Selective alteration of gene expression in response to natural and synthetic retinoids.

BACKGROUND: Retinoids are very potent inducers of cellular differentiation and apoptosis, and are efficient anti-tumoral agents. Synthetic retinoids are designed to restrict their toxicity and side effects, mostly by increasing their selectivity toward each isotype of retinoic acids receptors (RARα,β, γ and RXRα, β, γ). We however previously showed that retinoids displayed very different abilities to activate retinoid-inducible reporter genes, and that these differential properties were correlated to the ability of a given ligand to promote SRC-1 recruitment by DNA-bound RXR:RAR heterodimers. This suggested that gene-selective modulation could be achieved by structurally distinct retinoids. RESULTS: Using the differential display mRNA technique, we identified several genes on the basis of their differential induction by natural or synthetic retinoids in human cervix adenocarcinoma cells. Furthermore, this differential ability to regulate promoter activities was also observed in murine P19 cells for the RARβ2 and CRABPII gene, showing conclusively that retinoid structure has a dramatic impact on the regulation of endogenous genes. CONCLUSIONS: Our findings therefore show that some degree of selective induction or repression of gene expression may be achieved when using appropriately designed ligands for retinoic acid receptors, extending the concept of selective modulators from estrogen and peroxisome proliferator activated receptors to the class of retinoid receptors

Influenza A viruses are transmitted via the air from the nasal respiratory epithelium of ferrets

Human influenza A viruses are known to be transmitted via the air from person to person. It is unknown from which anatomical site of the respiratory tract influenza A virus transmission occurs. Here, pairs of genetically tagged and untagged influenza A/H1N1, A/H3N2 and A/H5N1 viruses that are transmissible via the air are used to co-infect donor ferrets via the intranasal and intratracheal routes to cause an upper and lower respiratory tract infection, respectively. In all transmission cases, we observe that the viruses in the recipient ferrets are of the same genotype as the viruses inoculated intranasally, demonstrating that they are expelled from the upper respiratory tract of ferrets rather than from trachea or the lower airways. Moreover, influenza A viruses that are transmissible via the air preferentially infect ferret and human nasal respiratory epithelium. These results indicate that virus replication in the upper respiratory tract, the nasal respiratory epithelium in particular, of donors is a driver for transmission of influenza A viruses via the air

The Rise and Fall of Passive Disk Galaxies: Morphological Evolution Along the Red Sequence Revealed by COSMOS

The increasing abundance of passive "red-sequence" galaxies since z=1-2 is mirrored by a coincident rise in the number of galaxies with spheroidal morphologies. In this paper, however, we show that in detail the correspondence between galaxy morphology and color is not perfect, providing insight into the physical origin of this evolution. Using the COSMOS survey, we study a significant population of red sequence galaxies with disk-like morphologies. These passive disks typically have Sa-Sb morphological types with large bulges, but they are not confined to dense environments. They represent nearly one-half of all red-sequence galaxies and dominate at lower masses (log Mstar < 10) where they are increasingly disk-dominated. As a function of time, the abundance of passive disks with log Mstar < 11 increases, but not as fast as red-sequence spheroidals in the same mass range. At higher mass, the passive disk population has declined since z~1, likely because they transform into spheroidals. We estimate that as much as 60% of galaxies transitioning onto the red sequence evolve through a passive disk phase. The origin of passive disks therefore has broad implications for understanding how star formation shuts down. Because passive disks tend to be more bulge-dominated than their star-forming counterparts, a simple fading of blue disks does not fully explain their origin. We explore several more sophisticated explanations, including environmental effects, internal stabilization, and disk regrowth during gas-rich mergers. While previous work has sought to explain color and morphological transformations with a single process, these observations open the way to new insight by highlighting the fact that galaxy evolution may actually proceed through several separate stages.Comment: 16 pages, Accepted version to appear in Ap

Human clade 2.3.4.4 A/H5N6 influenza virus lacks mammalian adaptation markers and does not transmit via the airborne route between ferrets

Since their emergence in 1997, A/H5N1 influenza viruses of the A/goose/ Guangdong/1/96 lineage have diversified in multiple genetic and antigenic clades upon continued circulation in poultry in several countries in Eurasia and Africa. Since 2009, reassortant viruses carrying clade 2.3.4.4 hemagglutinin (HA) and internal and neuraminidase (NA) genes of influenza A viruses of different avian origin have been detected, yielding various HA-NA combinations, such as A/H5N1, A/H5N2, A/H5N3, A/H5N5, A/H5N6, and A/H5N8. Previous studies reported on the low pathogenicity and lack of airborne transmission of A/H5N2 and A/H5N8 viruses in the ferret model. However, although A/H5N6 viruses are the only clade 2.3.4.4 viruses that crossed the species barrier and infected humans, the risk they pose for human health remains poorly characterized. Here, the characterization of A/H5N6 A/Guangzhou/39715/2014 virus in vitro and in ferrets is described. This A/H5N6 virus possessed high polymerase activity, mediated by the E627K substitution in the PB2 protein, which corresponds to only one biological trait out of the three that were previously shown to confer airborne transmissibility to A/H5N1 viruses between ferrets. This might explain its lack of airborne transmission between ferrets. After intranasal inoculation, A/H5N6 virus replicated to high titers in the respiratory tracts of ferrets and was excreted for at least 6 days. Moreover, A/H5N6 virus caused severe pneumonia in ferrets upon intratracheal inoculation. Thus, A/H5N6 virus causes a more severe disease in ferrets than previously investigated clade 2.3.4.4 viruses, but our results demonstrate that the risk from airborne spread is currently low

Local amplification of highly pathogenic avian influenza H5N8 viruses in wild birds in the Netherlands, 2016 to 2017

Introduction: Highly pathogenic avian influenza (HPAI) viruses of subtype H5N8 were re-introduced into the Netherlands by late 2016, after detections in southeast Asia and Russia. This second H5N8 wave resul

Influenza A (H10N7) virus causes respiratory tract disease in harbor seals and ferrets

Avian influenza viruses sporadically cross the species barrier to mammals, including humans, in which they may cause epidemic disease. Recently such an epidemic occurred due to the emergence of avian influenza virus of the subtype H10N7 (Seal/H10N7) in harbor seals (Phoca vitulina). This epidemic caused high mortality in seals along the north-west coast of Europe and represented a potential risk for human health. To characterize the spectrum of lesions and to identify the target cells and viral distribution, findings in 16 harbor seals spontaneously infected with Seal/H10N7 are described. The seals had respiratory tract inflammation extending from the nasal cavity to bronchi associated with intralesional virus antigen in respiratory epithelial cells. Virus infection was restricted to the respiratory tract. The fatal outcome of the viral infection in seals was most likely caused by secondary bacterial infections. To investigate the pathogenic potential of H10N7 infection for humans, we inoculated the seal virus intratracheally into six ferrets and performed pathological and virological analyses at 3 and 7 days post inoculation. These experimentally inoculated ferrets displayed mild clinical signs, virus excretion from the pharynx and respiratory tract inflammation extending from bronchi to alveoli that was associated with virus antigen expression exclusively in the respiratory epithelium. Virus was isolated only from the respiratory tract. In conclusion, Seal/H10N7 infection in naturally infected harbor seals and experimentally infected ferrets shows that respiratory epithelial cells are the permissive cells for viral replication. Fatal outcome in seals was caused by secondary bacterial pneumonia similar to that in fatal human cases during influenza pandemics. Productive infection of ferrets indicates that seal/H10N7 may possess a zoonotic potential. This outbreak of LPAI from wild birds to seals demonstrates the risk of such occasions for mammals and thus humans

Low virulence and lack of airborne transmission of the Dutch highly pathogenic avian influenza virus H5N8 in ferrets

Highly pathogenic avian influenza (HPAI) H5N8 viruses that emerged in poultry in East Asia spread to Europe and North America by late 2014. Here we show that the European HPAI H5N8 viruses differ from the Korean and Japanese HPAI H5N8 viruses by several amino acids and that a Dutch HPAI H5N8 virus had low virulence and was not transmitted via the airborne route in ferrets. The virus did not cross-react with sera raised against pre-pandemic H5 vaccine strains. This data is useful for public health risk assessments

Antiprotozoische Struktur‐Aktivitäts‐Beziehungen von synthetischen Leucinostatin‐Derivaten und Aufklärung ihres Wirkprinzips

Leucinostatin A ist eine der potentesten antiprotozoischen Verbindungen, die jemals beschrieben wurden, aber bisher war wenig über die Struktur-Aktivitäts-Beziehung (SAR) bekannt. Trypanosoma brucei wurde als Protozoen-Modellorganismus verwendet, um synthetisch modifizierte Derivate zu testen. Dabei wurden die vereinfachten, aber gleichermaßen aktiven Verbindungen 2 (ZHAWOC6025) und 4 (ZHAWOC6027) identifiziert. Anschließend wurden Modifikationen in allen Teilen des Moleküls durchgeführt, um ein besseres SAR-Verständnis zu erlangen. Die antiprotozoische SAR stimmte mit der SAR in Phospholipid-Liposomen überein, wobei die Membranintegrität, das Durchlässigkeitsverhalten und die Dynamik untersucht wurden. Die antiprotozoale Wirkung der natürlichen und synthetischen Leucinostatine liegt in der Destabilisierung der inneren Mitochondrienmembran, wie durch Ultrastrukturanalyse, Elektronenmikroskopie und Mitochondrienfärbung gezeigt wurde. Eine subletale Langzeitexposition von T. brucei (200 Passagen) und ein siRNA-Screening von 12′000 Mutanten zeigten keine Anzeichen einer Resistenzentwicklung gegenüber den synthetischen Derivaten

Wild ducks excrete highly pathogenic avian influenza virus H5N8 (2014-2015) without clinical or pathological evidence of disease article

Highly pathogenic avian influenza (HPAI) is essentially a poultry disease. Wild birds have traditionally not been involved in its spread, but the epidemiology of HPAI has changed in recent years. After its emergence in southeastern Asia in 1996, H5 HPAI virus of the Goose/Guangdong lineage has evolved into several sub-lineages, some of which have spread over thousands of kilometers via long-distance migration of wild waterbirds. In order to determine whether the virus is adapting to wild waterbirds, we experimentally inoculated the HPAI H5N8 virus clade 2.3.4.4 group A from 2014 into four key waterbird species-Eurasian wigeon (Anas penelope), common teal (Anas crecca), mallard (Anas platyrhynchos), and common pochard (Aythya ferina)-and compared virus excretion and disease severity with historical data of the HPAI H5N1 virus infection from 2005 in the same four species. Our results showed that excretion was highest in Eurasian wigeons for the 2014 virus, whereas excretion was highest in common pochards and mallards for the 2005 virus. The 2014 virus infection was subclinical in all four waterbird species, while the 2005 virus caused clinical disease and pathological changes in over 50% of the common pochards. In chickens, the 2014 virus infection caused systemic disease and high mortality, similar to the 2005 virus. In conclusion, the evidence was strongest for Eurasian wigeons as long-distance vectors for HPAI H5N8 virus from 2014. The implications of the switch in species-specific virus excretion and decreased disease severity may be that the HPAI H5 virus more easily spreads in the wild-waterbird population

Identification of a Small TAF Complex and Its Role in the Assembly of TAF-Containing Complexes

TFIID plays a role in nucleating RNA polymerase II preinitiation complex assembly on protein-coding genes. TFIID is a multisubunit complex comprised of the TATA box binding protein (TBP) and 14 TBP-associated factors (TAFs). Another class of multiprotein transcriptional regulatory complexes having histone acetyl transferase (HAT) activity, and containing TAFs, includes TFTC, STAGA and the PCAF/GCN5 complex. Looking for as yet undiscovered subunits by a proteomic approach, we had identified TAF8 and SPT7L in human TFTC preparations. Subsequently, however, we demonstrated that TAF8 was not a stable component of TFTC, but that it is present in a small TAF complex (SMAT), containing TAF8, TAF10 and SPT7L, that co-purified with TFTC. Thus, TAF8 is a subunit of both TFIID and SMAT. The latter has to be involved in a pathway of complex formation distinct from the other known TAF complexes, since these three histone fold (HF)-containing proteins (TAF8, TAF10 and SPT7L) can never be found together either in TFIID or in STAGA/TFTC HAT complexes. Here we show that TAF8 is absolutely necessary for the integration of TAF10 in a higher order TFIID core complex containing seven TAFs. TAF8 forms a heterodimer with TAF10 through its HF and proline rich domains, and also interacts with SPT7L through its C-terminal region, and the three proteins form a complex in vitro and in vivo. Thus, the TAF8-TAF10 and TAF10-SPT7L HF pairs, and also the SMAT complex, seem to be important regulators of the composition of different TFIID and/or STAGA/TFTC complexes in the nucleus and consequently may play a role in gene regulation