Gene therapy with mesenchymal stem cells expressing IFN-ß ameliorates neuroinflammation in experimental models of multiple sclerosis

[Background and Purpose]: Recombinant IFN‐ß is one of the first‐line treatments in multiple sclerosis (MS), despite its lack of efficacy in some patients. In this context, mesenchymal stem cells (MSCs) represent a promising therapeutic alternative due to their immunomodulatory properties and multipotency. Moreover, by taking advantage of their pathotropism, these cells can be genetically modified to be used as carriers for delivering or secreting therapeutic drugs into injured tissues. Here, we report the therapeutic effect of systemic delivery of adipose‐derived MSCs (AdMSCs), transduced with the IFN‐β gene, into mice with experimental autoimmune encephalomyelitis (EAE).[Experimental Approach]: Relapsing–remitting and chronic progressive EAE were induced in mice. Cells were injected i.v. Disease severity, inflammation and tissue damage were assessed clinically, by flow cytometry of spleens and histopathological evaluation of the CNS respectively.[Key Results]: Genetic engineering did not modify the biological characteristics of these AdMSCs (morphology, growth rate, immunophenotype and multipotency). Furthermore, the transduction of IFN‐ß to AdMSCs maintained and, in some cases, enhanced the functional properties of AdMSCs by ameliorating the symptoms of MS in EAE models and by decreasing indications of peripheral and central neuro‐inflammation.[Conclusion and Implications]: Gene therapy was found to be more effective than cell therapy in ameliorating several clinical parameters in both EAE models, presumably due to the continuous expression of IFN‐β. Furthermore, it has significant advantages over AdMSC therapy, and also over systemic IFN‐ß treatment, by providing long‐term expression of the cytokine at therapeutic concentrations and reducing the frequency of injections, while minimizing dose‐limiting side effects.This work was supported by Fondo de Investigaciones Sanitarias ISCIII (Spain) and Fondo Europeo de Desarrollo Regional (FEDER) from the European Union through the research grants PI12/01097 and PI15/00963 and ISCIII Red de Terapia Celular TerCel RD12/0019/0006 to F.M., by the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía‐FEDER/Fondo de Cohesion Europeo (FSE) de Andalucía through the research grants P09‐CTS‐04532, PI‐57069 and PAIDI‐Bio‐326 to F.M. and PI‐0160/2012 to K.B. M.J.P.‐M. has been supported by grants from Red Temática de Investigación Cooperativa Red Española de Esclerosis Múltiple REEM (RD07/0060 and RD12/0032). B.O. is financed by a contract from Excelent Project CTS‐7670/11 from Consejería de Economía, Innovación, Ciencia y Empleo (Junta de Andalucía)

Lung Megakaryocytes are Immune Modulatory Cells that Present Antigen to CD4+ T cells.

Although platelets are the cellular mediators of thrombosis, they are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered bone marrow–resident (BM-resident) cells. However, platelet-producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared with BM Mks. We therefore sought to define the immune functions of lung Mks. Using single-cell RNA sequencing of BM and lung myeloid-enriched cells, we found that lung Mks, which we term MkL, had gene expression patterns that are similar to antigen-presenting cells. This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment, as evidenced by BM Mks having an MkL-like phenotype under the influence of pathogen receptor challenge and lung-associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in an MHC II–dependent manner both in vitro and in vivo. These data indicated that MkL had key immune regulatory roles dictated in part by the tissue environment.pre-print236 K

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I$^{2}$ = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions

JWST-TST DREAMS: Quartz Clouds in the Atmosphere of WASP-17b

Clouds are prevalent in many of the exoplanet atmospheres that have been observed to date. For transiting exoplanets, we know if clouds are present because they mute spectral features and cause wavelength-dependent scattering. While the exact composition of these clouds is largely unknown, this information is vital to understanding the chemistry and energy budget of planetary atmospheres. In this work, we observe one transit of the hot Jupiter WASP-17b with JWST's MIRI LRS and generate a transmission spectrum from 5-12 $\rm{\mu}$m. These wavelengths allow us to probe absorption due to the vibrational modes of various predicted cloud species. Our transmission spectrum shows additional opacity centered at 8.6 $\rm{\mu}$m, and detailed atmospheric modeling and retrievals identify this feature as SiO$_2$(s) (quartz) clouds. The SiO$_2$(s) clouds model is preferred at 3.5-4.2$\sigma$ versus a cloud-free model and at 2.6$\sigma$ versus a generic aerosol prescription. We find the SiO$_2$(s) clouds are comprised of small ${\sim}0.01$ $\rm{\mu}$m particles, which extend to high altitudes in the atmosphere. The atmosphere also shows a depletion of H$_2$O, a finding consistent with the formation of high-temperature aerosols from oxygen-rich species. This work is part of a series of studies by our JWST Telescope Scientist Team (JWST-TST), in which we will use Guaranteed Time Observations to perform Deep Reconnaissance of Exoplanet Atmospheres through Multi-instrument Spectroscopy (DREAMS).Comment: 19 pages, 7 figures, accepted for publication in ApJ

T Regulatory Cells Control Susceptibility to Invasive Pneumococcal Pneumonia in Mice

Streptococcus pneumoniae is an important human pathogen responsible for a spectrum of diseases including pneumonia. Immunological and pro-inflammatory processes induced in the lung during pneumococcal infection are well documented, but little is known about the role played by immunoregulatory cells and cytokines in the control of such responses. We demonstrate considerable differences in the immunomodulatory cytokine transforming growth factor (TGF)-β between the pneumococcal pneumonia resistant BALB/c and susceptible CBA/Ca mouse strains. Immunohistochemistry and flow cytometry reveal higher levels of TGF-β protein in BALB/c lungs during pneumococcal pneumonia that correlates with a rapid rise in lung Foxp3+Helios+ T regulatory cells. These cells have protective functions during pneumococcal pneumonia, because blocking their induction with an inhibitor of TGF-β impairs BALB/c resistance to infection and aids bacterial dissemination from lungs. Conversely, adoptive transfer of T regulatory cells to CBA/Ca mice, prior to infection, prolongs survival and decreases bacterial dissemination from lungs to blood. Importantly, strong T regulatory cell responses also correlate with disease-resistance in outbred MF1 mice, confirming the importance of immunoregulatory cells in controlling protective responses to the pneumococcus. This study provides exciting new evidence for the importance of immunomodulation during pulmonary pneumococcal infection and suggests that TGF-β signalling is a potential target for immunotherapy or drug design

The First Habitable Zone Earth-Sized Planet From TESS II: Spitzer Confirms TOI-700 d

We present Spitzer 4.5 μm observations of the transit of TOI-700 d, a habitable-zone Earth-sized planet in a multiplanet system transiting a nearby M-dwarf star (TIC 150428135, 2MASS J06282325–6534456). TOI-700 d has a radius of 1.144^(+0.062)_(-0.061) R⊕ and orbits within its host star's conservative habitable zone with a period of 37.42 days (T_(eq) ~ 269 K). TOI-700 also hosts two small inner planets (R_b = 1.037^(+0.0065)_(-0.064) R⊕ and R_c = 2.65^(+0.16)_(-0.15) R⊕) with periods of 9.98 and 16.05 days, respectively. Our Spitzer observations confirm the Transiting Exoplanet Survey Satellite (TESS) detection of TOI-700 d and remove any remaining doubt that it is a genuine planet. We analyze the Spitzer light curve combined with the 11 sectors of TESS observations and a transit of TOI-700 c from the LCOGT network to determine the full system parameters. Although studying the atmosphere of TOI-700 d is not likely feasible with upcoming facilities, it may be possible to measure the mass of TOI-700 d using state-of-the-art radial velocity (RV) instruments (expected RV semiamplitude of ~70 cm s⁻¹)

<i>TESS</i> Spots a Compact System of Super-Earths around the Naked-eye Star HR 858

Transiting Exoplanet Survey Satellite (TESS) observations have revealed a compact multiplanet system around the sixth-magnitude star HR 858 (TIC 178155732, TOI 396), located 32 pc away. Three planets, each about twice the size of Earth, transit this slightly evolved, late F-type star, which is also a member of a visual binary. Two of the planets may be in mean motion resonance. We analyze the TESS observations, using novel methods to model and remove instrumental systematic errors, and combine these data with follow-up observations taken from a suite of ground-based telescopes to characterize the planetary system. The HR 858 planets are enticing targets for precise radial velocity observations, secondary eclipse spectroscopy, and measurements of the Rossiter–McLaughlin effect

A Giant Planet Candidate Transiting a White Dwarf

Astronomers have discovered thousands of planets outside the solar system, most of which orbit stars that will eventually evolve into red giants and then into white dwarfs. During the red giant phase, any close-orbiting planets will be engulfed by the star, but more distant planets can survive this phase and remain in orbit around the white dwarf. Some white dwarfs show evidence for rocky material floating in their atmospheres, in warm debris disks, or orbiting very closely, which has been interpreted as the debris of rocky planets that were scattered inward and tidally disrupted. Recently, the discovery of a gaseous debris disk with a composition similar to ice giant planets demonstrated that massive planets might also find their way into tight orbits around white dwarfs, but it is unclear whether the planets can survive the journey. So far, the detection of intact planets in close orbits around white dwarfs has remained elusive. Here, we report the discovery of a giant planet candidate transiting the white dwarf WD 1856+534 (TIC 267574918) every 1.4 days. The planet candidate is roughly the same size as Jupiter and is no more than 14 times as massive (with 95% confidence). Other cases of white dwarfs with close brown dwarf or stellar companions are explained as the consequence of common-envelope evolution, wherein the original orbit is enveloped during the red-giant phase and shrinks due to friction. In this case, though, the low mass and relatively long orbital period of the planet candidate make common-envelope evolution less likely. Instead, the WD 1856+534 system seems to demonstrate that giant planets can be scattered into tight orbits without being tidally disrupted, and motivates searches for smaller transiting planets around white dwarfs.Comment: 50 pages, 12 figures, 2 tables. Published in Nature on Sept. 17, 2020. The final authenticated version is available online at: https://www.nature.com/articles/s41586-020-2713-

Protection against live rotavirus challenge in mice induced by parenteral and mucosal delivery of VP6 subunit rotavirus vaccine

Live oral rotavirus (RV) vaccines are part of routine childhood immunization but are associated with adverse effects, particularly intussusception. We have developed a non-live combined RV – norovirus (NoV) vaccine candidate consisting of human RV inner-capsid rVP6 protein and NoV virus-like particles. To determine the effect of delivery route on induction of VP6-specific protective immunity, BALB/c mice were administered a vaccine containing RV rVP6 intramuscularly, intranasally or a combination of both, and challenged with murine RV. At least 65 % protection against RV shedding was observed regardless of delivery route. The levels of post-challenge serum VP6-specific IgA titers correlated with protection

Binary systems and their nuclear explosions

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