15 research outputs found
A Novel Keratocan Mutation Causing Autosomal Recessive Cornea Plana
PURPOSE:
Mutations in keratocan (KERA), a small leucine-rich proteoglycan, have recently been shown to be responsible for cases of autosomal recessive cornea plana (CNA2). A consanguineous pedigree in which cornea plana cosegregated with microphthalmia was investigated by linkage analysis and direct sequencing.
METHODS:
Linkage was sought to polymorphic microsatellite markers distributed around the CNA2 and microphthalmia loci (arCMIC, adCMIC, NNO1, and CHX10) using PCR and nondenaturing polyacrylamide gel electrophoresis before KERA was directly sequenced for mutations.
RESULTS:
Positive lod scores were obtained with markers encompassing the CNA2 locus, the maximum two-point lod scores of 2.18 at recombination fraction theta = 0 was obtained with markers D12S95 and D12S327. Mutation screening of KERA revealed a novel single-nucleotide substitution at codon 215, which results in the substitution of lysine for threonine at the start of a highly conserved leucine-rich repeat motif. Structural modeling predicts that the motifs are stacked into an arched beta-sheet array and that the effect of the mutation is to alter the length and position of one of these motifs.
CONCLUSIONS:
This report describes a novel mutation in KERA that alters a highly conserved motif and is predicted to affect the tertiary structure of the molecule. Normal corneal function is dependent on the regular spacing of collagen fibrils, and the predicted alteration of the tertiary structure of KERA is the probable mechanism of the cornea plana phenotype
SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion
Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era
Entropically-Driven Co-assembly of l-Histidine and l-Phenylalanine to Form Supramolecular Materials
Molecular self-and co-assembly allow the formation of diverse and well-defined supramolecular structures with notable physical properties. Among the associating molecules, amino acids are especially attractive due to their inherent biocompatibility and simplicity. The biologically active enantiomer of L-histidine (L-His) plays structural and functional roles in proteins but does not self-assemble to form discrete nanostructures. In order to expand the structural space to include L-His-containing materials, we explored the co-assembly of L-His with all aromatic amino acids, including phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), all in both enantiomeric forms. In contrast to pristine L-His, the combination of this building block with all aromatic amino acids resulted in distinct morphologies including fibers, rods, and flake-like structures. Electrospray ionization mass spectrometry (ESI-MS) indicated the formation of supramolecular co-assemblies in all six combinations, but time-of-flight secondary-ion mass spectrometry (ToF-SIMS) indicated the best seamless co-assembly occurs between L-His and L-Phe while in the other cases, different degrees of phase separation could be observed. Indeed, isothermal titration calorimetry (ITC) suggested the highest affinity between L-His and L-Phe where the formation of co-assembled structures was driven by entropy. In accordance, among all the combinations, the co-assembly of L-His and L-Phe produced single crystals. The structure revealed the formation of a 3D network with nanocavities stabilized by hydrogen bonding between-N (L-His) and-NH (L- Phe). Taken together, using the co-assembly approach we expanded the field of amino acid nanomaterials and showed the ability to obtain discrete supramolecular nanostructures containing L-His based on its specific interactions with L-Phe
Investigating the effect of surface modification on the dispersion process of polymer nanocomposites
Achieving controlled nanoparticle dispersion through melt processing has been challenging as processing-structure rules for polymer nanocomposites are still not well-defined. This work focuses on developing a quantitative understanding of the filler–matrix compatibility and melt mixing parameters on the dispersion of nanoparticles. Filler-matrix compatibility was varied by surface modification of silica nanoparticles. A twin screw extruder was used to prepare the nanocomposites and TEM imaging and image analysis were used to quantitively characterize the microstructure. It was found that matrix–filler compatibility strongly affected the method of agglomerate breakdown and dispersion. Under similar conditions, compatible systems tended to disperse via rupture of agglomerates while incompatible systems were found to disperse via erosion. A map was created to predict the dispersion mechanism as a function of processing conditions and system compatibility and systems from this study and literature were found to be in good agreement with the map
Predicting clinical outcomes in chronic liver disease: the ELF test is superior to histology and simple scores
The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease
Background and Aims: Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. Methods: Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data. Results: Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227
Some thoughts about the value of an OECD international assessment framework for early childhood services in Aotearoa New Zealand
Tunable Multiscale Nanoparticle Ordering by Polymer Crystallization
While ∼75% of commercially
utilized polymers are semicrystalline,
the generally low mechanical modulus of these materials, especially
for those possessing a glass transition temperature below room temperature,
restricts their use for structural applications. Our focus in this
paper is to address this deficiency through the controlled, multiscale
assembly of nanoparticles (NPs), in particular by leveraging the kinetics
of polymer crystallization. This process yields a multiscale NP structure
that is templated by the lamellar semicrystalline polymer morphology
and spans NPs engulfed by the growing crystals, NPs ordered into layers
in the interlamellar zone [spacing of O (10–100
nm)], and NPs assembled
into fractal objects at the interfibrillar scale, O (1–10
μm). The relative fraction
of NPs in this hierarchy is readily manipulated by the crystallization
speed. Adding NPs usually increases the Young’s modulus of
the polymer, but the effects of multiscale ordering are nearly an
order of magnitude larger than those for a state where the NPs are
not ordered, i.e., randomly dispersed in the matrix. Since the material’s
fracture toughness remains practically unaffected in this process,
this assembly strategy allows us to create high modulus materials
that retain the attractive high toughness and low density of polymers
Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk
Aims/hypothesis: We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes. Methods: Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10–14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05. Results: In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2–10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p \u3c 0.001 in time-varying Cox regression), and similarly with joint modelling. Conclusions/interpretation: In children at genetic risk of type 1 diabetes, being overweight at 2–10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes. Trial registration: ClinicalTrials.gov NCT00179777 Graphical abstract: [Figure not available: see fulltext.