A Genomic Survey of the Natural Product Biosynthetic Potential of Actinomycetes Isolated from New Zealand Lichens.

Actinomycetes are prolific producers of industrially valuable and medically important compounds. Historically, the most efficient method of obtaining compounds has been bioactivity-guided isolation and characterization of drug-like molecules from culturable soil actinomycetes. Unfortunately, this pipeline has been met with an increasing number of rediscoveries, to the point where it is no longer considered an attractive approach for drug discovery. To address this challenge and to continue finding new compounds, researchers have increasingly focused on alternative environmental niches and screening methods. Here, we report the genetic investigation of actinomycetes from an underexplored source, New Zealand lichens. In this work, we obtain draft genome sequences for 322 lichen-associated actinomycetes. We then explore this genetic resource with an emphasis on biosynthetic potential. By enumerating biosynthetic gene clusters (BGCs) in our data sets and comparing these to various reference collections, we demonstrate that actinomycetes sourced from New Zealand lichens have the genetic capacity to produce large numbers of natural products, many of which are expected to be broadly different from those identified in previous efforts predominantly based on soil samples. Our data shed light on the actinomycete assemblage in New Zealand lichens and demonstrate that lichen-sourced actinobacteria could serve as reservoirs for discovering new secondary metabolites. IMPORTANCE Lichens are home to complex and distinctive microbial cohorts that have not been extensively explored for the ability to produce novel secondary metabolites. Here, we isolate and obtain genome sequence data for 322 actinomycetes from New Zealand lichens. In doing so, we delineate at least 85 potentially undescribed species, and show that lichen associated actinomycetes have the potential to yield many new secondary metabolites, and as such, might serve as a productive starting point for drug discovery efforts.

Bringing Needed Change to Medical Student Well-Being: A Call to Expand Accreditation Requirements.

Issue: Noting high rates of burnout, depression, and suicidality among medical students, academic medical communities are trying to identify preventive and curricular measures that protect and promote student well-being. To date, the effectiveness of these efforts is unclear. In addition, evidence increasingly suggests that the major drivers of distress appear to be factors within the social, learning, and work environments. Specific to medical schools in the United States, neither the Liaison Committee on Medical Education nor the Commission on Osteopathic College Accreditation include accreditation standards regarding well-being curricula and, as such, these curricula are not well-integrated into students' medical school experience. Current accreditation standards also do not specifically require institutions to assess or address systemic factors of the learning environment that negatively affect student well-being. Evidence: This paper proposes expanding current Liaison Committee on Medical Education and Commission on Osteopathic College Accreditation standards on professionalism to incorporate well-being as a core component of professional identity formation by requiring individual and institutional-level actions. Proposed changes to accreditation standards include (1) institutional assessment of the impact of the learning environment on student well-being; (2) continuous quality improvement efforts to address structural factors associated with student well-being and modification of practices that impair student well-being; and (3) integrated curriculum with related assessment to educate students on empirically-supported strategies for well-being. Implications: Refining undergraduate medical education accreditation standards in the United States to include language specific to student well-being will facilitate long overdue changes to the learning environment. In the end, the goal is not just to improve medical student well-being, but to provide a workforce better equipped for a sustainable and meaningful career.

Medical School Strategies to Address Student Well-Being: A National Survey.

PURPOSE: To describe the breadth of strategies U.S. medical schools use to promote medical student well-being. METHOD: In October 2016, 32 U.S. medical schools were surveyed about their student well-being initiatives, resources, and infrastructure; grading in preclinical courses; and learning communities. RESULTS: Twenty-seven schools (84%) responded. Sixteen (59%) had a student well-being curriculum, with content scheduled during regular curricular hours at most (13/16; 81%). These sessions were held at least monthly (12/16; 75%), and there was a combination of optional and mandatory attendance (9/16; 56%). Most responding schools offered a variety of emotional/spiritual, physical, financial, and social well-being activities. Nearly one-quarter had a specific well-being competency (6/27; 22%). Most schools relied on participation rates (26/27; 96%) and student satisfaction (22/27; 81%) to evaluate effectiveness. Sixteen (59%) assessed student well-being from survey data, and 7 (26%) offered students access to self-assessment tools. Other common elements included an individual dedicated to overseeing student well-being (22/27; 82%), a student well-being committee (22/27; 82%), pass/fail grading in preclinical courses (20/27; 74%), and the presence of learning communities (22/27; 81%). CONCLUSIONS: Schools have implemented a broad range of well-being curricula and activities intended to promote self-care, reduce stress, and build social support for medical students, with variable resources, infrastructure, and evaluation. Implementing dedicated well-being competencies and rigorously evaluating their impact would help ensure appropriate allocation of time and resources and determine if well-being strategies are making a difference. Strengthening evaluation is an important next step in alleviating learner distress and ultimately improving student well-being.

Secondary metabolism in the lichen symbiosis.

Lichens, which are defined by a core symbiosis between a mycobiont (fungal partner) and a photobiont (photoautotrophic partner), are in fact complex assemblages of microorganisms that constitute a largely untapped source of bioactive secondary metabolites. Historically, compounds isolated from lichens have predominantly been those produced by the dominant fungal partner, and these continue to be of great interest for their unique chemistry and biotechnological potential. In recent years it has become apparent that many photobionts and lichen-associated bacteria also produce a range of potentially valuable molecules. There is evidence to suggest that the unique nature of the symbiosis has played a substantial role in shaping many aspects of lichen chemistry, for example driving bacteria to produce metabolites that do not bring them direct benefit but are useful to the lichen as a whole. This is most evident in studies of cyanobacterial photobionts, which produce compounds that differ from free living cyanobacteria and are unique to symbiotic organisms. The roles that these and other lichen-derived molecules may play in communication and maintaining the symbiosis are poorly understood at present. Nonetheless, advances in genomics, mass spectrometry and other analytical technologies are continuing to illuminate the wealth of biological and chemical diversity present within the lichen holobiome. Implementation of novel biodiscovery strategies such as metagenomic screening, coupled with synthetic biology approaches to reconstitute, re-engineer and heterologously express lichen-derived biosynthetic gene clusters in a cultivable host, offer a promising means for tapping into this hitherto inaccessible wealth of natural products.

Will loss of snow cover during climatic warming expose New Zealand alpine plants to increased frost damage?

If snow cover in alpine environments were reduced through climatic warming, plants that are normally protected by snow-lie in winter would become exposed to greater extremes of temperature and solar radiation. We examined the annual course of frost resistance of species of native alpine plants from southern New Zealand that are normally buried in snowbanks over winter (Celmisia haastii and Celmisia prorepens) or in sheltered areas that may accumulate snow (Hebe odora) and other species, typical of more exposed areas, that are relatively snow-free (Celmisia viscosa, Poa colensoi, Dracophyllum muscoides). The frost resistance of these principal species was in accord with habitat: those from snowbanks or sheltered areas showed the least frost resistance, whereas species from exposed areas had greater frost resistance throughout the year. P. colensoi had the greatest frost resistance (-32.5 degrees C). All the principal species showed a rapid increase in frost resistance from summer to early winter (February-June) and maximum frost resistance in winter (July-August). The loss of resistance in late winter to early summer (August-December) was most rapid in P. colensoi and D. muscoides. Seasonal frost resistance of the principal species was more strongly related to daylength than to temperature, although all species except C. viscosa were significantly related to temperature when the influence of daylength was accounted for. Measurements of chlorophyll fluorescence indicated that photosynthetic efficiency of the principal species declined with increasing daylength. Levels of frost resistance of the six principal alpine plant species, and others measured during the growing season, were similar to those measured in tropical alpine areas and somewhat more resistant than those recorded in alpine areas of Europe. The potential for frost damage was greatest in spring. The current relationship of frost resistance with daylength is sufficient to prevent damage at any time of year. While warmer temperatures might lower frost resistance, they would also reduce the incidence of frosts, and the incidence of frost damage is unlikely to be altered. The relationship of frost resistance with daylength and temperature potentially provides a means of predicting the responses of alpine plants in response to global warming.

Surface-active fungicidal D-peptide inhibitors of the plasma membrane proton pump that block azole resistance.

A 1.8-million-member D-octapeptide combinatorial library was constructed in which each member comprised a diversity-containing N-terminal pentapeptide and a C-terminal amidated triarginine motif. The C-terminal motif concentrated the library members at the fungal cell surface. A primary screen for inhibitors of Saccharomyces cerevisiae and Candida albicans growth, together with an in vitro secondary screen with the S. cerevisiae plasma membrane ATPase (Pma1p) as a target, identified the antifungal D-octapeptide BM0 (D-NH(2)-RFWWFRRR-CONH(2)). Optimization of BM0 led to the construction of BM2 (D-NH(2)-RRRFWWFRRR-CONH(2)), which had broad-spectrum fungicidal activity against S. cerevisiae, Candida species, and Cryptococcus neoformans; bound strongly to the surfaces of fungal cells; inhibited the physiological activity of Pma1p; and appeared to target Pma1p, with 50% inhibitory concentrations in the range of 0.5 to 2.5 microM. At sub-MICs (<5 microM), BM2 chemosensitized to fluconazole (FLC) S. cerevisiae strains functionally hyperexpressing fungal lanosterol 14alpha-demethylase and resistance-conferring transporters of azole drugs. BM2 chemosensitized to FLC some FLC-resistant clinical isolates of C. albicans and C. dubliniensis and chemosensitized to itraconazole clinical isolates of C. krusei that are intrinsically resistant to FLC. The growth-inhibitory concentrations of BM2 did not cause fungal cell permeabilization, significant hemolysis of red blood cells, or the death of cultured HEp-2 epithelial cells. BM2 represents a novel class of broad-spectrum, surface-active, Pma1p-targeting fungicides which increases the potencies of azole drugs and circumvents azole resistance.