Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate.

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2 (-/-)) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2 (-/-) mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation.

Advanced dynamic Doppler flow of the pulmonary artery in a normal population: reference values from 18 to 41 weeks of gestation calculated by automatic Doppler waveform analysis.

OBJECTIVE: The aim of the present cross-sectional prospective study was to establish Doppler reference ranges for blood flow velocity waveforms (V max, V mean and V min) and resistance indices (PI, RI) of the fetal pulmonary arteries using the new pulsed-wave color advanced dynamic flow (ADF) Doppler technique. METHOD: Data were collected in 206 low-risk pregnancies at 18-41 weeks of gestation. The measurements were obtained in the proximal pulmonary artery near the first bifurcation in the absence of fetal body or breathing movements. RESULTS: The pulsatility index (PI) in the pulmonary artery showed mean increases of 2.43-3.59 between gestational weeks 18 and 42. A similar pattern was observed for the resistance index (RI) with increases of 0.79-0.90. Increases in systolic (V max), mean (V mean) and end diastolic (V min) blood flow velocities of 36.0-63.3, 10.8-19.9 and 5.71-7.53 cm/s, respectively, were noted during the observation interval. CONCLUSIONS: The ranges for blood flow velocities and impedance indices in the fetal pulmonary artery calculated by the authors may serve as reference values to help distinguish a normal patient population from patients carrying fetuses at high risk for neonatal lung disease in antenatal examinations.

Blood flow velocity waveforms of the umbilical artery in a normal population: reference values from 18 weeks to 42 weeks of gestation.

PURPOSE: The aim of the present study was to calculate new Doppler reference ranges for systolic, intensity-weighted mean, and end-diastolic blood flow velocities (Vmax, Vmean, Vmin) and fetal heart rate and impedance indices (PI, RI) of the umbilical artery by automatic waveform analysis. MATERIALS AND METHODS: A cross-sectional prospective study of 1926 low-risk pregnancies was performed at 18 - 42 weeks of gestation. The measurements were carried out in the region of a free floating loop of cord. Reference ranges for the individual measuring parameters were constructed based on a growth function from a four-parameter class of monotonic continuous functions according to the smallest square principle. The intraobserver reliability was also assessed. RESULTS: A significant increase in umbilical blood flow velocity was observed at 18 - 42 weeks of gestation (Vmax = 33.7 cm/sec to 65 cm/sec (p < 0.001), Vmean = 18.2 cm/sec to 38.7 cm/sec (p < 0.001) and Vmin = 8.2 to 31 cm/sec (p < 0.001). Reference curves for the pulsatility and the resistance index were associated with significant decreases with increasing gestational age (PI: 18 weeks: 1.3; 28 weeks: 1.1; 42 weeks: 0.8 and RI: 18 weeks: 0.7; 28 weeks: 0.6; 42 weeks: 0.5). The fetal heart rate decreased from 147 - 134 bpm. The intraobserver reliability was low, but of no clinical relevance. CONCLUSION: The reference ranges for blood flow velocities and resistance indices in the umbilical artery calculated by the authors serve as the basis for Doppler ultrasound antenatal examinations in a normal patient population and enable the early diagnosis of fetal risk.

Reference values for blood flow velocity in the uterine artery in normal pregnancies from 18 weeks to 42 weeks of gestation calculated by automatic Doppler waveform analysis.

PURPOSE: The goal of the present study was to establish new Doppler reference ranges for maternal heart rate, intensity-weighted mean blood flow velocities (Vmean) and impedance indices (PI, RI) for the uterine artery by automated waveform analysis. MATERIALS AND METHODS: A cross-sectional prospective study of 921 low-risk pregnancies was performed at 18 - 42 weeks of gestation. Uterine blood flow velocities were derived with pulsed-wave color Doppler. Measurements were carried out 1 to 2 cm above the crossing of the uterine and external iliac arteries. Reference ranges for the individual measuring parameters were constructed based on a growth function from a four-parameter class of monotonic continuous functions according to the smallest square principle. RESULTS: A significant increase in intensity-weighted mean uterine blood flow velocities was observed at 18 - 42 weeks of gestation (Vmean = 43 cm/s to 50 cm/s (p < 0.001)). Reference curves for the pulsatility and resistance indices (PI, RI) significantly decreased with progressing gestation (PI: 18 weeks: 0.89; 42 weeks: 0.65 and RI: 18 weeks: 0.45; 42 weeks: 0.35). No significant PI and RI differences were observed when different placental locations were compared. The maternal heart rate decreased from 88 bpm to 77 bpm. CONCLUSION: Normal ranges for blood flow velocities and impedance indices in the uterine artery were established by Doppler ultrasound antenatal examinations of a large population of low-risk pregnancies. The data are proposed as reference curves to allow the early diagnosis of maternal and fetal risks.