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Aims/hypothesis: After birth, the neonatal islets gradually acquire glucose-responsive insulin secretion, a process that is subjected to maternal imprinting. Although NEFA are major components of breastmilk and insulin secretagogues, their role for functional maturation of neonatal beta cells is still unclear. NEFA are the endogenous ligands of fatty acid receptor 1 (FFA1, encoded by Ffar1 in mice), a Gq-coupled receptor with stimulatory effect on insulin secretion. This study investigates the role of FFA1 in neonatal beta cell function and in the adaptation of offspring beta cells to parental high-fat feeding. Methods: Wild-type (WT) and Ffar1−/− mice were fed high-fat (HFD) or chow diet (CD) for 8 weeks before mating, and during gestation and lactation. Blood variables, pancreas weight and insulin content were assessed in 1-, 6-, 11- and 26-day old (P1–P26) offspring. Beta cell mass and proliferation were determined in P1–P26 pancreatic tissue sections. FFA1/Gq dependence of insulin secretion was evaluated in isolated islets and INS-1E cells using pharmacological inhibitors and siRNA strategy. Transcriptome analysis was conducted in isolated islets. Results: Blood glucose levels were higher in CD-fed Ffar1−/− P6-offspring compared with CD-fed WT P6-offspring. Accordingly, glucose-stimulated insulin secretion (GSIS) and its potentiation by palmitate were impaired in CD Ffar1−/− P6-islets. In CD WT P6-islets, insulin secretion was stimulated four- to fivefold by glucose and five- and sixfold over GSIS by palmitate and exendin-4, respectively. Although parental HFD increased blood glucose in WT P6-offspring, it did not change insulin secretion from WT P6-islets. In contrast, parental HFD abolished glucose responsiveness (i.e. GSIS) in Ffar1−/− P6-islets. Inhibition of Gq by FR900359 or YM-254890 in WT P6-islets mimicked the effect of Ffar1 deletion, i.e. suppression of GSIS and of palmitate-augmented GSIS. The blockage of Gi/o by pertussis toxin (PTX) enhanced (100-fold) GSIS in WT P6-islets and rendered Ffar1−/− P6-islets glucose responsive, suggesting constitutive activation of Gi/o. In WT P6-islets, FR900359 cancelled 90% of PTX-mediated stimulation, while in Ffar1−/− P6-islets it completely abolished PTX-elevated GSIS. The secretory defect of Ffar1−/− P6-islets did not originate from insufficient beta cells, since beta cell mass increased with the offspring's age irrespective of genotype and diet. In spite of that, in the breastfed offspring (i.e. P1–P11) beta cell proliferation and pancreatic insulin content had a genotype- and diet-driven dynamic. Under CD, the highest proliferation rate was reached by the Ffar1−/− P6 offspring (3.95% vs 1.88% in WT P6), whose islets also showed increased mRNA levels of genes (e.g. Fos, Egr1, Jun) typically high in immature beta cells. Although parental HFD increased beta cell proliferation in both WT (4.48%) and Ffar1−/− (5.19%) P11 offspring, only the WT offspring significantly increased their pancreatic insulin content upon parental HFD (5.18 µg under CD to 16.93 µg under HFD). Conclusions/interpretation: FFA1 promotes glucose-responsive insulin secretion and functional maturation of newborn islets and is required for adaptive offspring insulin secretion in the face of metabolic challenge, such as parental HFD. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 Omicron subvariants BA.1 and BA.2 exhibit reduced lung cell infection relative to previously circulating SARS-CoV-2 variants, which may account for their reduced pathogenicity. However, it is unclear whether lung cell infection by BA.5, which displaced these variants, remains attenuated. Here, we show that the spike (S) protein of BA.5 exhibits increased cleavage at the S1/S2 site and drives cell-cell fusion and lung cell entry with higher efficiency than its counterparts from BA.1 and BA.2. Increased lung cell entry depends on mutation H69Δ/V70Δ and is associated with efficient replication of BA.5 in cultured lung cells. Further, BA.5 replicates in the lungs of female Balb/c mice and the nasal cavity of female ferrets with much higher efficiency than BA.1. These results suggest that BA.5 has acquired the ability to efficiently infect lung cells, a prerequisite for causing severe disease, suggesting that evolution of Omicron subvariants can result in partial loss of attenuation. The Omicron variant is partially attenuated, likely because it fails to efficiently infect lung cells. Here, Hoffmann et. al. show that this defect can be lost during Omicron evolution as demonstrated for the subvariant BA.5 that robustly infects lung cells in vitro and in vivo. [ABSTRACT FROM AUTHOR]

This study is seeking a better understanding of polyethylene glycol (PEG) as a solvent to promote its use in chemical synthesis. The effect of adding two solutes of interest, 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) and 5-tert-butylisophthalic acid (5-TBIPA) to PEG200 (average molar weight of 200 g·mol−1) on the solution density, viscosity, and self-diffusion coefficients is monitored in a temperature range of 298.15–358.15 K to deduce how these solutes interact with the PEG200 solvent. The effect of water, the most common impurity in PEGs, is also monitored and found to be nearly negligibly small. Addition of (5-TBIPA) increases solution density and viscosity. Combined with the observation that 5-TBIPA consistently self-diffuses at about half the rate as PEG200 at all investigated experimental conditions, this suggests strong attractive solute–solvent interactions likely through hydrogen bonding interactions. In contrast, addition of TEMPO causes lower solution densities and viscosities suggesting that the solute–solvent interactions of TEMPO lead to an overall weakening of the intermolecular interactions present compared to neat PEG200. Inspection of the viscosity and self-diffusion temperature dependence reveals slight deviations from the Arrhenius equation. Interestingly, the activation energies obtained from the viscosity and the self-diffusion data are essentially identical in values suggesting that the same dynamic processes and thus the same activation barriers govern translational motion and momentum transfer in these PEG200 solutions. [ABSTRACT FROM AUTHOR]

The availability of effective vaccines and a high vaccination rate allowed the recent mitigation, or even withdrawal, of many protective measures for containing the SARS CoV-2 pandemic. At the same time, new and highly mutated variants of the virus are found to have significantly higher transmissibility and reduced vaccine efficacy, thus causing high infection rates during the third year of the pandemic. The combination of reduced measures and increased infectivity poses a particular risk for unvaccinated individuals, including animals susceptible to the virus. Among the latter, non-human primates (NHPs) are particularly vulnerable. They serve as important models in various fields of biomedical research and because of their cognitive capabilities, they receive particular attention in animal welfare regulations around the world. Yet, although they played an extraordinarily important role for developing and testing vaccines against SARS-CoV-2, the protection of captive rhesus monkeys against Covid-19 has rarely been discussed. We here report upon twofold mRNA vaccination of a cohort of 19 elderly rhesus monkeys (Macaca mulatta) against infection by SARS-CoV-2. All animals were closely monitored on possible side effects of vaccination, and were tested for neutralising antibodies against the virus. The data show that vaccination of rhesus monkeys is a safe and reliable measure to protect these animals against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

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Alzheimer's disease (AD) is a neurodegenerative disease whose molecular mechanisms are activated several years before cognitive symptoms appear. Genotype-based prediction of the phenotype is thus a key challenge for the early diagnosis of AD. Machine learning techniques that have been proposed to address this challenge do not consider known biological interactions between the genes used as input features, thus neglecting important information about the disease mechanisms at play. To mitigate this, we first extracted AD subnetworks from several protein–protein interaction (PPI) databases and labeled these with genotype information (number of missense variants) to make them patient-specific. Next, we trained Graph Neural Networks (GNNs) on the patient-specific networks for phenotype prediction. We tested different PPI databases and compared the performance of the GNN models to baseline models using classical machine learning techniques, as well as randomized networks and input datasets. The overall results showed that GNNs could not outperform a baseline predictor only using the APOE gene, suggesting that missense variants are not sufficient to explain disease risk beyond the APOE status. Nevertheless, our results show that GNNs outperformed other machine learning techniques and that protein–protein interactions lead to superior results compared to randomized networks. These findings highlight that gene interactions are a valuable source of information in predicting disease status. [ABSTRACT FROM AUTHOR]

The discovery of topological states of matter has led to a revolution in materials research. When external or intrinsic parameters break symmetries, global properties of topological materials change drastically. A paramount example is the emergence of Weyl nodes under broken inversion symmetry. While a rich variety of non-trivial quantum phases could in principle also originate from broken time-reversal symmetry, realizing systems that combine magnetism with complex topological properties is remarkably elusive. Here, we demonstrate that giant open Fermi arcs are created at the surface of ultrathin hybrid magnets where the Fermi-surface topology is substantially modified by hybridization with a heavy-metal substrate. The interplay between magnetism and topology allows us to control the shape and the location of the Fermi arcs by tuning the magnetization direction. The hybridization points in the Fermi surface can be attributed to a non-trivial mixed topology and induce hot-spots in the Berry curvature, dominating spin and charge transport as well as magneto-electric coupling effects. It has been predicted that elemental Iron, with low dimensionality, will be a topological metal hosting Weyl nodes. Here, Chen et al. grow iron on tungsten, a heavy metal with a strong spin-orbit interaction, and using momentum microscopy, show the emergence of giant open Fermi arcs which can be shaped by varying the magnetization of the iron. [ABSTRACT FROM AUTHOR]

The transmembrane serine protease 2 (TMPRSS2) primes the SARS-CoV-2 Spike (S) protein for host cell entry and represents a promising target for COVID-19 therapy. Here we describe the in silico development and in vitro characterization of peptidomimetic TMPRSS2 inhibitors. Molecular docking studies identified peptidomimetic binders of the TMPRSS2 catalytic site, which were synthesized and coupled to an electrophilic serine trap. The compounds inhibit TMPRSS2 while demonstrating good off-target selectivity against selected coagulation proteases. Lead candidates are stable in blood serum and plasma for at least ten days. Finally, we show that selected peptidomimetics inhibit SARS-CoV-2 Spike-driven pseudovirus entry and authentic SARS-CoV-2 infection with comparable efficacy as camostat mesylate. The peptidomimetic TMPRSS2 inhibitors also prevent entry of recent SARS-CoV-2 variants of concern Delta and Omicron BA.1. In sum, our study reports antivirally active and stable TMPRSS2 inhibitors with prospects for further preclinical and clinical development as antiviral agents against SARS-CoV-2 and other TMPRSS2-dependent viruses. This study describes the development and characterization of peptidomimetic inhibitors of TMPRSS2, which primes the Spike protein of SARS-CoV-2. The inhibitors are shown to prevent SARS-CoV-2 infection in cells as efficiently as camostat mesylate. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air–liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation. [ABSTRACT FROM AUTHOR]

Several effective SARS-CoV-2 vaccines are currently in use, but effective boosters are needed to maintain or increase immunity due to waning responses and the emergence of novel variants. Here we report that intranasal vaccinations with adenovirus 5 and 19a vectored vaccines following a systemic plasmid DNA or mRNA priming result in systemic and mucosal immunity in mice. In contrast to two intramuscular applications of an mRNA vaccine, intranasal boosts with adenoviral vectors induce high levels of mucosal IgA and lung-resident memory T cells (TRM); mucosal neutralization of virus variants of concern is also enhanced. The mRNA prime provokes a comprehensive T cell response consisting of circulating and lung TRM after the boost, while the plasmid DNA prime induces mostly mucosal T cells. Concomitantly, the intranasal boost strategies lead to complete protection against a SARS-CoV-2 infection in mice. Our data thus suggest that mucosal booster immunizations after mRNA priming is a promising approach to establish mucosal immunity in addition to systemic responses. While current COVID-19 vaccines provide certain protection, more effective vaccination strategies are still desirable. Here the authors show, using mouse vaccination models, that priming with a systemic mRNA and boosting with an intranasal adenoviral vector vaccine induces comprehensive T cell and mucosal immunity. [ABSTRACT FROM AUTHOR]

The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, the cause of the COVID-19 pandemic. However, this bat virus was most likely unable to directly infect humans since its Spike (S) protein does not interact efficiently with the human ACE2 receptor. Here, we show that a single T403R mutation increases binding of RaTG13 S to human ACE2 and allows VSV pseudoparticle infection of human lung cells and intestinal organoids. Conversely, mutation of R403T in the SARS-CoV-2 S reduces pseudoparticle infection and viral replication. The T403R RaTG13 S is neutralized by sera from individuals vaccinated against COVID-19 indicating that vaccination might protect against future zoonoses. Our data suggest that a positively charged amino acid at position 403 in the S protein is critical for efficient utilization of human ACE2 by S proteins of bat coronaviruses. This finding could help to better predict the zoonotic potential of animal coronaviruses. The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, but its spike protein doesn't efficiently bind human ACE2. Here, the authors show that exchange of spike residue 403 between RaTG13 and SARS-CoV-2 spike proteins affects binding to human ACE2 and entry of pseudotyped viruses. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has emerged as a previously unknown zoonotic coronavirus that spread worldwide causing a serious pandemic. While reliable nucleic acid–based diagnostic assays were rapidly available, only a limited number of validated serological assays were available in the early phase of the pandemic. Here, we evaluated a novel flow cytometric approach to assess spike-specific antibody responses.HEK 293T cells expressing SARS-CoV-2 spike protein in its natural confirmation on the surface were used to detect specific IgG and IgM antibody responses in patient sera by flow cytometry. A soluble angiotensin-converting-enzyme 2 (ACE-2) variant was developed as external standard to quantify spike-specific antibody responses on different assay platforms. Analyses of 201 pre-COVID-19 sera proved a high assay specificity in comparison to commercially available CLIA and ELISA systems, while also revealing the highest sensitivity in specimens from PCR-confirmed SARS-CoV-2-infected patients. The external standard allowed robust quantification of antibody responses among different assay platforms. In conclusion, our newly established flow cytometric assay allows sensitive and quantitative detection of SARS-CoV-2-specific antibodies, which can be easily adopted in different laboratories and does not rely on external supply of assay kits. The flow cytometric assay also provides a blueprint for rapid development of serological tests to other emerging viral infections [ABSTRACT FROM AUTHOR]

Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target. The tumor microenvironment is composed of many cell types that crosstalk to modulate local immunity. Here the authors show that Amyloid β proteins from cancer-associated fibroblasts (CAF) induce neutrophil extracellular trap (NET) production by neutrophils, while NET feeds back to activate CAF, thereby implicating Amyloid β as a potential therapy target. [ABSTRACT FROM AUTHOR]

Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease. Immunoglobulin A (IgA) has two subclasses, IgA1 and IgA2, but differential effects on inflammation are unclear. Here the authors show that IgA2, when compared with IgA1, has stronger pro-inflammatory functions associated with changed glycosylation and higher disease scores in patients with rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

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. Expression of TMPRSS2—a protease that activates SARS-CoV-2 for entry into cells—renders SARS-CoV-2 insensitive to chloroquine. [ABSTRACT FROM AUTHOR]

Employing algorithms of scientific computing often comes in hand with finding a trade-off between accuracy and performance. Novel parallel hardware and algorithms only slightly improve these issues due to the increasing size of the problems. While high accuracy is inevitable for most problems, there are parts in scientific computing that allow us to introduce approximation. Therefore, in this paper we give answers to the following questions: (1) Can we exploit different approximate computing strategies in scientific computing? (2) Is there a strategy to combine approaches? To answer these questions, we apply different approximation strategies to a widely used iterative solver for linear systems of equations. We show the advantages and the limits of each strategy and a way to configure a combination of strategies according to a given relative error. Combining orthogonal strategies as an overall concept gives us significant opportunities to increase the performance. [ABSTRACT FROM AUTHOR]

The ferritic steel 16Mo3 coated with the nickel-base alloy IN625mod by high-velocity oxy-fuel (HVOF) spraying was investigated under uniaxial and biaxial fatigue loading at 200 and 500 °C. Furthermore, bulk HVOF-sprayed specimens of the coating material IN625mod were also investigated under uniaxial isothermal fatigue loading at 200 and 500 °C. Moreover, the thermo-mechanical fatigue behavior of 16Mo3 was studied under in-phase (IP) and out-of-phase (OP) loading between 200 and 500 °C. The fatigue lives of the bulk coating and the compound material are presented. In particular, the thermo-mechanical OP loading leads to a strong reduction of the lifetimes compared to the IP loading. A conservative estimation of the fatigue lives of the thermo-mechanical loading can be given by isothermal tests at 500 °C. The comparison of the uniaxial loading with the biaxial loading cases shows reasonable coincidence by using the distortion energy hypothesis according to von Mises. [ABSTRACT FROM AUTHOR]

Chiral magnets are an emerging class of topological matter harboring localized and topologically protected vortex-like magnetic textures called skyrmions, which are currently under intense scrutiny as an entity for information storage and processing. Here, on the level of micromagnetics we rigorously show that chiral magnets can not only host skyrmions but also antiskyrmions as least energy configurations over all non-trivial homotopy classes. We derive practical criteria for their occurrence and coexistence with skyrmions that can be fulfilled by (110)-oriented interfaces depending on the electronic structure. Relating the electronic structure to an atomistic spin-lattice model by means of density functional calculations and minimizing the energy on a mesoscopic scale by applying spin-relaxation methods, we propose a double layer of Fe grown on a W(110) substrate as a practical example. We conjecture that ultra-thin magnetic films grown on semiconductor or heavy metal substrates with C2v symmetry are prototype classes of materials hosting magnetic antiskyrmions. [ABSTRACT FROM AUTHOR]

Twenty-four aquatic neophytes have been introduced to Germany so far and at least 16 non-native species established stable populations in northern and north-western Germany. Invasive aquatic neophytes can cause serious ecological and economic problems in lakes and other freshwater ecosystems. In the presented study, a species distribution model was used to identify possible habitats for neophytes in Bavaria (Southern Germany) and to predict which Bavarian lakes might become suitable habitats for neophytes due to climate change. A total of 55 Bavarian lakes were fitted with high-resolution temperature loggers as part of this monitoring programme. Furthermore, the physical and chemical properties of the lakes were determined and verified in regular intervals. The presence or absence of the native thermophilic macrophyte Najas marina L. was used as an indicator to determine whether a lake was a suitable habitat for neophytes. The results revealed that the spread of neophytes in Bavaria is mainly limited by spring and summer water temperature. In contrast, nutrient concentrations in the water showed no significant influence. Suitable lakes reached temperatures of at least 15 °C for 2 months during spring and at least 20 °C for 2 months during summer. By comparison, the water temperatures in lakes classified as not suitable for neophytes were 2–5 °C lower. The computed predictions for the estimated temperature increase of 1.4 °C, for the period between 2021 and 2050, indicate that up to 70 % of Bavarian lakes might become suitable habitats for neophytes. [ABSTRACT FROM AUTHOR]

Neutrophil granulocytes possess a large arsenal of pro-inflammatory substances and mechanisms that empower them to drive local acute immune reactions to invading microorganisms or endogenous inflammatory triggers. The use of this armory needs to be tightly controlled to avoid chronic inflammation and collateral tissue damage. In gout, inflammation arises from precipitation of uric acid in the form of needle-shaped monosodium urate crystals. Inflammasome activation by these crystals in local immune cells results in a rapid and dramatic recruitment of neutrophils. This neutrophil influx is accompanied by the infamously intense clinical symptoms of inflammation during an acute gout attack. Neutrophilic inflammation however is equipped with a built-in safeguard; activated neutrophils form neutrophil extracellular traps (NETs). At the very high neutrophil densities that occur at the site of inflammation, NETs build aggregates that densely pack the monosodium urate (MSU) crystals and trap and degrade pro-inflammatory mediators by inherent proteases. Local removal of cytokines and chemokines by aggregated NETs explains how acute inflammation can stop in the consistent presence of the inflammatory trigger. Aggregated NETs resemble early stages of the typical large MSU deposits that constitute the pathognomonic structures of gout, tophi. Although tophi contribute to muscosceletal damage and mortality in patients with chronic gout, they can therefore be considered as a payoff that is necessary to silence the intense inflammatory response during acute gout. [ABSTRACT FROM AUTHOR]

Seven squamous cell carcinoma cell lines were disintegrated from biopsies of patients with head and neck cancer. Genotyping tests verified the authenticity and the human origin of all seven lines. The cell lines designated as University of Kiel, Head and Neck (UKHN) -1 to -3 and UKHN-6 to -9 were subjected to flow cytometry and indirect immunofluorescence to assess aberrant DNA content. To confirm the squamous epithelial origin of the cells, the cytokeratin profile was immunocytologically analysed. The cell lines showed individual differences in mitotic frequency. UKHN-1, -6, -7 and -9 grew as monolayers, whereas UKHN-2, -3, and -8 tend to multilayer stratification. Overexpression of LOXL4 and Pim-1 proteins as distinctive features of head and neck carcinomas were shown in all seven cell lines. Inoculating SCID mice with these cell lines resulted in tumour formation, hence corroborating the tumourigenicity of all seven cell lines. The cell lines were also tested for high-risk HPV types using different DNA-based assays and found to be negative. [ABSTRACT FROM AUTHOR]

Pulsed electron paramagnetic resonance (EPR) spectroscopy using microwaves at two frequencies can be employed to measure distances between pairs of paramagnets separated by up to 10 nm. The method, combined with site-directed mutagenesis, has become increasingly popular in structural biology for both its selectivity and capability of providing information not accessible through more standard methods such as nuclear magnetic resonance and X-ray crystallography. Despite these advantages, EPR distance measurements suffer from poor sensitivity. One contributing factor is technical: since 65 MHz typically separates the pump and detection frequencies, they cannot both be located at the center of the pseudo-Lorentzian microwave resonance of a single-mode resonator. To maximize the inversion efficiency, the pump pulse is usually placed at the center of the resonance, while the observer frequency is placed in the wing, with consequent reduction in sensitivity. Here, we consider an alternative configuration: by spacing pump and observer frequencies symmetrically with respect to the microwave resonance and by increasing the quality factor, valuable improvement in the signal-to-noise ratio can be obtained. [ABSTRACT FROM AUTHOR]

The quality of the adaptive immune response depends on the differentiation of distinct CD4+ helper T cell subsets, and the magnitude of an immune response is controlled by CD4+Foxp3+ regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the β-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3+ Treg cell subpopulation that was unable to control the maturation of IRF4+PD-L2+ dendritic cells required for the development of TH2 responses in vivo. [ABSTRACT FROM AUTHOR]