Subclass-switched anti-spike IgG3 oligoclonal cocktails strongly enhance Fc-mediated opsonization.

Antibodies play a central role in the immune defense against SARS-CoV-2. Emerging evidence has shown that nonneutralizing antibodies are important for immune defense through Fc-mediated effector functions. Antibody subclass is known to affect downstream Fc function. However, whether the antibody subclass plays a role in anti-SARS-CoV-2 immunity remains unclear. Here, we subclass-switched eight human IgG1 anti-spike monoclonal antibodies (mAbs) to the IgG3 subclass by exchanging their constant domains. The IgG3 mAbs exhibited altered avidities to the spike protein and more potent Fc-mediated phagocytosis and complement activation than their IgG1 counterparts. Moreover, combining mAbs into oligoclonal cocktails led to enhanced Fc- and complement receptor-mediated phagocytosis, superior to even the most potent single IgG3 mAb when compared at equivalent concentrations. Finally, in an in vivo model, we show that opsonic mAbs of both subclasses can be protective against a SARS-CoV-2 infection, despite the antibodies being nonneutralizing. Our results suggest that opsonic IgG3 oligoclonal cocktails are a promising idea to explore for therapy against SARS-CoV-2, its emerging variants, and potentially other viruses.

Identification of lectin receptors for conserved SARS-CoV-2 glycosylation sites.

New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. The 22 N-glycan sites of Spike remain highly conserved among SARS-CoV-2 variants, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate-binding proteins (lectins) to probe critical sugar residues on the full-length trimeric Spike and the receptor binding domain (RBD) of SARS-CoV-2. Two lectins, Clec4g and CD209c, were identified to strongly bind to Spike. Clec4g and CD209c binding to Spike was dissected and visualized in real time and at single-molecule resolution using atomic force microscopy. 3D modelling showed that both lectins can bind to a glycan within the RBD-ACE2 interface and thus interferes with Spike binding to cell surfaces. Importantly, Clec4g and CD209c significantly reduced SARS-CoV-2 infections. These data report the first extensive map and 3D structural modelling of lectin-Spike interactions and uncovers candidate receptors involved in Spike binding and SARS-CoV-2 infections. The capacity of CLEC4G and mCD209c lectins to block SARS-CoV-2 viral entry holds promise for pan-variant therapeutic interventions.

Civilian national service programs can powerfully increase youth voter turnout.

Low rates of youth voting are a feature of contemporary democracies the world over, with the United States having some of the lowest youth turnout rates in the world. However, far too little is known about how to address the dismal rates of youth voter participation found in many advanced democracies. In this paper, we examine the causal effect of a potentially scalable solution that has attracted renewed interest today: voluntary national service programs targeted at the youth civilian population. Leveraging the large pool of young people who apply each year to participate in the Teach For America (TFA) program-a prominent voluntary national service organization in the United States that integrates college graduates into teaching roles in low-income communities for 2 y-we examine the effect of service participation on voter turnout. To do so, we match TFA administrative records to large-scale nationwide voter files and employ a fuzzy regression discontinuity design around the recommended admittance cutoff for the TFA program. We find that serving as a teacher in the Teach For America national service program has a large effect on civic participation-substantially increasing voter turnout rates among applicants admitted to the program. This effect is noticeably larger than that of previous efforts to increase youth turnout. Our results suggest that civilian national service programs targeted at young people have great promise in helping to narrow the stubborn and enduring political engagement gap between younger and older citizens.

Mitigating the detrimental developmental impact of early fetal alcohol exposure using a maternal methyl donor-enriched diet.

Fetal alcohol exposure at any stage of pregnancy can lead to fetal alcohol spectrum disorder (FASD), a group of life-long conditions characterized by congenital malformations, as well as cognitive, behavioral, and emotional impairments. The teratogenic effects of alcohol have long been publicized; yet fetal alcohol exposure is one of the most common preventable causes of birth defects. Currently, alcohol abstinence during pregnancy is the best and only way to prevent FASD. However, alcohol consumption remains astoundingly prevalent among pregnant women; therefore, additional measures need to be made available to help protect the developing embryo before irreparable damage is done. Maternal nutritional interventions using methyl donors have been investigated as potential preventative measures to mitigate the adverse effects of fetal alcohol exposure. Here, we show that a single acute preimplantation (E2.5; 8-cell stage) fetal alcohol exposure (2 × 2.5 g/kg ethanol with a 2h interval) in mice leads to long-term FASD-like morphological phenotypes (e.g. growth restriction, brain malformations, skeletal delays) in late-gestation embryos (E18.5) and demonstrate that supplementing the maternal diet with a combination of four methyl donor nutrients, folic acid, choline, betaine, and vitamin B12, prior to conception and throughout gestation effectively reduces the incidence and severity of alcohol-induced morphological defects without altering DNA methylation status of imprinting control regions and regulation of associated imprinted genes. This study clearly supports that preimplantation embryos are vulnerable to the teratogenic effects of alcohol, emphasizes the dangers of maternal alcohol consumption during early gestation, and provides a potential proactive maternal nutritional intervention to minimize FASD progression, reinforcing the importance of adequate preconception and prenatal nutrition.

Viral G Protein-Coupled Receptors: Attractive Targets for Herpesvirus-Associated Diseases.

Herpesviruses are ubiquitous pathogens that establish lifelong, latent infections in their host. Spontaneous reactivation of herpesviruses is often asymptomatic or clinically manageable in healthy individuals, but reactivation events in immunocompromised or immunosuppressed individuals can lead to severe morbidity and mortality. Moreover, herpesvirus infections have been associated with multiple proliferative cardiovascular and post-transplant diseases. Herpesviruses encode viral G protein-coupled receptors (vGPCRs) that alter the host cell by hijacking cellular pathways and play important roles in the viral life cycle and these different disease settings. In this review, we discuss the pharmacological and signaling properties of these vGPCRs, their role in the viral life cycle, and their contribution in different diseases. Because of their prominent role, vGPCRs have emerged as promising drug targets, and the potential of vGPCR-targeting therapeutics is being explored. Overall, these vGPCRs can be considered as attractive targets moving forward in the development of antiviral, cancer, and/or cardiovascular disease treatments. SIGNIFICANCE STATEMENT: In the last decade, herpesvirus-encoded G protein-coupled receptors (GPCRs) have emerged as interesting drug targets with the growing understanding of their critical role in the viral life cycle and in different disease settings. This review presents the pharmacological properties of these viral receptors, their role in the viral life cycle and different diseases, and the emergence of therapeutics targeting viral GPCRs.

Pool-Based Surfboard Elicits Activation of Posterior Shoulder Muscles During a Surfing Stroke.

ABSTRACT: Pexa, BS, Johnston, CD, Elder, EE, Ford, KR, Patterson, MQ, and Myers, JB. Pool-based surfboard elicits activation of posterior shoulder muscles during a surfing stroke. J Strength Cond Res 38(7): 1300-1304, 2024-Surfboard paddling may activate posterior shoulder muscles, which are critical to baseball pitchers' injury risk and performance. The purpose of this study was to measure posterior shoulder muscle activation during different phases of the surf stroke (propulsion vs. recovery) on a pool-based surfboard. Twenty healthy active adult subjects completed a familiarization and testing session with the pool-based surfboard. During the testing session, electromyography (EMG) sensors were placed on 6 posterior shoulder muscles: latissimus dorsi, infraspinatus, posterior deltoid, upper trapezius, middle trapezius, and lower trapezius. Subjects completed 4 laps in a pool at 3 separate resistances (low, moderate, and heavy) in a randomized order. The peak EMG signal during each phase (propulsion and recovery) was recorded. A 2-way within subject ANOVA (resistance-by-phase) with post hoc Bonferroni's corrections was used to identify differences in EMG activation. There was a significant main effect of phase for the latissimus dorsi (F = 91.3, p < 0.001), upper trapezius (F = 36.5, p < 0.001), middle trapezius (F = 33.8, p < 0.001), and lower trapezius (F = 21.6, p < 0.001). The latissimus dorsi demonstrated higher activation during the propulsion phase (p < 0.001), and all trapezius muscles demonstrated higher activation during the recovery phase (p < 0.001). There was a significant main effect of resistance for the posterior deltoid (F = 3.4, p = 0.043), with higher muscle activation in the low resistance trials compared with the heavy resistance trials (p = 0.036). Recreationally active individuals demonstrate activation of the posterior shoulder when using a pool-based surfboard. This pool-based surfboard may be beneficial to activate the posterior musculature and may be more accessible than standard surfing to baseball athletes.

Human Cytomegalovirus Infection of Epithelial Cells Increases SARS-CoV-2 Superinfection by Upregulating the ACE2 Receptor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused widespread morbidity and mortality since its onset in late 2019. Here, we demonstrate that prior infection with human cytomegalovirus (HCMV) substantially increases infection with SARS-CoV-2 in vitro. HCMV is a common herpesvirus carried by 40%-100% of the population, which can reactivate in the lung under inflammatory conditions, such as those resulting from SARS-CoV-2 infection. We show in both endothelial and epithelial cell types that HCMV infection upregulates ACE2, the SARS-CoV-2 cell entry receptor. These observations suggest that HCMV reactivation events in the lung of healthy HCMV carriers could exacerbate SARS-CoV-2 infection and subsequent COVID-19 symptoms. This effect could contribute to the disparity of disease severity seen in ethnic minorities and those with lower socioeconomic status, due to their higher CMV seroprevalence. Our results warrant further clinical investigation as to whether HCMV infection influences the pathogenesis of SARS-CoV-2.

Regulation of host and viral promoters during human cytomegalovirus latency via US28 and CTCF.

Viral latency is an active process during which the host cell environment is optimized for latent carriage and reactivation. This requires control of both viral and host gene promoters and enhancers often at the level of chromatin, and several viruses co-opt the chromatin organiser CTCF to control gene expression during latency. While CTCF has a role in the latencies of alpha- and gamma-herpesviruses, it was not known whether CTCF played a role in the latency of the beta-herpesvirus human cytomegalovirus (HCMV). Here, we show that HCMV latency is associated with increased CTCF expression and CTCF binding to the viral major lytic promoter, the major immediate early promoter (MIEP). This increase in CTCF binding is dependent on the virally encoded G protein coupled receptor, US28, and contributes to suppression of MIEP-driven transcription, a hallmark of latency. Furthermore, we show that latency-associated upregulation of CTCF represses expression of the neutrophil chemoattractants S100A8 and S100A9 which we have previously shown are downregulated during HCMV latency. As with downregulation of the MIEP, CTCF binding to the enhancer region of S100A8/A9 drives their suppression, again in a US28-dependent manner. Taken together, we identify CTCF upregulation as an important mechanism for optimizing latent carriage of HCMV at both the levels of viral and cellular gene expression.

HCMV latency: what regulates the regulators?

Human cytomegalovirus (HCMV) latency and reactivation is regulated by the chromatin structure at the major immediate early promoter (MIEP) within myeloid cells. Both cellular and viral factors are known to control this promoter during latency, here we will review the known mechanisms for MIEP regulation during latency. We will then focus on the virally encoded G-protein coupled receptor, US28, which suppresses the MIEP in early myeloid lineage cells. The importance of this function is underlined by the fact that US28 is essential for HCMV latency in CD34+ progenitor cells and CD14+ monocytes. We will describe cellular signalling pathways modulated by US28 to direct MIEP suppression during latency and demonstrate how US28 is able to 'regulate the regulators' of HCMV latency. Finally, we will describe how cell-surface US28 can be a target for antiviral therapies directed at the latent viral reservoir.

Factors that contribute to turnover and retention amongst emergency department nurses: A scoping review.

BACKGROUND: Internationally, the emergency nursing workforce shortage is of critical concern. AIM: To synthesise the evidence and assess the scope of literature regarding factors that contribute to turnover and retention amongst emergency nurses. METHOD: A scoping review using the Joanna Briggs Institute approach was undertaken. Fivedatabases (Embase, MEDLINE, PsycINFO, CINAHL, and Business Source Complete) were searched for papers published in English between January 2011 and June 2023 where the population was nurses, context was the emergency department, and the concept was turnover or retention. A quality appraisal was performed on included studies. RESULTS: A total of 31 articles met the inclusion criteria. Twenty-six studies focussed on turnover and five studies focussed on retention. Factors that contribute to ED nursing turnover included workplace violence, personal aspects (e.g., burnout or depression), organisational characteristics, and environmental/ job characteristics. Factors that contributed to ED nursing retention included mentoring programs, the advancement in nursing skills, and the transition to practice speciality (emergency) programs. CONCLUSIONS: A large body of literature exists regarding ED nurses' reasons for leaving their area of practice, yet limited evidence exist on retention. Research exploring factors that promote retention of emergency nurses that leads to subsequent stability and growth in the emergency nursing workforce is needed.

Healthcare delivery to patients from culturally and linguistically diverse backgrounds in emergency care: a scoping review protocol.

BACKGROUND: Worldwide, the culturally and linguistically diverse (CALD) population is increasing, and is predicted to reach 405 million by 2050. The delivery of emergency care for the CALD population can be complex due to cultural, social, and language factors. The extent to which cultural, social, and contextual factors influence care delivery to patients from CALD backgrounds throughout their emergency care journey is unclear. Using a systematic approach, this review aims to map the existing evidence regarding emergency healthcare delivery for patients from CALD backgrounds and uses a social ecological framework to provide a broader perspective on cultural, social, and contextual influence on emergency care delivery. METHODS: The Joanna Briggs Institute (JBI) scoping review methodology will be used to guide this review. The population is patients from CALD backgrounds who received care and emergency care clinicians who provided direct care. The concept is healthcare delivery to patients from CALD backgrounds. The context is emergency care. This review will include quantitative, qualitative, and mixed-methods studies published in English from January 1, 2012, onwards. Searches will be conducted in the databases of CINAHL (EBSCO), MEDLINE (Ovid), Embase (Elsevier), SocINDEX (EBSCO), Scopus (Elsevier), and a web search of Google Scholar. A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram will be used to present the search decision process. All included articles will be appraised using the Mixed Methods Appraisal Tool (MMAT). Data will be presented in tabular form and accompanied by a narrative synthesis of the literature. DISCUSSION: Despite the increased use of emergency care service by patients from CALD backgrounds, there has been no comprehensive review of healthcare delivery to patients from CALD backgrounds in the emergency care context (ED and prehospital settings) that includes consideration of cultural, social, and contextual influences. The results of this scoping review may be used to inform future research and strategies that aim to enhance care delivery and experiences for people from CALD backgrounds who require emergency care. SYSTEMATIC REVIEW REGISTRATION: This scoping review has been registered in the Open Science Framework https://doi.org/10.17605/OSF.IO/HTMKQ.

Leadership conceptions of nurses and physicians in emergency care: A scoping review.

BACKGROUND: The Emergency Department (ED) is a setting where teamwork and leadership is imperative, however, the literature to date is mostly discipline (nursing or medical) specific. This scoping review aimed to map what is known about nurses' and physicians' conceptions of leadership in the ED to understand similarities, differences, and opportunities for leadership development and research. METHOD: Guided by the Joanna Briggs Institute approach, and Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Guidelines, a systematic search of three electronic databases was performed. The Mixed Methods Assessment Tool was used for quality appraisal of included articles. RESULTS: In total, 37 articles were included. Four key findings emerged: 1) leadership was rarely explicitly defined; 2) nurse leaders tended to be characterised as agents of continuity whilst physician leaders tended to be characterised as agents of change and continuity; 3) the clarification of expectations from nurse leaders was more evident than expectations from physician leaders; and 4) leadership discourse tended to be traditional rather than contemporary. CONCLUSION: Despite the proliferation of studies into ED nurse, physician and interprofessional leadership, opportunities exist to integrate learnings from other sectors to strengthen the development of current and next generation of ED leaders.

Crimean-Congo haemorrhagic fever virus uses LDLR to bind and enter host cells.

Climate change and population densities accelerated transmission of highly pathogenic viruses to humans, including the Crimean-Congo haemorrhagic fever virus (CCHFV). Here we report that the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids. The interaction between CCHFV and LDLR is highly specific, with other members of the LDLR protein family failing to bind to or neutralize the virus. Biosensor experiments demonstrate that LDLR specifically binds the surface glycoproteins of CCHFV. Importantly, mice lacking LDLR exhibit a delay in CCHFV-induced disease. Furthermore, we identified the presence of Apolipoprotein E (ApoE) on CCHFV particles. Our findings highlight the essential role of LDLR in CCHFV infection, irrespective of ApoE presence, when the virus is produced in tick cells. This discovery holds profound implications for the development of future therapies against CCHFV.

Effects of the STress-And-coping suppoRT (START) intervention on depression and coping of Chinese women seeking a first-trimester abortion: A randomized controlled trial.

BACKGROUND: Abortion is a stressful life event associated with wide variability in women's perceptions and adjustment. There is scarce evidence on interventions to help women cope with abortion and achieve positive psychological health outcomes. This study tested the effect of a stress and coping theory-formed intervention (START) on depression and coping of Chinese women undergoing a first-trimester abortion. METHODS: A randomized controlled trial was conducted at a Chinese metropolitan hospital. 110 participants were recruited and randomized to intervention group (START + standard care) or control group (standard care) with a 1:1 allocation ratio. The primary outcome was depression at two-week post-abortion. Surveys were completed by participants when they sought abortion services (baseline), two and six-week post-abortion. RESULTS: At two-week post-abortion, women allocated to the intervention group compared to the control group, had significantly lower depression scores (aOR -2.81 [-4.12 to -1.50]), higher problem-focused coping (aOR 1.64 [0.36-2.93]), lower dysfunctional coping (aOR -2.29 [-3.69 to -0.89]), higher self-efficacy (aOR 3.17 [-0.42-5.94]), and higher personal growth scores (aOR 4.41 [0.30-8.53]). Lower depression scores at two-weeks were mediated by lower dysfunctional coping (mediated effect 0.96 [0.25, 1.74]; proportion of overall effect 36 % [9 %, 65 %]). CONCLUSION: Chinese women allocated to receive START had lower depression and better coping at two-week post-abortion. This brief, online intervention contributed to women's self-efficacy and positive perceptions of social support, abortion experience, and personal growth. Maintenance of the effects need further research.

Grit, Athlete Burnout, and Well-Being in Female Collegiate Student-Athletes.

CONTEXT: Collegiate student-athletes are faced with significant athletic and academic demands, causing a substantial amount of stress, which can lead to athlete burnout. Problematically, little research has been done to find ways to prevent or mitigate the effect of athlete burnout in collegiate student-athletes. Grit is one characteristic that they could use as a coping mechanism to reduce the effects of burnout and to improve overall well-being. OBJECTIVE: To determine if grit had a main or buffering effect on well-being and athlete burnout in female collegiate student-athletes. DESIGN: Cross-sectional study. SETTING: National Collegiate Athletics Association Division I institution. PATIENTS OR OTHER PARTICIPANTS: A total of 174 female collegiate student-athletes. MAIN OUTCOME MEASURE(S): The Grit Scale, Athlete Burnout Questionnaire, and Warwick Edinburgh Mental Well-Being Scale were used to assess grit, athlete burnout, and well-being. RESULTS: Grit was a significant negative predictor for physical and emotional exhaustion (F1,172 = 28.25, P < .001), a reduced sense of accomplishment (F1,172 = 20.40, P < .001), and sport devaluation (F1,172 = 40.32, P < .001). Additionally, grit was a significant positive predictor of well-being (F1,172 = 29.68, P < .001). The moderated regression with grit did not reveal significant results. CONCLUSIONS: We provide new information on considerations for reducing athlete burnout and improving well-being in female collegiate student-athletes. Athletic trainers and sports medicine stakeholders should consider intervention strategies for improving grit to mitigate athlete burnout and diminished well-being while continuing to explore their effectiveness.

Protective immunity induced by an inhaled SARS-CoV-2 subunit vaccine.

Targeting the site of infection is a promising strategy for improving vaccine effectivity. To date, licensed COVID-19 vaccines have been administered intramuscularly despite the fact that SARS-CoV-2 is a respiratory virus. Here, we aim to induce local protective mucosal immune responses with an inhaled subunit vaccine candidate, ISR52, based on the SARS-CoV-2 Spike S1 protein. When tested in a lethal challenge hACE2 transgenic SARS-CoV-2 mouse model, intranasal and intratracheal administration of ISR52 provided superior protection against severe infection, compared to the subcutaneous injection of the vaccine. Interestingly for a protein-based vaccine, inhaled ISR52 elicited both CD4 and CD8 T-cell Spike-specific responses that were maintained for at least 6 months in wild-type mice. Induced IgG and IgA responses cross-reacting with several SARS- CoV-2 variants of concern were detected in the lung and in serum and protected animals displayed neutralizing antibodies. Based on our results, we are developing ISR52 as a dry powder formulation for inhalation, that does not require cold-chain distribution or the use of needle administration, for evaluation in a Phase I/II clinical trial.

The STress-And-Coping suppoRT Intervention (START) for Chinese Women Undergoing Abortion: A Randomized Controlled Trial Protocol.

BACKGROUND: Although undergoing an abortion is stressful for most women, little attention has been given to their psychological wellbeing. This protocol aims to assess the feasibility, acceptability, and primary effects of a complex intervention to promote positive coping behaviors and alleviate depression symptoms among Chinese women who have undergone an abortion. METHODS: A two-arm randomized controlled trial design will be used. Participants will be recruited at their first appointment with the abortion clinic and randomly allocated to receive either the Stress-And-Coping suppoRT (START) intervention (in addition to standard abortion care) or standard care only. All participants will be followed-up at two- and six-weeks post-abortion. Approval has been granted by local and university ethics committees. This research was supported by an Australian Government Research Training Program Scholarship. DISCUSSION: The results will assist refinement and further evaluations of the START intervention, contribute to improved abortion care practices in China, and enrich the evidence on improving women's psychological well-being following abortion in China. TRIAL REGISTRATION: Registered at the Chinese Clinical Trials.gov: ChiCTR2100046101. Date of registration: 4 May 2021.