'This Is What the Colour Green Smells Like!': Urban Forest Bathing Improved Adolescent Nature Connection and Wellbeing.

BACKGROUND: Research suggests that an early connection with nature can benefit wellbeing into adulthood. However, there is less research assessing whether adolescents benefit from formal nature connection interventions such as forest bathing (slow mindful nature walks). This research aimed to assess whether an urban nature connection intervention (called ParkBathe) could improve adolescents' nature connection and wellbeing. METHOD: In an experimental repeated measures design, 44 adolescents sampled opportunistically from Scouts groups, completed surveys and interviews before and after experiencing an urban nature connection intervention. RESULTS: Paired-samples t-tests between baseline and post-intervention survey scores revealed statistically significant improvements in anxiety (13% reduction); rumination (44% reduction); scepticism (17% reduction); nature connection (25% increase); and social connection (12% increase). The largest effect size was found for nature connection. Interviews revealed that before the session, participants had a mixed understanding and expectations of the intervention. CONCLUSIONS: After the session, the participants expressed enjoying the social aspects of being part of a group and being present in the moment by noticing nature. They expressed the effects of this as immediately calming and relaxing. Urban forest bathing improved nature connection and wellbeing in adolescents and could be implemented and/or signposted by schools and youth charities.

Tetraspanin Cd9b plays a role in fertility in zebrafish.

In mice, CD9 expression on the egg is required for efficient sperm-egg fusion and no effects on ovulation or male fertility are observed in CD9 null animals. Here we show that cd9b knockout zebrafish also appear to have fertility defects. In contrast to mice, fewer eggs were laid by cd9b knockout zebrafish pairs and, of the eggs laid, a lower percentage were fertilised. These effects could not be linked to primordial germ cell numbers or migration as these were not altered in the cd9b mutants. The decrease in egg numbers could be rescued by exchanging either cd9b knockout partner, male or female, for a wildtype partner. However, the fertilisation defect was only rescued by crossing a cd9b knockout female with a wildtype male. To exclude effects of mating behaviour we analysed clutch size and fertilisation using in vitro fertilisation techniques. Number of eggs and fertilisation rates were significantly reduced in the cd9b mutants suggesting the fertility defects are not solely due to courtship behaviours. Our results indicate that CD9 plays a more complex role in fish fertility than in mammals, with effects in both males and females.

B-cell intrinsic and extrinsic signals that regulate central tolerance of mouse and human B cells.

The random recombination of immunoglobulin V(D)J gene segments produces unique IgM antibodies that serve as the antigen receptor for each developing B cell. Hence, the newly formed B cell repertoire is comprised of a variety of specificities that display a range of reactivity with self-antigens. Newly generated IgM+ immature B cells that are non-autoreactive or that bind self-antigen with low avidity are licensed to leave the bone marrow with their intact antigen receptor and to travel via the blood to the peripheral lymphoid tissue for further selection and maturation. In contrast, clones with medium to high avidity for self-antigen remain within the marrow and undergo central tolerance, a process that revises their antigen receptor or eliminates the autoreactive B cell altogether. Thus, central B cell tolerance is critical for reducing the autoreactive capacity and avidity for self-antigen of our circulating B cell repertoire. Bone marrow cultures and mouse models have been instrumental for understanding the mechanisms that regulate the selection of bone marrow B cells. Here, we review recent studies that have shed new light on the contribution of the ERK, PI3K, and CXCR4 signaling pathways in the selection of mouse and human immature B cells that either bind or do not bind self-antigen.

Tetraspanin Cd9b and Cxcl12a/Cxcr4b have a synergistic effect on the control of collective cell migration.

Collective cell migration is essential for embryonic development and homeostatic processes. During zebrafish development, the posterior lateral line primordium (pLLP) navigates along the embryo flank by collective cell migration. The chemokine receptors, Cxcr4b and Cxcr7b, as well as their cognate ligand, Cxcl12a, are essential for this process. We corroborate that knockdown of the zebrafish cd9 tetraspanin orthologue, cd9b, results in mild pLL abnormalities. Through generation of CRISPR and TALEN mutants, we show that cd9a and cd9b function partially redundantly in pLLP migration, which is delayed in the cd9b single and cd9a; cd9b double mutants. This delay led to a transient reduction in neuromast numbers. Loss of both Cd9a and Cd9b sensitized embryos to reduced Cxcr4b and Cxcl12a levels. Together these results provide evidence that Cd9 modulates collective cell migration of the pLLP during zebrafish development. One interpretation of these observations is that Cd9 contributes to more effective chemokine signalling.

CD4+ T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope.

Löfgren's syndrome (LS) is an acute form of sarcoidosis characterized by a genetic association with HLA-DRB1*03 (HLA-DR3) and an accumulation of CD4+ T cells of unknown specificity in the bronchoalveolar lavage (BAL). Here, we screened related LS-specific TCRs for antigen specificity and identified a peptide derived from NAD-dependent histone deacetylase hst4 (NDPD) of Aspergillus nidulans that stimulated these CD4+ T cells in an HLA-DR3-restricted manner. Using ELISPOT analysis, a greater number of IFN-γ- and IL-2-secreting T cells in the BAL of DR3+ LS subjects compared with DR3+ control subjects was observed in response to the NDPD peptide. Finally, increased IgG antibody responses to A. nidulans NDPD were detected in the serum of DR3+ LS subjects. Thus, our findings identify a ligand for CD4+ T cells derived from the lungs of LS patients and suggest a role of A. nidulans in the etiology of LS.

COVID-19 Rapid Review cross-publisher initiative: What we have learned and what we are going to do next.

The global crisis sparked collaboration between publishers and service providers to successfully address an immediate problem and demonstrated the possibility for future partnerships.Encouraging experts to join a reviewer pool and quickly review the preprint and journal submissions, we were able to publish COVID-19 research more quickly.The initiative confirmed little author uptake of inter-publisher journal transfer option.The collaboration showed wide consensus on open science practices which will ensure faster and more reliable research findings.

The Pain at Work Toolkit for Employees with Chronic or Persistent Pain: A Collaborative-Participatory Study.

Self-management tools for people with chronic or persistent pain tend to focus on symptom reporting, treatment programmes or exercise and do not address barriers to work, facilitators of work ability, or workplace pain self-management strategies. We developed the Pain at Work (PAW) toolkit, an evidence-based digital toolkit to provide advice on how employees can self-manage their pain at work. In a collaborative-participatory design, 4-step Agile methodology (N = 452) was used to co-create the toolkit with healthcare professionals, employers and people with chronic or persistent pain. Step 1: stakeholder consultation event (n = 27) established content and format; Step 2: online survey with employees who have persistent pain (n = 274) showed employees fear disclosing their condition, and commonly report discrimination and lack of line manager support. Step 3: online employer survey (n = 107) showed employers rarely provide self-management materials or education around managing pain at work, occupational health recommendations for reasonable adjustments are not always actioned, and pain-related stigma is common. Step 4: Toolkit development integrated findings and recommendations from Steps 1-3, and iterative expert peer review was conducted (n = 40). The PAW toolkit provides (a) evidence-based guidelines and signposting around work-capacity advice and support; (b) self-management strategies around working with chronic or persistent pain, (c) promotion of healthy lifestyles, and quality of life at work; (d) advice on adjustments to working environments and workplace solutions to facilitate work participation.

Advanced Clinical Practitioners in Primary Care in the UK: A Qualitative Study of Workforce Transformation.

Escalating costs and changing population demographics are putting pressure on primary care systems to meet ever more complex healthcare needs. Non-medical 'advanced clinical practitioner' (ACP) roles are increasingly being introduced to support service transformation. This paper reports the findings of a qualitative evaluation of nursing ACP roles across General Practices in one region of the UK. Data collection involved telephone interviews with 26 participants from 3 different stakeholder groups based in 9 practice sites: ACPs (n = 9), general practitioners (n = 8) and practice managers (n = 9). The data was analysed thematically. The study found a high degree of acceptance of the ACP role and affirmation of the important contribution of ACPs to patient care. However, significant variations in ACP education, skills and experience led to a bespoke approach to their deployment, impeding system-wide innovation and creating challenges for recruitment and ongoing professional development. In addition, a context of high workforce pressures and high service demand were causing stress and there was a need for greater mentorship and workplace support. System wide changes to ACP education and support are required to enable ACPs to realise their full potential in primary care in the UK.

Adaptive Immunity in Pulmonary Sarcoidosis and Chronic Beryllium Disease.

Pulmonary sarcoidosis and chronic beryllium disease (CBD) are inflammatory granulomatous lung diseases defined by the presence of non-caseating granulomas in the lung. CBD results from beryllium exposure in the workplace, while the cause of sarcoidosis remains unknown. CBD and sarcoidosis are both immune-mediated diseases that involve Th1-polarized inflammation in the lung. Beryllium exposure induces trafficking of dendritic cells to the lung in a mechanism dependent on MyD88 and IL-1α. B cells are also recruited to the lung in a MyD88 dependent manner after beryllium exposure in order to protect the lung from beryllium-induced injury. Similar to most immune-mediated diseases, disease susceptibility in CBD and sarcoidosis is driven by the expression of certain MHCII molecules, primarily HLA-DPB1 in CBD and several HLA-DRB1 alleles in sarcoidosis. One of the defining features of both CBD and sarcoidosis is an infiltration of activated CD4+ T cells in the lung. CD4+ T cells in the bronchoalveolar lavage (BAL) of CBD and sarcoidosis patients are highly Th1 polarized, and there is a significant increase in inflammatory Th1 cytokines present in the BAL fluid. In sarcoidosis, there is also a significant population of Th17 cells in the lungs that is not present in CBD. Due to persistent antigen exposure and chronic inflammation in the lung, these activated CD4+ T cells often display either an exhausted or anergic phenotype. Evidence suggests that these T cells are responding to common antigens in the lung. In CBD there is an expansion of beryllium-responsive TRBV5.1+ TCRs expressed on pathogenic CD4+ T cells derived from the BAL of CBD patients that react with endogenous human peptides derived from the plexin A protein. In an acute form of sarcoidosis, there are expansions of specific TRAV12-1/TRBV2 T cell receptors expressed on BAL CD4+ T cells, indicating that these T cells are trafficking to and expanding in the lung in response to common antigens. The specificity of these pathogenic CD4+T cells in sarcoidosis are currently unknown.

Active PI3K abrogates central tolerance in high-avidity autoreactive B cells.

Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell-mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell-intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.

Corrigendum: Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance.

[This corrects the article DOI: 10.3389/fimmu.2018.00707.].

Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance.

Newly generated bone marrow B cells are positively selected into the peripheral lymphoid tissue only when they express a B cell receptor (BCR) that is nonautoreactive or one that binds self-antigen with only minimal avidity. This positive selection process, moreover, is critically contingent on the ligand-independent tonic signals transduced by the BCR. We have previously shown that when autoreactive B cells express an active form of the rat sarcoma (RAS) oncogene, they upregulate the receptor for the B cell activating factor (BAFFR) and undergo differentiation in vitro and positive selection into the spleen in vivo, overcoming central tolerance. Based on the in vitro use of pharmacologic inhibitors, we further showed that this cell differentiation process is critically dependent on the activation of the mitogen-activated protein kinase kinase pathway MEK (MAPKK)-extracellular signal-regulated kinase (ERK), which is downstream of RAS. Here, we next investigated if activation of ERK is not only necessary but also sufficient to break central B cell tolerance and induce differentiation of autoreactive B cells in vitro and in vivo. Our results demonstrate that activation of ERK is critical for upregulating BAFFR and overcoming suboptimal levels of tonic BCR signals or low amounts of antigen-induced BCR signals during in vitro B cell differentiation. However, direct activation of ERK does not lead high avidity autoreactive B cells to increase BAFFR levels and undergo positive selection and differentiation in vivo. B cell-specific MEK-ERK activation in mice is also unable to lead to autoantibody secretion, and this in spite of a general increase of serum immunoglobulin levels. These findings indicate that additional pathways downstream of RAS are required for high avidity autoreactive B cells to break central and/or peripheral tolerance.

"I'm a Medic" - a web-based, social capital approach to health careers.

This article was migrated. The article was marked as recommended. Widening access to medicine in U.K. requires outreach that engages schools in remote areas, schools with below average attainment, and schools serving disadvantaged communities in order to develop a more representative profession and meet serious workforce shortages. The approach reported here embodies ideas about how to develop social and educational capital by facilitating live web chats between school children (13-17 years) and teams of health practitioners. "I'm a Medic" comprised three 2-week events over a 10-month period with circa 900 school students and 22 health professionals from general (family) practices participating. A high proportion (78%) of the students was actively engaged in live chats, asking questions, and voting for the most valuable health practitioner. Questions covered education and training, the nature of the practitioners' work, political and ethical aspects of healthcare, and a variety of scientific and personal aspects. Evaluation showed a positive increase in career interest and aspiration for science, healthcare and medicine. Teachers would all recommend "I'm a Medic" to colleagues and all bar one would take part again. They reported it was effective in engaging students, improving their confidence in asking questions, and their awareness of general practice and the NHS. Practitioners reported improvements in their understanding of how school students view healthcare professions, their interest in public engagement, and their confidence in communicating their work. Logistic challenges included conflict between scheduled web chats in normal school time and practitioners' clinical commitments. Nevertheless, the project demonstrated effective engagement across geographic and social/educational barriers, and can provide a valuable mode of outreach, particularly about careers in healthcare.

CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)3Cl(glycinate)] Actions on a Heme-Deficient Mutant of Escherichia coli.

AIMS: Carbon monoxide-releasing molecules (CORMs) are being developed with the ultimate goal of safely utilizing the therapeutic potential of CO clinically, including applications in antimicrobial therapy. Hemes are generally considered the prime targets of CO and CORMs, so we tested this hypothesis using heme-deficient bacteria, applying cellular, transcriptomic, and biochemical tools. RESULTS: CORM-3 [Ru(CO)3Cl(glycinate)] readily penetrated Escherichia coli hemA bacteria and was inhibitory to these and Lactococcus lactis, even though they lack all detectable hemes. Transcriptomic analyses, coupled with mathematical modeling of transcription factor activities, revealed that the response to CORM-3 in hemA bacteria is multifaceted but characterized by markedly elevated expression of iron acquisition and utilization mechanisms, global stress responses, and zinc management processes. Cell membranes are disturbed by CORM-3. INNOVATION: This work has demonstrated for the first time that CORM-3 (and to a lesser extent its inactivated counterpart) has multiple cellular targets other than hemes. A full understanding of the actions of CORMs is vital to understand their toxic effects. CONCLUSION: This work has furthered our understanding of the key targets of CORM-3 in bacteria and raises the possibility that the widely reported antimicrobial effects cannot be attributed to classical biochemical targets of CO. This is a vital step in exploiting the potential, already demonstrated, for using optimized CORMs in antimicrobial therapy.

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies.

Newly generated immature B cells are selected to enter the peripheral mature B-cell pool only if they do not bind (or bind limited amount of) self-antigen. We previously suggested that this selection relies on basal extracellular signal-regulated kinase (Erk) activation mediated by tonic B-cell antigen receptor (BCR) signaling and that this signal can be replaced by an active rat sarcoma (Ras), which are small GTPase proteins. In this study we compared the activity of Ras and Erk in nonautoreactive and autoreactive immature B cells and investigated whether activation of Ras can break tolerance. Our results demonstrate lower levels of active Erk and Ras in autoreactive immature B cells, although this is evident only when these cells display medium/high avidity for self-antigen. Basal activation of Erk in immature B cells is proportional to surface IgM and dependent on sarcoma family kinases, whereas it is independent of B-cell activating factor, IFN, and Toll-like receptor signaling. Ectopic expression of the constitutively active mutant Ras form N-RasD12 in autoreactive cells raises active Erk, halts receptor editing via PI3 kinase, and promotes differentiation via Erk, breaking central tolerance. Moreover, when B cells coexpress autoreactive and nonautoreactive BCRs, N-RasD12 leads also to a break in peripheral tolerance with the production of autoantibodies. Our findings indicate that in immature B cells, basal activation of Ras and Erk are controlled by tonic BCR signaling, and that positive changes in Ras activity can lead to a break in both central and peripheral B-cell tolerance.