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Abstract The Charcot-Marie-Tooth-1E (CMT1E) disease is typically described as a peripheral neuropathy in humans, causing decreased nerve conduction, spastic paralysis, and tremor. The Trembler-J (TrJ) mice serve as a high fidelity model of this disease. Here, we use functional ultrasound (fUS) and functional connectivity (FC) to analyze TrJ mice’s brain activity during sensory stimulation and resting state experiments against wild type (WT) mice - the healthy counterpart. fUS is an imaging technique that measures cerebral blood volume (CBV) temporal changes. We study these changes in the primary somatosensory cortex barrel field (S1BF) of both mice populations during periodic vibrissae stimulation, measuring the number of pixels that correlate to the stimulation (i.e., the size of the activation area), the average correlation of these pixels (i.e., the response strength), and the CBV’s rate of change for each stimulation (i.e., the hemodynamic response). Then, we construct a FC matrix for each genotype and experiment by correlating the CBV signals from the eight cortical regions defined by the Paxinos and Franklin atlas. Our results show that TrJ mice have significantly diminished neurovascular responses and altered brain connectivity with respect to WT mice, pointing to central nervous system effects that could shift our understanding of the CMT1E disease.

Abstract. Quantifying the dust optical depth (DOD) and its uncertainty acrossspatiotemporal scales is key to understanding and constraining the dustcycle and its interactions with the Earth System. This study quantifies theDOD along with its monthly and year-to-year variability between 2003 and2017 at global and regional levels based on the MIDAS (ModIs Dust AeroSol)dataset, which combines Moderate Resolution Imaging Spectroradiometer (MODIS)-Aqua retrievals and Modern-Era Retrospective Analysis for Research andApplications, version 2 (MERRA-2), reanalysisproducts. We also describe the annual and seasonal geographicaldistributions of DOD across the main dust source regions and transportpathways. MIDAS provides columnar mid-visible (550 nm) DOD at fine spatialresolution (0.1∘×0.1∘), expanding the currentobservational capabilities for monitoring the highly variable spatiotemporalfeatures of the dust burden. We obtain a global DOD of 0.032±0.003 – approximately a quarter (23.4 %±2.4 %) of the global aerosoloptical depth (AOD) – with about 1 order of magnitude more DOD in theNorthern Hemisphere (0.056±0.004; 31.8 %±2.7 %) than inthe Southern Hemisphere (0.008±0.001; 8.2 %±1.1 %) andabout 3.5 times more DOD over land (0.070±0.005) than over ocean(0.019±0.002). The Northern Hemisphere monthly DOD is highlycorrelated with the corresponding monthly AOD (R2=0.94) andcontributes 20 % to 48 % of it, both indicating a dominant dustcontribution. In contrast, the contribution of dust to the monthly AOD doesnot exceed 17 % in the Southern Hemisphere, although the uncertainty inthis region is larger. Among the major dust sources of the planet, themaximum DODs (∼1.2) are recorded in the Bodélé Depressionof the northern Lake Chad Basin, whereas moderate-to-high intensities areencountered in the Western Sahara (boreal summer), along the eastern partsof the Middle East (boreal summer) and in the Taklamakan Desert (spring).Over oceans, major long-range dust transport is observed primarily along thetropical Atlantic (intensified during boreal summer) and secondarily in theNorth Pacific (intensified during boreal spring). Our calculated global andregional averages and associated uncertainties are consistent with some butnot all recent observation-based studies. Our work provides a simpleyet flexible method to estimate consistent uncertainties acrossspatiotemporal scales, which will enhance the use of the MIDAS dataset in avariety of future studies.

Soil dust aerosols are a key component of the climate system, as they interact with short- and long-wave radiation, alter cloud formation processes, affect atmospheric chemistry and play a role in biogeochemical cycles by providing nutrient inputs such as iron and phosphorus. The influence of dust on these processes depends on its physicochemical properties, which, far from being homogeneous, are shaped by its regionally varying mineral composition. The relative amount of minerals in dust depends on the source region and shows a large geographical variability. However, many state-of-the-art Earth system models (ESMs), upon which climate analyses and projections rely, still consider dust mineralogy to be invariant. The explicit representation of minerals in ESMs is more hindered by our limited knowledge of the global soil composition along with the resulting size-resolved airborne mineralogy than by computational constraints. In this work we introduce an explicit mineralogy representation within the state-of-the-art Multiscale Online Nonhydrostatic AtmospheRe CHemistry (MONARCH) model. We review and compare two existing soil mineralogy datasets, which remain a source of uncertainty for dust mineralogy modeling and provide an evaluation of multiannual simulations against available mineralogy observations. Soil mineralogy datasets are based on measurements performed after wet sieving, which breaks the aggregates found in the parent soil. Our model predicts the emitted particle size distribution (PSD) in terms of its constituent minerals based on brittle fragmentation theory (BFT), which reconstructs the emitted mineral aggregates destroyed by wet sieving. Our simulations broadly reproduce the most abundant mineral fractions independently of the soil composition data used. Feldspars and calcite are highly sensitive to the soil mineralogy map, mainly due to the different assumptions made in each soil dataset to extrapolate a handful of soil measurements to arid and semi-arid regions worldwide. For the least abundant or more difficult-to-determine minerals, such as iron oxides, uncertainties in soil mineralogy yield differences in annual mean aerosol mass fractions of up to ∼ 100 %. Although BFT restores coarse aggregates including phyllosilicates that usually break during soil analysis, we still identify an overestimation of coarse quartz mass fractions (above 2 µm in diameter). In a dedicated experiment, we estimate the fraction of dust with undetermined composition as given by a soil map, which makes up ∼ 10 % of the emitted dust mass at the global scale and can be regionally larger. Changes in the underlying soil mineralogy impact our estimates of climate-relevant variables, particularly affecting the regional variability of the single-scattering albedo at solar wavelengths or the total iron deposited over oceans. All in all, this assessment represents a baseline for future model experiments including new mineralogical maps constrained by high-quality spaceborne hyperspectral measurements, such as those arising from the NASA Earth Surface Mineral Dust Source Investigation (EMIT) mission.

Introduction: Astrocytes are the glial cells responsible for brain homeostasis, but if injured, they could damage neural cells even deadly. Genetic damage, DNA damage response (DDR), and its downstream cascades are dramatic events poorly studied in astrocytes.Hypothesis and methods: We propose that 1 h of 400 mmol/L ethanol and/or 1 μmol/L corticosterone exposure of cultured hippocampal astrocytes damages DNA, activating the DDR and eliciting functional changes. Immunolabeling against γH2AX (chromatin DNA damage sites), cyclin D1 (cell cycle control), nuclear (base excision repair, BER), and cytoplasmic (anti-inflammatory functions) APE1, ribosomal nucleolus proteins together with GFAP and S100β plus scanning electron microscopy studies of the astrocyte surface were carried out.Results: Data obtained indicate significant DNA damage, immediate cell cycle arrest, and BER activation. Changes in the cytoplasmic signals of cyclin D1 and APE1, nucleolus number, and membrane-attached vesicles strongly suggest a reactivity like astrocyte response without significant morphological changes.Discussion: Obtained results uncover astrocyte genome immediate vulnerability and DDR activation, plus a functional response that might in part, be signaled through extracellular vesicles, evidencing the complex influence that astrocytes may have on the CNS even upon short-term aggressions.

Astrocytes maintain CNS homeostasis but also critically contribute to neurological and psychiatric disorders. Such functional diversity implies an extensive signaling repertoire including extracellular vesicles (EVs) and nanotubes (NTs) that could be involved in protection or damage, as widely shown in various experimental paradigms. However, there is no information associating primary damage to the astrocyte genome, the DNA damage response (DDR), and the EV and NT repertoire. Furthermore, similar studies were not performed on hippocampal astrocytes despite their involvement in memory and learning processes, as well as in the development and maintenance of alcohol addiction. By exposing murine hippocampal astrocytes to 400 mM ethanol (EtOH) and/or 1 μM corticosterone (CTS) for 1 h, we tested whether the induced DNA damage and DDR could elicit significant changes in NTs and surface-attached EVs. Genetic damage and initial DDR were assessed by immunolabeling against the phosphorylated histone variant H2AX (γH2AX), DDR-dependent apoptosis by BAX immunoreactivity, and astrocyte activation by the glial acidic fibrillary protein (GFAP) and phalloidin staining. Surface-attached EVs and NTs were examined via scanning electron microscopy, and labeled proteins were analyzed via confocal microscopy. Relative to controls, astrocytes exposed to EtOH, CTS, or EtOH+CTS showed significant increases in nuclear γlH2AX foci, nuclear and cytoplasmic BAX signals, and EV frequency at the expense of the NT amount, mainly upon EtOH, without detectable signs of morphological reactivity. Furthermore, the largest and most complex EVs originated only in DNA-damaged astrocytes. Obtained results revealed that astrocytes exposed to acute EtOH and/or CTS preserved their typical morphology but presented severe DNA damage, triggered canonical DDR pathways, and early changes in the cell signaling mediated by EVs and NTs. Further deepening of this initial morphological and quantitative analysis is necessary to identify the mechanistic links between genetic damage, DDR, cell-cell communication, and their possible impact on hippocampal neural cells.

Aerosol reanalysis datasets are model-based, observationally constrained, continuous 3D aerosol fields with a relatively high temporal frequency that can be used to assess aerosol variations and trends, climate effects, and impacts on socioeconomic sectors, such as health. Here we compare and assess the recently published MONARCH (Multiscale Online Non-hydrostatic AtmospheRe CHemistry) high-resolution regional desert dust reanalysis over northern Africa, the Middle East, and Europe (NAMEE) with a combination of ground-based observations and space-based dust retrievals and products. In particular, we compare the total and coarse dust optical depth (DOD) from the new reanalysis with DOD products derived from MODIS (MODerate resolution Imaging Spectroradiometer), MISR (Multi-angle Imaging SpectroRadiometer), and IASI (Infrared Atmospheric Sounding Interferometer) spaceborne instruments. Despite the larger uncertainties, satellite-based datasets provide a better geographical coverage than ground-based observations, and the use of different retrievals and products allows at least partially overcoming some single-product weaknesses in the comparison. Nevertheless, limitations and uncertainties due to the type of sensor, its operating principle, its sensitivity, its temporal and spatial resolution, and the methodology for retrieving or further deriving dust products are factors that bias the reanalysis assessment. We, therefore, also use ground-based DOD observations provided by 238 stations of the AERONET (AErosol RObotic NETwork) located within the NAMEE region as a reference evaluation dataset. In particular, prior to the reanalysis assessment, the satellite datasets were evaluated against AERONET, showing moderate underestimations in the vicinities of dust sources and downwind regions, whereas small or significant overestimations, depending on the dataset, can be found in the remote regions. Taking these results into consideration, the MONARCH reanalysis assessment shows that total and coarse-DOD simulations are consistent with satellite- and ground-based data, qualitatively capturing the major dust sources in the area in addition to the dust transport patterns. Moreover, the MONARCH reanalysis reproduces the seasonal dust cycle, identifying the increased dust activity that occurred in the NAMEE region during spring and summer. The quantitative comparison between the MONARCH reanalysis DOD and satellite multi-sensor products shows that the reanalysis tends to slightly overestimate the desert dust that is emitted from the source regions and underestimate the transported dust over the outflow regions, implying that the model's removal of dust particles from the atmosphere, through deposition processes, is too effective. More specifically, small positive biases are found over the Sahara desert (0.04) and negative biases over the Atlantic Ocean and the Arabian Sea (−0.04), which constitute the main pathways of the long-range dust transport. Considering the DOD values recorded on average there, such discrepancies can be considered low, as the low relative bias in the Sahara desert (< 50 %) and over the adjacent maritime regions (< 100 %) certifies. Similarly, over areas with intense dust activity, the linear correlation coefficient between the MONARCH reanalysis simulations and the ensemble of the satellite products is significantly high for both total and coarse DOD, reaching 0.8 over the Middle East, the Atlantic Ocean, and the Arabian Sea and exceeding it over the African continent. Moreover, the low relative biases and high correlations are associated with regions for which large numbers of observations are available, thus allowing for robust reanalysis assessment.

Abstract. We present the dust module in the Multiscale Online Non-hydrostatic AtmospheRe CHemistry model (MONARCH) version 2.0, a chemical weather prediction system that can be used for regional and global modeling at a range of resolutions. The representations of dust processes in MONARCH were upgraded with a focus on dust emission (emission parameterizations, entrainment thresholds, considerations of soil moisture and surface cover), lower boundary conditions (roughness, potential dust sources), and dust–radiation interactions. MONARCH now allows modeling of global and regional mineral dust cycles using fundamentally different paradigms, ranging from strongly simplified to physics-based parameterizations. We present a detailed description of these updates along with four global benchmark simulations, which use conceptually different dust emission parameterizations, and we evaluate the simulations against observations of dust optical depth. We determine key dust parameters, such as global annual emission/deposition flux, dust loading, dust optical depth, mass-extinction efficiency, single-scattering albedo, and direct radiative effects. For dust-particle diameters up to 20 µm, the total annual dust emission and deposition fluxes obtained with our four experiments range between about 3500 and 6000 Tg, which largely depend upon differences in the emitted size distribution. Considering ellipsoidal particle shapes and dust refractive indices that account for size-resolved mineralogy, we estimate the global total (longwave and shortwave) dust direct radiative effect (DRE) at the surface to range between about −0.90 and −0.63 W m−2 and at the top of the atmosphere between −0.20 and −0.28 W m−2. Our evaluation demonstrates that MONARCH is able to reproduce key features of the spatiotemporal variability of the global dust cycle with important and insightful differences between the different configurations.

One of the challenges in studying desert dust aerosol along with its numerous interactions and impacts is the paucity of direct in situ measurements, particularly in the areas most affected by dust storms. Satellites typically provide column-integrated aerosol measurements, but observationally constrained continuous 3D dust fields are needed to assess dust variability, climate effects and impacts upon a variety of socio-economic sectors. Here, we present a high-resolution regional reanalysis data set of desert dust aerosols that covers Northern Africa, the Middle East and Europe along with the Mediterranean Sea and parts of central Asia and the Atlantic and Indian oceans between 2007 and 2016. The horizontal resolution is 0.1∘ latitude × 0.1∘ longitude in a rotated grid, and the temporal resolution is 3 h. The reanalysis was produced using local ensemble transform Kalman filter (LETKF) data assimilation in the Multiscale Online Nonhydrostatic AtmospheRe CHemistry model (MONARCH) developed at the Barcelona Supercomputing Center (BSC). The assimilated data are coarse-mode dust optical depth retrieved from the Moderate Resolution Imaging Spectroradiometer (MODIS) Deep Blue Level 2 products. The reanalysis data set consists of upper-air variables (dust mass concentrations and the extinction coefficient), surface variables (dust deposition and solar irradiance fields among them) and total column variables (e.g. dust optical depth and load). Some dust variables, such as concentrations and wet and dry deposition, are expressed for a binned size distribution that ranges from 0.2 to 20 µm in particle diameter. Both analysis and first-guess (analysis-initialized simulation) fields are available for the variables that are diagnosed from the state vector. A set of ensemble statistics is archived for each output variable, namely the ensemble mean, standard deviation, maximum and median. The spatial and temporal distribution of the dust fields follows well-known dust cycle features controlled by seasonal changes in meteorology and vegetation cover. The analysis is statistically closer to the assimilated retrievals than the first guess, which proves the consistency of the data assimilation method. Independent evaluation using Aerosol Robotic Network (AERONET) dust-filtered optical depth retrievals indicates that the reanalysis data set is highly accurate (mean bias = −0.05, RMSE = 0.12 and r = 0.81 when compared to retrievals from the spectral de-convolution algorithm on a 3-hourly basis). Verification statistics are broadly homogeneous in space and time with regional differences that can be partly attributed to model limitations (e.g. poor representation of small-scale emission processes), the presence of aerosols other than dust in the observations used in the evaluation and differences in the number of observations among seasons. Such a reliable high-resolution historical record of atmospheric desert dust will allow a better quantification of dust impacts upon key sectors of society and economy, including health, solar energy production and transportation. The reanalysis data set (Di Tomaso et al., 2021) is distributed via Thematic Real-time Environmental Distributed Data Services (THREDDS) at BSC and is freely available at http://hdl.handle.net/21.12146/c6d4a608-5de3-47f6-a004-67cb1d498d98 (last access: 10 June 2022).

Behind the science of breast cancer in Canada, as well as globally, are the stories of thousands of women, their families, and their communities. These include stories from those who have died or those suffering from the realities of stage III and stage IV breast cancer due to late detection, misinformation, and dismissal. The reality for these women is that, whilst grateful for the latest developments in cancer research, much of this knowledge is not reflected in policy and practice. Canadian guidelines do not reflect the recommended screening by experts within the field and inequities in screening practices and practitioner knowledge exist in different areas within Canada. Told through the stories of women with lived experiences of late-stage breast cancer and supported by scientific evidence, this paper explores the impact of outdated breast cancer screening practices on the lives of women. Recent patient advocacy is driving changes, such as notifying women of their breast density in a few jurisdictions in Canada, but we call for the whole medical community to take responsibility and ensure breast screening is optimised to save more lives.

This study is focused on a non-conventional profitability measure, at least in terms of assets pricing models, where dividends or profits are widely used. The attention is focused on a proxy measure of Operating Cash Flows: the "Ebitda after Capex". The relationship returns – cash flows' volatility has been examined through an empirical analysis conducted on the stocks of the S&P500 Index combining the main quantitative and statistical approach with a qualitative overview respect the macroeconomic background. Starting from a correlation rolling window approach, three different regressions techniques have been implemented; the simple Ordinary Least Squares regressions (OLS), the linear Quantile (LQR) regression and the Multiple regression model (MLR), all performed at different levels in terms of stocks (QoQ and YoY) and sectors (MoM, QoQ, YoY). The cross-sectional and time-series results support the effects of cash flow volatility on the stocks' performance and highlighted its sensitivity respect not only the different short-term and long-term horizons, but also in terms of sector' exposure.

Quantifying the dust optical depth (DOD) and its uncertainty across spatiotemporal scales is key to understanding and constraining the dust cycle and its interactions with the Earth System. This study quantifies the DOD along with its monthly and year-to-year variability between 2003 and 2017 at global and regional levels based on the MIDAS (ModIs Dust AeroSol) dataset, which combines Moderate Resolution Imaging Spectroradiometer (MODIS)-Aqua retrievals and Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2), reanalysis products. We also describe the annual and seasonal geographical distributions of DOD across the main dust source regions and transport pathways. MIDAS provides columnar mid-visible (550 nm) DOD at fine spatial resolution (0.1∘×0.1∘), expanding the current observational capabilities for monitoring the highly variable spatiotemporal features of the dust burden. We obtain a global DOD of 0.032±0.003 – approximately a quarter (23.4 %±2.4 %) of the global aerosol optical depth (AOD) – with about 1 order of magnitude more DOD in the Northern Hemisphere (0.056±0.004; 31.8 %±2.7 %) than in the Southern Hemisphere (0.008±0.001; 8.2 %±1.1 %) and about 3.5 times more DOD over land (0.070±0.005) than over ocean (0.019±0.002). The Northern Hemisphere monthly DOD is highly correlated with the corresponding monthly AOD (R2=0.94) and contributes 20 % to 48 % of it, both indicating a dominant dust contribution. In contrast, the contribution of dust to the monthly AOD does not exceed 17 % in the Southern Hemisphere, although the uncertainty in this region is larger. Among the major dust sources of the planet, the maximum DODs (∼1.2) are recorded in the Bodélé Depression of the northern Lake Chad Basin, whereas moderate-to-high intensities are encountered in the Western Sahara (boreal summer), along the eastern parts of the Middle East (boreal summer) and in the Taklamakan Desert (spring). Over oceans, major long-range dust transport is observed primarily along the tropical Atlantic (intensified during boreal summer) and secondarily in the North Pacific (intensified during boreal spring). Our calculated global and regional averages and associated uncertainties are consistent with some but not all recent observation-based studies. Our work provides a simple yet flexible method to estimate consistent uncertainties across spatiotemporal scales, which will enhance the use of the MIDAS dataset in a variety of future studies.

Endocrine therapy (ET) for hormone receptor-positive (HR+) breast cancer can contribute to gynecologic symptoms (GS) that impact vaginal health, sexual function, and quality of life (QoL). A cross-sectional study was conducted at St. Michael’s Hospital in Toronto, Canada between July 2017 and June 2018 to examine the occurrence and frequency of GS among HR+ breast cancer patients on ET, patient-provider communication, female sexual dysfunction (FSD), and QoL. A Treatment Experience questionnaire was developed for this study and the Female Sexual Function Index (FSFI) and Menopause-Specific Quality of Life questionnaire (MENQOL) were also administered. Of 151 patients surveyed, 77 (51.0%) were on tamoxifen and 74 (49.0%) on an aromatase inhibitor. Most patients (84.1%, 95% confidence interval [CI] 77.3% to 89.5%) experienced at least one GS “all the time” or “often”, or one or more infections, in the past year. Only 44 (31.9%) patients reported that their oncologist had ever previously asked them about experiencing GS. The prevalence of FSD was 61.2% (95% CI 46.2% to 74.8%) among 49 sexually active patients that completed the FSFI. Symptoms captured in the MENQOL’s vasomotor domain were deemed most bothersome. Side effect management and patient-provider communication should be prioritized to optimize GS, vaginal health, and sexual function of ET users.

Atmospheric mineral dust has a rich tri-dimensional spatial and temporal structure that is poorly constrained in forecasts and analyses when only column-integrated aerosol optical depth (AOD) is assimilated. At present, this is the case of most operational global aerosol assimilation products. Aerosol vertical distributions obtained from spaceborne lidars can be assimilated in aerosol models, but questions about the extent of their benefit upon analyses and forecasts along with their consistency with AOD assimilation remain unresolved. Our study thoroughly explores the added value of assimilating spaceborne vertical dust profiles, with and without the joint assimilation of dust optical depth (DOD). We also discuss the consistency in the assimilation of both sources of information and analyse the role of the smaller footprint of the spaceborne lidar profiles in the results. To that end, we have performed data assimilation experiments using dedicated dust observations for a period of 2 months over northern Africa, the Middle East, and Europe. We assimilate DOD derived from the Visible Infrared Imaging Radiometer Suite (VIIRS) on board Suomi National Polar-Orbiting Partnership (SUOMI-NPP) Deep Blue and for the first time Cloud-Aerosol Lidar with Orthogonal Polarisation (CALIOP)-based LIdar climatology of Vertical Aerosol Structure for space-based lidar simulation studies (LIVAS) pure-dust extinction coefficient profiles on an aerosol model. The evaluation is performed against independent ground-based DOD derived from AErosol RObotic NETwork (AERONET) Sun photometers and ground-based lidar dust extinction profiles from the Cyprus Clouds Aerosol and Rain Experiment (CyCARE) and PREparatory: does dust TriboElectrification affect our ClimaTe (Pre-TECT) field campaigns. Jointly assimilating LIVAS and Deep Blue data reduces the root mean square error (RMSE) in the DOD by 39 % and in the dust extinction coefficient by 65 % compared to a control simulation that excludes assimilation. We show that the assimilation of dust extinction coefficient profiles provides a strong added value to the analyses and forecasts. When only Deep Blue data are assimilated, the RMSE in the DOD is reduced further, by 42 %. However, when only LIVAS data are assimilated, the RMSE in the dust extinction coefficient decreases by 72 %, the largest improvement across experiments. We also show that the assimilation of dust extinction profiles yields better skill scores than the assimilation of DOD under an equivalent sensor footprint. Our results demonstrate the strong potential of future lidar space missions to improve desert dust forecasts, particularly if they foresee a depolarization lidar channel to allow discrimination of desert dust from other aerosol types.

We present the dust module in the Multiscale Online Non-hydrostatic AtmospheRe CHemistry model (MONARCH) version 2.0, a chemical weather prediction system that can be used for regional and global modeling at a range of resolutions. The representations of dust processes in MONARCH were upgraded with a focus on dust emission (emission parameterizations, entrainment thresholds, considerations of soil moisture and surface cover), lower boundary conditions (roughness, potential dust sources), and dust–radiation interactions. MONARCH now allows modeling of global and regional mineral dust cycles using fundamentally different paradigms, ranging from strongly simplified to physics-based parameterizations. We present a detailed description of these updates along with four global benchmark simulations, which use conceptually different dust emission parameterizations, and we evaluate the simulations against observations of dust optical depth. We determine key dust parameters, such as global annual emission/deposition flux, dust loading, dust optical depth, mass-extinction efficiency, single-scattering albedo, and direct radiative effects. For dust-particle diameters up to 20 µm, the total annual dust emission and deposition fluxes obtained with our four experiments range between about 3500 and 6000 Tg, which largely depend upon differences in the emitted size distribution. Considering ellipsoidal particle shapes and dust refractive indices that account for size-resolved mineralogy, we estimate the global total (longwave and shortwave) dust direct radiative effect (DRE) at the surface to range between about −0.90 and −0.63 W m−2 and at the top of the atmosphere between −0.20 and −0.28 W m−2. Our evaluation demonstrates that MONARCH is able to reproduce key features of the spatiotemporal variability of the global dust cycle with important and insightful differences between the different configurations.

Chemotherapy-associated steatosis is poorly understood in the context of colorectal cancer. In this study, Stage II–III colorectal cancer patients were retrospectively selected to evaluate the frequency of chemotherapy-associated steatosis and to determine whether patients on statins throughout adjuvant chemotherapy develop chemotherapy-associated steatosis at a lower frequency. Baseline and incident steatosis for up to one year from chemotherapy start date was assessed based on radiology. Of 269 patients, 76 (28.3%) had steatosis at baseline. Of the remaining 193 cases, patients receiving adjuvant chemotherapy (n = 135) had 1.57 (95% confidence interval [CI], 0.89 to 2.79) times the adjusted risk of developing steatosis compared to patients not receiving chemotherapy (n = 58). Among patients who underwent chemotherapy, those using statins for pre-existing hyperlipidemia (n = 37) had 0.71 (95% CI, 0.10 to 2.75) times the risk of developing steatosis compared to patients who were not prevalent users of statins (n = 98). Chemotherapeutic treatment of Stage II–III colorectal cancer appears to be consistent with a moderately increased risk of steatosis, although larger studies are necessary to assess the significance of this observation. Prospective trials should be considered to further explore the potential for protective use of statins in this curative patient population.

BackgroundPhosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.MethodsThe BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants.FindingsBetween Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [

Monitoring and describing the spatiotemporal variability in dust aerosols is crucial for understanding their multiple effects, related feedbacks, and impacts within the Earth system. This study describes the development of the ModIs Dust AeroSol (MIDAS) data set. MIDAS provides columnar daily dust optical depth (DOD) at 550 nm at a global scale and fine spatial resolution (0.1∘ × 0.1∘) over a 15-year period (2003–2017). This new data set combines quality filtered satellite aerosol optical depth (AOD) retrievals from MODIS-Aqua at swath level (Collection 6.1; Level 2), along with DOD-to-AOD ratios provided by the Modern-Era Retrospective analysis for Research and Applications version 2 (MERRA-2) reanalysis to derive DOD on the MODIS native grid. The uncertainties of the MODIS AOD and MERRA-2 dust fraction, with respect to the AEronet RObotic NETwork (AERONET) and LIdar climatology of vertical Aerosol Structure for space-based lidar simulation (LIVAS), respectively, are taken into account for the estimation of the total DOD uncertainty. MERRA-2 dust fractions are in very good agreement with those of LIVAS across the dust belt in the tropical Atlantic Ocean and the Arabian Sea; the agreement degrades in North America and the Southern Hemisphere, where dust sources are smaller. MIDAS, MERRA-2, and LIVAS DODs strongly agree when it comes to annual and seasonal spatial patterns, with colocated global DOD averages of 0.033, 0.031, and 0.029, respectively; however, deviations in dust loading are evident and regionally dependent. Overall, MIDAS is well correlated with AERONET-derived DODs (R=0.89) and only shows a small positive bias (0.004 or 2.7 %). Among the major dust areas of the planet, the highest R values (>0.9) are found at sites of North Africa, the Middle East, and Asia. MIDAS expands, complements, and upgrades the existing observational capabilities of dust aerosols, and it is suitable for dust climatological studies, model evaluation, and data assimilation.

Abstract Defective functionality of thymic epithelial cells (TECs), due to genetic mutations or injuring causes, results in altered T‐cell development, leading to immunodeficiency or autoimmunity. These defects cannot be corrected by hematopoietic stem cell transplantation (HSCT), and thymus transplantation has not yet been demonstrated to be fully curative. Here, we provide proof of principle of a novel approach toward thymic regeneration, involving the generation of thymic organoids obtained by seeding gene‐modified postnatal murine TECs into three‐dimensional (3D) collagen type I scaffolds mimicking the thymic ultrastructure. To this end, freshly isolated TECs were transduced with a lentiviral vector system, allowing for doxycycline‐induced Oct4 expression. Transient Oct4 expression promoted TECs expansion without drastically changing the cell lineage identity of adult TECs, which retain the expression of important molecules for thymus functionality such as Foxn1, Dll4, Dll1, and AIRE. Oct4‐expressing TECs (iOCT4 TEC) were able to grow into 3D collagen type I scaffolds both in vitro and in vivo, demonstrating that the collagen structure reproduced a 3D environment similar to the thymic extracellular matrix, perfectly recognized by TECs. In vivo results showed that thymic organoids transplanted subcutaneously in athymic nude mice were vascularized but failed to support thymopoiesis because of their limited in vivo persistence. These findings provide evidence that gene modification, in combination with the usage of 3D biomimetic scaffolds, may represent a novel approach allowing the use of postnatal TECs for thymic regeneration. Stem Cells Translational Medicine 2019;8:1107–1122

Charcot-Marie-Tooth (CMT) syndrome is the most common progressive human motor and sensory peripheral neuropathy. CMT type 1E is a demyelinating neuropathy affecting Schwann cells due to peripheral-myelin-protein-22 (PMP22) mutations, modelized by Trembler-J mice. Curcumin, a natural polyphenol compound obtained from turmeric (Curcuma longa), exhibits dose- and time-varying antitumor, antioxidant and neuroprotective properties, however, the neurotherapeutic actions of curcumin remain elusive. Here, we propose curcumin as a possible natural treatment capable of enhancing cellular detoxification mechanisms, resulting in an improvement of the neurodegenerative Trembler-J phenotype. Using a refined method for obtaining enriched Schwann cell cultures, we evaluated the neurotherapeutic action of low dose curcumin treatment on the PMP22 expression, and on the chaperones and autophagy/mammalian target of rapamycin (mTOR) pathways in Trembler-J and wild-type genotypes. In wild-type Schwann cells, the action of curcumin resulted in strong stimulation of the chaperone and macroautophagy pathway, whereas the modulation of ribophagy showed a mild effect. However, despite the promising neuroprotective effects for the treatment of neurological diseases, we demonstrate that the action of curcumin in Trembler-J Schwann cells could be impaired due to the irreversible impact of ethanol used as a common curcumin vehicle necessary for administration. These results contribute to expanding our still limited understanding of PMP22 biology in neurobiology and expose the intrinsic lability of the neurodegenerative Trembler-J genotype. Furthermore, they unravel interesting physiological mechanisms of cellular resilience relevant to the pharmacological treatment of the neurodegenerative Tremble J phenotype with curcumin and ethanol. We conclude that the analysis of the effects of the vehicle itself is an essential and inescapable step to comprehensibly assess the effects and full potential of curcumin treatment for therapeutic purposes.

Myelination of the peripheral nervous system requires Schwann cells (SC) differentiation into the myelinating phenotype. The peripheral myelin protein-22 (PMP22) is an integral membrane glycoprotein, expressed in SC. It was initially described as a growth arrest-specific (gas3) gene product, up-regulated by serum starvation. PMP22 mutations were pathognomonic for human hereditary peripheral neuropathies, including the Charcot-Marie-Tooth disease (CMT). Trembler-J (TrJ) is a heterozygous mouse model carrying the same pmp22 point mutation as a CMT1E variant. Mutations in lamina genes have been related to a type of peripheral (CMT2B1) or central (autosomal dominant leukodystrophy) neuropathy. We explore the presence of PMP22 and Lamin B1 in Wt and TrJ SC nuclei of sciatic nerves and the colocalization of PMP22 concerning the silent heterochromatin (HC: DAPI-dark counterstaining), the transcriptionally active euchromatin (EC), and the nuclear lamina (H3K4m3 and Lamin B1 immunostaining, respectively). The results revealed that the number of TrJ SC nuclei in sciatic nerves was greater, and the SC volumes were smaller than those of Wt. The myelin protein PMP22 and Lamin B1 were detected in Wt and TrJ SC nuclei and predominantly in peripheral nuclear regions. The level of PMP22 was higher, and those of Lamin B1 lower in TrJ than in Wt mice. The level of PMP22 was higher, and those of Lamin B1 lower in TrJ than in Wt mice. PMP22 colocalized more with Lamin B1 and with the transcriptionally competent EC, than the silent HC with differences between Wt and TrJ genotypes. The results are discussed regarding the probable nuclear role of PMP22 and the relationship with TrJ neuropathy.

Astrocytes maintain CNS homeostasis but also critically contribute to neurological and psychiatric disorders. Such functional diversity implies an extensive signaling repertoire including extracellular vesicles (EVs) and nanotubes (NTs) that could be involved in protection or damage, as widely shown in various experimental paradigms. However, there is no information associating primary damage to the astrocyte genome, the DNA damage response (DDR), and the EV and NT repertoire. Furthermore, similar studies were not performed on hippocampal astrocytes despite their involvement in memory and learning processes, as well as in the development and maintenance of alcohol addiction. By exposing murine hippocampal astrocytes to 400 mM ethanol (EtOH) and/or 1 μM corticosterone (CTS) for 1 h, we tested whether the induced DNA damage and DDR could elicit significant changes in NTs and surface-attached EVs. Genetic damage and initial DDR were assessed by immunolabeling against the phosphorylated histone variant H2AX (γH2AX), DDR-dependent apoptosis by BAX immunoreactivity, and astrocyte activation by the glial acidic fibrillary protein (GFAP) and phalloidin staining. Surface-attached EVs and NTs were examined via scanning electron microscopy, and labeled proteins were analyzed via confocal microscopy. Relative to controls, astrocytes exposed to EtOH, CTS, or EtOH+CTS showed significant increases in nuclear γlH2AX foci, nuclear and cytoplasmic BAX signals, and EV frequency at the expense of the NT amount, mainly upon EtOH, without detectable signs of morphological reactivity. Furthermore, the largest and most complex EVs originated only in DNA-damaged astrocytes. Obtained results revealed that astrocytes exposed to acute EtOH and/or CTS preserved their typical morphology but presented severe DNA damage, triggered canonical DDR pathways, and early changes in the cell signaling mediated by EVs and NTs. Further deepening of this initial morphological and quantitative analysis is necessary to identify the mechanistic links between genetic damage, DDR, cell-cell communication, and their possible impact on hippocampal neural cells. [ABSTRACT FROM AUTHOR]