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BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.
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Neoplasias del Colon , Estudio de Asociación del Genoma Completo , Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia Adyuvante , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Fluorouracilo/uso terapéutico , Humanos , Recurrencia Local de Neoplasia , Oxaliplatino/efectos adversos , Estudios ProspectivosRESUMEN
The aberrant redox regulation and anti-oxidative defense is one of the main causes of age-induced decline in oocytes quality and embryo development in mammals. The present study aimed to elucidate the effect of glutathione ethyl ester (GSH-OEt), a cell-permeable glutathione (GSH) donor, on the developmental competence of oocytes in cows with advanced reproductive age. Oocytes were collected from cows aged 30-50 months or >120 months, which were defined as young or aged, respectively, and subjected to in vitro maturation (IVM) in the presence of 5 mM of GSH-OEt. In aged cows, the GSH level in follicular fluid was lower, and the intracellular levels of reactive oxygen species (ROS) in post-IVM oocytes was higher than those in young cows. GSH-OEt supplementation during IVM reduced the ROS contents of oocyte in aged cows but not in young cows. GSH-OEt treatment promoted the meiotic progression and increased the proportion of oocytes with mature cytoplasm containing evenly dispersed cortical granules in aged cows. After in vitro fertilization, the normal fertilization and development to the blastocyst stage were enhanced by GSH-OEt in aged cows to levels comparable to those in young cows. Further, oocyte maturation in the presence of GSH-OEt increased the proportion of diploid blastocyst in aged cows. In contrast, GSH-OEt failed to enhance the oocyte maturation, fertilization, and embryo development in young cows. Taken together, the exogenous supplementation of GSH-OEt during IVM modulated the age-related oxidative damage of bovine oocytes and improved the developmental competence of oocytes in aged cows. Oocytes presented a distinct response to GSH-OEt treatment depending on the donor age. GSH-OEt supplementation during IVM could be of practical value through the efficiency improvement of chromosomally normal embryo production in aged cows.
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Glutatión , Oocitos , Animales , Blastocisto , Bovinos , Femenino , Fertilización In Vitro/veterinaria , Glutatión/análogos & derivados , Técnicas de Maduración In Vitro de los Oocitos/veterinaria , OogénesisRESUMEN
The present study aimed to elucidate the developmental kinetics, growth potential, and viability of bovine embryos produced in vitro with sexed semen. Bovine oocytes were fertilized in vitro using unsorted and X-sorted semen from the same Holstein bulls, and the kinetics of in vitro development were continuously monitored for 10 d through time-lapse cinematography. The blastocyst formation rate was lower in the X-sorted group than in the unsorted group (P < 0.01), whereas the normal fertilization rate did not differ between groups. Morphokinetic evaluation revealed that the incidence of blastomere fusion during the first cleavage division, termed reverse cleavage, was higher in the X-sorted group (P < 0.01). Furthermore, embryos produced with X-sorted semen showed slower growth throughout the developmental period than embryos produced with unsorted semen (P < 0.01). The cell number of the trophectoderm and inner cell mass of blastocysts was reduced in the X-sorted group (P < 0.01). In embryos that developed to the blastocyst stage, the hatchability (P < 0.05), chromosomal normality (P < 0.01), and survivability after the conventional frozen-thawing process (P < 0.05) were reduced in the X-sorted group compared to that in the unsorted group, indicating a compromised viability of embryos derived from X-sorted semen. Taken together, the first cleavage dysmorphism, delayed embryo growth, and impaired viability of embryos developed to the blastocyst stage may explain the mechanism of reduced fertility in embryos derived from sexed semen. The kinetic evaluation of early embryo development and de-selection of embryos presenting the aberrant first cleavage would be valid for clinical application to produce sexed embryos with high implantation potential.
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Fertilización In Vitro , Semen , Animales , Blastocisto , Bovinos , Desarrollo Embrionario , Fertilización In Vitro/veterinaria , Cinética , Masculino , EspermatozoidesRESUMEN
Previous evidence suggests the association of lower educational attainment and depressive symptoms with tooth loss. The hypothesis of this study was that these factors may exacerbate the effect on tooth loss beyond the sum of their individual effects. We aimed to clarify the independent and interactive effects of educational attainment and depressive symptoms on the number of missing teeth among community residents. Cross-sectional data of 9,647 individuals were collected from the general Japanese population. Dental examination was conducted by dentists. Educational attainment was categorized into 3 levels based on the number of educational years: ≤9, >9 to ≤12, and >12 y. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms; a total score of ≥16 and/or the use of medications for depression indicate the presence of depressive symptoms. In the multivariate analysis with adjustment for conventional risk factors, educational attainment was identified as a determinant of the number of missing teeth (>9 to ≤12 y of education: coefficient = 0.199, 95% confidence interval [CI], 0.135 to 0.263, P < 0.001; ≤9 y of education: coefficient = 0.318, 95% CI, 0.231 to 0.405, P < 0.001: reference, >12 y of education). An analysis that included interaction terms revealed that the relationship between "≤9 y of education" and the number of missing teeth differed depending on the depressive symptoms, indicating a positive interactive association (coefficient for interaction = 0.198; 95% CI, 0.033 to 0.364, P for interaction = 0.019: reference, >12 y of education). Our study suggests the presence of a significant association between educational attainment and tooth loss, as well as a partial interactive association between "≤9 y of education" and "depressive symptoms" in the general Japanese population.
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Depresión , Pérdida de Diente , Estudios Transversales , Depresión/epidemiología , Escolaridad , Humanos , Factores de Riesgo , Pérdida de Diente/epidemiologíaRESUMEN
We present the design and laboratory evaluation of a cryogenic continuously rotating half-wave plate (CHWP) for the POLARBEAR-2b (PB-2b) cosmic microwave background receiver, the second installment of the Simons Array. PB-2b will observe at 5200 m elevation in the Atacama Desert of Chile in two frequency bands centered at 90 GHz and 150 GHz. In order to suppress atmospheric 1/f noise and mitigate systematic effects that arise when differencing orthogonal detectors, PB-2b modulates linear sky polarization using a CHWP rotating at 2 Hz. The CHWP has a 440 mm clear aperture diameter and is cooled to ≈50 K in the PB-2b receiver cryostat. It consists of a low-friction superconducting magnetic bearing and a low-torque synchronous electromagnetic motor, which together dissipate <2 W. During cooldown, a grip-and-release mechanism centers the rotor to <0.5 mm, and during continuous rotation, an incremental optical encoder measures the rotor angle with a noise level of 0.1 µrad/Hz. We discuss the experimental requirements for the PB-2b CHWP, the designs of its various subsystems, and the results of its evaluation in the laboratory. The presented CHWP has been deployed to Chile and is expected to see first light on PB-2b in 2020 or 2021.
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Using only cosmic microwave background polarization data from the polarbear experiment, we measure B-mode polarization delensing on subdegree scales at more than 5σ significance. We achieve a 14% B-mode power variance reduction, the highest to date for internal delensing, and improve this result to 22% by applying for the first time an iterative maximum a posteriori delensing method. Our analysis demonstrates the capability of internal delensing as a means of improving constraints on inflationary models, paving the way for the optimal analysis of next-generation primordial B-mode experiments.
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We describe the Fourier Transform Spectrometer (FTS) used for in-field testing of the POLARBEAR receiver, an experiment located in the Atacama Desert of Chile which measures the cosmic microwave background (CMB) polarization. The POLARBEAR-FTS (PB-FTS) is a Martin-Puplett interferometer designed to couple to the Huan Tran Telescope (HTT) on which the POLARBEAR receiver is installed. The PB-FTS measured the spectral response of the POLARBEAR receiver with signal-to-noise ratio >20 for â¼69% of the focal plane detectors due to three features: a high throughput of 15.1 sr cm2, optimized optical coupling to the POLARBEAR optics using a custom designed output parabolic mirror, and a continuously modulated output polarizer. The PB-FTS parabolic mirror is designed to mimic the shape of the 2.5 m-diameter HTT primary reflector, which allows for optimum optical coupling to the POLARBEAR receiver, reducing aberrations and systematics. One polarizing grid is placed at the output of the PB-FTS and modulated via continuous rotation. This modulation allows for decomposition of the signal into different harmonics that can be used to probe potentially pernicious sources of systematic error in a polarization-sensitive instrument. The high throughput and continuous output polarizer modulation features are unique compared to other FTS calibrators used in the CMB field. In-field characterization of the POLARBEAR receiver was accomplished using the PB-FTS in April 2014. We discuss the design, construction, and operation of the PB-FTS and present the spectral characterization of the POLARBEAR receiver. We introduce future applications for the PB-FTS in the next-generation CMB experiment, the Simons Array.
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Time-lapse monitoring (TLM) has emerged as a novel technology for the continuous and noninvasive evaluation of embryos. TLM has revealed the prevalence of specific dysmorphisms such as abnormal development during the early-cleavage stage of embryos. However, little information is available on the prevalence and consequences of abnormal cleavage in bovine embryos. Hence, this study aimed to investigate growth potential of bovine embryos presenting abnormal cleavage, such as reverse cleavage (RC), direct cleavage (DC), and irregular and unsmooth ruffling of the oolema membrane (ruffling). Bovine embryos derived through in vitro fertilization (IVF) were cultured in the microwell culture dishes, and the kinetics of in vitro development were observed through TLM at 20-min intervals for 10â¯d. Approximately 36% of embryos that developed into a blastocyst presented abnormal cleavage. Morphokinetic evaluations revealed that RC, DC, and ruffling embryos showed slower development compared to embryos with normal cleavage (Pâ¯<â¯0.01). Embryos with RC and DC, but not ruffling, revealed impaired hatchability (Pâ¯<â¯0.05) with increased collapses of the blastocyst cavity until hatching (Pâ¯<â¯0.0001). Moreover, the RC and DC embryos presented increased chromosomal aneuploidy (Pâ¯<â¯0.05). These results suggest a compromised viability of embryos with RC and DC. This is the first report that clarified the effect of abnormal cleavage on the morphokinetics and growth potential of bovine IVF embryos. Results indicate that the kinetic evaluation of bovine embryos using the time-lapse imaging system will be beneficial for selecting embryos with a high viability.
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Bovinos/embriología , Desarrollo Embrionario , Aneuploidia , Animales , Blastocisto/citología , Técnicas de Cultivo de Embriones/veterinaria , Femenino , Fertilización In Vitro/veterinaria , Imagen de Lapso de Tiempo/veterinariaRESUMEN
Pulsatile gonadotropin-releasing hormone (GnRH) secretion is indispensable for reproduction in mammals. Kisspeptin neurons in the hypothalamic arcuate nucleus (ARC), referred to as KNDy neurons because of the coexpression of neurokinin B and dynorphin A, are considered as components of the GnRH pulse generator that produces rhythmic GnRH secretion. The present study aimed to investigate if peripheral administration of PF-4455242, a κ-opioid receptor (KOR, a dynorphin A receptor) antagonist, facilitates pulsatile luteinizing hormone (LH) secretion and GnRH pulse generator activity in estrogen-treated ovariectomized Shiba goats to determine the possibility of using KOR antagonists to artificially control ovarian activities. PF-4455242 was intravenously infused for 4 h (1 or 10 µmol/kg body weight/4 h) or as a single subcutaneous injection (1 or 10 µmol/kg body weight). In a separate experiment, the same KOR antagonist (10 µmol/kg body weight/4 h) was intravenously infused during the recording of multiple unit activity (MUA) in the ARC that reflects the activity of the GnRH pulse generator to test the effects of KOR antagonist administration on GnRH pulse generator activity. Intravenous infusion and single subcutaneous injection of the KOR antagonist significantly increased the frequency of LH pulses compared with controls. Intravenous infusion of KOR antagonist also significantly increased the frequency of episodic bursts in the MUA. The present study demonstrates that peripherally administered KOR antagonist stimulates pulsatile LH secretion by acting on the GnRH pulse generator, and peripheral administration of PF-4455242 can be used to facilitate pulsatile LH secretion, which in turn facilitates ovarian activities in farm animals.
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Compuestos de Bifenilo/farmacología , Estrógenos/administración & dosificación , Cabras/fisiología , Hormona Liberadora de Gonadotropina/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Compuestos de Bifenilo/administración & dosificación , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Ovariectomía/veterinaria , Sulfonamidas/administración & dosificaciónRESUMEN
Retinoblastoma (RB) protein inactivation during tumor progression is often associated with acquisition of immature phenotypes and resistance to therapy. Determination of an RB inactivation signature in a context of gaining undifferentiated phenotype in a p53-null sarcoma system revealed a critical role for interleukin (IL)-6. Using a Gene Set Enrichment Analysis (GSEA), we discovered that poorly differentiated breast cancers are enriched for this RB inactivation signature. Accelerated IL-6 secretion following RB inactivation in an RB-intact luminal-type breast cancer cell line MCF-7 promoted a positive feed forward loop between IL-6 and STAT3 driving tumor growth and endocrine therapy resistance. In addition, some of RB-intact basal-like type breast cancer cell lines exhibited a similar phenotype following RB depletion. The mechanism whereby RB inactivation increases IL-6 production in MCF-7 cells appeared to involve fatty acid oxidation (FAO)-dependent mitochondrial metabolism and c-Jun NH(2)-terminal kinase (JNK). In addition, IL-6, via STAT3-mediated feedback to mitochondria, autonomously adjusts mitochondrial superoxide to levels suitable to maintain stem cell-like activity. The gene expression profile of luminal-type breast cancer patients with low RB expression revealed high enrichment of genes involved in mitochondrial respiration and downstream targets of IL-6. These findings unveiled an unexpected strategy whereby RB suppresses malignant features of cancer cells through metabolic reprogramming and cell-autonomous inflammation.
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Neoplasias de la Mama/patología , Autorrenovación de las Células/efectos de los fármacos , Resistencia a Antineoplásicos , Interleucina-6/metabolismo , Mitocondrias/patología , Proteína de Retinoblastoma/metabolismo , Tamoxifeno/farmacología , Animales , Antineoplásicos Hormonales/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácidos Grasos/química , Ácidos Grasos/metabolismo , Femenino , Humanos , Interleucina-6/genética , Metaboloma , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteína de Retinoblastoma/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/fisiología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/genética , Farmacogenética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante/efectos adversos , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Femenino , Fluorouracilo/efectos adversos , Humanos , Japón , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/patología , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Allergic rhinitis, a known risk factor for asthma onset, often accompanies mouth breathing. Mouth breathing may bypass the protective function of the nose and is anecdotally considered to increase asthma morbidity. However, there is no epidemiological evidence that mouth breathing is independently associated with asthma morbidity and sensitization to allergens. In this study, we aimed to clarify the association between mouth breathing and asthma morbidity and allergic/eosinophilic inflammation, while considering the effect of allergic rhinitis. METHODS: This community-based cohort study, the Nagahama Study, contained a self-reporting questionnaire on mouth breathing and medical history, blood tests, and pulmonary function testing. We enrolled 9804 general citizens of Nagahama City in the Shiga Prefecture, Japan. RESULTS: Mouth breathing was reported by 17% of the population and was independently associated with asthma morbidity. The odds ratio for asthma morbidity was 1.85 (95% CI, 1.27-2.62) and 2.20 (95% CI, 1.72-2.80) in subjects with mouth breathing alone and allergic rhinitis alone, which additively increased to 4.09 (95% CI, 3.01-5.52) when mouth breathing and allergic rhinitis coexisted. Mouth breathing in nonasthmatics was a risk for house dust mite sensitization, higher blood eosinophil counts, and lower pulmonary function after adjusting for allergic rhinitis. CONCLUSION: Mouth breathing may increase asthma morbidity, potentially through increased sensitization to inhaled allergens, which highlights the risk of mouth-bypass breathing in the 'one airway, one disease' concept. The risk of mouth breathing should be well recognized in subjects with allergic rhinitis and in the general population.
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Asma/epidemiología , Asma/etiología , Respiración por la Boca , Adulto , Anciano , Asma/diagnóstico , Biomarcadores , Estudios de Cohortes , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Morbilidad , Oportunidad Relativa , Vigilancia de la Población , Pruebas de Función Respiratoria , Factores de Riesgo , AutoinformeRESUMEN
A luteinising hormone (LH) surge is fundamental to the induction of ovulation in mammalian females. The administration of a preovulatory level of oestrogen evokes an LH surge in ovariectomised females, whereas the response to oestrogen in castrated males differs among species; namely, the LH surge-generating system is sexually differentiated in some species (e.g. rodents and sheep) but not in others (e.g. primates). In the present study, we aimed to determine whether there is a functional LH surge-generating system in male goats, and whether hypothalamic kisspeptin neurones in male goats are involved in the regulation of surge-like LH secretion. By i.v. infusion of oestradiol (E2; 6 µg/h) for 16 h, a surge-like LH increase occurred in both castrated male and ovariectomised female goats, although the mean peak LH concentration was lower and the mean peak of the LH surge was later in males compared to females. Dual staining with KISS1 in situ hybridisation and c-Fos immunohistochemistry revealed that E2 treatment significantly increased c-Fos expression in the medial preoptic area (mPOA) KISS1 cells in castrated males, as well as ovariectomised females. By contrast, dual-labelled cells were scarcely detected in the arcuate nucleus (ARC) after E2 treatment in both sexes. These data suggest that kisspeptin neurones in the mPOA, but not those in the ARC, are involved in the induction of surge-like LH secretion in both male and female goats. In summary, our data show that the mechanism that initiates the LH surge in response to oestrogen, the mPOA kisspeptin neurones, is functional in male goats. Thus, sexual differentiation of the LH surge-generating system would not be applicable to goats.
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Kisspeptinas/metabolismo , Hormona Luteinizante/biosíntesis , Neuronas/metabolismo , Área Preóptica/metabolismo , Animales , Femenino , Cabras , Hibridación in Situ , Kisspeptinas/genética , Hormona Luteinizante/sangre , Masculino , Área Preóptica/citologíaRESUMEN
Several epidemiologic studies have suggested that oral disease is a risk factor for cardiovascular disease (CVD). However, whether a clinically significant association exists between the 2 disorders remains controversial. Here, we investigated the association between tooth loss, as an indicator of oral disease, and arterial stiffness, as a marker of atherosclerosis, in Japanese adults. Cross-sectional data were collected for 8,124 persons aged 30 to 75 y with no history of tooth loss for noninflammatory reasons, such as orthodontic treatment, malposition, and trauma. Participants received a comprehensive dental examination and extensive in-person measurements of CVD risk factors, and arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI). We examined the association between CAVI and tooth loss using general linear models with adjustment for age, sex, body mass index, smoking status, hemoglobin A1c, and a history of insulin or hypoglycemic medication depending on the model. In addition, we performed an analysis that included interaction terms of the centered variables tooth loss, sex, and age. The results of the multiple regression analysis that included the interaction terms detected that the relationship between CAVI and tooth loss was dependent on sex, with only men showing a positive correlation (ß for interaction = 0.04; 95% confidence interval, 0.02-0.06). The findings from this study suggest that a linear relationship exists between tooth loss and degree of arterial stiffness and that the association differed depending on sex.
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Aterosclerosis/epidemiología , Pérdida de Diente/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Estudios de Cohortes , Atención Odontológica Integral , Estudios Transversales , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Japón/epidemiología , Modelos Lineales , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Estudios Prospectivos , Factores de Riesgo , Factores Sexuales , Fumar/epidemiología , Rigidez Vascular/fisiologíaRESUMEN
Gravitational lensing due to the large-scale distribution of matter in the cosmos distorts the primordial cosmic microwave background (CMB) and thereby induces new, small-scale B-mode polarization. This signal carries detailed information about the distribution of all the gravitating matter between the observer and CMB last scattering surface. We report the first direct evidence for polarization lensing based on purely CMB information, from using the four-point correlations of even- and odd-parity E- and B-mode polarization mapped over â¼30 square degrees of the sky measured by the POLARBEAR experiment. These data were analyzed using a blind analysis framework and checked for spurious systematic contamination using null tests and simulations. Evidence for the signal of polarization lensing and lensing B modes is found at 4.2σ (stat+sys) significance. The amplitude of matter fluctuations is measured with a precision of 27%, and is found to be consistent with the Lambda cold dark matter cosmological model. This measurement demonstrates a new technique, capable of mapping all gravitating matter in the Universe, sensitive to the sum of neutrino masses, and essential for cleaning the lensing B-mode signal in searches for primordial gravitational waves.
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We reconstruct the gravitational lensing convergence signal from cosmic microwave background (CMB) polarization data taken by the Polarbear experiment and cross-correlate it with cosmic infrared background maps from the Herschel satellite. From the cross spectra, we obtain evidence for gravitational lensing of the CMB polarization at a statistical significance of 4.0σ and indication of the presence of a lensing B-mode signal at a significance of 2.3σ. We demonstrate that our results are not biased by instrumental and astrophysical systematic errors by performing null tests, checks with simulated and real data, and analytical calculations. This measurement of polarization lensing, made via the robust cross-correlation channel, not only reinforces POLARBEAR auto-correlation measurements, but also represents one of the early steps towards establishing CMB polarization lensing as a powerful new probe of cosmology and astrophysics.
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AIMS/HYPOTHESIS: Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. METHODS: Bscl2 (-/-) mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation. RESULTS: As observed in humans, Bscl2 (-/-) mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However, Bscl2 (-/-) mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in Bscl2 (-/-) MEFs. In vivo treatment of Bscl2 (-/-) mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice. CONCLUSIONS/INTERPRETATION: Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in Bscl2 (-/-) mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.
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Proteínas de Unión al GTP Heterotriméricas/deficiencia , Tiazolidinedionas/uso terapéutico , Adipocitos/citología , Adipocitos/metabolismo , Animales , Células Cultivadas , Metabolismo Energético/fisiología , Femenino , Subunidades gamma de la Proteína de Unión al GTP , Proteínas de Unión al GTP Heterotriméricas/genética , Lipodistrofia Generalizada Congénita/tratamiento farmacológico , Lipodistrofia Generalizada Congénita/metabolismo , Ratones , Ratones Mutantes , Pioglitazona , EmbarazoRESUMEN
Pegylated interferon-α (PEG-IFN-α) plus ribavirin (RBV) treatment fails to achieve a sustained virological response (SVR) in approximately 20-50% of patients with chronic hepatitis C virus (HCV) infection. We assessed the contribution of an anti-IFN-α neutralizing antibody (NAb) on the nonresponse to treatment. NAbs were detected using an antiviral assay that assessed the neutralizing effects of serum samples against IFN. Serum samples were obtained at the end of the treatment and evaluated for the presence of NAbs using recombinant IFN-α as a standard. We studied 129 PEG-IFN-α/RBV-treated patients. In the 82 end-of-treatment responders, no NAbs were detected. Of the 47 patients who did not respond, seven (15%) were positive for NAbs. We also examined an additional 83 patients who had not responded to PEG-IFN-α treatment, and detected 12 with NAbs. Patients with good IFN-responsive characteristics, including HCV genotype 2/3 and major allele homozygotes for interleukin-28B, were included in the 19 patients with NAbs. No NAbs interfered with the antiviral activity of natural human IFN-ß (nIFN-ß) and re-treatement of patients with NAbs with nIFN-ß/RBV achieved SVR. Our analyses revealed that the emergence of anti-IFN-α NAbs was a candidate causal factor of PEG-IFN-α-treatment failure. Therefore, these antibodies should be assayed in patients who do not respond to PEG-IFN-α therapy, and if detected, other effective treatments, i.e., medications that are not neutralized by anti-IFN-α NAbs, should be considered.