Glial cells of the developing amphioxus: a molecular study

Glial cells play important roles in the development and homeostasis of metazoan nervous systems. However, while their involvement in the development and function in the central nervous system (CNS) of vertebrates is increasingly well understood, much less is known about invertebrate glia and the evolutionary history of glial cells more generally. An investigation into amphioxus glia is therefore timely, as this organism is the best living proxy for the last common ancestor of all chordates, and hence provides a window on the role of glial cells development and function at the transition between invertebrates and vertebrates. We report here our findings on amphioxus glia as characterized by molecular probes correlated with anatomical data at the TEM level. The results show amphioxus glial lineages express genes typical of vertebrate astroglia and radial glia and segregate early in development, forming what appears to be a spatially separated cell proliferation zone positioned laterally, between the dorsal and ventral zones of neural cell proliferation. Our study provides strong evidence for the presence of vertebrate-type glial cells in amphioxus while highlighting the role played by segregated progenitor cell pools in CNS development. There are implications also for our understanding of glial cells in a broader evolutionary context and insights into patterns of precursor cell deployment in the chordate nerve cord

Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander's Disease

Alexander's disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a "threshold hypothesis" has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization

The Arrangement of the Peripheral Olfactory System of Pleuragramma antarcticum: A Well-Exploited Small Sensor, an Aided Water Flow, and a Prominent Effort in Primary Signal Elaboration

The olfactory system is constituted in a consistent way across vertebrates. Nasal structures allow water/air to enter an olfactory cavity, conveying the odorants to a sensory surface. There, the olfactory neurons form, with their axons, a sensory nerve projecting to the telencephalic zone\u2014named the olfactory bulb. This organization comes with many different arrangements, whose meaning is still a matter of debate. A morphological description of the olfactory system of many teleost species is present in the literature; nevertheless, morphological investigations rarely provide a quantitative approach that would help to provide a deeper understanding of the structures where sensory and elaborating events happen. In this study, the peripheral olfactory system of the Antarctic silverfish, which is a keystone species in coastal Antarctica ecosystems, has also been described, employing some quantitative methods. The olfactory chamber of this species is connected to accessory nasal sacs, which probably aid water movements in the chamber; thus, the head of the Antarctic silverfish is specialized to assure that the olfactory organ keeps in contact with a large volume of water\u2014even when the fish is not actively swimming. Each olfactory organ, shaped like an asymmetric rosette, has, in adult fish, a sensory surface area of about 25 mm2, while each olfactory bulb contains about 100,000 neurons. The sensory surface area and the number of neurons in the primary olfactory brain region show that this fish invests energy in the detection and elaboration of olfactory signals and allow comparisons among different species. The mouse, for example\u2014which is considered a macrosmatic vertebrate\u2014has a sensory surface area of the same order of magnitude as that of the Antarctic silverfish, but ten times more neurons in the olfactory bulb. Catsharks, on the other hand, have a sensory surface area that is two orders of magnitude higher than that of the Antarctic silverfish, while the number of neurons has the same order of magnitude. The Antarctic silverfish is therefore likely to rely considerably on olfaction

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated With Expansion and Maturation of NK Cells

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the "adaptive" NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation

Case Report: A Peculiar Case of Inflammatory Colitis After SARS-CoV-2 Infection

open14noWe report a case of inflammatory colitis after SARS-CoV-2 infection in a patient with no additional co-morbidity who died within three weeks of hospitalization. As it is becoming increasingly clear that SARS-CoV-2 infection can cause immunological alterations, we investigated the expression of the inhibitory checkpoint PD-1 and its ligand PD-L1 to explore the potential role of this axis in the break of self-tolerance. The presence of the SARS-CoV-2 virus in colon tissue was demonstrated by qRT-PCR and immunohistochemical localization of the nucleocapsid protein. Expression of lymphocyte markers, PD-1, and PD-L1 in colon tissue was investigated by IHC. SARSCoV- 2-immunoreactive cells were detected both in the ulcerated and non-ulcerated mucosal areas. Compared to healthy tissue, where PD-1 is weakly expressed and PD-L1 is absent, PD-1 and PD-L1 expression appears in the inflamed mucosal tissue, as expected, but was mainly confined to non-ulcerative areas. At the same time, these markers were virtually undetectable in areas of mucosal ulceration. Our data show an alteration of the PD-1/PD-L1 axis and suggest a link between SARS-CoV-2 infection and an aberrant autoinflammatory response due to concomitant breakdown of the PD-1/ PD-L1 interaction leading to early death of the patient.openRutigliani, Mariangela; Bozzo, Matteo; Barberis, Andrea; Greppi, Marco; Anelli, Emanuela; Castellaro, Luca; Bonsignore, Alessandro; Azzinnaro, Antonio; Pesce, Silvia; Filauro, Marco; Rollandi, Gian Andrea; Castagnola, Patrizio; Candiani, Simona; Marcenaro, EmanuelaRutigliani, Mariangela; Bozzo, Matteo; Barberis, Andrea; Greppi, Marco; Anelli, Emanuela; Castellaro, Luca; Bonsignore, Alessandro; Azzinnaro, Antonio; Pesce, Silvia; Filauro, Marco; Rollandi, Gian Andrea; Castagnola, Patrizio; Candiani, Simona; Marcenaro, Emanuel

A magnetar giant flare in the nearby starburst galaxy M82

Giant flares, short explosive events releasing up to 10$^{47}$ erg of energy in the gamma-ray band in less than one second, are the most spectacular manifestation of magnetars, young neutron stars powered by a very strong magnetic field, 10$^{14-15}$ G in the magnetosphere and possibly higher in the star interior. The rate of occurrence of these rare flares is poorly constrained, as only three have been seen from three different magnetars in the Milky Way and in the Large Magellanic Cloud in about 50 years since the beginning of gamma-ray astronomy. This sample can be enlarged by the discovery of extragalactic events, since for a fraction of a second giant flares reach peak luminosities above 10$^{46}$ erg/s, which makes them visible by current instruments up to a few tens of Mpc. However, at these distances they appear similar to, and difficult to distinguish from, regular short gamma-ray bursts (GRBs). The latter are much more energetic events, 10$^{50-53}$ erg, produced by compact binary mergers and originating at much larger distances. Indeed, only a few short GRBs have been proposed, with different levels of confidence, as magnetar giant flare candidates in nearby galaxies. Here we report the discovery of a short GRB positionally coincident with the central region of the starburst galaxy M82. Its spectral and timing properties, together with the limits on its X-ray and optical counterparts obtained a few hours after the event and the lack of an associated gravitational wave signal, qualify with high confidence this event as a giant flare from a magnetar in M82.Comment: Submitted version. New figures. Accepted for publication in Nature with minor modification

The NuSTAR ULX program

We present the results of the first large program of broadband ULX observations with NuSTAR, XMM-Newton and Suzaku, yielding high-quality spectra and timing measurements from 0.3-30 keV in 6 ULXs, providing powerful information for understanding the accretion modes and nature of the central BHs. In particular, we find that all ULXs in our sample have a clear cutoff above 10 keV. This cutoff is less pronounced than expected by Comptonization from a cold, thick corona. We confirm the presence of a soft excess at low energies in the brightest ULXs, with temperatures below ~ 0.5 keV. We make an estimates on the masses of several ULXs based on spectral variability and model fitting

The multi-outburst activity of the magnetar in Westerlund I

After two major outbursts in 2006 and 2011, on 2017 May 16 the magnetar CXOU J164710.2−455216, hosted within the massive star cluster Westerlund I, emitted a short (∼20 ms) burst, which marked the onset of a new active phase. We started a long-term monitoring campaign with Swift (45 observations), Chandra (five observations), and NuSTAR (four observations) from the activation until 2018 April. During the campaign, Swift Burst Alert Telescope (BAT) registered the occurrence of multiple bursts, accompanied by two other enhancements of the X-ray persistent flux. The long time span covered by our observations allowed us to study the spectral and the timing evolution of the source. After ∼11 months since the 2017 May outburst onset, the observed flux was ∼15 times higher than its historical minimum level and a factor of ∼3 higher than the level reached after the 2006 outburst. This suggests that the crust has not fully relaxed to the quiescent level, or that the source quiescent level has changed following the multiple outburst activities in the past 10 yr or so. This is another case of multiple outbursts from the same source on a yearly time-scale, a somehow recently discovered behaviour in magnetars.AB, NR, and PE are supported by an NWO Vidi Grant (PI: Rea). NR is also supported by grants AYA2015-71042-P and SGR 2014-1073. PE acknowledges funding in the framework of the project ‘Understanding the X-ray Variable and Transient Sky’ (ULTraS), ASI-INAF contract no. 2017-14-H.0. JAP acknowledges support by the Spanish MINECO/FEDER grant AYA2015-66899-C2-2-P, and the grant of Generalitat Valenciana PROMETEOII-2014-069. FCZ is supported by grants AYA2015-71042-P and SGR 2014-1073. DG acknowledges the financial support of the UnivEarthS Labex program at Sorbonne Paris Citeé (ANR-10-LABX-0023 and ANR-11-IDEX-0005-02). We thank the referee for his comments and the COST Action PHAROS (CA16214) for partial support

NuSTAR detection of 4s Hard X-ray Lags from the Accreting Pulsar GS 0834-430

The NuSTAR hard X-ray telescope observed the transient Be/X-ray binary GS 0834-430 during its 2012 outburst. The source is detected between 3 - 79 keV with high statistical significance, and we were able to perform very accurate spectral and timing analysis. The phase-averaged spectrum is consistent with that observed in many other magnetized accreting pulsars. We fail to detect cyclotron resonance scattering features in either phase-averaged nor phase-resolved spectra that would allow us to constrain the pulsar's magnetic field. We detect a pulse period of ~ 12:29 s in all energy bands. The pulse profile can be modeled with a double Gaussian and shows a strong and smooth hard lag of up to 0.3 cycles in phase, or about 4s between the pulse at ~ 3 and ≳ 30 keV. This is the first report of such a strong lag in high-mass X-ray binary (HMXB) pulsars. Previously reported lags have been significantly smaller in phase and restricted to low-energies (E<10 keV). We investigate the possible mechanisms that might produce such lags. We find the most likely explanation for this effect to be a complex beam geometry