Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren's syndrome. However, it is unclear whether Ro60 and its associated RNAs contribute to disease ...pathogenesis. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60–positive SLE immune complexes contained Alu RNAs, and Alu transcripts were up-regulated in SLE whole blood samples relative to controls. These findings establish a link among the lupus autoantigen Ro60, Alu retroelements, and type I interferon.
Pautas de ISUOG para la práctica: evaluación ecográfica de la biometría y el crecimiento fetal
INTRODUCCIÓN
El objetivo de estas Pautas es describir la evaluación adecuada de la biometría fetal y el ...diagnóstico de los trastornos del crecimiento fetal. Estos trastornos consisten principalmente en la restricción del crecimiento fetal (RCF), también conocida como restricción del crecimiento intrauterino (RCIU), que a menudo está asociada con un tamaño pequeño para la edad gestacional (PEG) o grande para la edad gestacional (GEG), que pueden dar lugar a la macrosomía fetal; ambos se han asociado con una variedad de resultados maternos y perinatales adversos. La detección y el tratamiento adecuado de las anomalías del crecimiento fetal son componentes esenciales de la atención prenatal, y la ecografía fetal desempeña un papel fundamental en la evaluación de estas afecciones. Los parámetros biométricos fetales medidos con mayor frecuencia son (todas las siglas procedentes del inglés) el diámetro biparietal (BPD), el perímetro cefálico (HC), el perímetro abdominal (AC) y la longitud de la diáfisis del fémur (FL). Estas mediciones biométricas se pueden utilizar para estimar el peso del feto (PEF) mediante fórmulas diferentes1. Es importante diferenciar entre el concepto de tamaño fetal en un momento dado y el crecimiento fetal en sí, siendo este último un proceso dinámico cuya evaluación requiere al menos dos ecografías separadas en el tiempo. La historia y los síntomas de la madre, la evaluación del líquido amniótico y la velocimetría Doppler pueden proporcionar información adicional que se puede utilizar para identificar los fetos bajo riesgo de resultados adversos del embarazo. La estimación precisa de la edad gestacional es un prerrequisito para determinar si el tamaño del feto es apropiado para la edad gestacional (AEG). Excepto en el caso de los embarazos procedentes de tecnologías de reproducción asistida, la fecha de concepción no se puede determinar con precisión. Clínicamente, la fecha de la mayoría de los embarazos se establece en función del último período menstrual, aunque a veces esto puede ser incierto o poco fiable. Por lo tanto, el fechado de los embarazos mediante ecografía temprana a las 8‐14 semanas, mediante la medición de la longitud céfalo‐caudal (LCC) fetal, parece ser el método más fiable para establecer la edad gestacional. Una vez que la LCC excede los 84 mm, se debe usar el HC2–4 para establecer la fecha del embarazo. El HC, con o sin FL, se puede utilizar para estimar la edad gestacional a partir de la mitad del primer trimestre si no se dispone de una ecografía del primer trimestre y el historial menstrual no es fiable. Cuando se ha establecido la fecha prevista del parto mediante una exploración temprana precisa, no se deben utilizar exploraciones posteriores para recalcular la edad gestacional1. Las exploraciones en serie se pueden utilizar para determinar si el intervalo del crecimiento ha sido normal. En estas Pautas se asume que la edad gestacional es conocida y ha sido determinada según lo anterior, que el embarazo es de feto único y que la anatomía fetal es normal. En el Apéndice 1 se detallan los grados de recomendación utilizados en estas Pautas. El informe sobre los niveles de evidencia no es aplicable a estas Pautas.
摘要
ISUOG实践指南:胎儿生物测量与生长的超声评估
引言
本指南旨在描述胎儿生物测量的正确评估及胎儿生长障碍的诊断。这些疾病主要包括又称为宫内生长受限(IUGR)且往往与小于胎龄(SGA)有关的胎儿生长受限(FGR)，以及可能导致胎儿巨大的大于胎龄(LGA)。这两种疾病都与各种孕产期围产期不良结局有关。胎儿生长异常的筛查和适当处理是产前保健的重要组成部分，胎儿超声检测在这些疾病的评估中起着关键作用。最常测量的胎儿生物特征参数有双顶径(BPD)、头围(HC)、腹围(AC)和股骨骨干长度(FL)。可以根据这些生物特征测量值，运用各种不同的公式估算胎儿体重(EFW)。1务必要区分给定时间点胎儿大小与胎儿生长这两个不同的概念，后者是一个动态的过程。胎儿生长评估至少需要不同时间点的两次超声波扫描检测。产妇的病史和症状、羊水评估和多普勒测速可以提供更多信息，可以据此识别有不良妊娠结局风险的胎儿。准确估算胎龄是确定胎儿大小是否适合胎龄(AGA)的先决条件。无法精确确定受孕日期，辅助生殖技术引发的妊娠除外。临床上主要将末次月经日期定为受孕日期，虽然有时可能不太确定或不太可靠。因此，根据胎冠臀长(CRL)测量结果和第8‐14周早期超声波检测结果确定受孕日期，似乎是确定胎龄的最可靠方法。如果CRL超过84毫米，就要根据HC来确定受孕日期。2–4如果无法进行孕早期扫描且月经史不可靠，就可以通过HC——不管有没有FL——来估算孕中期孕龄。通过准确的孕早期扫描确定预产期后，就不要再做后续扫描来重新估算胎龄了。1可以通过连续扫描确定胎儿间隔生长是否正常。在本指南中，我们假设胎龄已知且已通过上述方式确定胎龄，孕产单生儿且胎儿解剖正常。本指南所用的推荐等级详情如附录1所示。本指南不适用报告证据等级。
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This paper presents a view of the current state of monitoring track geometry condition from in-service vehicles. It considers technology used to provide condition monitoring; some issues of ...processing and the determination of location; how things have evolved over the past decade; and what is being, or could/should be done in future research. Monitoring railway track geometry from an in-service vehicle is an attractive proposition that has become a reality in the past decade. However, this is only the beginning. Seeing the same track over and over again provides an opportunity for observing track geometry degradation that can potentially be used to inform maintenance decisions. Furthermore, it is possible to extend the use of track condition information to identify if maintenance is effective, and to monitor the degradation of individual faults such as dipped joints. There are full unattended track geometry measurement systems running on in-service vehicles in the UK and elsewhere around the world, feeding their geometry measurements into large databases. These data can be retrieved, but little is currently done with the data other than the generation of reports of track geometry that exceeds predefined thresholds. There are examples of simpler systems that measure some track geometry parameters more or less directly and accurately, but forego parameters such as gauge. Additionally, there are experimental systems that use mathematics and models to infer track geometry using data from sensors placed on an in-service vehicle. Finally, there are systems that do not claim to measure track geometry, but monitor some other quantity such as ride quality or bogie acceleration to infer poor track geometry without explicitly measuring it.
Genome-wide association studies have revealed that single nucleotide polymorphisms in fat mass and obesity-associated transcript (FTO) are robustly associated with body mass index and obesity. ...Expression of Fto in the hypothalamic arcuate nucleus is bidirectionally regulated as a function of nutritional status; decreasing following a 48-h fast and increasing after 10-week exposure to a high-fat diet. Here, we utilize an in vitro approach to determine which nutrients could regulate FTO levels at a cellular level. Using mouse and human cell lines, we find that FTO levels are not influenced by serum starvation. We demonstrate, however, that both glucose and total amino-acid deprivation regulates FTO expression. In particular, we have found that FTO mRNA and protein levels are dramatically downregulated by total amino-acid deprivation in mouse hypothalamic N46 cells, mouse embryonic fibroblasts and in human HEK293 cells. The drop rate of Fto mRNA is faster than its rate of natural degradation, pointing to regulation at the transcriptional level, which is reversible upon amino-acid replacement. Strikingly, this downregulation was seen only with essential amino-acid deficiency and not nonessential amino acids. These data suggest that FTO might have a role in the sensing of essential amino-acid availability.
The PNPLA3 I148M variant (rs738409) is robustly associated with hepatic steatosis. Intriguingly, initial findings in cohorts with a mean body mass index (BMI) of 30 kg m(-2) also suggested that it is ...associated with elevated liver enzymes but not with insulin resistance and dyslipidaemia.
To determine whether the PNPLA3 variant alters the susceptibility of morbidly obese subjects to develop liver injury and metabolic sequelae.
The study was carried out in 678 obese Italians (mean BMI = 41 kg m(-2)) who were genotyped for the I148M variant. All participants provided fasting blood samples and then underwent oral glucose tolerance tests.
Indices of liver injury (alanine transaminase (ALT), aspartate transaminase (AST)), glucose tolerance and insulin resistance were measured.
Markers of hepatic injury such as ALT and AST were significantly higher in carriers of the 148M allele (P = 2.2 x 10(-5) and 0.001, respectively). In all, 50% of 148M risk allele homozygotes had pathological levels of ALT (>40 U l(-1)) compared with 25% of 148I allele homozygotes (P = 0.005). Glucose tolerance and insulin sensitivity were similar in all three genotypes.
Obese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance.
GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic ...understanding is lacking
. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high
, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.
Human neural progenitors derived from pluripotent stem cells develop into electrophysiologically active neurons at heterogeneous rates, which can confound disease-relevant discoveries in neurology ...and psychiatry. By combining patch clamping, morphological and transcriptome analysis on single-human neurons in vitro, we defined a continuum of poor to highly functional electrophysiological states of differentiated neurons. The strong correlations between action potentials, synaptic activity, dendritic complexity and gene expression highlight the importance of methods for isolating functionally comparable neurons for in vitro investigations of brain disorders. Although whole-cell electrophysiology is the gold standard for functional evaluation, it often lacks the scalability required for disease modeling studies. Here, we demonstrate a multimodal machine-learning strategy to identify new molecular features that predict the physiological states of single neurons, independently of the time spent in vitro. As further proof of concept, we selected one of the potential neurophysiological biomarkers identified in this study-GDAP1L1-to isolate highly functional live human neurons in vitro.
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