BACKGROUND: In preterm birth germinal matrix hemorrhages (GMHs) and the consequent posthemorrhagic hydrocephalus (PHH), the neuroepithelium/ependyma development is disrupted. This work is aimed to explore the possibilities of ependymal repair in GMH/PHH using a combination of neural stem cells, ependymal progenitors (EpPs), and mesenchymal stem cells. METHODS: GMH/PHH was induced in 4-day-old mice using collagenase, blood, or blood serum injections. PHH severity was characterized 2 weeks later using magnetic resonance, immunofluorescence, and protein expression quantification with mass spectrometry. Ependymal restoration and wall regeneration after stem cell treatments were tested in vivo and in an ex vivo experimental approach using ventricular walls from mice developing moderate and severe GMH/PHH. The effect of the GMH environment on EpP differentiation was tested in vitro. Two-tailed Student t or Wilcoxon-Mann-Whitney U test was used to find differences between the treated and nontreated groups. ANOVA and Kruskal-Wallis tests were used to compare >2 groups with post hoc Tukey and Dunn multiple comparison tests, respectively. RESULTS: PHH severity was correlated with the extension of GMH and ependymal disruption (means, 88.22% severe versus 19.4% moderate). GMH/PHH hindered the survival rates of the transplanted neural stem cells/EpPs. New multiciliated ependymal cells could be generated from transplanted neural stem cells and more efficiently from EpPs (15% mean increase). Blood and TNFα (tumor necrosis factor alpha) negatively affected ciliogenesis in cells committed to ependyma differentiation (expressing Foxj1 [forkhead box J1] transcription factor). Pretreatment with mesenchymal stem cells improved the survival rates of EpPs and ependymal differentiation while reducing the edematous (means, 18% to 0.5% decrease in severe edema) and inflammatory conditions in the explants. The effectiveness of this therapeutical strategy was corroborated in vivo (means, 29% to 0% in severe edema). CONCLUSIONS: In GMH/PHH, the ependyma can be restored and edema decreased from either neural stem cell or EpP transplantation in vitro and in vivo. Mesenchymal stem cell pretreatment improved the success of the ependymal restoration.

IntroductionDysgenesis of the corpus callosum is present in neurodevelopmental disorders and coexists with hydrocephalus in several human congenital syndromes. The mechanisms that underlie the etiology of congenital hydrocephalus and agenesis of the corpus callosum when they coappear during neurodevelopment persist unclear. In this work, the mechanistic relationship between both disorders is investigated in the hyh mouse model for congenital hydrocephalus, which also develops agenesis of the corpus callosum. In this model, hydrocephalus is generated by a defective program in the development of neuroepithelium during its differentiation into radial glial cells.MethodsIn this work, the populations implicated in the development of the corpus callosum (callosal neurons, pioneering axons, glial wedge cells, subcallosal sling and indusium griseum glial cells) were studied in wild-type and hyh mutant mice. Immunohistochemistry, mRNA in situ hybridization, axonal tracing experiments, and organotypic cultures from normal and hyh mouse embryos were used.ResultsOur results show that the defective program in the neuroepithelium/radial glial cell development in the hyh mutant mouse selectively affects the glial wedge cells. The glial wedge cells are necessary to guide the pioneering axons as they approach the corticoseptal boundary. Our results show that the pioneering callosal axons arising from neurons in the cingulate cortex can extend projections to the interhemispheric midline in normal and hyh mice. However, pioneering axons in the hyh mutant mouse, when approaching the area corresponding to the damaged glial wedge cell population, turned toward the ipsilateral lateral ventricle. This defect occurred before the appearance of ventriculomegaly.DiscussionIn conclusion, the abnormal development of the ventricular zone, which appears to be inherent to the etiology of several forms of congenital hydrocephalus, can explain, in some cases, the common association between hydrocephalus and corpus callosum dysgenesis. These results imply that further studies may be needed to understand the corpus callosum dysgenesis etiology when it concurs with hydrocephalus.

AbstractGerminal matrix hemorrhages (GMH) and the consequent posthemorrhagic hydrocephalus (PHH) are among the most common and severe neurological complications of preterm birth that require lifelong complex neurosurgical care. GMH and PHH provoke disruption of neuroepithelium/ependyma development, a key structure implicated in brain development and homeostasis. Neuroepithelial/ependymal damage causes lifelong cognitive and motor deficits; however, no therapy is directed to recover the damaged ependyma. This study is aimed to test the possibilities of ependymal repair in GMH/PHH using neural stem cells (NSCs) or ependymal progenitors (EpPs). Thus, it sets the basis for a therapeutic approach to treating ependymal damage and preventing brain developmental deficits. GMH/PHH was induced in 4-day-old mice using different experimental procedures involving collagenase, blood, or blood serum injections. PHH severity was characterized using magnetic resonance, immunofluorescence, and protein expression quantification with mass spectrometry. Additionally, a newexvivoapproach using ventricular walls from mice developing moderate and severe GMH/PHH was generated to study ependymal restoration and wall regeneration after stem cell treatments. NSCs or EpPs obtained from newborn mice were transplanted in the explants, and pretreatment with mesenchymal stem cells (MSCs) was tested. Ependymal differentiation and the effect of MSC-conditioned microenvironment were investigated in both explants and primary cultures. In the animals, PHH severity was correlated with the extension of GMH, ependymal disruption, astroglial/microglial reactions, and ventriculomegaly. In the explants, the severity and extension of GMH hindered the survival rates of the transplanted NSCs/EpPs. In the explants affected with GMH, new multiciliated ependymal cells could be generated from transplanted NSCs and, more efficiently, from EpPs. Blood and TNFα negatively affected ciliogenesis in cells expressing Foxj1. Pretreatment with mesenchymal stem cells (MSC) improved the survival rates of EpPs and ependymal differentiation while reducing the edematous and inflammatory conditions in the explants. In conclusion, in GMH/PHH, the ependyma can be restored from either NSC or EpP transplantation, being EpPs in an MSC-conditioned microenvironment more efficient for this purpose. Modifying the neuroinflammatory microenvironment by MSC pretreatment positively influenced the success of the ependymal restoration.

The photometric time series of solar-like stars can exhibit rotational modulation due to active regions co-rotating with the stellar surface, allowing us to constrain stellar rotation and magnetic activity. In this work we investigate the behavior, particularly the variability, of the photometric magnetic activity of Kepler solar-like stars and compare it with that of the Sun. We adopted the photometric magnetic activity proxy Sph, which was computed with a cadence of 5 x the rotation period, Prot. The average Sph was taken as the mean activity level, and the standard deviation was taken as a measure of the temporal variation of the magnetic activity over the observations. We also analyzed Sun-as-a-star photometric data from VIRGO. Sun-like stars were selected from a very narrow parameter space around the solar properties. We also looked into KIC 8006161 (HD 173701), an active metal-rich G dwarf, and we compared its magnetic activity to that of stars with similar stellar parameters. We find that the amplitude of Sph variability is strongly correlated with its mean value, independent of spectral type. An equivalent relationship has been found for ground-based observations of chromospheric activity emission and magnetic field strength, but in this work we show that photometric Kepler data also present the same behavior. While, depending on the cycle phase, the Sun is among the less active stars, we find that the solar Sph properties are consistent with those observed in Kepler Sun-like stars. KIC 8006161 is, however, among the most active of its peers, which tend to be metal-rich. This results from an underlying relationship between Prot and metallicity and supports the following interpretation of the magnetic activity of KIC 8006161: its strong activity is a consequence of its high metallicity, which affects the depth of the convection zone and, consequently, the efficiency of the dynamo.

The epithelium covering the surfaces of the cerebral ventricular system is known as the ependyma, and is essential for maintaining the physical and functional integrity of the central nervous system. Additionally, the ependyma plays an essential role in neurogenesis, neuroinflammatory modulation and neurodegenerative diseases. Ependyma barrier is severely affected by perinatal hemorrhages and infections that cross the blood brain barrier. The recovery and regeneration of ependyma after damage are key to stabilizing neuroinflammatory and neurodegenerative processes that are critical during early postnatal ages. Unfortunately, there are no effective therapies to regenerate this tissue in human patients. Here, the roles of the ependymal barrier in the context of neurogenesis and homeostasis are reviewed, and future research lines for development of actual therapeutic strategies are discussed.

Aquaporin-4 (AQP4) plays a crucial role in brain water circulation and is considered a therapeutic target in hydrocephalus. Congenital hydrocephalus is associated with a reaction of astrocytes in the periventricular white matter both in experimental models and human cases. A previous report showed that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplanted into the lateral ventricles of hyh mice exhibiting severe congenital hydrocephalus are attracted by the periventricular astrocyte reaction, and the cerebral tissue displays recovery. The present investigation aimed to test the effect of BM-MSC treatment on astrocyte reaction formation. BM-MSCs were injected into the lateral ventricles of four-day-old hyh mice, and the periventricular reaction was detected two weeks later. A protein expression analysis of the cerebral tissue differentiated the BM-MSC-treated mice from the controls and revealed effects on neural development. In in vivo and in vitro experiments, BM-MSCs stimulated the generation of periventricular reactive astrocytes overexpressing AQP4 and its regulatory protein kinase D-interacting substrate of 220 kDa (Kidins220). In the cerebral tissue, mRNA overexpression of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF1α), and transforming growth factor beta 1 (TGFβ1) could be related to the regulation of the astrocyte reaction and AQP4 expression. In conclusion, BM-MSC treatment in hydrocephalus can stimulate a key developmental process such as the periventricular astrocyte reaction, where AQP4 overexpression could be implicated in tissue recovery.

The NASA K2 mission that succeeded the nominal Kepler mission observed several hundred thousand stars during its operations. While most of the stars were observed in single campaigns of ∼80 days, some of them were targeted for more than one campaign. We perform an asteroseismic study of a sample of eight solar-like stars observed during K2 Campaigns 6 and 17, allowing us access to up to 160 days of data. With these two observing campaigns, we determine not only the stellar parameters but also study the rotation and magnetic activity of these stars. We first extract the light curves for the two campaigns using two different pipelines, EVEREST and Lightkurve. The seismic analysis is done on the combined light curve of C6 and C17, where the gap between them was removed and the two campaigns were ‘stitched’ together. We determine the global seismic parameters of the solar-like oscillations using two different methods: one using the A2Z pipeline and the other the Bayesian apollinaire code. With the latter, we also perform the peak-bagging of the modes to characterize their individual frequencies. By combining the frequencies with the Gaia DR2 effective temperature and luminosity, and metallicity for five of the targets, we determine the fundamental parameters of the targets using the IACgrids based on the MESA (Modules for Experiments in Stellar Astrophysics) code. We find that four of the stars are on the main sequence, two stars are about to leave it, and two stars are more evolved (a subgiant and an early red giant). While the masses and radii of our targets probe a similar parameter space compared to the Kepler solar-like stars, with detailed modeling, we find that for a given mass our more evolved stars seem to be older than previous seismic stellar ensembles. We calculate the stellar parameters using two different grids of models, one incorporating and one excluding the treatment of diffusion, and find that the results agree generally within the uncertainties, except for the ages. The ages obtained using the models that exclude diffusion are older, with differences of greater than 10% for most stars. The seismic radii and the Gaia DR2 radii present an average difference of 4% with a dispersion of 5%. Although the agreement is relatively good, the seismic radii are slightly underestimated compared to Gaia DR2 for our stars, the disagreement being greater for the more evolved ones. Our rotation analysis provides two candidates for potential rotation periods but longer observations are required to confirm them.

In species that regenerate the injured spinal cord, the ependymal region is a source of new cells and a prominent coordinator of regeneration. In mammals, cells at the ependymal region proliferate in normal conditions and react after injury, but in humans, the central canal is lost in the majority of individuals from early childhood. It is replaced by a structure that does not proliferate after damage and is formed by large accumulations of ependymal cells, strong astrogliosis and perivascular pseudo-rosettes. We inform here of two additional mammals that lose the central canal during their lifetime: the Naked Mole-Rat (NMR, Heterocephalus glaber) and the mutant hyh (hydrocephalus with hop gait) mice. The morphological study of their spinal cords shows that the tissue substituting the central canal is not similar to that found in humans. In both NMR and hyh mice, the central canal is replaced by tissue reminiscent of normal lamina X and may include small groups of ependymal cells in the midline, partially resembling specific domains of the former canal. However, no features of the adult human ependymal remnant are found, suggesting that this structure is a specific human trait. In order to shed some more light on the mechanism of human central canal closure, we provide new data suggesting that canal patency is lost by delamination of the ependymal epithelium, in a process that includes apical polarity loss and the expression of signaling mediators involved in epithelial to mesenchymal transitions.

Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with the major manifestation of ventriculomegaly caused by the accumulation of high amounts of cerebrospinal fluid (CSF). The molecules and pathomechanisms underlying cerebral ventricular enlargement are widely unknown. Kinase D interacting substrate of 220 kDa ( KIDINS220) gene has been recently associated with schizophrenia and with a novel syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity (SINO syndrome), diseases frequently occurring with ventriculomegaly. Here we show that Kidins220, a transmembrane protein effector of various key neuronal signalling pathways, is a critical regulator of CSF homeostasis. We observe that both KIDINS220 and the water channel aquaporin-4 (AQP4) are markedly downregulated at the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. We also find that Kidins220 deficient mice develop ventriculomegaly accompanied by water dyshomeostasis and loss of AQP4 in the brain ventricular ependymal layer and astrocytes. Kidins220 is a known cargo of the SNX27-retromer, a complex that redirects endocytosed plasma membrane proteins (cargos) back to the cell surface, thus avoiding their targeting to lysosomes for degradation. Mechanistically, we show that AQP4 is a novel cargo of the SNX27-retromer and that Kidins220 deficiency promotes a striking and unexpected downregulation of the SNX27-retromer that results in AQP4 lysosomal degradation. Accordingly, SNX27 silencing decreases AQP4 levels in wild-type astrocytes whereas SNX27 overexpression restores AQP4 content in Kidins220 deficient astrocytes. Together our data suggest that the KIDINS220-SNX27-retromer-AQP4 pathway is involved in human ventriculomegaly and open novel therapeutic perspectives.

Since the onset of the “space revolution” of high-precision high-cadence photometry, asteroseismology has been demonstrated as a powerful tool for informing Galactic archeology investigations. The launch of the NASA Transiting Exoplanet Survey Satellite (TESS) mission has enabled seismic-based inferences to go full sky—providing a clear advantage for large ensemble studies of the different Milky Way components. Here we demonstrate its potential for investigating the Galaxy by carrying out the first asteroseismic ensemble study of red giant stars observed by TESS. We use a sample of 25 stars for which we measure their global asteroseimic observables and estimate their fundamental stellar properties, such as radius, mass, and age. Significant improvements are seen in the uncertainties of our estimates when combining seismic observables from TESS with astrometric measurements from the Gaia mission compared to when the seismology and astrometry are applied separately. Specifically, when combined we show that stellar radii can be determined to a precision of a few percent, masses to 5%–10%, and ages to the 20% level. This is comparable to the precision typically obtained using end-of-mission Kepler data.

Background In obstructive congenital hydrocephalus, cerebrospinal fluid accumulation is associated with high intracranial pressure and the presence of periventricular edema, ischemia/hypoxia, damage of the white matter, and glial reactions in the neocortex. The viability and short time effects of a therapy based on bone marrow-derived mesenchymal stem cells (BM-MSC) have been evaluated in such pathological conditions in the hyh mouse model. Methods BM-MSC obtained from mice expressing fluorescent mRFP1 protein were injected into the lateral ventricle of hydrocephalic hyh mice at the moment they present a very severe form of the disease. The effect of transplantation in the neocortex was compared with hydrocephalic hyh mice injected with the vehicle and non-hydrocephalic littermates. Neural cell populations and the possibility of transdifferentiation were analyzed. The possibility of a tissue recovering was investigated using 1 H High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance ( 1 H HR-MAS NMR) spectroscopy, thus allowing the detection of metabolites/osmolytes related with hydrocephalus severity and outcome in the neocortex. An in vitro assay to simulate the periventricular astrocyte reaction conditions was performed using BM-MSC under high TNFα level condition. The secretome in the culture medium was analyzed in this assay. Results Four days after transplantation, BM-MSC were found undifferentiated and scattered into the astrocyte reaction present in the damaged neocortex white matter. Tissue rejection to the integrated BM-MSC was not detected 4 days after transplantation. Hyh mice transplanted with BM-MSC showed a reduction in the apoptosis in the periventricular neocortex walls, suggesting a neuroprotector effect of the BM-MSC in these conditions. A decrease in the levels of metabolites/osmolytes in the neocortex, such as taurine and neuroexcytotoxic glutamate, also indicated a tissue recovering. Under high TNFα level condition in vitro, BM-MSC showed an upregulation of cytokine and protein secretion that may explain homing, immunomodulation, and vascular permeability, and therefore the tissue recovering. Conclusions BM-MSC treatment in severe congenital hydrocephalus is viable and leads to the recovery of the severe neurodegenerative conditions in the neocortex. NMR spectroscopy allows to follow-up the effects of stem cell therapy in hydrocephalus.

Most previous efforts to calibrate how rotation and magnetic activity depend on stellar age and mass have relied on observations of clusters, where isochrones from stellar evolution models are used to determine the properties of the ensemble. Asteroseismology employs similar models to measure the properties of an individual star by matching its normal modes of oscillation, yielding the stellar age and mass with high precision. We use 27 days of photometry from the Transiting Exoplanet Survey Satellite to characterize solar-like oscillations in the G8 subgiant of the 94 Aqr triple system. The resulting stellar properties, when combined with a reanalysis of 35 yr of activity measurements from the Mount Wilson HK project, allow us to probe the evolution of rotation and magnetic activity in the system. The asteroseismic age of the subgiant agrees with a stellar isochrone fit, but the rotation period is much shorter than expected from standard models of angular momentum evolution. We conclude that weakened magnetic braking may be needed to reproduce the stellar properties, and that evolved subgiants in the hydrogen shell-burning phase can reinvigorate large-scale dynamo action and briefly sustain magnetic activity cycles before ascending the red giant branch.

Over the course of its history, the Milky Way has ingested multiple smaller satellite galaxies 1 . Although these accreted stellar populations can be forensically identified as kinematically distinct structures within the Galaxy, it is difficult in general to date precisely the age at which any one merger occurred. Recent results have revealed a population of stars that were accreted via the collision of a dwarf galaxy, called Gaia–Enceladus 1 , leading to substantial pollution of the chemical and dynamical properties of the Milky Way. Here we identify the very bright, naked-eye star ν Indi as an indicator of the age of the early in situ population of the Galaxy. We combine asteroseismic, spectroscopic, astrometric and kinematic observations to show that this metal-poor, alpha-element-rich star was an indigenous member of the halo, and we measure its age to be 11.0± 0.7 (stat) ± 0.8 (sys) billion years. The star bears hallmarks consistent with having been kinematically heated by the Gaia–Enceladus collision. Its age implies that the earliest the merger could have begun was 11.6 and 13.2 billion years ago, at 68

The SONG spectrograph has recently demonstrated its ability to perform solar radial velocity measurement during the first test run of the Solar-SONG initiative. A preliminary assessment of its performance is carried out here by comparing the results of Solar-SONG during the summer 2018 test run, with GOLF and VIRGO/SPM taken as reference instruments.

The Exoplanets-A project is a collaboration comprised of 7 institutions in Europe to study exoplanets and their host stars. The project aims to develop new tools for modelling exoplanet atmospheres. Itk includes improving our understanding of the stellar radiation environment through gathering observations and creating models of stellar atmospheres. Variability of stellar XUV radiation on short (days) to long (Gyr) time-scales can have a profound influence on the evolution and potential habitability of orbiting exoplanets. Data, models and software developed during the project will be made publicly available to aid the next stages of exoplanet research with JWST and beyond.

Solar-like oscillations in red-giant stars are now commonly detected in thousands of stars with space telescopes such as the NASA Kepler mission. Parallel radial velocity and photometric measurements would help to better understand the physics governing the amplitudes of solar-like oscillators. Yet, most target stars for space photometry are too faint for light-demanding ground-based spectroscopy. The BRITE Constellation satellites provide a unique opportunity of two-color monitoring of the flux variations of bright luminous red giants. Those targets are also bright enough to be monitored with high-resolution spectrographs on small telescopes, such as the SONG Network. In these proceedings, we provide a first overview of our comprehensive, multi-year campaign utilizing both BRITE and SONG to seismically characterize Aldebaran, one of the brightest red giants in the sky. Because luminous red giants can be seen at large distances, such well-characterized objects will serve as benchmark stars for galactic archeology.