Toward identification of larval sailfish (Istiophorus platypterus), white marlin (Tetrapturus albidus), and blue marlin (Makaira nigricans) in the western North Atlantic Ocean*

The identification of larval istiophorid billfishes from the western North Atlantic Ocean has long been problematic. In the present study, a molecular technique was used to positively identify 27 larval white marlin (Tetrapturus albidus), 96 larval blue marlin (Makaira nigricans), and 591 larval sailfish (Istiophorus platypterus) from the Straits of Florida and the Bahamas. Nine morphometric measurements were taken for a subset of larvae (species known), and lower jaw pigment patterns were recorded on a grid. Canonical variates analysis (CVA) was used to reveal the extent to which the combination of morphometric, pigment pattern, and month of capture information was diagnostic to species level. Linear regression revealed species-specific relationships between the ratio of snout length to eye orbit diameter and standard length (SL). Confidence limits about these relationships served as defining characters for sailfish >10 mm SL and for blue and white marlin >17 mm SL. Pigment pattern analysis indicated that 40% of the preflexion blue marlin examined possessed a characteristic lower jaw pigment pattern and that 62% of sailfish larvae were identifiable by lower jaw pigments alone. An identification key was constructed based on pigment patterns, month of capture, and relationships between SL and the ratio of snout length to eye orbit diameter. The key yielded identifications for 69.4% of 304 (blind sample) larvae used to test it; only one of these identifications was incorrect. Of the 93 larvae that could not be identified by the key, 71 (76.3%) were correctly identified with CVA. Although identif ication of certain larval specimens may always require molecular techniques, it is encouraging that the majority (92.4%) of istiophorid larvae examined were ultimately identifiable from external characteristics alone

Translation inhibition by rocaglates activates a species-specific cell death program in the emerging fungal pathogen Candida auris

Fungal infections are a major contributor to infectious disease-related deaths worldwide. Recently, global emergence of the fungal pathogen Candida auris has caused considerable concern because most C. auris isolates are resistant to fluconazole, the most commonly administered antifungal, and some isolates are resistant to drugs from all three major antifungal classes. To identify novel agents with bioactivity against C. auris, we screened 2,454 compounds from a diversity-oriented synthesis collection. Of the five hits identified, most shared a common rocaglate core structure and displayed fungicidal activity against C. auris These rocaglate hits inhibited translation in C. auris but not in its pathogenic relative Candida albicans Species specificity was contingent on variation at a single amino acid residue in Tif1, a fungal member of the eukaryotic initiation factor 4A (eIF4A) family of translation initiation factors known to be targeted by rocaglates. Rocaglate-mediated inhibition of translation in C. auris activated a cell death program characterized by loss of mitochondrial membrane potential, increased caspase-like activity, and disrupted vacuolar homeostasis. In a rocaglate-sensitized C. albicans mutant engineered to express translation initiation factor 1 (Tif1) with the variant amino acid that we had identified in C. auris, translation was inhibited but no programmed cell death phenotypes were observed. This surprising finding suggests divergence between these related fungal pathogens in their pathways of cellular responses to translation inhibition. From a therapeutic perspective, the chemical biology that we have uncovered reveals species-specific vulnerability in C. auris and identifies a promising target for development of new, mechanistically distinct antifungals in the battle against this emerging pathogen. IMPORTANCE Emergence of the fungal pathogen Candida auris has ignited intrigue and alarm within the medical community and the public at large. This pathogen is unusually resistant to antifungals, threatening to overwhelm current management options. By screening a library of structurally diverse molecules, we found that C. auris is surprisingly sensitive to translation inhibition by a class of compounds known as rocaglates (also known as flavaglines). Despite the high level of conservation across fungi in their protein synthesis machinery, these compounds inhibited translation initiation and activated a cell death program in C. auris but not in its relative Candida albicans Our findings highlight a surprising divergence across the cell death programs operating in Candida species and underscore the need to understand the specific biology of a pathogen in attempting to develop more-effective treatments against it.Published versio

Movements and spawning of white marlin (Tetrapturus albidus) and blue marlin (Makaira nigricans) off Punta Cana, Dominican Republic

With a focus on white marlin (Tetrapturus albidus), a concurrent electronic tagging and larval sampling effort was conducted in the vicinity of Mona Passage (off southeast Hispaniola), Dominican Republic, during April and May 2003. Objectives were 1) to characterize the horizontal and vertical movement of adults captured from the area by using pop-up satellite archival tags (PSATs); and 2) by means of larval sampling, to investigate whether fish were reproducing. Trolling from a sportfishing vessel yielded eight adult white marlin and one blue marlin (Makaira nigricans); PSAT tags were deployed on all but one of these individuals. The exception was a female white marlin that was unsuitable for tagging because of injury; the reproductive state of its ovaries was examined histologically. Seven of the PSATs reported data summaries for water depth, temperature, and light levels measured every minute for periods ranging from 28 to 40 days. Displacement of marlin from the location of release to the point of tag pop-up ranged from 3l.6 to 267.7 nautical miles (nmi) and a mean displacement was 3.4 nmi per day for white marlin. White and blue marlin mean daily displacements appeared constrained compared to the results of other marlin PSAT tagging studies. White marlin ovarian sections contained postovulatory follicles and final maturation-stage oocytes, which indicated recent and imminent spawning. Neuston tows (n=23) yielded 18 istiophorid larvae: eight were white marlin, four were blue marlin, and six could not be identified to species. We speculate that the constrained movement patterns of adults may be linked to reproductive activity for both marlin species, and, if true, these movement patterns may have several implications for management. Protection of the potentially important white marlin spawning ground near Mona Passage seems warranted, at least until further studies can be conducted on the temporal and spatial extent of reproduction and associated adult movement

Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections

Interprofessional Integrative Medicine Training for Preventive Medicine Residents

Integrative medicine training was incorporated into the Rutgers New Jersey Medical School Preventive Medicine residency at the Rutgers Biomedical and Health Sciences Newark Campus as a collaboration between the Rutgers New Jersey Medical School and the School of Health Related Professions. Beginning in 2012, an interdisciplinary faculty team organized an Integrative Medicine program in a Preventive Medicine residency that leveraged existing resources across Rutgers Biomedical and Health Sciences. The overarching aim of the programs was to introduce residents and faculty to the scope and practice of integrative medicine in the surrounding Newark community and explore evidence-based research on integrative medicine. The faculty team tapped into an interprofessional network of healthcare providers to organize rotations for the preventive medicine residents that reflected the unique nature of integrative medicine in the greater Newark area. Residents provided direct care as part of interdisciplinary teams at clinical affiliates and shadowed health professionals from diverse disciplines as they filled different roles in providing patient care. The residents also participated in research projects. A combination of formal and informal programs on integrative medicine topics was offered to residents and faculty. The Integrative Medicine program, which ran from 2013 through 2014, was successful in exposing residents and faculty to the unique nature of integrative medicine across professions in the community served by Rutgers Biomedical and Health Sciences

Planning the Future of U.S. Particle Physics (Snowmass 2013): Chapter 4: Cosmic Frontier

These reports present the results of the 2013 Community Summer Study of the APS Division of Particles and Fields ("Snowmass 2013") on the future program of particle physics in the U.S. Chapter 4, on the Cosmic Frontier, discusses the program of research relevant to cosmology and the early universe. This area includes the study of dark matter and the search for its particle nature, the study of dark energy and inflation, and cosmic probes of fundamental symmetries.Comment: 61 page

PKC Signaling Regulates Drug Resistance of the Fungal Pathogen Candida albicans via Circuitry Comprised of Mkc1, Calcineurin, and Hsp90

Fungal pathogens exploit diverse mechanisms to survive exposure to antifungal drugs. This poses concern given the limited number of clinically useful antifungals and the growing population of immunocompromised individuals vulnerable to life-threatening fungal infection. To identify molecules that abrogate resistance to the most widely deployed class of antifungals, the azoles, we conducted a screen of 1,280 pharmacologically active compounds. Three out of seven hits that abolished azole resistance of a resistant mutant of the model yeast Saccharomyces cerevisiae and a clinical isolate of the leading human fungal pathogen Candida albicans were inhibitors of protein kinase C (PKC), which regulates cell wall integrity during growth, morphogenesis, and response to cell wall stress. Pharmacological or genetic impairment of Pkc1 conferred hypersensitivity to multiple drugs that target synthesis of the key cell membrane sterol ergosterol, including azoles, allylamines, and morpholines. Pkc1 enabled survival of cell membrane stress at least in part via the mitogen activated protein kinase (MAPK) cascade in both species, though through distinct downstream effectors. Strikingly, inhibition of Pkc1 phenocopied inhibition of the molecular chaperone Hsp90 or its client protein calcineurin. PKC signaling was required for calcineurin activation in response to drug exposure in S. cerevisiae. In contrast, Pkc1 and calcineurin independently regulate drug resistance via a common target in C. albicans. We identified an additional level of regulatory control in the C. albicans circuitry linking PKC signaling, Hsp90, and calcineurin as genetic reduction of Hsp90 led to depletion of the terminal MAPK, Mkc1. Deletion of C. albicans PKC1 rendered fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuated virulence in a murine model of systemic candidiasis. This work establishes a new role for PKC signaling in drug resistance, novel circuitry through which Hsp90 regulates drug resistance, and that targeting stress response signaling provides a promising strategy for treating life-threatening fungal infections

Once and Future Gulf of Mexico Ecosystem: Restoration Recommendations of an Expert Working Group

The Deepwater Horizon (DWH) well blowout released more petroleum hydrocarbons into the marine environment than any previous U.S. oil spill (4.9 million barrels), fouling marine life, damaging deep sea and shoreline habitats and causing closures of economically valuable fisheries in the Gulf of Mexico. A suite of pollutants—liquid and gaseous petroleum compounds plus chemical dispersants—poured into ecosystems that had already been stressed by overfishing, development and global climate change. Beyond the direct effects that were captured in dramatic photographs of oiled birds in the media, it is likely that there are subtle, delayed, indirect and potentially synergistic impacts of these widely dispersed, highly bioavailable and toxic hydrocarbons and chemical dispersants on marine life from pelicans to salt marsh grasses and to deep-sea animals. As tragic as the DWH blowout was, it has stimulated public interest in protecting this economically, socially and environmentally critical region. The 2010 Mabus Report, commissioned by President Barack Obama and written by the secretary of the Navy, provides a blueprint for restoring the Gulf that is bold, visionary and strategic. It is clear that we need not only to repair the damage left behind by the oil but also to go well beyond that to restore the anthropogenically stressed and declining Gulf ecosystems to prosperity-sustaining levels of historic productivity. For this report, we assembled a team of leading scientists with expertise in coastal and marine ecosystems and with experience in their restoration to identify strategies and specific actions that will revitalize and sustain the Gulf coastal economy. Because the DWH spill intervened in ecosystems that are intimately interconnected and already under stress, and will remain stressed from global climate change, we argue that restoration of the Gulf must go beyond the traditional "in-place, in-kind" restoration approach that targets specific damaged habitats or species. A sustainable restoration of the Gulf of Mexico after DWH must: 1. Recognize that ecosystem resilience has been compromised by multiple human interventions predating the DWH spill; 2. Acknowledge that significant future environmental change is inevitable and must be factored into restoration plans and actions for them to be durable; 3. Treat the Gulf as a complex and interconnected network of ecosystems from shoreline to deep sea; and 4. Recognize that human and ecosystem productivity in the Gulf are interdependent, and that human needs from and effects on the Gulf must be integral to restoration planning. With these principles in mind, the authors provide the scientific basis for a sustainable restoration program along three themes: 1. Assess and repair damage from DWH and other stresses on the Gulf; 2. Protect existing habitats and populations; and 3. Integrate sustainable human use with ecological processes in the Gulf of Mexico. Under these themes, 15 historically informed, adaptive, ecosystem-based restoration actions are presented to recover Gulf resources and rebuild the resilience of its ecosystem. The vision that guides our recommendations fundamentally imbeds the restoration actions within the context of the changing environment so as to achieve resilience of resources, human communities and the economy into the indefinite future