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1.
Bioresour Technol ; 282: 118-124, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30852331

RESUMO

This study investigated the biomass/lipid production, nutrient removal and fatty acid composition of an isolated mixotrophic microalga (Chlorella sp. G-9) cultured in simulated wastewater with different TOC/TN ratio. As the TOC/TN ratio of wastewater increased from 0 to 24, the growth rate of Chlorella sp. G-9 increased gradually, but did not increase further at 30. Nutrient removal was related to microalgae growth. In the wastewater with TOC/TN ratio of 24 and 30, 99.58% and 99.61% nitrogen was removed, respectively. In conditions of initial TOC/TN ratios of 24 and 30, Chlorella sp. G-9 could accumulate lipid as high as 35.3% and 36.5%, respectively. The corresponding lipid productivities were 34.2 and 32.6 mg L-1 d-1, respectively, which were 13.7 and 13.0 times higher than those in photoautotrophic condition. Increasing the initial TOC/TN ratio of the wastewater could slightly increase the saturated degree in fatty acid, thereby improving the stability of biodiesel.


Assuntos
Carbono/metabolismo , Chlorella/metabolismo , Lipídeos/biossíntese , Microalgas/metabolismo , Nitrogênio/metabolismo , Nutrientes , Águas Residuárias/química , Biomassa , Ácidos Graxos/metabolismo
2.
Molecules ; 23(11)2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30400218

RESUMO

Selenium is a trace element essential for human health that has received considerable attention due to its nutritional value. Selenium's bioactivity and toxicity are closely related to its chemical form, and several studies have suggested that the organic form of selenium (i.e., selenomethionine) is more bioavailable and less toxic than its inorganic form (i.e., sodium selenite). Probiotics, especially Bifidobacteriium and Lactobacillus spp., have received increasing attention in recent years, due to their intestinal microbial balancing effects and nutraceutical benefits. Recently, the bioconversion (a.k.a biotransformation) of various bioactive molecules (e.g., minerals, primary and secondary metabolites) using probiotics has been investigated to improve substrate biofunctional properties. However, there have been few reports of inorganic selenium conversion into its organic form using Bifidobacterium and Lactobacillus spp. Here we report that the biosynthesis of organic selenium was accomplished using the whole cell bioconversion of sodium selenite under controlled Bifidobacterium bifidum BGN4 culture conditions. The total amount of organic and inorganic selenium was quantified using an inductively coupled plasma-atomic emission spectrometer (ICP-AES). The selenium species were separated via anion-exchange chromatography and analyzed with inductively coupled plasma-mass spectrometry (ICP-MS). Our findings indicated that the maximum level of organic selenium was 207.5 µg/g in selenium-enriched B. bifidum BGN4. Selenomethionine was the main organic selenium in selenium-enriched B. bifidum BGN4 (169.6 µg/g). Considering that B. bifidum BGN4 is a commercial probiotic strain used in the functional food industry with clinically proven beneficial effects, selenium-enriched B. bifidum BGN4 has the potential to provide dual healthy functions as a daily supplement of selenium and regulator of intestinal bacteria. This is the first report on the production of organic selenium using B. bifidum spp.

3.
Genet Med ; 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30158690

RESUMO

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective. METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

4.
ACS Med Chem Lett ; 9(7): 761-767, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034615

RESUMO

The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.

5.
Nat Commun ; 9(1): 2055, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29795383

RESUMO

Electrical interactions between bacteria and the environment are delicate and essential. In this study, an external electrical current is applied to capacitive titania nanotubes doped with carbon (TNT-C) to evaluate the effects on bacteria killing and the underlying mechanism is investigated. When TNT-C is charged, post-charging antibacterial effects proportional to the capacitance are observed. This capacitance-based antibacterial system works well with both direct and alternating current (DC, AC) and the higher discharging capacity in the positive DC (DC+) group leads to better antibacterial performance. Extracellular electron transfer observed during early contact contributes to the surface-dependent post-charging antibacterial process. Physiologically, the electrical interaction deforms the bacteria morphology and elevates the intracellular reactive oxygen species level without impairing the growth of osteoblasts. Our finding spurs the design of light-independent antibacterial materials and provides insights into the use of electricity to modify biomaterials to complement other bacteria killing measures such as light irradiation.

6.
Adv Sci (Weinh) ; 5(2): 1700678, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29610729

RESUMO

Understanding cell-biomaterial interactions is critical for the control of cell fate for tissue engineering and regenerative medicine. Here, cerium oxide nanoparticles (CeONPs) are applied at different Ce4+/Ce3+ ratios (i.e., 0.46, 1.23, and 3.23) to titanium substrate surfaces by magnetron sputtering and vacuum annealing. Evaluation of the cytotoxicity of the modified surface to cultured rat bone marrow mesenchymal stem cells (BMSCs) reveals that the cytocompatibility and cell proliferation are proportional to the increases in Ce4+/Ce3+ ratio on titanium surface. The bone formation capability induced by these surface modified titanium alloys is evaluated by implanting various CeONP samples into the intramedullary cavity of rat femur for 8 weeks. New bone formation adjacent to the implant shows a close relationship to the surface Ce4+/Ce3+ ratio; higher Ce4+/Ce3+ ratio achieves better osseointegration. The mechanism of this in vivo outcome is explored by culturing rat BMSCs and RAW264.7 murine macrophages on CeONP samples for different durations. The improvement in osteogenic differentiation capability of BMSCs is directly proportional to the increased Ce4+/Ce3+ ratio on the titanium surface. Increases in the Ce4+/Ce3+ ratio also elevate the polarization of the M2 phenotype of RAW264.7 murine macrophages, particularly with respect to the healing-associated M2 percentage and anti-inflammatory cytokine secretion. The manipulation of valence states of CeONPs appears to provide an effective modulation of the osteogenic capability of stem cells and the M2 polarization of macrophages, resulting in favorable outcomes of new bone formation and osseointegration.

7.
J Control Release ; 253: 110-121, 2017 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-28302581

RESUMO

Overexpression of erythroblastosis virus E26 oncogene homolog 1 (ETS1) gene is correlated with both tumor progression and poor response to chemotherapy in cancer treatment, and the exploitation of RNA interference (RNAi) technology to downregulate ETS1 seems to be a promising approach to reverse multidrug-resistant cancer cells to chemotherapy. Hence, the RNAi-based nanomedicine which is able to simultaneously downregulate ETS1 expression and to deliver chemotherapeutic agents may improve multidrug-resistant cancer therapy synergistically. In this study, we developed a supramolecular nanoassembly that could deliver siRNA targeting ETS1 (siETS1) and doxorubicin (DOX) as an effective nanomedicine to achieve successful chemotherapy towards multidrug-resistant breast cancer. The nanotherapeutic system was prepared by loading adamantane-conjugated doxorubicin (AD) into polyethyleneimine-modified (2-hydroxypropyl)-γ-cyclodextrin (HP) through the supramolecular assembly to form AD-loaded HP (HPAD), followed by electrostatically-driven self-assembly between siETS1 and HPAD. When the HPAD/siETS1 nanoassemblies were delivered into drug-resistant MCF-7/ADR cells, the drug efflux was significantly reduced as a result of simultaneous silencing of ETS1 and MDR1 genes. Importantly, the HPAD/siETS1 nanoassembly could enhance drug residence time at tumor site, and effectively inhibit drug-resistant tumor growth due to the inhibition of angiogenesis and necrosis in tumor tissues. Western blot analysis indicated that the gene expression of both ETS1 and MDR1 in vivo was considerably downregulated after the drug-resistant tumor-bearing mouse was treated with HPAD/siETS1 nanoassemblies. This study offers a new therapeutic delivery strategy targeting ETS1 for the effective multidrug-resistant chemotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Proteína Proto-Oncogênica c-ets-1/genética , RNA Interferente Pequeno/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Proteínas de Fluorescência Verde/genética , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoimina/química , Proteína Proto-Oncogênica c-ets-1/metabolismo , Interferência de RNA , RNA Interferente Pequeno/química , RNA Interferente Pequeno/uso terapêutico , Carga Tumoral , gama-Ciclodextrinas/química
8.
Biomaterials ; 129: 83-97, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28329693

RESUMO

Cancer treatment can in principle be enhanced by the synergistic effects of chemo- and nucleic acid-based combination therapies but the lack of efficient drug nanocarriers and occurrence of multidrug resistance (MDR) are major obstacles adversely affecting the effectiveness. Herein, a lanthanide-integrated supramolecular polymeric nanoassembly that delivers anticancer drugs and siRNA for more effective cancer therapy is described. This nanotherapeutic system is prepared by loading adamantane-modified doxorubicin (Dox) into polyethylenimine-crosslinked-γ-cyclodextrin (PC) through the supramolecular assembly to form the interior Dox-loaded PC (PCD) followed by electrostatically driven self-assembly of siRNA and PCD to produce the PCD/siRNA nanocomplexes. The PCD/siRNA nanocomplex is further decorated with the exterior neodymium (Nd)-integrated PC (Nd-PC) layer to obtain the PCD/siRNA/Nd-PC nanoassembly in which the interior PC serves as an efficient carrier for simultaneous delivery of Dox and siRNA to the human breast cancer cell line, Dox-resistant MCF-7 (MCF-7/ADR) both in vitro and in vivo. The exterior Nd-PC layer improves the drug sensitivity to the MCF-7/ADR cells as a result of the improved nanoassembly uptake, reduced drug efflux, and enhanced apoptosis, as evidenced by multiple regulation of a series of intracellular proteins related to MDR. Furthermore, in vivo delivery of the PCD/siRNA/Nd-PC nanoassembly is demonstrated to inhibit tumor growth in the mouse model with MCF-7/ADR tumor xenografts as a result of reduced angiogenesis and increased necrosis at the tumor site. This study reveals a simple and universal strategy to transform polymer-based nanoassemblies into advanced organic-inorganic nanotherapeutics suitable for cancer MDR therapy.


Assuntos
Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Elementos da Série dos Lantanídeos/química , Nanopartículas/química , Polímeros/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endocitose , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Neodímio/química , Polietilenoimina/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , gama-Ciclodextrinas/química
9.
Biomaterials ; 124: 25-34, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28182874

RESUMO

Although titanium embedded with silver nanoparticles (Ag-NPs@Ti) are suitable for biomedical implants because of the good cytocompatibility and antibacterial characteristics, the exact antibacterial mechanism is not well understood. In the present work, the antibacterial mechanisms of Ag-NPs@Ti prepared by plasma immersion ion implantation (PIII) are explored in details. The antibacterial effects of the Ag-NPs depend on the conductivity of the substrate revealing the importance of electron transfer in the antibacterial process. In addition, electron transfer between the Ag-NPs and titanium substrate produces bursts of reactive oxygen species (ROS) in both the bacteria cells and culture medium. ROS leads to bacteria death by inducing intracellular oxidation, membrane potential variation, and cellular contents release and the antibacterial ability of Ag-NPs@Ti is inhibited appreciably after adding ROS scavengers. Even though ROS signals are detected from osteoblasts cultured on Ag-NPs@Ti, the cell compatibility is not impaired. This electron-transfer-based antibacterial process which produces ROS provides insights into the design of biomaterials with both antibacterial properties and cytocompatibility.


Assuntos
Antibacterianos/administração & dosagem , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Prata/administração & dosagem , Prata/química , Titânio/química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/química , Condutividade Elétrica , Transporte de Elétrons , Teste de Materiais , Nanopartículas Metálicas/química
10.
Genet Med ; 19(8): 936-944, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28125085

RESUMO

PURPOSE: To investigate pan-ethnic SMN1 copy-number and sequence variation by hybridization-based target enrichment coupled with massively parallel sequencing or next-generation sequencing (NGS). METHODS: NGS reads aligned to SMN1 and SMN2 exon 7 were quantified to determine the total combined copy number of SMN1 and SMN2. The ratio of SMN1 to SMN2 was calculated based on a single-nucleotide difference that distinguishes the two genes. SMN1 copy-number results were compared between the NGS and quantitative polymerase chain reaction and/or multiplex ligation-dependent probe amplification. The NGS data set was also queried for the g.27134T>G single-nucleotide polymorphism (SNP) and other SMN1 sequence pathogenic variants. RESULTS: The sensitivity of the test to detect spinal muscular atrophy (SMA) carriers with one copy of SMN1 was 100% (95% confidence interval (CI): 95.9-100%; n = 90) and specificity was 99.6% (95% CI: 99.4-99.7%; n = 6,648). Detection of the g.27134T>G SNP by NGS was 100% concordant with an restriction fragment-length polymorphism method (n = 493). Ten single-nucleotide variants in SMN1 were detectable by NGS and confirmed by gene-specific amplicon-based sequencing. This comprehensive approach yielded SMA carrier detection rates of 90.3-95.0% in five ethnic groups studied. CONCLUSION: We have developed a novel, comprehensive SMN1 copy-number and sequence variant analysis method by NGS that demonstrated improved SMA carrier detection rates across the entire population examined.Genet Med advance online publication 19 January 2017.


Assuntos
Triagem de Portadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Atrofia Muscular Espinal/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Dosagem de Genes , Humanos , Atrofia Muscular Espinal/etnologia , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteína 2 de Sobrevivência do Neurônio Motor/genética
11.
ACS Appl Mater Interfaces ; 8(37): 24509-16, 2016 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-27580379

RESUMO

Titania loaded with noble metal nanoparticles exhibits enhanced photocatalytic killing of bacteria under light illumination due to the localized surface plasmon resonance (LSPR) property. It has been shown recently that loading with Au or Ag can also endow TiO2 with the antibacterial ability in the absence of light. In this work, the antibacterial mechanism of Au-loaded TiO2 nanotubes (Au@TiO2-NT) in the dark environment is studied, and a novel type of extracellular electron transfer (EET) between the bacteria and the surface of the materials is observed to cause bacteria death. Although the EET-induced bacteria current is similar to the LSPR-related photocurrent, the former takes place without light, and no reactive oxygen species (ROS) are produced during the process. The EET is also different from that commonly attributed to microbial fuel cells (MFC) because it is dominated mainly by the materials' surface, but not the bacteria, and the environment is aerobic. EET on the Au@TiO2-NT surface kills Staphylococcus aureus, but if it is combined with special MFC bacteria, the efficiency of MFC may be improved significantly.

12.
ACS Appl Mater Interfaces ; 8(15): 9662-73, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-27043895

RESUMO

Magnesium-based materials are preferred in temporary orthopedic implants because of their biodegradability, mechanical properties, and intrinsic antibacterial properties. However, the fundamental mechanism of bacteria killing and roles of various factors are not clearly understood. In this study, we performed a systematic study of the antibacterial properties of two common Mg-based materials using a biofilm forming bacterium. Complete annihilation of the initial 3 × 10(4) bacteria is achieved with both materials in 0.1 mL LB medium in 24 h, whereas in the control, they proliferate to 10(10). The bacteria are killed more effectively in the solution than on the surface, and the bacteria killing efficiency depends more on the concentrations of the magnesium ions and hydroxyl ions than the corrosion rate. The killing process is reproduced using formula solutions, and killing is revealed to stem from the synergetic effects of alkalinity and magnesium ions instead of either one of them or Mg(OH)2 precipitate. Reactive oxygen species (ROS) are detected from the bacteria during the killing process but are not likely produced by the redox reaction directly, because they are detected at least 3 h after the reaction has commenced. The average cell size increases during the killing process, suggesting that the bacteria have difficulty with normal division which also contributes to the reduced bacteria population.


Assuntos
Antibacterianos/farmacologia , Materiais Biocompatíveis/farmacologia , Magnésio/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Contagem de Colônia Microbiana , Corrosão , Concentração de Íons de Hidrogênio , Íons , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Soluções , Staphylococcus aureus/citologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Propriedades de Superfície
13.
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(6): 4433-4435, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26486169

RESUMO

The banjofish (Banjos banjos) is the only species in the monotypic genus Banjos and in the family Banjosidae. To understand the phylogenetic relationship of banjofish in teleost, we firstly determined the complete mitochondrial genome of banjofish. The entire mitochondrial genome of banjofish is 16 485 bp in length, including 13 protein-coding genes and 2 ribosomal RNA genes (rRNA), 22 transfer RNA genes (tRNA) and a control region (CR). The overall base composition is T, 26.2%; C, 29.2%; A, 28.6% and G, 16.0%. The central conserved sequence blocks (CSB) were identified and the core sequence (ACATATATGT) of terminal-associated sequences was recognized in the control region. The gene arrangement, base composition, and tRNA structures of the complete mitochondrial genome of banjofish is consistent with those of other teleost. The complete mitochondrial genome of banjofish was used to construct phylogenetic tree, which shows that banjofish is clustered with the fishes of the family Histiopteridae. We expect that the availability of mitochondrial genome of banjofish will facilitate the further investigations of the taxonomic resolution, biogeography and molecular systematic.


Assuntos
Peixes/genética , Genoma Mitocondrial/genética , Mitocôndrias/genética , Animais , Composição de Bases/genética , Sequência Conservada/genética , DNA Mitocondrial/genética , Ordem dos Genes/genética , Genes Mitocondriais/genética , Filogenia , RNA Ribossômico/genética , RNA de Transferência/genética , Análise de Sequência de DNA/métodos
14.
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(6): 4436-4438, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26487483

RESUMO

In the present study, the complete mitochondrial genome of Serranidae sp. was determined first. The entire mitochondrial genome of Serranidae sp. is 16 512 bp in length, containing 13 protein-coding genes and 2 ribosomal RNA genes (rRNA), 22 transfer RNA genes (tRNA) and 2 main non-coding regions (the control region and the origin of the light-strand replication). The gene arrangement, base composition and tRNA structures of Serranidae sp. are similar to most of the bony fishes. The central conserved sequence blocks (CSB-1, CSB-2, and CSB-3) and the core sequence (ACATATATGT) of terminal-associated sequences were recognized in the control region. Meanwhile, the conserved motif 5'-GCCGG-3' was identified in the origin of light-strand replication of Serranidae sp. Phylogenetic tree, which is constructed based on the complete mitochondrial genome sequences of Serranidae sp., shows that Serranidae sp. is clustered with the fishes of the family Pentacerotidae. We expect that the mitochondrial genome of Serranidae sp. would play a key role in phylogenetic analysis of Serranidae.


Assuntos
Genoma Mitocondrial/genética , Mitocôndrias/genética , Perciformes/genética , Animais , Composição de Bases/genética , Teorema de Bayes , Sequência Conservada/genética , Ordem dos Genes/genética , Genes Mitocondriais/genética , Genes de RNAr/genética , Filogenia , RNA de Transferência/genética , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos
15.
Eur J Hum Genet ; 23(7): 915-21, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25315662

RESUMO

Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.


Assuntos
Transtorno Autístico/genética , Deficiências do Desenvolvimento/genética , Duplicação Gênica , Predisposição Genética para Doença/genética , Proteínas Serina-Treonina Quinases/genética , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Autístico/diagnóstico , Sequência de Bases , Criança , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente , Padrões de Herança , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Megalencefalia/diagnóstico , Megalencefalia/genética , Dados de Sequência Molecular , Análise de Sequência de DNA , Inativação do Cromossomo X
16.
BMC Med Genet ; 15: 128, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25472632

RESUMO

BACKGROUND: Point mutations or genomic deletions of FOXF1 result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. However, the clinical consequences of the constitutively increased dosage of FOXF1 are unknown. METHODS: Copy-number variations and their parental origin were identified using a combination of array CGH, long-range PCR, DNA sequencing, and microsatellite analyses. Minisatellite sequences across different species were compared using a gready clustering algorithm and genome-wide analysis of the distribution of minisatellite sequences was performed using R statistical software. RESULTS: We report four unrelated families with 16q24.1 duplications encompassing entire FOXF1. In a 4-year-old boy with speech delay and a café-au-lait macule, we identified an ~15 kb 16q24.1 duplication inherited from the reportedly healthy father, in addition to a de novo ~1.09 Mb mosaic 17q11.2 NF1 deletion. In a 13-year-old patient with autism and mood disorder, we found an ~0.3 Mb duplication harboring FOXF1 and an ~0.5 Mb 16q23.3 duplication, both inherited from the father with bipolar disorder. In a 47-year old patient with pyloric stenosis, mesenterium commune, and aplasia of the appendix, we identified an ~0.4 Mb duplication in 16q24.1 encompassing 16 genes including FOXF1. The patient transmitted the duplication to her daughter, who presented with similar symptoms. In a fourth patient with speech and motor delay, and borderline intellectual disability, we identified an ~1.7 Mb FOXF1 duplication adjacent to a large minisatellite. This duplication has a complex structure and arose de novo on the maternal chromosome, likely as a result of a DNA replication error initiated by the adjacent large tandem repeat. Using bioinformatic and array CGH analyses of the minisatellite, we found a large variation of its size in several different species and individuals, demonstrating both its evolutionarily instability and population polymorphism. CONCLUSIONS: Our data indicate that constitutional duplication of FOXF1 in humans is not associated with any pediatric lung abnormalities. We propose that patients with gut malrotation, pyloric or duodenal stenosis, and gall bladder agenesis should be tested for FOXF1 alterations. We suggest that instability of minisatellites greater than 1 kb can lead to structural variation due to DNA replication errors.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Fatores de Transcrição Forkhead/genética , Duplicação Gênica , Anormalidades Múltiplas/patologia , Adolescente , Animais , Pré-Escolar , Evolução Molecular , Feminino , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Linhagem
17.
J Med Chem ; 57(21): 8817-26, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25313996

RESUMO

An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound 4 to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which 4 can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity.


Assuntos
Anilidas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirrolidinas/metabolismo , Marcadores de Afinidade , Anilidas/farmacologia , Cristalografia por Raios X , Concentração Inibidora 50 , Espectrometria de Massas/métodos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinas/farmacologia , Relação Estrutura-Atividade
18.
Bioresour Technol ; 167: 441-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25006019

RESUMO

This study investigated the microalgae biomass production and nutrients removal efficiency from treated sewage by newly developed membrane photobioreactor in which Chlorella vulgaris was cultured in batch flow mode. Its performance was compared with conventional photobioreactor. The results show that the volumetric microalgae productivity was 39.93 and 10.36 mg L(-1)d(-1) in membrane photobioreactor and conventional photobioreactor, respectively. The nutrients removal rate in membrane photobioreactor was 4.13 mg N L(-1)d(-1) and 0.43 mg P L(-1)d(-1), which was obviously higher than that in conventional photobioreactor (0.59 mg N L(-1)d(-1) and 0.08 mg P L(-1)d(-1)). The better performance of membrane photobioreactor was due to the submerged membrane module in the reactor which acted as a solid-liquid separator and thereby enabled the reactor to operate with higher supply flow rate of cultivation medium. Moreover, in the outflow stage of the membrane photobioreactor, the microalgae culture liquor in the reactor could be further concentrated.


Assuntos
Técnicas de Cultura Celular por Lotes/instrumentação , Técnicas de Cultura Celular por Lotes/métodos , Membranas Artificiais , Microalgas/crescimento & desenvolvimento , Fotobiorreatores/microbiologia , Esgotos/microbiologia , Biomassa , Chlorella vulgaris/crescimento & desenvolvimento , Chlorella vulgaris/metabolismo , Nitrogênio/análise , Fósforo/análise
19.
Small ; 10(19): 4012-9, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24947686

RESUMO

Common methods to prepare SERS (surface-enhanced Raman scattering) probes rely on random conjugation of Raman dyes onto metal nanostructures, but most of the Raman dyes are not located at Raman-intense electromagnetic hotspots thus not contributing to SERS enhancement substantially. Herein, a competitive reaction between transverse gold overgrowth and dye conjugation is described to achieve site selective conjugation of Raman dyes to the hotspots (ends) on gold nanorods (GNRs). The preferential overgrowth on the nanorod side surface creates a barrier to prevent the Raman dyes from binding to the side surface except the ends of the GNRs, where the highest SERS enhancement factors are expected. The SERS enhancement observed from this special structure is dozens of times larger than that from conjugates synthesized by conventional methods. This simple and powerful strategy to prepare SERS probes can be extended to different anisotropic metal nanostructures with electromagnetic hotspots and has immense potential in in-depth SERS-based biological imaging and single-molecule detection.


Assuntos
Nanotecnologia , Nanotubos/química , Análise Espectral Raman , Anisotropia , Corantes/química , Meios de Contraste/química , Radiação Eletromagnética , Ouro/química , Nanopartículas Metálicas/química , Metais/química , Microscopia Eletrônica de Transmissão , Nanoestruturas/química , Espalhamento de Radiação , Ressonância de Plasmônio de Superfície , Propriedades de Superfície
20.
Biomaterials ; 35(1): 479-88, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24103650

RESUMO

Cationic polymer PEI-CyD is doped with Nd by plasma technology to produce the gene vector: Nd@PEI-CyD. Luciferase expression and EGFP transfection experiments performed in vitro reveal that Nd@PEI-CyD has significantly higher transfection efficiency than lipofectamine 2000 and PEI-CyD and the mechanism is studied and proposed. The rare-earth element, Nd, stimulates the energy metabolism of cells, enhances cell uptake of complexes/pDNA, and regulates the cellular pathways. These special features suggest a new strategy involving metal-incorporated non-viral gene vectors.


Assuntos
Técnicas de Transferência de Genes , Vetores Genéticos , Metais Terras Raras/química , Polímeros/química , Sequência de Bases , Primers do DNA , Células HEK293 , Humanos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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