Targeted Assembly of Short Sequence Reads

As next-generation sequence (NGS) production continues to increase, analysis is becoming a significant bottleneck. However, in situations where information is required only for specific sequence variants, it is not necessary to assemble or align whole genome data sets in their entirety. Rather, NGS data sets can be mined for the presence of sequence variants of interest by localized assembly, which is a faster, easier, and more accurate approach. We present TASR, a streamlined assembler that interrogates very large NGS data sets for the presence of specific variants, by only considering reads within the sequence space of input target sequences provided by the user. The NGS data set is searched for reads with an exact match to all possible short words within the target sequence, and these reads are then assembled strin-gently to generate a consensus of the target and flanking sequence. Typically, variants of a particular locus are provided as different target sequences, and the presence of the variant in the data set being interrogated is revealed by a successful assembly outcome. However, TASR can also be used to find unknown sequences that flank a given target. We demonstrate that TASR has utility in finding or confirming ge-nomic mutations, polymorphism, fusion and integration events. Targeted assembly is a powerful method for interrogating large data sets for the presence of sequence variants of interest. TASR is a fast, flexible and easy to use tool for targeted assembly

Hybrid-MST: A hybrid active sampling strategy for pairwise preference aggregation

In this paper we present a hybrid active sampling strategy for pairwise preference aggregation, which aims at recovering the underlying rating of the test candidates from sparse and noisy pairwise labelling. Our method employs Bayesian optimization framework and Bradley-Terry model to construct the utility function, then to obtain the Expected Information Gain (EIG) of each pair. For computational efficiency, Gaussian-Hermite quadrature is used for estimation of EIG. In this work, a hybrid active sampling strategy is proposed, either using Global Maximum (GM) EIG sampling or Minimum Spanning Tree (MST) sampling in each trial, which is determined by the test budget. The proposed method has been validated on both simulated and real-world datasets, where it shows higher preference aggregation ability than the state-of-the-art methods

Progressive ataxia with oculo-palatal tremor and optic atrophy

The final publication is available at Springer via doi: 10.​1007/​s00415-013-7136-

Chronic TLR stimulation controls NLRP3 inflammasome activation through IL-10 mediated regulation of NLRP3 expression and caspase-8 activation

While the molecular mechanisms promoting activation of the Nod-like Receptor (NLR) family member NLRP3 inflammasome are beginning to be defined, little is known about the mechanisms that regulate the NLRP3 inflammasome. Acute (up to 4 hours) LPS stimulation, followed by ATP is frequently used to activate the NLRP3 inflammasome in macrophages. Interestingly, we observed that the ability of LPS to license NLRP3 is transient, as prolonged (12 to 24 hours) LPS exposure was a relatively ineffective priming stimulus. This suggests that relative to acute LPS, chronic LPS exposure triggers regulatory mechanisms to dampen NLRP3 activation. Transfer of culture supernatants from macrophages stimulated with LPS for 24 hours dramatically reduced ATP- and nigericin-induced NLRP3 inflammasome activation in naive macrophages. We further identified IL-10 as the secreted inflammasome-tolerizing factor that acts in an autocrine manner to control activation of the NLRP3 inflammasome. Finally, we demonstrated that IL-10 dampens NLRP3 expression to control NLRP3 inflammasome activation and subsequent caspase-8 activation. In conclusion, we have uncovered a mechanism by which chronic, but not acute, LPS exposure induces IL-10 to dampen NLRP3 inflammasome activation to avoid overt inflammation

Meta-Regression on the Heterogenous Factors Contributing to the Prevalence of Mental Health Symptoms During the COVID-19 Crisis Among Healthcare Workers.

Objective: This paper used meta-regression to analyze the heterogenous factors contributing to the prevalence rate of mental health symptoms of the general and frontline healthcare workers (HCWs) in China under the COVID-19 crisis. Method: We systematically searched PubMed, Embase, Web of Science, and Medrxiv and pooled data using random-effects meta-analyses to estimate the prevalence rates, and ran meta-regression to tease out the key sources of the heterogeneity. Results: The meta-regression results uncovered several predictors of the heterogeneity in prevalence rates among published studies, including severity (e.g., above severe vs. above moderate, p < 0.01; above moderate vs. above mild, p < 0.01), type of mental symptoms (PTSD vs. anxiety, p = 0.04), population (frontline vs. general HCWs, p < 0.01), sampling location (Wuhan vs. Non-Wuhan, p = 0.04), and study quality (p = 0.04). Conclusion: The meta-regression findings provide evidence on the factors contributing to the prevalence rate of mental health symptoms of the general and frontline healthcare workers (HCWs) to guide future research and evidence-based medicine in several specific directions. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=220592, identifier: CRD42020220592

Revealing the Hidden Details of Nanostructure in a Pharmaceutical Cream

Creams are multi-component semi-solid emulsions that find widespread utility across a wide range of pharmaceutical, cosmetic, and personal care products, and they also feature prominently in veterinary preparations and processed foodstuffs. The internal architectures of these systems, however, have to date been inferred largely through macroscopic and/or indirect experimental observations and so they are not well-characterized at the molecular level. Moreover, while their long-term stability and shelf-life, and their aesthetics and functional utility are critically dependent upon their molecular structure, there is no real understanding yet of the structural mechanisms that underlie the potential destabilizing effects of additives like drugs, anti-oxidants or preservatives, and no structure-based rationale to guide product formulation. In the research reported here we sought to address these deficiencies, making particular use of small-angle neutron scattering and exploiting the device of H/D contrast variation, with complementary studies also performed using bright-field and polarised light microscopy, small-angle and wide-angle X-ray scattering, and steady-state shear rheology measurements. Through the convolved findings from these studies we have secured a finely detailed picture of the molecular structure of creams based on Aqueous Cream BP, and our findings reveal that the structure is quite different from the generic picture of cream structure that is widely accepted and reproduced in textbooks

Electrostatically gated membrane permeability in inorganic protocells

Although several strategies are now available to produce functional microcompartments analogous to primitive cell-like structures, little progress has been made in generating protocell constructs with self-controlled membrane permeability. Here we describe the preparation of water-dispersible colloidosomes based on silica nanoparticles and delineated by a continuous semipermeable inorganic membrane capable of self-activated, electrostatically gated permeability. We use crosslinking and covalent grafting of a pH-responsive copolymer to generate an ultrathin elastic membrane that exhibits selective release and uptake of small molecules. This behaviour, which depends on the charge of the copolymer coronal layer, serves to trigger enzymatic dephosphorylation reactions specifically within the protocell aqueous interior. This system represents a step towards the design and construction of alternative types of artificial chemical cells and protocell models based on spontaneous processes of inorganic self-organization

Hydrogen adsorption capacity of adatoms on double carbon vacancies of graphene: A trend study from first principles

Structural stability and hydrogen adsorption capacity are two key quantities in evaluating the potential of metal-adatom decorated graphene for hydrogen storage and related devices. We have carried out extensive density functional theory calculations for the adsorption of hydrogen molecules on 12 different adatom (Ag, Au, Ca, Li, Mg, Pd, Pt, Sc, Sr, Ti, Y, and Zr) decorated graphene surfaces where the adatoms are found to be stabilized on double carbon vacancies, thus overcoming the "clustering problem" that occurs for adatoms on pristine graphene. Ca and Sr are predicted to bind the greatest number, namely six, of H2 molecules. We find an interesting correlation between the hydrogen capacity and the change of charge distribution with increasing H2 adsorption, where Ca, Li, Mg, Sc, Ti, Y, Sr, and Zr adatoms are partial electron donors and Ag, Au, Pd, and Pt are partial electron acceptors. The "18-electron rule" for predicting maximum hydrogen capacity is found not to be a reliable indicator for these systems. © 2013 American Physical Society

Direct observation of local K variation and its correlation to electronic inhomogeneity in (Ba1-xKx)Fe2As2 Pnictide

Local fluctuations in the distribution of dopant atoms are a suspected cause of nanoscale electronic disorder or phase separation observed within the pnictide superconductors. Atom probe tomography results present the first direct observations of dopant nano-clustering in a K-doped 122-phase pnictides. First-principles calculations suggest the coexistence of static magnetism and superconductivity on a lattice parameter length scale over a large range of doping concentrations. Collectively, our results provide evidence for a mixed scenario of phase coexistence and phase separation originating from variation of dopant atom experiments distroibutions.Comment: 4 pages, 4 figures and 1 table, accepted by Physical Review Letter 201