Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Neuroimage Clin ; 25: 102182, 2020 Jan 14.
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.

2.
Arthritis Rheumatol ; 71(10): 1642-1650, 2019 Oct.
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.

3.
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
4.
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.

5.
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.

6.
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
7.
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
8.
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.

9.
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.

10.
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
Proteínas/química , Software , Sequência de Aminoácidos , Bases de Dados de Proteínas , Modelos Moleculares , Dobramento de Proteína , Estrutura Secundária de Proteína
12.
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.

13.
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.

14.
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 , Proteínas/química
15.
Rev Sci Instrum ; 87(10): 103114, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27802770

RESUMO

Based on the requirement of squeezed state generation, we build the phase relationship between two electronic local oscillators for the cavity- and phase-locking branches, and a 2-way 90° power splitter is adopted to satisfy the phase relationship simultaneously, which greatly simplifies the experimental setup and adjusting process. A LC parallel resonant circuit, which is composed by the inherent capacitance of a photodiode and an extra inductor, is adopted in the resonant photodetector to improve the gain factor at the expected frequency. The gain of the resonant photodetector is about 30 dB higher than that of the broadband photodetector at the resonant frequency. The peak-to-peak value of the error signal for cavity-locking (phase-locking) with the resonant photodetector is 240 (260) times of that with the broadband photodetector, which can improve the locking performance on the premise of not affecting the squeezing degree.

16.
Opt Lett ; 41(14): 3331-4, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27420528

RESUMO

We report an electro-optic modulator (EOM) with a wedged MgO: LiNbO3 as the modulation crystal to reduce the zero baseline drift (ZBD) of the Pound-Drever-Hall (PDH) error signal. When the input linear polarization is not along the modulation direction, the wedged design can separate the two orthogonal polarizations in space after the EOM and eliminate the interference between the carrier and the two orthogonal sidebands. Therefore, the residual amplitude modulation (RAM) of phase modulation process caused by the input polarization misalignment and the etalon effect can be significantly reduced. The noise power spectrum of phase-modulated light with wedged crystal EOM is suppressed from -24 to -69 dBm, which is much lower than that with conventional EOM. The peak-to-peak value of the ZBD of the PDH error signal is reduced effectively to +70/-50 ppm during the 10 h, which meets the requirements for stable squeezed light generation.

17.
PLoS One ; 11(4): e0153939, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27100390

RESUMO

Blockade of IL-10 signalling clears chronic viral and bacterial infections. Immunization together with blockade of IL-10 signalling or relatively low level of IL-10 further enhances viral and bacterial clearance. IL-10 functions through binding to interleukin 10 receptor (IL-10R). Here we showed that peptides P1 and P2 with the hydrophobic and hydrophilic pattern of the IL10R-binding helix in IL-10 could bind with either IL-10R1 or IL-10, and inhibit inflammatory signals with long duration and negligible cytotoxicity in vitro. Furthermore, P2 can enhance antigen specific CD8+ T cell responses in mice induced by the vaccine based on a long peptide of protein E7 in a human papillomavirus type 16.


Assuntos
Interleucina-10/antagonistas & inibidores , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Vacinas de Subunidades/química , Vacinas de Subunidades/farmacologia , Sequência de Aminoácidos , Animais , Feminino , Papillomavirus Humano 16/imunologia , Humanos , Imunização , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Conformação Proteica , Homologia de Sequência de Aminoácidos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Ressonância de Plasmônio de Superfície , Vacinas de Subunidades/imunologia
18.
BMC Med Genet ; 17: 14, 2016 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-26892242

RESUMO

BACKGROUND: Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant cutaneous disorder caused by the mutations of adenosine deaminase acting on RNA1 (ADAR1) gene. We present a clinical and genetic study of seven unrelated families and two sporadic cases with DSH for mutations in the full coding sequence of ADAR1 gene. METHODS: ADAR1 gene was sequenced in seven unrelated families and two sporadic cases with DSH and 120 controls. Functional significance of the observed ADAR1 mutations was analyzed using PolyPhen 2, SIFT and DDIG-in. RESULTS: We describe six novel mutations of the ADAR1 gene in Chinese patients with DSH including a nonstop mutation p.Stop1227R, which was firstly reported in ADAR1 gene. In silico analysis proves that all the mutations reported here are pathogenic. CONCLUSION: This study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ADAR1 gene. A three-generation family exhibiting phenotypic variability with a single germline ADAR1 mutation suggests that chilblain might aggravate the clinical phenotypes of DSH.


Assuntos
Adenosina Desaminase/genética , Grupo com Ancestrais do Continente Asiático/genética , Transtornos da Pigmentação/congênito , Proteínas de Ligação a RNA/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Mutação , Fenótipo , Transtornos da Pigmentação/genética
19.
Bioinformatics ; 31(10): 1599-606, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25573915

RESUMO

MOTIVATION: Frameshifting (FS) indels and nonsense (NS) variants disrupt the protein-coding sequence downstream of the mutation site by changing the reading frame or introducing a premature termination codon, respectively. Despite such drastic changes to the protein sequence, FS indels and NS variants have been discovered in healthy individuals. How to discriminate disease-causing from neutral FS indels and NS variants is an understudied problem. RESULTS: We have built a machine learning method called DDIG-in (FS) based on real human genetic variations from the Human Gene Mutation Database (inherited disease-causing) and the 1000 Genomes Project (GP) (putatively neutral). The method incorporates both sequence and predicted structural features and yields a robust performance by 10-fold cross-validation and independent tests on both FS indels and NS variants. We showed that human-derived NS variants and FS indels derived from animal orthologs can be effectively employed for independent testing of our method trained on human-derived FS indels. DDIG-in (FS) achieves a Matthews correlation coefficient (MCC) of 0.59, a sensitivity of 86%, and a specificity of 72% for FS indels. Application of DDIG-in (FS) to NS variants yields essentially the same performance (MCC of 0.43) as a method that was specifically trained for NS variants. DDIG-in (FS) was shown to make a significant improvement over existing techniques.


Assuntos
Algoritmos , Códon sem Sentido/genética , Doença/genética , Mutação da Fase de Leitura/genética , Mutação INDEL/genética , Nucleotídeos/química , Proteínas/química , Inteligência Artificial , Sequência Conservada , Bases de Dados Genéticas , Humanos , Nucleotídeos/genética , Proteínas/genética , Proteínas/metabolismo
20.
Proteins ; 82(10): 2565-73, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24898915

RESUMO

Locating sequences compatible with a protein structural fold is the well-known inverse protein-folding problem. While significant progress has been made, the success rate of protein design remains low. As a result, a library of designed sequences or profile of sequences is currently employed for guiding experimental screening or directed evolution. Sequence profiles can be computationally predicted by iterative mutations of a random sequence to produce energy-optimized sequences, or by combining sequences of structurally similar fragments in a template library. The latter approach is computationally more efficient but yields less accurate profiles than the former because of lacking tertiary structural information. Here we present a method called SPIN that predicts Sequence Profiles by Integrated Neural network based on fragment-derived sequence profiles and structure-derived energy profiles. SPIN improves over the fragment-derived profile by 6.7% (from 23.6 to 30.3%) in sequence identity between predicted and wild-type sequences. The method also reduces the number of residues in low complex regions by 15.7% and has a significantly better balance of hydrophilic and hydrophobic residues at protein surface. The accuracy of sequence profiles obtained is comparable to those generated from the protein design program RosettaDesign 3.5. This highly efficient method for predicting sequence profiles from structures will be useful as a single-body scoring term for improving scoring functions used in protein design and fold recognition. It also complements protein design programs in guiding experimental design of the sequence library for screening and directed evolution of designed sequences. The SPIN server is available at http://sparks-lab.org.


Assuntos
Modelos Moleculares , Fragmentos de Peptídeos/química , Engenharia de Proteínas/métodos , Proteínas/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Inteligência Artificial , Biologia Computacional , Humanos , Interações Hidrofóbicas e Hidrofílicas , Internet , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Biblioteca de Peptídeos , Conformação Proteica , Dobramento de Proteína , Proteínas/genética , Proteínas/metabolismo , Homologia de Sequência de Aminoácidos , Software , Propriedades de Superfície
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA