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1.
Mem Inst Oswaldo Cruz ; 114: e190120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553370

RESUMO

BACKGROUND: In recent years, South America has suffered the burden of continuous high impact outbreaks of dengue, chikungunya and Zika. Aedes aegypti is the main mosquito vector of these arboviruses and its control is the only solution to reduce transmission. OBJECTIVES: In order to improve vector control it is essential to study mosquito population genetics in order to better estimate the population structures and the geneflow among them. METHODS: We have analysed microsatellites and knockdown resistance (kdr) mutations from a trans-border region in Amazonia between the state of Amapá (Brazil) and French Guiana (overseas territory of France), to provide further knowledge on these issues. These two countries have followed distinct vector control policies since last century. For population genetic analyses we evaluated variability in 13 well-established microsatellites loci in Ae. aegypti from French Guiana (Saint Georges and Cayenne) and Brazil (Oiapoque and Macapá). The occurrence and frequency of kdr mutations in these same populations were accessed by TaqMan genotype assays for the sites 1016 (Val/Ile) and 1534 (Phe/Cys). FINDINGS: We have detected high levels of gene flow between the closest cross-border samples of Saint-Georges and Oiapoque. These results suggest one common origin of re-colonisation for the populations of French Guiana and Oiapoque in Brazil, and a different source for Macapá, more similar to the other northern Brazilian populations. Genotyping of the kdr mutations revealed distinct patterns for Cayenne and Macapá associated with their different insecticide use history, and an admixture zone between these two patterns in Saint Georges and Oiapoque, in accordance with population genetic results. MAIN CONCLUSIONS: The present study highlights the need for regional-local vector surveillance and transnational collaboration between neighboring countries to assess the impact of implemented vector control strategies, promote timely actions and develop preparedness plans.


Assuntos
Aedes/efeitos dos fármacos , Aedes/genética , Resistência a Inseticidas/genética , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/genética , Mutação/genética , Animais , Biodiversidade , Brasil , Guiana Francesa , Genótipo , Resistência a Inseticidas/efeitos dos fármacos
2.
Medicina (B Aires) ; 79(4): 265-270, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31487245

RESUMO

Malignant melanoma (MM) is the more aggressive form of skin cancer with a mortality rate in Argentina 1997-2001 = 1.1/100 000 in men and 0.6 in women. BRAF proto-oncogene is focus of intense research; its mutation is one of the main tumor promoters and occurs in approximately 50% of MM. Several drugs with clinical activity on BRAF mutations have been approved. The aim of the study is to evaluate the mutational status of BRAF (exon 15) in cutaneous MM biopsies and its relationship with histopathological characteristics. We carried out an observational, retrospective study of samples fixed in formaldehyde and paraffin embedded; reviewing age, sex, diagnosis, histopathological data, tumor size and percentage, viability for molecular analysis and melanin presence. We evaluated BRAF mutations with PCR/Sanger sequencing. For statistics we used Student's t test, Chi square, Wilcoxon and Fisher's exact test. We were able to purify and sequence 76% (38/49) samples, 13/38 (34%) from women and 25/38 (66%) from men, the median age being 70 years. Most frequent location: thorax 14/35 (40%). Histological type: Superficial spreading 18/38 (47%). Clark's levels, 11/38 (29%): I-II and 27/38 (71%): III, IV and V. Breslow's median: 1.6 mm. Radial growth phase 11/38 (29%) and 27/38 (71%) vertical. Presented mutations 16/38 (42%). As reported by other authors, no association was found between the mutational state of exon 15 and clinical or histopathological parameters.


Assuntos
Melanoma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Neoplasias Cutâneas/patologia
3.
An Acad Bras Cienc ; 91(3): e20180882, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553368

RESUMO

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by dynamic mutations of a CGG repetition segment in an X chromosome's single gene. It is considered the leading hereditary cause of both Autism Spectrum Disorders and Intellectual Disability. Some authors suggest that all individuals diagnosed with some of these latter conditions to be clinically and molecularly trialled for FXS due to the high levels of comorbidity between both conditions and also due to the variable expressiveness of this syndrome. This study has focused on verifying the presence of FMR1 expanded alleles since there is a lack of information about this kind of mutation in autism patients from the northern region of Brazil. The presence of large alleles for this gene could offer new therapeutic or pharmacological methods for the treatment of these patients. Both the presence and the frequency of CGG expansions were verified in 90 autism males by molecular analysis. Four of them had intermediate alleles and four others presented premutated alleles. Premutation carriers are on the propensity of developing the late onset Fragile X-associated tremor/ataxia syndrome. No full mutation alleles were found. Further studies are necessary to obtain more accurate statistical data about this kind of dynamic mutation.


Assuntos
Transtorno do Espectro Autista/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Mutação/genética , Adolescente , Alelos , Criança , Pré-Escolar , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Adulto Jovem
4.
Phys Chem Chem Phys ; 21(37): 20628-20640, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31495862

RESUMO

Methionine synthase (MetH) is a methylcobalamin (MeCbl)-dependent mammalian enzyme which plays a critical role in carrying out the transfer of a methyl group from methyl tetrahydrofolate to homocysteine to generate methionine and tetrahydrofolate. This catalytic cycle proceeds via cleavage of a Co-C bond which is formally heterolytic. This cleavage results in a structural change in the MeCbl cofactor bound to an enzyme. Unlike the native catalysis, upon photoexcitation, the Co-C bond in MeCbl-bound MetH generates the Co(ii)/CH3 radical pairs (RPs). Protein residues of the cap domain, particularly phenylalanine708 (F708) and leucine 715 (L715), which surrounds the upper face of the MeCbl cofactor, inhibit the photolysis of MeCbl by caging the CH3 radical and inducing the geminate recombination of the Co(ii)/CH3 RP. A molecular-level understanding of these effects requires a detailed investigation of the low-lying electronic states. Toward this, we have mutated the F708 residue with alanine (A708) and constructed the potential energy surfaces (PESs) for the low-lying S1 electronic state using a combined quantum mechanics/molecular mechanics (QM/MM) approach. The S1 PESs for the wild-type (WT) and mutant enzymes are the result of crossing of two electronic states, namely metal-to-ligand charge transfer (MLCT) and ligand field (LF) states, indicated by a seam. It is shown that the topologies of the S1 PESs are significantly modulated by introducing a mutation at the F708 position. Specifically, for the WT enzyme, the energy barrier of photoreaction and the energy difference between MLCT and LF minima are markedly higher than those of its mutant counterpart. Moreover, mutation influences the photoactivation of the Co-C bond in enzyme-bound MeCbl by decreasing the rate of geminate recombination and altering the rate of radical pair formation. This theoretical insight was also compared with transient absorption spectroscopic (TAS) studies which are in good agreement with the present findings.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Carbono/química , Cobalto/química , Vitamina B 12/análogos & derivados , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Modelos Químicos , Estrutura Molecular , Mutação/genética , Fotólise , Domínios Proteicos/genética , Vitamina B 12/metabolismo
5.
Phys Chem Chem Phys ; 21(37): 20951-20964, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31524891

RESUMO

As a promising drug target in the treatment of lung cancer, anaplastic lymphoma kinase (ALK) and its mutations have been studied widely through the development of multiple generations of inhibitors. Experiments have found that compared with the wild-type, the L1198F and C1156Y/L1198F mutations resulted in resistance to 5P8 inhibitors, and the C1156Y mutation resulted in resistance to VGH inhibitors. In this study, the newly developed interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field was utilized to explore the origin of the resistance mechanism of the ALK mutant system. The calculated binding free energy was consistent with the experimental results. Per-residue binding free energy decomposition showed that the predicted hot-spot residues (LEU1122, LEU/PHE1198, MET1199, GLY1202 and LEU1256) were almost identical across systems. Especially, the GLU1197 residue played an important role in inducing drug-resistance for both inhibitors. The electrostatic interaction of GLU1197, PHE1198 and MET1199 mainly resulted in the resistances of the L1198F and C1156Y/L1198F mutations to 5P8. And the van der Waals interaction energy of LEU1256 residue, and electrostatic energy and entropy change of GLU1197 resulted in the resistances of the C1156Y mutations to VGH. The indicated origins of the drug-resistance in the ALK systems provide a theoretical foundation for the design of potent inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Entropia , Mutação/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Eletricidade Estática
6.
Pestic Biochem Physiol ; 159: 17-21, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400779

RESUMO

Capsella bursa-pastoris is a serious broadleaf weed in winter wheat fields in China. It has evolved high levels of resistance to acetolactate synthase (ALS) inhibiting herbicides and has caused substantial losses of wheat yield in recent years. We monitored the herbicide resistance of Capsella bursa-pastoris collected from 18 regions of Shandong Province in 2009, 2013 and 2017, respectively. Compared with the 2009 populations, the number of populations resistant to florasulam had increased in 2013 and 2017. Resistance to tribenuron-methyl increased in 2013, but decreased in 2017. The 2009 and 2013 populations developed resistance only to tribenuron-methyl, but some 2017 populations developed cross-resistance to imazethapyr and florasulam as well. Mutations in ALS (Pro-197-Thr/Ser/His/Arg/Leu/Gln) were identified in the 2009 and 2013 populations; however, two ALS mutations (Pro197 and/or Trp574) were identified in 2017 plants. Meanwhile, plants containing both point mutations (Pro197 + Trp574) were identified in the 2017 populations. This study demonstrated that target site gene mutations were the main reason for Capsella bursa-pastoris resistance to ALS-inhibiting herbicides. Although target-site mutation is the reason for resistance to ALS-inhibiting herbicides in Capsella bursa-pastoris, the resistance patterns and mutations identified have changed over time.


Assuntos
Acetolactato Sintase/genética , Capsella/efeitos dos fármacos , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Proteínas de Plantas/genética , Sulfonatos de Arila/farmacologia , Capsella/enzimologia , Capsella/genética , Mutação/genética , Ácidos Nicotínicos/farmacologia , Mutação Puntual/genética , Pirimidinas/farmacologia , Sulfonamidas/farmacologia
7.
Pestic Biochem Physiol ; 159: 80-84, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400787

RESUMO

The plastid acetyl coenzyme carboxylase (ACCase) Trp1999Leu mutation was identified in a Beckmannia syzigachne population resistant to fenoxaprop-p-ethyl. The pattern of cross-resistance for the Trp1999Leu mutation is still ambiguous. In this paper, mutant homozygote (1999Leu/Leu, RR) and wild type (1999Trp/Trp, SS) B. syzigachne plants with the same genetic background were purified from the JS-26 population using the dCAPS method. The activity of ACCase in RR and SS was determined. Then, the cross-resistance pattern to ACCase inhibiting herbicides of the Trp1999Leu mutation was determined using the whole-plant method. ACCase activity showed that the Trp1999Leu mutation decreased ACCase sensitivity to fenoxaprop-p-ethyl by 2.73-fold. A dose-response experiment indicated that the Trp1999Leu mutation conferred high resistance to quizalofop-p-ethyl (20.29-fold), metamifop (12.22-fold) and pinoxaden (18.60-fold), moderate resistance to fenoxaprop-p-ethyl (8.20-fold) and sethoxydim (6.38-fold), low resistance to cyhalofop-butyl (2.73-fold) and no resistance to clodinafop-propargyl (1.42 fold) and clethodim (1.59-fold). This is the first report of the role of Trp1999Leu in fenoxaprop-p-ethyl resistance and of the patterns of cross-resistance to ACCase-inhibiting herbicides in B. syzigachne.


Assuntos
Acetil-CoA Carboxilase/genética , Herbicidas/farmacologia , Poaceae/efeitos dos fármacos , Poaceae/genética , Anilidas/farmacologia , Benzoxazóis/farmacologia , Cicloexanonas/farmacologia , Resistência a Herbicidas/genética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Mutação/genética , Propionatos/farmacologia , Piridinas/farmacologia , Quinoxalinas/farmacologia
8.
Pestic Biochem Physiol ; 158: 12-17, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378346

RESUMO

Lithospermum arvense is a troublesome dicotyledonous winter annual weed of wheat in China. A L. arvense population (HN01) suspected of being resistant to acetolactate synthase (ALS) inhibitors was found in Henan Province, China. This study aimed to testify the sensitivity of this HN01 population to eight herbicides from 3 different modes of action, and to explore the potential target-site-resistance mechanism to tribenuron-methyl. The whole-plant bioassays indicated that the population was highly resistant to tribenuron-methyl (SU, 350-fold), pyrithiobac sodium (PTB, 151-fold), pyroxsulam (TP, 62.7-fold), florasulam (TP, 80.6-fold), and imazethapyr (IMI, 136-fold), but was sensitive to carfentrazone-ethyl and fluroxypyr-meptyl. ALS gene sequencing revealed that the Trp (TGG) was substituted by Leu (TTG) at codon 574 in resistant plants. In in vitro ALS assays, the concentration of tribenuron-methyl required to inhibit 50% ALS activity (I50) for HN01 was 117-fold greater than that required to inhibit a susceptible population (HN05), indicating that resistance was due to reduced sensitivity of the ALS enzyme to tribenuron-methyl. To the best of our knowledge, this is the first report of ALS gene Trp-574-Leu amino acid mutation confer resistance to tribenuron-methyl in L. arvense.


Assuntos
Acetolactato Sintase/genética , Lithospermum/efeitos dos fármacos , Lithospermum/enzimologia , Mutação/genética , Sulfonatos de Arila/toxicidade , Benzoatos/toxicidade , Resistência a Herbicidas/genética , Herbicidas/toxicidade , Lithospermum/genética , Ácidos Nicotínicos/toxicidade , Proteínas de Plantas/genética , Pirimidinas/toxicidade , Sulfonamidas/toxicidade
9.
Pestic Biochem Physiol ; 158: 32-39, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378358

RESUMO

Mutations in the GABA-gated chloride channel are associated with resistance to cyclodiene organochlorine and phenyl pyrazole insecticides. The best characterised of these is A301S, which was initially identified in a Dieldrin resistant strain of Drosophila melanogaster. The orthologous mutation has been found in a variety of different crop pests including the diamond back moth Plutella xylostella. However, the contribution of this mutation to resistance in this species remains unclear. We have used the CRISPR/Cas9 system in order to edit Plutella xylostella PxGABARalpha1 to Serine at the 301 orthologous position (282 in PxGABARalpha1) in an insecticide sensitive strain isolated from Vero Beach (VB) USA. In this edited line, no high level of resistance is conferred to Dieldrin, Endosulfan or Fipronil, rather only a subtle shift in sensitivity which could not confer commercially important resistance. We conclude that the high level of commercial resistance to cyclodiene organochlorine and phenyl pyrazole insecticides observed in some field isolates of Plutella xylostella cannot arise from A282S in PxGABARalpha1 alone.


Assuntos
Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Animais , Sistemas CRISPR-Cas/genética , Dieldrin/farmacologia , Endossulfano/farmacologia , Resistência a Inseticidas/genética , Mariposas/genética , Mutação/genética , Pirazóis/farmacologia , Receptores de GABA-A/genética
10.
Pestic Biochem Physiol ; 158: 77-87, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378364

RESUMO

Pyrethroid-resistance in onion thrips, Thrips tabaci, has been reported in many countries including Japan. Identifying factors of the resistance is important to correctly monitoring the resistance in field populations. To identify pyrethroid-resistance related genes in T. tabaci in Japan, we performed RNA-Seq analysis of seven T. tabaci strains including two pyrethroid-resistant and five pyrethroid-susceptible strains. We identified a pair of single point mutations, T929I and K1774N, introducing two amino acid mutations, in the voltage-gated sodium channel gene, a pyrethroid target gene, in the two resistant strains. The K1774N is a newly identified mutation located in the fourth repeat domain of the sodium channel. Genotyping analysis of field-collected populations showed that most of the T. tabaci individuals in resistant populations carried the mutation pair, indicating that the mutation pair is closely associated with pyrethroid-resistance in Japan. Another resistance-related mutation, M918L, was also identified in part of the resistant populations. Most of the individuals with the mutation pair were arrhenotokous while all individuals with the M918L single mutation were thelytokous. The result of differentially expressed gene analysis revealed a small number of up-regulated detoxification genes in each resistant strain which might be involved in resistance to pyrethroid. However, no up-regulated detoxification genes common to the two resistant strains were detected. Our results indicate that the mutation pair in the sodium channel gene is the most important target for monitoring pyrethroid-resistance in T. tabaci, and that pyrethroid-resistant arrhenotokous individuals with the mutation pair are likely to be widely distributed in Japan.


Assuntos
Piretrinas/farmacologia , Tisanópteros/efeitos dos fármacos , Tisanópteros/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Japão , Mutação/genética , Mutação Puntual/genética , Tisanópteros/genética , Canais de Sódio Disparados por Voltagem/genética
11.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(8): 596-601, 2019 Aug 12.
Artigo em Chinês | MEDLINE | ID: mdl-31378021

RESUMO

Objective: To evaluate the feasibility of cell-free tumor DNA in pleural effusion supernatant for assessing the tumor mutational burden (TMB) of advanced lung cancers. Methods: From December 2016 to August 2018, 34 lung cancer patients (19 males and 15 females) with pleural effusion were enrolled at Zhongshan Hospital, Fudan University. The median age of the patients was 65 (range, 34-85) years. Before systemic or local antitumor therapy, tumor specific mutations in tumor tissue, pleural effusion supernatant, pleural effusion sediment, and plasma samples from these patients were examined using targeted next-generation sequencing, and TMB levels were calculated respectively. Subgroup analysis was based on smoking history and driver mutation status. Statistical differences were determined using SPSS 16.0 software, and individual groups were compared using the one-way analysis of variance (ANOVA) and LSD-t test. Results: The median TMB level of pleural effusion supernatant was 6.23 mutations/Mb, similar to that of tumor tissue (6.23 vs 6.86 mutations/Mb, t=1.174, P=0.245), but significantly higher than that of pleural effusion sediment (2.49 mutations/Mb, t=3.044, P=0.003) and plasma (2.49 mutations/Mb, t=2.464, P=0.016). Compared with tumor tissue in TMB assessment, pleural effusion supernatant had a positive percentage agreement of 52% (9/17), and a negative percentage agreement of 65% (11/17). Subgroup analysis showed that the TMB level was higher in smokers (n=11) than that in non-smokers (n=23, 14.4 vs 5.4 mutations/Mb, t=3.238, P=0.003). Conclusion: For advanced lung cancer patients with pleural effusion, pleural effusion supernatant is a promising substitute to tumor tissue for TMB assessment, which is a potential biomarker for immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , DNA Tumoral Circulante , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Derrame Pleural , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Resultado do Tratamento
12.
Arch Endocrinol Metab ; 63(4): 385-393, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365626

RESUMO

INTRODUCTION: Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. MATERIALS AND METHODS: Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. RESULTS: All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. CONCLUSIONS: This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.


Assuntos
Adenoma/terapia , Gigantismo/terapia , Neoplasias Hipofisárias/terapia , Adenoma/diagnóstico , Adolescente , Colômbia , Seguimentos , Gigantismo/diagnóstico , Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mutação/genética , Linhagem , Neoplasias Hipofisárias/diagnóstico , Estudos Retrospectivos , Distribuição por Sexo , Resultado do Tratamento , Adulto Jovem
15.
Zhonghua Er Ke Za Zhi ; 57(7): 543-547, 2019 Jul 02.
Artigo em Chinês | MEDLINE | ID: mdl-31269555

RESUMO

Objective: To characterize fever-induced paroxysmal weakness and encephalopathy (FIPWE) caused by ATP1A3 gene pathogenic variant. Methods: Phenotypic and genotypic characteristics of 4 FIPWE patients (3 boys and 1 girl), who were ascertained from October 2016 to March 2018 in Beijing Children's Hospital due to ATP1A3 heterozygous variants, were retrospectively analyzed. The whole exsome sequencing was used for genetic testing. Results: The onset ages of 4 patients were 2 years and 9 months, 2 years and 4 months, 8 months, 2 years and 5 months respectively. The episode ranged from 1 to 3 times, and at 3 months to 2 years and 10 months intervals. All 4 patients had symptoms of limb weakness and encephalopathy, accompanied with mild to severe ataxia or athetosis. The tendon reflex was absent in all patients, and the Babinski's sign was positive. Three patients had dysphagia and 3 patients had slurred speech. Three patients had abnormal eye movements, including strabismus and opsoclonus. None of the 4 patients exhibited visual impairment, auditory impairment or talipes cavus. The duration of acute phase ranged from 1 week to 3 months. In 3 relapsing patients, symptoms became progressively worse, with relapses occurring frequently and recovery being more difficult, and various sequelae were found after the last relapse. All patients carried heterozygous variant in ATP1A3 gene. The missense variants result in the substitution of an arginine residue at position 756. Three variants were identified, including C. 2267G > T (p. R756L) (1 case), C. 2266C > T (p. R756C) (2 cases), and C. 2267G > A (p. R756H) (1 case). Three were de novo and one inherited from his father, but the grandparents did not carry the variant. All variants were reported as pathogenic. Conclusions: FIPWE is one of new clinical phenotypes of ATP1A3 spectrum disease and most cases are sporadic. The missense variants result in the substitution of an arginine residue at position 756. This report provided insights into the phenotype-genotype association in patients with FIPWE caused by pathogenic variants of ATP1A3.


Assuntos
Encefalopatias/etiologia , Febre/complicações , Febre/genética , Debilidade Muscular/complicações , Mutação/genética , ATPase Trocadora de Sódio-Potássio/genética , Criança , Pré-Escolar , Feminino , Testes Genéticos , Genótipo , Humanos , Masculino , Fenótipo , Estudos Retrospectivos
16.
BMC Evol Biol ; 19(1): 147, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324139

RESUMO

BACKGROUND: For the understanding of human nature, the evolutionary roots of human moral behaviour are a key precondition. Our question is as follows: Can the altruistic moral rule "Risk your life to save your family members, if you want them to save your life" be evolutionary stable? There are three research approaches to investigate this problem: kin selection, group selection and population genetics modelling. The present study is strictly based on the last approach. RESULTS: We consider monogamous and exogamous families, where at an autosomal locus, dominant-recessive alleles determine the phenotypes in a sexual population. Since all individuals' survival rate is determined by their altruistic family members, we introduce a new population genetics model based on the mating table approach and adapt the verbal definition of evolutionary stability to genotypes. In general, when the resident is recessive, a homozygote is an evolutionarily stable genotype (ESG), if the number of survivors of the resident genotype of the resident homozygote family is greater than that of non-resident heterozygote survivors of the family of the resident homozygote and mutant heterozygote genotypes. Using the introduced genotype dynamics we proved that in the recessive case ESG implies local stability of the altruistic genotype. We apply our general ESG conditions for self-sacrificing life history strategy when the number of new-born offspring does not depend on interactions within the family and the interactions are additive. We find that in this case our ESG conditions give back Hamilton's rule for evolutionary stability of the self-sacrificing life history strategy. CONCLUSIONS: In spite of the fact that the kidney transplantations was not a selection factor during the earlier human evolution, nowadays "self-sacrificing" can be observed in the live donor kidney transplantations, when the donor is one of the family members. It seems that selection for self-sacrificing in family produced an innate moral tendency in modulating social cognition in human brain.


Assuntos
Evolução Biológica , Estágios do Ciclo de Vida , Comportamento Sexual , Animais , Genética Populacional , Genótipo , Humanos , Mutação/genética , Fenótipo
17.
Pestic Biochem Physiol ; 157: 53-59, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153477

RESUMO

Indian hedge mustard (Sisymbrium orientale) (IHM) is an important broadleaf weed across southern Australia. Resistance to sulfonylurea (SU) herbicides that inhibit acetohydroxyacid synthase (AHAS) is extensive in Australia, but resistance to imidazolinone (IMI) herbicides has only been reported recently. The AHAS-mutation profile of 65 IHM populations collected randomly from cropped fields was investigated to better understand the extent and types of resistance present. Resistance to SU herbicides was present in 40% of the populations and resistance to IMI herbicides in 11%. Mutations were identified in SoAHAS by sequence analysis, and included previously reported amino-acid substitutions at Pro197 and Trp574, but also new substitutions at Pro197 and Asp376 for this species. One population with possible non-target-site resistance was identified. Germination studies with fresh seed found no significant effect by mutations in SoAHAS on germination; however, population factors had a large effect on germination in S. orientale. Resistance to AHAS-inhibiting herbicides in populations of S. orientale is endowed by mutations in SoAHAS in all but one population examined. Mutations at Pro197 conferring resistance to SU herbicides were most common, while mutations at Trp574 that provide resistance to IMI herbicides are also present.


Assuntos
Acetolactato Sintase/genética , Herbicidas/farmacologia , Mostardeira/genética , Mutação/genética , Austrália , Germinação/efeitos dos fármacos , Germinação/genética , Mostardeira/efeitos dos fármacos
19.
BMC Bioinformatics ; 20(1): 324, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31195961

RESUMO

BACKGROUND: As DNA sequencing technologies are improving and getting cheaper, genomic data can be utilized for diagnosis of many diseases such as cancer. Human raw genome data is huge in size for computational systems. Therefore, there is a need for a compact and accurate representation of the valuable information in DNA. The occurrence of complex genetic disorders often results from multiple gene mutations. The effect of each mutation is not equal for the development of a disease. Inspired from the field of information retrieval, we propose using the term frequency (tf) and BM25 term weighting measures with the inverse document frequency (idf) and relevance frequency (rf) measures to weight genes based on their mutations. The underlying assumption is that the more mutations a gene has in patients with a certain disease and the less mutations it has in other patients, the more discriminative that gene is. RESULTS: We evaluated the proposed representations on the task of cancer type classification. We applied various machine learning techniques using the tf-idf and tf-rf schemes and their BM25 versions. Our results show that the BM25-tf-rf representation leads to improved classification accuracy and f-score values compared to the other representations. The highest accuracy (76.44%) and f-score (76.95%) are achieved with the BM25-tf-rf based data representation. CONCLUSIONS: As a result of our experiments, the BM25-tf-rf scheme and the proposed neural network model is shown to be the best performing classification system for our case study of cancer type classification. This system is further utilized for causal gene analysis. Examples from the most effective genes that are used for decision making are found to be in the literature as target or causal genes.


Assuntos
Genômica/métodos , Modelos Genéticos , Modelos Estatísticos , Mutação/genética , Bases de Dados Genéticas , Éxons/genética , Humanos , Íntrons/genética , Aprendizado de Máquina , Neoplasias/genética , Redes Neurais (Computação)
20.
Plant Sci ; 285: 200-213, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203885

RESUMO

NONRACE-SPECIFIC DISEASE RESISTANCE (NDR1) is a widely characterized gene that plays a key role in defense against multiple bacterial, fungal, oomycete and nematode plant pathogens. NDR1 is required for activation of resistance by multiple NB and LRR-containing (NLR) protein immune sensors and contributes to basal defense. The role of NDR1 in positively regulating salicylic acid (SA)-mediated plant defense responses is well documented. However, ndr1-1 plants flower earlier and show accelerated development in comparison to wild type (WT) Arabidopsis plants, indicating that NDR1 is a negative regulator of flowering and growth. Exogenous application of gibberellic acid (GA) further accelerates the early flowering phenotype in ndr1-1 plants, while the GA biosynthesis inhibitor paclobutrazol attenuated the early flowering phenotype of ndr1-1, but not to WT levels, suggesting partial resistance to paclobutrazol and enhanced GA response in ndr1-1 plants. Mass spectroscopy analyses confirmed that ndr1-1 plants have 30-40% higher levels of GA3 and GA4, while expression of various GA metabolic genes and major flowering regulatory genes is also altered in the ndr1-1 mutant. Taken together this study provides evidence of crosstalk between the ndr1-1-mediated defense and GA-regulated developmental programs in plants.


Assuntos
Arabidopsis/genética , Flores/crescimento & desenvolvimento , Giberelinas/fisiologia , Reguladores de Crescimento de Planta/fisiologia , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/fisiologia , Proteínas de Arabidopsis/fisiologia , Resistência à Doença/genética , Resistência à Doença/fisiologia , Giberelinas/metabolismo , Mutação/genética , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Reguladores de Crescimento de Planta/metabolismo , Ácido Salicílico/metabolismo , Fatores de Transcrição/fisiologia , Transcriptoma , Verticillium
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