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Objective: Menopause is associated with multiple health risks. In several studies, a higher incidence or a higher risk for obstructive sleep apnea (OSA) in post-menopausal than pre-menopausal women is reported. This study was designed to verify such a connection between menopause and OSA in a population-based sample. Methods: For a subsample (N = 1209) of the Study of Health in Pomerania (N = 4420), complete polysomnography data was available. Of these, 559 females completed a structured interview about their menstrual cycle. Splines and ordinal regression analysis were used to analyze the resulting data. Results: In the ordinal regression analysis, a significant association between the apnea–hypopnea index (AHI) and menopause indicated that post-menopausal women had a substantially higher risk of OSA. In accordance with previous studies, risk indicators such as body mass index (BMI), age, and the influence of hysterectomies or total oophorectomies were included in the model. Conclusions: Our results clearly confirmed the assumed connection between menopause and OSA. This is important because OSA is most often associated with male patients, and it warrants further research into the underlying mechanisms.

Obstructive sleep apnea is known to be an overall public health problem that, among other things, increases morbidity and mortality. Risk factors as well as symptoms of this multidimensional sleep-related breathing disorder negatively affect quality of life. With our study we aimed to expose the association between obstructive sleep apnea and quality of life in the population of Pomerania, Germany. We utilized data from the population-based Study of Health in Pomerania (SHIP). Information on health status and risk factors about 4420 participants (2275 women) were gathered within the cohort SHIP-TREND, of which 1209 (559 women) underwent an overnight polysomnography and completed sleep questionnaires. The quality of life of the participants was measured using the Short-Form 12 questionnaire. For our study, an ordinal regression analysis with age, sex, body mass index and the Short-Form 12 health survey as predictors for apnea-hypopnea index was computed. The potential factors affecting quality of life are different between physical and mental dimensions of quality of life. Significant effects were found regarding age, sex, body mass index and the Short-Form 12 Mental Component Score, but not the Physical Component Score.

The environmental prevalence of antimicrobial resistance (AMR) has come into focus under the One Health concept. Wastewater treatment systems are among the significant sources of AMR in the environment. In such systems, it is uncertain to which extent antimicrobials present at sub-inhibitory concentrations constitute a selective pressure for bacterial maintenance and acquisition of antibiotic resistance (AR) genes. Here, we mapped AMR to inhibitors of folate biosynthesis in an aerated and a non-aerated horizontal subsurface flow treatment wetland receiving the same pre-treated municipal wastewater. General water characteristics and the concentrations of folate inhibitors were determined to define the ambient conditions over the longitudinal axis of the two treatment wetlands. Profiling of AMR as well as class 1 integrons, a carrier of AR genes against folate inhibitors and other antimicrobials, was conducted by cultivation-dependent and -independent methods. The wetlands achieved mean reductions of AR gene copy numbers in the effluents of at least 2 log, with the aerated system performing better. The folate inhibitors had no noticeable effect on the prevalence of respective AR genes. However, there was a transient increase of AR gene copy numbers and AR gene cassette composition in class 1 integrons in the aerated wetland. The comparison of all data from both wetlands suggests that higher levels of cellular stress in the aerated system promoted the mobility of AR genes via enhancing the activity of the DNA recombinase of the class 1 integron. The findings highlight that environmental conditions that modulate the activity of this genetic element can be more important for the fate of associated AR genes in treatment wetlands than the ambient concentration of the respective antimicrobial agents. By extrapolation, the results suggest that cellular stress also contributes to the mobility of AR gene in other wastewater treatment systems.

Purpose Socioeconomic factors are known to modulate health. Concerning sleep apnea, influences of income, education, work, and living in a partnership are established. However, results differ between national and ethnic groups. Results also differ between various clinical studies and population-based approaches. The goal of our study was to determine if such factors can be verified in the population of Pomerania, Germany. Methods A subgroup from the participants of the population-based Study of Health in Pomerania volunteered for an overnight polysomnography. Their data were subjected to an ordinal regressions analysis with age, sex, body mass index (BMI), income, education, work, and life partner as predictors for the apnea–hypopnea index. Results Among the subgroup (N = 1209) from the population-based study (N = 4420), significant effects were found for age, sex, and BMI. There were no significant effects for any of the socioeconomic factors. Conclusion Significant effects for well-established factors as age, sex, and BMI show that our study design has sufficient power to verify meaningful associations with sleep apnea. The lack of significant effects for the socioeconomic factors suggests their clinical irrelevance in the tested population.

Background We previously reported on a pilot study to assess the incorporation of a novel wellness assessment device, the Preventiometer (iPEx5 GmbH, Greifswald, Germany), into an academic medical practice. The present follow-up study expands on those data and evaluates the acceptability of the assessment process in a larger sample population. Objective The aim of this study was to evaluate participant satisfaction with the Preventiometer wellness assessment. Methods A total of 60 healthy volunteers participated. Each participant underwent a comprehensive wellness assessment with the Preventiometer and received data from more than 30 diagnostic tests. A 32-question survey (with a numeric rating scale from 0 to 10) was used to rate the wellness assessment tests and participants’ impressions of the wellness assessment. Results Each assessment had a significantly higher rating than 7 ( P < .001), and the majority of participants agreed or strongly agreed that they were satisfied (98.3%), and they strongly agreed that they were engaged the entire time (93.2%), and liked the instant test results feature of the Preventiometer device (93.2%). Conclusion This study confirms findings from our previous pilot study regarding the feasibility of the Preventiometer as a wellness assessment tool. The study further demonstrated that 98% of participants were satisfied with the assessment and that all of them would recommend it to others.

The terrestrial subsurface contains nearly all of Earth’s freshwater reserves1 and harbors upwards of 60% of our planet’s total prokaryotic biomass2,3. While genetic surveys suggest these organisms rely on in situ carbon fixation, rather than the translocation of photosynthetically derived organic carbon4–6, corroborating measurements of carbon fixation in the subsurface are absent. Using a novel ultra-low level 14C-labeling technique, we show that in situ carbon fixation rates in a carbonate aquifer reached 10% of the median rates measured in oligotrophic marine surface waters, and were up to six-fold greater than those observed in lower euphotic zone waters where deep chlorophyll levels peak. Empirical carbon fixation rates were substantiated by both nitrification and anammox rate data. Metagenomic analyses revealed a remarkable abundance of putative chemolithoautotrophic members of an uncharacterized order of Nitrospiria – the first representatives of this class expected to fix carbon via the Wood-Ljungdahl pathway. Based on these fixation rates, we extrapolate global primary production in carbonate groundwaters to be 0.11 Pg of carbon per year.

In times of climate change, the reduction in embodied greenhouse gas emissions is a premise for sustainable concrete infrastructure. As Portland cement clinker is mainly responsible for the high CO2 emissions of concrete, its reduction is necessary. In order to be sustainable, the concrete must meet processing, mechanical and durability properties while taking cost aspects into account. The paper presents (i) the “micro-filler/eco-filler concept” for achieving a clinker reduced, optimised binder and (ii) a performance-based approach to put sustainable “Eco-concrete” into practice. Clinker is substituted by locally available inert fillers by at least two different particle size fractions and supplementary cementitious materials. The method is based on particle packing optimisation, reduction in water demand and optimisation of the mix ratio of the binder blend, which allows the performance requirements to be met. The new Eco-concretes deliver the desired performance in terms of processability, strength and durability (water penetration, frost, carbonation and chloride resistance) while lowering the environmental impact in comparison to standard concrete. One of the new mixes was used for a small animal passage tunnel. The direct comparison of the developed Eco-concrete and standard concrete showed a 24% reduction in CO2, while achieving satisfactory workability, stripping strength and durability performance.

Integrity of mitochondrial DNA (mtDNA), encoding several subunits of the respiratory chain, is essential to maintain mitochondrial fitness. Mitochondria, as a central hub for metabolism, are affected in a wide variety of human diseases but also during normal ageing, where mtDNA integrity is compromised. Mitochondrial quality control mechanisms work at different levels, and mitophagy and its variants are critical to remove dysfunctional mitochondria together with mtDNA to maintain cellular homeostasis. Understanding the mechanisms governing a selective turnover of mutation-bearing mtDNA without affecting the entire mitochondrial pool is fundamental to design therapeutic strategies against mtDNA diseases and ageing. Here we show that mtDNA depletion after expressing a dominant negative version of the mitochondrial helicase Twinkle, or by chemical means, is due to an exacerbated mtDNA turnover. Targeting of nucleoids is controlled by Twinkle which, together with the mitochondrial transmembrane proteins ATAD3 and SAMM50, orchestrate mitochondrial membrane remodeling to form extrusions. mtDNA removal depends on autophagy and requires the vesicular trafficking protein VPS35 which binds to Twinkle-enriched mitochondrial subcompartments upon mtDNA damage. Stimulation of autophagy by rapamycin selectively removes mtDNA deletions which accumulated during muscle regenerationin vivo, but without affecting mtDNA copy number. With these results we unveil a new complex mechanism specifically targeting and removing mutant mtDNA which occurs outside the mitochondrial network. We reveal the molecular targets involved in a process with multiple potential benefits against human mtDNA related diseases, either inherited, acquired or due to normal ageing.

Nitrification in forest soils is often associated with increased leaching of nitrate to deeper soil layers with potential impacts on groundwater resources, further enhanced under scenarios of anthropogenic atmospheric nitrogen deposition and predicted weather extremes. We aimed to disentangle the relationships between soil nitrification potential, seepage-mediated nitrate leaching and the vertical translocation of nitrifiers in soils of a temperate mixed beech forest in central Germany before, during and after the severe summer drought 2018. Leaching of nitrate assessed below the litter layer and in 4, 16 and 30 cm soil depth showed high temporal and vertical variation with maxima at 16 and 30 cm during and after the drought period. Maximum of soil potential nitrification activity of 4.4 mg N kg-1d-1only partially coincided with maximum nitrate leaching of 10.5 kg N ha-2. Both ammonia oxidizing bacteria (AOB) and ammonia oxidizing archaea (AOA) were subject to translocation by seepage, and AOB decreased at least by half and AOA increased by one to three orders of magnitude in their abundance in seepage with increasing soil depth. On the level of the total bacterial population, an increasing trend with depth was also observed forCand. Patescibacteria while Bacteroidetes were strongly mobilized from the litter layer but poorly transported further down. Despite stable population densities in soil over time, abundances of AOA, AOB and total bacteria in seepage increased by one order of magnitude after the onset of autumn rewetting. Predicted future higher frequency of drought periods in temperate regions may result in more frequent seepage-mediated seasonal flushes of nitrate and bacteria from forest soils. Moreover, the observed translocation patterns point to taxon-specific differences in the susceptibility to mobilization, suggesting that only selected topsoil derived microbial groups are likely to affect subsoil or groundwater microbial communities and their functional potential.

This paper addresses the prediction of the spread-flow of water-powder mixes, which is of particular interest in the mix design of cementitious pastes, mortar and concrete. The model introduced, splits the total water demand which is necessary to achieve a specific spread of water-powder mixes into three parts: (i) water to fill the voids between the solid particles, (ii) water to reach the onset of flow and (iii) water to reach a specific spread. An algorithm developed allows the systematic calculation of the total water demand of mixes with varying proportions of powders after the individual characterization of the source materials regarding their void volume and spread-flow coefficients (i.e. retained water ratio and deformation coefficient). With this approach it is possible to optimize the proportion of mixture in cement-based binders (blended cements) with regard to a minimum water demand for a target spread. An example for the optimization of blends of ordinary Portland cement (OPC) and supplementary cementitious materials (SCM) in terms of clinker-efficiency is given leading to improved strength with reduced environmental impact in comparison to OPC based mixes.

Adults' mental rotation performance with body-like stimuli is enhanced if these stimuli are anatomically compatible with a human body, but decreased by anatomically incompatible stimuli. In this study, we investigated these effects for kindergartners and first-graders: When asked to mentally rotate cube configurations attached with human body parts in an anatomically compatible way, allowing for the projection of a human body, children performed better than with pure cube combinations. By contrast, when body parts were attached in an anatomically incompatible way, disallowing the projection of a human body, children performed worse than with pure combinations. This experiment is of specific interest against the background of two different theoretical approaches concerning imagery and the motor system in development: One approach assumes an increasing integration of motor processes and imagery over time that enables older children and adults to requisition motor resources for imagery processes, while the other postulates that imagery stems from early sensorimotor processes in the first place, and is disentangled from it over time. The finding that children of the two age groups tested show exactly the same effects as adults when mentally rotating anatomically compatible and incompatible stimuli is interpreted in favour of the latter approach. Statement of contribution What is already known on this subject? In mental rotation, adults perform better when rotating anatomically possible stimuli as compared to rotating standard cube combinations. Performance is worse when rotating anatomically impossible stimuli. What does this study add? The present study shows that children's mental transformations mirror those of adults in these respects. In case of the anatomically impossible stimuli, this highlights an inflexible use of embodiment in both age groups. This is in line with the Piagetian assumption of imagery being based on sensorimotor processes.

Mainly for methodological reasons, little is known about the course of development of early cognitive competencies diagnosed with the violation of expectation (VoE) method in infants. The goal of this research was to evaluate the use of pupillometry as a unified approach to assess expectancy violations during and beyond the "dark ages" between 1 and 3 years. We tested children aged 1-6 years and adults (N = 279) with pictures of animals combined with matching or mismatching animal sounds. All age groups exhibited significantly greater pupil dilation in mismatched than matched trials. We conclude that pupillometry is a viable alternative to the VoE method that, by contrast to the latter, can be used throughout the life span.

The durability of eco-efficient, clinker reduced concrete is a key factor of its performance. In the presented study, different durability indicators of a newly developed eco-concrete composition (ECO) are tested versus standard normal concrete as reference (REF). The tested durability indicators are open porosity, water penetration depth, rate of water absorption by capillarity and two different methods of measuring air permeability (PermeaTORR AC device versus Testing bubble counter). The ECO mix and in particular its cementitious matrix is designed by a combined filler concept substituting Portland cement partially by properly selected limestone fillers of different grain sizes. The approach is based on a combination of particle packing optimization techniques and the reduction of water demand for certain flowability of the paste. Cement content is below the limits of traditional standards while w/c-ratio exceed such limits. While the performance of the eco-concrete in terms of workability and strength is at least equivalent to the standard mix, ecological impact indicators as global warming potential and embodied energy are substantially improved. Durability indicators overall show nearly equivalent performance of ECO and REF. In detail, the resulting air permeability coefficient tested with a bubble counter differs significantly from the coefficient tested by PermeaTORR.

Rationale: In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition. Objective: The aim of this study was to identify the mechanism of regulation of the methyl-CpG–binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading. Methods and Results: MeCP2 was identified as a reversibly repressed gene in mouse hearts after transverse aortic constriction and was normalized after removal of the constriction. Similarly, MeCP2 repression in human failing hearts resolved after unloading by a left ventricular assist device. The cluster miR-212/132 was upregulated after transverse aortic constriction or on activation of α 1 - and β 1 -adrenoceptors and miR-212/132 led to repression of MeCP2. Prevention of MeCP2 repression by a cardiomyocyte-specific, doxycycline-regulatable transgenic mouse model aggravated cardiac hypertrophy, fibrosis, and contractile dysfunction after transverse aortic constriction. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after reversible transverse aortic constriction. Genome-wide expression analysis, chromatin immunoprecipitation experiments, and DNA methylation analysis identified mitochondrial genes and their transcriptional regulators as MeCP2 target genes. Coincident with its repression, MeCP2 was removed from its target genes, whereas DNA methylation of MeCP2 target genes remained stable during pressure overload. Conclusions: These data connect adrenergic activation with a microRNA—MeCP2 epigenetic pathway that is important for cardiac adaptation during the development and recovery from heart failure.

Three-year-olds and 4-year-olds have severe difficulties solving standard mental rotation tasks. Only 5-year-olds solve such tasks above chance reliably. In contrast studies relying on simplified mental rotation tasks indicate that infants discriminate between an object and its mirror image. Furthermore in another simplified mental rotation task with 3-year-olds, a linear relation between angular disparity and reaction time typical for mental rotation was revealed. Therefore it was assumed that 3-year-olds’ capabilities are underestimated. In the current study, 3-year-olds were trained in two isolated sessions to solve standard mental rotation tasks and were tested in a third session. Three-year-olds solved this test above chance as a group – a substantial number of them doing so on an individual level. However, a linear relation between angular disparity and reaction time, that would indicate an analog mental transformation, was not discernable. Nevertheless, these findings are in accordance with a continuous line describing mental rotation in infants and older children. And, these also indicate that children’s mental rotation capabilities might be underestimated.

Summary Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between these processes remained unclear. Here we demonstrate that the C16:0 sphingolipid synthesizing ceramide synthases, CerS5 and CerS6, affect distinct sphingolipid pools and that abrogation of CerS6 but not of CerS5 protects from obesity and insulin resistance. We identify proteins that specifically interact with C16:0 sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C16:0 sphingolipids bind the mitochondrial fission factor (Mff). CerS6 and Mff deficiency protect from fatty acid-induced mitochondrial fragmentation in vitro, and the two proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid signaling depending on specific synthesizing enzymes, provide a mechanistic link between hepatic lipid deposition and mitochondrial fragmentation in obesity, and define the CerS6-derived sphingolipid/Mff interaction as a therapeutic target for metabolic diseases.

Polymer composite materials combine high strength with low weight. This makes composites an interesting material for different industrial applications. In the aerospace industry, the use of composites is already common practice, while in the automotive industry carbon fiber-reinforced polymers have begun to replace metal in some parts. However, the nature of damage within composites is different from that within metal parts, so common techniques available for damage detection in metal may not work for composites thus new techniques for damage detection need to be developed. A technique that is often used but requires experienced technicians is the so-called coin tapping test where changes in sound waves generated by the impact of a hard object are detected. LARS is a (new) technique that avoids the errors due to variations in operator technique by using a instrumented impact device to generate controlled sound signals. If a hammer is used as an impact device it could be equipped with a dynamic force sensor to measure and record the excitation force of the sound signal. The force and the excited sound signal are related to the contact stiffness between the hammer and the test part. Flaws such as voids and delaminations affect the contact stiffness and can be detected under certain conditions. To the knowledge of the authors, no such technique has appeared in the literature. In regard to the frequencies, LARS is operated at much shorter wavelengths than in vibration analysis techniques (making it “local”) and at much larger wavelengths than in ultrasound. The material is excited to frequencies that are recorded by a microphone. To demonstrate the method, it is applied to the inspection of wind turbine rotor blades.

Rationale: Myocardial diastolic stiffness and cardiomyocyte passive force (F passive ) depend in part on titin isoform composition and phosphorylation. Ca 2+ /calmodulin-dependent protein kinase-II (CaMKII) phosphorylates ion channels, Ca 2+ -handling proteins, and chromatin-modifying enzymes in the heart, but has not been known to target titin. Objective: To elucidate whether CaMKII phosphorylates titin and modulates F passive in normal and failing myocardium. Methods and Results: Titin phosphorylation was assessed in CaMKIIδ/γ double-knockout (DKO) mouse, transgenic CaMKIIδC-overexpressing mouse, and human hearts, by Pro-Q-Diamond/Sypro-Ruby staining, autoradiography, and immunoblotting using phosphoserine-specific titin-antibodies. CaMKII-dependent site-specific titin phosphorylation was quantified in vivo by mass spectrometry using s table isotope labeling by amino acids in cell culture mouse heart mixed with wild-type (WT) or DKO heart. F passive of single permeabilized cardiomyocytes was recorded before and after CaMKII-administration. All-titin phosphorylation was reduced by >50% in DKO but increased by up to ≈100% in transgenic versus WT hearts. Conserved CaMKII-dependent phosphosites were identified within the PEVK-domain of titin by quantitative mass spectrometry and confirmed in recombinant human PEVK-fragments. CaMKII also phosphorylated the cardiac titin N2B-unique sequence. Phosphorylation at specific PEVK/titin N2B-unique sequence sites was decreased in DKO and amplified in transgenic versus WT hearts. F passive was elevated in DKO and reduced in transgenic compared with WT cardiomyocytes. CaMKII-administration lowered F passive of WT and DKO cardiomyocytes, an effect blunted by titin antibody pretreatment. Human end-stage failing hearts revealed higher CaMKII expression/activity and phosphorylation at PEVK/titin N2B-unique sequence sites than nonfailing donor hearts. Conclusions: CaMKII phosphorylates the titin springs at conserved serines/threonines, thereby lowering F passive . Deranged CaMKII-dependent titin phosphorylation occurs in heart failure and contributes to altered diastolic stress.

Children as young as 3 years can remember an object’s location within an arrangement and can retrieve it from a novel viewpoint (Nardini et al., 2006). However, this ability is impaired if the arrangement is rotated to compensate for the novel viewpoint, or, if the arrangement is rotated and children stand still. There are two dominant explanations for this phenomenon: self-motion induces an automatic spatial updating process which is beneficial if children move around the arrangement, but misleading if the children’s movement is matched by the arrangement and not activated if children stand still and only the arrangement is moved (see spatial updating; Simons and Wang, 1998). Another explanation concerns reference frames: spatial representations might depend on peripheral spatial relations concerning the surrounding room instead on proximal relations within the arrangement, even if these proximal relations are sufficient or more informative. To evaluate these possibilities, we rotated children (N = 120) aged between 3 and 6 years with an occluded arrangement. When the arrangement was in misalignment to the surrounding room, 3- and 4-year-olds’ spatial memory was impaired and 5-year-olds’ was lightly impaired suggesting that they relied on peripheral references of the surrounding room for retrieval. In contrast, 6-years-olds’ spatial representation seemed robust against misalignment indicating a successful integration of spatial representations.

So far, the inspection of building structures and especially of bridges is mainly done visually. Therefore, the condition of the structure is examined from the surface and the interpretation and assessment is based on the experience of the expert. However, the main purpose of monitoring civil structures is not to substitute visual inspection. Continuous structural health monitoring should provide data from the inside of a structure to better understand its structural performance and to predict its durability and remaining life time. Monitoring should render objective data and observable alterations in the structure continuously, which cannot be done by visual inspection. More detailed information is needed with respect to different exposure due to dynamic and static loads and also temperature and moisture. Today mainly wired monitoring systems are used to monitor structures, which are relatively expensive and time consuming to install. In this paper the basic principle of a wireless monitoring system equipped with MEMS sensors is presented, which can be easily installed at different structures. Microelectromechanical systems (MEMS) are small integrated devices or systems that combine electrical and mechanical components. A wireless monitoring sensor network equipped with such MEMS could be produced with a very low budget and becomes very efficient. This permits a wide area of applications not only in civil engineering. With respect to different applications relevant properties of a wireless monitoring system are described. In detail network configuration, power consumption, data acquisition and data aggregation, signal analysis and data reduction as well as reliability and robustness are discussed.

Many attempts have been focused on the textile reinforced mortar structures. The advantages of textiles are mainly a very good load bearing capacity, excellent ductility, thin size and light weight of components, resistance to corrosion, and no magnetic disturbances. Such structures are expected to have wide application foregrounds. The transfer of forces from reinforcement to mortar is accomplished through a bond. Therefore, understanding and further improving bond properties of textiles in mortar are important. In the paper, bond characteristics of various textiles in mortar obtained from pull-out tests and numerical simulations are shown and compared. The textiles used include carbon, alkali resistant glass and aramid. They were plain and impregnated with epoxy resin. Prestressed and nonprestressed specimens were tested. The experimental results show that epoxy resin impregnating and prestressing can strongly enhance the bond strength. Numerical simulations show good agreement with the experimental results and significantly contribute to a better understanding of the bond characteristics of textiles in mortar.

The neuronal stem cell leukemia (NSCL) basic helix-loop-helix factors are neural cell-specific transcription factors. We have disrupted the NSCL-1 gene by homologous recombination and replaced the coding region with a beta-galactosidase reporter cassette to study the role of NSCL-1 in neuronal development and to follow the fate of NSCL-1 mutant cells. NSCL-1 mutant mice are viable and fertile on various genetic backgrounds and do not show any obvious signs of neurological malfunction. No differences in the distribution of NSCL-1 mutant or heterozygous neuronal cells were observed in the diencephalon, hippocampus, neocortex, and cerebellum at different stages of development. Likewise, no defects were found in the laminar organization of the cortex, and the distinct neuronal subpopulation appeared normal during development of the neocortex. Analysis of sensory neurons which strongly express NSCL-1 revealed that the spatiotemporal expression of neuronal differentiation factors, such as NeuroD and SCG-10, was not altered in developing distal and proximal cranial ganglia of mutant mice. In the cerebellum expression of NSCL-1 was confined to the proliferative and premigratory zone of the external granular layer and the internal granular layer. Interestingly, unlike cerebella of Math1(-/-) or NeuroD2(-/-) mice, NSCL-1-deficient mice have no obvious developmental defect, and neurons of the cerebellum appeared fully differentiated. Despite similar expression patterns of NSCL-1 and NSCL-2 in various areas of the diencephalon, including the arcuate nucleus and paraventricular nucleus, NSCL-1(-/-) mice are fertile and show no adult onset of obesity like NSCL-2 mutant mice. Double-mutant NSCL-1(-/-)-NSCL-2(-/-) mice do not show any additional obvious malformations of the central nervous system, although both genes are expressed in a largely overlapping pattern. Our results argue against a simple functional redundancy within the NSCL gene family.

Myelination depends on the synthesis of large amounts of myelin transcripts and proteins and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on stable isotope labeling with amino acids in cell culture (SILAC) to measure the dynamics of myelin protein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system, and myelination then slows down. Remarkably, sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination, resulting in continuous myelin growth. MAPK activation leads to minor changes in transcript levels but massively up-regulates protein production. Pharmacological interference in vivo demonstrates that the effects of activated MAPK signaling on translation are mediated by mTOR-independent mechanisms but in part also by mTOR-dependent mechanisms. Previous work demonstrated that loss of ErbB3/Shp2 signaling impairs Schwann cell development and disrupts the myelination program. We found that activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination.

International audience; We examined whether body parts attached to abstract stimuli automatically force embodiment in a mental rotation task. In Experiment 1, standard cube combinations reflecting a human pose were added with (1) body parts on anatomically possible locations, (2) body parts on anatomically impossible locations, (3) colored end cubes, and (4) simple end cubes. Participants (N=30) had to decide whether two simultaneously presented stimuli, rotated in the picture plane, were identical or not. They were fastest and made less errors in the possible-body condition, but were slowest and least accurate in the impossible-body condition. A second experiment (N=32) replicated the results and ruled out that the poor performance in the impossible-body condition was due to the specific stimulus material. The findings of both experiments suggest that body parts automatically trigger embodiment, even when it is counterproductive and dramatically impairs performance, as in the impossible-body condition. It can furthermore be concluded that body parts cannot be used flexibly for spatial orientation in mental rotation tasks, compared to colored end cubes. Thus, embodiment appears to be a strong and inflexible mechanism that may, under certain conditions, even impede performance.

The terrestrial subsurface contains nearly all of Earth's freshwater reserves and harbours the majority of our planet's total prokaryotic biomass. Although genetic surveys suggest these organisms rely on in situ carbon fixation, rather than the photosynthetically derived organic carbon transported from surface environments, direct measurements of carbon fixation in the subsurface are absent. Using an ultra-low level C-14-labelling technique, we estimate in situ carbon fixation rates in a carbonate aquifer. We find these rates are similar to those measured in oligotrophic marine surface waters and up to six-fold greater than those observed in the lower euphotic zone. Our empirical carbon fixation rates agree with nitrification rate data. Metagenomic analyses reveal abundant putative chemolithoautotrophic members of an uncharacterized order of Nitrospiria that may be behind the carbon fixation. On the basis of our determined carbon fixation rates, we conservatively extrapolate global primary production in carbonate groundwaters (10% of global reserves) to be 0.11 Pg carbon per year. These rates fall within the range found for oligotrophic marine surface waters, indicating a substantial contribution of in situ primary production to subsurface ecosystem processes. We further suggest that, just as phototrophs are for marine biogeochemical cycling, such subsurface carbon fixation is potentially foundational to subsurface trophic webs. Direct measurements of carbon fixation rates in groundwater suggest a substantial contribution of in situ primary production to subsurface ecosystem processes.

Rationale: Myocardial diastolic stiffness and cardiomyocyte passive force (Fpassive) depend in part on titin isoform composition and phosphorylation. Ca2+/calmodulin-dependent protein kinase-IIδ (CaMKIIδ) phosphorylates ion channels, Ca2+-handling and myofilament proteins in the heart, but has not been known to target titin.Objective: To elucidate whether CaMKIIδ phosphorylates titin and regulates Fpassive in normal and failing myocardium.Methods and Results: Titin phosphorylation was assessed in CaMKIIδ/γ double-knockout (DKO) and transgenic CaMKIIδC-overexpressing (TG) mouse hearts, as well as human hearts, by Pro-Q-Diamond/Sypro-Ruby staining, autoradiography, and immunoblotting using phosphospecific titin antibodies. CaMKII-dependent site-specific titin phosphorylation was quantified in vivo by mass spectrometry using SILAC mouse heart tissue mixed with wildtype (WT) or DKO heart. Fpassive of single permeabilized cardiomyocytes was recorded before and after CaMKII administration. We detected hypophosphorylation of all-titin in DKO and hyperphosphorylation in TG compared to WT hearts. Conserved CaMKII-dependent phosphosites were identified within titin's PEVK-domain by quantitative mass spectrometry and confirmed in recombinant human PEVK-fragments. CaMKII also phosphorylated the cardiac titin N2B-unique sequence (N2Bus). Phosphorylation at specific PEVK/N2Bus sites was decreased in DKO and amplified in TG versus WT hearts. Fpassive was elevated in DKO and reduced in TG compared to WT cardiomyocytes. CaMKII-administration lowered Fpassive of WT and DKO cardiomyocytes, an effect blunted by titin-phosphoantibody pretreatment. Human failing hypertrophic hearts revealed higher CaMKII expression/activity and phosphorylation at PEVK/N2Bus sites than nonfailing donor hearts.Conclusions: CaMKIIδ phosphorylates the titin springs at conserved serines/threonines, thereby lowering Fpassive. Deranged CaMKIIδ-dependent titin phosphorylation occurs in heart failure and contributes to altered diastolic stress.