The mutational landscape of normal human endometrial epithelium.

All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium1,2. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.

Asthma and COPD exacerbation in relation to outdoor air pollution in the metropolitan area of Berlin, Germany.

BACKGROUND: Ambient air pollution poses a major risk for the development and aggravation of respiratory diseases. Evidence suggests that even in low-level air pollution environments there is a risk for an increase in adverse respiratory symptoms. We examined whether variations in daily air pollution levels of nitrogen dioxide, ozone, or particulate matter in Berlin, Germany were associated with hospital admissions of chronic obstructive pulmonary disease (COPD) and asthma patients in a time series analysis. METHODS: We calculated single and multi-pollutant models, investigated possible lags in effect, and analysed the influence of meteorological variables on the results. Data from January 2005 through December 2015 were used to quantify the concentration-response. RESULTS: The risk ratio for asthma patients to be hospitalised on the same day of NO2 exposure was 1.101 per 10 µg/m3 NO2 increase (95% CI: 1.013 to 1.195), for COPD patients 1.123 (95% CI: 1.081 to 1.168). Neither the exposure to ozone (95% CI: 0.904 to 1.020), PM10 (95% CI: 0.990 to 1.127), nor PM2.5 (95% CI: 0.981 to 1.148) was associated with an increased risk ratio for asthma patients to be hospitalised. Risk ratios for the hospital admission of COPD patients were also not increased due to ozone (95% CI: 0.981 to 1.033), PM10 (95% CI: 0.988 to 1.032), or PM2.5 (95% CI: 0.966 to 1.019) exposure. The presented risk ratios and confidence intervals relate to the day of exposure. We found no increased hospitalisation risks with a delayed occurrence on subsequent days. CONCLUSIONS: A quantifiable, statistically significant increase in risk for asthma and COPD exacerbations owing to NO2 exposure at levels well below European regulatory limit values was observed.

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment.

The p75 neurotrophin receptor (p75(NTR); also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75(NTR)-derived trophic cell-permeable peptide, c29, to inhibit p75(NTR)-mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1(G93A) mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75(NTR) cleavage products. Although c29 treatment inhibited mature- and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75(NTR) in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75(NTR) cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1(G93A) mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo.

Effect of VOC Emissions from Vegetation on Air Quality in Berlin during a Heatwave.

The potential of emissions from urban vegetation combined with anthropogenic emissions to produce ozone and particulate matter has long been recognized. This potential increases with rising temperatures and may lead to severe problems with air quality in densely populated areas during heat waves. Here, we investigate how heat waves affect emissions of volatile organic compounds from urban/suburban vegetation and corresponding ground-level ozone and particulate matter. We use the Weather Research and Forecasting Model with atmospheric chemistry (WRF-Chem) with emissions of volatile organic compounds (VOCs) from vegetation simulated with MEGAN to quantify some of these feedbacks in Berlin, Germany, during the heat wave in 2006. The highest ozone concentration observed during that period was ∼200 µg/m3 (∼101 ppbV). The model simulations indicate that the contribution of biogenic VOC emissions to ozone formation is lower in June (9-11%) and August (6-9%) than in July (17-20%). On particular days within the analyzed heat wave period, this contribution increases up to 60%. The actual contribution is expected to be even higher as the model underestimates isoprene concentrations over urban forests and parks by 0.6-1.4 ppbv. Our study demonstrates that biogenic VOCs can considerably enhance air pollution during heat waves. We emphasize the dual role of vegetation for air quality and human health in cities during warm seasons, which is removal and lessening versus enhancement of air pollution. The results of our study suggest that reduction of anthropogenic sources of NOx, VOCs, and PM, for example, reduction of the motorized vehicle fleet, would have to accompany urban tree planting campaigns to make them really beneficial for urban dwellers.

A fully integrated isoprenoid emissions model coupling emissions to photosynthetic characteristics.

The lack of a mechanistic basis has hampered modelling isoprene emission responses to environmental drivers, in particular the simulation of isoprene emissions under different CO2 concentrations. Here, we advance previous semi-mechanistic model formulations by introducing a model that explicitly links electron availability for other purpose than carbon assimilation (or available energy for secondary metabolism processes; supply-constraint) and enzyme activity (capacity-constraint) to emissions. We furthermore investigate the sensitivity of the model to variations in photosynthetic and emission-specific parameters. By comparing species-specific simulations with experimental data, we demonstrate that differences in photosynthetic characteristics can explain inter-species differences in emissions. Interestingly, the seasonal development of emissions could also be explained to some degree by the change in energy supply from photosynthesis throughout the season. In addition, we show that the principal responses are not limited to isoprene but can be formulated to describe the emission of other light-dependent volatile species. The proposed model is suitable for implementation into regional and global models, particularly those that already provide species-specific photosynthesis estimates.

Transgenic mice overexpressing mutant TDP-43 show aberrant splicing of neurological disorders-associated gene Zmynd11 prior to onset of motor symptoms.

Mutations in TDP-43 are known to cause Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). TDP-43 binds to and regulates splicing of several RNA including Zmynd11 . Zmynd11 is a transcriptional repressor and a potential E3 ubiquitin ligase family member, known for its role in neuron and muscle differentiation. Mutations in Zmynd11 have been associated with autism with significant developmental motor delays, intellectual disability, and ataxia. Here, we show that Zmynd11 is aberrantly spliced in the brain and spinal cord of transgenic mice overexpressing a mutant human TDP-43 (A315T), and that these changes occur before the onset of motor symptoms.

Clonal diversification and histogenesis of malignant germ cell tumours.

Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we study the relationship of histogenesis and clonal diversification in GCTs by analysing the genomes and transcriptomes of 547 microdissected histological units. We find no correlation between genomic and histological heterogeneity. However, we identify unifying features including the retention of fetal developmental transcripts across tissues, expression changes on chromosome 12p, and a conserved somatic evolutionary sequence of whole genome duplication followed by clonal diversification. While this pattern is preserved across all GCTs, the developmental timing of the duplication varies between prepubertal and postpubertal cases. In addition, tumours of younger children exhibit distinct substitution signatures which may lend themselves as potential biomarkers for risk stratification. Our findings portray the extensive diversification of GCT tissues and genetic subclones as randomly distributed, while identifying overarching transcriptional and genomic features.

Magnetic resonance microimaging of the spinal cord in the SOD1 mouse model of amyotrophic lateral sclerosis detects motor nerve root degeneration.

Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. Current imaging studies have concentrated on areas of the brain and spinal cord that contain mixed populations of sensory and motor neurons. In this study, ex vivo magnetic resonance microimaging (MRM) was used to separate motor and sensory components by visualizing individual dorsal and ventral roots in fixed spinal cords. MRM at 15µm in plane resolution enabled the axons of pure populations of sensory and motor neurons to be measured in the lumbar region of the SOD1 mouse model of ALS. MRM signal intensity increased by 38.3% (p<0.05) exclusively in the ventral motor nerve roots of the lumbar spinal cord of ALS-affected SOD1 mice compared to wildtype littermates. The hyperintensity was therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were unchanged. Significant decreases in ventral nerve root volume were also detected in the SOD1 mice, which correlated with the axonal degeneration observed by microscopy. These results demonstrate the usefulness of MRM in visualizing the ultrastructure of the mouse spinal cord. The detailed 3D anatomy allowed the processes of pure populations of sensory and motor neurons to be compared.

Non-invasive diffusion tensor imaging detects white matter degeneration in the spinal cord of a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. Here we examine the ability of magnetic resonance imaging (MRI) to measure axonal degeneration in the lumbar spinal cord of the SOD1 mouse model of ALS. Diffusion tensor imaging (DTI) was successful in detecting axonal spinal cord damage in vivo. Fractional anisotropy (FA) values were reduced exclusively in the ventral white matter tracts of the lumbar spinal cord of ALS-affected SOD1 mice compared to wild-type littermates, with this effect becoming more pronounced with disease progression. The reduced FA values were therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were preserved. Significant decreases in water diffusion parallel to the white matter fibers or axial diffusivity were observed in the SOD1 mice, which can be attributed to the axonal degeneration observed by electron microscopy. At the same time, radial diffusivity perpendicular to the spinal column increased in the SOD1 mice, reflecting reduced myelination. These results demonstrate the usefulness of MRI in tracking disease progression in live animals and will aid in the assessment of treatment efficacy. This method could also potentially be adapted to aid the diagnosis and assessment of ALS progression in humans.

Learning from the COVID-19 lockdown in berlin: Observations and modelling to support understanding policies to reduce NO2.

Urban air pollution is a substantial threat to human health. Traffic emissions remain a large contributor to air pollution in urban areas. The mobility restrictions put in place in response to the COVID-19 pandemic provided a large-scale real-world experiment that allows for the evaluation of changes in traffic emissions and the corresponding changes in air quality. Here we use observational data, as well as modelling, to analyse changes in nitrogen dioxide, ozone, and particulate matter resulting from the COVID-19 restrictions at the height of the lockdown period in Spring of 2020. Accounting for the influence of meteorology on air quality, we found that reduction of ca. 30-50 % in traffic counts, dominated by changes in passenger cars, corresponded to reductions in median observed nitrogen dioxide concentrations of ca. 40 % (traffic and urban background locations) and a ca. 22 % increase in ozone (urban background locations) during weekdays. Lesser reductions in nitrogen dioxide concentrations were observed at urban background stations at weekends, and no change in ozone was observed. The modelled reductions in median nitrogen dioxide at urban background locations were smaller than the observed reductions and the change was not significant. The model results showed no significant change in ozone on weekdays or weekends. The lack of a simulated weekday/weekend effect is consistent with previous work suggesting that NOx emissions from traffic could be significantly underestimated in European cities by models. These results indicate the potential for improvements in air quality due to policies for reducing traffic, along with the scale of reductions that would be needed to result in meaningful changes in air quality if a transition to sustainable mobility is to be seriously considered. They also confirm once more the highly relevant role of traffic for air quality in urban areas.

Technical note: AQMEII4 Activity 1: evaluation of wet and dry deposition schemes as an integral part of regional-scale air quality models.

We present in this technical note the research protocol for phase 4 of the Air Quality Model Evaluation International Initiative (AQMEII4). This research initiative is divided into two activities, collectively having three goals: (i) to define the current state of the science with respect to representations of wet and especially dry deposition in regional models, (ii) to quantify the extent to which different dry deposition parameterizations influence retrospective air pollutant concentration and flux predictions, and (iii) to identify, through the use of a common set of detailed diagnostics, sensitivity simulations, model evaluation, and reduction of input uncertainty, the specific causes for the current range of these predictions. Activity 1 is dedicated to the diagnostic evaluation of wet and dry deposition processes in regional air quality models (described in this paper), and Activity 2 to the evaluation of dry deposition point models against ozone flux measurements at multiple towers with multiyear observations (to be described in future submissions as part of the special issue on AQMEII4). The scope of this paper is to present the scientific protocols for Activity 1, as well as to summarize the technical information associated with the different dry deposition approaches used by the participating research groups of AQMEII4. In addition to describing all common aspects and data used for this multi-model evaluation activity, most importantly, we present the strategy devised to allow a common process-level comparison of dry deposition obtained from models using sometimes very different dry deposition schemes. The strategy is based on adding detailed diagnostics to the algorithms used in the dry deposition modules of existing regional air quality models, in particular archiving diagnostics specific to land use-land cover (LULC) and creating standardized LULC categories to facilitate cross-comparison of LULC-specific dry deposition parameters and processes, as well as archiving effective conductance and effective flux as means for comparing the relative influence of different pathways towards the net or total dry deposition. This new approach, along with an analysis of precipitation and wet deposition fields, will provide an unprecedented process-oriented comparison of deposition in regional air quality models. Examples of how specific dry deposition schemes used in participating models have been reduced to the common set of comparable diagnostics defined for AQMEII4 are also presented.

Ozone damage, detoxification and the role of isoprenoids - new impetus for integrated models.

High concentrations of ozone (O3) can have significant impacts on the health and productivity of agricultural and forest ecosystems, leading to significant economic losses. In order to estimate this impact under a wide range of environmental conditions, the mechanisms of O3 impacts on physiological and biochemical processes have been intensively investigated. This includes the impact on stomatal conductance, the formation of reactive oxygen species and their effects on enzymes and membranes, as well as several induced and constitutive defence responses. This review summarises these processes, discusses their importance for O3 damage scenarios and assesses to which degree this knowledge is currently used in ecosystem models which are applied for impact analyses. We found that even in highly sophisticated models, feedbacks affecting regulation, detoxification capacity and vulnerability are generally not considered. This implies that O3 inflicted alterations in carbon and water balances cannot be sufficiently well described to cover immediate plant responses under changing environmental conditions. Therefore, we suggest conceptual models that link the depicted feedbacks to available process-based descriptions of stomatal conductance, photosynthesis and isoprenoid formation, particularly the linkage to isoprenoid models opens up new options for describing biosphere-atmosphere interactions.

Computer generated holograms for carbon nanotube arrays.

Multiwalled carbon nanotubes are highly diffractive structures in the optical regime. Their metallic character and large scattering cross-section allow their usage as diffractive elements in Fraunhofer holograms. This work elaborates some important features of the far field diffraction patterns produced from periodic arrays of nanotubes. A theoretical approach for the interaction of arrays of nanotubes with light is presented and a computer generated hologram is calculated by means of periodical patterns. Based on the results, fabrication of carbon nanotube arrays (in holographic patterns) was performed. Experimentally measured diffraction patterns were in good agreement with the calculations.

Identification of RNA bound to the TDP-43 ribonucleoprotein complex in the adult mouse brain.

Cytoplasmic inclusions containing TDP-43 are a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. TDP-43 is an RNA binding protein involved in gene regulation through control of RNA transcription, splicing and transport. However, the function of TDP-43 in the nervous system is largely unknown and its role in the pathogenesis of ALS is unclear. The aim of this study was to identify genes in the central nervous system that are regulated by TDP-43. RNA-immunoprecipitation with anti-TDP-43 antibody, followed by microarray analysis (RIP-chip), was used to isolate and identify RNA bound to TDP-43 protein from mouse brain. This analysis produced a list of 1839 potential TDP-43 gene targets, many of which overlap with previous studies and whose functions include RNA processing and synaptic function. Immunohistochemistry demonstrated that the TDP-43 protein could be found at the presynaptic membrane of axon terminals in the neuromuscular junction in mice. In conclusion, the finding that TDP-43 binds to RNA that codes for genes related to synaptic function, together with the localization of TDP-43 protein at axon terminals, suggests a role for TDP-43 in the transport of synaptic mRNAs into distal processes.

DNA variation in the SNAP25 gene confers risk to ADHD and is associated with reduced expression in prefrontal cortex.

BACKGROUND: The Coloboma mouse carries a ∼2 cM deletion encompassing the SNAP25 gene and has a hyperactive phenotype similar to that of ADHD. Such mice are 3 fold more active compared to their control littermates. Genetic association studies support a role for allelic variants of the human SNAP25 gene in predisposing to ADHD. METHODS/PRINCIPAL FINDINGS: We performed association analysis across the SNAP25 gene in 1,107 individuals (339 ADHD trios). To assess the functional relevance of the SNAP25-ADHD associated allele, we performed quantitative PCR on post-mortem tissue derived from the inferior frontal gyrus of 89 unaffected adults. Significant associations with the A allele of SNP rs362990 (χ(2) = 10, p-corrected = 0.019, OR = 1.5) and three marker haplotypes (rs6108461, rs362990 and rs362998) were observed. Furthermore, a significant additive decrease in the expression of the SNAP25 transcript as a function of the risk allele was also observed. This effect was detected at the haplotype level, where increasing copies of the ADHD-associated haplotype reduced the expression of the transcript. CONCLUSIONS: Our data show that DNA variation at SNAP25 confers risk to ADHD and reduces the expression of the transcript in a region of the brain that is critical for the regulation of attention and inhibition.

Carbon nanotube based high resolution holograms.

Carbon nanotubes are used as the smallest possible scattering element for diffracting light in a highly controlled manner to produce a 2D image. An array of carbon nanotubes is elegantly patterned to produce a high resolution hologram. In response to incident light on the hologram, a high contrast and wide field of view CAMBRIDGE image is produced.

Nanoscale memory cell based on a nanoelectromechanical switched capacitor.

The demand for increased information storage densities has pushed silicon technology to its limits and led to a focus on research on novel materials and device structures, such as magnetoresistive random access memory and carbon nanotube field-effect transistors, for ultra-large-scale integrated memory. Electromechanical devices are suitable for memory applications because of their excellent 'ON-OFF' ratios and fast switching characteristics, but they involve larger cells and more complex fabrication processes than silicon-based arrangements. Nanoelectromechanical devices based on carbon nanotubes have been reported previously, but it is still not possible to control the number and spatial location of nanotubes over large areas with the precision needed for the production of integrated circuits. Here we report a novel nanoelectromechanical switched capacitor structure based on vertically aligned multiwalled carbon nanotubes in which the mechanical movement of a nanotube relative to a carbon nanotube based capacitor defines 'ON' and 'OFF' states. The carbon nanotubes are grown with controlled dimensions at pre-defined locations on a silicon substrate in a process that could be made compatible with existing silicon technology, and the vertical orientation allows for a significant decrease in cell area over conventional devices. We have written data to the structure and it should be possible to read data with standard dynamic random access memory sensing circuitry. Simulations suggest that the use of high-k dielectrics in the capacitors will increase the capacitance to the levels needed for dynamic random access memory applications.