AGN impact on the molecular gas in galactic centers as probed by CO lines

We present a detailed analysis of the X-ray, infrared, and carbon monoxide (CO) emission for a sample of 35 local ($z \leq 0.15$), active ($L_X \geq 10^{42}$ erg s$^{-1}$) galaxies. Our goal is to infer the contribution of far-ultraviolet (FUV) radiation from star formation (SF), and X-ray radiation from the active galactic nuclei (AGN), respectively producing photodissociation regions (PDRs) and X-ray dominated regions (XDRs), to the molecular gas heating. To this aim, we exploit the CO spectral line energy distribution (CO SLED) as traced by Herschel, complemented with data from single-dish telescopes for the low-J lines, and high-resolution ALMA images of the mid-J CO emitting region. By comparing our results to the Schmidt-Kennicutt relation, we find no evidence for AGN influence on the cold and low-density gas on kpc-scales. On nuclear (r = 250 pc) scales, we find weak correlations between the CO line ratios and either the FUV or X-ray fluxes: this may indicate that neither SF nor AGN radiation dominates the gas excitation, at least at r = 250 pc. From a comparison of the CO line ratios with PDR and XDR models, we find that PDRs can reproduce observations only in presence of extremely high gas densities ($n > 10^5$ cm$^{-3}$). In the XDR case, instead, the models suggest moderate densities ($n \approx 10^{2-4}$ cm$^{-3}$). We conclude that a mix of the two mechanisms (PDR for the mid-J, XDR or possibly shocks for the high-J) is necessary to explain the observed CO excitation in active galaxies

SINEUP Non-coding RNA Targeting GDNF Rescues Motor Deficits and Neurodegeneration in a Mouse Model of Parkinson's Disease.

International audience; Glial cell-derived neurotrophic factor (GDNF) has a potent action in promoting the survival of dopamine (DA) neurons. Several studies indicate that increasing GDNF levels may be beneficial for the treatment of Parkinson's disease (PD) by reducing neurodegeneration of DA neurons. Despite a plethora of preclinical studies showing GDNF efficacy in PD animal models, its application in humans remains questionable for its poor efficacy and side effects due to its uncontrolled, ectopic expression. Here we took advantage of SINEUPs, a new class of antisense long non-coding RNA, that promote translation of partially overlapping sense protein-coding mRNAs with no effects on their mRNA levels. By synthesizing a SINEUP targeting Gdnf mRNA, we were able to increase endogenous GDNF protein levels by about 2-fold. Adeno-associated virus (AAV)9-mediated delivery in the striatum of wild-type (WT) mice led to an increase of endogenous GDNF protein for at least 6 months and the potentiation of the DA system's functions while showing no side effects. Furthermore, SINEUP-GDNF was able to ameliorate motor deficits and neurodegeneration of DA neurons in a PD neurochemical mouse model. Our data indicate that SINEUP-GDNF could represent a new strategy to increase endogenous GDNF protein levels in a more physiological manner for therapeutic treatments of PD

Maturation signatures of conventional dendritic cell subtypes in COVID‐19 suggest direct viral sensing

Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, which negatively affects T-cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T-cell responses limit disease severity. Understanding how cDCs cope with SARS-CoV-2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures, with the upregulation of interferon-stimulated genes and interleukin (IL)-6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti-apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS-CoV-2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T-cell activation

Prolonged contact with dendritic cells turns lymph node‐resident NK cells into anti‐tumor effectors

Abstract Natural killer (NK) cells are critical players against tumors. The outcome of anti‐tumor vaccination protocols depends on the efficiency of NK‐cell activation, and efforts are constantly made to manipulate them for immunotherapeutic approaches. Thus, a better understanding of NK‐cell activation dynamics is needed. NK‐cell interactions with accessory cells and trafficking between secondary lymphoid organs and tumoral tissues remain poorly characterized. Here, we show that upon triggering innate immunity with lipopolysaccharide (LPS), NK cells are transiently activated, leave the lymph node, and infiltrate the tumor, delaying its growth. Interestingly, NK cells are not actively recruited at the draining lymph node early after LPS administration, but continue their regular homeostatic turnover. Therefore, NK cells resident in the lymph node at the time of LPS administration become activated and exert anti‐tumor functions. NK‐cell activation correlates with the establishment of prolonged interactions with dendritic cells (DCs) in lymph nodes, as observed by two‐photon microscopy. Close DC and NK‐cell contacts are essential for the localized delivery of DC‐derived IL‐18 to NK cells, a strict requirement in NK‐cell activation

AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy

Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans

Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration

The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases

IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity

Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signalling pathways and inflammation. Natural killer (NK) cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses. NK cells mediate resistance against haematopoietic neoplasms but are generally considered to play a minor role in solid tumour carcinogenesis. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection

Trade-off between sexual activities and parental care: an experimental test using handicapped mates

Electing to invest in parental care is an adaptive decision thought to involve a trade-off between remating and continuing parental effort. The rock sparrow, Petronia petronia, is an unusual species in which parental investment is highly variable and both sexes may desert the brood. Males contemporaneously engage in parental care, mate guarding, and courting their current or new females. In this study we experimentally handicapped male rock sparrows during the nestling period by increasing their body mass in order to study the effects on male behaviour and the female response. Handicapped males exhibited lower sexual activity than control males but handicapped males did not reduce their offspring feeding rates. Females with a handicapped partner significantly increased the number of sexual soliciting postures towards their mates compared to females paired with control males. The females' behaviour is probably a response to the sexual behaviour change of their partners. Our results suggest that with choices involving a trade-off between mating investment and parental investment, handicapped males chose the parental investment option

ECOAP: Experimental assessment of congestion control strategies for CoAP using the wishful platform

Future Smart Cities will be enabled by a pervasive fabric of sensors and actuators, seamlessly integrated within information systems. This large-scale Internet of Things (IoT) will bring a new level of challenges to existing communication networks and wireless standards. In order to analyze these issues and study possible solutions, a quick and rapid experimentation is of paramount importance to ensure that IoT protocols and network architectures can handle such challenges. In this paper, we present the ECOAP project that aims at evaluating the performance of the Constrained Application Protocol (CoAP), the application protocol defined to interconnect IoT devices with information systems. The project will carry out an evaluation of CoAP through the WiSHFUL platform, a platform for large-scale experimentation of network systems. The project will focus on assessing different congestion control strategies in order to evaluate the scalability of the protocol in future large-scale scenarios

Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

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