Conformational dynamics of a membrane protein chaperone enables spatially regulated substrate capture and release

Membrane protein biogenesis poses enormous challenges to cellular protein homeostasis and requires effective molecular chaperones. Compared with chaperones that promote soluble protein folding, membrane protein chaperones require tight spatiotemporal coordination of their substrate binding and release cycles. Here we define the chaperone cycle for cpSRP43, which protects the largest family of membrane proteins, the light harvesting chlorophyll a/b-binding proteins (LHCPs), during their delivery. Biochemical and NMR analyses demonstrate that cpSRP43 samples three distinct conformations. The stromal factor cpSRP54 drives cpSRP43 to the active state, allowing it to tightly bind substrate in the aqueous compartment. Bidentate interactions with the Alb3 translocase drive cpSRP43 to a partially inactive state, triggering selective release of LHCP’s transmembrane domains in a productive unloading complex at the membrane. Our work demonstrates how the intrinsic conformational dynamics of a chaperone enables spatially coordinated substrate capture and release, which may be general to other ATP-independent chaperone systems

WMAP constraint on the P-term inflationary model

In light of WMAP results, we examine the observational constraint on the P-term inflation. With the tunable parameter $f$, P-term inflation contains richer physics than D-term and F-term inflationary models. We find the logarithmic derivative spectral index with $n>1$ on large scales and $n<1$ on small scales in agreement to observation. We obtained a reasonable range for the choice of the gauge coupling constant $g$ in order to meet the requirements of WMAP observation and the expected number of the e-foldings. Although tuning $f$ and $g$ we can have larger values for the logarithmic derivative of the spectral index, it is not possible to satisfy all observational requirements for both, the spectral index and its logarithmic derivative at the same time.Comment: 6 pages, double column, 13 figures included. Version appearing in the Physical Review

The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: A randomised placebo-controlled study

We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h−1) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (

A New Sliding Mode Control Strategy for Variable-Speed Wind Turbine Power Maximization

This is the peer reviewed version of the following article: Khalfallah Tahir, Cheikh Belfedal, Tayeb Allaoui, Mouloud Denai, and M’hamed Doumi, ‘A new sliding mode control strategy for variable‐speed wind turbine power maximization’, International Transactions on Electrical Energy Systems, Vol. 28 (4): e2513, April 2018, which has been published in final form at https://doi.org/10.1002/etep.2513. Under embargo until 10 January 2019. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.The paper proposes a new sliding mode power control strategy for a wound-field synchronous generator-based variable speed wind energy conversion systems to maximize the power extracted from the wind turbine. The proposed controller can handle the inherent nonlinearities in wind energy conversion systems and the randomness of the wind speed as well as the uncertainties of the model and external disturbances. To reduce the chattering phenomenon that characterizes conventional sliding mode control, a sigmoid function with a variable boundary layer is proposed. The adaptive switching gains are adjusted on-line by using a fuzzy logic-based technique. Several simulation scenarios were performed to evaluate the performance of the proposed control scheme. The results demonstrate that this controller provides excellent response characteristics, is robust against parameter variations, and free from chattering phenomenon as compared with the conventional sliding mode control.Peer reviewedFinal Accepted Versio

Preterm birth a long distance from home and its significant social and financial stress

The present paper reports a retrospective cohort of preterm infants admitted to our hospital who delivered outside the normal geographical catchment area of the mother's local level three neonatal nursery. Nineteen mothers had 21 preterm infants (23.1-34.9 weeks, 500-2330 g born) where 14 infants required ventilation (median 57 h, range 3-428). Eighteen survivors had a median length of stay of 41 days (range 3-91). Twelve of 19 mothers were interviewed: all described isolation, loneliness, poor social support and significant financial hardship related to getting their infants back to a local hospital or home. To avoid these problems, we recommend confining travel to within a short distance from home or local maternity unit after 22 weeks

Hierarchical cluster analysis of polychlorinated dioxins and furans in Michigan, USA, soils: Evaluation of industrial and background congener profiles

As part of the University of Michigan Dioxin Exposure Study, soil samples were collected from 766 residential properties near the Tittabawassee River between Midland and Saginaw; near the Dow Chemical Facility in Midland; and, for comparison, in the other areas of Midland and Saginaw Counties and in Jackson and Calhoun Counties, all located in the state of Michigan, USA. A total of 2,081 soil samples were analyzed for 17 polychlorinated dibenzo- p -dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). In order to better understand the distribution and sources of the PCDD/F congeners in the study area, hierarchical cluster analysis (HCA) was used to statistically group samples with similar congener patterns. The analysis yielded a total of 13 clusters, including: 3 clusters among the soils impacted by contamination present in the Tittabawassee River sediments, a cluster comprised mainly of samples collected within the depositional area of the Dow incinerator complex, a small cluster of samples with elevated 2,3,7,8-tetrachlorinated dibenzo- p -dioxin (TCDD), and several clusters exhibiting background patterns. The clusters related to the Tittabawassee River floodplain contamination all contained elevated PCDF levels and were differentiated from one another primarily by their relative concentrations of higher-chlorinated PCDDs, a difference likely related to both extent and timing of impacts from Tittabawassee sediments. The background clusters appear to be related to combustion processes and are differentiated, in part, by their relative fractions of TCDD. Thus, HCA was useful for identifying congener profile characteristics in both contaminated and background soil samples. Environ. Toxicol. Chem. 2010;29:64–72. © 2009 SETACPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64530/1/24_ftp.pd

Approximate Thumbnail Preserving Encryption

Thumbnail preserving encryption (TPE) was suggested by Wright et al. as a way to balance privacy and usability for online image sharing. The idea is to encrypt a plaintext image into a ciphertext image that has roughly the same thumbnail as well as retaining the original image format. At the same time, TPE allows users to take advantage of much of the functionality of online photo management tools, while still providing some level of privacy against the service provider. In this work we present three new approximate TPE encryption schemes. In our schemes, ciphertexts and plaintexts have perceptually similar, but not identical, thumbnails. Our constructions are the first TPE schemes designed to work well with JPEG compression. In addition, we show that they also have provable security guarantees that characterize precisely what information about the plaintext is leaked by the ciphertext image. We empirically evaluate our schemes according to the similarity of plaintext and ciphertext thumbnails, increase in file size under JPEG compression, preservation of perceptual image hashes, among other aspects. We also show how approximate TPE can be an effective tool to thwart inference attacks by machine-learning image classifiers, which have shown to be effective against other image obfuscation techniques

Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination

In meiotic DNA recombination, the Hop2-Mnd1 complex promotes Dmc1-mediated single-stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2-Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra ?-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle-like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2-Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasion

Business exit and strategic change: Sticking to the knitting or striking a new strategic path?

The purpose of this study is to examine the potential of business exit for initiating strategic change in divesting parent firms. In contrast to prior literature that mainly investigates the impact of different antecedents on the likelihood of business exit in general, this study additionally tests the influence of these antecedents on the choice between two exit types with a cross-industry sample of divesting firms listed in the German CDAX over the time period 1999-2004. A divestiture involving strategic change is a strategic business exit; otherwise it is denoted as status quo-preserving. The findings reveal that a relatively highly dissipated focus does not automatically enhance the likelihood of business exit in general and status quo-preserving business exit in particular. CEO turnover and pressures exerted by institutional investors predict neither strategic nor status quo-preserving business exit. Low firm performance does not nurture the likelihood of business exit per se but especially promotes status quo-preserving business exit