Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2

Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogen-activated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacceptor sites in a Slt2-dependent manner and diminished TORC2-mediated phosphorylation of its major downstream effector, protein kinase Ypk1. Deletion of Avo2 or expression of a phosphomimetic Avo2 allele rendered cells sensitive to two stresses (myriocin treatment and elevated exogenous acetic acid) that the cell requires Ypk1 activation by TORC2 to survive. Thus, Avo2 is necessary for optimal TORC2 activity, and Slt2-mediated phosphorylation of Avo2 down-regulates TORC2 signaling. Compared with wild-type Avo2, phosphomimetic Avo2 shows significant displacement from the plasma membrane, suggesting that Slt2 inhibits TORC2 by promoting Avo2 dissociation. Our findings are the first demonstration that TORC2 function is regulated by MAPK-mediated phosphorylation.Comment: This work was supported by National Institutes of Health (NIH) Predoctoral Traineeship GM07232 and a University of California at Berkeley MacArthur and Lakhan-Pal Graduate Fellowship to K.L.L., Erwin Schroedinger Fellowship J3787-B21 from the Austrian Science Fund to AE-A, Marie Sklodowska-Curie Action H2020-MSCA-IF-2016 InsiliCardio, GA 75083 to CMA, and NIH R01 research grant GM21841 to J

Nonparametric predictive inference and interval probability

This paper presents the unique position of A(n)-based nonparametric predictive inference within the theory of interval probability. It provides a completely new understanding, leading to powerful new results and a well-founded justification of such inferences by proving strong internal consistency results

A nonparametric predictive alternative to the Imprecise Dirichlet Model: the case of a known number of categories

Nonparametric Predictive Inference (NPI) is a general methodology to learn from data in the absense of prior knowledge and without adding unjustified assumptions. This paper develops NPI for multinominal data where the total number of possible categories for the data is known. We present the general upper and lower probabilities and several of their properties. We also comment on differences between this NPI approach and corresponding inferences based on Walley's Imprecise Dirichlet Model

Testing of the LSST's photometric calibration strategy at the CTIO 0.9 meter telescope

The calibration hardware system of the Large Synoptic Survey Telescope (LSST) is designed to measure two quantities: a telescope's instrumental response and atmospheric transmission, both as a function of wavelength. First of all, a "collimated beam projector" is designed to measure the instrumental response function by projecting monochromatic light through a mask and a collimating optic onto the telescope. During the measurement, the light level is monitored with a NIST-traceable photodiode. This method does not suffer from stray light effects or the reflections (known as ghosting) present when using a flat-field screen illumination, which has a systematic source of uncertainty from uncontrolled reflections. It allows for an independent measurement of the throughput of the telescope's optical train as well as each filter's transmission as a function of position on the primary mirror. Second, CALSPEC stars can be used as calibrated light sources to illuminate the atmosphere and measure its transmission. To measure the atmosphere's transfer function, we use the telescope's imager with a Ronchi grating in place of a filter to configure it as a low resolution slitless spectrograph. In this paper, we describe this calibration strategy, focusing on results from a prototype system at the Cerro Tololo Inter-American Observatory (CTIO) 0.9 meter telescope. We compare the instrumental throughput measurements to nominal values measured using a laboratory spectrophotometer, and we describe measurements of the atmosphere made via CALSPEC standard stars during the same run

Sets of Priors Reflecting Prior-Data Conflict and Agreement

In Bayesian statistics, the choice of prior distribution is often debatable, especially if prior knowledge is limited or data are scarce. In imprecise probability, sets of priors are used to accurately model and reflect prior knowledge. This has the advantage that prior-data conflict sensitivity can be modelled: Ranges of posterior inferences should be larger when prior and data are in conflict. We propose a new method for generating prior sets which, in addition to prior-data conflict sensitivity, allows to reflect strong prior-data agreement by decreased posterior imprecision.Comment: 12 pages, 6 figures, In: Paulo Joao Carvalho et al. (eds.), IPMU 2016: Proceedings of the 16th International Conference on Information Processing and Management of Uncertainty in Knowledge-Based Systems, Eindhoven, The Netherland

Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria

Besides existing artemisinin-based combination therapies, alternative safe, effective and affordable drug combinations against falciparum malaria are needed. Methylene blue (MB) was the first synthetic antimalarial drug ever used, and recent studies have been promising with regard to its revival in malaria therapy. The objective of this study was to assess the safety and efficacy of two MB-based malaria combination therapies, MB-artesunate (AS) and MB-amodiaquine (AQ), compared to the local standard of care, AS-AQ, in Burkina Faso. Open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria in Nouna, north-western Burkina Faso. Follow-up was for 28 days and analysis by intention-to-treat. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. No drug-related serious adverse events and no deaths occurred. MB-containing regimens were associated with mild vomiting and dysuria. No early treatment failures were observed. Parasite clearance time differed significantly among groups and was the shortest with MB-AS. By day 14, the rates of adequate clinical and parasitological response after PCR-based correction for recrudescence were 87% for MB-AS, 100% for MB-AQ (p = 0.004), and 100% for AS-AQ (p = 0.003). By day 28, the respective figure was lowest for MB-AS (62%), intermediate for the standard treatment AS-AQ (82%; p = 0.015), and highest for MB-AQ (95%; p<0.001; p = 0.03). MB-AQ is a promising alternative drug combination against malaria in Africa. Moreover, MB has the potential to further accelerate the rapid parasite clearance of artemisinin-based combination therapies. More than a century after the antimalarial properties of MB had been described, its role in malaria control deserves closer attention. ClinicalTrials.gov NCT00354380

Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria

With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso. An open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB-artesunate (AS), MB-amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline. MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies