Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle.

Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex

Study protocol: a mixed methods study to assess mental health recovery, shared decision-making and quality of life (Plan4Recovery)

BACKGROUND: Recovery in mental health care is complex, highly individual and can be facilitated by a range of professional and non-professional support. In this study we will examine how recovery from mental health problems is promoted in non-medical settings. We hypothesise a relationship between involvement in decisions about care, social support and recovery and quality of life outcomes. METHODS: We will use standardised validated instruments of involvement in decision-making, social contacts, recovery and quality of life with a random sample of people accessing non-statutory mental health social care services in Wales. We will add to this important information with detailed one to one case study interviews with people, their family members and their support workers. We will use a series of these interviews to examine how people build recovery over time to help us understand more about their involvement in decisions and the social links they build. DISCUSSION: We want to see how being involved in decisions about care and the social links people have are related to recovery and quality of life for people with experience of using mental health support services. We want to understand the different perspectives of the people involved in making recovery possible. We will use this information to guide further studies of particular types of social interventions and their use in helping recovery from mental health problems

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×1020 protons on target in which neutrinos of energies between ~500¿¿MeV and 120 GeV are produced predominantly as ¿µ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ¿µ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles ¿24 and ¿34 are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime t3/m3>2.1×10-12¿¿s/eV at 90% C.L

Impacts of climate change on plant diseases – opinions and trends

There has been a remarkable scientific output on the topic of how climate change is likely to affect plant diseases in the coming decades. This review addresses the need for review of this burgeoning literature by summarizing opinions of previous reviews and trends in recent studies on the impacts of climate change on plant health. Sudden Oak Death is used as an introductory case study: Californian forests could become even more susceptible to this emerging plant disease, if spring precipitations will be accompanied by warmer temperatures, although climate shifts may also affect the current synchronicity between host cambium activity and pathogen colonization rate. A summary of observed and predicted climate changes, as well as of direct effects of climate change on pathosystems, is provided. Prediction and management of climate change effects on plant health are complicated by indirect effects and the interactions with global change drivers. Uncertainty in models of plant disease development under climate change calls for a diversity of management strategies, from more participatory approaches to interdisciplinary science. Involvement of stakeholders and scientists from outside plant pathology shows the importance of trade-offs, for example in the land-sharing vs. sparing debate. Further research is needed on climate change and plant health in mountain, boreal, Mediterranean and tropical regions, with multiple climate change factors and scenarios (including our responses to it, e.g. the assisted migration of plants), in relation to endophytes, viruses and mycorrhiza, using long-term and large-scale datasets and considering various plant disease control methods

Statistical sensitivity of the nEDM apparatus at PSI to n - n' oscillations

The neutron and its hypothetical mirror counterpart, a sterile state degenerate in mass, could spontaneously mix in a process much faster than the neutron β-decay. Two groups have performed a series of experiments in search of neutron - mirror-neutron (n − n')oscillations. They reported no evidence, thereby setting stringent limits on the oscillation time τnn. Later, these data sets have been further analyzed by Berezhiani et al.(2009-2017), and signals, compatible with n - n' oscillations in the presence of mirror magnetic fields, have been reported. The Neutron Electric Dipole Moment Collaboration based at the Paul Scherrer Institute performed a new series of experiments to further test these signals. In this paper, we describe and motivate our choice of run configurations with an optimal filling time of 29 s, storage times of 180 s and 380 s, and applied magnetic fields of 10 µT and 20 µT. The choice of these run configurations ensures a reliable overlap in settings with the previous efforts and also improves the sensitivity to test the signals. We also elaborate on the technique of normalizing the neutron counts, making such a counting experiment at the ultra-cold neutron source at the Paul Scherrer Institute possible. Furthermore, the magnetic field characterization to meet the requirements of this n − n oscillation search is demonstrated. Finally, we show that this effort has a statistical sensitivity to n − n' oscillations comparable to the current leading constraints for B' = 0

First observations of separated atmospheric nu_mu and bar{nu-mu} events in the MINOS detector

The complete 5.4 kton MINOS far detector has been taking data since the beginning of August 2003 at a depth of 2070 meters water-equivalent in the Soudan mine, Minnesota. This paper presents the first MINOS observations of nuµ and [overline nu ]µ charged-current atmospheric neutrino interactions based on an exposure of 418 days. The ratio of upward- to downward-going events in the data is compared to the Monte Carlo expectation in the absence of neutrino oscillations, giving Rup/downdata/Rup/downMC=0.62-0.14+0.19(stat.)±0.02(sys.). An extended maximum likelihood analysis of the observed L/E distributions excludes the null hypothesis of no neutrino oscillations at the 98% confidence level. Using the curvature of the observed muons in the 1.3 T MINOS magnetic field nuµ and [overline nu ]µ interactions are separated. The ratio of [overline nu ]µ to nuµ events in the data is compared to the Monte Carlo expectation assuming neutrinos and antineutrinos oscillate in the same manner, giving R[overline nu ][sub mu]/nu[sub mu]data/R[overline nu ][sub mu]/nu[sub mu]MC=0.96-0.27+0.38(stat.)±0.15(sys.), where the errors are the statistical and systematic uncertainties. Although the statistics are limited, this is the first direct observation of atmospheric neutrino interactions separately for nuµ and [overline nu ]µ