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)

Strategies for meiotic sex chromosome dynamics and telomeric elongation in Marsupials

During meiotic prophase I, homologous chromosomes pair, synapse and recombine in a tightly regulated process that ensures the generation of genetically variable haploid gametes. Although the mechanisms underlying meiotic cell division have been well studied in model species, our understanding of the dynamics of meiotic prophase I in non-traditional model mammals remains in its infancy. Here, we reveal key meiotic features in previously uncharacterised marsupial species (the tammar wallaby and the fat-tailed dunnart), plus the fat-tailed mouse opossum, with a focus on sex chromosome pairing strategies, recombina tion and meiotic telomere homeostasis. We uncovered differences between phylogroups with important functional and evolutionary implications. First, sex chromosomes, which lack a pseudo-autosomal region in marsupials, had species specific pairing and silencing strategies, with implications for sex chromosome evolution. Second, we detected two waves of γH2AX accumulation during prophase I. The first wave was accompanied by low γH2AX lev els on autosomes, which correlated with the low recombination rates that distinguish marsupials from eutherian mammals. In the second wave, γH2AX was restricted to sex chromosomes in all three species, which correlated with transcription from the X in tammar wallaby. This suggests non-canonical functions of γH2AX on meiotic sex chromosomes. Finally, we uncover evidence for telomere elongation in primary spermatocytes of the fattailed dunnart, a unique strategy within mammals. Our results provide new insights into meiotic progression and telomere homeostasis in marsupials, highlighting the importance of capturing the diversity of meiotic strategies within mammalsThis work was supported by the Ministry of Economy, Industry and Competitiveness (CGL2017-83802-P to A.R-H. and CGL2014- 53106-P to J.P.), the Spanish Ministry of Science and Innovation (PID2020-112557GB-I00 to A.R H.) and the Agència de Gestio´ d’Ajuts Universitaris i de Recerca, AGAUR (SGR1215 to A.R-H.

Divergent patterns of meiotic double strand breaks and synapsis initiation dynamics suggest an evolutionary shift in the meiosis program between American and Australian marsupials

In eutherian mammals, hundreds of programmed DNA double-strand breaks (DSBs) are generated at the onset of meiosis. The DNA damage response is then triggered. Although the dynamics of this response is well studied in eutherian mammals, recent findings have revealed different patterns of DNA damage signaling and repair in marsupial mammals. To better characterize these differences, here we analyzed synapsis and the chromosomal distribution of meiotic DSBs markers in three different marsupial species (Thylamys elegans, Dromiciops gliorides, and Macropus eugenii) that represent South American and Australian Orders. Our results revealed inter-specific differences in the chromosomal distribution of DNA damage and repair proteins, which were associated with differing synapsis patterns. In the American species T. elegans and D. gliroides, chromosomal ends were conspicuously polarized in a bouquet configuration and synapsis progressed exclusively from the telomeres towards interstitial regions. This was accompanied by sparse H2AX phosphorylation, mainly accumulating at chromosomal ends. Accordingly, RAD51 and RPA were mainly localized at chromosomal ends throughout prophase I in both American marsupials, likely resulting in reduced recombination rates at interstitial positions. In sharp contrast, synapsis initiated at both interstitial and distal chromosomal regions in the Australian representative M. eugenii, the bouquet polarization was incomplete and ephemeral, γH2AX had a broad nuclear distribution, and RAD51 and RPA foci displayed an even chromosomal distribution. Given the basal evolutionary position of T. elegans, it is likely that the meiotic features reported in this species represent an ancestral pattern in marsupials and that a shift in the meiotic program occurred after the split of D. gliroides and the Australian marsupial clade. Our results open intriguing questions about the regulation and homeostasis of meiotic DSBs in marsupials. The low recombination rates observed at the interstitial chromosomal regions in American marsupials can result in the formation of large linkage groups, thus having an impact in the evolution of their genomesThis work was supported by grants CGL 2014-53106-P to JP (Ministerio de Ecomonía y Competitividad, Spain), BIOUAM02- 2020 to JP and RG (Departamento de Biología, Universidad Autónoma de Madrid), PID 2020-112557 GB-I00 to AR-H. (Ministerio de Ciencia e Innovación, Spain) and from the Australian Research Council to MBR, GS, and PDW. (DP21103512 and DP220101429). PW is also supported by the NHMRC (APP1182667 and APP2021172). LM-G was supported by a FPU predoctoral fellowship from the Ministry of Science, Innovation and University (FPU18/03867

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286

Co-infections and superinfections complicating COVID-19 in cancer patients: A multicentre, international study

Background: We aimed to describe the epidemiology, risk factors, and clinical outcomes of co-infections and superinfections in onco-hematological patients with COVID-19. Methods: International, multicentre cohort study of cancer patients with COVID-19. All patients were included in the analysis of co-infections at diagnosis, while only patients admitted at least 48 h were included in the analysis of superinfections. Results: 684 patients were included (384 with solid tumors and 300 with hematological malignancies). Co-infections and superinfections were documented in 7.8% (54/684) and 19.1% (113/590) of patients, respectively. Lower respiratory tract infections were the most frequent infectious complications, most often caused by Streptococcus pneumoniae and Pseudomonas aeruginosa. Only seven patients developed opportunistic infections. Compared to patients without infectious complications, those with infections had worse outcomes, with high rates of acute respiratory distress syndrome, intensive care unit (ICU) admission, and case-fatality rates. Neutropenia, ICU admission and high levels of C-reactive protein (CRP) were independent risk factors for infections. Conclusions: Infectious complications in cancer patients with COVID-19 were lower than expected, affecting mainly neutropenic patients with high levels of CRP and/or ICU admission. The rate of opportunistic infections was unexpectedly low. The use of empiric antimicrobials in cancer patients with COVID-19 needs to be optimized

A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE

In this small note we are concerned with the solution of Forward-Backward Stochastic Differential Equations (FBSDE) with drivers that grow quadratically in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem is a comparison result that allows comparing componentwise the signs of the control processes of two different qgFBSDE. As a byproduct one obtains conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio

Transverse sphericity of primary charged particles in minimum bias proton-proton collisions at s=0.9\sqrt{s}=0.9, 2.76 and 7 TeV

Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at $\sqrt{s}=0.9$, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with $p_{\rm T}\geq0.5$ GeV/c in $|\eta|\leq0.8$. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity ($N_{\rm ch}$) is reported for events with different $p_{\rm T}$ scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low $N_{\rm ch}$, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean $p_{\rm T}$ with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.Comment: 21 pages, 9 captioned figures, 3 tables, authors from page 16, published version, figures from http://aliceinfo.cern.ch/ArtSubmission/node/308

Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm{NN}}} = 2.76 TeV

The inclusive transverse momentum ($p_{\rm T}$) distributions of primary charged particles are measured in the pseudo-rapidity range $|\eta|<0.8$ as a function of event centrality in Pb-Pb collisions at $\sqrt{s_{\rm{NN}}}=2.76$ TeV with ALICE at the LHC. The data are presented in the $p_{\rm T}$ range $0.15<p_{\rm T}<50$ GeV/$c$ for nine centrality intervals from 70-80% to 0-5%. The Pb-Pb spectra are presented in terms of the nuclear modification factor $R_{\rm{AA}}$ using a pp reference spectrum measured at the same collision energy. We observe that the suppression of high-$p_{\rm T}$ particles strongly depends on event centrality. In central collisions (0-5%) the yield is most suppressed with $R_{\rm{AA}}\approx0.13$ at $p_{\rm T}=6$-7 GeV/$c$. Above $p_{\rm T}=7$ GeV/$c$, there is a significant rise in the nuclear modification factor, which reaches $R_{\rm{AA}} \approx0.4$ for $p_{\rm T}>30$ GeV/$c$. In peripheral collisions (70-80%), the suppression is weaker with $R_{\rm{AA}} \approx 0.7$ almost independently of $p_{\rm T}$. The measured nuclear modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/284

Anisotropic flow of charged hadrons, pions and (anti-)protons measured at high transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}=2.76 TeV

The elliptic, $v_2$, triangular, $v_3$, and quadrangular, $v_4$, azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions and (anti-)protons in Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range $|\eta|<0.8$ at different collision centralities and as a function of transverse momentum, $p_{\rm T}$, out to $p_{\rm T}=20$ GeV/$c$. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for $p_{\rm T}>8$ GeV/$c$. The small $p_{\rm T}$ dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to $p_{\rm T}=8$ GeV/$c$. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least $p_{\rm T}=8$ GeV/$c$ indicating that the particle type dependence persists out to high $p_{\rm T}$.Comment: 16 pages, 5 captioned figures, authors from page 11, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/186

Measurement of charm production at central rapidity in proton-proton collisions at s=2.76\sqrt{s} = 2.76 TeV

The $p_{\rm T}$-differential production cross sections of the prompt (B feed-down subtracted) charmed mesons D$^0$, D$^+$, and D$^{*+}$ in the rapidity range $|y|<0.5$, and for transverse momentum $1< p_{\rm T} <12$ GeV/$c$, were measured in proton-proton collisions at $\sqrt{s} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. The analysis exploited the hadronic decays D$^0 \rightarrow$K$\pi$, D$^+ \rightarrow$K$\pi\pi$, D$^{*+} \rightarrow$D$^0\pi$, and their charge conjugates, and was performed on a $L_{\rm int} = 1.1$ nb$^{-1}$ event sample collected in 2011 with a minimum-bias trigger. The total charm production cross section at $\sqrt{s} = 2.76$ TeV and at 7 TeV was evaluated by extrapolating to the full phase space the $p_{\rm T}$-differential production cross sections at $\sqrt{s} = 2.76$ TeV and our previous measurements at $\sqrt{s} = 7$ TeV. The results were compared to existing measurements and to perturbative-QCD calculations. The fraction of cdbar D mesons produced in a vector state was also determined.Comment: 20 pages, 5 captioned figures, 4 tables, authors from page 15, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/307