Characterization of the Folding of a 52_{2}-Knotted Protein Using Engineered Single-Tryptophan Variants

An increasing number of proteins that contain topological knots have been identified over the past two decades; however, their folding mechanisms are still not well understood. UCH-L1 has a 5$_{2}$-knotted topology. Here, we constructed a series of variants that contain a single tryptophan at different locations along the polypeptide chain. A study of the thermodynamic properties of the variants shows that the structure of UCH-L1 is remarkably tolerant to incorporation of bulky tryptophan side chains. Comprehensive kinetic studies of the variants reveal that they fold via parallel pathways on which there are two intermediate states very similar to wild-type UCH-L1. The structures of the intermediate states do not change significantly with mutation and therefore occupy local minima on the energy landscape that have relatively narrow basins. The kinetic studies also establish that there are considerably more tertiary interactions in the intermediate states than results from previous NMR studies suggested. The two intermediates differ from each other in the extent to which tertiary interactions between the highly stable central β-sheet and flanking α-helices and loop regions are formed. There is strong evidence that these states are aggregation prone. The transition states from both I$_{1}$ and I$_{2}$ to the native state are plastic and change with mutation and denaturant concentration. Previous studies indicated that the threading event that creates the 5$_{2}$ knot occurs during these steps, suggesting that there is a broad energy barrier consistent with the chain undergoing some searching of conformational space as the threading takes place.Family Funds (Hong-yu Zhang), University of Cambridg

Matrix Metalloproteinase Inhibitors (MMPIs) from Marine Natural Products: the Current Situation and Future Prospects

Matrix metalloproteinases (MMPs) are a family of more than twenty five secreted and membrane-bound zinc-endopeptidases which can degrade extracellular matrix (ECM) components. They also play important roles in a variety of biological and pathological processes. Matrix metalloproteinase inhibitors (MMPIs) have been identified as potential therapeutic candidates for metastasis, arthritis, chronic inflammation and wrinkle formation. Up to present, more than 20,000 new compounds have been isolated from marine organisms, where considerable numbers of these naturally occurring derivatives are developed as potential candidates for pharmaceutical application. Eventhough the quantity of marine derived MMPIs is less when compare with the MMPIs derived from terrestrial materials, huge potential for bioactivity of these marine derived MMPIs has lead to large number of researches. Saccharoids, flavonoids and polyphones, fatty acids are the most important groups of MMPIs derived from marine natural products. In this review we focus on the progress of MMPIs from marine natural products

Testing nonclassicality and non-Gaussianity in phase space

We theoretically propose and experimentally demonstrate a nonclassicality test of single-mode field in phase space, which has an analogy with the nonlocality test proposed by Banaszek and Wodkiewicz [Phys. Rev. Lett. 82, 2009 (1999)]. Our approach to deriving the classical bound draws on the fact that the Wigner function of a coherent state is a product of two independent distributions as if the orthogonal quadratures (position and momentum) in phase space behave as local realistic variables. Our method detects every pure nonclassical Gaussian state, which can also be extended to mixed states. Furthermore, it sets a bound for all Gaussian states and their mixtures, thereby providing a criterion to detect a genuine quantum non-Gaussian state. Remarkably, our phase-space approach with invariance under Gaussian unitary operations leads to an optimized test for a given non-Gaussian state. We experimentally show how this enhanced method can manifest quantum non-Gaussianity of a state by simply choosing phase-space points appropriately, which is essentially equivalent to implementing a squeezing operation on a given state.Comment: 5 pages and 3 figures with Supplemental Material, published versio

The Shape of LITTLE THINGS Dwarf Galaxies DDO 46 and DDO 168: Understanding the stellar and gas kinematics

We present the stellar and gas kinematics of DDO 46 and DDO 168 from the LITTLE THINGS survey and determine their respective Vmax/sigma_z,0 values. We used the KPNO's 4-meter telescope with the Echelle spectrograph as a long-slit spectrograph. We acquired spectra of DDO 168 along four position angles by placing the slit over the morphological major and minor axes and two intermediate position angles. However, due to poor weather conditions during our observing run for DDO 46, we were able to extract only one useful data point from the morphological major axis. We determined a central stellar velocity dispersion perpendicular to the disk, sigma_z,0, of 13.5+/-8 km/s for DDO 46 and of 10.7+/-2.9 km/s for DDO 168. We then derived the maximum rotation speed in both galaxies using the LITTLE THINGS HI data. We separated bulk motions from non-circular motions using a double Gaussian decomposition technique and applied a tilted-ring model to the bulk velocity field. We corrected the observed HI rotation speeds for asymmetric drift and found a maximum velocity, Vmax, of 77.4 +/- 3.7 and 67.4 +/- 4.0 km/s for DDO 46 and DDO 168, respectively. Thus, we derived a kinematic measure, Vmax/sigma_z,0, of 5.7 +/- 0.6 for DDO 46 and 6.3 +/- 0.3 for DDO 168. Comparing these values to ones determined for spiral galaxies, we find that DDO 46 and DDO 168 have Vmax/sigma_z,0 values indicative of thin disks, which is in contrast to minor-to-major axis ratio studies

Deep Learning using K-space Based Data Augmentation for Automated Cardiac MR Motion Artefact Detection

Quality assessment of medical images is essential for complete automation of image processing pipelines. For large population studies such as the UK Biobank, artefacts such as those caused by heart motion are problematic and manual identification is tedious and time-consuming. Therefore, there is an urgent need for automatic image quality assessment techniques. In this paper, we propose a method to automatically detect the presence of motion-related artefacts in cardiac magnetic resonance (CMR) images. As this is a highly imbalanced classification problem (due to the high number of good quality images compared to the low number of images with motion artefacts), we propose a novel k-space based training data augmentation approach in order to address this problem. Our method is based on 3D spatio-temporal Convolutional Neural Networks, and is able to detect 2D+time short axis images with motion artefacts in less than 1ms. We test our algorithm on a subset of the UK Biobank dataset consisting of 3465 CMR images and achieve not only high accuracy in detection of motion artefacts, but also high precision and recall. We compare our approach to a range of state-of-the-art quality assessment methods.Comment: Accepted for MICCAI2018 Conferenc

Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors

BACKGROUND: Alzheimer’s disease (AD) is characterized by progressive memory loss and impaired cognitive function. Early-onset familial forms of the disease (FAD) are caused by inheritance of mutant genes encoding presenilin 1 (PS1) variants. We have demonstrated that prion promoter (PrP)-driven expression of human FAD-linked PS1 variants in mice leads to impairments in environmental enrichment (EE)-induced adult hippocampal neural progenitor cell (AHNPC) proliferation and neuronal differentiation, and have provided evidence that accessory cells in the hippocampal niche expressing PS1 variants may modulate AHNPC phenotypes, in vivo. While of significant interest, these latter studies relied on transgenic mice that express human PS1 variant transgenes ubiquitously and at high levels, and the consequences of wild type or mutant PS1 expressed under physiologically relevant levels on EE-mediated AHNPC phenotypes has not yet been tested. RESULTS: To assess the impact of mutant PS1 on EE-induced AHNPC phenotypes when expressed under physiological levels, we exposed adult mice that constitutively express the PSEN1 M146V mutation driven by the endogenous PSEN1 promoter (PS1 M146V “knock-in” (KI) mice) to standard or EE-housed conditions. We show that in comparison to wild type PS1 mice, AHNPCs in mice carrying homozygous (PS1(M146V/M146V)) or heterozygous (PS1(M146V/+)) M146V mutant alleles fail to exhibit EE-induced proliferation and commitment towards neurogenic lineages. More importantly, we report that the survival of newborn progenitors are diminished in PS1 M146V KI mice exposed to EE-conditions compared to respective EE wild type controls. CONCLUSIONS: Our findings reveal that expression at physiological levels achieved by a single PS1 M146V allele is sufficient to impair EE-induced AHNPC proliferation, survival and neuronal differentiation, in vivo. These results and our finding that microglia expressing a single PS1 M146V allele impairs the proliferation of wild type AHNPCs in vitro argue that expression of mutant PS1 in the AHNPC niche impairs AHNPCs phenotypes in a dominant, non-cell autonomous manner

A new Jurassic lizard from China

The Jurassic record of lizards in eastern Asia is poor by comparison with that of the Cretaceous. In China, to date, the only confirmed records from this period are an armoured lizard from Shishugou, Xinjiang Uygur Autonomous Region, of probable Oxfordian age, and two unnamed juvenile specimens from the slightly older, Callovian-Oxfordian, Daohugou locality of Nei Mongol. Here we describe the first lizard from the locality of Guancaishan, Jianping County, Liaoning Province. This locality is close to Daohugou, and is considered t o be of similar age. The new skeleton is articulated and well-preserved. It is distinguished from other Jurassic-Cretaceous lizards by a unique combination of derived characters, notably a long frontal with posterior processes that clasp the short parietal; cranial osteoderms limited to the lower temporal and supraocular regions; and an elongated manus and pes. Phylogenetic analysis using morphological data alone places the new taxon on the stem of a traditional ‘Scleroglossa’, but when the same data is run with a backbone constraint tree based on molecular data, the new taxon is placed on the stem of Squamata as a whole. Thus its position, and that of other Jurassic and Early Cretaceous taxa, seem to be influenced primarily by the position of Gekkota

Anterior Hippocampus and Goal-Directed Spatial Decision Making

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