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Zusammenfassung Hintergrund Ein rechtlich zulässiges medizinisches Altersfeststellungsverfahren mit möglichst schonenden und zuverlässigen Methoden bei unbegleiteten und fraglich minderjährigen Ausländern ist erforderlich, um den tatsächlich Minderjährigen den für sie gesetzlich vorgesehenen besonderen Schutz zukommen zu lassen. Ziel der Arbeit Studiendesign und erste Ergebnisse einer Studie zur forensischen Altersdiagnostik mittels Niederfeld-Magnetresonanztomographie werden vorgestellt. Material und Methoden Geplant ist die prospektive Untersuchung von 650 Studienteilnehmenden, gleichmäßig verteilt innerhalb der Altersgruppe 12 bis 24 Jahre zu je 25 Personen je Geschlecht. Es sollen Entwicklungsstadien von distalem Radius, distaler Ulna, distalem Femur und proximaler Tibia mithilfe eines 0,31-Tesla(T)-Niederfeld-MRT-Scanners erfasst und mittels Anwendung der Vieth-Klassifikation ausgewertet werden. Ergebnisse Nach Auswertung der Untersuchungen der bisher 487 untersuchten Studienteilnehmenden ist ersichtlich, dass die gewählten Sequenzen die für die Vieth-Klassifikation relevanten Charakteristika der Ossifikation der untersuchten Epiphysen erfassen. Die Untersuchungen erweisen sich überdies als einfach in der Durchführung. Schlussfolgerung Untersuchungen zur forensischen Altersschätzung am Lebenden unter Anwendung der Vieth-Klassifikation sind mit Niederfeld-MRT-Scannern bei einer Feldstärke von 0,31 T durchführbar. Es bleibt zu klären, ob die mit einem 0,31-T-Niederfeld-MRT-Scanner nachweisbaren Ossifikationsmerkmale am Handgelenk und am Knie einen zweifelsfreien Volljährigkeitsnachweis erlauben.

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitates viral entry into host cells and is the key target for neutralizing antibodies. The SARS-CoV-2 lineage B.1.620 carries fifteen mutations in the S protein and is spread in Africa, the US and Europe, while lineage R.1 harbors four mutations in S and infections were observed in several countries, particularly Japan and the US. However, the impact of the mutations in B.1.620 and R.1 S proteins on antibody-mediated neutralization and host cell entry are largely unknown. Here, we report that these mutations are compatible with robust ACE2 binding and entry into cell lines, and they markedly reduce neutralization by vaccine-induced antibodies. Our results reveal evasion of neutralizing antibodies by B.1.620 and R.1, which might have contributed to the spread of these lineages.

B cell hyperactivity plays an important role in primary Sjögren's syndrome (pSS). To better understand the B cell effector branch, namely antibody-secreting cells (ASC; plasmablasts and plasma cells) in pSS, this study examines abundance, maturation and inflammatory properties of ASCs in pSS patients.Circulating ASCs, defined as CD3ASCs were more abundant in peripheral blood of pSS patients than healthy controls (3.1±5.1 vs. 1.1±1.0 cells/μl; p=0.048) and displayed a more mature phenotype (0.37±1.21 vs. 0.06±0.11 CD19Numbers and maturation stage of ASCs in pSS patients are increased and correlate with disease parameters. A higher maturity index of ASCs marks a pro-survival and pro-inflammatory phenotype. Altogether, B cell hyperactivity in pSS extends to the peripheral ASC compartment raising potential for ASCs as future biomarker or target for pSS treatment. This article is protected by copyright. All rights reserved.

To monitor infection by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and successful vaccination against coronavirus disease 2019 (COVID‐19), the kinetics of neutralizing or blocking anti‐SARS‐CoV‐2 antibody titers need to be assessed. Here, we report the development of a quick and inexpensive surrogate SARS‐CoV‐2 blocking assay (SUBA) using immobilized recombinant human angiotensin‐converting enzyme 2 (hACE2) and human cells expressing the native form of surface SARS‐CoV‐2 spike protein. Spike protein‐expressing cells bound to hACE2 in the absence or presence of blocking antibodies were quantified by measuring the optical density of cell‐associated crystal violet in a spectrophotometer. The advantages are that SUBA is a fast and inexpensive assay, which does not require biosafety level 2‐ or 3‐approved laboratories. Most importantly, SUBA detects blocking antibodies against the native trimeric cell‐bound SARS‐CoV‐2 spike protein and can be rapidly adjusted to quickly pre‐screen already approved therapeutic antibodies or sera from vaccinated individuals for their ACE2 blocking activities against any emerging SARS‐CoV‐2 variants., A simple, inexpensive surrogate SARS‐CoV‐2 neutralization assay is introduced. Ectopic expression of the SARS‐CoV‐2 spike protein confers binding of Ramos‐Ig ‐ or HEK293 cells to plate‐bound recombinant human angiotensin‐converting‐enzyme‐2. This interaction can be blocked with reconvalescent or immune serum or with anti‐receptor‐binding domain antibodies. Bound spike‐expressing cells are quantitated with crystal violet.

The autophagy-flux-promoting protein TFG (Trk-fused gene) is up-regulated during B cell differentiation into plasma cells and supports survival of CH12 B cells. We hypothesized that quantitative proteomics analysis of CH12tfgKO B cells with intact or blocked autophagy-lysosome flux (via NH4Cl) will identify mechanisms of TFG-dependent autophagy, plasma cell biology and B cell survival. Analysis of CH12WT B cells in the presence of NH4Cl will identify proteins whose presence is continuously regulated by lysosomes independent of TFG. We determined hundreds of proteins to be controlled by TFG and/or NH4Cl. Notably, NH4Cl treatment alone increased the abundance of a cluster of cytosolic and mitochondrial translational proteins while it also reduced a number of proteins. Within the B cell relevant protein pool, BCL10 was reduced, while JCHAIN was increased in CH12tfgKO B cells. Furthermore, TFG regulated the abundance of transcription factors, such as JUNB, metabolic enzymes, such as the short-chain fatty acid activating enzyme ACOT9 or the glycolytic enzyme ALDOC. Gene ontology enrichment analysis revealed that TFG-regulated proteins localized to mitochondria and membrane-bounded organelles. Due to these findings we performed shotgun lipidomics of glycerophospholipids, uncovering that a particular phosphatidylethanolamine (PE) species, 32:0 PE, which lipidates LC3 most efficiently, was less abundant while phosphatidylglycerol (PG) was more abundant in CH12tfgKO B cells. In line with the role of PG as precursor for Cardiolipin (CL), the CL content was higher in CH12tfgKO B cells and addition of PG liposomes to B cells increased the amount of CL. We propose a role for TFG in B cell activation and plasma cell biology via regulation of proteins involved in germinal center and plasma cell development, such as BCL10 or JCHAIN, as well as in lipid homeostasis, mitochondria and metabolism.

Establishment of long-lived plasma cells (PC) in the bone marrow (BM) is important for the development of long-term specific humoral immunity. While SARS-CoV-2-specific, resting, affinity-matured, IgG-secreting plasma cells were described in human bone marrow approx. 6-7 months after infection or vaccination, the long-term durability of these PC remains unclear. We here show that approximately 20% of SARS-CoV-2-specific human BM plasma cells, including RBD-specific PC accommodate the phenotype of long-lived plasma cells, characterized by the lack of CD19 and/or CD45. This result provides evidence in support of the emergence of persistent SARS-CoV-2 specific plasma cells in humans sustaining the durable production of specific serum IgG protecting against severe courses of COVID-19.

Full list of authors: Adams, E. A. K.; Adebahr, B.; de Blok, W. J. G.; Denes, H.; Hess, K. M.; van der Hulst, J. M.; Kutkin, A.; Lucero, D. M.; Morganti, R.; Moss, V. A.; Oosterloo, T. A.; Orru, E.; Schulz, R.; van Amesfoort, A. S.; Berger, A.; Boersma, O. M.; Bouwhuis, M.; van den Brink, R.; van Cappellen, W. A.; Connor, L.; Coolen, A. H. W. M.; Damstra, S.; van Diepen, G. N. J.; Dijkema, T. J.; Ebbendorf, N.; Grange, Y. G.; de Goei, R.; Gunst, A. W.; Holties, H. A.; Hut, B.; Ivashina, M., V; Jozsa, G. I. G.; van Leeuwen, J.; Loose, G. M.; Maan, Y.; Mancini, M.; Mika, A.; Mulder, H.; Norden, M. J.; Offringa, A. R.; Oostrum, L. C.; Pastor-Marazuela, I; Pisano, D. J.; Ponomareva, A. A.; Romein, J. W.; Ruiter, M.; Schoenmakers, A. P.; van der Schuur, D.; Sluman, J. J.; Smits, R.; Stuurwold, K. J. C.; Verstappen, J.; Vilchez, N. P. E.; Vohl, D.; Wierenga, K. J.; Wijnholds, S. J.; Woestenburg, E. E. M.; Zanting, A. W.; Ziemke, J.--Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Context. Apertif is a phased-array feed system for the Westerbork Synthesis Radio Telescope, providing forty instantaneous beams over 300 MHz of bandwidth. A dedicated survey program utilizing this upgrade started on 1 July 2019, with the last observations taken on 28 February 2022. The imaging survey component provides radio continuum, polarization, and spectral line data. Aims. Public release of data is critical for maximizing the legacy of a survey. Toward that end, we describe the release of data products from the first year of survey operations, through 30 June 2020. In particular, we focus on defining quality control metrics for the processed data products. Methods. The Apertif imaging pipeline, Apercal, automatically produces non-primary beam corrected continuum images, polarization images and cubes, and uncleaned spectral line and dirty beam cubes for each beam of an Apertif imaging observation. For this release, processed data products are considered on a beam-by-beam basis within an observation. We validate the continuum images by using metrics that identify deviations from Gaussian noise in the residual images. If the continuum image passes validation, we release all processed data products for a given beam. We apply further validation to the polarization and line data products and provide flags indicating the quality of those data products. Results. We release all raw observational data from the first year of survey observations, for a total of 221 observations of 160 independent target fields, covering approximately one thousand square degrees of sky. Images and cubes are released on a per beam basis, and 3374 beams (of 7640 considered) are released. The median noise in the continuum images is 41.4 uJy beam−1, with a slightly lower median noise of 36.9 uJy beam−1 in the Stokes V polarization image. The median angular resolution is 11.6″/sin δ. The median noise for all line cubes, with a spectral resolution of 36.6 kHz, is 1.6 mJy beam−1, corresponding to a 3-σ H I column density sensitivity of 1.8 × 1020 atoms cm−2 over 20 km s−1 (for a median angular resolution of 24″ × 15″). Line cubes at lower frequency have slightly higher noise values, consistent with the global RFI environment and overall Apertif system performance. We also provide primary beam images for each individual Apertif compound beam. The data are made accessible using a Virtual Observatory interface and can be queried using a variety of standard tools. © E. A. K. Adams et al. 2022., This work makes use of data from the Apertif system installed at the Westerbork Synthesis Radio Telescope owned by ASTRON. ASTRON, the Netherlands Institute for Radio Astronomy, is an institute of the Dutch Research Council (“De Nederlandse Organisatie voor Wetenschappelijk Onderzoek, NWO). Apertif was partly financed by the NWO Groot projects Apertif (175.010.2005.015) and Apropos (175.010.2009.012). This work was partly supported by funding from the European Research Council under the European Union’s Seventh Frame-work Programme (FP/2007-2013), through ERC Grant Agreement No. 291531 (‘HIStoryNU’, PI: JMvdH) and ERC Advanced Grant RADIOLIFE-320745 (PI: RM), in addition to funding from NWO via grant TOP1EW.14.105 (PI: TAO). E.A.K.A. is supported by the WISE research programme, which is financed by NWO. B.A. acknowledges funding from the German Science Foundation DFG, within the Collaborative Research Center SFB1491 “Cosmic Interacting Matters - From Source to Signal”. KMH acknowledges financial support from the State Agency for Research of the Spanish Ministry of Science, Innovation and Universities through the “Center of Excellence Severo Ochoa” awarded to the Instituto de Astrofísica de Andalucía (SEV-2017-0709), from the coordination of the participation in SKA-SPAIN, funded by the Ministry of Science and Innovation (MCIN). OMB and JvL acknowledge funding from NWO under the Vici research program “ARGO” with project number 639.043.815. Y.M., L.C.O., R.S. and J.vL. acknowledge funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement No. 617199 (“ALERT”). IPM acknowledges funding from the Netherlands Research School for Astronomy (grant no. NOVA5-NW3-10.3.5.14). A.A.P. acknowledges support of the STFC consolidated grant ST/S000488/1. DV acknowledges support from the Netherlands eScience Center (NLeSC) under grant ASDI.15.406. This research has made use of NASA’s Astrophysics Data System Bibliographic Services and Astropy, (http://www.astropy.org) a community-developed core Python package for Astronomy (Astropy Collaboration 2013, 2018).

Context. The characteristics of the polarised radio sky are a key ingredient in constraining evolutionary models of magnetic fields in the Universe and their role in feedback processes. The origin of the polarised emission and the characteristics of the intergalactic medium on the line of sight can be investigated using large samples of polarised sources. Ancillary infrared (IR) and optical data can be used to study the nature of the emitting objects. Aims. We analyse five early science datasets from the APERture Tile in Focus (Apertif) phased array feed system to verify the polarisation capabilities of Apertif in view of future larger data releases. We aim to characterise the source population of the polarised sky in the L-Band using polarised source information in combination with IR and optical data. Methods. We use automatic routines to generate full field-of-view Q- and U-cubes and perform rotation measure (RM)-Synthesis, source finding, and cross-matching with published radio, optical, and IR data to generate polarised source catalogues. All sources were inspected individually by eye for verification of their IR and optical counterparts. Spectral energy distribution (SED)-fitting routines were used to determine photometric redshifts, star-formation rates, and galaxy masses. IR colour information was used to classify sources as active galactic nuclei (AGN) or star-forming-dominated and early- or late-type. Results. We surveyed an area of 56 deg2 and detected 1357 polarised source components in 1170 sources. The fraction of polarised sources is 10.57% with a median fractional polarisation of 4.70 ± 0.14%. We confirmed the reliability of the Apertif measurements by comparing them with polarised cross-identified NVSS sources. Average RMs of the individual fields lie within the error of the best Milky Way foreground measurements. All of our polarised sources were found to be dominated by AGN activity in the radio regime with most of them being radio-loud (79%) and of the Fanaroff-Riley (FR)II class (87%). The host galaxies of our polarised source sample are dominated by intermediate disc and star-forming disc galaxies. The contribution of star formation to the radio emission is on the order of a few percent for ≈10% of the polarised sources while for ≈90% it is completely dominated by the AGN. We do not see any change in fractional polarisation for different star-formation rates of the AGN host galaxies. Conclusions. The Apertif system is suitable for large-area high-sensitivity polarised sky surveys. The data products of the polarisation analysis pipeline can be used to investigate the Milky Way magnetic field on projected scales of several arcminutes as well as the origin of the polarised emission in AGN and the properties of their host galaxies. © ESO 2022., This research made use of Montage. It is funded by the National Science Foundation under Grant Number ACI-1440620, and was previously funded by the National Aeronautics and Space Administration’s Earth Science Technology Office, Computation Technologies Project, under Cooperative Agreement Number NCC5-626 between NASA and the California Institute of Technology. The Montage distribution includes an adaptation of the MOPEX algorithm developed at the Spitzer Science Center. BA and AB acknowledge funding from the German Science Foundation DFG, within the Collaborative Research Center SFB1491 “Cosmic Interacting Matters - From Source to Signal”. EAKA is supported by the WISE research programme, which is financed by the Dutch Research Council (NWO). K.M.H. acknowledges funding from the State Agency for Research of the Spanish Ministry of Science, Innovation and Universities through the “Center of Excellence Severo Ochoa” awarded to the Instituto de Astrofísica de Andalucía (SEV-2017-0709); from grant RTI2018-096228-B-C31 (Ministry of Science, Innovation and Universities/State Agency for Research/European Regional Development Funds, European Union); and from the coordination of the participation in SKA-SPAIN, funded by the Ministry of Science and innovation (MICIN). J.M.vdH. and K.M.H. acknowledge funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement No. 291531 (‘HIStoryNU’). J.vL. acknowledges funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement no. 617199 (‘ALERT’), and from Vici research programme ‘ARGO’ with project number 639.043.815, financed by the Dutch Research Council (NWO). DV acknowledges support from the Netherlands eScience Center (NLeSC) under grant ASDI.15.406. RS acknowledges funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement No. 617199. LCO acknowledges funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement No. 617199.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program and OTKA-FK 134751); MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary We have previously identified several cardiac microRNAs that are involved in cardioprotection and termed them as ProtectomiRs. mRNA targets of these ProtectomiRs may reveal new drug targets for cardioprotection. Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction. Network theoretical approach was utilized to identify 882 potential target genes of 18 previously described protectomiRs. Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, expression of Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of acute myocardial infarction and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning. This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection.

A complex and tissue-specific network of cells including T lymphocytes maintains intestinal homeostasis. To address disease and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with Crohn’s disease (CD) and healthy donor PBMCs. We compared inflamed and not inflamed tissue areas of bowel resections. Chronic inflammation enforced activation, exhaustion and terminal differentiation of CD4+ and CD8+ T cells and an enrichment of CD4+Foxp3+ cells (Tregs) in inflamed intestine. However, tissue-repairing Tregs decreased, while enigmatic rare Foxp3+ T-cell subsets appeared upon inflammation. In vitro assays revealed that those subsets, e.g. CD4+Foxp3+HLA-DR+TIGIT− and CD4+Foxp3+CD56+, express pro-inflammatory IFN-γ. Some T-conventional (Tcon) cells tended towards innateness. In blood of CD patients, not well studied CD4+ and CD8+ subsets of CD16+CCR6+CD127+ T cells appeared anew, a phenotype reproducible by incubation of healthy blood T cells with patient blood plasma. Together, these findings suggest a bias towards innate-like pro-inflammatory Tregs and innate-like Tcon, which act with less specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.Graphical Abstract

Introduction The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the health-care system both in Australia and internationally, and has rapidly transformed the delivery of health care in hospitals and the community. Implementation of social isolation and distancing measures to stop the spread of the disease and to reduce potential harm to patients has necessitated the use of alternate models of health-care delivery. Changes that would normally take months or years have occurred within days to weeks. Methods We conducted analysis of outpatient clinic data during the period of the pandemic and compared this to previous telehealth use. We also present the results of clinician and patient telehealth experience surveys. Results We describe a 2255% increase in the use of telehealth at a tertiary hospital within a period of six weeks, and a significant simultaneous reduction in the outpatient clinic failure-to-attend rate. The vast majority of patients and clinicians agreed that the standard of care provided by telehealth was the same as that provided by on-site appointments. Discussion Telehealth that previously had only limited utilisation has now become a main method for the delivery of outpatient care. Clinicians and patients agreed that consultations provided by telehealth were of the same standard as those provided on site. Health care in the post-pandemic period should embed the use of telehealth for outpatient care and consider the range of other clinical contexts where this can be utilised.

ZusammenfassungEs wird über einen Fall häuslicher Gewalt berichtet, bei dem die 86-jährige Ehefrau ihren gleichaltrigen, an Demenz leidenden Ehemann durch vielfache stumpfe Gewalteinwirkungen tötete. Als Tatwerkzeug kam ein Schrubber zum Einsatz. Richtungweisend für die Identifizierung des Schrubbers als Tatwaffe waren die zahlreichen gruppiert angeordneten, rundlichen, kleinfleckigen Hautabschürfungen sowie die gruppiert angeordneten, kleinfleckigen Hautunterblutungen, die sich den Borstenbüscheln eines Schrubbers zuordnen ließen. Todesursächlich war ein Verbluten in die Weichteile. Eine Fettembolie wurde histologisch ausgeschlossen. In einem Sicherungsverfahren wurde für die Ehefrau aufgrund einer Alzheimer-Demenz mit dadurch bedingter mangelnder Steuerungsfähigkeit die Unterbringung in einem psychiatrischen Krankenhaus angeordnet.

Effective vaccines and monoclonal antibodies have been developed against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the appearance of virus variants with higher transmissibility and pathogenicity is a major concern because of their potential to escape vaccines and clinically approved SARS-CoV-2- antibodies. Here, we use flow cytometry-based binding and pseudotyped SARS-CoV-2 neutralization assays to determine the efficacy of boost immunization and therapeutic antibodies to neutralize the dominant Omicron variant. We provide compelling evidence that the third vaccination with BNT162b2 increases the amount of neutralizing serum antibodies against Delta and Omicron variants, albeit to a lower degree when compared to the parental Wuhan strain. Therefore, a third vaccination is warranted to increase titers of protective serum antibodies, especially in the case of the Omicron variant. We also found that most clinically approved and otherwise potent therapeutic antibodies against the Delta variant failed to recognize and neutralize the Omicron variant. In contrast, some antibodies under preclinical development potentially neutralized the Omicron variant. Our studies also support using a flow cytometry-based antibody binding assay to rapidly monitor therapeutic candidates and serum titers against emerging SARS-CoV-2 variants.

We describe the APERture Tile In Focus (Apertif) system, a phased array feed (PAF) upgrade of the Westerbork Synthesis Radio Telescope that transforms this telescope into a high-sensitivity, wide-field-of-view L-band imaging and transient survey instrument. Using novel PAF technology, up to 40 partially overlapping beams are formed on the sky simultaneously, significantly increasing the survey speed of the telescope. With this upgraded instrument, an imaging survey covering an area of 2300 deg2 is being performed that will deliver both continuum and spectral line datasets, of which the first data have been publicly released. In addition, a time domain transient and pulsar survey covering 15 000 deg2 is in progress. An overview of the Apertif science drivers, hardware, and software of the upgraded telescope is presented, along with its key performance characteristics.

Resident memory T lymphocytes (T

TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS‐CoV‐2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS‐CoV‐2 spike protein. Nine antibodies neutralize SARS‐CoV‐2 infection at IC50 values in the subnanomolar range. ELISA‐binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor‐binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N‐terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS‐CoV‐2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS‐CoV‐2‐induced weight loss. The two clusters of potent non‐competing SARS‐CoV‐2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID‐19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives. This article is protected by copyright. All rights reserved

Objective: B cell hyperactivity plays an important role in primary Sjögren's syndrome (SS). We undertook this study to better understand the B cell effector branch, namely antibody-secreting cells (ASCs) in primary SS, and to examine the quantity, maturity, and inflammatory properties of ASCs in primary SS patients. Methods: Circulating ASCs, defined as CD3–CD14–CD27+CD38++ cells, from 21 primary SS patients and 10 healthy controls were assessed using spectral flow cytometry. Expression levels of relevant ASC markers relating to maturity, survival, and inflammatory status were analyzed using a t-distributed stochastic neighbor embedding approach. Correlation of ASC properties with primary SS disease parameters was assessed. Results: ASCs were more abundant in peripheral blood from primary SS patients than from healthy controls (mean ± SD 3.1 ± 5.1 cells/μl versus 1.1 ± 1.0 cells/μl, respectively; P = 0.048) and displayed a more mature phenotype (mean ± SD CD19– ASCs 0.37 ± 1.21 cells/μl versus 0.06 ± 0.11 cells/μl, respectively; P = 0.005). An inflammatory CXCR3+ phenotype of ASCs correlated positively with our newly developed ASC maturity index (r = 0.568, P = 0.007) but correlated negatively with antiinflammatory interleukin-10 expression (r = –0.769, P < 0.001). ASCs with a higher maturity index also demonstrated higher levels of the pro-survival protein myeloid cell leukemia 1 (r = 0.567, P = 0.007). Frequency and/or maturity of ASCs correlated with several primary SS disease parameters, such as antinuclear antibody and anti-La/SSB titers, salivary gland focus scores, and ocular staining scores. Conclusion: Quantity and maturity of ASCs in primary SS patients are increased and correlate with disease parameters. A higher maturity index of ASCs marks a pro-survival and proinflammatory phenotype. Altogether, B cell hyperactivity in primary SS extends to the peripheral ASC compartment, raising potential for ASCs as future biomarkers or targets for primary SS treatment. (Figure presented.).

Krüppel-like factor 2 (KLF2) is a potent regulator of lymphocyte differentiation, activation and migration. However, its functional role in adaptive and humoral immunity remains elusive. Therefore, by using mice with a B cell-specific deletion of KLF2, we investigated plasma cell differentiation and antibody responses. We revealed that the deletion of KLF2 resulted in perturbed IgA plasma cell compartmentalization, characterized by the absence of IgA plasma cells in the bone marrow, their reductions in the spleen, the blood and the lamina propria of the colon and the small intestine, concomitant with their accumulation and retention in mesenteric lymph nodes and Peyer's patches. Most intriguingly, secretory IgA in the intestinal lumen was almost absent, dimeric serum IgA was drastically reduced and antigen-specific IgA responses to soluble Salmonella flagellin were blunted in KLF2-deficient mice. Perturbance of IgA plasma cell localization was caused by deregulation of CCR9, Integrin chains αM, α4, β7, and sphingosine-1-phosphate receptors. Hence, KLF2 not only orchestrates the localization of IgA plasma cells by fine-tuning chemokine receptors and adhesion molecules but also controls IgA responses to Salmonella flagellin.

Objectives There have been efforts to promote timely antimicrobial administration for patients with sepsis, but the importance for other infections is uncertain. This study analysed whether time to first antimicrobial dose (TFAD) in patients with lower limb cellulitis influenced outcome measures such as acute length of stay (LOS) in hospital and 30-day hospital readmission rates for cellulitis. Methods Medical records of patients admitted with lower limb cellulitis or erysipelas over a 15-month period (1 May 2019 to 30 November 2019 and 1 March 2020 to 31 October 2020) were reviewed. Patients requiring intensive care unit (ICU) admission were excluded. The TFAD was the difference (in minutes) between the emergency department triage time and the time that the antimicrobial was first recorded as administered. Analysis included log-transformed linear regression (for LOS) and logistic regression (for 30-day readmission with cellulitis), controlling for confounders where possible. Results The study included 282 patients with lower limb cellulitis. The median TFAD was 177 min (interquartile range, 98–290 min). Linear regression suggested a weak association between TFAD and LOS (P = 0.05; adjusted R2 = 0.01), which was non-significant after adjusting for confounders (P = 0.18). There were too few patients readmitted within 30 days with cellulitis for meaningful analysis. Conclusion After controlling for confounders, no association between increased TFAD and increased acute LOS was identified for patients with lower limb cellulitis who did not require ICU admission (i.e. without septic shock). Conclusions could not be made for 30-day readmission rates for cellulitis.