Results
- Showing results for:
- Reset all filters
Search results
-
Journal articleJamshidiha M, Pérez-Dorado I, Murray JW, et al., 2019,
Coping with strong translational noncrystallographic symmetry and extreme anisotropy in molecular replacement with Phaser: human Rab27a
, Acta Crystallographica Section D Structural Biology, Vol: 75, Pages: 342-353, ISSN: 2059-7983Data pathologies caused by effects such as diffraction anisotropy and translational noncrystallographic symmetry (tNCS) can dramatically complicate the solution of the crystal structures of macromolecules. Such problems were encountered in determining the structure of a mutant form of Rab27a, a member of the Rab GTPases. Mutant Rab27a constructs that crystallize in the free form were designed for use in the discovery of drugs to reduce primary tumour invasiveness and metastasis. One construct, hRab27a<jats:sup>Mut</jats:sup>, crystallized within 24 h and diffracted to 2.82 Å resolution, with a unit cell possessing room for a large number of protein copies. Initial efforts to solve the structure using molecular replacement by <jats:italic>Phaser</jats:italic> were not successful. Analysis of the data set revealed that the crystals suffered from both extreme anisotropy and strong tNCS. As a result, large numbers of reflections had estimated standard deviations that were much larger than their measured intensities and their expected intensities, revealing problems with the use of such data at the time in <jats:italic>Phaser</jats:italic>. By eliminating extremely weak reflections with the largest combined effects of anisotropy and tNCS, these problems could be avoided, allowing a molecular-replacement solution to be found. The lessons that were learned in solving this structure have guided improvements in the numerical analysis used in <jats:italic>Phaser</jats:italic>, particularly in identifying diffraction measurements that convey very little information content. The calculation of information content could also be applied as an alternative to ellipsoidal truncation. The post-mortem analysis also revealed an oversight in accounting for measurement errors in the fast rotation function. While the crystal of mutant Rab27a is not amenable to drug screening, the structure can guide new modifications to obtain more sui
-
Conference paperWang K, Elliot J, Saglani S, et al., 2019,
THICKENING OF THE AIRWAY SMOOTH MUSCLE LAYER FROM LATE GESTATION TO CHILDHOOD IS FACILITATED BY INCREASED MEAN CELL VOLUME
, Publisher: WILEY, Pages: 76-76, ISSN: 1323-7799- Cite
- Citations: 1
-
Journal articleNagelkerke SQ, Tacke CE, Breunis WB, et al., 2019,
Extensive ethnic variation and linkage disequilibrium at the FCGR2/3 locus: Different genetic associations revealed in Kawasaki Disease
, Frontiers in Immunology, Vol: 10, ISSN: 1664-3224The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C-ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C-ORF haplotype showed strong LD with, among others, rs201218628 (FCGR2A-Q27W, r2 = 0.63). LD between these two variants was weaker (r2 = 0.17) in Africans, whereas the FCGR2C-ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C-ORF haplotype and rs1801274 (FCGR2A-H131R) were in weak LD (r2 = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the FCGR2C-ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the FCGR2/3 locus with knowledge of LD and ethnic variation.
-
Conference paperBriggs E, Greer O, Shah NM, et al., 2019,
Hyponatraemia and pre-eclampsia
, Publisher: WILEY, Pages: 41-41, ISSN: 1470-0328 -
Journal articleThursz M, Kamath PS, Mathurin P, et al., 2019,
Alcohol-related liver disease: Areas of consensus, unmet needs and opportunities for further study
, JOURNAL OF HEPATOLOGY, Vol: 70, Pages: 521-530, ISSN: 0168-8278- Author Web Link
- Cite
- Citations: 58
-
Journal articleDhillo WS, 2019,
Kisspeptin, Neurokinin B and New Players in Reproduction Preface
, SEMINARS IN REPRODUCTIVE MEDICINE, Vol: 37, Pages: 45-45, ISSN: 1526-8004 -
Journal articleGhosh B, Gaike AH, Pyasi K, et al., 2019,
Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass-smoke COPD
, European Respiratory Journal, Vol: 53, Pages: 1-14, ISSN: 0903-1936Lower airway colonisation with potentially pathogenic bacterial species (PPBs) is associated with defective bacterial phagocytosis, in monocyte-derived macrophages (MDMs) and alveolar macrophages, from tobacco-smoke associated COPD (S-COPD) subjects. In developing world, COPD among non-smokers is largely due to biomass-smoke (BMS) exposure. Yet, little is known about PPBs colonisation and its association with impaired innate immunity in these subjects.We investigated the PPBs load (Streptococcus pneumoniae, SP; Haemophilus influenzae, HI; Moraxella catarrhalis, MC; and Pseudomonas aeruginosa, PA) in BMS-exposed COPD (BMS-COPD) compared with S-COPD and spirometrically normal subjects. We also examined the association between load of PPBs with phagocytic activity of MDMs and lung function.Induced sputum and peripheral venous blood samples were collected from 18 healthy non-smokers, 15 smokers without COPD, 16 BMS-exposed healthy, 19 S-COPD and 23 BMS-COPD subjects. PPBs load in induced sputum and MDMs phagocytic activity were determined using qPCR and fluorimetry respectively.Higher bacterial load of SP, HI, and PA were observed in BMS-COPD. Increased PPBs load in BMS-exposed subjects was significantly negatively associated with defective phagocytosis in MDMs, and spirometric lung function indices (p<0.05).Increased load of PPBs in airways of BMS-COPD subjects is inversely associated with defective bacterial phagocytosis and lung function.
-
Journal articleBagnoli M, Shi TY, Gourley C, et al., 2019,
Gynecological cancers translational, research implementation, and harmonization: Gynecologic Cancer InterGroup consensus and still open questions
, Cells, Vol: 8, ISSN: 2073-4409In the era of personalized medicine, the introduction of translational studies in clinical trials has substantially increased their costs, but provides the possibility of improving the productivity of trials with a better selection of recruited patients. With the overall goal of creating a roadmap to improve translational design for future gynecological cancer trials and of defining translational goals, a main discussion was held during a brainstorming day of the Gynecologic Cancer InterGroup (GCIG) Translational Research Committee and overall conclusions are here reported. A particular emphasis was dedicated to the new frontier of the immunoprofiling of gynecological cancers. The discussion pointed out that to maximize patients’ benefit, translational studies should be integral to clinical trial design with standardization and optimization of procedures including a harmonization program of Standard Operating Procedures. Pathology-reviewed sample collection should be mandatory and ensured by dedicated funding. Biomarker validation and development should be made public and transparent to ensure rapid progresses with positive outcomes for patients. Guidelines/templates for patients’ informed consent are needed. Importantly for the public, recognized goals are to increase the involvement of advocates and to improve the reporting of translational data in a forum accessible to patients.
-
Journal articleMoulton CD, Norton C, Powell N, et al., 2019,
Depression in inflammatory bowel disease: risk factor, prodrome or extraintestinal manifestation?
, Gut, Vol: 69, Pages: 609-610, ISSN: 0017-5749 -
OtherParks T, Elliott K, Lamagni T, et al., 2019,
Elevated risk of invasive group A streptococcal disease and host genetic variation in the human leukocyte antigen locus
Invasive group A streptococcal (GAS) disease is uncommon but carries a high case-fatality rate relative to other infectious diseases. Given the ubiquity of mild GAS infections, it remains unclear why healthy individuals will occasionally develop life-threatening infections, raising the possibility of host genetic predisposition. Here, we present the results of a case-control study including 43 invasive GAS cases and 1,540 controls. Using HLA imputation and linear mixed-models, we find each copy of the HLA-DQA1 *01:03 allele associates with a two-fold increased risk of disease (odds ratio 2.3, 95% confidence interval 1.3-4.4, P =0.009), an association which persists with classical HLA typing of a subset of cases and analysis with an alternative large control dataset with validated HLA data. Moreover, we propose the association is driven by the allele itself rather than the background haplotype. Overall this finding provides impetus for further investigation of the immunogenetic basis of this devastating bacterial disease.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.