Memory B cell differentiation from germinal centers.

Establishment of humoral immune memory depends on two layers of defense: pre-existing antibodies secreted by long-lived plasma cells; and the antibodies produced by antigen-reactivated memory B cells. Memory B cells can now be considered as a second layer of defense upon re-infection by variant pathogens that have not been cleared by the long-lived plasma cell-mediated defense. Affinity-matured memory B cells are derived from the germinal center (GC) reaction, but the selection mechanism of GC B cells into the memory compartment is still incompletely understood. Recent studies have revealed the critical determinants of cellular and molecular factors for memory B cell differentiation from the GC reaction. In addition, the contribution of antibody-mediated feedback regulation to B cell selection, as exemplified by the B cell response upon COVID-19 mRNA vaccination, has now garnered considerable attention, which may provide valuable implications for future vaccine design.

Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees.

In contrast to a second dose of the SARS-CoV-2 mRNA vaccine, a third dose elicits potent neutralizing activity against the Omicron variant. To address the underlying mechanism for this differential antibody response, we examined spike receptor-binding domain (RBD)-specific memory B cells in vaccinated individuals. Frequency of Omicron-reactive memory B cells increased ∼9 mo after the second vaccine dose. These memory B cells show an altered distribution of epitopes from pre-second memory B cells, presumably due to an antibody feedback mechanism. This hypothesis was tested using mouse models, showing that an addition or a depletion of RBD-induced serum antibodies results in a concomitant increase or decrease, respectively, of Omicron-reactive germinal center (GC) and memory B cells. Our data suggest that pre-generated antibodies modulate the selection of GC and subsequent memory B cells after the second vaccine dose, accumulating more Omicron-reactive memory B cells over time, which contributes to the generation of Omicron-neutralizing antibodies elicited by the third vaccine dose.

Doping control analyses during the Tokyo 2020 Olympic and Paralympic Games.

The doping control analyses at the XXXII Olympic Games (July 23 to August 8, 2021) and the XVI Paralympic Games (August 24 to September 5, 2021) held in Tokyo, Japan, after a year of delay due to the COVID-19 pandemic are summarized in this paper. A new satellite facility at the existing World Anti-Doping Agency (WADA)-accredited Tokyo laboratory was established and fully operated by 278 staff, including 33 Tokyo laboratory staff, 49 international experts, and 196 Japanese temporary staff. The numbers of urine samples were 5081 (Olympics) and 1519 (Paralympics), and the numbers of blood samples were 1103 (Olympics) and 500 (Paralympics). The laboratory could prepare for analysis in advance using a paperless chain-of-custody system, allowing for faster turnaround time reporting. For the first time, a new polymerase chain reaction method for detecting erythropoietin (EPO) gene doping was used. The laboratory also analyzed blood samples for detecting steroid esters following the spotting of collected venous EDTA blood onto dried blood spot cards. Moreover, full-scan data acquisition using high-resolution mass spectrometers was performed for all urine samples, allowing for detecting traces of doping substances, which are not currently analyzed in the subsequent data processing. The presence of some prohibited substances was confirmed, resulting in 8 atypical findings (ATFs) and 11 adverse analytical findings (AAFs), including homologous blood transfusion (2 cases) and recombinant EPO in the blood (1 case), at the Olympics, whereas 2 ATFs and 10 AAFs were reported at the Paralympics.

Remote Work Decreases Psychological and Physical Stress Responses, but Full-Remote Work Increases Presenteeism.

Introduction: Remote work was widely promoted in 2020, as a result of the COVID-19 pandemic. However, the effects of remote work on psychological and physical stress responses and presenteeism of workers remain unclear. This research aims to provide empirical evidence of the implications for people and organizations of this new scenario of working from home. Methods: A two-wave panel survey of before and after the pandemic was performed to investigate the effects of remote work on these aspects among office workers. A total of 3,123 office workers from 23 tertiary industries responded to a questionnaire. Participants were surveyed about their job stress conditions and sleep practices in both 2019 and 2020, who had not done remote work as of 2019 were included in the study. The effects of remote work on psychological and physical stress responses and presenteeism were analyzed by multivariate analysis, with the adjustment of age, gender, overtime, job stressors, social support, and sleep status. Results: The multivariate logistic regression analysis demonstrated that remote work was associated with the reduction of psychological and physical stress responses independently of changes of job stressors, social support, sleep disturbance, and total sleep time on workdays. On the other hand, remote work of 5 days a week (full-remote) was associated with the reduction of work productivity. Conclusion: Promoting remote work can reduce psychological and physical stress responses, however, full-remote work has the risk of worsening presenteeism. From the viewpoint of mental health, the review of working styles is expected to have positive effects, even after the end of the COVID-19 pandemic.

Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients.

Adaptive immunity is a fundamental component in controlling COVID-19. In this process, follicular helper T (Tfh) cells are a subset of CD4+ T cells that mediate the production of protective antibodies; however, the SARS-CoV-2 epitopes activating Tfh cells are not well characterized. Here, we identified and crystallized TCRs of public circulating Tfh (cTfh) clonotypes that are expanded in patients who have recovered from mild symptoms. These public clonotypes recognized the SARS-CoV-2 spike (S) epitopes conserved across emerging variants. The epitope of the most prevalent cTfh clonotype, S864-882, was presented by multiple HLAs and activated T cells in most healthy donors, suggesting that this S region is a universal T cell epitope useful for booster antigen. SARS-CoV-2-specific public cTfh clonotypes also cross-reacted with specific commensal bacteria. In this study, we identified conserved SARS-CoV-2 S epitopes that activate public cTfh clonotypes associated with mild symptoms.

Glycan engineering of the SARS-CoV-2 receptor-binding domain elicits cross-neutralizing antibodies for SARS-related viruses.

Broadly protective vaccines against SARS-related coronaviruses that may cause future outbreaks are urgently needed. The SARS-CoV-2 spike receptor-binding domain (RBD) comprises two regions, the core-RBD and the receptor-binding motif (RBM); the former is structurally conserved between SARS-CoV-2 and SARS-CoV. Here, in order to elicit humoral responses to the more conserved core-RBD, we introduced N-linked glycans onto RBM surfaces of the SARS-CoV-2 RBD and used them as immunogens in a mouse model. We found that glycan addition elicited higher proportions of the core-RBD-specific germinal center (GC) B cells and antibody responses, thereby manifesting significant neutralizing activity for SARS-CoV, SARS-CoV-2, and the bat WIV1-CoV. These results have implications for the design of SARS-like virus vaccines.

Case report of restless anal syndrome as restless legs syndrome variant after COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has a broad spectrum from respiratory and nasopharyngeal symptoms, cerebrovascular diseases, impaired consciousness, and skeletal muscle injury. Emerging evidence has indicated the neural spread of this novel coronavirus. Restless legs syndrome (RLS) is a common neurological, sensorimotor disorder, but highly under diagnosis disorder. Restless anal syndrome as restless legs syndrome variant associated with COVID-19 has been previously not published. We report a case presenting with restless anal syndrome following COVID-19. CASE PRESENTATION: Although a 77-year-old male with COVID-19 improved to normal respiratory function 21 days after admission and treatment of favipiravir 200 mg per day for 14 days and dexamethasone 6.6 mg per day for 5 days, the insomnia and anxiety symptoms remained. Several weeks after discharge, he gradually began to experience restless, deep anal discomfort, approximately 10 cm from the perineal region. The following features were observed in the anal region; urge to move is essential, with worsening with rest, improvement with exercise, and worsening at evening. Colonoscopy revealed internal haemorrhoids without other rectal lesions. Neurological findings including deep tendon reflex, perineum loss of sensory and spinal cord injury, revealed no abnormalities. Diabetes militias, kidney dysfunction and iron deficiency status were not confirmed. Family history of RLS and periodic limb movements were not observed. Clonazepam at 1.5 mg per day resulted in the alleviation restless anal discomfort. CONCLUSIONS: We reported a case presenting with restless anal syndrome following affection of COVID-19 as restless legs syndrome variant. This case fulfilled 4 essential features of RLS, urge to move, worsening with rest, improvement with exercise, and worsening at evening. To date, no case of restless anal syndrome associated with COVID-19 has been previously published. This case report may reflect the associative impacts of COVID-19 on the neuropsychiatric state. The long-term outcomes of neuropsychiatric conditions should continue to be monitored.

A SARS-CoV-2 antibody broadly neutralizes SARS-related coronaviruses and variants by coordinated recognition of a virus-vulnerable site.

Potent neutralizing SARS-CoV-2 antibodies often target the spike protein receptor-binding site (RBS), but the variability of RBS epitopes hampers broad neutralization of multiple sarbecoviruses and drifted viruses. Here, using humanized mice, we identified an RBS antibody with a germline VH gene that potently neutralized SARS-related coronaviruses, including SARS-CoV and SARS-CoV-2 variants. X-ray crystallography revealed coordinated recognition by the heavy chain of non-RBS conserved sites and the light chain of RBS with a binding angle mimicking the angiotensin-converting enzyme 2 (ACE2) receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by immunoglobulin G3 (IgG3) class switching. The coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Low-dose therapeutic antibody treatment in hamsters reduced the virus titers and morbidity during SARS-CoV-2 challenge. The structural basis for broad neutralizing activity may inform the design of a broad spectrum of therapeutics and vaccines.

Mediating Roles of Cognitive Complaints on Relationships between Insomnia, State Anxiety, and Presenteeism in Japanese Adult Workers.

Complaints of cognitive functions (CCFs), defined as subjective cognitive dysfunction, affect social function; additionally, for workers, this condition is an important factor in presenteeism and mediates the effect of depressive symptoms on presenteeism. This study aimed to investigate whether CCFs mediate the relationships among insomnia, state anxiety (SA), and presenteeism. Participants were 471 Japanese adult workers evaluated using the Athens Insomnia Scale, State-Trait Anxiety Inventory (Form Y), Cognitive Complaints in Bipolar Disorder Rating Assessment, and Work Limitations Questionnaire 8 to assess insomnia, SA, CCFs, and presenteeism, respectively. Path analysis was used to evaluate the correlations between variables. CCFs significantly mediated the associations among insomnia, SA, and presenteeism. To address the presenteeism associated with insomnia and SA, it may be useful to assess the mediating roles of CCFs.