Dissecting the oxidative folding of circular cystine knot miniproteins

Cyclotides are plant proteins with exceptional stability owing to the presence of a cyclic backbone and three disulfide bonds arranged in a cystine knot motif. Accordingly, they have been proposed as templates to stabilize bioactive epitopes in drug-design applications. The two main subfamilies, referred to as the Möbius and bracelet cyclotides, require dramatically different in vitro folding conditions to achieve the native fold. To determine the underlying elements that influence cyclotide folding, we examined the in vitro folding of a suite of hybrid cyclotides based on combination of the Möbius cyclotide kalata B1 and the bracelet cyclotide cycloviolacin O1. The folding pathways of the two cyclotide subfamilies were found to be different and influenced by specific residues within intercysteine loops 2 and 6. Two changes in these loops, a substitution in loop 2 and an addition in loop 6, enabled the folding of a cycloviolacin O1 analogue under conditions in which folding does not occur in vitro for the native peptide. A key intermediate contains a native-like hairpin structure that appears to be a nucleation locus early in the folding process. Overall, these mechanistic findings on the folding of cyclotides are potentially valuable for the design of new drug leads. Copyright Mary Ann Liebert, Inc

Study of Bc+B_c^+ decays to the K+K−π+K^+K^-\pi^+ final state and evidence for the decay Bc+→χc0π+B_c^+\to\chi_{c0}\pi^+

A study of $B_c^+\to K^+K^-\pi^+$ decays is performed for the first time using data corresponding to an integrated luminosity of 3.0 $\mathrm{fb}^{-1}$ collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of $7$ and $8$ TeV. Evidence for the decay $B_c^+\to\chi_{c0}(\to K^+K^-)\pi^+$ is reported with a significance of 4.0 standard deviations, resulting in the measurement of $\frac{\sigma(B_c^+)}{\sigma(B^+)}\times\mathcal{B}(B_c^+\to\chi_{c0}\pi^+)$ to be $(9.8^{+3.4}_{-3.0}(\mathrm{stat})\pm 0.8(\mathrm{syst}))\times 10^{-6}$. Here $\mathcal{B}$ denotes a branching fraction while $\sigma(B_c^+)$ and $\sigma(B^+)$ are the production cross-sections for $B_c^+$ and $B^+$ mesons. An indication of $\bar b c$ weak annihilation is found for the region $m(K^-\pi^+)<1.834\mathrm{\,Ge\kern -0.1em V\!/}c^2$, with a significance of 2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html, link to supplemental material inserted in the reference

Observation of Bc+ →j /ψD (∗)K (∗) decays

A search for the decays B+c→J/ψD(*)0K+ and B+c→J/ψD(*)+K*0 is performed with data collected at the LHCb experiment corresponding to an integrated luminosity of 3 fb−1. The decays B+c→J/ψ0K+ and B+c→J/ψD*0K+ are observed for the first time, while first evidence is reported for the B+c→JψD*+K*0 and B+c→J/ψD+K*0 decays. The branching fractions of these decays are determined relative to the B+c→J/ψπ+ decay. The B+c mass is measured, using the J/ψD0K+ final state, to be 6274.28±1.40(stat)±0.32(syst) MeV/c2. This is the most precise single measurement of the B+c mass to date

Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

Precision measurement of the B0s-B¯0s oscillation frequency with the decay B0s → D−sπ+

A key ingredient to searches for physics beyond the Standard Model in B0s mixing phenomena is the measurement of the B0s– ${{\overline{ {\mathrm {B}}}{}}^0_{\mathrm { s}}}$ oscillation frequency, which is equivalent to the mass difference Δms of the B0s mass eigenstates. Using the world's largest B0s meson sample accumulated in a dataset, corresponding to an integrated luminosity of 1.0 fb−1, collected by the LHCb experiment at the CERN LHC in 2011, a measurement of Δms is presented. A total of about 34 000 B0s → D−sπ+ signal decays are reconstructed, with an average decay time resolution of 44 fs. The oscillation frequency is measured to be Δms = 17.768 ± 0.023 (stat) ± 0.006 (syst) ps−1, which is the most precise measurement to date

Multiple List Learning in Adults with Autism Spectrum Disorder: Parallels with Frontal Lobe Damage or Further Evidence of Diminished Relational Processing?

To test the effects of providing relational cues at encoding and/or retrieval on multi-trial, multi-list free recall in adults with high-functioning autism spectrum disorder (ASD), 16 adults with ASD and 16 matched typical adults learned a first followed by a second categorised list of 24 words. Category labels were provided at encoding, retrieval, both or not at all. Both groups showed enhanced recall when labels were available during encoding or throughout the task. ASD individuals showed reduced recall of the second list and reduced clustering. Clustering and recall were correlated in both groups, which also showed similar levels of subjective organisation. The findings are discussed in relation to theories of frontal and medial temporal lobe contributions to memory in ASD

Transparent Meta-Analysis of Prospective Memory and Aging

Prospective memory (ProM) refers to our ability to become aware of a previously formed plan at the right time and place. After two decades of research on prospective memory and aging, narrative reviews and summaries have arrived at widely different conclusions. One view is that prospective memory shows large age declines, larger than age declines on retrospective memory (RetM). Another view is that prospective memory is an exception to age declines and remains invariant across the adult lifespan. The present meta-analysis of over twenty years of research settles this controversy. It shows that prospective memory declines with aging and that the magnitude of age decline varies by prospective memory subdomain (vigilance, prospective memory proper, habitual prospective memory) as well as test setting (laboratory, natural). Moreover, this meta-analysis demonstrates that previous claims of no age declines in prospective memory are artifacts of methodological and conceptual issues afflicting prior research including widespread ceiling effects, low statistical power, age confounds, and failure to distinguish between various subdomains of prospective memory (e.g., vigilance and prospective memory proper)

Cognitive and Tactile Factors Affecting Human Haptic Performance in Later Life

Background: Vision and haptics are the key modalities by which humans perceive objects and interact with their environment in a target-oriented manner. Both modalities share higher-order neural resources and the mechanisms required for object exploration. Compared to vision, the understanding of haptic information processing is still rudimentary. Although it is known that haptic performance, similar to many other skills, decreases in old age, the underlying mechanisms are not clear. It is yet to be determined to what extent this decrease is related to the age-related loss of tactile acuity or cognitive capacity. Methodology/Principal Findings: We investigated the haptic performance of 81 older adults by means of a cross-modal object recognition test. Additionally, we assessed the subjects ’ tactile acuity with an apparatus-based two-point discrimination paradigm, and their cognitive performance by means of the non-verbal Raven-Standard-Progressive matrices test. As expected, there was a significant age-related decline in performance on all 3 tests. With the exception of tactile acuity, this decline was found to be more distinct in female subjects. Correlation analyses revealed a strong relationship between haptic and cognitive performance for all subjects. Tactile performance, on the contrary, was only significantly correlated with male subjects ’ haptic performance. Conclusions: Haptic object recognition is a demanding task in old age, especially when it comes to the exploration o