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1.
Proc Natl Acad Sci U S A ; 113(37): E5425-33, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27582469

RESUMO

Testicular tumors, the most common cancer in young men, arise from abnormalities in germ cells during fetal development. Unconventional inheritance for testicular germ cell tumor (TGCT) risk both in humans and mice implicates epigenetic mechanisms. Apolipoprotein B mRNA-editing enzyme complex 1 (APOBEC1) cytidine deaminase and Deadend-1, which are involved in C-to-U RNA editing and microRNA-dependent mRNA silencing, respectively, are potent epigenetic modifiers of TGCT susceptibility in the genetically predisposed 129/Sv inbred mouse strain. Here, we show that partial loss of either APOBEC1 complementation factor (A1CF), the RNA-binding cofactor of APOBEC1 in RNA editing, or Argonaute 2 (AGO2), a key factor in the biogenesis of certain noncoding RNAs, modulates risk for TGCTs and testicular abnormalities in both parent-of-origin and conventional genetic manners. In addition, non-Mendelian inheritance was found among progeny of A1cf and Ago2 mutant intercrosses but not in backcrosses and without fetal loss. Together these findings suggest nonrandom union of gametes rather than meiotic drive or preferential lethality. Finally, this survey also suggested that A1CF contributes to long-term reproductive performance. These results directly implicate the RNA-binding proteins A1CF and AGO2 in the epigenetic control of germ-cell fate, urogenital development, and gamete functions.


Assuntos
Desaminase APOBEC-1/genética , Proteínas Argonautas/genética , Neoplasias Embrionárias de Células Germinativas/genética , Proteínas de Ligação a RNA/genética , Neoplasias Testiculares/genética , Desaminase APOBEC-1/metabolismo , Animais , Proteínas Argonautas/metabolismo , Modelos Animais de Doenças , Epigênese Genética/genética , Predisposição Genética para Doença , Células Germinativas/metabolismo , Células Germinativas/patologia , Humanos , Masculino , Meiose/genética , Camundongos , MicroRNAs/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Edição de RNA/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias Testiculares/patologia
2.
Life Sci ; 86(3-4): 103-6, 2010 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-19932120

RESUMO

AIMS: To determine whether increased N-acetyltransferase (NAT) activity might have a toxic effect during development and an influence on folate levels since previous work has shown that only low levels of exogenous NAT can be achieved in constitutionally transgenic mice (Cao et al. 2005). MAIN METHODS: A human NAT1 tet-inducible construct was used that would not be expressed until the inducer was delivered. Human NAT1 cDNA was cloned into pTRE2 and injected into mouse oocytes. Two transgenic lines were crossed to mouse line TgN(rtTahCMV)4Uh containing the CMV promoted "tet(on)". Measurements of red blood cell folate levels in inbred strains of mice were performed. KEY FINDINGS: Only low levels of human NAT1 could be achieved in kidney (highly responsive in other studies) whether the inducer, doxycycline, was given by gavage or in drinking water. An inverse correlation of folate levels with Nat2 enzyme activity was found. SIGNIFICANCE: Since increasing NAT1 activity decreases folate in at least one tissue, the detrimental effect of expression of human NAT1 in combination with endogenous mouse Nat2 may be a consequence of increased catabolism of folate.


Assuntos
Arilamina N-Acetiltransferase/metabolismo , Ácido Fólico/sangue , Acetilação , Animais , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/fisiologia , Clonagem Molecular , Citomegalovirus/genética , Doxiciclina/farmacologia , Eritrócitos/metabolismo , Feminino , Ácido Fólico/metabolismo , Genes Reporter , Vetores Genéticos , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Isoenzimas/fisiologia , Rim/enzimologia , Fígado/enzimologia , Masculino , Camundongos , Camundongos Transgênicos , Especificidade da Espécie , Transgenes
3.
Mol Reprod Dev ; 75(6): 1071-6, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18161794

RESUMO

Previous work on Dilantin- and hydrocortisone-induced cleft palate and cleft lip with or without cleft palate using congenics for the N-acetyltransferase loci (Nat1 and Nat2 are closely linked) and recombinant inbred lines implicated the Nat1,2 region in susceptibility to teratogen-induced orofacial clefting. Since Nat1 does not differ between the two strains, Nat2 appeared to be responsible. We have now tested this conclusion using transgenics and knockouts. Transgenics for human NAT1 (equivalent to mouse Nat2) and knockouts for Nat2 were tested for susceptibility to Dilantin, hydrocortisone, and 6-aminonicotinamide-induced orofacial clefting. We found that Nat2 greatly influences teratogen-induced orofacial clefting on the A/J background but not on the C57BL/6J background. The magnitude and direction of the effects depended on which teratogen was used. The Nat2 knockout did not make C57BL/6J susceptible or A/J (already with very low activity) more susceptible but significantly decreased sporadic clefting in the A/J strain. We conclude that only the A/J strain, with several loci affecting orofacial clefting, is influenced by Nat2.


Assuntos
Arilamina N-Acetiltransferase/metabolismo , Fissura Palatina/enzimologia , Fissura Palatina/genética , 6-Aminonicotinamida/toxicidade , Animais , Arilamina N-Acetiltransferase/deficiência , Arilamina N-Acetiltransferase/genética , Sequência de Bases , Fenda Labial/induzido quimicamente , Fenda Labial/enzimologia , Fenda Labial/genética , Fissura Palatina/induzido quimicamente , Primers do DNA/genética , Feminino , Humanos , Hidrocortisona/toxicidade , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fenitoína/toxicidade , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Especificidade da Espécie , Teratogênicos/toxicidade
4.
Nucl Instrum Methods Phys Res A ; 591(1): 272-275, 2008 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-19526045

RESUMO

Recent advances have been made with the BazookaSPECT detector, a high-resolution CCD-based gamma camera which utilizes an MCP-based image intensifier for upfront optical gain. Operating the gamma camera at high frame rates leads to a massive amount of data throughput, thereby inducing the need for real-time processing. We have developed and implemented a list-mode algorithm which allows for real-time data acquisition and processing at high frame rates. This is accomplished with a graphics processing unit (GPU), which provides processing capabilities in addition to the CPU. We have also developed a gamma-ray microscope based on the BazookaSPECT detector and micro-coded apertures. Experimental phantom images show the gamma-ray microscope having an estimated reconstruction resolution of ~30 µm, an unprecedented resolution in gamma-ray imaging.

5.
Brachytherapy ; 6(4): 304-10, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17991627

RESUMO

PURPOSE: To examine the variance in dose to the bladder and rectum during high-dose-rate brachytherapy for cervical cancer for two imaging techniques. An investigation into the patient skin dose from both techniques was also undertaken. METHODS AND MATERIALS: We examined how the variance in dose to critical structures (bladder and rectum) was affected by the degradation of image quality introduced by increasing the lateral separation in a phantom-based study. We also examined the interobserver variation and the reproducibility of C-arm alignment on the variance of the calculated values of the rectal and bladder doses. The relationship between lateral separation and skin entrance dose from collecting images was also investigated. All of these factors were investigated for the standard orthogonal imaging technique and the simple stereo method. RESULTS: It was found that imaging technique and lateral separation had little effect on the variation in the calculated doses to the bladder and rectum. However, it was found that at separations greater than 50 cm, the skin dose from a lateral x-ray increased sharply. CONCLUSIONS: The degradation of image quality for lateral images used to reconstruct cervix applicators does not result in loss of precision in the dose estimates to organs at risk when using the orthogonal technique. However, the skin dose from the lateral image increases markedly with increasing patient separation, making the simple stereo technique a better option for large patients.


Assuntos
Braquiterapia/métodos , Reto/diagnóstico por imagem , Bexiga Urinária/diagnóstico por imagem , Neoplasias do Colo do Útero/radioterapia , Feminino , Fluoroscopia , Humanos , Variações Dependentes do Observador , Doses de Radiação
6.
Dev Dyn ; 236(8): 2346-55, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17584866

RESUMO

Recent advances in molecular lymphology and lymphatic phenotyping techniques in small animals offer new opportunities to delineate mutant mouse models. Chy-3 mutant mice were originally named for their chylous ascites, but the underlying lymphatic disorder was not defined. We now re-examined these mice and applied advanced genotyping and lymphatic phenotyping techniques to pinpoint the specific lymphatic defect in this mouse model. We demonstrated that Chy-3 mice carry a large chromosomal deletion that includes Vegfc and narrowed this region by monitoring the heterozygosity of genetic markers. We found that Chy-3 mice not only exhibited chylous ascites but also lymphedema of the hind paws and, in approximately half of the males, lymphedema of the penis. Visual lymphangiography and immunofluorescence staining showed a hypoplastic dermal lymphatic network, whereas the blood vasculature appeared unaffected. This hypoplastic lymphatic network was functional, and all adult Chy-3 mice exhibited a lateral lymphatic pathway directly connecting the inguinal to the axillary lymph node. The dermal superficial to deep lymphatic connections in upper limbs and in all cervical regions were intact and functionally drained the upper body. Lymphatic tracer was not transported from the dermal to the deep truncal lymphatic system in the lower limbs, even though the deep lymphatic vessels and nodes were present and patent. These findings further delineate the lymphatic phenotype of Chy-3 mice, identify a collateral lymph drainage pathway previously undescribed in other genetic models of lymphedema, and demonstrate a predilection for lymphatic abnormalities of the lower limbs.


Assuntos
Sistema Linfático/patologia , Linfedema/genética , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Ascite , Deleção Cromossômica , Genótipo , Extremidade Inferior , Linfonodos/patologia , Vasos Linfáticos/patologia , Linfedema/etiologia , Masculino , Camundongos , Camundongos Mutantes , Fenótipo , Fator C de Crescimento do Endotélio Vascular/deficiência
7.
Langmuir ; 22(1): 84-7, 2006 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-16378404

RESUMO

Oil-in-water emulsions of slightly soluble oils such as tetralin prepared by high-pressure homogenization and stabilized by sodium dodecyl sulfate undergo depletion flocculation induced by an initially polydisperse droplet size distribution. The smaller droplets flocculate the larger ones; the flocculation can be reversed by gentle sonication. After aging, the flocs disappear because the smaller droplets dissolve through Ostwald ripening. These effects were observed by electroacoustic measurements, supplemented by light scattering.

8.
Am J Physiol Gastrointest Liver Physiol ; 289(2): G300-7, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15790756

RESUMO

Cholestatic hepatitis is frequently found in Niemann-Pick C (NPC) disease. We studied the influence of diet and the low density lipoprotein receptor (LDLR, Ldlr in mice, known to be the source of most of the stored cholesterol) on liver disease in the mouse model of NPC. Npc1-/- mice of both sexes, with or without the Ldlr knockout, were fed a 18% fat, 1% cholesterol ("high-fat") diet and were evaluated by chemical and histological methods. Bile acid transporters [multidrug resistance protein (Mrps) 1-5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR. Many mice died prematurely (within 6 wk) with hepatomegaly. Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype. Non-zone-dependent diffuse fibrosis was found in the surviving mice. Serum alanine aminotransferase was elevated in Npc1-/- mice on the regular diet and frequently became markedly elevated with the high-fat diet. Serum cholesterol was increased in the controls but not the Npc1-/- mice on the high-fat diet; it was massively increased in the Ldlr-/- mice. Esterified cholesterol was greatly increased by the high-fat diet, independent of Ldlr genotype. gamma-Glutamyltransferase was also elevated in Npc1-/- mice, more so on the high-fat diet. Mrps 1-5 were elevated in Npc1-/- liver and became more elevated with the high-fat diet; Ntcp, Bsep, and OatP2 were elevated in Npc1-/- liver and were suppressed by the high-fat diet. In conclusion, Npc1-/- mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colesterol na Dieta/farmacocinética , Hepatite/metabolismo , Doenças de Niemann-Pick/metabolismo , Animais , Feminino , Hepatite/etiologia , Peptídeos e Proteínas de Sinalização Intracelular , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteína C1 de Niemann-Pick , Doenças de Niemann-Pick/complicações , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas/genética , Receptores de LDL/genética
9.
J Appl Genet ; 45(4): 461-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15523158

RESUMO

Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is the result of deficient intracellular cholesterol movement. We investigated the effects of tamoxifen and vitamin E (D-alpha tocopherol) treatment on patterns of weight loss and motor function in the mouse model of Niemann-Pick C disease (Npc1-/- mice). Tamoxifen has multiple metabolic effects, including reducing oxidative damage, while vitamin E primarily has this property. Npc1-/- mice were identified and treatment was initiated at an approximate age of 21 days. Tamoxifen suspended in peanut oil was administered via intraperitoneal injection (weekly, at a dose calculated to deliver 0.023 microg/g/day). Vitamin E (25 IU) was administered orally via gavage once a week. Weight loss and Rota-Rod performance were analyzed by using Kaplan-Meyer survival curves. Tamoxifen treatment by itself significantly delayed weight loss (an endpoint of neurodegeneration) in male and female mice compared to untreated controls. Motor function was evaluated by performance on a Rota-Rod. Tamoxifen maintained Rota-Rod performance for about an extra week. Vitamin E treatment significantly delayed weight loss in females only. Rota-Rod performance was maintained slightly longer in mice treated with vitamin E. Simultaneous use of both treatments did not delay weight loss longer than tamoxifen-only treatment but had a greater effect than either treatment alone on Rota-Rod performance and demonstrated a significant positive effect on the early "learning curve" portion of the Rota-Rod evaluations. We found significant but relatively small improvements in rate of disease progression by treating Npc1-/- mice with tamoxifen and/or vitamin E. Some sex differences in response and an early improvement in Rota-Rod performance suggest areas for further study.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Doenças de Niemann-Pick/tratamento farmacológico , Tamoxifeno/uso terapêutico , Vitamina E/uso terapêutico , Animais , Quimioterapia Combinada , Feminino , Peptídeos e Proteínas de Sinalização Intracelular , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Proteína C1 de Niemann-Pick , Doenças de Niemann-Pick/genética , Doenças de Niemann-Pick/patologia , Proteínas/genética , Proteínas/fisiologia , Redução de Peso/efeitos dos fármacos
10.
J Colloid Interface Sci ; 265(1): 56-64, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12927164

RESUMO

Stagnant layer conduction (or anomalous surface conduction) in perfluoromethyldecalin (PFMD) and n-hexadecane emulsions has been measured by electroacoustics and verified by high-frequency dielectric response experiments. The electroacoustic technique can detect the presence of stagnant layer conduction from the salt dependence of the dynamic mobility. As the indifferent electrolyte concentration is increased from low values (<5 mM), the zeta-potential and droplet size, estimated from the dynamic mobility by the normal procedures, gradually increase in magnitude until the size plateaus and the zeta-potential begins to decrease with added salt in the usual fashion. When stagnant layer conduction is taken into account, the dynamic mobility can be fitted to a constant size distribution and more realistic zeta-potential values with varying electrolyte concentration. High-frequency dielectric response has been used to measure the total conduction in a PFMD emulsion system. Very good agreement between these two independent techniques verifies the existence of conduction behind the shear plane and demonstrates that electroacoustics alone can detect and quantify its extent. This is possible because of the unique character of the AcoustoSizer procedure, which estimates both particle size and zeta-potential from the same signal.

11.
Phys Med Biol ; 47(2): 193-208, 2002 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-11837612

RESUMO

A dual wavelength time-resolved reflectance system was developed for monitoring haemoglobin saturation noninvasively. At each wavelength, the time-resolved reflectance data were fitted to a diffusion model of light propagation in a homogeneous, semi-infinite medium to yield the absolute scattering and absorption coefficients. The absorption coefficients were then used to calculate haemoglobin saturation. A two-layer phantom containing human erythrocytes in a scattering solution in the bottom layer was used to study system performance under more realistic conditions. The top layer was chosen to simulate either skin or fat and the oxygenation of the bottom layer, which corresponded to muscle, was controlled. The thickness of the fat layer was varied from 1.5 to 10 mm to investigate the effects of increasing the top layer thickness. These results, obtained with the simple diffusion model, were compared with simultaneous measurements of oxygenation made directly in the bottom layer. Errors in estimating haemoglobin saturation with this method ranged from 5-11% depending on the thickness of the top layer and its optical properties.


Assuntos
Hemoglobinas/metabolismo , Oxigênio/metabolismo , Espectrofotometria/métodos , Humanos , Modelos Estatísticos , Imagens de Fantasmas , Fatores de Tempo
12.
J Colloid Interface Sci ; 238(1): 70-79, 2001 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-11350138

RESUMO

Electroacoustics was used to study SDS-stabilized sunflower oil-in-water emulsions, with oil volume fractions between 2% and 50%. The dynamic mobility of the oil droplets was measured; the size and electric charge on the drops were calculated using formulas derived for dilute and concentrated systems and the results were compared. The relation derived for concentrated systems appears to be valid up to at least 50% provided the particles remain within the size range of the instrument, which shifts upward with rising concentration. Conductivity and pH had little effect on particle properties in the range studied; higher oil volume fraction (φ) had a substantial influence on the particle size produced in a homogenizer, but not on the zeta potential. Both median size and spread decreased with increases in φ. In contrast, both size and charge were hardly affected at volume fractions less than 10%. Dilution of the emulsion with a surfactant solution of the same composition as the water phase changed neither the particle size nor the zeta potential. The temperature of the emulsification process had a significant influence on the particle size but the zeta potential was hardly affected. Surfactant concentration had some effect on size at low volume fractions but not for φ>10%. The electroacoustic method hence could be applied to analyze both the dilute and the concentrated emulsions directly. Copyright 2001 Academic Press.

13.
J Colloid Interface Sci ; 235(2): 371-379, 2001 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-11254316

RESUMO

The dynamic mobility spectra of suspensions of semiconducting tin(IV) oxide particles doped with antimony have been measured with the technique of electroacoustics. The magnitude of the complex mobility decreases essentially monotonically with increasing frequency, just as for a nonconducting (dielectric) particle under the same conditions. Unlike the case for a dielectric particle, however, the magnitudes at low frequency increase with increasing conductivity. The phase angle behavior is also different from that of a normal dielectric particle. The change in the phase angle behavior is most obvious at low suspension conductivity and high frequency where the phase angles showed a much smaller phase lag than at high conductivities. Reasonable agreement was found between the experimental mobility and the theoretical dynamic mobility spectra obtained with O'Brien's theory for the enhanced permittivity of semiconductors. Copyright 2001 Academic Press.

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