SDSS IV MaNGA: Metallicity and ionisation parameter in local star-forming galaxies from Bayesian fitting to photoionisation models

We measured gas-phase metallicity, ionisation parameter and dust extinction for 1795 representative local star-forming galaxies using integral field spectroscopy from the SDSS-IV MaNGA survey. We self-consistently derive these quantities by comparing observed line fluxes with photoionisation models using a Bayesian framework. We also present the first comprehensive study of the [SIII]$\lambda\lambda$9069,9532 nebular lines, which have long been predicted to be ideal tracers of the ionisation parameter. Unfortunately, we find that current photoionisation models substantially over-predict [SIII] lines intensity, while broadly reproducing other observed optical line ratios. We discuss how to nonetheless make use of the information provided by [SIII] lines by setting a prior on the ionisation parameter. Following this approach, we derive spatially-resolved maps and radial profiles of metallicity and ionisation parameter. The metallicity radial profiles are comparable with previous works, with metallicity declining toward the outer parts and a flattening in the central regions, in agreement with infall models of galaxy formation, that predict that spiral discs build up through accretion of material, which leads to an inside-out growth. On the other hand, ionisation parameter radial profiles are flat for low-mass galaxies, while their slope becomes positive as galaxy mass increases. However, the ionisation parameter maps we obtain are clumpy, especially for low-mass galaxies. Ionisation parameter is tightly correlated with the H$\alpha$ equivalent width [EW(H$\alpha$)], following a nearly universal relation, which we attribute to the change of the spectral shape of ionising sources due to ageing of HII regions. We derive a positive correlation between ionisation parameter and metallicity at fixed EW(H$\alpha$), in disagreement with previous theoretical works expecting an anti-correlation.STFC and ER

Whole mitochondrial genome sequencing provides new insights into the phylogeography of loggerhead turtles (Caretta caretta) in the Mediterranean Sea

Population structure and phylogeography of the loggerhead sea turtle (Caretta caretta) have so far been assessed mainly by mitochondrial DNA (mtDNA) single-gene sequencing studies. However, phylogenetic relationships amongst matrilines, genetic characterisation of rookeries and mixed-stock analyses have suffered from the limited resolution obtained by comparison of relatively short sequences such as from the mtDNA control region. Whole mitogenome sequencing can significantly improve population genetics, particularly in marine organisms showing female natal philopatry. Despite mitogenomics becoming increasingly common in biodiversity monitoring and conservation, only a few complete mitogenomes are available for C. caretta. In this study, we sequenced the complete mtDNA of 61 loggerhead turtles sampled between 2008 and 2021 along the Italian coastline and central Mediterranean Sea. We assigned complete mtDNA haplotypes to dead embryos and bycatch samples, and introduced a first nomenclature for loggerhead mitogenomes. Analysis of mtDNA diversity, Maximum Parsimony and Bayesian phylogenetic reconstruction allowed improved resolution of lineages with respect to studies reporting on partial mtDNA control region sequence comparisons, and we were able to further inform previous analyses on loggerhead ancestry based on control region haplogroups. Overall, whole mitogenome analysis has potential for considerable improvement of evolutionary history and phylogeographic investigations as well as mixed-stock surveys of loggerhead turtles

Bubbles and outflows. The novel JWST/NIRSpec view of the z = 1.59 obscured quasar XID2028

Quasar feedback in the form of powerful outflows is invoked as a key mechanism to quench star formation in galaxies, although direct observational evidence is still scarce and debated. Here we present Early Release Science JWST NIRSpec IFU observations of the z'='1.59 prototypical obscured Active Galactic Nucleus (AGN) XID2028: This target represents a unique test case for studying quasar feedback at the peak epoch of AGN-galaxy co-evolution because extensive multi-wavelength coverage is available and a massive and extended outflow is detected in the ionised and molecular components. With the unprecedented sensitivity and spatial resolution of the JWST, the NIRSpec dataset reveals a wealth of structures in the ionised gas kinematics and morphology that were previously hidden in the seeing-limited ground-based data. In particular, we find evidence of an interaction between the interstellar medium of the galaxy and the quasar-driven outflow and radio jet that produces an expanding bubble from which the fast and extended wind detected in previous observations emerges. The new observations confirm the complex interplay between the AGN jet, wind and the interstellar medium of the host galaxy, highlighting the role of low-luminosity radio jets in AGN feedback. They also clearly show the new window that NIRSpec opens for detailed studies of feedback at high redshift

GASP XXXVIII: The LOFAR-MeerKAT-VLA View on the Nonthermal Side of a Jellyfish Galaxy

Ram pressure stripping is a crucial evolutionary driver for cluster galaxies. It is thought to be able to accelerate the evolution of their star formation, trigger the activity of their central active galactic nucleus (AGN) and the interplay between galactic and environmental gas, and eventually dissipate their gas reservoirs. We explored the outcomes of ram pressure stripping by studying the nonthermal radio emission of the jellyfish galaxy JW100 in the cluster A2626 (z = 0.055), by combining LOw Frequency Array, MeerKAT, and Very Large Array observations from 0.144 to 5.5 GHz. We studied the integrated spectra of the stellar disk, the stripped tail, and the AGN; mapped the spectral index over the galaxy; and constrained the magnetic field intensity to between 11 and 18 μG in the disk and <10 μG in the tail. The stellar disk radio emission is dominated by a radiatively old plasma, likely related to an older phase of a high star formation rate. This suggests that the star formation was quickly quenched by a factor of 4 in a few 107 yr. The radio emission in the tail is consistent with the stripping scenario, where the radio plasma that originally accelerated in the disk is subsequently displaced in the tail. The morphology of the radio and X-ray emissions supports the scenario of the accretion of magnetized environmental plasma onto the galaxy. The AGN nonthermal spectrum indicates that relativistic electron acceleration may have occurred simultaneously with a central ionized gas outflow, thus suggesting a physical connection between the two processes

Characterization of a FGF19 Variant with Altered Receptor Specificity Revealed a Central Role for FGFR1c in the Regulation of Glucose Metabolism

Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the βKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

AAV-mediated human PEDF inhibits tumor growth and metastasis in murine colorectal peritoneal carcinomatosis model

<p>Abstract</p> <p>Background</p> <p>Angiogenesis plays an important role in tumor growth and metastasis, therefore antiangiogenic therapy was widely investigated as a promising approach for cancer therapy. Recently, pigment epithelium-derived factor (PEDF) has been shown to be the most potent inhibitor of angiogenesis. Adeno-associated virus (AAV) vectors have been intensively studied due to their wide tropisms, nonpathogenicity, and long-term transgene expression <it>in vivo</it>. The objective of this work was to evaluate the ability of AAV-mediated human PEDF (hPEDF) as a potent tumor suppressor and a potential candidate for cancer gene therapy.</p> <p>Methods</p> <p>Recombinant AAV₂encoding hPEDF (rAAV₂-hPEDF) was constructed and produced, and then was assigned for <it>in vitro </it>and <it>in vivo </it>experiments. Conditioned medium from cells infected with rAAV₂-hPEDF was used for cell proliferation and tube formation tests of human umbilical vein endothelial cells (HUVECs). Subsequently, colorectal peritoneal carcinomatosis (CRPC) mouse model was established and treated with rAAV₂-hPEDF. Therapeutic efficacy of rAAV₂-hPEDF were investigated, including tumor growth and metastasis, survival time, microvessel density (MVD) and apoptosis index of tumor tissues, and hPEDF levels in serum and ascites.</p> <p>Results</p> <p>rAAV₂-hPEDF was successfully constructed, and transmission electron microscope (TEM) showed that rAAV₂-hPEDF particles were non-enveloped icosahedral shape with a diameter of approximately 20 nm. rAAV₂-hPEDF-infected cells expressed hPEDF protein, and the conditioned medium from infected cells inhibited proliferation and tube-formation of HUVECs <it>in vitro</it>. Furthermore, in CRPC mouse model, rAAV₂-hPEDF significantly suppressed tumor growth and metastasis, and prolonged survival time of treated mice. Immunofluorescence studies indicated that rAAV₂-hPEDF could inhibit angiogenesis and induce apoptosis in tumor tissues. Besides, hPEDF levels in serum and ascites of rAAV₂-hPEDF-treated mice were significant higher than those in rAAV₂-null or normal saline (NS) groups.</p> <p>Conclusions</p> <p>Thus, our results suggest that rAAV₂-hPEDF may be a potential candidate as an antiangiogenic therapy agent.</p

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

Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses

Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can “cloak” the vector from inducing unwanted immune responses in multiple, but not all, models. This “coupled immunomodulation” strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods