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Human bone marrow (BM) plasma cells are heterogeneous, ranging from newly arrived antibody-secreting cells (ASCs) to long-lived plasma cells (LLPCs). We provide single-cell transcriptional resolution of 17,347 BM ASCs from five healthy adults. Fifteen clusters are identified ranging from newly minted ASCs (cluster 1) expressing MKI67 and high major histocompatibility complex (MHC) class II that progress to late clusters 5-8 through intermediate clusters 2-4. Additional ASC clusters include the following: immunoglobulin (Ig) M predominant (likely of extra-follicular origin), interferon responsive, and high mitochondrial activity. Late ASCs are distinguished by G2M checkpoints, mammalian target of rapamycin (mTOR) signaling, distinct metabolic pathways, CD38 expression, utilization of tumor necrosis factor (TNF)-receptor superfamily members, and two distinct maturation pathways involving TNF signaling through nuclear factor κB (NF-κB). This study provides a single-cell atlas and molecular roadmap of LLPC maturation trajectories essential in the BM microniche. Altogether, understanding BM ASC heterogeneity in health and disease enables development of new strategies to enhance protective ASCs and to deplete pathogenic ones.

Abstract Background Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion. Methods In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia. Results Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice. Conclusion These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile.

Convalescing coronavirus disease 2019 (COVID-19) patients mount robust T cell responses against SARS-CoV-2, suggesting an important role of T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells and predominantly Tcm cells with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can proliferate homeostatically, and can persist for over 2 months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection and support an important role of SARS-CoV-2-specific T cells in host control of COVID-19.

Abstract Micromagnetic Tomography (MMT) is a new technique that allows the determination of magnetic moments of individual grains in volcanic rocks. Current MMT studies either showed that it is possible to obtain magnetic moments of relatively small numbers of grains in ideal sample material or provided important theoretical advances in MMT inversion theory and/or its statistical framework. Here, we present a large‐scale application of MMT on a sample from the 1907‐flow from Hawaii's Kilauea volcano producing magnetic moments of 1,646 grains. We produced 261,305 magnetic moments in total for these 1,646 grains, an increase of three orders of magnitude compared to earlier studies to assess the robustness of the MMT results, and a major step toward the number of grains that is necessary for paleomagnetic applications of MMT. Furthermore, we show that the recently proposed signal strength ratio is a powerful tool to scrutinize and select MMT results. Despite this progress, still only relatively large iron‐oxide grains with diameters >1.5–2 μm can be reliably resolved, impeding a reliable paleomagnetic interpretation. To determine the magnetic moments of smaller (

Preexisting anti–interferon-α (anti–IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti–IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti–IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti–IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti–SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti–IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti–IFN-α response. In contrast, systemic IgG1 anti–IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti–IFN-α in the immunopathology of COVID-19 and suggest that anti–IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa. Editor's summary: Autoantibodies targeting interferon-α (IFN-α) have been found in the circulation of those with severe COVID-19 and are considered a bad sign for disease progression. However, less is known about IFN-α–specific autoantibodies in other tissues, such as the mucosa. Here, Babcock et al. used a multiparameter flow cytometry technique called FlowBEAT to show that IgA1 autoantibodies targeting IFN-α could be found in the nasal mucosa and were associated with improved responses to SARS-CoV-2. The induction of these anti–IFN-α autoantibodies was temporally linked to a decline in IFN-α itself, suggesting that elicitation of these autoantibodies may be a mechanism to temper inflammation in the respiratory mucosa. These data suggest that there is a complex, location-dependent, role for antibodies against IFN-α and that these antibodies may tip the balance between protection and pathology. —Courtney Malo [ABSTRACT FROM AUTHOR]

Recent advances in developmental immunology have revealed a hematopoietic stem cell (HSC)-independent origin for various innate immune lineages, including mast cells (MCs). It is now established that adult bone marrow (BM) long-term HSCs do not regenerate MCs but, instead, the physiological production of MCs starts before the emergence of HSCs in the aorta-gonad-mesonephros (AGM) region and is mostly completed before birth. However, while the AGM region represents a major site of MC generation during ontogeny, whether the first emerging HSCs in the AGM or fetal liver (FL) possess the potential to regenerate MCs is unknown. Here, we combined three fate-mapping mouse models with detailed HSC transplantation assays to determine the potential of AGM and FL HSCs to produce MCs. We show that HSCs from E11.5 AGM and E12.5 FL efficiently repopulated MCs in recipients. In stark contrast, HSCs from ≥E14.5 FL failed to reconstitute MCs. An Endothelial (EC) fate-mapping study confirmed the EC origin of the majority of MCs. Additionally, our HSC-labeling showed that HSCs do not produce MCs in a physiological setting. Hence, although most MCs are generated and maintained via an HSC-independent pathway, the earliest HSCs to emerge in the AGM and seed the early FL can produce MCs, but only during a minimal time window. Our results challenge the stem cell theory in hematology and EC-derived mast cells may contribute to the pathogenesis of postnatal mast cell disorders.

IntroductionSoundscapes in nursing homes are often suboptimal for residents. This can cause them feeling anxious and unsafe, or develop behavioral and psychological problems. Residents with dementia cannot adapt nursing home environments to their needs due to cognitive and physical limitations. It is up to the staff of psycho-geriatric wards to improve the soundscape. We evaluated the effect of the sound awareness intervention Mobile Soundscape Appraisal and Recording Technology (MoSART+) on soundscapes in nursing homes.MethodsThe MoSART+ intervention was carried out in four nursing homes and took three months in each home. The MoSART+ intervention involved training ambassadors, assessing the soundscape with the MoSART application by the nursing staff to raise their sound awareness on random time points, discussing the measurements, and implementing micro-interventions. Soundscapes were assessed from 0 to 100 on four attributes: pleasantness, eventfulness, complexity, and range of affordances. Based on these scores, soundscapes were classified in four dimensions: calm, lively, boring, and chaotic. Nursing staff graded the environment on a scale of 0 to 10. T-test and Z-tests were used to analyze data.ResultsStaff recorded 1882 measurements with the MoSART app. “People,” “music, TV, and radio,” and “machines and appliances” were the most prevalent sound sources before and after the implementation of micro-interventions. Post-implementation of micro-interventions, soundscapes were pleasant (median 69.0; IQR 54.0–81.0), of low complexity (33.0; 18.0–47.0), uneventful (27.0; 14.0–46.5), and gave moderate affordances (50.0; 35.0–67.0). Changes in attributes were statistically significant (p < 0.01). The proportion of the dimension calm increased (z = 12.7, p < 0.01), the proportion of chaotic decreased (z = 15.0, p < 0.01), and the proportion of lively decreased not statically significant (z = 0.68, p = 0.79). The proportion of boring was unchanged. The proportion of grades ≥6 increased after implementation of the micro-interventions (z = 15.3, p < 0.01). The micro-interventions focused on removing or reducing disturbing sounds and were unique for each nursing home.DiscussionThe MoSART+ intervention resulted in a statistically significantly improvement of soundscapes, and more favorable evaluations of the nursing staff. The intervention empowered staff to adapt soundscapes. Nursing homes can improve soundscapes by raising sound awareness among staff.Trial RegistrationNetherlands National Trial Register (NL6831).

We initiate the study of a new class of polynomials which we call quasi-subfield polynomials. First, we show that this class of polynomials could lead to more efficient attacks for the elliptic curve discrete logarithm problem via the index calculus approach. Specifically, we use these polynomials to construct factor bases for the index calculus approach and we provide explicit complexity bounds. Next, we investigate the existence of quasi-subfield polynomials.

Introduction The rising prevalence and burden of depression worldwide disproportionately affect low- and middle-income countries. (1-4) Major depressive and bipolar disorders independently increase the risk for other chronic diseases, including [...], Objective To evaluate the development and implementation of clinical practice guidelines for the management of depression globally. Methods We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries. Findings We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence. Conclusion Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes. [phrase omitted] [phrase omitted] Objectif Evaluer le developpement et la mise en reuvre des directives de pratique clinique pour la gestion de la depression dans le monde. Methodes Nous avons effectue une revue systematique des directives existantes en matiere de gestion de la depression chez les adultes souffrant de troubles depressifs majeurs ou de troubles bipolaires. Pour chaque directive identifiee, nous avons verifie le degre de conformite vis-a-vis des mesures de qualite du developpement des directives (transparence des processus d'elaboration des directives et de leur financement, composition multidisciplinaire du groupe d'auteurs, revue systematique des etudes d'efficacite comparative) ainsi que de la mise en reuvre (indicateurs de qualite). Nous avons confronte les directives des pays a faible et moyen revenu avec celles des pays a haut revenu. Resultats Nous avons identifie 82 directives de pratique clinique nationales et 13 directives de pratique clinique internationales dans 83 pays et en 27 langues. Les processus d'elaboration des directives et les sources de financement etaient explicitement indiquees dans une moindre proportion chez les pays a faible et moyen revenu (8/29; 28%) par rapport aux pays a haut revenu (35/58; 60%). Le nombre de directives redigees par un groupe d'auteurs multidisciplinaire etait moins eleve dans les pays a faible et moyen revenu (2/29; 7%) que dans les pays a haut revenu (22/58; 38%). Une revue systematique de l'efficacite comparative a ete menee pour 31% (9/29) des directives dans les pays a faible et moyen revenu, contre 71% (41/58) des directives dans les pays a haut revenu. Seulement 10% (3/29) des directives emises par les pays a faible et moyen revenu et 19% (11/58) de celles emises par les pays a haut revenu comprenaient un programme d'evaluation des indicateurs de qualite ou de l'adherence aux recommandations. Conclusion La mise en reuvre des directives est mal planifiee, mal analysee et mal mesuree. Reduire les disparites de developpement et de mise en reuvre des directives dans les pays a faible et moyen revenu est une priorite. A l'avenir, ces directives devraient prevoir des strategies d'execution des recommandations, mais aussi d'evaluation de la faisabilite, de la rentabilite et de l'impact sur l'etat de sante. [phrase omitted] Objetivo Evaluar la elaboracion e implementacion de las directrices de practica clinica para el tratamiento de la depresion a nivel mundial. Metodos Se realizo una revision sistematica de las directrices existentes para el tratamiento de la depresion en adultos con trastorno depresivo mayor o bipolar. Por cada directriz identificada, se evaluo el cumplimiento de las medidas de calidad de elaboracion de directrices (como la transparencia en los procesos de elaboracion de directrices y su financiamiento, la composicion del grupo multidisciplinario de autores, la revision sistematica del estudio de eficacia comparativo) y la implementacion (como los indicadores de calidad). En este contexto, se compararon las directrices de los paises de ingresos bajos y medios con las de los paises de ingresos altos. Resultados Se identificaron las directrices de practica clinica a nivel nacional (82) y a nivel internacional (13) de 83 paises en 27 idiomas. Los procesos de elaboracion de directrices y las fuentes de financiamiento se especificaron de manera explicita en un porcentaje menor de directrices de los paises de ingresos bajos y medios (8/29; 28 %) en relacion con las de los paises de ingresos altos (35/58; 60 %). Un grupo de desarrollo multidisciplinario elaboro menos directrices (2/29; 7 %) para los paises de ingresos bajos y medios, en relacion con las de los paises de ingresos altos (22/58; 38 %). Ademas, se realizo una revision sistematica sobre la efectividad comparativa en el 31 % (9/29) de las directrices de los paises de ingresos bajos y medios, frente al 71 % (41/58) de las directrices de los paises de ingresos altos. Solo el 10 % (3/29) de las directrices de los paises de ingresos bajos y medios y el 19 % (11/58) de las directrices de los paises de ingresos altos describieron planes para evaluar los indicadores de calidad o el cumplimiento de las recomendaciones. Conclusion La implementacion de las directrices no se planifica, notifica ni evalua de manera adecuada a nivel mundial. Es prioritario reducir las desigualdades en la elaboracion y la implementacion de las directrices en los paises de ingresos bajos y medios. Las directrices que se elaboren en el futuro deberan presentar estrategias para implementar las recomendaciones y evaluar la viabilidad, la rentabilidad y el impacto en los resultados sanitarios.