Phylogenetic Distribution of Fungal Sterols

BACKGROUND: Ergosterol has been considered the "fungal sterol" for almost 125 years; however, additional sterol data superimposed on a recent molecular phylogeny of kingdom Fungi reveals a different and more complex situation. METHODOLOGY/PRINCIPAL FINDINGS: The interpretation of sterol distribution data in a modern phylogenetic context indicates that there is a clear trend from cholesterol and other Delta(5) sterols in the earliest diverging fungal species to ergosterol in later diverging fungi. There are, however, deviations from this pattern in certain clades. Sterols of the diverse zoosporic and zygosporic forms exhibit structural diversity with cholesterol and 24-ethyl -Delta(5) sterols in zoosporic taxa, and 24-methyl sterols in zygosporic fungi. For example, each of the three monophyletic lineages of zygosporic fungi has distinctive major sterols, ergosterol in Mucorales, 22-dihydroergosterol in Dimargaritales, Harpellales, and Kickxellales (DHK clade), and 24-methyl cholesterol in Entomophthorales. Other departures from ergosterol as the dominant sterol include: 24-ethyl cholesterol in Glomeromycota, 24-ethyl cholest-7-enol and 24-ethyl-cholesta-7,24(28)-dienol in rust fungi, brassicasterol in Taphrinales and hypogeous pezizalean species, and cholesterol in Pneumocystis. CONCLUSIONS/SIGNIFICANCE: Five dominant end products of sterol biosynthesis (cholesterol, ergosterol, 24-methyl cholesterol, 24-ethyl cholesterol, brassicasterol), and intermediates in the formation of 24-ethyl cholesterol, are major sterols in 175 species of Fungi. Although most fungi in the most speciose clades have ergosterol as a major sterol, sterols are more varied than currently understood, and their distribution supports certain clades of Fungi in current fungal phylogenies. In addition to the intellectual importance of understanding evolution of sterol synthesis in fungi, there is practical importance because certain antifungal drugs (e.g., azoles) target reactions in the synthesis of ergosterol. These findings also invalidate use of ergosterol as an indicator of biomass of certain fungal taxa (e.g., Glomeromycota). Data from this study are available from the Assembling the Fungal Tree of Life (AFTOL) Structural and Biochemical Database: http://aftol.umn.edu

PENGUIn multi‐instrument observations of dayside high‐latitude injections during the 23 March 2007 substorm

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94875/1/jgra19563.pd

Pc1-Pc2 waves and energetic particle precipitation during and after magnetic storms: superposed epoch analysis and case studies

Magnetic pulsations in the Pc1-Pc2 frequency range (0.1-5 Hz) are often observed on the ground and in the Earth's magnetosphere during the aftermath of geomagnetic storms. Numerous studies have suggested that they may play a role in reducing the fluxes of energetic ions in the ring current; more recent studies suggest they may interact parasitically with radiation belt electrons as well. We report here on observations during 2005 from search coil magnetometers and riometers installed at three Antarctic stations, Halley (-61.84 degrees magnetic latitude, MLAT), South Pole (-74.18 degrees MLAT), and McMurdo (-79.96 degrees MLAT), and from energetic ion detectors on the NOAA Polar-orbiting Operational Environment Satellites (POES). A superposed epoch analysis based on 13 magnetic storms between April and September 2005 as well as case studies confirm several earlier studies that show that narrowband Pc1-Pc2 waves are rarely if ever observed on the ground during the main and early recovery phases of magnetic storms. However, intense broadband Pi1-Pi2 ULF noise, accompanied by strong riometer absorption signatures, does occur during these times. As storm recovery progresses, the occurrence of Pc1-Pc2 waves increases, at first in the daytime and especially afternoon sectors but at essentially all local times later in the recovery phase (typically by days 3 or 4). During the early storm recovery phase the propagation of Pc1-Pc2 waves through the ionospheric waveguide to higher latitudes was more severely attenuated. These observations are consistent with suggestions that Pc1-Pc2 waves occurring during the early recovery phase of magnetic storms are generated in association with plasmaspheric plumes in the noon-to-dusk sector, and these observations provide additional evidence that the propagation of waves to ground stations is inhibited during the early phases of such storms. Analysis of 30- to 250-keV proton data from four POES satellites during the 24-27 August and 18-19 July 2005 storm intervals showed that the location of the inner edge of the ring current matched well with the plasmapause model of O'Brien and Moldwin (2003). However, the POES data showed no evidence of the consequences of electromagnetic ion cyclotron waves (localized proton precipitation) during main and early recovery phase. During later stages of the recovery phase, when such precipitation was observed, it was coincident with intense wave events at Halley, and it occurred at L shells near or up to 1 RE outside the modeled plasmapause but well equatorward of the isotropy boundary

A Project Portfolio Management Approach to Tacklingthe Exploration/Exploitation Trade-off

Organizational ambidexterity (OA) is an essen-tial capability for surviving in dynamic business environ-ments that advocates the simultaneous engagement inexploration and exploitation. Over the last decades,knowledge on OA has substantially matured, coveringinsights into antecedents, outcomes, and moderators of OA.However, there is little prescriptive knowledge that offersguidance on how to put OA into practice and to tackle thetrade-off between exploration and exploitation. To addressthis gap, the authors adopt the design science researchparadigm and propose an economic decision model asartifact. The decision model assists organizations inselecting and scheduling exploration and exploitation pro-jects to become ambidextrous in an economically reason-able manner. As for justificatory knowledge, the decisionmodel draws from prescriptive knowledge on projectportfolio management and value-based management, andfrom descriptive knowledge related to OA to structure thefield of action. To evaluate the decision model, its designspecification is discussed against theory-backed designobjectives and with industry experts. The paper alsoinstantiates the decision model as a software prototype andapplies the prototype to a case based on real-world data

Deiminated proteins and extracellular vesicles - novel serum biomarkers in whales and Orca

Peptidylarginine deiminases (PADs) are a family of phylogenetically conserved calcium-dependent enzymes which cause post-translational protein deimination. This can result in neoepitope generation, affect gene regulation and allow for protein moonlighting via functional and structural changes in target proteins. Extracellular vesicles (EVs) carry cargo proteins and genetic material and are released from cells as part of cellular communication. EVs are found in most body fluids where they can be useful biomarkers for assessment of health status. Here, serum-derived EVs were profiled, and post-translationally deiminated proteins and EV-related microRNAs are described in 5 ceataceans: minke whale, fin whale, humpback whale, Cuvier's beaked whale and orca. EV-serum profiles were assessed by transmission electron microscopy and nanoparticle tracking analysis. EV profiles varied between the 5 species and were identified to contain deiminated proteins and selected key inflammatory and metabolic microRNAs. A range of proteins, critical for immune responses and metabolism were identified to be deiminated in cetacean sera, with some shared KEGG pathways of deiminated proteins relating to immunity and physiology, while some KEGG pathways were species-specific. This is the first study to characterise and profile EVs and to report deiminated proteins and putative effects of protein-protein interaction networks via such post-translationald deimination in cetaceans, revealing key immune and metabolic factors to undergo this post-translational modification. Deiminated proteins and EVs profiles may possibly be developed as new biomarkers for assessing health status of sea mammals

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Advanced triage to redirect non-urgent emergency department visits to alternative care centers: the PERSEE algorithm

peer reviewedObjectives: Primary care treatable visits in the Emergency Department (ED) are part of the different factors leading to the overcrowding. Their triage and diversion to alternative care centers could potentially help manage the increasing inflow provided the establishment of an advanced triage to ensure patients’ safety. We aim to suggest a new triage tool, PERSEE, and prove its feasibility, safety and performance. Methods: All self-referrals presented to the ED were triaged with the PERSEE algorithm: first, patients were classified with a five-level ED acuity scale and then evaluated by algorithms to determine their appropriate category (ED or Primary Care). Patients were eligible for a redirection if they were triaged by the acuity scale as level 3 or lower, considered as ambulatory patients and finally categorized as primary care patients. We defined appropriate redirections as patients requiring less than three emergency resources, no emergency-specific treatment and no hospitalization. Results: During the study, 1999 patients were admitted to the ED. Among those, 1333 patients were self-referred (66.9%) of whom 1167 patients were triaged as level 3 or below (58.6%) and 775 patients triaged as ambulatory (39.0%). Among the 775 patients, 200 patients were categorized as primary care treatable (10.0%) and thereby, as potentially eligible for a redirection. We noticed an error rate of 7%, sensitivity of 24.06% and specificity of 97.6%. The redirection rate reached 15% of the self-referrals. Conclusion: These results indicate that PERSEE triage could lead to a safe redirection and could be an efficient tool to reduce ED crowding provided several adjustments