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T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during dextran sulfate sodium (DSS)-induced colitis and Salmonella entericaTyphimurium infection. Similar to conventional CD101−/−mice, animals with a regulatory T cell-specific Cd101deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of T helper 1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonellaas revealed by studying CD101−/−x interferon-g−/−mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonellainfection in vitroand in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonellainfection required the expression of Irg-1and Nox2and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of inflammatory bowel disease patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonellainfection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways.

Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine–hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.

The physicochemical effects of decorating pore walls of high surface area materials with functional groups are not sufficiently understood, despite the use of these materials in a multitude of applications such as catalysis, separations, or drug delivery. In this study, the influence of 3-amino-propyl triethoxysilane (APTES)-modified SBA-15 on the dynamics of deuterated ethylene glycol (EG-d4) is inspected by comparing three systems: EG-d4in the bulk phase (sample 1), EG-d4confined in SBA-15 (sample 2), and EG-d4confined in SBA-15 modified with APTES (sample 3). The phase behavior (i.e., melting, crystallization, glass formation, etc.) of EG-d4in these three systems is studied by differential scanning calorimetry. Through line shape analysis of the 2H solid-state NMR (2H ssNMR) spectra of the three systems recorded at different temperatures, two signal patterns, (i) a Lorentzian (liquid-like) and (ii) a Pake pattern (solid-like), are identified from which the distribution of activation energies for the dynamic processes is calculated employing a two-phase model.

Two different mesoporous silica materials (SBA-15 and MCM 41) were impregnated with four different, commercially available surfactants, namely, E5, PEG 200, C10E6, and Triton X-100. Differential scanning calorimetry was employed to confirm the confinement of the surfactants in the pores of their host materials. Dynamic nuclear polarization enhanced solid state 13C magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra were recorded for these materials, showing that both the direct as well as the indirect polarization transfer pathways are active for the carbons of the polyethylene glycol moieties of the surfactants. The presence of the indirect polarization pathway implies the presence of molecular motion with correlation times faster than the inverse Larmor frequency of the observed signals. The intensities of the signals were determined, and an approach based on relative intensities was employed to ensure comparability throughout the samples. From these data, the interactions of the surfactants with the pore walls could be determined. Additionally, a model describing the surfactants’ arrangement in the pores was developed. It was concluded that all carbons of the hydrophilic surfactants, E5and PEG 200, interact with the silica walls in a similar fashion, leading to similar polarization transfer pathway patterns for all observed signals. For the amphiphilic surfactants C10E6and Triton X-100, the terminal hydroxyl group mediates the majority of the interactions with the pore walls and the polarizing agent.

New consumer demands, enforced by tire performance labeling, are affecting the global tire industry with increased demands on the tires' fuel economy and wet grip behavior (ref. 1). It has [...]

Molecular dynamics (MD) simulations are reported for [polyethylene glycol (PEG)200], a polydisperse mixture of ethylene glycol oligomers with an average molar weight of 200 g·mol–1. As a first step, available force fields for describing ethylene glycol oligomers were tested on how accurately they reproduced experimental properties. They were found to all fall short on either reproducing density, a static property, or the self-diffusion coefficient, a dynamic property. Discrepancies with the experimental data increased with the increasing size of the tested ethylene glycol oligomer. From the available force fields, the optimized potential for liquid simulation (OPLS) force field was used to further investigate which adjustments to the force field would improve the agreement of simulated physical properties with experimental ones. Two parameters were identified and adjusted, the (HO)–C–C–O proper dihedral potential and the polarity of the hydroxy group. The parameter adjustments depended on the size of the ethylene glycol oligomer. Next, PEG200 was simulated with the OPLS force field with and without modifications to inspect their effects on the simulation results. The modifications to the OPLS force field significantly decreased hydrogen bonding overall and increased the propensity of intramolecular hydrogen bond formation at the cost of intermolecular hydrogen bond formation. Moreover, some of the tri- and more so tetraethylene glycol formed intramolecular hydrogen bonds between the hydroxy end groups while still maintaining strong intramolecular interactions with the ether oxygen atoms. These observations allowed the interpretation of the obtained RDFs as well as structural properties such as the average end-to-end distances and the average radii of gyration. The MD simulations with and without the modifications showed no evidence of preferential association of like-oligomers to form clusters nor any evidence of long-range ordering such as a side-by-side stacking of ethylene glycol oligomers. Instead, the simulation results support the picture of PEG200 being a random mixture of its ethylene glycol oligomer components. Finally, additional MD simulations of a binary mixture of tri-and hexaethylene glycol with the same average molar weight as PEG200 revealed very similar structural and physical properties as for PEG200.

The leakage of quantum information out of the two computational states of a qubit into other energy states represents a major challenge for quantum error correction. During the operation of an error-corrected algorithm, leakage builds over time and spreads through multi-qubit interactions. This leads to correlated errors that degrade the exponential suppression of the logical error with scale, thus challenging the feasibility of quantum error correction as a path towards fault-tolerant quantum computation. Here, we demonstrate a distance-3 surface code and distance-21 bit-flip code on a quantum processor for which leakage is removed from all qubits in each cycle. This shortens the lifetime of leakage and curtails its ability to spread and induce correlated errors. We report a tenfold reduction in the steady-state leakage population of the data qubits encoding the logical state and an average leakage population of less than 1 × 10−3throughout the entire device. Our leakage removal process efficiently returns the system back to the computational basis. Adding it to a code circuit would prevent leakage from inducing correlated error across cycles. With this demonstration that leakage can be contained, we have resolved a key challenge for practical quantum error correction at scale.

This review gives an overview of current trends in the investigation of confined molecules such as higher alcohols, ethylene glycol and polyethylene glycol as guest molecules in neat and functionalized mesoporous silica materials. All these molecules have both hydrophobic and hydrophilic parts. They are characteristic role-models for the investigation of confined surfactants. Their properties are studied by a combination of solid-state NMR and relaxometry with other physicochemical techniques and molecular dynamics techniques. It is shown that this combination delivers unique insights into the structure, arrangement, dynamical properties and the guest-host interactions inside the confinement.

Der Beitrag geht der Frage nach, ob und inwiefern sich die Nutzung von digitalen Medien als bedeutsam für die Form und Funktion von Interaktionspraktiken erweist, die Lehrkräfte zur Gestaltung von Gruppenarbeiten realisieren. Die Ergebnisse der hierzu durchgeführten videographischen Untersuchungen in einer Tabletklasse geben einen Einblick in komplexe Formen inkrementeller Transformation, in denen sich Persistenz und Wandel auf verschiedenen Ebenen der Interaktionsorganisation verschränken. Bestätigt wird einerseits der Befund vorliegender Studien, dass der Einbezug digitaler Medien keine grundlegende Veränderung pädagogischer Interaktionsordnungen zur Folge hat. Gezeigt werden kann jedoch andererseits, dass die Nutzung von Tablets mit bedeutsamen Konsequenzen für die lehrkraftseitige Ausgestaltung von Interaktionspraktiken einhergeht, mit denen sich kontextbezogen auf modifizierte Zugänge zu Wissensressourcen und auf die digitale Verfasstheit von Wissensprodukten bezogen wird.

ObjectiveBleeding ulcers and erosions are hallmarks of active ulcerative colitis (UC). However, the mechanisms controlling bleeding and mucosal haemostasis remain elusive.DesignWe used high-resolution endoscopy and colon tissue samples of active UC (n = 36) as well as experimental models of physical and chemical mucosal damage in mice deficient for peptidyl-arginine deiminase-4 (PAD4), gnotobiotic mice and controls. We employed endoscopy, histochemistry, live-cell microscopy and flow cytometry to study eroded mucosal surfaces during mucosal haemostasis.ResultsErosions and ulcerations in UC were covered by fresh blood, haematin or fibrin visible by endoscopy. Fibrin layers rather than fresh blood or haematin on erosions were inversely correlated with rectal bleeding in UC. Fibrin layers contained ample amounts of neutrophils coaggregated with neutrophil extracellular traps (NETs) with detectable activity of PAD. Transcriptome analyses showed significantly elevated PAD4expression in active UC. In experimentally inflicted wounds, we found that neutrophils underwent NET formation in a PAD4-dependent manner hours after formation of primary blood clots, and remodelled clots to immunothrombi containing citrullinated histones, even in the absence of microbiota. PAD4-deficient mice experienced an exacerbated course of dextrane sodium sulfate-induced colitis with markedly increased rectal bleeding (96 % vs 10 %) as compared with controls. PAD4-deficient mice failed to remodel blood clots on mucosal wounds eliciting impaired healing. Thus, NET-associated immunothrombi are protective in acute colitis, while insufficient immunothrombosis is associated with rectal bleeding.ConclusionOur findings uncover that neutrophils induce secondary immunothrombosis by PAD4-dependent mechanisms. Insufficient immunothrombosis may favour rectal bleeding in UC.

Currently approved viral vector-based and mRNA-based vaccine approaches against coronavirus disease 2019 (COVID-19) consider only homologous prime-boost vaccination. After reports of thromboembolic events, several European governments recommended using AstraZeneca’s ChAdOx1-nCov-19 (ChAd) only in individuals older than 60 years, leaving millions of already ChAd-primed individuals with the decision to receive either a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical School’s COVID-19 Contact Study cohort of healthcare professionals to monitor ChAd-primed immune responses before and 3 weeks after booster with ChAd (n= 32) or BioNTech/Pfizer’s BNT162b2 (n= 55). Although both vaccines boosted prime-induced immunity, BNT162b2 induced significantly higher frequencies of spike-specific CD4+and CD8+T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and P.1 variants of concern of severe acute respiratory syndrome coronavirus 2.

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.

An experimental study is presented for the reverse micellar system of 15% by mass polydisperse hexaethylene glycol monodecylether (C10E6) in cyclohexane with varying amounts of added water up to 4% by mass. Measurements of viscosity and self-diffusion coefficients were taken as a function of temperature between 10 and 45 °C at varying sample water loads but fixed C10E6/cyclohexane composition. The results were used to inspect the validity of the Stokes–Einstein equation for this system. Unreasonably small reverse average micelle radii and aggregation numbers were obtained with the Stokes–Einstein equation, but reasonable values for these quantities were obtained using the ratio of surfactant-to-cyclohexane self-diffusion coefficients. While bulk viscosity increased with increasing water load, a concurrent expected decrease of self-diffusion coefficient was only observed for the surfactant and water but not for cyclohexane, which showed independence of water load. Moreover, a spread of self-diffusion coefficients was observed for the protons associated with the ethylene oxide repeat unit in samples with polydisperse C10E6but not in a sample with monodisperse C10E6. These findings were interpreted by the presence of reverse micelle to reverse micelle hopping motions that with higher water load become increasingly selective toward C10E6molecules with short ethylene oxide repeat units, while those with long ethylene oxide repeat units remain trapped within the reverse micelle because of the increased hydrogen bonding interactions with the water inside the growing core of the reverse micelle. Despite the observed breakdown of the Stokes–Einstein equation, the temperature dependence of the viscosities and self-diffusion coefficients was found to follow Arrhenius behavior over the investigated range of temperatures.

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.

Mesoporous silica materials (SBA-15) with surfaces modified with aminopropyltriethoxysilane (APTES) of two different surface coverages were synthesized, and their structural pore characteristics were analyzed. These two mesoporous silica materials were impregnated with various solutions of radicals in a nonionic surfactant solvent. Differential scanning calorimetry (DSC) analysis of the impregnated mesoporous silica materials confirmed that the surfactant solutions were confined into the pores. Dynamic nuclear polarization (DNP)-enhanced solid-state 13C magic-angle spinning (MAS) NMR spectra recorded for these impregnated mesoporous silica materials showed the presence of superimposed spectra from direct and indirect channel polarization transfer processes not only for the confined surfactant solvent but also for the APTES surface modification. The observation of the indirect channel resonances implies that the surfactant solvents as well as the APTES exhibit molecular motions with correlation times on the order of or faster than the inverse Larmor frequency. Such motions are unexpected at the experimental temperature conditions of ∼120 K in particular for the immobilized APTES. Spectral line widths and intensities of the observed 13C MAS NMR spectra were sensitive to the specific combination of the radical, surfactant solvent, and APTES surface coverage. One particular combination showed identical widths and intensities for the direct and the oppositely phased indirect channel resonances, resulting in a blank spectrum. The differences in line widths and intensities are discussed with respect to the structural organization of the polarizing agent and surfactant within the pores and the complex interplay of intermolecular interactions between these constituents.

Density, viscosity, and self-diffusion coefficients are reported for octan-1-ol and the related ether-alcohols 2-pentoxy-ethan-1-ol, 3-butoxypropan-1-ol, 4-propoxybutan-1-ol, 5-ethoxypentan-1-ol, and 6-methoxyhexan-1-ol covering temperature ranges from 298.15 to 359.15 K. These new data reveal structure–property relationships affected by the presence and the position of the ether moiety in the molecular structure of the ether-alcohols. Compared to octan-1-ol, the presence of the ether moiety causes an increase in intermolecular hydrogen bonding interactions, resulting in higher densities. The increase in density is less pronounced for those ether-octanols that engage in intramolecular hydrogen bonding. As for the effects of the ether moiety on the dynamics, these are generally faster for the ether-alcohols compared to octan-1-ol, suggesting that hydrogen bonding between ether oxygen and hydroxy hydrogen is weaker compared to hydrogen bonding between two hydroxy groups. The activation energies obtained from an Arrhenius analysis are higher for translational motion than for momentum transfer for all alcohols. There are additional finer details across the ether alcohols for these activation barriers. These differences cancel out for the mathematical product of self-diffusion coefficient and viscosity (Dη). The effect of water impurities on the studied properties was also investigated and found to lead to small increases in densities for all alcohols. Viscosities decrease for octan-1-ol and 2-pentoxyethan-1-ol but increase for the other ether-alcohols that can engage in intramolecular hydrogen bonding.

The promise of quantum computers is that certain computational tasks might be executed exponentially faster on a quantum processor than on a classical processor1. A fundamental challenge is to build a high-fidelity processor capable of running quantum algorithms in an exponentially large computational space. Here we report the use of a processor with programmable superconducting qubits2–7to create quantum states on 53 qubits, corresponding to a computational state-space of dimension 253(about 1016). Measurements from repeated experiments sample the resulting probability distribution, which we verify using classical simulations. Our Sycamore processor takes about 200 seconds to sample one instance of a quantum circuit a million times—our benchmarks currently indicate that the equivalent task for a state-of-the-art classical supercomputer would take approximately 10,000 years. This dramatic increase in speed compared to all known classical algorithms is an experimental realization of quantum supremacy8–14for this specific computational task, heralding a much-anticipated computing paradigm.

This review is a call for mindfulness and precision when applying TNM 8 in oropharyngeal cancers. Implications, intentions, and weaknesses of TNM 8 are addressed in light of our own investigations and the published literature. In TNM 8, the impact of p16INK4Astatus on the staging of oropharyngeal SCC highlights i) that underlying evidence is scarce, ii) its stage grouping exclusively has prognostic intention, and iii) that a noncritical application of TNM 8 might negatively impact the patients' survival as the perception of TNM 8 as having therapeutic intention may lead to de-escalating treatment regimens in p16INK4A-positive cases, specifically when grouped into stage I despite the presence of neck metastasis. If other parameters from HPV positivity that also have a negative impact on the patient's survival, such as smoking or the presence of comorbidity, are neglected in therapy planning, survival outcomes might even become worse. Future studies applying TNM 8 and further investigating the value of p16INK4Aas surrogate marker for active HPV infections will identify whether or not changes in TNM 8 should have therapeutic implications in HPV-associated, only p16INK4A-positive cases or whether this impact additionally holds true for nontonsillar cancers.

Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.

In HNSCC, protein- and mRNA-expression of the antileukoproteinase SLPIare significantly inverse correlated with HPV-infection suggesting that elevated expression of SLPI protects against HPV-infections. Moreover, SLPI-expression is up-regulated in HNSCC-patients reporting a smoking habit. Here, we investigate the described correlation in other HPV-driven cancers, namely vulvar squamous cell carcinoma (VSCC). FFPE samples of 99 VSCC were analyzed by PCR for HPV-DNA-expression and by RT-qPCR for SLPI-mRNA-expression. Of 99 VSCC 10 (10.1%) are HPV-positive; 9 were HPV16; 1 HPV18; all were E6/E7 mRNA-positive. 33 of the 99 patients (33.3%) reported a smoking habit; 7 (21.1%) of these were HPV-positive. Of 66 (66.7%) non-smokers 3 (4.5%) were HPV-positive. SLPI-expression was 4.0-fold lower in HPV-positive than HPV-negative patients. Smoking resulted in 2.3-fold higher SLPI expression. The data presented here indicate that SLPI plays a pivotal role in HPV-infection not only in HNSCC but also in VSCC and possibly also in other HPV-driven cancers. This however, needs to be analyzed in future studies. Furthermore these data lead to the hypothesis that the smoking induced SLPI-increase is systemic rather than local, as assumed based on the HNSCC data.

The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with more than 780,000 deaths worldwide (as of 20 August 2020). To develop antiviral interventions quickly, drugs used for the treatment of unrelated diseases are currently being repurposed to treat COVID-19. Chloroquine is an anti-malaria drug that is used for the treatment of COVID-19 as it inhibits the spread of SARS-CoV-2 in the African green monkey kidney-derived cell line Vero1–3. Here we show that engineered expression of TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells4, renders SARS-CoV-2 infection of Vero cells insensitive to chloroquine. Moreover, we report that chloroquine does not block infection with SARS-CoV-2 in the TMPRSS2-expressing human lung cell line Calu-3. These results indicate that chloroquine targets a pathway for viral activation that is not active in lung cells and is unlikely to protect against the spread of SARS-CoV-2 in and between patients.

Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.

The ambient solubility of the mineral salts NaCl, KCl, CsCl, KBr, K2SO4and CuSO4is reported as a function of composition of mixed binary solvents consisting of water with polyethylene glycol (PEG 200), ethoxylated C9–11alcohols (C10E6) and ethoxylated, or propoxylated C10–12alcohols (C11E6P1). Solubility gradually decreases with decreasing water content and follows the order PEG 200 > C10E6> C11E6P1. Solubility of CsCl and KBr was found to be surprisingly high in neat PEG 200, on the order of 1 mol kg−1, and in neat C10E6, on the order of 0.1 mol · kg−1. The observed solubility trends are explained by the theory of hard and soft acids and bases under the consideration of the polarity of the surfactants.

Synthesis of novel trityl-nitroxyl biradicals and their performance as polarization agents in DNP-enhanced solid-state MAS NMR spectroscopy is presented. Signal enhancements in 1H, 1H → 13C CP MAS, and 13C MAS experiments obtained with these radicals dissolved in 1,1,2,2-tetrachloroethane (TCE) solution are compared with the enhancements obtained from TCE solutions of binitroxyl radicals. The signal enhancements are correlated with the distance between the radical centers of the biradicals, as determined by theoretical structure calculations. Some of the biradical TCE solutions display direct-channel resonances in 13C MAS experiments as well as indirect channel resonances induced via the proton spin reservoir. Differential scanning calorimetry reveals that only these solutions do not form any solid crystalline phases upon rapid cooling, suggesting that molecular motions needed for polarization transfer from radicals to 13C via the proton spin reservoir remain active at the experimental low temperatures of nominal 120 K. DNP magnetic field sweep enhancement profiles for selected new biradicals are presented as well. These indicate that the DNP transfer is dominated by the cross-effect mechanism.

Abstract

The aim of this study was to determine if micro-(mi-)RNAs are involved in the previously reported inverse correlation between the antileukoproteinase SLPI, HPV, and smoking habit of head and neck squamous cells carcinoma (HNSCC) patients.

Clodronate liposomes (Clo-Lip) have been widely used to deplete mononuclear phagocytes (MoPh) to study the function of these cells in vivo. Here, we revisited the effects of Clo-Lip together with genetic models of MoPh deficiency, revealing that Clo-Lip exert their anti-inflammatory effects independent of MoPh. Notably, not only MoPh but also polymorphonuclear neutrophils (PMN) ingested Clo-Lip in vivo, which resulted in their functional arrest. Adoptive transfer of PMN, but not of MoPh, reversed the anti-inflammatory effects of Clo-Lip treatment, indicating that stunning of PMN rather than depletion of MoPh accounts for the anti-inflammatory effects of Clo-Lip in vivo. Our data highlight the need for a critical revision of the current literature on the role of MoPh in inflammation.

A detailed study of the magnetic field dependent signal enhancement in solid-state dynamic nuclear polarization (DNP) experiments is presented for a specific sample consisting of AMUPol dissolved in the nonionic surfactant C10E6. C10E6displays a superposition of “direct” and “indirect channel” resonances in 13C MAS DNP NMR spectra. The shapes of the DNP enhancement profiles are essentially identical for the 1H MAS, 1H ? 13C CP MAS, and 13C MAS indirect channel signals, which confirms that the same polarization transfer process from electron to proton is responsible for the obtained enhancements of these experiments. The shape of the DNP enhancement profiles of 1H and of 13C direct channel resonances reveals that the cross effect is the dominant polarization transfer mechanism for the studied sample. The magnitudes of the 13C MAS DNP enhancement profiles for 1H ? 13C CP MAS, direct and indirect channel signals were found to be not uniform. For 1H ? 13C CP MAS and the indirect channel signals, this observation is related to relaxation effects of the methyl group carbon. For the 13C MAS direct channel resonances, differences in magnitudes are discussed in terms of preferential structural orientation of the polar ethylene oxide headgroup of C10E6toward the AMUPol radical.

Polyethylene glycol (PEG) and three related surfactants were studied by dynamic nuclear polarization (DNP) enhanced solid state NMR spectroscopy and differential scanning calorimetry (DSC). DNP enhanced solid state NMR surprisingly reveals the presence of local molecular motions that are normally understood to be inactive at temperatures ∼100 K. This surprising phenomenon could be explained by the experimentally necessary rapid freezing of the studied samples. Specifically, DSC shows that PEG 200 forms a glass upon freezing and that the three PEG-related surfactants are at least partially in a glass state or some other thermodynamic nonequilibrium state when rapidly frozen to the temperatures of the DNP enhanced solid state NMR experiments. This effect of preserving local molar motions by rapid freezing also holds true for solutions of organic solutes in the PEG 200 solvent matrix.

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A study of dynamic nuclear polarization (DNP) in polyethylene glycol and related nonionic surfactants is presented. In these experiments, we found the surprising result that DNP enhanced 13C magic angle spinning (MAS) spectra display two sets of resonances, one with broad and one with sharp spectral features that are 180° opposite in phase. These two sets indicate the presence of a direct polarization transfer channel as expected for 13C MAS experiments, and a second unexpected indirect polarization transfer channel. Plots of DNP enhancements as a function of applied magnetic field for the two resonances show a superposition of two DNP enhancement profiles for AMUpol in the nonionic surfactant C10E6. The indirect polarization channel can be suppressed by application of a string of 1H 180° pulses during 13C DNP buildup. The presence of direct and indirect polarization channels is observed in a total of four different nonionic surfactants and with three different radicals, showing that these concurring polarization mechanisms are of general nature. Therefore, the presented findings, including the demonstration of how the indirect polarization channel can be suppressed, are of high importance for all future applications of direct 13C MAS DNP.

Mutations in spike (S) protein epitopes allow SARS-CoV-2 variants to evade antibody responses induced by infection and/or vaccination. In contrast, mutations in glycosylation sites across SARS-CoV-2 variants are very rare, making glycans a potential robust target for developing antivirals. However, this target has not been adequately exploited for SARS-CoV-2, mostly due to intrinsically weak monovalent protein–glycan interactions. We hypothesize that polyvalent nano-lectins with flexibly linked carbohydrate recognition domains (CRDs) can adjust their relative positions and bind multivalently to S protein glycans, potentially exerting potent antiviral activity. Herein, we displayed the CRDs of DC-SIGN, a dendritic cell lectin known to bind to diverse viruses, polyvalently onto 13 nm gold nanoparticles (named G13-CRD). G13-CRD bound strongly and specifically to target glycan-coated quantum dots with sub-nM Kd. Moreover, G13-CRD neutralized particles pseudotyped with the S proteins of Wuhan Hu-1, B.1, Delta variant and Omicron subvariant BA.1 with low nM EC50. In contrast, natural tetrameric DC-SIGN and its G13 conjugate were ineffective. Further, G13-CRD potently inhibited authentic SARS-CoV-2 B.1 and BA.1, with <10 pM and <10 nM EC50, respectively. These results identify G13-CRD as the 1st polyvalent nano-lectin with broad activity against SARS-CoV-2 variants that merits further exploration as a novel approach to antiviral therapy.

Background: Coronavirus disease 2019 (COVID‐19) as global pandemic disease has been adversely affecting public health and social life with considerable loss of human life worldwide. Therefore, there is an urgent need for developing novel therapeutics to combat COVID‐19. The causative agent of COVID‐19 is SARS‐CoV‐2 which targets human angiotensin converting enzyme 2 (ACE2) as cellular receptor via its spike (S) protein. In this context, interfering with the binding of SARS‐CoV‐2 S protein to target molecules could provide a promising strategy to find novel therapeutic agents against SARS‐CoV‐2. The purpose of the current study was to identify potential peptidomimetics against S protein with a combination of structure‐based virtual screening methods and in vitroassays. Methods: The candidates were inspected in terms of ADME properties, drug‐likeness, as well as toxicity profiles. Additionally, molecular docking and dynamics simulations were performed to predict binding of the studied ligands to spike protein. Results: Biological evaluation of the compounds revealed that PM2 molecule exhibits some antiviral activity. Conclusion: In summary, this study highlights the importance of combining in silicoand in vitrotechniques in order to identify antiviral compound to tackle COVID‐19 and presents a new scaffold that may be structurally optimized for improved antiviral activity.

Rapid spread of SARS-CoV-2 variants C.1.2 and B.1.621 (Mu variant) in Africa and the Americas, respectively, as well as a high number of mutations in the viral spike proteins raised concerns that these variants might pose an elevated threat to human health. Here, we show that C.1.2 and B.1.621 spike proteins mediate increased entry into certain cell lines but do not exhibit increased ACE2 binding. Further, we demonstrate that C.1.2 and B.1.621 are resistant to neutralization by bamlanivimab but remain sensitive to inhibition by antibody cocktails used for COVID-19 therapy. Finally, we show that C.1.2 and B.1.621 partially escape neutralization by antibodies induced upon infection and vaccination, with escape of vaccine-induced antibodies being as potent as that measured for B.1.351 (Beta variant), which is known to be highly neutralization resistant. Collectively, C.1.2 and B.1.621 partially evade control by vaccine-induced antibodies, suggesting that close monitoring of these variants is warranted.

Snow and ice during the winter period is one of the main factors for low skid resistance resulting in elevated road accident levels and economic cost. Winter maintenance with the application of sodium chloride causes ecological damage due to chloride in road run-off. However these salt application in combination with snow ploughing is, for lack of alternatives, the weapon of choice for road authorities in order to maintain safe roads. The timing and amount of scattered de-icing agents, e.g. sodium chloride, is commonly decided by the winter service vehicle driver based on experience and/or rigid tables. With this common neglect of the variable environmental factors such as traffic intensity, precipitation, surface temperature and gradient, suboptimal results are very likely. Based on an intense research program and statistical analysis funded by all regional and national road authorities in Austria, a model to simulate the impact of these factors on skid resistance was developed. The key factor is the determination of the residual salt depending on traffic and precipitation over time, resulting in an increased freezing point of water on the road. The goal of salting is to lower the freezing point of the brine on the road below surface temperature, thus preventing freezing with significantly lowered skid resistance. Based on the presented model, it is possible to simulate the impact of winter maintenance and optimize the timing and amount of applied de-icing agents under any condition over time. Excessive or unnecessary treatments can be detected in the simulation process and therefore be eliminated by specific instructions leading to optimized winter maintenance with decreasing costs, ecological damage and consumption of resources without lowering the level of safety.

Autoimmune responses directed to macromolecular nucleic acid-protein complexes such as the nucleosome or the spliceosome are a hallmark of systemic lupus erythematosus (SLE) and related autoimmune diseases. In SLE and its animal models reactivity to these targets is believed to be caused by a defective apoptotic waste disposal system and is associated with a type I Interferon (IFN) signature. Furthermore, inappropriate activation of nucleic-acid binding Toll-like receptors (TLR) has been revealed in lupus-like conditions. Similar mechanisms may also be relevant for other systemic autoimmune diseases such as systemic sclerosis, poly/dermatomyositis and primary Sjogrens syndrome where autoantibodies to nucleic acid binding proteins are commonly observed. In contrast to these disorders, rheumatoid arthritis (RA), the most severe and most destructive joint disease, is characterized by the presence of rheumatoid factors and antibodies to citrullinated proteins, while autoimmune reactions to nucleic acid-binding proteins occur less frequently. However, data from RA patients and animal models suggest that they may nevertheless play an important role in the pathogenesis of autoimmune arthritis, as recently proposed for the heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2). To address the pathogenic role of these autoantigens animal models are indispensable. Of particular interest are models in which disease develops either spontaneously or is induced by immunization with a non-antigenic compound such as the alkane pristane. Unspecific proinflammatory stimuli such as the mineral oil pristane may trigger pathogenic autoimmune reactions which in genetically susceptible individuals may drive chronic inflammation and eventually lead to the development of disease. This review provides an overview of the involvement of RNA- and DNA-associated antigens in systemic autoimmune disorders and discusses recent data from animal models that point to a fundamental role of nucleic-acid associated autoantigens also in arthritic conditions. We will also outline a role of pristane as an inducer of apoptosis and concomitant trigger of autoimmune events.

Mutations in the spike protein generated a highly infectious and transmissible D614G variant, which is present in newly evolved fast-spreading variants. The D614G, Alpha, Beta, and Delta spike variants of SARS-CoV-2 appear to expedite membrane fusion process for entry, but the mechanism of spike-mediated fusion is unknown. Here, we reconstituted an in vitropseudovirus-liposome fusion reaction and report that SARS-CoV-2 wild-type spike is a dynamic Ca2+sensor, and D614G mutation enhances dynamic calcium sensitivity of spike protein for facilitating membrane fusion. This dynamic calcium sensitivity for fusion is found to be higher in Alpha and Beta variants and highest in Delta spike variant. We find that efficient fusion is dependent on Ca2+concentration at low pH, and the fusion activity of spike dropped as the Ca2+level rose beyond physiological levels. Thus, evolved spike variants may control the high fusion probability for entry by increasing Ca2+sensing ability.

Catalyzed and uncatalyzed rearrangement reactions of terpenoids play a major role in laboratory and industrial‐scale synthesis of fine chemicals. Herein, we present our results on the thermally induced isomerization of pinane (1). Investigation of the thermal behavior of (+)‐cis‐ (1 a) and (−)‐trans‐pinane (1 b) in a flow‐type reactor reveals significant differences in both reactivity and selectivity concerning the formation of (−)‐β‐citronellene (2) and (+)‐isocitronellene (3) as main products. Possible explanations for these results are discussed on the basis of reaction mechanism and ground‐state geometries for 1 aand 1 b. To identify side reactions caused from ene cyclizations of 2and 3, additional pyrolysis experiments were conducted that enabled the identification of almost all compounds in the network of C10H18‐hydrocarbon products formed from 1.