The multiphase starburst-driven galactic wind in NGC 5394

We present a detailed study of the neutral and ionized gas phases in the galactic wind for the nearby starburst galaxy NGC 5394 based on new integral field spectroscopy obtained with the INTEGRAL fibre system at the William Herschel Telescope. The neutral gas phase in the wind is detected via the interstellar Na I D doublet absorption. After a careful removal of the stellar contribution to these lines, a significant amount of neutral gas (∼10^7 M_⊙) is detected in a central region of ∼1.75 kpc size. This neutral gas is blueshifted by ∼165 km s^−1 with respect to the underlying galaxy. The mass outflow of neutral gas is comparable to the star formation rate of the host galaxy. Simultaneously, several emission lines (Hα, [N II], [S II]) are also analysed looking for the ionized warm phase counterpart of the wind. A careful kinematic decomposition of the line profiles reveals the presence of a secondary, broader, kinematic component. This component is found roughly in the same region where the Na I D absorption is detected. It presents higher [N II]/Hα and [S II]/Hα line ratios than the narrow component at the same locations, indicative of contamination by shock ionization. This secondary component also presents blueshifted velocities, although smaller than those measured for the neutral gas, averaging to ∼−30 km s^−1. The mass and mass outflow rate of the wind is dominated by the neutral gas, of which a small fraction might be able to escape the gravitational potential of the host galaxy. The observations in this system can be readily understood within a bipolar gas flow scenario

A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects

Purpose: We aimed to generate and phenotype a mouse model of foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA), a rare disease associated with mutations in Slc38a8 that causes severe visual alterations similar to albinism without affecting pigmentation. Methods: The FHONDA mouse model was generated with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology using an RNA guide targeting the Scl38a8 murine locus. The resulting mice were backcrossed to C57BL/6J. Melanin content was measured using spectrophotometry. Retinal cell architecture was analyzed through light and electron microscopy. Retinal projections to the brain were evaluated with anterograde labelling in embryos and adults. Visual function was assessed by electroretinography (ERG) and the optomotor test (OT). Results: From numerous Slc38a8 mouse mutant alleles generated, we selected one that encodes a truncated protein (p.196Pro*, equivalent to p.199Pro* in the human protein) closely resembling a mutant allele described in patients (p.200Gln*). Slc38a8 mutant mice exhibit wild-type eye and coat pigmentation with comparable melanin content. Subcellular abnormalities were observed in retinal pigment epithelium cells of Slc38a8 mutant mice. Anterograde labeling experiments of retinal projections in embryos and adults showed a reduction of ipsilateral fibers. Functional visual analyses revealed a decreased ERG response in scotopic conditions and a reduction of visual acuity in mutant mice measured by OT. Conclusions: Slc38a8 mutant mice recapitulate the phenotype of patients with FHONDA concerning their normal pigmentation and their abnormal visual system, in the latter being a hallmark of all types of albinism. These mice will be helpful in better understanding the pathophysiology of this genetic condition.Funded by the Spanish Ministry of Economy and Competitiveness under BIO2015-70978-R, the Spanish Ministry of Science and Innovation under RTI2018-101223-B-I00, CIBERER and Fundación Ramón Areces to L.M. Additionally, Spanish Ministry of Science and Innovation (FEDER-PID2019-106230RB-I00, 2019) and Generalitat Valenciana IDIFEDER/2017/064, 2017, PROMETEO/2021/024, 2021 supported the work of N.C. Funds from INSERM, Sorbonne Université, Retina France and Genespoir supported the work of A.R., as well as LabEx LIFESENSES (ANR-10-LABX-65) and IHU FOReSIGHT (ANR-18-IAHU-01) for the Institut de la Vision, a doctoral fellowship from the French Ministry of Education and Research to V.C

Genotype–phenotype correlation in patients with Usher syndrome and pathogenic variants in MYO7A: implications for future clinical trials

Purpose: We aimed to establish correlations between the clinical features of a cohort of Usher syndrome (USH) patients with pathogenic variants in MYO7A, type of pathogenic variant, and location on the protein domain. Methods: Sixty-two USH patients from 46 families with biallelic variants in MYO7A were examined for visual and audiological features. Participants were evaluated based on self-reported ophthalmological history and ophthalmological investigations (computerized visual field testing, best-corrected visual acuity, and ophthalmoscopic and electrophysiological examination). Optical coherence tomography and fundus autofluorescence imaging were performed when possible. Auditory and vestibular functions were evaluated. Patients were classified according to the type of variant and the protein domain where the variants were located. Results: Most patients displayed a typical USH1 phenotype, that is, prelingual severe-profound sensorineural hearing loss, prepubertal retinitis pigmentosa (RP) and vestibular dysfunction. No statistically significant differences were observed for the variables analysed except for the onset of hearing loss due to the existence of two USH2 cases, defined as postlingual sensorineural hearing loss, postpubertal onset of RP, and absence of vestibular dysfunction, and one atypical case of USH. Conclusion: We were unable to find a correlation between genotype and phenotype for MYO7A. However, our findings could prove useful for the assessment of efficacy in clinical trials, since the type of MYO7A variant does not seem to change the onset, severity or course of visual disease.This project was financially supported by the Center for Biomedical Network Research on Rare Diseases (CIBERER), FIS (PI16/00425, PI16/00539 and IIS‐FJD Biobank PT13/0010/0012). LG‐M and IPR were supported by the Río Hortega and predoctoral Programs (CM16/00126 and FI17/00192, respectively) from Institute of Health Carlos III (ISCIII, Spanish Ministry of the Economy, Industry and Competitiveness), Regional Government of Madrid (CAM, B2017/BMD37), and Regional Government of the Valencian Community (PROMETEU/2018/135), with partial support from the European Regional Development Fund (ERDF). Additional support was received from the Ramon Areces Foundation, the University Chair UAM‐IIS‐FJD of Genomic Medicine, ONCE Foundation and the Spanish National Organization of the Blind (ONCE). Drafting of this manuscript was possible thanks to the UshTher project (Clinical trial of gene therapy with dual AAV vectors for retinitis pigmentosa in patients with Usher syndrome type IB), which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 754848. The authors are grateful to the families that participated in this study and to the colleagues who referred patients to us. We also thank the Genetics and Ophthalmology Departments of Fundación Jimenez Diaz University Hospital (FJD, Madrid) and Asunción Giménez, Cristina Villaverde, and Ignacio Mahillo for their technical assistance

Impacts of Bar-driven Shear and Shocks on Star Formation

Bars drive gas inflow. As the gas flows inward, shocks and shear occur along the bar dust lanes. Such shocks and shear can affect the star formation (SF) and change the gas properties. For four barred galaxies, we present Hα velocity gradient maps that highlight bar-driven shocks and shear using data from the PHANGS-MUSE and PHANGS-ALMA surveys, which allow us to study bar kinematics in unprecedented detail. Velocity gradients are enhanced along the bar dust lanes, where shocks and shear are shown to occur in numerical simulations. Velocity gradient maps also efficiently pick up H ii regions that are expanding or moving relative to the surroundings. We put pseudo-slits on the regions where velocity gradients are enhanced and find that Hα and CO velocities jump up to ∼170 km s−1, even after removing the effects of circular motions due to the galaxy rotation. Enhanced velocity gradients either coincide with the peak of CO intensity along the bar dust lanes or are slightly offset from CO intensity peaks, depending on the objects. Using the Baldwin–Philips–Terlevich BPT diagnostic, we identify the source of ionization on each spaxel and find that SF is inhibited in the high-velocity gradient regions of the bar, and the majority of those regions are classified as a low-ionization nuclear emission-line region (LINER) or composite. This implies that SF is inhibited where bar-driven shear and shocks are strong. Our results are consistent with the results from the numerical simulations that show SF is inhibited in the bar where the shear force is strong

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations. They include retinal ciliopathies, other well-defined clinical syndromes presenting with retinal alterations and cases of non-specific multisystemic diseases. The heterogeneity of these conditions makes molecular and clinical characterization of patients challenging in daily clinical practice. We explored the capacity of targeted resequencing and copy-number variation analysis to improve diagnosis of a heterogeneous cohort of 47 patients mainly comprising atypical cases that did not clearly fit a specific clinical diagnosis. Thirty-three likely pathogenic variants were identified in 18 genes (ABCC6, ALMS1, BBS1, BBS2, BBS12, CEP41, CEP290, IFT172, IFT27, MKKS, MYO7A, OTX2, PDZD7, PEX1, RPGRIP1, USH2A, VPS13B, and WDPCP). Molecular findings and additional clinical reassessments made it possible to accurately characterize 14 probands (30% of the total). Notably, clinical refinement of complex phenotypes was achieved in 4 cases, including 2 de novo OTX2-related syndromes, a novel phenotypic association for the ciliary CEP41 gene, and the co-existence of biallelic USH2A variants and a Koolen-de-Vries syndrome–related 17q21.31 microdeletion. We demonstrate that combining next-generation sequencing and CNV analysis is a comprehensive and useful approach to unravel the extensive phenotypic and genotypic complexity of inherited syndromic retinopathiesFEDER (Fondo Europeo de Desarrollo Regional) | Ref. PI016/00425Instituto de Salud Carlos III | Ref. PT13/0010/001

Anti-Spike antibodies 3 months after SARS-CoV-2 mRNA vaccine booster dose in patients on hemodialysis: the prospective SENCOVAC study

Background: Patients on hemodialysis are at high-risk for complications derived from coronavirus disease 2019 (COVID-19). The present analysis evaluated the impact of a booster vaccine dose and breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on humoral immunity 3 months after the booster dose. Methods: This is a multicentric and prospective study assessing immunoglobulin G anti-Spike antibodies 6 and 9 months after initial SARS-CoV-2 vaccination in patients on hemodialysis that had also received a booster dose before the 6-month assessment (early booster) or between the 6- and 9-month assessments (late booster). The impact of breakthrough infections, type of vaccine, time from the booster and clinical variables were assessed. Results: A total of 711 patients [67% male, median age (range) 67 (20-89) years] were included. Of these, 545 (77%) received an early booster and the rest a late booster. At 6 months, 64 (9%) patients had negative anti-Spike antibody titers (3% of early booster and 29% of late booster patients, P =. 001). At 9 months, 91% of patients with 6-month negative response had seroconverted and there were no differences in residual prevalence of negative humoral response between early and late booster patients (0.9% vs 0.6%, P =. 693). During follow-up, 35 patients (5%) developed breakthrough SARS-CoV-2 infection. Antibody titers at 9 months were independently associated with mRNA-1273 booster (P =. 001), lower time from booster (P =. 043) and past breakthrough SARS-CoV-2 infection (P <. 001). Conclusions: In hemodialysis patients, higher titers of anti-Spike antibodies at 9 months were associated with mRNA-1273 booster, lower time from booster and past breakthrough SARS-CoV-2 infectionThe present project has been supported by Fresenius Medical Care, Diaverum, Vifor Pharma, Vircell, Fundación Renal Iñigo Álvarez de Toledo and ISCIII FEDER funds RICORS2040 (RD21/0005

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Occurrence of SARS-CoV-2 viremia is associated with genetic variants of genes related to COVID-19 pathogenesis

IntroductionSARS-CoV-2 viral load has been related to COVID-19 severity. The main aim of this study was to evaluate the relationship between SARS-CoV-2 viremia and SNPs in genes previously studied by our group as predictors of COVID-19 severity.Materials and methodsRetrospective observational study including 340 patients hospitalized for COVID-19 in the University Hospital La Princesa between March 2020 and December 2021, with at least one viremia determination. Positive viremia was considered when viral load was above the quantifiable threshold (20 copies/ml). A total of 38 SNPs were genotyped. To study their association with viremia a multivariate logistic regression was performed.ResultsThe mean age of the studied population was 64.5 years (SD 16.6), 60.9% patients were male and 79.4% white non-Hispanic. Only 126 patients (37.1%) had at least one positive viremia. After adjustment by confounders, the presence of the minor alleles of rs2071746 (HMOX1; T/T genotype OR 9.9 p &lt; 0.0001), rs78958998 (probably associated with SERPING1 expression; A/T genotype OR 2.3, p = 0.04 and T/T genotype OR 12.9, p &lt; 0.0001), and rs713400 (eQTL for TMPRSS2; C/T + T/T genotype OR 1.86, p = 0.10) were associated with higher risk of viremia, whereas the minor alleles of rs11052877 (CD69; A/G genotype OR 0.5, p = 0.04 and G/G genotype OR 0.3, p = 0.01), rs2660 (OAS1; A/G genotype OR 0.6, p = 0.08), rs896 (VIPR1; T/T genotype OR 0.4, p = 0.02) and rs33980500 (TRAF3IP2; C/T + T/T genotype OR 0.3, p = 0.01) were associated with lower risk of viremia.ConclusionGenetic variants in HMOX1 (rs2071746), SERPING1 (rs78958998), TMPRSS2 (rs713400), CD69 (rs11052877), TRAF3IP2 (rs33980500), OAS1 (rs2660) and VIPR1 (rs896) could explain heterogeneity in SARS-CoV-2 viremia in our population