Beschreibung: Perfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants, and human exposure to these substances may be related to preeclampsia, a common pregnancy complication. Previous studies have found serum concentrations of PFAS to be positively associated with pregnancy-induced hypertension and preeclampsia in a population with high levels of exposure to perfluorooctanoate. Whether this association exists among pregnant women with background levels of PFAS exposure is unknown. Using data from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health, we carried out a study of nulliparous pregnant women enrolled in 2003–2007 (466 cases, 510 noncases) to estimate associations between PFAS concentrations and an independently validated diagnosis of preeclampsia. We measured levels of 9 PFAS in maternal plasma extracted midpregnancy; statistical analyses were restricted to 7 PFAS that were quantifiable in more than 50% of samples. In proportional hazards models adjusted for maternal age, prepregnancy body mass index (weight (kg)/height (m) 2 ), educational level, and smoking status, we observed no strongly positive associations between PFAS levels and preeclampsia. We found an inverse association between preeclampsia and the highest quartile of perfluoroundecanoic acid concentration relative to the lowest quartile (hazard ratio = 0.55, 95% confidence interval: 0.38, 0.81). Overall, our findings do not support an increased risk of preeclampsia among nulliparous Norwegian women with background levels of PFAS exposure.

Beschreibung: Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1–3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80–85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFRα+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome.

Beschreibung: The three FET (FUS, EWSR1, and TAF15) family RNA binding proteins are expressed in all tissues and almost all cell types. The disordered N-terminal parts are always present in FET fusion oncoproteins of sarcomas and leukemia. Mutations in FUS and TAF15 cause aggregation of FET proteins in neurological disorders. Here we used recombinant proteins in pulldown experiments and mass spectrometry to identify major interaction partners of the FET N-terminal parts. We report that FUS, EWSR1, and TAF15 form homo- and heterocomplexes as major binding partners and identify an evolutionarily conserved N-terminal motif (FETBM1) that is required for this interaction. The binding is RNA and DNA independent and robust up to 1 M of NaCl. The localization of FETBM1 and its target sequences supports a simple model for FET protein aggregation as reported in neurological disorders such as amyotrophic lateral sclerosis, frontotemporal dementia, and essential tremor. The FETBM1 localization also explains the binding of normal full-length FET proteins to their oncogenic fusion proteins.—Thomsen, C., Grundevik, P., Elias, P., Ståhlberg, A., Åman, P. A conserved N-terminal motif is required for complex formation between FUS, EWSR1, TAF15 and their oncogenic fusion proteins.

Beschreibung: Positive-pressure ventilation (PPV) is widely used for treatment of acute cardiorespiratory failure, occasionally at the expense of compromised cardiac function and arterial blood pressure. The explanation why has largely rested on interpretation of intracardiac pressure changes. We evaluated the effect of PPV on the central circulation by studying cardiac chamber volumes with cardiac magnetic resonance imaging (CMR). We hypothesized that PPV lowers cardiac output (CO) mainly via the Frank-Starling relationship. In 18 healthy volunteers, cardiac chamber volumes and flow in aorta and the pulmonary artery were measured by CMR during PPV levels of 0, 10, and 20 cmH 2 O applied via a respirator and a face mask. All cardiac chamber volumes decreased in proportion to the level of PPV. Following 20-cmH 2 O PPV, the total diastolic and systolic cardiac volumes (±SE) decreased from 605 (±29) ml to 446 (±29) ml ( P 〈 0.001) and from 265 (±17) ml to 212 (±16) ml ( P 〈 0.001). Left ventricular stroke volume decreased by 27 (±4) ml/beat; heart rate increased by 7 (±2) beats/min; and CO decreased by 1.0 (±0.4) l/min ( P 〈 0.001). From 0 to 20 cmH 2 O, right and left ventricular peak filling rates decreased by –146 (±32) and –187 (±64) ml/s ( P 〈 0.05) but maximal emptying rates were unchanged. Cardiac filling and output decrease with increasing PPV in healthy volunteers. The decrease is seen even at low levels of PPV and should be taken into account when submitting patients to mechanical ventilation with positive pressures. The decrease in CO is fully explained by the Frank-Starling mechanism.

Beschreibung: The ability to mount a strong immune response against pathogens is crucial for mammalian survival. However, excessive and uncontrolled immune reactions can lead to autoimmunity. Unraveling how the reactive versus tolerogenic state is controlled might point toward novel therapeutic strategies to treat autoimmune diseases. The surface receptor Toso/Faim3 has been...

Beschreibung: Magnetic reconnection is an important process that occurs at the magnetopause boundary of Earth's magnetosphere because it leads to transport of solar wind energy into the system, driving magnetospheric dynamics. However, the nature of magnetopause reconnection in the case of Saturn's magnetosphere is unclear. Based on a combination of Cassini spacecraft observations and simulations we propose that plasma β conditions adjacent to Saturn's magnetopause largely restrict reconnection to regions of the boundary where the adjacent magnetic fields are close to anti-parallel, severely limiting the fraction of the magnetopause surface that can become open. Under relatively low magnetosheath β conditions we suggest that this restriction becomes less severe. Our results imply that the nature of solar wind-magnetosphere coupling via reconnection can vary between planets, and we should not assume that the nature of this coupling is always Earth-like. Studies of reconnection signatures at Saturn's magnetopause will test this hypothesis.

Beschreibung: Perfluorooctane sulfonate and perfluorooctanoic acid are perfluorinated compounds (PFCs) widely distributed in the environment. Previous studies of PFCs and birth weight are equivocal. The authors examined this association in the Norwegian Mother and Child Cohort Study (MoBa), using data from 901 women enrolled from 2003 to 2004 and selected for a prior case-based study of PFCs and subfecundity. Maternal plasma samples were obtained around 17 weeks of gestation. Outcomes included birth weight z scores, preterm birth, small for gestational age, and large for gestational age. The adjusted birth weight z scores were slightly lower among infants born to mothers in the highest quartiles of PFCs compared with infants born to mothers in the lowest quartiles: for perfluorooctane sulfonate, β = –0.18 (95% confidence interval: –0.41, 0.05) and, for perfluorooctanoic acid, β = –0.21 (95% confidence interval: –0.45, 0.04). No clear evidence of an association with small for gestational age or large for gestational age was observed. Perfluorooctane sulfonate and perfluorooctanoic acid were each associated with decreased adjusted odds of preterm birth, although the cell counts were small. Whether some of the associations suggested by these findings may be due to a noncausal pharmacokinetic mechanism remains unclear.

Beschreibung: The purpose of this study was to examine if fat oxidation was affected by menopausal status and to investigate if this could be related to the oxidative capacity of skeletal muscle. Forty-one healthy women were enrolled in this cross-sectional study [premenopausal ( n = 19), perimenopausal ( n = 8), and postmenopausal ( n = 14)]. Estimated insulin sensitivity was obtained from an oral glucose tolerance test. Body composition was measured by dual-energy X-ray absorptiometry and magnetic resonance imaging. Fat oxidation and energy expenditure were measured during an acute exercise bout of 45 min of ergometer biking at 50% of maximal oxygen consumption (V o 2 max ). Muscle biopsies from the vastus lateralis of the quadriceps muscle were obtained before and immediately after the exercise bout. Postmenopausal women had 33% [confidence interval (CI) 95%: 12–55] lower whole body fat oxidation ( P = 0.005) and 19% (CI 95%: 9–22) lower energy expenditure ( P = 0.02) during exercise, as well as 4.28 kg lower lean body mass (LBM) than premenopausal women. Correction for LBM reduced differences in fat oxidation to 23% ( P = 0.05), whereas differences in energy expenditure disappeared ( P = 0.22). No differences between groups were found in mRNA [carnitine palmitoyltransferase I, β-hydroxyacyl-CoA dehydrogenase (β-HAD), peroxisome proliferator-activated receptor-α, citrate synthase (CS), pyruvate dehydrogenase kinase 4, peroxisome proliferator-activated receptor- coactivator-1α (PGC-1α)], protein [phosphorylated AMP-activated protein kinase (AMPK), vascular endothelial growth factor, pyruvate dehydrogenase-1Eα, cytochrome oxidase I], or enzyme activities (β-HAD, CS) in resting skeletal muscle, except for an increased protein level of cytochrome c in the post- and perimenopausal women relative to premenopausal women. Postmenopausal women demonstrated a trend to a blunted exercise-induced increase in phosphorylation of AMPK compared with premenopausal women ( P = 0.06). We conclude that reduced whole body fat oxidation after menopause is associated with reduced LBM.

Beschreibung: [1]  The plume of Enceladus is a remarkable plasma environment containing several charged particle species. These include cold magnetospheric electrons, negative and positive water clusters, charged nanograins and ‘magnetospheric photoelectrons’ produced from ionization of neutrals throughout the magnetosphere near Enceladus. Here we discuss observations of a population newly identified by the CAPS ELS instrument – photoelectrons produced in the plume ionosphere itself. These were found during the E19 encounter, in the energetic particle shadow where penetrating particles are absent. Throughout E19, CAPS was oriented away from the ram direction where the clusters and nanograins are observed during other encounters. Plume photoelectrons are also clearly observed during the E9 encounter, and are also seen at all other Enceladus encounters where electron spectra are available. This new population, warmer than the ambient plasma population, is distinct from, but adds to, the magnetospheric photoelectrons. Here we discuss the observations and examine the implications, including the ionization source these electrons provide.

Beschreibung: The plasma properties, especially the flow parameters, obtained from numerical integration of Cassini/CAPS Ion Mass Spectrometer measurements during intervals when the CAPS field of view encompassed both inward and outward flow directions relative to corotation are examined for nightside data (18–06 local time) during 2006, 2009, and 2010. The results show good agreement with previously-reported values derived using different selection criteria and a different analysis technique. Nightside flows are dominantly in or near the corotation direction, indicating continuing influence of connection to the ionosphere. There is no evidence for a quasi-steady reconnection x-line within the surveyed region of the tail, although dynamic events attributable to transient reconnection have been observed. There is a net radial mass outflow, leading to an estimated net mass loss between 18 and 03 local time of ~34 kg/s. Part of this mass loss occurs as a “planetary wind” along the dusk flank. The remainder probably occurs ultimately much deeper in the tail and along the distant dawn magnetopause, when the mass disconnects from the weakened planetary magnetic field.