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Booster doses for COVID-19 vaccinations have been shown to amplify the waning immune response after primary vaccination and to enhance protection against emerging variants of concern (VoCs). Here, we aimed to assess the immunogenicity and safety of a booster dose of an inactivated whole-virus COVID-19 vaccine (VLA2001) after primary vaccination with 2 doses of either VLA2001 or ChAdOx1-S (Oxford-Astra Zeneca), including the cross-neutralization capacity against the Delta and Omicron VoCs. This interim analysis of an open-label extension of a randomized, controlled phase 3 trial assessed a single booster dose of an inactivated whole-virus COVID-19 vaccine (VLA2001) in healthy or medically stable adults aged 18 years and above, recruited in 21 clinical sites in the UK, who had previously received two doses of either VLA2001 or ChAdOx1-S. Safety outcomes were frequency and severity of solicited injection site and systemic reactions within 7 days after booster vaccination as well as frequency and severity of any unsolicited adverse events (AE) after up to 6 months. Immunogenicity outcomes were the immune response to ancestral SARS-CoV-2 assessed 14 days post booster expressed as geometric mean titres (GMT), GMT fold ratios and seroconversion of specific neutralizing antibodies and S-protein binding IgG antibodies. Immunogenicity against the Delta and Omicron VoCs was assessed as a post-hoc outcome with a pseudovirus neutralization antibody assay. This study is registered with ClinicalTrials.gov, NCT04864561 , and is ongoing. A booster dose of VLA2001 was administered to 958 participants, of whom 712 had been primed with VLA2001, and 246 with ChAdOx1-S. Within 7 days following these booster doses, 607 (63.4%) participants reported solicited injection site reactions, and 487 (50.8%) reported solicited systemic reactions. Up to 14 days post booster, 751 (78.4%) participants reported at least one adverse event. The tolerability profile of a booster dose of VLA2001 was similar in VLA2001-primed and ChAdOx1-S-primed participants. In VLA2001-primed participants, the GMT (95% CI) of neutralizing antibodies increased from 32.5 (22.8, 46.3) immediately before to 521.5 (413.0, 658.6) 2 weeks after administration of the booster dose, this corresponds to a geometric mean fold rise (GMFR) of 27.7 (20.0, 38.5). Compared to 2 weeks after the second priming dose, the GMFR was 3.6 (2.8, 4.7). In the ChAdOx1-S primed group, the GMT (95% CI) of neutralizing antibodies increased from 65.8 (43.9, 98.4) immediately before to 188.3 (140.3, 252.8) 2 weeks after administration of the booster dose, a geometric mean fold rise (GMFR) of 3.0 (2.2, 4.0). Compared to 2 weeks after the second priming dose, the GMFR was 1.6 (1.1, 2.2). For S-protein binding IgG antibodies, the pre- versus post-booster GMT fold ratio (95% CI) was 34.6 (25.0, 48.0) in the VLA2001-primed group and 4.0 (3.0, 5.2) in the ChAdOx1-S-primed group. Compared to 2 weeks after the second priming dose, the GMT fold rise of IgG antibodies was 3.8 (3.2, 4.6) in the VLA2001-primed group and 1.2 (0.9, 1.6) in the ChAdOx1-S-primed group. The GMT against Delta (B.1.617.2) and Omicron (BA.4/5) increased from 4.2 to 260, and from 2.7 to 56.7, respectively, when boosting subjects previously primed with VLA2001. Following the boost, 97% of subjects primed with VLA2001 had detectable Delta- and 94% Omicron-neutralizing antibodies. In subjects primed with ChAdOx1-S, the GMT against Delta and Omicron titres increased from 9.1 to 92.5, and from 3.6 to 12.3, respectively. After boosting, 99% of subjects primed with ChAdOx1-S had detectable Delta- and 70% Omicron-neutralizing antibodies. In both VLA2001 and ChAdOx1-S primed subjects, the additional VLA2001 dose boosted T cell responses against SARS-CoV-2 antigens to levels above those observed before the booster dose. A booster dose of VLA2001 was safe and well tolerated after primary immunization with VLA2001 and ChAdOx1-S. The tolerability of a booster dose of VLA2001 was similar to the favourable profile observed after the first and second priming doses. Both in a homologous and a heterologous setting, boosting resulted in higher neutralizing antibody titres than after primary immunization and significant increases in cross-neutralization titres against Delta and Omicron were observed after the booster dose. These data support the use of VLA2001 in booster programmes in ChadOx1-S primed groups. • A booster dose of VLA2001 was well-tolerated in participants previously primed with 2 doses of either ChAdOx1-S or VLA2001. • Neutralizing titers after a booster dose of VLA2001 were higher than after priming. • Neutralizing titers after a booster doses were 28-fold (VLA2001 primed) and 3-fold (ChAdOx1-S primed) higher than after booster. [ABSTRACT FROM AUTHOR]

• Stromal cells are of mesenchymal origin and provide the structure and support the function of organs. • Multiomics has unveiled the origins and previously unknown functional diversity of stromal cells. • Stromal cells such as fibroblasts are now considered members of the innate immune system. • Specific therapeutic targeting of pathogenic fibroblast subsets shows promise for curing inflammatory diseases. In the last fifteen years it has become apparent that tissue-resident mesenchymal cells such as fibroblasts, which are the structural elements of all organs, play a cardinal role in the pathology of immune-mediated inflammatory diseases. We now know that all fibroblasts originate from universal pan-organ cellular ancestors and that they are diversified into more specific subsets according to the functional needs of their home tissue-and its activation state. In arthritis, a plethora of activated joint-resident and migrating fibroblast types have been recently described that are central for pathogenesis and persistence of inflammatory joint-disease. Here we provide a current overview on the multiple inflammatory and immune-related functions of fibroblasts and how they could be curbed to induce long-lasting abatement of disease. [ABSTRACT FROM AUTHOR]

The influenza virus hemagglutinin (HA) facilitates viral entry into target cells. Cleavage of HA by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease (TTSP) TMPRSS2 has been identified as an HA activator in cell culture and in the infected host. However, it is less clear whether TMPRSS2-related enzymes can also activate HA for spread in target cells. Moreover, the activity of cellular serine protease inhibitors against HA-activating TTSPs is poorly understood. Here, we show that TMPRSS11A, another member of the TTSP family, cleaves and activates the influenza A virus (FLUAV) HA and the Middle East respiratory syndrome coronavirus spike protein (MERS-S). Moreover, we demonstrate that TMPRSS11A is expressed in murine tracheal epithelium, which is a target of FLUAV infection, and in human trachea, suggesting that the protease could support FLUAV spread in patients. Finally, we show that HA activation by the TMPRSS11A-related enzymes human airway tryptase and DESC1, but not TMPRSS11A itself, is blocked by the cellular serine protease inhibitor hepatocyte growth factor activator inhibitor type-1 (HAI-1). Our results suggest that TMPRSS11A could promote FLUAV spread in target cells and that HA-activating TTSPs exhibit differential sensitivity to blockade by cellular serine protease inhibitors. [ABSTRACT FROM AUTHOR]

Abstract Reactive oxygen species (ROS) are created in cells during oxidative phosphorylation by the respiratory chain in the mitochondria or by the family of NADPH oxidase (NOX) complexes. The first discovered and most studied of these complexes, NOX2, mediates the oxidative burst in phagocytes. ROS generated by NOX2 are dreadful weapons: while being essential to kill ingested pathogens they can also cause degenerative changes on tissue if production and release are not balanced by sufficient detoxification. In the last fifteen years evidence has been accumulating that ROS are also integral signaling molecules and are important for regulating autoimmunity and immune-mediated inflammatory diseases. It seems that an accurate redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity (the bright side of ROS) and minimizes collateral tissue damage (the dark side of ROS). Herein, we review studies from rodent models of arthritis, lupus, and neurodegenerative diseases that show that low NOX2-derived ROS production is linked to disease and elaborate on the underlying cellular and molecular mechanisms and the translation of these results to disease in humans. Highlights • ROS are created during oxidative phosphorylation and by NADPH oxidase complexes. • ROS-induced signaling regulates immune reactions and can prevent autoimmunity. • Prolonged and uncontrolled ROS production can cause collateral tissue damage. • Temporally and spatial balance of ROS levels is essential to sustain homeostasis. [ABSTRACT FROM AUTHOR]

Abstract Preoperative discrimination of solitary cervical branchial cleft cysts from cystic lymph node metastasis often is challenging. Surgical excision of the cystic formation and consecutive histopathological examination of tissue specimens are the only means resulting in the correct diagnosis. However, in case of malignancies surgery on the lateral neck prior to the definitive treatment is considered to negatively influence the patients' outcome. The rate of cystic lymph node metastasis in patients presenting with a lateral branchial cleft cyst, localization of the primary tumour and oncological outcome were investigated. Retrospective chart review of 131 patients presenting clinically with solitary lateral cervical cysts between. A malignant tumour was detected in 12 patients (9.2%). Malignant tumours were significantly more frequent in patients older than 40 years of age (22.0%; p = 0.0001). In patients older than 40 years of age with solitary lateral cervical cysts a malignancy should be presumed. [ABSTRACT FROM AUTHOR]

The positive prognostic value of HPV-infections in oropharyngeal squamous cell cancer (OSCC) patients has led to the initiation of prospective clinical trials testing the value of treatment de-escalation. It is unclear how to define patients potentially benefiting from de-escalated treatment, whether a positive smoking history impacts survival data and what kind of de-escalation might be best. Here, we investigate the effect of HPV-status, smoking habit and treatment design on overall survival (OS) and progression free survival (PFS) of 126 patients with tonsillar SCC (TSCC) who underwent CO2-laser-surgery and risk adapted adjuvant treatment. HPV-DNA-, HPV-mRNA-, and p16INK4A-expression were analysed and results were correlated to OS and PFS. Factors tested for prognostic value included HPV-status, p16INK4A-protein expression, therapy and smoking habit. Log rank test and p-values ≤0.05 defined significant differences between groups. The highest accuracy of data with highest significance in this study is given when the HPV-RNA-status is considered. Using p16INK4A-expression alone or in combination with HPV-DNA-status, would have misclassified 23 and 7 patients, respectively. Smoking fully abrogates the positive impact of HPV-infection in TSCC on survival. Non-smoking HPV-positive TSCC patients show 10-year OS of 100% and 90.9% PFS when treated with adjuvant RCT. The presented data show that high-precision HPV-detection methods are needed, specifically when treatment decisions are based on the results. Furthermore, smoking habit should be included in all studies and clinical trials testing HPV-associated survival. Adjuvant RCT especially for HPV-positive non-smokers may help to avoid distant failure. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • C.1.2 and B.1.621 spike proteins mediate increased entry into certain cell lines • Augmented cell entry is not caused by increased ACE2 binding • C.1.2 and B.1.621 are resistant to neutralization by bamlanivimab • C.1.2 and B.1.621 partially escape neutralization by vaccine-induced antibodies SARS-CoV-2 variants C.1.2 and B.1.621 (Mu) rapidly spread in Africa and the Americas, respectively. Arora et el. show that C.1.2 and B.1.621 spike proteins enable increased entry into certain cell lines, are resistant to neutralization by the therapeutic antibody bamlanivimab, and partially escape neutralization by infection- or vaccination-induced antibodies. [ABSTRACT FROM AUTHOR]

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 vitro pseudovirus-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. [Display omitted] • SARS-CoV-2 spike protein is a dynamic calcium sensor • Ca2+ and low pH triggers spike conformational change for membrane fusion • Evolved spike variants show correlation in calcium sensitivity and fusion activity • Pre-triggering spike virion with low pH and Ca2+ attenuates membrane fusion Singh et al. show that low pH and Ca2+ facilitate SARS-CoV-2 spike-driven membrane fusion. Ca2+ drives a pre- to post-fusion conformational change of the spike protein. SARS-CoV-2 spike variants of concern have evolved with enhanced dynamic calcium sensitivity, which increases fusion activity and cell entry. [ABSTRACT FROM AUTHOR]

Polyethylene glycol (PEG) is an industrial commodity produced for applications foremost in the medial and personal care business. This review focuses on the much less explored application of using PEG as a chemical solvent. This review highlights some of the successful chemical synthesis strategies to illustrate the advantages of using PEG as an environmentally friendly reaction medium. These advantages include its ability to (a) dissolve a wide range of chemicals including mineral salts, (b) serve as a catalyst because of its acid/base functionalities, (c) complex metal cations, and (d) engage in redox chemistry. New developments of combining PEG with other green solvents and/or functionalizing PEGs are covered as well. The present state of physicochemical studies of PEG as a solvent is also provided and clearly shows the need for future research in this area to further promote the effective use of PEG as a medium for chemistry. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Najas marina ssp. intermedia (Wolfg. ex Gorski) Casper (Najas intermedia) is a thermophile macrophyte species native to Central Europe, which started mass spreading across Southern Germany about 10 years ago, almost reaching the intensity of the invasive neophyte Elodea nuttallii. As part of a study to examine the spread of N. intermedia with regard to climate change, predominant populations of N. intermedia were continuously monitored. The observations revealed that some areas and lakes remained free of N. intermedia, although water temperatures and light conditions were similar to locations with predominant populations of N. intermedia. As a result, growth experiments were conducted to show that the properties of the lake sediment can affect the growth of N. intermedia. Four lakes without populations of N. intermedia and with different environmental conditions were chosen as experimental sites. During the experiments eight different sediments from four different lakes were used. Five sediments were collected from sites with extensive or predominant Najas populations, three sediments originated from locations with no or minor amounts of N. intermedia. The experiments revealed that the sediment from different lakes as well as from different locations within the same lake significantly differs in nutrient concentration and density and that those differences can affect the growth of N. intermedia. Plants growing in nutrient-rich sediment (SRP: 15mg 100g−1 soil, Total-P: 50mg 100g−1 soil) reached with 43.1 (±6.9)mmday−1, compared to 6.9 (±2.0)mmday−1 in sediment with lower nutrient concentrations (SRP: 2mg 100g−1 soil, Total-P: 10mg 100g−1 soil), higher growth rates and were less affected by the density of the sediment. The density of the sediment, on the other hand, played a significant role under conditions with low nutrient concentrations, respectively when sediments with similar nutrient concentrations were compared. For example, a comparison of sediments with a soluble phosphor concentration of 2mg 100g−1 soil and a total phosphor concentration of 10mg 100g−1 soil showed that plants growing in sediment with 75.7% particles>0.063mm reached twice the growth rates (6.9±2.0mmday−1) than plant growing in sediment with only 47% particles >0.063mm (1.7±0.6mmday−1). Nutrient-poor sediment (SRP: <1mg 100g−1 soil, Total-P: <1mg 100g−1 soil), inhibited the growth of N. intermedia (0.8±0.2mmday−1). The significantly different growth rates of N. intermedia show that the lake sediment, respectively the nutrient concentration and density must be included in assessments and models regarding the growth and spread of N. intermedia. [Copyright &y& Elsevier]

Abstract: It has been proposed that p16INK4A qualifies as a surrogate marker for viral oncogene activity in head and neck cancer (HNSCC). By analyzing 78 HNSCC we sought to validate the accuracy of p16INK4A as a reliable marker of active HPV infections in HNSCC. To this end we determined HPV DNA (HPVD) and E6*I mRNA (HPVR) expression status and correlated these results with p16INK4A staining. In tonsillar SCC 12/20 were HPVD+ and 12/12 of these showed active HPV infections whereas in non-tonsillar SCC 10/58 were HPVD+ and 5/10 showed active HPV infections. Thus, we prove about 8% of non-tonsillar SCC to be also correlated with HPV-associated carcinogenesis. Strikingly, 3/14 (21.4%) of tonsillar and non-tonsillar HPVD+/HPVR+ cases did not show p16INK4A overexpression and these cases would have been missed when applying initial p16INK4A staining only. However, in 13 cases negative for HPV, DNA p16INK4A was overexpressed. In conclusion, our data confirm tonsillar SCC to be predominantly but not only associated with active HPV infections. Furthermore, our data show that p16INK4A overexpression is not evident in a subgroup of HNSCC with active HPV infection. Definitive HPV data should therefore be utilized in diagnostics and treatment modalities of HPV positive and HPV negative HNSCC patients, resulting in a paradigm shift regarding these obviously different tumor entities. [Copyright &y& Elsevier]

The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B.1.617.2, emerged in India and has spread to over 80 countries. B.1.617.2 replaced B.1.1.7 as the dominant virus in the United Kingdom, resulting in a steep increase in new infections, and a similar development is expected for other countries. Effective countermeasures require information on susceptibility of B.1.617.2 to control by antibodies elicited by vaccines and used for coronavirus disease 2019 (COVID-19) therapy. We show, using pseudotyping, that B.1.617.2 evades control by antibodies induced upon infection and BNT162b2 vaccination, although to a lesser extent as compared to B.1.351. We find that B.1.617.2 is resistant against bamlanivimab, a monoclonal antibody with emergency use authorization for COVID-19 therapy. Finally, we show increased Calu-3 lung cell entry and enhanced cell-to-cell fusion of B.1.617.2, which may contribute to augmented transmissibility and pathogenicity of this variant. These results identify B.1.617.2 as an immune evasion variant with increased capacity to enter and fuse lung cells. [Display omitted] • B.1.617.2 spike mediates enhanced entry into Calu-3 and Caco-2 cells • B.1.617.2 spike fuses cells more efficiently than wild-type spike • B.1.617.2 spike is bamlanivimab resistant • B.1.617.2 spike evades neutralizing antibodies induced by infection or vaccination The B.1.617.2 (Delta) variant challenges efforts to control the COVID-19 pandemic. Arora et al. provide evidence that B.1.617.2 may enter human lung cells and fuse neighboring cells more efficiently than the initially circulating virus. Further, the study suggests that B.1.617.2 may evade neutralization by antibodies elicited upon infection and vaccination. [ABSTRACT FROM AUTHOR]

Abstract: Infections with human papillomaviruses are divided basically into three different infection types: those producing specific clinically visible lesions, those remaining subclinical, and those being latent. The assumed infection type thought to be present in tissue specimens has influence on the conclusions that can be made from an analysis, i.e. whether or not the HPV infection has a causal relationship with other epidemiological or molecular investigation observations. To determine whether HPV DNA detection in different entities of the upper aerodigestive tract represents a coincidental, persistent/latent or specific infection, 20 clinically intact mucosa specimens of the upper aerodigestive tract, 20 sinonasal polyps, 26 inverted papillomas, and 20 squamous cell carcinomas of the paranasal sinuses were investigated. HPV DNA was not detectable in specimens derived from clinically intact mucosa or in nasal polyps. Yet, three out of 26 inverted papillomas were HPV-positive, each showing double infection with HPV6 and 11. Four out of 20 squamous cell carcinomas were HPV16 positive. To our knowledge, we are presenting the first study contemporaneously analyzing benign as well as malignant non-proliferative and proliferative mucosal entities whilst applying identical methodical standards. The data corroborate the hypothesis that HPV DNA demonstration in tissue specimens represents a specific infection of the mucosa of the upper aerodigestive tract. It can thus be assumed that there is a causative involvement of HPV infections in the alteration of cell proliferation and in the case of infection with high risk HPV types even on progression to malignant transformation. [Copyright &y& Elsevier]

Abstract: Depending on the primary tumour''s anatomical location, squamous cell carcinoma of the head and neck (HNSCC) shows HPV prevalences between 20 and 30% for oro-, hypopharyngeal as well as laryngeal SCC and up to over 50% for SCC of the Waldeyer''s tonsillar ring. There is persistent controversy on the role of HPV infection in HNSCC-progression, and on the influence of these infections on the final clinical outcome. To evaluate the possible relevance of HPV infection on survival and prognosis, 73 patients with HNSCC were investigated statistically with a median follow-up time of 28 (0.3–94) months. The statistical analysis revealed no differences in the overall survival of HPV-positive and HPV-negative cancer patients. A correlation between decreased survival and increased lymph node status was expected. Patients with carcinomas of the Waldeyer''s tonsillar ring with a high HPV prevalence rate as compared to tumours of other anatomical locations revealed a better survival. Moreover, an association between HPV positivity and higher lymph node status at time of first diagnosis, and a better survival of HPV-positive patients compared to HPV-negative patients given the same initial nodal status (N0 vs. N1-N2b vs. N2c-N3) could be demonstrated. The influence of HPV on the patient''s survival can only be observed statistically in combination with other prognostic factors, as the lymph nodal status of the patients. The better prognosis of survival of HPV-positive vs. the HPV-negative patients with lymph node neck metastasis is attributable to a better response of the HPV-positive group to therapy, especially radiotherapy. [Copyright &y& Elsevier]

Human papillomavirus type 16 (HPV16) is associated with squamous cell carcinomas of the head and neck (HNSCC) particularly from the Waldeyer’s tonsillar ring. A causal role of HPV16 in carcinogenesis is linked to the activity of the viral oncoproteins E6 and E7 which inactivate the cellular tumor suppressors p53 and pRB, respectively. Lack of E6 expression in HPV16-positive HNSCC has been reported, in some cases caused by disruption of the E6 gene. We have examined the status of the HPV16 E6–E7 gene region in tumor and metastasis samples of 24 HNSCC patients employing genomic PCR. No cases with a disrupted E6–E7 region could be identified. Sequence analysis of the E6–E7 segments revealed three different HPV16 E6–E7 genotypes: the HPV16 prototype (6 of 21 cases), the E6 variant T350G (8 of 21 cases), and the E6–E7 variant A131G/C712A (7 of 21 cases). The E6 variants T350G and A131G have been associated with increased oncogenic potential in cervical cancer patients depending on host genetic factors. Their high prevalence in the HNSCC samples studied indicates that they may be important also in HNSCC development. [Copyright &y& Elsevier]

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant. [Display omitted] • B.1.617 spike mediates enhanced entry into Calu-3 and Caco-2 cells • Entry by the B.1.617 spike is blocked by soluble ACE2 and camostat • The therapeutic antibody bamlanivimab fails to neutralize the B.1.617 spike • B.1.617 spike evades neutralizing antibodies triggered by infection and vaccination Between March and May 2021, India reported a steep increase in COVID-19 cases that was linked to SARS-CoV-2 variants, including B.1.617. Hoffmann et al. show that the B.1.617 spike protein mediates robust entry into human cells and evades neutralization by antibodies produced upon infection and vaccination. [ABSTRACT FROM AUTHOR]

Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to farmed mink has been observed in Europe and the US. In the infected animals, viral variants arose that harbored mutations in the spike (S) protein, the target of neutralizing antibodies, and these variants were transmitted back to humans. This raised concerns that mink might become a constant source of human infection with SARS-CoV-2 variants associated with an increased threat to human health and resulted in mass culling of mink. Here, we report that mutations frequently found in the S proteins of SARS-CoV-2 from mink are mostly compatible with efficient entry into human cells and its inhibition by soluble angiotensin-converting enzyme 2 (ACE2). In contrast, mutation Y453F reduces neutralization by an antibody with emergency use authorization for coronavirus disease 2019 (COVID-19) therapy and sera/plasma from COVID-19 patients. These results suggest that antibody responses induced upon infection or certain antibodies used for treatment might offer insufficient protection against SARS-CoV-2 variants from mink. [Display omitted] • SARS-CoV-2 from mink harbor up to five mutations in the spike protein • Entry inhibitors under clinical evaluation block mink spike proteins • Mutation Y453F confers partial escape from a therapeutic antibody • Y453F allows evasion of antibodies induced by SARS-CoV-2 infection of humans Transmission of SARS-CoV-2 between humans and farmed mink has caused concern because viruses from mink have acquired mutations in the spike protein. Hoffmann et al. show that these mink-specific mutations do not increase entry into human cells but do cause partial evasion from neutralization by a therapeutic antibody and convalescent plasma/sera. [ABSTRACT FROM AUTHOR]

Summary The Ebola virus glycoprotein (EBOV-GP) forms GP-containing microvesicles, so-called virosomes, which are secreted from GP-expressing cells. However, determinants of GP-virosome release and their functionality are poorly understood. We characterized GP-mediated virosome formation and delineated the role of the antiviral factor tetherin (BST2, CD317) in this process. Residues in the EBOV-GP receptor-binding domain (RBD) promote GP-virosome secretion, while tetherin suppresses GP-virosomes by interactions involving the GP-transmembrane domain. Tetherin from multiple species interfered with GP-virosome release, and tetherin from the natural fruit bat reservoir showed the highest inhibitory activity. Moreover, analyses of GP from various ebolavirus strains, including the EBOV responsible for the West African epidemic, revealed the most efficient GP-virosome formation by highly pathogenic ebolaviruses. Finally, EBOV-GP-virosomes were immunomodulatory and acted as decoys for EBOV-neutralizing antibodies. Our results indicate that GP-virosome formation might be a determinant of EBOV immune evasion and pathogenicity, which is suppressed by tetherin. Graphical Abstract Highlights • The Ebola virus glycoprotein (GP) drives the release of GP-containing virosomes • Tetherin restricts GP-virosome release through transmembrane domain interactions • GP-virosome release is most efficient for GPs of highly pathogenic Ebola viruses • Immunomodulatory GP-virosomes serve as decoys for EBOV-neutralizing antibodies Nehls et al. demonstrate that the glycoprotein of the highly pathogenic Ebola virus is incorporated into secretory vesicles, called GP-virosomes, to dampen the immune response and capture neutralizing antibodies. The lack of replication competence and the incorporation of antigenically intact GP might qualify GP-virosomes as safe vaccine candidates. [ABSTRACT FROM AUTHOR]

Summary Bats harbor a plethora of viruses with an unknown zoonotic potential. In-depth functional characterization of such viruses is often hampered by a lack of virus isolates. The genome of a virus closely related to human mumps viruses (hMuV) was detected in African fruit bats, batMuV. Efforts to characterize batMuV were based on directed expression of the batMuV glycoproteins or use of recombinant chimeric hMuVs harboring batMuV glycoprotein. Although these studies provided initial insights into the functionality of batMuV glycoproteins, the host range, replication competence, immunomodulatory functions, virulence, and zoonotic potential of batMuV remained elusive. Here, we report the successful rescue of recombinant batMuV. BatMuV infects human cells, is largely resistant to the host interferon response, blocks interferon induction and TNF-α activation, and is neurotoxic in rats. Anti-hMuV antibodies efficiently neutralize batMuV. The striking similarities between hMuV and batMuV point at the putative zoonotic potential of batMuV. Graphical Abstract Highlights • Bat mumps virus can readily replicate in human cells • Host cell entry factors of bat mumps virus are identical to those of human viruses • Bat mumps virus can evade innate immune responses in human and in bat cells • Neurotoxic properties of bat mumps virus are comparable to human field isolates Humans were considered the only natural host of mumps viruses until the discovery of a closely related virus in bats. By reconstitution of the bat mumps virus, Krüger et al. show that the virus efficiently replicates in bat and in human cells, can evade innate immune responses in both hosts, and possesses neurotoxic properties. [ABSTRACT FROM AUTHOR]

The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [14C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spikeinduced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019. [ABSTRACT FROM AUTHOR]

Sodium chloride (SC) is by far the most cost-effective deicing agent in winter road maintenance and therefore is used by road authorities worldwide. However, chloride ions foster high corrosivity, which significantly reduces the service lifetime of metals and reinforced concrete of transport infrastructures. Hence, a holistic evaluation with the main criteria of deicing performance and corrosion is demanded and, if possible, alternatives should be considered. This paper focuses on the deicing performance of sodium chloride and other common acetate-, carbonate-, chloride- and formate-based deicing agents. A newly developed test method is presented, enabling high volume testing at good repeatability. From its results a nonlinear model is derived to predict deicing performance up to five hours after application. Subsequently, this model is compared with both existing empirical and theoretical approaches for evaluating the deicing performance. In addition, the impact of added corrosion-inhibiting substances like sugars on deicing performance is investigated. Finally, a comparison of all tested substances in terms of corrosivity and deicing performance is presented, with corrosion being investigated in detail in another paper. • A new method for evaluation of deicing performance is presented (called CEDA). • CEDA is compared to other theoretical and empirical evaluation methods, showing the possible limit of the theoretical approach. • CEDA is a more reliable and more efficient testing method compared to the common SHRP method. • Statistical analysis shows the variation of the time-dependent deicing performance of different deicing agents. • Deicing performance is compared to mass loss due to corrosion, showing advantages of certain deicing agents and inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: The binary system of water and the ionic liquid 1-ethyl-3-methylimidazolium methanesulfonate, [emim][MeSO3], was carefully studied with the initial hypothesis that water might be tightly bound to the ionic liquid up to water mole fractions of 0.5, which would explain why water has been observed to seemingly be deactivated for interfering with water sensitive chemical reactions. Measurement results as a function of composition (generally 0–0.9 water mole fractions) and temperature (generally 40–85°C) were obtained for heat capacity, heats of dissolution, density, viscosity, conductivity, as well as NMR measurements on diffusion, proton chemical shift and T 1 relaxation times of cation, anion and water. The combined results do not confirm our initial hypothesis. An activation energy analysis showed that the same barrier hinders translational motion (self-diffusion) of anion, cation and water, as well as momentum transfer (viscosity) and the water T 1 relaxation. While the activation energy was observed to be linearly dependent on the mol fraction composition, most of the measured physicochemical properties show linear or near linear dependencies to the composition expressed in mass%. A further detailed analysis of the combined experimental data is supportive that the ionic liquid medium remains highly structured even when loaded with water to very high mole fractions. The main structural motif is hypothesized to contain nonpolar domains in close resemblance to micellar aggregation. Thus, the deactivation of the water in chemical reactions may rather be explained by a highly structured ionic liquid framework keeping water physically separated from the reactant. [Copyright &y& Elsevier]

Sphingosine has been shown to prevent and eliminate bacterial infections of the respiratory tract, but it is unknown whether sphingosine can be also employed to prevent viral infections. To test this hypothesis, we analyzed whether sphingosine regulates the infection of cultured and freshly isolated ex vivo human epithelial cells with pseudoviral particles expressing SARS-CoV-2 spike (pp-VSV-SARS-CoV-2 spike) that served as a bona fide system mimicking SARS-CoV-2 infection. We demonstrate that exogenously applied sphingosine suspended in 0.9% NaCl prevents cellular infection with pp-SARS-CoV-2 spike. Pretreatment of cultured Vero epithelial cells or freshly isolated human nasal epithelial cells with low concentrations of sphingosine prevented adhesion of and infection with pp-VSV-SARS- CoV-2 spike. Mechanistically, we demonstrate that sphingosine binds to ACE2, the cellular receptor of SARS-CoV-2, and prevents the interaction of the receptor-binding domain of the viral spike protein with ACE2. These data indicate that sphingosine prevents at least some viral infections by interfering with the interaction of the virus with its receptor. Our data also suggest that further preclinical and finally clinical examination of sphingosine is warranted for potential use as a prophylactic or early treatment for coronavirus disease-19. [ABSTRACT FROM AUTHOR]

Baseline sympathetic activity was found to be elevated in rheumatoid arthritis (RA) patients and it is related to increased cardiovascular risk in these patients. Although many studies have highlighted the association between RA and increased cardiac sympathetic activity, the underlying mechanistic links remain unclear. The aim of the present study was to understand how diseases-triggered changes in gene expression may result in maladaptive physiological changes. Our results suggest that the equilibrium between noradrenaline synthesis, release and reuptake was disrupted in the ventricles of arthritic rats. In the acute phase of the arthritic process, decreased gene expression of MAO-A might lead to accumulation of noradrenaline in myocardial interstitial space, whereas increased gene expression of NET protected cardiomyocytes from the deleterious effects of enhanced noradrenaline. During the chronic phase, reduced expression of β 1 -adrenoceptor and decreased efficiency of noradrenaline reuptake contribute to progressive damage of the myocardium and limits heart efficiency. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Infection with human papillomavirus (HPV) is linked to oropharyngeal cancer. This analysis investigated possible associations between HPV status, smoking history and survival outcome in patients with neck metastasis and carcinoma of unknown primary (CUP). Materials and methods: Registries at the Universities of Hamburg and Kiel were searched for patients with CUP diagnosed from 2002 to 2011 who had formalin-fixed and paraffin-embedded metastatic lymph node samples available. All patients underwent routine diagnostic procedures to establish the primary site and received radiotherapy (60Gy using conventional fractionation) with or without concurrent cisplatin-based chemotherapy depending on disease extent. Genotyping was performed using polymerase chain reaction; p16[INK4a] expression was assessed using immunohistochemistry. Results: Sixty-three patients were included; 23 (37%) had HPV DNA/p16+ samples and 40 (63%) were negative for either/both markers. A high proportion of patients had a history of tobacco smoking; significantly fewer patients with HPV+/p16+ samples were smokers than those who were negative for either/both markers (61% vs. 90%, respectively; p =0.0067). There were no statistically significant differences between overall or recurrence-free survival in HPV+/p16+ patients vs. those negative for either/both markers. Overall survival appeared to be superior in patients with <10 pack-years smoking history and HPV+/p16+ disease. Conclusions: This study, the largest to date investigating HPV status in head and neck CUP, identified HPV and p16 overexpression in over one-third of patients. Tobacco smoking history appeared to affect survival in HPV+/p16+ patients. Smoking status should be considered as a prognostic factor in patients with CUP, along with HPV DNA status. [ABSTRACT FROM AUTHOR]

Abstract: Studies report an increasing incidence of oropharyngeal cancers linked to infection by human papillomavirus (HPV). We reviewed trials assessing outcomes by HPV DNA status in patients with locally advanced oropharyngeal cancer. Seven of the eight studies identified showed significantly better survival in patients with HPV DNA-positive tumors vs. HPV DNA-negative tumors. The review also describes what needs to be defined regarding optimal treatments. Future trials should incorporate HPV DNA status as a risk determinant and explore treatments for high-risk patients needing therapy intensification, and low- and intermediate-risk patients needing treatment de-intensification to improve tolerability, without compromising survival. [Copyright &y& Elsevier]

Abstract: Selective up-regulation of the mRNA of LOXL4, a member of the LOX matrix amine oxidase family, significantly correlated with lymph node metastases and higher tumour stages in head and neck squamous cell carcinomas (HNSCC). To evaluate the diagnostic and prognostic value of the protein we produced an antibody specific for LOXL4 and assessed the expression in 317 human HNSCC specimens. The LOXL4 protein was detected in 92.7% of primary tumours, in 97.8% of lymph node metastases and in affected oral mucosa with high-grade dysplasia, but was absent in various non-neoplastic tissues of the head and neck. TNM categories and overall survival did not link to grades of immunoreactivity. Studies in cultured primary hypopharyngeal HTB-43 carcinoma cells detected perinuclear and cell surface expression of LOXL4, but no nuclear localisation. Therefore, its interactive SRCR-domains and catalytic activity combined with tumour cell specific expression and cell surface associated location indicate multiple functions in tumour cell adhesion and interactions with the extracellular matrix. Our data suggest that LOXL4 is useful both as tumour marker and target in the treatment of HNSCC. [Copyright &y& Elsevier]

Examines the key features of SOILNDB, a decision support tool for the assessment of nitrogen leaching losses from arable land. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on environmental modeling and software.