The Local Volume HI Survey: star formation properties

We built a multi-wavelength dataset for galaxies from the Local Volume HI Survey (LVHIS), which comprises 82 galaxies. We also select a sub-sample of ten large galaxies for investigating properties in the galactic outskirts. The LVHIS sample covers nearly four orders of magnitude in stellar mass and two orders of magnitude in HI mass fraction (fHI). The radial distribution of HI gas with respect to the stellar disc is correlated with fHI but with a large scatter. We confirm the previously found correlations between the total HI mass and star formation rate (SFR), and between HI surface densities and SFR surface densities beyond R25. However, the former correlation becomes much weaker when the average surface densities rather than total mass or rate are considered, and the latter correlation also becomes much weaker when the effect of stellar mass is removed or controlled. Hence the link between SFR and HI is intrinsically weak in these regions, consistent with what was found on kpc scales in the galactic inner regions. We find a strong correlation between the SFR surface density and the stellar mass surface density, which is consistent with the star formation models where the gas is in quasi-equilibrium with the mid-plane pressure. We find no evidence for HI warps to be linked with decreasing star forming efficiencies.Comment: 31 pages, 20 figures, 4 tables. Accepted for publication at MNRA

Immunogenicity and Protective Capacity of a Virosomal Respiratory Syncytial Virus Vaccine Adjuvanted with Monophosphoryl Lipid A in Mice

Respiratory Syncytial Virus (RSV) is a major cause of viral brochiolitis in infants and young children and is also a significant problem in elderly and immuno-compromised adults. To date there is no efficacious and safe RSV vaccine, partially because of the outcome of a clinical trial in the 1960s with a formalin-inactivated RSV vaccine (FI-RSV). This vaccine caused enhanced respiratory disease upon exposure to the live virus, leading to increased morbidity and the death of two children. Subsequent analyses of this incident showed that FI-RSV induces a Th2-skewed immune response together with poorly neutralizing antibodies. As a new approach, we used reconstituted RSV viral envelopes, i.e. virosomes, with incorporated monophosphoryl lipid A (MPLA) adjuvant to enhance immunogenicity and to skew the immune response towards a Th1 phenotype. Incorporation of MPLA stimulated the overall immunogenicity of the virosomes compared to non-adjuvanted virosomes in mice. Intramuscular administration of the vaccine led to the induction of RSV-specific IgG2a levels similar to those induced by inoculation of the animals with live RSV. These antibodies were able to neutralize RSV in vitro. Furthermore, MPLA-adjuvanted RSV virosomes induced high amounts of IFNγ and low amounts of IL5 in both spleens and lungs of immunized and subsequently challenged animals, compared to levels of these cytokines in animals vaccinated with FI-RSV, indicating a Th1-skewed response. Mice vaccinated with RSV-MPLA virosomes were protected from live RSV challenge, clearing the inoculated virus without showing signs of lung pathology. Taken together, these data demonstrate that RSV-MPLA virosomes represent a safe and efficacious vaccine candidate which warrants further evaluation

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Van der Knoop et al. describe the clinical features of 21 individuals with biallelic pathogenic variants in ADAM22 and confirm the deleteriousness of the variants with functional studies. Clinical hallmarks of this rare disorder comprise progressive encephalopathy and infantile-onset refractory epilepsy.Peer reviewe

A virosomal respiratory syncytial virus vaccine candidate with a Toll-like receptor ligand as built-in adjuvant

Infectie met het respiratoir syncytieel virus (RSV) is de voornaamste oorzaak van virale bronchiolitis (longsteking) bij jonge kinderen. Daarnaast is RSV-infectie ook verantwoordelijk voor een groot deel van de lagere-luchtweginfecties bij ouderen en mensen met een verzwakt immuunsysteem. RSV wordt al sinds de ontdekking van het virus in de jaren ‘50 van de vorige eeuw gezien als een belangrijk doel voor vaccinatie, maar tot op heden is er nog geen RSV-vaccin op de markt. De oorzaken hiervan lopen uiteen van het ontbreken van een goed diermode om experimentele vaccins in te testen, en de onvolledige bescherming die een infectie met levend RSV met zich meebrengt, tot de dramatische uitkomst van een klinische studie met een formaline-geïnactiveerd RSV-vaccin in de jaren ‘60 van de vorige eeuw. RSV komt het lichaam binnen via de luchtwegen. Dat kan gebeuren door contact met een geïnfecteerd persoon of door contact met gecontamineerde oppervlakken van bijvoorbeeld speelgoed. Eenmaal in de luchtpijp en de bronchiën infecteert RSV het epitheel en kan daar vervolgens repliceren. RSV verspreidt zich binnen een individu door het vrijkomen van infectieus virus uit geïnfecteerde epitheelcellen, dat weer nieuwe cellen infecteert, maar ook door het fuseren van geïnfecteerde cellen met nog niet geïnfecteerde cellen. Dit fusieproces wordt teweeg gebracht door het virale fusie-eiwit dat op de membraan van geïnfecteerde cellen tot expressie wordt gebracht en leidt tot het ontstaan van grote klompen gefuseerde cellen, ook wel syncytia genoemd. De virale infectie en het ontstaan van syncytia worden gedetecteerd door het immuunsysteem dat vervolgens het virus uitschakelt en de geïnfecteerde cellen opruimt. In de meeste gevallen duurt de ziekte niet lang en verdwijnen de symptomen na ongeveer een week. In ergere gevallen kan het virus zich verspreiden naar de lagere luchtwegen en hier een longontsteking veroorzaken. Bij mensen met een verzwakt immuunsysteem kan dit de dood tot gevolg hebben. Na het succes van het geïnactiveerde poliovaccin in de jaren ‘50 en later, is er ook een poging gedaan om een formaline-geïnactiveerd RSV-vaccin (FI-RSV) te maken. Halverwege de jaren ‘60 is dit vaccin getest in een drietal klinische studies bij jonge kinderen. Het FI-RSV leek aanvankelijk goed te werken: het induceerde een afweerreactie met vorming van RSV-specifieke antistoffen. Deze antistoffen zouden bescherming moeten bieden tegen infectie met RSV. Echter, toen een aantal van de gevaccineerde kinderen een RSV-infectie doormaakten, bleken zij vatbaarder te zijn geworden voor het virus dan de niet-gevaccineerde kinderen in de controlegroep. Vooral de jongste kinderen, die voor de vaccinatie nog seronegatief waren voor RSV, maakten een verergerde vorm van RSV-infectie door. Dit leidde tot een toename in ziekenhuisopnames, terwijl twee van de jongste kinderen in de gevaccineerde groep zelfs kwamen te overleiden. Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants and young children. Infection with RSV also causes significant morbidity and mortality in elderly people. A vaccine against RSV would significantly reduce the health burden caused by RSV infection. In this study, we evaluated a virosomal RSV vaccine. A virosome is a virus particle without the genetic material. It does contain the surface proteins causing the immune response after vaccination. A virosome therefore is similar to a virus particle for the immune system, but is incapable of replication and therefore cannot cause disease. To improve the immune response induced by the virosomes, we included a so-called TLR ligand in the virosomal structure. Inclusion of this TLR ligand stimulates and skews the immune response. It has a positive influence on both safety and efficacy of the vaccine. In this study, we showed that is it feasible to produce RSV virosomes with a built-in TLR ligand. We subsequently tested this vaccine candidate in animal models. These tests showed the vaccine to be immunogenic and safe when administered to animals. Vaccinated animals were protected against infection with live virus.

Nanoaggregates of micropurified lipopolysaccharide identified using dynamic light scattering, zeta potential measurement, and TLR4 signaling activity

Nanoaggregates composed of selected glycoforms from Escherichia coli 055:B5 lipopolysaccharide (LPS) were prepared by combining sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, zinc-imidazole reverse staining, zinc chelation after cutting gel slices, elution with either 0.5% triethylamine (TEA) or 0.4% to 0.5% surfactant (SDS or deoxycholate [DOC]) from extrusion-generated gel microparticles, and centrifugal diafiltration after appropriate surfactant dilution. Dynamic light scattering allows detecting these aggregates, giving a size distribution from 10 to 100 nm in diameter. The formation of the aggregates prepared with selected DOC-eluted LPS glycoforms was notably improved over those prepared with TEA-eluted glycoforms. As the O-side chain length increased in the composition of the former aggregates, there was a gradual decrease in the electrophoretic mobility (from -1.2 to 0.01 10(-8) m(2)/V s), giving a calculated zeta potential from -15 to 0.1 mV at pH 6.8. These aggregates were further characterized for their abilities to elicit agonistic effects on human Toll-like receptor 4, as shown by in vitro activation of nuclear factor kappa light chain enhancer of activated B cells (NF-kappa B) in engineered HEK293 cells. (C) 2012 Elsevier Inc. All rights reserved

Efficacy and safety of an intranasal virosomal respiratory syncytial virus vaccine adjuvanted with monophosphoryl lipid A in mice and cotton rats

<p>Respiratory syncytial virus infection remains a serious health problem, not only in infants but also in immunocompromised adults and the elderly. An effective and safe vaccine is not available due to several obstacles: non-replicating RSV vaccines may prime for excess Th2-type responses and enhanced respiratory disease (ERD) upon natural RSV infection of vaccine recipients. We previously found that inclusion of the Toll-like receptor 4 (TLR4) ligand monophosphoryl lipid A (MPLA) in reconstituted RSV membranes (virosomes) potentiates vaccine-induced immunity and skews immune responses toward a Th1-phenotype, without priming for ERD. As mucosal immunization is an attractive approach for induction of RSV-specific systemic and mucosal antibody responses and TLR ligands could potentiate such responses, we explored the efficacy and safety of RSV-MPLA virosomes administered intranasally (IN) to mice and cotton rats. In mice, we found that incorporation of MPLA in IN-administered RSV virosomes increased both systemic IgG and local secretory-IgA (S-IgA) antibody levels and resulted in significantly reduced lung viral titers upon live virus challenge. Also, RSV MPLA virosomes induced more Th1-skewed responses compared to responses induced by FI-RSV. Antibody responses and Th1/Th2-cytokine responses induced by RSV-MPLA virosomes were comparable to those induced by live RSV infection. By comparison, formalin-inactivated RSV (FI-RSV) induced serum IgG that inhibited viral shedding upon challenge, but also induced Th2-skewed responses. In cotton rats, similar effects of incorporation of MPLA in virosomes were observed with respect to induction of systemic antibodies and inhibition of lung viral shedding upon challenge, but mucosal sS-IgA responses were only moderately enhanced. Importantly, IN immunization with RSV-MPLA virosomes, like live virus infection, did not lead to any signs of ERD upon live virus challenge of vaccinated animals, whereas IM immunization with FI-RSV did induce severe lung immunopathology under otherwise comparable conditions. Taken together, these data show that mucosally administered RSV-MPLA virosomes hold promise for a safe and effective vaccine against RSV. (C) 2013 Elsevier Ltd. All rights reserved.</p>

Lipopeptide-adjuvanted respiratory syncytial virus virosomes:A safe and immunogenic non-replicating vaccine formulation

Respiratory syncytial virus (RSV) causes severe respiratory disease in children and the elderly. There is no registered RSV vaccine. Early experimental non-replicating vaccines have been found to exacerbate RSV symptoms upon infection causing enhanced respiratory disease. Here we show that immunization of mice with reconstituted virosomes produced from RSV envelopes and containing the lipopeptide adjuvant (P3CSK4), induces high-titer virus-neutralizing antibodies, and the secretion of IFN-gamma through both MHC-I and MHC-II presentation of antigen, with a balanced Th1/Th2 profile. Immunization with RSV virosomes provides sterilizing immunity to virus challenge in mice and cotton rats, while not producing symptoms of enhanced disease. Therefore, these virosomes represent a promising candidate inactivated RSV vaccine formulation. (C) 2010 Elsevier Ltd. All rights reserved