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Algal blooms can devastate marine mammal communities through the production of neurotoxins that accumulate within the food web. Brunson et al. identified a cluster of genes associated with biosynthesis of the neurotoxin domoic acid in a marine diatom (see the Perspective by Pohnert et al. ). In vitro experiments established a series of enzymes that create the core structure of the toxin. Knowledge of the genes involved in domoic acid production will allow for genetic monitoring of algal blooms and aid in identifying conditions that trigger toxin production. Science , this issue p. 1356 ; see also p. 1308 Marine algae cluster genes involved in production of a toxin that causes neurological disorders. Oceanic harmful algal blooms of Pseudo-nitzschia diatoms produce the potent mammalian neurotoxin domoic acid (DA). Despite decades of research, the molecular basis for its biosynthesis is not known. By using growth conditions known to induce DA production in Pseudo-nitzschia multiseries , we implemented transcriptome sequencing in order to identify DA biosynthesis genes that colocalize in a genomic four-gene cluster. We biochemically investigated the recombinant DA biosynthetic enzymes and linked their mechanisms to the construction of DA’s diagnostic pyrrolidine skeleton, establishing a model for DA biosynthesis. Knowledge of the genetic basis for toxin production provides an orthogonal approach to bloom monitoring and enables study of environmental factors that drive oceanic DA production.

Paneth cells are major secretory cells located in the crypts of Lieberkühn in the small intestine. Our understanding of the diverse roles that Paneth cells play in homeostasis and disease has grown substantially since their discovery over a hundred years ago. Classically, Paneth cells have been characterized as a significant source of antimicrobial peptides and proteins important in host defense and shaping the composition of the commensal microbiota. More recently, Paneth cells have been shown to supply key developmental and homeostatic signals to intestinal stem cells in the crypt base. Paneth cell dysfunction leading to dysbiosis and a compromised epithelial barrier have been implicated in the etiology of Crohn’s disease and susceptibility to enteric bacterial infection. Our understanding of the impact of Paneth cells on viral infection is incomplete. Enteric α-defensins, produced by Paneth cells, can directly alter viral infection. In addition, α-defensins and other antimicrobial Paneth cell products may modulate viral infection indirectly by impacting the microbiome. Here, we discuss recent insights into Paneth cell biology, models to study their function, and the impact, both direct and indirect, of Paneth cells on enteric viral infection.

Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo . We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo . In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms.

Antiviral immunity compromises the efficacy of adeno-associated virus (AAV) vectors used for gene therapy. This is well understood for the adaptive immune response. However, innate immune effectors like alpha-defensin antimicrobial peptides also block AAV infection, although their mechanisms of action are unknown. To address this gap in knowledge, we investigated AAV2 and AAV6 neutralization by human neutrophil peptide 1 (HNP1), a myeloid alpha-defensin, and human defensin 5 (HD5), an enteric alpha-defensin. We found that both defensins bind to AAV2 and inhibit infection at low micromolar concentrations, similar to our prior studies of AAV6. While HD5 prevents AAV2 and AAV6 from binding to cells, HNP1 does not. However, AAV2 and AAV6 exposed to HD5 after binding to cells are still neutralized, indicating an additional block to infection. Accordingly, both HD5 and HNP1 inhibit externalization of the VP1 unique domain of both AAV2 and AAV6, which contains a phospholipase A 2 enzyme required for endosome escape and nuclear localization signals required for nuclear entry. Consequently, both defensins prevent AAV from reaching the nucleus. Disruption of intracellular trafficking of the viral genome to the nucleus is reminiscent of how alpha-defensins neutralize other non-enveloped viruses, suggesting a common mechanism of inhibition. These results will inform the development of vectors capable of overcoming these hurdles to improve the efficiency of gene therapy.

α-Defensins are an important class of abundant innate immune effectors that are potently antiviral against a number of nonenveloped viral pathogens; however, a common mechanism to explain their ability to block infection by these unrelated viruses is lacking. We previously found that human defensin 5 (HD5) blocks a critical host-mediated proteolytic processing step required for human papillomavirus (HPV) infection. Here, we show that bypassing the requirement for this cleavage failed to abrogate HD5 inhibition. Instead, HD5 altered HPV trafficking in the cell. In the presence of an inhibitory concentration of HD5, HPV was internalized and reached the early endosome. The internalized capsid became permeable to antibodies and proteases; however, HD5 prevented dissociation of the viral capsid from the genome, reduced viral trafficking to the trans -Golgi network, redirected the incoming viral particle to the lysosome, and accelerated the degradation of internalized capsid proteins. This mechanism is equivalent to the mechanism by which HD5 inhibits human adenovirus. Thus, our data support capsid stabilization and redirection to the lysosome during infection as a general antiviral mechanism of α-defensins against nonenveloped viruses. IMPORTANCE Although the antiviral activity of α-defensins against enveloped viruses can be largely explained by interference with receptor binding and fusion, a common mechanism for inhibition of nonenveloped viruses remains elusive. In studies of a prominent human α-defensin that is expressed in the gut and in the male and female genitourinary tract, we discovered striking parallels between the mechanisms of inhibition of HPV and human adenovirus infection. Thus, detailed studies of the impact of α-defensins on the intracellular trafficking of two disparate viruses support a general mechanism of α-defensin antiviral activity against nonenveloped viruses. Although the antiviral activity of α-defensins against enveloped viruses can be largely explained by interference with receptor binding and fusion, a common mechanism for inhibition of nonenveloped viruses remains elusive. In studies of a prominent human α-defensin that is expressed in the gut and in the male and female genitourinary tract, we discovered striking parallels between the mechanisms of inhibition of HPV and human adenovirus infection. Thus, detailed studies of the impact of α-defensins on the intracellular trafficking of two disparate viruses support a general mechanism of α-defensin antiviral activity against nonenveloped viruses.

IntroductionPharmacists provide a spectrum of services and comprehensive medication management for patients with substance use disorders (SUDs) with many providing timely and increased access to care for patients. Prior studies have evaluated other healthcare professionals’ attitudes, knowledge and practice in regard to SUD treatment and harm reduction services. However, no reviews to date summarise the available literature on the attitudes, knowledge and practice in regard to SUD treatment and harm reduction services from the pharmacist perspective. This scoping review aims to systematically map the extent, range and nature of available evidence and identify and describe gaps in knowledge, practice and attitudes towards SUD treatment among pharmacists with the goal of providing information for meaningful integration of pharmacists into SUD care.Methods and analysisWe will use the framework proposed by Arksey and O’Malley (2005) updated with recommendations by Levac et al (2010) and the Joanna Briggs Institute (2020). The protocol is registered via Open Science Framework (https://osf.io/92dek). We will search for peer-reviewed literature containing empirical evidence investigating SUD treatment or harm reduction with outcomes pertaining to the knowledge, practice or attitudes of pharmacists. Findings will be guided and assessed by research objectives and summarised using descriptive statistics and thematically for quantitative and qualitative findings, respectively. This review will be conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews.Ethics and disseminationOur findings will provide crucial information and support for future interventions and programmes which aim to meaningfully integrate pharmacists into SUD care. We will disseminate findings at conferences and publish in a peer-reviewed journal. In addition, we will integrate feedback on search strategy, data extraction and our dissemination approach from multidisciplinary collaborators including those within our team’s institution and outside experts with clinical or administrative knowledge in SUD care.

IntroductionHealth coaching is the process of working with a trained coach, peer, or healthcare professional towards self-determined health and wellness goals. Health coaching is being increasingly adopted in multiple healthcare settings and has been shown to improve overall health outcomes and long-term maintenance of chronic conditions in multiple countries and healthcare settings. Research surrounding the costs of implementing health coaching and its effects on healthcare costs, particularly long-term costs, has been limited. Although analysis of healthcare costs has become an important priority in recent years, the available literature looking at the cost impacts of health coaching is small and inconclusive, finding mixed results with a variety of methodologies. This scoping review aims to identify gaps in the literature and help set a research agenda regarding the costs of health coaching implementation and its impacts.Methods and analysisThe scoping review will be structured according to Levac et al’s enhancement to Arksey and O’Malley’s framework for conducting scoping reviews. PubMed, Embase, and the Health and Medicine Collection will be searched for peer-reviewed research that includes health and wellness coaching and some measurement of cost. Details about the type of study, cost analysis, methodology and results from the included articles will be extracted and summarised. Full-text publications, excluding editorials and opinion pieces, included in this scoping review will be published in 2017 or later, will be written in English, will align with the definition of health coaching as described by the National Board for Health and Wellness Coaching, and will include cost measurement. This review will include publications not captured in the previous integrative literature review looking at the cost-effectiveness of health coaching.Ethics and disseminationFindings will be disseminated through a peer-reviewed publication and through presentations to both health system and community-based entities currently using or considering adopting health coaching. Ethics approval is not a requirement for this review as no human research participants will be involved. All data will be obtained from publicly available literature, with no primary data generated.

The small intestinal epithelium produces numerous antimicrobial peptides and proteins, including abundant enteric α-defensins. Although they most commonly function as potent antivirals in cell culture, enteric α-defensins have also been shown to enhance some viral infections in vitro. Efforts to determine the physiologic relevance of enhanced infection have been limited by the absence of a suitable cell culture system. To address this issue, here we use primary stem cell-derived small intestinal enteroids to examine the impact of naturally secreted α-defensins on infection by the enteric mouse pathogen, mouse adenovirus 2 (MAdV-2). MAdV-2 infection was increased when enteroids were inoculated across an α-defensin gradient in a manner that mimics oral infection but not when α-defensin levels were absent or bypassed through other routes of inoculation. This increased infection was a result of receptor-independent binding of virus to the cell surface. The enteroid experiments accurately predicted increased MAdV-2 shedding in the feces of wild type mice compared to mice lacking functional α-defensins. Thus, our studies have shown that viral infection enhanced by enteric α-defensins may reflect the evolution of some viruses to utilize these host proteins to promote their own infection.

Recurrent blooms of harmful algae and cyanobacteria (HABs) plague many coastal and inland waters throughout the USA and have significant socioeconomic impacts to the adjacent communities. Notable HAB events in recent years continue to underscore the many remaining gaps in knowledge and increased needs for technological advances leading to early detection. This review summarizes the main research and management priorities that can be addressed through ocean observation-based approaches and technological solutions for harmful algal blooms, provides an update to the state of the technology to detect HAB events based on recent activities of the Alliance for Coastal Technology (ACT), offers considerations for ensuring data quality, and highlights both ongoing challenges and opportunities for solutions in integrating HAB-focused technologies in research and management. Specifically, technological advances are discussed for remote sensing (both multispectral satellite and hyperspectral); deployable in situ detection of HAB species on fixed or mobile platforms (based on bulk or taxa-specific biomass, images, or molecular approaches); and field-based and/or rapid quantitative detection of HAB toxins (via molecular and analytical chemistry methods). Suggestions for addressing challenges to continued development and adoption of new technologies are summarized, based on a consensus-building workshop hosted by ACT, including dealing with the uncertainties in investment for HAB research, monitoring, and management. Challenges associated with choosing appropriate technologies for a given ecosystem and/or management concern are also addressed, and examples of programs that are leveraging and combining complementary approaches are highlighted.

Enteric alpha-defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant to defensins and even appropriate them to enhance infection despite neutralization of closely related microbes. We therefore hypothesized that defensins impose selective pressure during fecal-oral transmission. Upon passaging a defensin-sensitive serotype of adenovirus in the presence of a human defensin, mutations in the major capsid protein hexon accumulated. In contrast, prior studies identified the vertex proteins as important determinants of defensin antiviral activity. Infection and biochemical assays suggest that a balance between increased cell binding and a downstream block in intracellular trafficking mediated by defensin interactions with all of the major capsid proteins dictates the outcome of infection. These results extensively revise our understanding of the interplay between defensins and non-enveloped viruses. Furthermore, they provide a feasible rationale for defensins shaping viral evolution, resulting in differences in infection phenotypes of closely related viruses.