Targeting the MR1-MAIT cell axis improves vaccine efficacy and affords protection against viral pathogens.

Mucosa-associated invariant T (MAIT) cells are MR1-restricted, innate-like T lymphocytes with tremendous antibacterial and immunomodulatory functions. Additionally, MAIT cells sense and respond to viral infections in an MR1-independent fashion. However, whether they can be directly targeted in immunization strategies against viral pathogens is unclear. We addressed this question in multiple wild-type and genetically altered but clinically relevant mouse strains using several vaccine platforms against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a riboflavin-based MR1 ligand of bacterial origin, can synergize with viral vaccines to expand MAIT cells in multiple tissues, reprogram them towards a pro-inflammatory MAIT1 phenotype, license them to bolster virus-specific CD8+ T cell responses, and potentiate heterosubtypic anti-influenza protection. Repeated 5-OP-RU administration did not render MAIT cells anergic, thus allowing for its inclusion in prime-boost immunization protocols. Mechanistically, tissue MAIT cell accumulation was due to their robust proliferation, as opposed to altered migratory behavior, and required viral vaccine replication competency and Toll-like receptor 3 and type I interferon receptor signaling. The observed phenomenon was reproducible in female and male mice, and in both young and old animals. It could also be recapitulated in a human cell culture system in which peripheral blood mononuclear cells were exposed to replicating virions and 5-OP-RU. In conclusion, although viruses and virus-based vaccines are devoid of the riboflavin biosynthesis machinery that supplies MR1 ligands, targeting MR1 enhances the efficacy of vaccine-elicited antiviral immunity. We propose 5-OP-RU as a non-classic but potent and versatile vaccine adjuvant against respiratory viruses.

Classic costimulatory interactions in MAIT cell responses: from gene expression to immune regulation.

Mucosa-associated invariant T (MAIT) cells are evolutionarily conserved, innate-like T lymphocytes with enormous immunomodulatory potentials. Due to their strategic localization, their invariant T cell receptor (iTCR) specificity for major histocompatibility complex-related protein 1 (MR1) ligands of commensal and pathogenic bacterial origin, and their sensitivity to infection-elicited cytokines, MAIT cells are best known for their antimicrobial characteristics. However, they are thought to also play important parts in the contexts of cancer, autoimmunity, vaccine-induced immunity, and tissue repair. While cognate MR1 ligands and cytokine cues govern MAIT cell maturation, polarization, and peripheral activation, other signal transduction pathways, including those mediated by costimulatory interactions, regulate MAIT cell responses. Activated MAIT cells exhibit cytolytic activities and secrete potent inflammatory cytokines of their own, thus transregulating the biological behaviors of several other cell types, including dendritic cells, macrophages, natural killer cells, conventional T cells, and B cells, with significant implications in health and disease. Therefore, an in-depth understanding of how costimulatory pathways control MAIT cell responses may introduce new targets for optimized MR1/MAIT cell-based interventions. Herein, we compare and contrast MAIT cells and mainstream T cells for their expression of classic costimulatory molecules belonging to the immunoglobulin superfamily and the tumor necrosis factor (TNF)/TNF receptor superfamily, based not only on the available literature but also on our transcriptomic analyses. We discuss how these molecules participate in MAIT cells' development and activities. Finally, we introduce several pressing questions vis-à-vis MAIT cell costimulation and offer new directions for future research in this area.

Origins of symbiosis: shared mechanisms underlying microbial pathogenesis, commensalism and mutualism of plants and animals.

Regardless of the outcome of symbiosis, whether it is pathogenic, mutualistic or commensal, bacteria must first colonize their hosts. Intriguingly, closely related bacteria that colonize diverse hosts with diverse outcomes of symbiosis have conserved host-association and virulence factors. This review describes commonalities in the process of becoming host associated amongst bacteria with diverse lifestyles. Whether a pathogen, commensal or mutualist, bacteria must sense the presence of and migrate towards a host, compete for space and nutrients with other microbes, evade the host immune system, and change their physiology to enable long-term host association. We primarily focus on well-studied taxa, such as Pseudomonas, that associate with diverse model plant and animal hosts, with far-ranging symbiotic outcomes. Given the importance of opportunistic pathogens and chronic infections in both human health and agriculture, understanding the mechanisms that facilitate symbiotic relationships between bacteria and their hosts will help inform the development of disease treatments for both humans, and the plants we eat.

Developmental Neuropathology and Neurodegeneration of Down Syndrome: Current Knowledge in Humans.

Individuals with Down syndrome (DS) suffer from developmental delay, intellectual disability, and an early-onset of neurodegeneration, Alzheimer's-like disease, or precocious dementia due to an extra chromosome 21. Studying the changes in anatomical, cellular, and molecular levels involved may help to understand the pathogenesis and develop target treatments, not just medical, but also surgical, cell and gene therapy, etc., for individuals with DS. Here we aim to identify key neurodevelopmental manifestations, locate knowledge gaps, and try to build molecular networks to better understand the mechanisms and clinical importance. We summarize current information about the neuropathology and neurodegeneration of the brain from conception to adulthood of foetuses and individuals with DS at anatomical, cellular, and molecular levels in humans. Understanding the alterations and characteristics of developing Down syndrome will help target treatment to improve the clinical outcomes. Early targeted intervention/therapy for the manifestations associated with DS in either the prenatal or postnatal period may be useful to rescue the neuropathology and neurodegeneration in DS.

Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer.

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.

Effects of Delayed Radical Prostatectomy and Active Surveillance on Localised Prostate Cancer-A Systematic Review and Meta-Analysis.

External factors, such as the coronavirus disease 2019 (COVID-19), can lead to cancellations and backlogs of cancer surgeries. The effects of these delays are unclear. This study summarised the evidence surrounding expectant management, delay radical prostatectomy (RP), and neoadjuvant hormone therapy (NHT) compared to immediate RP. MEDLINE and EMBASE was searched for randomised controlled trials (RCTs) and non-randomised controlled studies pertaining to the review question. Risks of biases (RoB) were evaluated using the RoB 2.0 tool and the Newcastle-Ottawa Scale. A total of 57 studies were included. Meta-analysis of four RCTs found overall survival and cancer-specific survival were significantly worsened amongst intermediate-risk patients undergoing active monitoring, observation, or watchful waiting but not in low- and high-risk patients. Evidence from 33 observational studies comparing delayed RP and immediate RP is contradictory. However, conservative estimates of delays over 5 months, 4 months, and 30 days for low-risk, intermediate-risk, and high-risk patients, respectively, have been associated with significantly worse pathological and oncological outcomes in individual studies. In 11 RCTs, a 3-month course of NHT has been shown to improve pathological outcomes in most patients, but its effect on oncological outcomes is apparently limited.

Mechanisms in plant-microbiome interactions: lessons from model systems.

The use of genetically tractable plant-microbe pairs has driven research in plant immunity and mutualistic symbiosis. Clear functional readouts for the outcomes of symbiosis or immunity have facilitated forward genetic screening and identification of signals, molecules and mechanisms that determine the outcome of these interactions. Plants also associate with beneficial microbial communities that form the microbiome. However, the complexity of the microbiome, combined with relatively subtle effects on plant growth and immunity, has impeded forward genetic screening to identify plant and bacterial genes that shape the microbiome. As a result, microbiome research has relied largely on reverse genetics approaches, based on what is known about plant nutrient uptake and immunity, to identify mechanisms in plant-microbiome research. Here we revisit the features of reductionist model systems that have made them so powerful for studying plant-microbe interactions, and how modeling microbiome research after these systems can propel discovery of novel mechanisms.

Commensal Pseudomonas fluorescens Strains Protect Arabidopsis from Closely Related Pseudomonas Pathogens in a Colonization-Dependent Manner.

Plants form commensal associations with soil microorganisms, creating a root microbiome that provides benefits, including protection against pathogens. While bacteria can inhibit pathogens through the production of antimicrobial compounds in vitro, it is largely unknown how microbiota contribute to pathogen protection in planta. We developed a gnotobiotic model consisting of Arabidopsis thaliana and the opportunistic pathogen Pseudomonas sp. N2C3, to identify mechanisms that determine the outcome of plant-pathogen-microbiome interactions in the rhizosphere. We screened 25 phylogenetically diverse Pseudomonas strains for their ability to protect against N2C3 and found that commensal strains closely related to N2C3, including Pseudomonas sp. WCS365, were more likely to protect against pathogenesis. We used comparative genomics to identify genes unique to the protective strains and found no genes that correlate with protection, suggesting that variable regulation of components of the core Pseudomonas genome may contribute to pathogen protection. We found that commensal colonization level was highly predictive of protection, so we tested deletions in genes required for Arabidopsis rhizosphere colonization. We identified a response regulator colR, and two ColR-dependent genes with predicted roles in membrane modifications (warB and pap2_2), that are required for Pseudomonas-mediated protection from N2C3. We found that WCS365 also protects against the agricultural pathogen Pseudomonas fuscovaginae SE-1, the causal agent of bacterial sheath brown rot of rice, in a ColR-dependent manner. This work establishes a gnotobiotic model to uncover mechanisms by which members of the microbiome can protect hosts from pathogens and informs our understanding of the use of beneficial strains for microbiome engineering in dysbiotic soil systems. IMPORTANCE Microbiota can protect diverse hosts from pathogens, and microbiome dysbiosis can result in increased vulnerability to opportunistic pathogens. Here, we developed a rhizosphere commensal-pathogen model to identify bacterial strains and mechanisms that can protect plants from an opportunistic Pseudomonas pathogen. Our finding that protective strains are closely related to the pathogen suggests that the presence of specific microbial taxa may help protect plants from disease. We found that commensal colonization level was highly correlated with protection, suggesting that competition with pathogens may play a role in protection. As we found that commensal Pseudomonas were also able to protect against an agricultural pathogen, this system may be broadly relevant for identifying strains and mechanisms to control agriculturally important pathogens. This work also suggests that beneficial plant-associated microbes may be useful for engineering soils where microbial complexity is low, such as hydroponic, or disturbed agricultural soils.

Current and Future Trends in Life Sciences Training: Questionnaire Study.

BACKGROUND: Every year, the life science field spends billions of dollars on educational activities worldwide. The continuing professional development of employees, especially in this field, encompasses great challenges. Emerging technologies appear to offer opportunity, but relatively little research has been done on the effectiveness of pedagogies and tools that have been used in the life sciences, and even less research has been devoted to understanding the potential power of emerging options that might determine the field's future. OBJECTIVE: In collaboration with the Life Sciences Trainers & Educators Network (LTEN), this study investigated the current state of the pedagogies and tools currently adopted by corporate training professionals in the life sciences as well as the professionals' perceptions of the impacts of emerging technologies on training. METHODS: This study adopted a mixed methods approach that included a survey and a follow-up interview. The survey consists of 18 broad questions with 15 subquestions in each of the five specific sectors of the life sciences field. Interviews were conducted by phone and lasted approximately 40 minutes, covering 18 questions designed to follow-up on findings from the survey items. RESULTS: Both survey and interview results indicated that the professionals were not satisfied with the status quo and that training and education in this field need to change. Most of the techniques and tools currently used have been used for some time. The professionals surveyed were not satisfied with the current techniques and tools and did not find them cost-effective. In addition, the respondents pictured the future of training in this field to be more engaging and effective. CONCLUSIONS: This is the first study in a series designed to better understand education and training in the life sciences on a macro level, in order to build a foundation for progress and evolution of the future landscape. Next steps involve developing strategies for how to extend this vision throughout individual organizations.

Sustainability of an Evidence-Based Practice in Community Mental Health Agencies Serving Children.

OBJECTIVE: The authors documented rates of sustained use of an evidence-based practice following training sponsored by New York State (NYS), and they identified clinician characteristics related to sustained use. METHODS: Clinicians (N=89) who were employed in licensed NYS Office of Mental Health agencies serving children and adolescents and who were trained to proficiency in Managing and Adapting Practice (MAP) in 2016 were contacted between 9 and 18 months later and asked whether they were still using (users) or had stopped using (nonusers) MAP and their reason for doing so. RESULTS: Responses were received from 57% of trainees and of those, 80% reported continued use of MAP. Score on the appeal subscale of the Evidence-Based Practices Attitude Scale (EBPAS) was the only significant difference between users and nonusers. CONCLUSIONS: Most clinicians reported sustained use of MAP. The EBPAS appeal subscale can be used to identify clinicians who are likely to discontinue use.

Evaluation of a Train-The-Trainers Model for Family Peer Advocates in Children's Mental Health.

Standardized training and credentialing is increasingly important to states and healthcare systems. Workforce shortages in children's mental health can be addressed through training and credentialing of professional peer parents (called family peer advocates or FPAs), who deliver a range of services to caregivers. A theory-based training program for FPAs targeting skills and knowledge about childhood mental health services (Parent Empowerment Program, or PEP) was developed through a partnership among a statewide family-run organization, state policy leaders, and academic researchers. Prior studies by this team using highly-experienced family peer advocates (who were also co-developers of the training program) as trainers found improvements in knowledge about mental health services and self-efficacy. In 2010, to meet demands and scale the model, a training of trainers (TOT) model was developed to build a cohort of locally-trained FPAs to deliver PEP training. A pre/post design was used to evaluate the impact of TOT model on knowledge and self-efficacy among 318 FPAs across the state. Participants showed significant pre-post (6 month) changes in knowledge about mental health services and self-efficacy. There were no significant associations between any FPA demographic characteristics and their knowledge or self-efficacy scores. A theory-based training model for professional peer parents working in the children's mental health system can be taught to local FPAs, and it improves knowledge about the mental health system and self-efficacy. Studies that evaluate the effectiveness of different training modalities are critical to ensure that high-quality trainings are maintained.

Developing a sustainable child and family service system after a community tragedy: Lessons from Sandy Hook.

This paper describes a systematic approach to assessing community services post-Sandy Hook shooting. An evaluation team was invited to develop a sustainability plan for community services in Newtown. Service organizations, providers and families were interviewed. Descriptive statistics were used to characterize the range of services; respondent perspectives were coded using content analysis. We found that Newtown has a broad array of community services, but respondent groups varied in their perceptions of service adequacy. Consensus existed about core components of an ideal service system, including centralizing access; coordinating care; personalizing and tailoring services for families; and providing evidence-based care. The strategic community assessment approach developed here may inform how communities examine their service capacity and develop sustainability plans post-disaster.