NT2 Derived Neuronal and Astrocytic Network Signalling

A major focus of stem cell research is the generation of neurons that may then be implanted to treat neurodegenerative diseases. However, a picture is emerging where astrocytes are partners to neurons in sustaining and modulating brain function. We therefore investigated the functional properties of NT2 derived astrocytes and neurons using electrophysiological and calcium imaging approaches. NT2 neurons (NT2Ns) expressed sodium dependent action potentials, as well as responses to depolarisation and the neurotransmitter glutamate. NT2Ns exhibited spontaneous and coordinated calcium elevations in clusters and in extended processes, indicating local and long distance signalling. Tetrodotoxin sensitive network activity could also be evoked by electrical stimulation. Similarly, NT2 astrocytes (NT2As) exhibited morphology and functional properties consistent with this glial cell type. NT2As responded to neuronal activity and to exogenously applied neurotransmitters with calcium elevations, and in contrast to neurons, also exhibited spontaneous rhythmic calcium oscillations. NT2As also generated propagating calcium waves that were gap junction and purinergic signalling dependent. Our results show that NT2 derived astrocytes exhibit appropriate functionality and that NT2N networks interact with NT2A networks in co-culture. These findings underline the utility of such cultures to investigate human brain cell type signalling under controlled conditions. Furthermore, since stem cell derived neuron function and survival is of great importance therapeutically, our findings suggest that the presence of complementary astrocytes may be valuable in supporting stem cell derived neuronal networks. Indeed, this also supports the intriguing possibility of selective therapeutic replacement of astrocytes in diseases where these cells are either lost or lose functionality

Effectiveness of an mHealth intervention combining a smartphone app and smart band on body composition in an overweight and obese population: Randomized controlled trial (EVIDENT 3 study)

Background: Mobile health (mHealth) is currently among the supporting elements that may contribute to an improvement in health markers by helping people adopt healthier lifestyles. mHealth interventions have been widely reported to achieve greater weight loss than other approaches, but their effect on body composition remains unclear. Objective: This study aimed to assess the short-term (3 months) effectiveness of a mobile app and a smart band for losing weight and changing body composition in sedentary Spanish adults who are overweight or obese. Methods: A randomized controlled, multicenter clinical trial was conducted involving the participation of 440 subjects from primary care centers, with 231 subjects in the intervention group (IG; counselling with smartphone app and smart band) and 209 in the control group (CG; counselling only). Both groups were counselled about healthy diet and physical activity. For the 3-month intervention period, the IG was trained to use a smartphone app that involved self-monitoring and tailored feedback, as well as a smart band that recorded daily physical activity (Mi Band 2, Xiaomi). Body composition was measured using the InBody 230 bioimpedance device (InBody Co., Ltd), and physical activity was measured using the International Physical Activity Questionnaire. Results: The mHealth intervention produced a greater loss of body weight (–1.97 kg, 95% CI –2.39 to –1.54) relative to standard counselling at 3 months (–1.13 kg, 95% CI –1.56 to –0.69). Comparing groups, the IG achieved a weight loss of 0.84 kg more than the CG at 3 months. The IG showed a decrease in body fat mass (BFM; –1.84 kg, 95% CI –2.48 to –1.20), percentage of body fat (PBF; –1.22%, 95% CI –1.82% to 0.62%), and BMI (–0.77 kg/m2, 95% CI –0.96 to 0.57). No significant changes were observed in any of these parameters in men; among women, there was a significant decrease in BMI in the IG compared with the CG. When subjects were grouped according to baseline BMI, the overweight group experienced a change in BFM of –1.18 kg (95% CI –2.30 to –0.06) and BMI of –0.47 kg/m2 (95% CI –0.80 to –0.13), whereas the obese group only experienced a change in BMI of –0.53 kg/m2 (95% CI –0.86 to –0.19). When the data were analyzed according to physical activity, the moderate-vigorous physical activity group showed significant changes in BFM of –1.03 kg (95% CI –1.74 to –0.33), PBF of –0.76% (95% CI –1.32% to –0.20%), and BMI of –0.5 kg/m2 (95% CI –0.83 to –0.19). Conclusions: The results from this multicenter, randomized controlled clinical trial study show that compared with standard counselling alone, adding a self-reported app and a smart band obtained beneficial results in terms of weight loss and a reduction in BFM and PBF in female subjects with a BMI less than 30 kg/m2 and a moderate-vigorous physical activity level. Nevertheless, further studies are needed to ensure that this profile benefits more than others from this intervention and to investigate modifications of this intervention to achieve a global effect

A few StePS forward in unveiling the complexity of galaxy evolution: light-weighted stellar ages of intermediate-redshift galaxies with WEAVE

Context. The upcoming new generation of optical spectrographs on four-meter-class telescopes, with their huge multiplexing capabilities, excellent spectral resolution, and unprecedented wavelength coverage, will provide invaluable information for reconstructing the history of star formation in individual galaxies up to redshifts of about 0.7. Aims. We aim at defining simple but robust and meaningful physical parameters that can be used to trace the coexistence of widely diverse stellar components: younger stellar populations superimposed on the bulk of older ones. Methods. We produced spectra of galaxies closely mimicking data from the forthcoming Stellar Populations at intermediate redshifts Survey (StePS), a survey that uses the WEAVE spectrograph on the William Herschel Telescope. First, we assessed our ability to reliably measure both ultraviolet and optical spectral indices in galaxies of different spectral types for typically expected signal-to-noise ratios. We then analyzed such mock spectra with a Bayesian approach, deriving the probability density function of r- and u-band light-weighted ages as well as of their difference. Results. We find that the ultraviolet indices significantly narrow the uncertainties in estimating the r- and u-band light-weighted ages and their difference in individual galaxies. These diagnostics, robustly retrievable for large galaxy samples even when observed at moderate signal-to-noise ratios, allow us to identify secondary episodes of star formation up to an age of similar to 0.1 Gyr for stellar populations older than similar to 1.5 Gyr, pushing up to an age of similar to 1 Gyr for stellar populations older than similar to 5 Gyr. Conclusions. The difference between r-band and u-band light-weighted ages is shown to be a powerful diagnostic to characterize and constrain extended star-formation histories and the presence of young stellar populations on top of older ones. This parameter can be used to explore the interplay between different galaxy star-formation histories and physical parameters such as galaxy mass, size, morphology, and environment

The carbonyl scavengers aminoguanidine and tenilsetam protect against the neurotoxic effects of methylglyoxal

Advanced glycation end products (AGEs) have been identified in age-related intracellular protein deposits of Alzheimer’s disease (amyloid plaques and neurofibrillary tangles) and Parkinson disease (Lewy bodies), suggesting that these protein deposits have been exposed to AGE precursors such as the reactive dicarbonyl compound methylglyoxal. In ageing tissue and under diabetic pseudohypoxia, intracellular methylglyoxal levels rise through an impairment of triosephosphate utilization. Furthermore, methylglyoxal detoxification is impaired when reduced glutathione levels are low, conditions, which have all been described in Alzheimer’s disease. However, there is less known about the toxicity of methylglyoxal, particularly about therapeutic strategies to scavenge such dicarbonyl compounds and attenuate their toxicity. In our study, extracellularly applied methylglyoxal was shown to be toxic to human neuroblastoma cells in a dose-dependent manner above concentrations of 150 µM with a LD50 of approximately 1.25 mM. Pre-incubation of methylglyoxal with a variety of carbonyl scavengers such as aminoguanidine or tenilsetam and the thiol antioxidant lipoic acid significantly reduced its toxicity. In summary, carbonyl scavengers might offer a promising therapeutic strategy to reduce the neurotoxicity of reactive carbonyl compounds, providing a potential benefit for patients with age-related neurodegenerative diseases

Biological and clinical significance of dysplastic hematopoiesis in patients with newly diagnosed multiple myeloma

Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/ GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD341 progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P 5.02) and overall survival (hazard ratio, 1.7; P 5.01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC

The Pristine survey - X. A large population of low-metallicity stars permeates the Galactic disc

Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement. FS thanks the Initiative dExcellence IdEx from the University of Strasbourg and the Programme Doctoral International PDI for funding his Ph.D. This work has been published under the framework of the IdEx Unistra and benefits from a funding from the state managed by the French National Research Agency as part of the investments for the future program. FS, NFM, and RAI gratefully acknowledge support from the French National Research Agency (ANR) funded project ‘Pristine’ (ANR-18-CE31-0017) along with funding from CNRS/INSU through the Programme National Galaxies et Cosmologie and through the CNRS grant PICS07708. ES, AA, and KY gratefully acknowledge funding by the Emmy Noether program from the Deutsche Forschungsgemeinschaft (DFG). The authors acknowledge the support and funding of the International Space Science Institute (ISSI) for the international team ‘Pristine’. FS acknowledges the support and funding of the Erasmus + programme of the European Union.The orbits of the least chemically enriched stars open a window on the formation of our Galaxy when it was still in its infancy. The common picture is that these low-metallicity stars are distributed as an isotropic, pressure-supported component since these stars were either accreted from the early building blocks of the assembling Milky Way (MW), or were later brought by the accretion of faint dwarf galaxies. Combining the metallicities and radial velocities from the Pristine and LAMOST surveys and Gaia DR2 parallaxes and proper motions for an unprecedented large and unbiased sample of 1027 very metal poor stars at [Fe/H] ≤ −2.5 dex, we show that this picture is incomplete. We find that 31 per cent31 per cent of the stars that currently reside spatially in the disc (⁠|Z|≤3kpc|Z|≤3kpc⁠) do not venture outside of the disc plane throughout their orbit. Moreover, this sample shows strong statistical evidence (at the 5.0σ level) of asymmetry in their kinematics, favouring prograde motion. The discovery of this population implies that a significant fraction of stars with iron abundances [Fe/H] ≤ −2.5 dex merged into, formed within, or formed concurrently with the MW disc and that the history of the disc was quiet enough to allow them to retain their disc-like orbital properties, challenging theoretical and cosmological models.Publisher PDFPeer reviewe