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Abstract The idea of using ultrashort X-ray pulses to obtain images of single proteins frozen in time has fascinated and inspired many. It was one of the arguments for building X-ray free-electron lasers. According to theory, the extremely intense pulses provide sufficient signal to dispense with using crystals as an amplifier, and the ultrashort pulse duration permits capturing the diffraction data before the sample inevitably explodes. This was first demonstrated on biological samples a decade ago on the giant mimivirus. Since then, a large collaboration has been pushing the limit of the smallest sample that can be imaged. The ability to capture snapshots on the timescale of atomic vibrations, while keeping the sample at room temperature, may allow probing the entire conformational phase space of macromolecules. Here we show the first observation of an X-ray diffraction pattern from a single protein, that of Escherichia coli GroEL which at 14 nm in diameter is the smallest biological sample ever imaged by X-rays, and demonstrate that the concept of diffraction before destruction extends to single proteins. From the pattern, it is possible to determine the approximate orientation of the protein. Our experiment demonstrates the feasibility of ultrafast imaging of single proteins, opening the way to single-molecule time-resolved studies on the femtosecond timescale.

Summary: Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-receptor-binding motif (RBM). We tested 717 longitudinal samples from 295 COVID-19 patients and showed a 2- to 10-fold increase of enzymatically active sACE2 (a-sACE2), with up to 1 μg/mL total sACE2 in moderate and severe patients. Fifty percent of COVID-19 sera inhibited ACE2 activity, in contrast to 1.3% of healthy donors and 4% of non-COVID-19 pneumonia patients. A mild inverse correlation of a-sACE2 with RBM-directed serum antibodies was observed. In silico, we show that sACE2 concentrations measured in COVID-19 sera can disrupt germinal center formation and inhibit timely production of high-affinity antibodies. We suggest that sACE2 is a biomarker for COVID-19 and that soluble receptors may contribute to immune suppression informing vaccine design.

Abstract Understanding the interaction of intense, femtosecond X-ray pulses with heavy atoms is crucial for gaining insights into the structure and dynamics of matter. One key aspect of nonlinear light–matter interaction was, so far, not studied systematically at free-electron lasers—its dependence on the photon energy. Here, we use resonant ion spectroscopy to map out the transient electronic structures occurring during the complex charge-up pathways of xenon. Massively hollow atoms featuring up to six simultaneous core holes determine the spectra at specific photon energies and charge states. We also illustrate how different X-ray pulse parameters, which are usually intertwined, can be partially disentangled. The extraction of resonance spectra is facilitated by the possibility of working with a constant number of photons per X-ray pulse at all photon energies and the fact that the ion yields become independent of the peak fluence beyond a saturation point. Our study lays the groundwork for spectroscopic investigations of transient atomic species in exotic, multiple-core-hole states that have not been explored previously.

GQ Lup B is a forming brown dwarf companion ( M ∼ 10–30 M _J ) showing evidence for an infrared excess associated with a disk surrounding the companion itself. Here we present mid-infrared (MIR) observations of GQ Lup B with the Medium Resolution Spectrometer (MRS) on JWST, spanning 4.8–11.7 μ m. We remove the stellar contamination using reference differential imaging based on principal component analysis, demonstrating that the MRS can perform high-contrast science. Our observations provide a sensitive probe of the disk surrounding GQ Lup B. We find no sign of a silicate feature, similar to other disks surrounding very low-mass objects, which likely implies significant grain growth ( ${a}_{\min }\gtrsim 5$ μ m) and potentially dust settling. Additionally, we find that if the emission is dominated by an inner wall, the disk around the companion might have an inner cavity larger than the one set by sublimation. Conversely, if our data probe the emission from a thin flat disk, we find the disk to be very compact. More observations are required to confirm this findings and assess the vertical structure of the disk. This approach paves the path to the future study of circumplanetary disks and their physical properties. Our results demonstrate that MIR spectroscopic observations can reveal the physical characteristics of disks around forming companions, providing unique insights into the formation of giant planets, brown dwarfs, and their satellites.

Transmission measurements of the soft X-ray beamline to the Small Quantum Systems (SQS) scientific instrument at the SASE3 undulator of European XFEL are presented. Measurements are reported for a wide range of photon energies (650 eV to 2400 eV), using X-ray gas monitors as well as a bolometric radiometer. The results are in good agreement with simulations for the beam transport and show a transmission of up to 80% over the whole photon energy range. The contribution of second- and third-harmonic radiation of the soft X-ray undulator is determined at selected photon energies by performing transmission measurements using a gas absorber to provide variable attenuation of the incoming photon flux. A comparison of the results with semi-analytic calculations for the generation of free-electron laser pulses in the SASE3 undulator reveals an influence of apertures along the beam transport on the exact harmonic content to be accounted for at the experiment. The second-harmonic content is measured to be in the range of 0.1% to 0.3%, while the third-harmonic contributed a few percent to the SASE3 emission. For experiments at the SQS instrument, these numbers can be reduced through specific selections of the mirror reflection angles.

Introduction Dural arteriovenous fistulas (dAVFs) have been associated with rapidly progressive dementia in relatively young patients. However, the specific angioarchitecture and characteristics of these dAVFs remain to be fully described. To better understand the specific characteristics of dAVFs associated with cognitive impairment (dAVF‐CI), we utilized the CONDOR multicenter database, which provides a large cohort of dAVF available. By analyzing data from patients with dAVFs‐ CI, we aimed to identify the key features distinguishing these cases and elaborate on the pathophysiology of dAVF‐CI. Methods CONDOR is an international multicenter database comprising 1077 (dAVFs) from 14 international centers. We conducted a retrospective analysis of the CONDOR database, focusing on patients diagnosed with dAVFs‐CI. Propensity score matching analysis was performed to compare Borden type II and type III dAVFs with and without cognitive impairment as control groups. Only dAVFs with cortical venous drainage were included as this aggressive subtype can present with non‐hemorrhagic neurologic deficits. Additionally, logistic regression was then employed to identify significant characteristics associated with dAVF‐CI. Results A total of 60 patients with dAVF‐CI and 60 control dAVFs were included in the analysis. The patients with dAVF‐CI had a mean age of 58 ± 18 years. It was found that all cases of dAVF‐CI exhibited venous hypertension. Additionally, there was a significant association between sinus stenosis and dAVF‐CI (OR: 2.85, 95% CI: 1.16‐7.55, p = 0.027). Moreover, dAVF‐CI cases were characterized by the presence of multiple arteriovenous shunts, with more arterial feeders (OR 1.56, 95% CI 1.22‐2.05, p

The selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite being outnumbered compared to their helper counterpart, the ablation of T follicular regulatory cells (Tfrs) results in enhanced dissemination of self-reactive antibody-secreting cells (ASCs). The specific mechanisms by which Tfrs exert their regulatory action on self-reactive B cells are largely unknown. We developed computer simulations to investigate how Tfrs regulate either selection or differentiation of B cells to prevent auto-reactivity. We observed that Tfr-induced apoptosis of self-reactive B cells during the selection phase impedes self-reactivity with physiological Tfr numbers, especially when Tfrs can access centrocyte-enriched GC areas. While this aided in selecting non-self-reactive B cells by restraining competition, higher Tfr numbers distracted non-self-reactive B cells from receiving survival signals from Tfhs. Thus, the location and number of Tfrs must be regulated to circumvent such Tfr distraction and avoid disrupting GC evolution. In contrast, when Tfrs regulate differentiation of selected centrocytes by promoting recycling to the dark zone phenotype of self-reactive GC resident pre-plasma cells (GCPCs), higher Tfr numbers were required to impede the circulation of self-reactive ASCs (s–ASCs). On the other hand, Tfr-engagement with GCPCs and subsequent apoptosis of s–ASCs can control self-reactivity with low Tfr numbers, but does not confer selection advantage to non-self-reactive B cells. The simulations predict that to restrict auto-reactivity, natural redemption of self-reactive B cells is insufficient and that Tfrs should increase the mutation probability of self-reactive B cells.

Abstract Sequencing of B-cell and T-cell immune receptor repertoires helps us to understand the adaptive immune response, although it only provides information about the clonotypes (lineages) and their frequencies and not about, for example, their affinity or antigen (Ag) specificity. To further characterize the identified clones, usually with special attention to the particularly abundant ones (dominant), additional time-consuming or expensive experiments are generally required. Here, we present an extension of a multiscale model of the germinal center (GC) that we previously developed to gain more insight in B-cell repertoires. We compare the extent that these simulated repertoires deviate from experimental repertoires established from single GCs, blood, or tissue. Our simulations show that there is a limited correlation between clonal abundance and affinity and that there is large affinity variability among same-ancestor (same-clone) subclones. Our simulations suggest that low-abundance clones and subclones, might also be of interest since they may have high affinity for the Ag. We show that the fraction of plasma cells (PCs) with high B-cell receptor (BcR) mRNA content in the GC does not significantly affect the number of dominant clones derived from single GCs by sequencing BcR mRNAs. Results from these simulations guide data interpretation and the design of follow-up experiments.

The Small Quantum Systems instrument is one of the six operating instruments of the European XFEL, dedicated to the atomic, molecular and cluster physics communities. The instrument started its user operation at the end of 2018 after a commissioning phase. The design and characterization of the beam transport system are described here. The X-ray optical components of the beamline are detailed, and the beamline performances, transmission and focusing capabilities are reported. It is shown that the X-ray beam can be effectively focused as predicted by ray-tracing simulations. The impact of non-ideal X-ray source conditions on the focusing performances is discussed.

The launch of the James Webb Space Telescope (JWST) marks a pivotal moment for precise atmospheric characterization of Y dwarfs, the coldest brown dwarf spectral type. In this study, we leverage moderate spectral resolution observations ( R ∼ 2700) with the G395H grating of the Near-Infrared Spectrograph (NIRSpec) on board JWST to characterize the nearby (9.9 pc) Y dwarf WISEPA J182831.08+265037.8. With the NIRSpec G395H 2.88–5.12 μ m spectrum, we measure the abundances of CO, CO _2 , CH _4 , H _2 S, NH _3 , and H _2 O, which are the major carbon-, nitrogen-, oxygen-, and sulfur-bearing species in the atmosphere. Based on the retrieved volume mixing ratios with the atmospheric retrieval framework CHIMERA, we report that the C/O ratio is 0.45 ± 0.01, close to the solar C/O value of 0.458, and the metallicity is +0.30 ± 0.02 dex. Comparison between the retrieval results and the forward modeling results suggests that the model bias for C/O and metallicity could be as high as 0.03 and 0.97 dex, respectively. We also report a lower limit of the ^12 CO/ ^13 CO ratio of >40, being consistent with the nominal solar value of 90. Our results highlight the potential for JWST to measure the C/O ratios down to percent-level precision and characterize isotopologues of cold planetary atmospheres similar to WISE 1828.

Objective: The aim of this study was to determine how the coronavirus disease 2019 (COVID-19) pandemic affects the health-related quality of life (HRQoL) of children and adolescents with congenital heart disease (CHD), as well as how the parents perceive the HRQoL of their children. Patients and Methods: HRQoL was assessed by the KINDL® questionnaire during the COVID-19 pandemic and compared to recent questionnaire data of children of the Functional Outcome in children and adolescents with congenital heart disease (FOOTLOOSE) study. From May 27 to June 29, 2020, 160 children with various CHD (15.2 ± 2.5 years, 62 girls, age range: 10–18 years) completed this re-assessment of HRQoL. Results: HRQoL in children with CHD was significantly lower during the COVID-19 pandemic compared to before in total KINDL® score (by −2.1 ± 12.3, P = 0.030), and the subscales emotional well-being (by −5.4 ± 1.2, P < 0.001) and friends (by −4.5 ± 1.7, P = 0.009). Parents of children with CHD rate the HRQoL in total KINDL® score (mean difference: 3.9 ± 1.2, P = 0.002), and the subscales family (mean difference: 8.8 ± 1.7 standard estimate error [SEE], P < 0.001) and friends (mean difference: 7.6 ± 2.2 SEE, P < 0.001) even worse than their children. Only moderate degree of agreement was found between most of the sub-categorical HRQoL assessment of children with CHD and their parents. Conclusions: The COVID-19 pandemic had a negative impact on HRQoL in children and adolescents with CHD and their families. The psychological concerns of children with CHD and their families need special consideration by health-care providers during the COVID-19 pandemic.

The elections in Turkey/Türkiye showed the dilemma for the political opposition in competitive authoritarian regimes: They have to create momentum for change. They must believe it is possible to win elections. If they don’t believe this, their voters won’t. It is difficult to avoid this dilemma, but there is something journalists, experts and officials from other countries can do: Always stress the unfairness of the conditions in which the elections are being held. Do not get a carried away by the excitement of the race. Focus on the fact that the race is not being run on level ground.

A variety of B cell clones seed the germinal centers, where a selection stringency expands the fitter clones to generate higher affinity antibodies. However, recent experiments suggest that germinal centers often retain a diverse set of B cell clones with a range of affinities and concurrently carry out affinity maturation. Amid a tendency to flourish germinal centers with fitter clones, how several B cell clones with differing affinities can be concurrently selected remains poorly understood. Such a permissive selection may allow non-immunodominant clones, which are often rare and of low-affinity, to somatically hypermutate and result in a broad and diverse B cell response. How the constituent elements of germinal centers, their quantity and kinetics may modulate diversity of B cells, has not been addressed well. By implementing a state-of-the-art agent-based model of germinal center, here, we study how these factors impact temporal evolution of B cell clonal diversity and its underlying balance with affinity maturation. While we find that the extent of selection stringency dictates clonal dominance, limited antigen availability on follicular dendritic cells is shown to expedite the loss of diversity of B cells as germinal centers mature. Intriguingly, the emergence of a diverse set of germinal center B cells depends on high affinity founder cells. Our analysis also reveals a substantial number of T follicular helper cells to be essential in balancing affinity maturation with clonal diversity, as a low number of T follicular helper cells impedes affinity maturation and also contracts the scope for a diverse B cell response. Our results have implications for eliciting antibody responses to non-immunodominant specificities of the pathogens by controlling the regulators of the germinal center reaction, thereby pivoting a way for vaccine development to generate broadly protective antibodies.

X-ray free-electron lasers (XFELs) are powerful tools to explore x-ray interactions in atomic and molecular systems at femtosecond timescales. The authors demonstrate a transparent beamsplitter that uses photoelectron spectroscopy combined with a ghost-imaging algorithm to characterize the spiky spectral structure of individual XFEL pulses.

Die sogenannte ‚Schlachtfeldarchäologie‘ ist – nach Anfängen seit den 1910er Jahren und einem ersten Höhepunkt in den 80er und 90er Jahren – mittlerweile eine eigene Forschungsrichtung innerhalb der Archäologie geworden, die über immer mehr Erfahrungen im Umgang mit diesen ungewöhnlichen Fundplätzen verfügt. Sie erforscht Fundplätze von der Steinzeit bis in die Zeitgeschichte und leistet einen wichtigen Beitrag zur frühen Entwicklung von Krieg und Gewalt. Dabei liefert sie – anders als die meisten archäologischen Quellen – einen Einblick in ganz konkrete Ereignisse und deren Verlauf. Gerade am Übergang zur Frühgeschichte können archäologisch untersuchte Kampfplätze zentrale Ergänzungen und ganz neue Einsichten zu bekannten historischen Konstellationen liefern.

Bandyopadhyay, Schips et al. model the factors contributing to overloading of healthcare facilities during the first COVID-19 wave in Italy. They predict that an early test and isolate intervention could have reduced healthcare usage and death rates but would not have kept hospitalizations within pre-pandemic hospital limits.

A set of electron time-of-flight spectrometers for high-resolution angle-resolved spectroscopy was developed for the Small Quantum Systems (SQS) instrument at the SASE3 soft X-ray branch of the European XFEL. The resolving power of this spectrometer design is demonstrated to exceed 10 000 (E/ΔE), using the well known Ne 1s−13p resonant Auger spectrum measured at a photon energy of 867.11 eV at a third-generation synchrotron radiation source. At the European XFEL, a width of ∼0.5 eV full width at half-maximum for a kinetic energy of 800 eV was demonstrated. It is expected that this linewidth can be reached over a broad range of kinetic energies. An array of these spectrometers, with different angular orientations, is tailored for the Atomic-like Quantum Systems endstation for high-resolution angle-resolved spectroscopy of gaseous samples.

Abstract Background Despite the vaccination process in Germany, a large share of the population is still susceptible to SARS-CoV-2. In addition, we face the spread of novel variants. Until we overcome the pandemic, reasonable mitigation and opening strategies are crucial to balance public health and economic interests. Methods We model the spread of SARS-CoV-2 over the German counties by a graph-SIR-type, metapopulation model with particular focus on commuter testing. We account for political interventions by varying contact reduction values in private and public locations such as homes, schools, workplaces, and other. We consider different levels of lockdown strictness, commuter testing strategies, or the delay of intervention implementation. We conduct numerical simulations to assess the effectiveness of the different intervention strategies after one month. The virus dynamics in the regions (German counties) are initialized randomly with incidences between 75 and 150 weekly new cases per 100,000 inhabitants (red zones) or below (green zones) and consider 25 different initial scenarios of randomly distributed red zones (between 2 and 20% of all counties). To account for uncertainty, we consider an ensemble set of 500 Monte Carlo runs for each scenario. Results We find that the strength of the lockdown in regions with out of control virus dynamics is most important to avoid the spread into neighboring regions. With very strict lockdowns in red zones, commuter testing rates of twice a week can substantially contribute to the safety of adjacent regions. In contrast, the negative effect of less strict interventions can be overcome by high commuter testing rates. A further key contributor is the potential delay of the intervention implementation. In order to keep the spread of the virus under control, strict regional lockdowns with minimum delay and commuter testing of at least twice a week are advisable. If less strict interventions are in favor, substantially increased testing rates are needed to avoid overall higher infection dynamics. Conclusions Our results indicate that local containment of outbreaks and maintenance of low overall incidence is possible even in densely populated and highly connected regions such as Germany or Western Europe. While we demonstrate this on data from Germany, similar patterns of mobility likely exist in many countries and our results are, hence, generalizable to a certain extent.

Coincidence experiments at free-electron lasers enable time resolved site-specific investigations of molecular photochemistry at high signal rates, but isolating individual dissociation processes still poses a considerable technical challenge. Here, the authors use electron-ion partial covariance imaging to isolate otherwise elusive chemical shifts in UV-induced photofragmentation pathways of the prototypical chiral molecule 1-iodo-2-methylbutane.

We report the discovery of the first brown dwarf binary system with a Y dwarf primary, WISE J033605.05−014350.4, observed with NIRCam on JWST with the F150W and F480M filters. We employed an empirical point-spread function binary model to identify the companion, located at a projected separation of 0.″084, position angle of 295°, and with contrasts of 2.8 and 1.8 mag in F150W and F480M, respectively. At a distance of 10 pc based on its Spitzer parallax, and assuming a random inclination distribution, the physical separation is approximately 1 au. Evolutionary models predict for that an age of 1–5 Gyr, the companion mass is about 4–12.5 Jupiter masses around the 7.5–20 Jupiter mass primary, corresponding to a companion-to-host mass fraction of q = 0.61 ± 0.05. Under the assumption of a Keplerian orbit the period for this extreme binary is in the range of 5–9 yr. The system joins a small but growing sample of ultracool dwarf binaries with effective temperatures of a few hundreds of Kelvin. Brown dwarf binaries lie at the nexus of importance for understanding the formation mechanisms of these elusive objects, as they allow us to investigate whether the companions formed as stars or as planets in a disk around the primary.

Summary: Staphylococcus aureus can lead to chronic infections and abscesses in internal organs including kidneys, which are associated with the expansion of myeloid-derived suppressor cells (MDSCs) and their suppressive effect on T cells. Here, we developed a mathematical model of chronic S. aureus infection that incorporates the T-cell suppression by MDSCs and suggests therapeutic strategies for S. aureus clearance. A therapeutic protocol with heat-killed S. aureus (HKSA) was quantified in silico and tested in vivo. Contrary to the conventional administration of heat-killed bacteria as vaccination prior to infection, we administered HKSA as treatment in chronically infected hosts. Our treatment eliminated S. aureus in kidneys of all chronically S. aureus-infected mice, reduced MDSCs, and reversed T-cell dysfunction by inducing acute inflammation during ongoing, chronic infection. This study is a guideline for a treatment protocol against chronic S. aureus infection and renal abscesses by repurposing heat-killed treatments, directed by mathematical modeling.

Fiber-shaped materials have great potential for tissue engineering applications as they provide structural support and spatial patterns within a three-dimensional construct. Here we demonstrate the fabrication of mechanically stable, meter-long collagen hollow filaments by a direct extrusion printing process. The fibres are permeable for oxygen and proteins and allow cultivation of primary human endothelial cells (ECs) at the inner surface under perfused conditions. The cells show typical characteristics of a well-organized EC lining including VE-cadherin expression, cellular response to flow and ECM production. The results demonstrate that the collagen tubes are capable of creating robust soft tissue filaments. The mechanical properties and the biofunctionality of these collagen hollow filaments facilitate the engineering of prevascularised tissue engineering constructs.

X-ray free-electron lasers (XFELs) have brought new ways to probe and manipulate atomic and molecular dynamics with unprecedented spatial and temporal resolutions. A quantitative comparison of experimental results with their simulated theoretical counterpart, however, generally requires a precise characterization of the spatial and temporal x-ray pulse profile, providing a nonuniform photon distribution. The determination of the pulse profile constitutes a major, yet inevitable, challenge. Here, we propose a calibration scheme for intense XFEL pulses utilizing a set of experimental charge-state distributions of light noble gas atoms at a series of pulse energies in combination with first-principles simulations of the underlying atomic x-ray multiphoton ionization dynamics. The calibration builds on Bayesian optimization, which is a powerful, machine-learning-based tool particularly well suited for computationally expensive numerical optimization. We demonstrate the presented scheme to calibrate the pulse duration as well as the spatial fluence distribution profile of XFEL pulses. Our proposed method can serve as a comprehensive tool for characterizing ultraintense and ultrafast x-ray pulses.

Successful anterior cruciate ligament (ACL) reconstructions strive for a firm bone-ligament integration. With the aim to establish an enthesis-like construct, embroidered functionalized scaffolds were colonized with spheroids of osteogenically differentiated human mesenchymal stem cells (hMSCs) and lapine (l) ACL fibroblasts in this study. These triphasic poly(L-lactide-co-ε-caprolactone) and polylactic acid (P(LA-CL)/PLA) scaffolds with a bone-, a fibrocartilage transition- and a ligament zone were colonized with spheroids directly after assembly (DC) or with 14-day pre-cultured lACL fibroblast and 14-day osteogenically differentiated hMSCs spheroids (=longer pre-cultivation, LC). The scaffolds with co-cultures were cultured for 14 days. Cell vitality, DNA and sulfated glycosaminoglycan (sGAG) contents were determined. The relative gene expressions of collagen types I and X, Mohawk, Tenascin C and runt-related protein (RUNX) 2 were analyzed. Compared to the lACL spheroids, those with hMSCs adhered more rapidly. Vimentin and collagen type I immunoreactivity were mainly detected in the hMSCs colonizing the bone zone. The DNA content was higher in the DC than in LC whereas the sGAG content was higher in LC. The gene expression of ECM components and transcription factors depended on cell type and pre-culturing condition. Zonal colonization of triphasic scaffolds using spheroids is possible, offering a novel approach for enthesis tissue engineering.

Ultrashort circularly polarised light pulses from free-electron lasers offer a route for exploring chiral molecules and their dynamics, but remain challenging to harness. Here, X-ray pump-probe experiments enable a site-specific photoelectron circular dichroism measurement on a dissociating chiral molecule.

Abstract Leather, which is regularly tanned from whole hides of up to 5 m2, needs a constant thickness over the entire surface in order to be processed into high-quality consumer goods such as shoes, furniture and car interiors. Precise adjustment of the thickness is achieved by shaving. On an industrial scale, rotating knife rollers are used to remove chips from the flesh side of semi-finished leathers whereby adjusting the specified thickness and generating a smooth surface. Care must be taken to prevent the temperature from rising above the denaturation temperature of the leather during shaving in order to avoid any loss of quality. Beside this, temperature rise is always a sign of friction showing avoidable energy expenditure. In order to localize the source of friction during shaving, actual temperature development at the roller knife is studied. Different measuring methods are used to evaluate the temperature increase at the blade roll of the shaving machine. The finite element method is used to thermally simulate the process. Measured temperatures, the geometry of the blade roll and process data are taken into account for modelling the temperature development close to the blade edge. The obtained results enhance the understanding of temperature generating processes during machine operation and allow conclusions about potential improvements in the design of the machine and blades. Graphical abstract

Germinal centers (GCs) are transient structures where affinity maturation of B cells gives rise to high affinity plasma and memory cells. The mechanism of GC shutdown is unclear, despite being an important phenomenon maintaining immune homeostasis. In this study, we used a mathematical model to identify mechanisms that can independently promote contraction of GCs leading to shutdown. We show that GC shutdown can be promoted by antigen consumption by B cells, antigen masking by soluble antibodies, alterations in follicular dendritic cell (FDC) network area, modulation of immune complex cycling rate constants, alterations in T follicular helper signaling, increased terminal differentiation and reduced B cell division capacity. Proposed mechanisms promoted GC contraction by ultimately decreasing the number of B cell divisions and recycling cells. Based on the in-silico predictions, we suggest a combination of experiments that can be potentially employed by future studies to unravel the mechanistic basis of GC shutdown such as measurements of the density of pMHC presentation of B cells, FDC network size per B cell, fraction of cells expressing differentiation markers. We also show that the identified mechanisms differentially affect the efficiency of GC reaction estimated based on the quantity and quality of resulting antibodies.

Finding the lowest energy configuration of N unit charges on a sphere, known as Thomson's problem, is a long-standing query which has only been studied via numerical simulations. We present its physical realization using multiply charged He nanodroplets. The charge positions are determined by x-ray coherent diffractive imaging with Xe as a contrast agent. In neutral droplets, filaments resulting from Xe atoms condensing on quantum vortices are observed. Unique to charged droplets, however, Xe clusters that condense on charges are distributed on the surface in lattice-like structures, introducing He droplets as experimental model systems for the study of Thomson's problem.

Affinity maturation is an evolutionary process by which the affinity of antibodies (Abs) against specific antigens (Ags) increases through rounds of B-cell proliferation, somatic hypermutation, and positive selection in germinal centres (GC). The positive selection of B cells depends on affinity, but the underlying mechanisms of affinity discrimination and affinity-based selection are not well understood. It has been suggested that selection in GC depends on both rapid binding of B-cell receptors (BcRs) to Ags which is kinetically favourable and tight binding of BcRs to Ags, which is thermodynamically favourable; however, it has not been shown whether a selection bias for kinetic properties is present in the GC. To investigate the GC selection bias towards rapid and tight binding, we developed an agent-based model of GC and compared the evolution of founder B cells with initially identical low affinities but with different association/dissociation rates for Ag presented by follicular dendritic cells in three Ag collection mechanisms. We compared an Ag collection mechanism based on association/dissociation rates of B-cell interaction with presented Ag, which includes a probabilistic rupture of bonds between the B-cell and Ag (Scenario-1) with a reference scenario based on an affinity-based Ag collection mechanism (Scenario-0). Simulations showed that the mechanism of Ag collection affects the GC dynamics and the GC outputs concerning fast/slow (un)binding of B cells to FDC-presented Ags. In particular, clones with lower dissociation rates outcompete clones with higher association rates in Scenario-1, while remaining B cells from clones with higher association rates reach higher affinities. Accordingly, plasma cell and memory B cell populations were biased towards B-cell clones with lower dissociation rates. Without such probabilistic ruptures during the Ag extraction process (Scenario-2), the selective advantage for clones with very low dissociation rates diminished, and the affinity maturation level of all clones decreased to the reference level.

Abstract In the present study, the tannins from stem and root barks of Tessmannia burttii Harms (Caesalpiniaceae), a plant species abundantly growing in Tanzania and other parts of Africa, were investigated for their suitability in hides tanning. Tannin powder was extracted at selected temperatures (30, 50 and 80 °C) and the influence of each temperature on the crosslinking capacity was evaluated. The interaction mechanism between hide powder collagen and the tannins was studied by Differential Scanning Calorimetry (DSC), trinitrobenzensulfonic (TNBS) acid assay and amino acid hydrolysis methods. Extraction temperatures showed low influence on crosslinking capacity of the tannins. However, extract obtained at 50 °C exhibited best performance in terms of gap size between Tonset and Tpeak. The stem bark extract yield was higher than that from the root bark, but both were within the recommended ranges. The tannin content (61%) of T. burttii stem bark extract was above recommended value (10%), whereas its total phenolic content and total flavonoic content were found to be above that of commercial Acacia mearnsii tannin. The study of cross-linking parameters as a function of pH showed cross-linking to occur via a covalent mechanism at the basic amino groups. However, the bonds were not resistant to acid hydrolysis. The observed interaction mechanism indicated that tannins from stem and root barks of T. burttii belong to the condensed tannin, similar to A. mearnsii (black wattle), a commercial tannin source that was used in this study as a reference. Findings from this study depict that T. burttii extracts are auspicious eco-friendly alternative source of vegetable tannins to overcome the use of chromium salts in the leather industry. Graphical abstract

We analyze the relaxation of non-pharmaceutical interventions (NPIs) under an increasing number of vaccinations in Germany. For the spread of SARS-CoV-2 we employ a SIR-type model that accounts for age-dependence and includes realistic contact patterns between age groups. The implementation of NPIs occurs on changed contact patterns, improved isolation, or reduced infectiousness when, e.g., wearing masks. We account for spatial heterogeneity and commuting activities in between regions in Germany, and the testing of commuters is considered as a further NPI. We include the ongoing vaccination process and analyze the effect of the B.1.617.2 (Delta) variant, which is considered to be 40%-60% more infectious then the currently dominant B.1.1.7 (Alpha) variant. We explore different opening scenarios under the ongoing vaccination process by assuming that local restrictions are either lifted in early July or August with or without continued wearing of masks and testing. Our results indicate that we can counteract the resurgence of SARS-CoV-2 despite the Delta variant with appropriate timing for the relaxation of NPIs. In all cases, however, school children are hit the hardest.

On an organismal level, metabolism needs to react in a well-orchestrated manner to metabolic challenges such as nutrient uptake. Key metabolic hubs in human blood are pyruvate and lactate, both of which are constantly interconverted by very fast exchange fluxes. The quantitative contribution of different food sources to these metabolite pools remains unclear. Here, we applied in vivo stable isotope labeling to determine postprandial metabolic fluxes in response to two carbohydrate sources of different complexity. Depending on the ingested carbohydrate source, glucose or wheat flour, the net direction of the lactate dehydrogenase, and the alanine amino transferase fluxes were adjusted in a way to ensure sufficient availability, while, at the same time, preventing an overflow in the respective metabolite pools. The systemic lactate pool acts as a metabolic buffer which is fueled in the early- and depleted in the late-postprandial phase and thus plays a key role for systemic metabolic homeostasis.

BackgroundExclusive breastmilk is the desired enteral nutrition for babies born moderate- and late-preterm between 32+0 and 36+6 weeks' gestation; however, this goal is often difficult to achieve.MethodsA prospective cohort of babies 32+0 −35+6 weeks' gestation enrolled in the DIAMOND trial were randomized to a condition specifying that babies should receive mother's own milk (MOM) as the only enteral feed. Factors associated with the successful transition to MOM, defined as MOM being the sole enteral feeding at the time of the first cessation of intravenous (IV) fluids, were investigated by logistic regression. Time to commencement of a milk other than MOM was analyzed by Kaplan–Meier survival curves.ResultsA total of 151 eligible babies (60% boys) were included, 93 (63%) of whom successfully transitioned from IV fluids onto MOM only. Alternative sources of milk, mostly formula, were used to transition from IV fluids onto enteral feeds more often in multiples and Māori, and was commenced earlier in Māori than other ethnicities (p = 0.007) and in late-preterm compared with moderate-preterm babies (p=0.01). Receiving exclusively breastmilk at discharge was more likely for babies who successfully transitioned from IV fluids onto MOM only [OR (95% confidence intervals) 4.9 (2.3–10.6)] and who received only MOM in the first week after birth [4.8 (2.2–10.4)], both p < 0.0001. Receiving breastmilk exclusively at discharge was less likely for Māori than Caucasian babies [0.2 (0.1–0.6), p < 0.0006]. There was no difference in the use of alternative sources of milk in babies who received parenteral nutrition or dextrose or between small-for-gestational-age and appropriate-for-gestational-age babies.ConclusionsDespite an intention to provide only MOM, significant numbers of moderate- and late-preterm babies received formula to transition from IV fluids, and this differed by ethnicity. The drivers underlying these decisions require further investigation. These data highlight an urgent need for quality initiatives to support and encourage mothers of moderate- and late-preterm babies in their lactation.

The Y-dwarf WISE 1828+2650 is one of the coldest known brown dwarfs with an effective temperature of ∼300 K. Located at a distance of just 10 pc, previous model-based estimates suggest WISE1828+2650 has a mass of ∼5–10 M _J , making it a valuable laboratory for understanding the formation, evolution, and physical characteristics of gas giant planets. However, previous photometry and spectroscopy have presented a puzzle, with the near impossibility of simultaneously fitting both the short- (0.9–2.0 μ m) and long-wavelength (3–5 μ m) data. A potential solution to this problem has been the suggestion that WISE 1828+2650 is a binary system whose composite spectrum might provide a better match to the data. Alternatively, new models being developed to fit JWST/NIRSpec, and MIRI spectroscopy might provide new insights. This article describes JWST/NIRCam observations of WISE 1828+2650 in six filters to address the binarity question and to provide new photometry to be used in model fitting. We also report adaptive optics imaging with the Keck I0 m telescope. We find no evidence for multiplicity for a companion beyond 0.5 au with either JWST or Keck. Companion articles will present low- and high-resolution spectra of WISE 1828 obtained with both NIRSpec and MIRI.

We observed HD 19467 B with JWST’s NIRCam in six filters spanning 2.5–4.6 μ m with the long-wavelength bar coronagraph. The brown dwarf HD 19467 B was initially identified through a long-period trend in the radial velocity of the G3V star HD 19467. HD 19467 B was subsequently detected via coronagraphic imaging and spectroscopy, and characterized as a late-T type brown dwarf with an approximate temperature ∼1000 K. We observed HD 19467 B as a part of the NIRCam GTO science program, demonstrating the first use of the NIRCam Long Wavelength Bar coronagraphic mask. The object was detected in all six filters (contrast levels of 2 × 10 ^−4 to 2 × 10 ^−5 ) at a separation of 1.″6 using angular differential imaging and synthetic reference differential imaging. Due to a guide star failure during the acquisition of a preselected reference star, no reference star data were available for post-processing. However, reference differential imaging was successfully applied using synthetic point-spread functions developed from contemporaneous maps of the telescope’s optical configuration. Additional radial velocity data (from Keck/HIRES) are used to constrain the orbit of HD 19467 B. Photometric data from TESS are used to constrain the properties of the host star, particularly its age. NIRCam photometry, spectra, and photometry from the literature, and improved stellar parameters are used in conjunction with recent spectral and evolutionary substellar models to derive the physical properties of HD 19467 B. Using an age of 9.4 ± 0.9 Gyr inferred from spectroscopy, Gaia astrometry, and TESS asteroseismology, we obtain a model-derived mass of 62 ± 1 M _J , which is consistent within 2 σ with the dynamically derived mass of ${81}_{-12}^{+14}$ M _J .

Abstract Background SARS-CoV-2 has induced a worldwide pandemic and subsequent non-pharmaceutical interventions (NPIs) to control the spread of the virus. As in many countries, the SARS-CoV-2 pandemic in Germany has led to a consecutive roll-out of different NPIs. As these NPIs have (largely unknown) adverse effects, targeting them precisely and monitoring their effectiveness are essential. We developed a compartmental infection dynamics model with specific features of SARS-CoV-2 that allows daily estimation of a time-varying reproduction number and published this information openly since the beginning of April 2020. Here, we present the transmission dynamics in Germany over time to understand the effect of NPIs and allow adaptive forecasts of the epidemic progression. Methods We used a data-driven estimation of the evolution of the reproduction number for viral spreading in Germany as well as in all its federal states using our model. Using parameter estimates from literature and, alternatively, with parameters derived from a fit to the initial phase of COVID-19 spread in different regions of Italy, the model was optimized to fit data from the Robert Koch Institute. Results The time-varying reproduction number (R t) in Germany decreased to

Abstract Collective migration is commonly observed in groups of migrating cells, in the form of swarms or aggregates. Mechanistic models have proven very useful in understanding collective cell migration. Such models, either explicitly consider the forces involved in the interaction and movement of individuals or phenomenologically define rules which mimic the observed behavior of cells. However, mechanisms leading to collective migration are varied and specific to the type of cells involved. Additionally, the precise and complete dynamics of many important chemomechanical factors influencing cell movement, from signalling pathways to substrate sensing, are typically either too complex or largely unknown. The question is how to make quantitative/qualitative predictions of collective behavior without exact mechanistic knowledge. Here we propose the least microenvironmental uncertainty principle (LEUP) that may serve as a generative model of collective migration without precise incorporation of full mechanistic details. Using statistical physics tools, we show that the famous Vicsek model is a special case of LEUP. Finally, to test the biological applicability of our theory, we apply LEUP to construct a model of the collective behavior of spherical Serratia marcescens bacteria, where the underlying migration mechanisms remain elusive.

Mountain areas provide essential resources for a significant proportion of the Earth's population. This study presents the development of mountain research between 1900 and 2019 based on peer-reviewed articles in English listed in Web of ScienceTM (WOS). We analyzed the number of publications over time, journals and scientific categories, frequent topics, and geographical distributions based on 40 mountain ranges and authors' countries as well as institutional contributions. From 1900-2019, 195k ±10% mountain research papers were published; over 50% from 2010-2019. While papers were published in more than 1000 different journals, indicating a wide range of disciplines engaged in mountain research, 94% of the papers were assigned to "Science & Technology", only

Antibody diversification and selection of B cells occur in dynamic structures called germinal centers (GCs). Passively administered soluble antibodies regulate the GC response by masking the antigen displayed on follicular dendritic cells (FDCs). This suggests that GCs might intercommunicate via naturally produced soluble antibodies, but the role of such GC–GC interactions is unknown. In this study, we performed in silico simulations of interacting GCs and predicted that intense interactions by soluble antibodies limit the magnitude and lifetime of GC responses. With asynchronous GC onset, we observed a higher inhibition of late formed GCs compared to early ones. We also predicted that GC–GC interactions can lead to a bias in the epitope recognition even in the presence of equally dominant epitopes due to differences in founder cell composition or initiation timing of GCs. We show that there exists an optimal range for GC–GC interaction strength that facilitates the affinity maturation towards an incoming antigenic variant during an ongoing GC reaction. These findings suggest that GC–GC interactions might be a contributing factor to the unexplained variability seen among individual GCs and a critical factor in the modulation of GC response to antigenic variants during viral infections.

The competitive dynamics of mitochondrial haplotypes juxtaposed within the same cell are poorly studied. Here the authors show, in the context of a transmissible cancer, that one haplotype has recurrently entered cancer cells by horizontal transfer and appears to have a ‘selfish’ selective advantage.

Abstract Chromium shavings are wet by-products of the leather industry, of which thousands of tons accrue worldwide during leather manufacture. Due to their chromium content, chromium shavings are responsible for the most important ecological challenges caused by the leather industry. They are stable towards temperatures of up to 110 °C and enzymatic degradation. This high stability is caused by the three-dimensional native structure, typical for collagen, and additional chemical cross-links between the collagen fibres achieved by Cr3+ salts in the tanning process. Therefore, hitherto chromium shavings are not utilized industrially to produce biogas. In order to generate biogas, this stable structure has to be denatured. Chromium shavings were pre-treated by extrusion and hydrothermal methods. To prove the enzymatic degradability, the different pre-treatments were evaluated by differential scanning calorimetry (DSC), enzymatic assays, and by measuring the solubility in water. The biogas production potential was investigated using batch trials to examine feasibility. Results demonstrated that both pre-treatments allowed enzymatic attack and increased degradability of the chromium shavings reducing the lag-phase of biogas production and the remaining waste. Graphical abstract

Summary: Small immunoglobulin superfamily (sIGSF) adhesion complexes form a corolla of microdomains around an integrin ring and secretory core during immunological synapse (IS) formation. The corolla recruits and retains major costimulatory/checkpoint complexes, such as CD28, making forces that govern corolla formation of particular interest. Here, we investigated the mechanisms underlying molecular reorganization of CD2, an adhesion and costimulatory molecule of the sIGSF family during IS formation. Computer simulations showed passive distal exclusion of CD2 complexes under weak interactions with the ramified F-actin transport network. Attractive forces between CD2 and CD28 complexes relocate CD28 from the IS center to the corolla. Size-based sorting interactions with large glycocalyx components, such as CD45, or short-range CD2 self-attraction successfully explain the corolla ‘petals.’ This establishes a general simulation framework for complex pattern formation observed in cell-bilayer and cell-cell interfaces, and the suggestion of new therapeutic targets, where boosting or impairing characteristic pattern formation can be pivotal.

Summary: Vaccine development is challenged by the hierarchy of immunodominance between target antigen epitopes and the emergence of antigenic variants by pathogen mutation. The strength and breadth of antibody responses relies on selection and mutation in the germinal center and on the structural similarity between antigens. Computational methods for assessing the breadth of germinal center responses to multivalent antigens are critical to speed up vaccine development. Yet, such methods have poorly reflected the 3D antigen structure and antibody breadth. Here, we present Ymir, a new 3D-lattice-based framework that calculates in silico antibody-antigen affinities. Key physiological properties naturally emerge from Ymir such as affinity jumps, cross-reactivity, and differential epitope accessibility. We validated Ymir by replicating known features of germinal center dynamics. We show that combining antigens with mutated but structurally related epitopes enhances vaccine breadth. Ymir opens a new avenue for understanding vaccine potency based on the structural relationship between vaccine antigens.

Abstract Background There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage. Methods We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls. Results Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution. Conclusions The results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP.

Abstract Agricultural landscapes are globally dominated by monocultures under intensive management. This is one of the main reasons for biodiversity loss and insect population decline in many regions all over the world. Agroecosystem biodiversity in these areas can be enhanced by cropping system diversification, such as crop rotations. Yet, long‐term studies on effects of crop rotations on aboveground agrobiodiversity are lacking. We set up a 10‐year long‐term crop rotation experiment in Central Germany and monitored the temporal dynamics of aboveground arthropods over a full cultivation period to investigate influence of current and preceding crop identity and cropping system diversification on activity density, species richness, and community structure. We found that species composition was strongly influenced by currently grown crop although effect on arthropods varied between species groups. Especially, winter oilseed rape strongly affects arthropod community structure. Interestingly, we were also able to show an influence of the preceding crops, indicating an ecological memory effect in the aboveground arthropod community. Our results show that crop identity of both currently and previously grown crops in crop rotations may lead to an increase in arthropod activity density and changes in species composition. Diversified crop rotations including appropriate crops can be an easily implemented tool to increase arthropod biodiversity and biomass at large spatial and temporal scales, particularly in areas dominated by a single crop (e.g., wheat, maize). Our results may help to design optimized crop rotations for large‐scale enhancement of insect biodiversity in agroecosystems.

This paper introduces a new key space for CSIDH and a new algorithm for constant-time evaluation of the CSIDH group action. The key space is not useful with previous algorithms, and the algorithm is not useful with previous key spaces, but combining the new key space with the new algorithm produces speed records for constant-time CSIDH. For example, for CSIDH-512 with a 256-bit key space, the best previous constant-time results used 789000 multiplications and more than 200 million Skylake cycles; this paper uses 438006 multiplications and 125.53 million cycles.

Memory B cells and antibody-secreting plasma cells are generated within germinal centers during affinity maturation in which B-cell proliferation, selection, differentiation, and self-renewal play important roles. The mechanisms behind memory B cell and plasma cell differentiation in germinal centers are not well understood. However, it has been suggested that cell fate is (partially) determined by asymmetric cell division, which involves the unequal distribution of cellular components to both daughter cells. To investigate what level and/or probability of asymmetric segregation of several fate determinant molecules, such as the antigen and transcription factors (BCL6, IRF4, and BLIMP1) recapitulates the temporal switch and DZ-to-LZ ratio in the germinal center, we implemented a multiscale model that combines a core gene regulatory network for plasma cell differentiation with a model describing the cellular interactions and dynamics in the germinal center. Our simulations show that BLIMP1 driven plasma cell differentiation together with coupled asymmetric division of antigen and BLIMP1 with a large segregation between the daughter cells results in a germinal center DZ-to-LZ ratio and a temporal switch from memory B cells to plasma cells that have been observed in experiments.

Summary: The selection of B cells (BCs) in germinal centers (GCs) is pivotal to the generation of high-affinity antibodies and memory BCs, but it lacks global understanding. Based on the idea of a single Tfh-cell signal that controls BC selection and division, experiments appear contradictory. Here, we use the current knowledge on the molecular pathways of GC BCs to develop a theory of GC BC selection and division based on the dynamics of molecular factors. This theory explains the seemingly contradictory experiments by the separation of signals for BC fate decision from signals controlling the number of BC divisions. Three model variants are proposed and experiments are predicted that allow one to distinguish those. Understanding information processing in molecular BC states is critical for targeted immune interventions, and the proposed theory implies that selection and division can be controlled independently in GC reactions.

Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, ‘normal’ GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question – what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.