Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
1.
Rheumatology (Oxford) ; 59(Supplement_4): iv58-iv66, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33053195

RESUMO

The axial SpAs (axSpAs) are clearly clinically a heterogeneous set of diseases with markedly varying extra-articular features. These diseases are all highly heritable and have overlapping but differing genetic origins. Shared features include association with HLA class I alleles and genes of the IL-23 pathway, among other things. Significant differences do exist however, both in the genetic loci involved and at specific loci in the individual genetic variants associated with each disease. These similarities and differences are of great interest in regards to disease pathogenesis and treatment development, although individually they are too small in effect to be of prognostic or diagnostic value. Polygenic risk scores, which capture a high proportion of the genetic variation between disorders, have been shown to have clinically useful discriminatory capacity in axSpA. This suggests they have the potential to enable improved disease classification, incorporating basic pathogenic features such as genomics, and ultimately benefitting clinical care. The aim of this article is to review the genetic characteristics of the spectrum of axSpAs and to discuss how this influences our understanding of the disease pathogenesis and the clinical implications of this understanding.

2.
Nat Rev Rheumatol ; 16(8): 448-463, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32606474

RESUMO

The term axial spondyloarthritis (axSpA) encompasses a heterogeneous group of diseases that have variable presentations, extra-articular manifestations and clinical outcomes, and that will respond differently to treatments. The prototypical type of axSpA, ankylosing spondylitis, is thought to be caused by interaction between the genetically primed host immune system and gut microbiota. Currently used biomarkers such as HLA-B27 status, C-reactive protein and erythrocyte sedimentation rate have, at best, moderate diagnostic and predictive value. Improved biomarkers are needed for axSpA to assist with early diagnosis and to better predict treatment responses and long-term outcomes. Advances in a range of 'omics' technologies and statistical approaches, including genomics approaches (such as polygenic risk scores), microbiome profiling and, potentially, transcriptomic, proteomic and metabolomic profiling, are making it possible for more informative biomarker sets to be developed for use in such clinical applications. Future developments in this field will probably involve combinations of biomarkers that require novel statistical approaches to analyse and to produce easy to interpret metrics for clinical application. Large publicly available datasets from well-characterized case-cohort studies that use extensive biological sampling, particularly focusing on early disease and responses to medications, are required to establish successful biomarker discovery and validation programmes.


Assuntos
Biomarcadores/sangue , Espondilartrite/sangue , Humanos
3.
Invest Ophthalmol Vis Sci ; 61(6): 3, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32492107

RESUMO

Purpose: Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. Methods: We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering. Results: We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10-8, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10-7, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10-7, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10-6, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10-7, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10-6, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10-7, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. Conclusions: We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.

4.
EBioMedicine ; 57: 102840, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32580138

RESUMO

BACKGROUND: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease. METHODS: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS. FINDINGS: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 × 10-8

5.
Nat Commun ; 11(1): 3150, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561755

RESUMO

MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, MlklD139V, that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of MlklD139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Sistema Hematopoético/patologia , Necroptose/genética , Proteínas Quinases/genética , Animais , Animais Recém-Nascidos , Doenças Hereditárias Autoinflamatórias , Humanos , Inflamação/genética , Camundongos , Mutação de Sentido Incorreto , Osteomielite/genética , Proteínas Quinases/metabolismo
6.
Arthritis Res Ther ; 22(1): 74, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32272966

RESUMO

BACKGROUND: The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort. METHODS: A total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects. RESULTS: A strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10-244). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10-19), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10-4). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10-241), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians. CONCLUSIONS: This study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.

7.
Neuroimage Clin ; 25: 102182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978826

RESUMO

Dementia affects 47 million individuals worldwide, and assuming the status quo is projected to rise to 150 million by 2050. Prevention of age-related cognitive impairment in older persons with lifestyle interventions continues to garner evidence but whether this can combat underlying neurodegeneration is unknown. The Study of Mental Activity and Resistance Training (SMART) trial has previously reported within-training findings; the aim of this study was to investigate the long-term neurostructural and cognitive impact of resistance exercise in Mild Cognitive Impairment (MCI). For the first time we show that hippocampal subareas particularly susceptible to volume loss in Alzheimer's disease (AD) are protected by resistance exercise for up to one year after training. One hundred MCI participants were randomised to one of four training groups: (1) Combined high intensity progressive resistance and computerised cognitive training (PRT+CCT), (2) PRT+Sham CCT, (3) CCT+Sham PRT, (4) Sham physical+sham cognitive training (SHAM+SHAM). Physical, neuropsychological and MRI assessments were carried out at baseline, 6 months (directly after training) and 18 months from baseline (12 months after intervention cessation). Here we report neuro-structural and functional changes over the 18-month trial period and the association with global cognitive and executive function measures. PRT but not CCT or PRT+CCT led to global long-term cognitive improvements above SHAM intervention at 18-month follow-up. Furthermore, hippocampal subfields susceptible to atrophy in AD were protected by PRT revealing an elimination of long-term atrophy in the left subiculum, and attenuation of atrophy in left CA1 and dentate gyrus when compared to SHAM+SHAM (p = 0.023, p = 0.020 and p = 0.027). These neuroprotective effects mediated a significant portion of long-term cognitive benefits. By contrast, within-training posterior cingulate plasticity decayed after training cessation and was unrelated to long term cognitive benefits. Neither general physical activity levels nor fitness change over the 18-month period mediated hippocampal trajectory, demonstrating that enduring hippocampal subfield plasticity is not a simple reflection of post-training changes in fitness or physical activity participation. Notably, resting-state fMRI analysis revealed that both the hippocampus and posterior cingulate participate in a functional network that continued to be upregulated following intervention cessation. Multiple structural mechanisms may contribute to the long-term global cognitive benefit of resistance exercise, developing along different time courses but functionally linked. For the first time we show that 6 months of high intensity resistance exercise is capable of not only promoting better cognition in those with MCI, but also protecting AD-vulnerable hippocampal subfields from degeneration for at least 12 months post-intervention. These findings emphasise the therapeutic potential of resistance exercise; however, future work will need to establish just how long-lived these outcomes are and whether they are sufficient to delay dementia.

8.
Arthritis Rheumatol ; 71(10): 1642-1650, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31038287

RESUMO

OBJECTIVE: HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype-disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA-B27 and HLA-DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. METHODS: Five hundred sixty-eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. RESULTS: Associations were observed between the overall microbial composition and both the HLA-B27 genotype and the HLA-DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). CONCLUSION: This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA-B27 and HLA-DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.


Assuntos
Artrite Reumatoide/genética , Microbioma Gastrointestinal/genética , Antígeno HLA-B27/genética , Cadeias HLA-DRB1/genética , Espondilite Anquilosante/genética , Adulto , Idoso , Alelos , Artrite Reumatoide/microbiologia , Estudos de Coortes , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Espondilite Anquilosante/microbiologia
9.
PLoS Genet ; 15(4): e1008038, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946743

RESUMO

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , Espondilite Anquilosante/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Febre Familiar do Mediterrâneo/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígeno HLA-B27/genética , Antígeno HLA-B51/genética , Humanos , Interleucina-1beta/sangue , Interleucina-23/sangue , Irã (Geográfico) , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/imunologia , Turquia
10.
Opt Express ; 27(5): 7064-7071, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30876278

RESUMO

We theoretically analyze and experimentally investigate the dependence of residual amplitude modulation (RAM) on the beam radius within the electro-optic crystal (EOC), the wedge angle of the EOC and the overlap efficiency between the extraordinary and ordinary beams, and the overlap efficiency is determined by the distance from the wedge facet to the downstream polarizer. The results show that the RAM with the maximum optical path difference Δ at the edge of light spot presents a sinc-like curve,and the magnitude of Δ is directly proportional to the beam radius and the wedge angle. As a scaling factor, with the decrease of the overlap efficiency between the ordinary and extraordinary beams, the RAM can be further reduced.

11.
Front Physiol ; 10: 19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804794

RESUMO

There is heterogeneity in the observed O2peak response to similar exercise training, and different exercise approaches produce variable degrees of exercise response (trainability). The aim of this study was to combine data from different laboratories to compare O2peak trainability between various volumes of interval training and Moderate Intensity Continuous Training (MICT). For interval training, volumes were classified by the duration of total interval time. High-volume High Intensity Interval Training (HIIT) included studies that had participants complete more than 15 min of high intensity efforts per session. Low-volume HIIT/Sprint Interval Training (SIT) included studies using less than 15 min of high intensity efforts per session. In total, 677 participants across 18 aerobic exercise training interventions from eight different universities in five countries were included in the analysis. Participants had completed 3 weeks or more of either high-volume HIIT (n = 299), low-volume HIIT/SIT (n = 116), or MICT (n = 262) and were predominately men (n = 495) with a mix of healthy, elderly and clinical populations. Each training intervention improved mean O2peak at the group level (P < 0.001). After adjusting for covariates, high-volume HIIT had a significantly greater (P < 0.05) absolute O2peak increase (0.29 L/min) compared to MICT (0.20 L/min) and low-volume HIIT/SIT (0.18 L/min). Adjusted relative O2peak increase was also significantly greater (P < 0.01) in high-volume HIIT (3.3 ml/kg/min) than MICT (2.4 ml/kg/min) and insignificantly greater (P = 0.09) than low-volume HIIT/SIT (2.5 mL/kg/min). Based on a high threshold for a likely response (technical error of measurement plus the minimal clinically important difference), high-volume HIIT had significantly more (P < 0.01) likely responders (31%) compared to low-volume HIIT/SIT (16%) and MICT (21%). Covariates such as age, sex, the individual study, population group, sessions per week, study duration and the average between pre and post O2peak explained only 17.3% of the variance in O2peak trainability. In conclusion, high-volume HIIT had more likely responders to improvements in O2peak compared to low-volume HIIT/SIT and MICT.

12.
FASEB J ; 33(2): 2095-2104, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30260702

RESUMO

Bacterial infection is one of the leading causes of death in young, elderly, and immune-compromised patients. The rapid spread of multi-drug-resistant (MDR) bacteria is a global health emergency and there is a lack of new drugs to control MDR pathogens. We describe a heretofore-unexplored discovery pathway for novel antibiotics that is based on self-targeting, structure-disrupting peptides. We show that a helical peptide, KFF- EcH3, derived from the Escherichia coli methionine aminopeptidase can disrupt secondary and tertiary structure of this essential enzyme, thereby killing the bacterium (including MDR strains). Significantly, no detectable resistance developed against this peptide. Based on a computational analysis, our study predicted that peptide KFF- EcH3 has the strongest interaction with the structural core of the methionine aminopeptidase. We further used our approach to identify peptide KFF- NgH1 to target the same enzyme from Neisseria gonorrhoeae. This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model. These findings present an exciting new paradigm in antibiotic discovery using self-derived peptides that can be developed to target the structures of any essential bacterial proteins.-Zhan, J., Jia, H., Semchenko, E. A., Bian, Y., Zhou, A. M., Li, Z., Yang, Y., Wang, J., Sarkar, S., Totsika, M., Blanchard, H., Jen, F. E.-C., Ye, Q., Haselhorst, T., Jennings, M. P., Seib, K. L., Zhou, Y. Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides.


Assuntos
Aminopeptidases/antagonistas & inibidores , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Proliferação de Células/efeitos dos fármacos , Gonorreia/tratamento farmacológico , Metionina/metabolismo , Neisseria gonorrhoeae/efeitos dos fármacos , Células Cultivadas , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Colo do Útero/microbiologia , Farmacorresistência Bacteriana Múltipla , Feminino , Gonorreia/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/enzimologia
13.
J Neuroimmunol ; 323: 109-114, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30196823

RESUMO

Guillain-Barré syndrome (GBS) is considered to have an immune-mediated basis, but the genetic contribution to GBS is unclear. We conducted a GWAS involving 215 GBS patients and 1,105 healthy controls. No significant associations of individual SNPs or imputed HLA types were observed. We performed a genome-wide complex trait analysis for evaluation of the heritability of GBS, and found that common SNPs contribute up to 25% of susceptibility to the disease. Genetic risk score analysis showed no evidence of overlap in genetic susceptibility factors of GBS and multiple sclerosis. Given the unexplained heritability of the trait further larger GWAS are indicated.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/epidemiologia , Síndrome de Guillain-Barré/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Opt Express ; 26(15): 18957-18968, 2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30114155

RESUMO

We present an analysis on how the optical parametric oscillator (OPO) detuning and the relative phase drift deteriorate the stability of the squeezed states, including the output power and the squeezed degree, and investigate the influence of RAM on the cavity detuning and the relative phase drift under different cases. Subsequently, the RAM is experimentally measured. In term of the measurement results, we perform a comparative study about RAM's influence on the cavity and phase locking in two cases. As a result, with the error signal extracted from the transmission of the OPO, the output power stability of the squeezed light is greatly improved. With the phase modulation imposed on the signal beam, the long-term stability of the squeezed degree is significantly enhanced.

15.
RMD Open ; 4(1): e000677, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018800

RESUMO

Objectives: Ankylosing spondylitis (AS) is the most prevalent form of spondyloarthritis, with a known genetic association with the HLA-B27 molecule. The aim of this study was to assess the contribution of the HLA-G, HLA-E and HLA-F to AS susceptibility/protection in Portuguese patients with HLA-B27 AS and HLA-B27 unaffected controls. Methods: High-resolution typing of HLA-G, HLA-E and HLA-F was performed in 228 patients with HLA-B27 AS and 244 HLA-B27 unaffected controls. Allelic, genotypic and haplotypic frequencies were compared between cohorts. To replicate the results, single nucleotide polymorphisms (SNPs) in HLA-E and HLA-F genes were typed in Australian cohorts. For further confirmation, a group of European-descent patients with AS and unaffected controls were genotyped for Major Histocompatibility Complex SNPs using the Illumina microarray. Results: In the Portuguese population, no significant differences were found in HLA-G. For HLA-E, a significant difference was detected for the genotype HLA-E*01:01:01/01:03:01 (p=0.009; pc=0.009; OR=0.51), with a protection effect. For HLA-F, significant differences were detected in the allele HLA-F*01:01:02 (p=0.0049; pc=0.0098; OR=0.60) and corresponding SNP rs2075682 (p=0.0004; pc=0.0008; OR=0.53), suggesting protection and in the genotype HLA-F*01:01:01/01:03:01 (p=0.011; pc=0.043; OR=2.00), suggesting a susceptibility effect. Three G-E-F haplotypes with significant differences were detected but occur in a very small number of individuals. The only significant differences detected in the replication studies were for HLA-E rs1059510 in the Australians and for HLA-F rs1736924 in the European-descent cohorts. Conclusion: Our results reveal suggestive AS protective and susceptibility effects from both HLA-E and HLA-F loci, however with population differences. To our knowledge, this is the first study showing association of HLA-F with AS.

16.
Proteins ; 86(6): 629-633, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29508448

RESUMO

Designing protein sequences that can fold into a given structure is a well-known inverse protein-folding problem. One important characteristic to attain for a protein design program is the ability to recover wild-type sequences given their native backbone structures. The highest average sequence identity accuracy achieved by current protein-design programs in this problem is around 30%, achieved by our previous system, SPIN. SPIN is a program that predicts sequences compatible with a provided structure using a neural network with fragment-based local and energy-based nonlocal profiles. Our new model, SPIN2, uses a deep neural network and additional structural features to improve on SPIN. SPIN2 achieves over 34% in sequence recovery in 10-fold cross-validation and independent tests, a 4% improvement over the previous version. The sequence profiles generated from SPIN2 are expected to be useful for improving existing fold recognition and protein design techniques. SPIN2 is available at http://sparks-lab.org.


Assuntos
Redes Neurais de Computação , Proteínas/química , Software , Sequência de Aminoácidos , Bases de Dados de Proteínas , Modelos Moleculares , Dobramento de Proteína , Estrutura Secundária de Proteína
18.
Sci Rep ; 7: 41405, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28145483

RESUMO

Non-classical squeezed states of light at a compatible atomic wavelength have a potential application in quantum information protocols for quantum states delaying or storaging. An optical parametric oscillator (OPO) with periodically poled potassium titanyl phosphate (PPKTP) is the most effective method for generating this squeezed state. However, it is a challege for the nonlinear interaction in PPKTP crystal at the D1 line of rubidium atomic, due to a strong blue-light-induced infrared absorption (BLIIRA). In this paper, we report an indirect measurement method for the BLIIRA through measuring the mode-matching efficiency in an optical parametric oscillator. In contrast to previous works, our method is not limited by the absolute power variation induced from the change of frequency conversion loss and the impedance matching originated from the change of absorption loss. Therefore, the measurement process is performed at the phase-matching condition. The measured results show that BLIIRA coefficient is quadratic dependence of blue light intensity below 1 kW per square centimeter in our PPKTP device, which will provide important basis for optimizing squeezed state generation at 795 nm.

19.
Methods Mol Biol ; 1484: 159-174, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27787826

RESUMO

Over the past decade, it has become evident that a large proportion of proteins contain intrinsically disordered regions, which play important roles in pivotal cellular functions. Many computational tools have been developed with the aim of identifying the level and location of disorder within a protein. In this chapter, we describe a neural network based technique called SPINE-D that employs a unique three-state design and can accurately capture disordered residues in both short and long disordered regions. SPINE-D was trained on a large database of 4229 non-redundant proteins, and yielded an AUC of 0.86 on a cross-validation test and 0.89 on an independent test. SPINE-D can also detect a semi-disordered state that is associated with induced folders and aggregation-prone regions in disordered proteins and weakly stable or locally unfolded regions in structured proteins. We implement an online web service and an offline stand-alone program for SPINE-D, they are freely available at http://sparks-lab.org/SPINE-D/ . We then walk you through how to use the online and offline SPINE-D in making disorder predictions, and examine the disorder and semi-disorder prediction in a case study on the p53 protein.


Assuntos
Conformação Proteica , Proteínas/genética , Software , Algoritmos , Sequência de Aminoácidos/genética , Biologia Computacional , Bases de Dados de Proteínas , Redes Neurais de Computação , Proteínas/química
20.
Clin Transl Immunology ; 6(12): e163, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29333268

RESUMO

Ankylosing spondylitis (AS) is an immune-mediated arthritis which primarily affects the spine and sacroiliac joints. Significant progress has been made in discovery of genetic associations with AS by genome-wide association studies (GWAS) over past decade. These findings have uncovered novel pathways involved pathogenesis of the disease and have led to introduction of novel therapeutic treatments for AS. In this Review, we discuss the genetic variations associated with AS identified by GWAS, the major pathways revealed by these AS-associated variations and critical cell types involved in AS development.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA