils, but a similar species potency shift was not observed in B cells. The lower potency in rat basophils was confirmed in both ex vivo inhibition of bronchoconstriction in precision-cut rat lung slices and in reversal of anaphylaxis-driven airway resistance in rats. The different cellular potencies translated into different in vivo efficacy; full efficacy in a rat ovalbumin model (that contains an element of mast cell dependence) was achieved with a trough plasma concentration of 340 nM, whereas full efficacy in a rat collagen-induced arthritis model (that contains an element of B-cell dependence) was achieved with a trough plasma concentration of 1400 nM. Taken together, these data provide a platform from which different estimates of human efficacious exposures can be made according to the relevant cell type for the indication intended to be treated.

ABSTRACTImmigrants from regions with a high incidence of tuberculosis (TB) are a risk group for TB in low-incidence countries such as Switzerland. In a previous analysis of a nationwide collection of 520 Mycobacterium tuberculosisisolates from 2000 to 2008, we identified 35 clusters comprising 90 patients based on standard genotyping (24-locus mycobacterial interspersed repetitive-unit–variable-number tandem-repeat [MIRU-VNTR] typing and spoligotyping). Here, we used whole-genome sequencing (WGS) to revisit these transmission clusters. Genome-based transmission clusters were defined as isolate pairs separated by =12 single nucleotide polymorphisms (SNPs). WGS confirmed 17/35 (49%) MIRU-VNTR typing clusters; the other 18 clusters contained pairs separated by >12 SNPs. Most transmission clusters (3/4) of Swiss-born patients were confirmed by WGS, as opposed to 25% (4/16) of the clusters involving only foreign-born patients. The overall clustering proportion was 17% (90 patients; 95% confidence interval [CI], 14 to 21%) by standard genotyping but only 8% (43 patients; 95% CI, 6 to 11%) by WGS. The clustering proportion was 17% (67/401; 95% CI, 13 to 21%) by standard genotyping and 7% (26/401; 95% CI, 4 to 9%) by WGS among foreign-born patients and 19% (23/119; 95% CI, 13 to 28%) and 14% (17/119; 95% CI, 9 to 22%), respectively, among Swiss-born patients. Using weighted logistic regression, we found weak evidence of an association between birth origin and transmission (adjusted odds ratio of 2.2 and 95% CI of 0.9 to 5.5 comparing Swiss-born patients to others). In conclusion, standard genotyping overestimated recent TB transmission in Switzerland compared to WGS, particularly among immigrants from regions with a high TB incidence, where genetically closely related strains often predominate. We recommend the use of WGS to identify transmission clusters in settings with a low incidence of TB.

Strong coupling between light and mechanical strain forms the foundation for next-generation optical micro- and nano-electromechanical systems. Such optomechanical responses in two-dimensional materials present novel types of functionalities arising from the weak van der Waals bond between atomic layers. Here, by using structure-sensitive megaelectronvolt ultrafast electron diffraction, we report the experimental observation of optically driven ultrafast in-plane strain in the layered group IV monochalcogenide germanium sulfide (GeS). Surprisingly, the photoinduced structural deformation exhibits strain amplitudes of order 0.1% with a 10 ps fast response time and a significant in-plane anisotropy between zigzag and armchair crystallographic directions. Rather than arising due to heating, experimental and theoretical investigations suggest deformation potentials caused by electronic density redistribution and converse piezoelectric effects generated by photoinduced electric fields are the dominant contributors to the observed dynamic anisotropic strains. Our observations define new avenues for ultrafast optomechanical control and strain engineering within functional devices.

Saxifraga, the most species-rich and taxonomically complex genus of Saxifragaceae, is a characteristic component of temperate to polar climatic zones and of montane to alpine vegetation belts in mountain ranges of the Northern Hemisphere. The genus encompasses more than 440 species, which display notable diversity in growth form, vegetative and reproductive characters, as well as in micromorphology of pollen grains and seeds. Using a large taxon set including representatives attributed to nearly all recognised subgenera, sections and subsections of Saxifraga(altogether 254 species), as well as a broad coverage of outgroup taxa, we inferred evolutionary relationships within Saxifraga, explored the reasons of the striking inconsistencies between previous taxonomic treatments of Saxifraga, estimated the degree of homoplasy in characters frequently employed for classification, assessed the role of hybridisation in the evolution of the genus and, finally, provided a phylogeny-based framework upon which to revise its taxonomy. The phylogenetic trees based on nuclear ribosomal internal transcribed spacer (ITS) and plastid trnL-trnFDNA markers, including more than 460 newly generated sequences, were generally highly congruent, except within a single clade (sect. Saxifraga), in which incomplete lineage sorting and presumably allopolyploid speciation plays an important evolutionary role. Major lineages of Saxifragaare concordantly resolved by the DNA markers from both organelles with mostly strong node support. Our molecular phylogenetic results support the recognition of at least 13 sections and 9 subsections within Saxifraga. A part of these lineages agrees well with previously recognised infrageneric groupings, whereas others are differently delineated. Some of the groups identified by molecular phylogenetics are characterised only by the combination of different morphological characters. Frequently, micromorphological characters support the clades in the phylogenetic tree comparatively well. We here provide new ranks for three infrageneric epithets, namely for sect. Saxifragasubsect. Androsaceaeand subsect. Arachnoideaeand sect. Porphyrionsubsect. Squarrosae. Finally, our study identifies remaining taxonomic uncertainties within Saxifraga.

Catheter ablation is a common treatment option for atrial fibrillation (AF). Interventional C-arm X-ray systems are used for guiding AF procedures, employing standard view positions. Since the projection angles are not adapted to the individual patient anatomy, standard projections do not necessarily offer the best views of important anatomical structures. Using a pre-procedural 3D data set acquired with MRI or CT, suitable ablation sites (lines) can be identified in advance so an ablation plan can be superimposed on fluoroscopic images to guide the procedure. A method was developed to estimate optimized projection views for biplane X-ray C-arm systems based on planning data for AF ablation procedures. The estimated viewing angles were compared to standard angulations using an objective quality metric, the length of the planned ablation line as seen under X-ray. This method was tested using 35 clinical datasets annotated with planned ablation lines for ipsilateral pulmonary vein isolation. The optimized views computed using the new method yielded 28 % less foreshortening of pre-planned ablation lines on average. In one case, anatomy-based view calculation lead to a 69 % reduction in foreshortening. The commonly used standard views provide reasonable a priori choices, and some improvement is possible by switching among common angulations depending on the treatment region. Further gains are possible by using anatomy-optimized biplane C-arm angulations.

Cytomegalovirus (CMV) retinitis is a major cause of visual impairment and blindness among patients with uncontrolled HIV infections. Whereas polymorphisms in interferon-lambda 3 (IFNL3, previously named IL28B) strongly influence the clinical course of hepatitis C, few studies examined the role of such polymorphisms in infections due to viruses other than hepatitis C virus.

As proteins are the main effectors inside cells, their levels need to be tightly regulated. This is partly achieved by specific protein degradation via the Ubiquitin-26S proteasome system (UPS). In plants, an exceptionally high number of proteins are involved in Ubiquitin-26S proteasome system-mediated protein degradation and it is known to regulate most, if not all, important cellular processes. Here, we investigated the response to the inhibition of the proteasome at the protein level treating leaves with the specific inhibitor Syringolin A (SylA) in a daytime specific manner and found 109 accumulated and 140 decreased proteins. The patterns of protein level changes indicate that the accumulating proteins cause proteotoxic stress that triggers various responses. Comparing protein level changes in SylA treated with those in a transgenic line over-expressing a mutated ubiquitin unable to form polyubiquitylated proteins produced little overlap pointing to different response pathways. To distinguish between direct and indirect targets of the UPS we also enriched and identified ubiquitylated proteins after inhibition of the proteasome, revealing a total of 1791 ubiquitylated proteins in leaves and roots and 1209 that were uniquely identified in our study. The comparison of the ubiquitylated proteins with those changing in abundance after SylA-mediated inhibition of the proteasome confirmed the complexity of the response and revealed that some proteins are regulated both at transcriptional and post-transcriptional level. For the ubiquitylated proteins that accumulate in the cytoplasm but are targeted to the plastid or the mitochondrion, we often found peptides in their target sequences, demonstrating that the UPS is involved in controlling organellar protein levels. Attempts to identify the sites of ubiquitylation revealed that the specific properties of this post-translational modification can lead to incorrect peptide spectrum assignments in complex peptide mixtures in which only a small fraction of peptides is expected to carry the ubiquitin footprint. This was confirmed with measurements of synthetically produced peptides and calculating the similarities between the different spectra.

ABSTRACTCo-trimoxazole reduces mortality in HIV-infected adults with tuberculosis (TB), and in vitrodata suggest potential antimycobacterial activity of co-trimoxazole. We aimed to evaluate whether prophylaxis with co-trimoxazole is associated with a decreased risk of incident TB in Swiss HIV Cohort Study (SHCS) participants. We determined the incidence of TB per 1,000 person-years from January 1992 to December 2012. Rates were analyzed separately in participants with current or no previous antiretroviral treatment (ART) using Poisson regression adjusted for CD4 cell count, sex, region of origin, injection drug use, and age. A total of 13,431 cohort participants contributed 107,549 person-years of follow-up: 182 patients had incident TB—132 (73%) before and 50 (27%) after ART initiation. The multivariable incidence rate ratios for cumulative co-trimoxazole exposure per year for persons with no previous ART and current ART were 0.70 (95% confidence interval [CI], 0.55 to 0.89) and 0.87 (95% CI, 0.74 to 1.0), respectively. Co-trimoxazole may prevent the development of TB among HIV-positive persons, especially among those with no previous ART.

The neural cell adhesion molecule (NCAM) is a member of the immunoglobulin superfamily and involved in the development and regeneration of the nervous system. NCAM is expressed in three major isoforms. Two of them have large intracellular domains of different lengths and are named according to their apparent molecular weight as NCAM140 or NCAM180. NCAM140 is known to promote neurite outgrowth, whereas NCAM180 stabilizes cell–cell contacts. Beside its role in neurite outgrowth, NCAM also shows ATPase activity on its extracellular domain. Here, we quantified neurite outgrowth of neuroblastoma cells, which were transfected with either NCAM140 or NCAM180 in the absence or presence of ATP. We could confirm that NCAM140 strongly promotes neurite outgrowth, whereas NCAM180 stimulates neurite outgrowth only to a minor extent. Furthermore, application of ATP reduced the NCAM-induced neurite outgrowth to background levels in a concentration-dependent and isoform-dependent manner.

ABSTRACTProsthetic valve endocarditis (PVE) due to fast-growing nontuberculous mycobacteria (NTM) has been reported anecdotally. Reports of PVE with slowly growing NTM, however, are lacking. We present here one case of PVE and one case of bloodstream infection caused by Mycobacterium chimaera. Randomly amplified polymorphic DNA (RAPD)-PCR indicated a relatedness of the two M. chimaerastrains. Both patients had heart surgery 2 years apart from each other. A nosocomial link was not detected.

Recently, subcutaneous implantable cardioverter-defibrillator (S-ICD) has become available. The aim of our study was to assess the efficacy of S-ICD in a clinical setting.

We report on nonlinear propagation of single-cycle THz pulses with peak electric fields reaching 300 kV/cm in n-type semiconductors at room temperature. Dramatic THz saturable absorption effects are observed in GaAs, GaP, and Ge, which are caused by the nonlinear electron transport in THz fields. The semiconductor conductivity, and hence the THz absorption, is modulated due to the acceleration of carriers in strong THz fields, leading to an increase of the effective mass of the electron population, as the electrons are redistributed from the low-momentum, low-effective-mass states to the high-momentum, high-effective-mass states in the energy-momentum space of the conduction band. Further, we observe the typical accompanying effects of saturable absorption on the THz pulses, such as an increase of the group delay, as the peak electric field of the pulse increases. In this paper we present the results of nonlinear THz time-domain spectroscopy, and of THz pump - THz probe spectroscopy.

AbstractIn this article Weber’s famous theory concerning “The Protestant Ethic and the Spirit of Capitalism” is taken as a theory of civilization. It is shown that in his analysis of ascetic Puritanism, and also of the Calvinistic doctrine of predestination, Weber comes to depict the principle of self-control as the main feature of the Puritan which makes him “the father of modern self-discipline”. Self-discipline in turn is the principal ability of modern man in Norbert Elias’ theory of civilization. But all these categories that Elias uses to describe the status of being civilized – self-control, control of emotion, methodical moderation of spontaneity, punctuality etc. – already appear in the work of Max Weber in his attempt to explain the religious genesis of such attitudes.