Exciton-polariton topological insulator.

Topological insulators-materials that are insulating in the bulk but allow electrons to flow on their surface-are striking examples of materials in which topological invariants are manifested in robustness against perturbations such as defects and disorder1. Their most prominent feature is the emergence of edge states at the boundary between areas with different topological properties. The observable physical effect is unidirectional robust transport of these edge states. Topological insulators were originally observed in the integer quantum Hall effect2 (in which conductance is quantized in a strong magnetic field) and subsequently suggested3-5 and observed6 to exist without a magnetic field, by virtue of other effects such as strong spin-orbit interaction. These were systems of correlated electrons. During the past decade, the concepts of topological physics have been introduced into other fields, including microwaves7,8, photonic systems9,10, cold atoms11,12, acoustics13,14 and even mechanics15. Recently, topological insulators were suggested to be possible in exciton-polariton systems16-18 organized as honeycomb (graphene-like) lattices, under the influence of a magnetic field. Exciton-polaritons are part-light, part-matter quasiparticles that emerge from strong coupling of quantum-well excitons and cavity photons19. Accordingly, the predicted topological effects differ from all those demonstrated thus far. Here we demonstrate experimentally an exciton-polariton topological insulator. Our lattice of coupled semiconductor microcavities is excited non-resonantly by a laser, and an applied magnetic field leads to the unidirectional flow of a polariton wavepacket around the edge of the array. This chiral edge mode is populated by a polariton condensation mechanism. We use scanning imaging techniques in real space and Fourier space to measure photoluminescence and thus visualize the mode as it propagates. We demonstrate that the topological edge mode goes around defects, and that its propagation direction can be reversed by inverting the applied magnetic field. Our exciton-polariton topological insulator paves the way for topological phenomena that involve light-matter interaction, amplification and the interaction of exciton-polaritons as a nonlinear many-body system.

Propagative Oscillations in Codirectional Polariton Waveguide Couplers.

We report on novel exciton-polariton routing devices created to study and purposely guide light-matter particles in their condensate phase. In a codirectional coupling device, two waveguides are connected by a partially etched section that facilitates tunable coupling of the adjacent channels. This evanescent coupling of the two macroscopic wave functions in each waveguide reveals itself in real space oscillations of the condensate. This Josephson-like oscillation has only been observed in coupled polariton traps so far. Here, we report on a similar coupling behavior in a controllable, propagative waveguide-based design. By controlling the gap width, channel length, or propagation energy, the exit port of the polariton flow can be chosen. This codirectional polariton device is a passive and scalable coupler element that can serve in compact, next generation logic architectures.

[The German Standing Committee on Vaccination: organization and mode of functioning]. / Ständige Impfkommission: Organisation und Arbeitsweise.

By law the Standing Committee on Vaccination (STIKO) has the mandate to develop recommendations for carrying out vaccinations and other measures of specific prophylaxis of communicable diseases. Currently, the committee has 18 members who meet 3 times per year to discuss and vote on recommendations. The secretariat of STIKO is located at the Immunization Unit of the Robert Koch Institute (RKI). In 2011 the STIKO adopted a new standard operating procedure (SOP) for the development of evidence-based vaccination recommendations. Using methods of evidence-based medicine, the respective STIKO working group, comprised of STIKO members, RKI staff and external experts, develops a draft recommendation on which the commission votes. After conclusion of the external consultation procedure the vaccination recommendation is considered by the Federal Joint Committee and in the case of a positive vote, is incorporated into the guidelines for protective vaccination and therefore becomes a mandatory service of the statutory health insurance. This article provides an overview on the organization and modes of functioning of the STIKO.

Emergence of a novel cluster of influenza A(H5N1) virus clade 2.2.1.2 with putative human health impact in Egypt, 2014/15.

A distinct cluster of highly pathogenic avian influenzaviruses of subtype A(H5N1) has been found to emergewithin clade 2.2.1.2 in poultry in Egypt since summer2014 and appears to have quickly become predominant.Viruses of this cluster may be associated withincreased incidence of human influenza A(H5N1) infectionsin Egypt over the last months.

Nucleic acid-based detection of influenza A virus subtypes H7 and N9 with a special emphasis on the avian H7N9 virus.

In 2013, a novel influenza A virus of subtype H7N9 was transmitted from avian sources to humans in China, causing severe illness and substantial mortality. Rapid and sensitive diagnostic approaches are the basis of epidemiological studies and of utmost importance for the detection of infected humans and animals. We developed various quantitative reverse transcriptase PCR (RT-qPCR) assays for (i) the generic detection of the haemagglutinin (HA) gene of H7 viruses or the neuraminidase (NA) gene of N9 viruses, and (ii) the specific detection of HA and NA of the novel avian H7N9/2013 virus. The sensitivity of the newly developed assays was compared with previously published PCRs, and the specificity of all RT-qPCRs was examined using a panel of 42 different H7 and 16 different N9 isolates. Furthermore, we analysed the performance of the RT-qPCR assays with dilution series and diagnostic samples obtained from animal experiments. Our study provides a comprehensive set of RT-qPCR assays for the reliable detection of the novel avian H7N9 virus, with high sensitivity and improved and tailored specificity values compared with published assays. Finally, we also present data about the robustness of a duplex assay for the simultaneous detection of HA and NA of the avian influenza H7N9/2013 virus.

Comparing introduction to Europe of highly pathogenic avian influenza viruses A(H5N8) in 2014 and A(H5N1) in 2005.

Since the beginning of November 2014, nine outbreaks of highly pathogenic avian influenza virus (HPAIV) A(H5N8) in poultry have been detected in four European countries. In this report, similarities and differences between the modes of introduction of HPAIV A(H5N1) and A(H5N8) into Europe are described. Experiences from outbreaks of A(H5N1) in Europe demonstrated that early detection to control HPAIV in poultry has proven pivotal to minimise the risk of zoonotic transmission and prevention of human cases.

Towards a new, ecologically targeted approach to monitoring wild bird populations for avian influenza viruses.

Prevalence monitoring of avian influenza in wild bird populations is important to estimate risks for the occurrence of potentially zoonotic and economically disastrous outbreaks of highly pathogenic avian influenza virus (AIV) in poultry worldwide. A targeted, cost-effective monitoring method for AIV in wild birds was developed, which is based on monitoring results for AIV in Germany and information on the distribution and abundance of wild bird species in selected habitat types. Spatial data were combined with virological and outbreak data for the period of 1 January 2006 to 31 December 2010. Using Germany as an example, we identified 11 indicator species. By concentrating monitoring efforts on these species in spatially confined locations, we propose a targeted and more cost-effective risk-based AIV monitoring approach that can be adapted universally for the identification of wild bird indicator species worldwide with the perspective of reducing sample sizes (and costs) without impairing the validity of the results.

Background paper to the recommendation for the preferential use of live-attenuated influenza vaccine in children aged 2-6 years in Germany.

The German Standing Committee on Vaccination (STIKO) recommends seasonal influenza vaccination for children and adolescents with chronic medical conditions that put them at risk for severe influenza illness. In addition to trivalent inactivated influenza vaccines (TIV), a trivalent live-attenuated influenza vaccine (LAIV) was licensed for children and adolescents aged 2-17 years in the European Union in 2011. Employing the methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, we examined the evidence for efficacy and safety of LAIV relative to TIV to guide STIKO's decision on whether LAIV should be preferentially recommended for at-risk children. In our meta-analysis of data from two randomized trials directly comparing LAIV and TIV in children aged ≤ 6 years, the protective efficacy of LAIV against laboratory-confirmed influenza was 53 % [95 % confidence interval (CI): 45-61 %] higher than that of TIV. A similar study in individuals aged 6-17 years showed a 32 % (95 % CI: 3-52 %) higher efficacy of LAIV. The quality of the evidence for a superior protective efficacy of LAIV against all relevant clinical outcomes was rated 'moderate' for children aged 2-6 years and 'low' for the age group 7-17 years. Regarding safety outcomes, the available data suggest no significant differences between LAIV and TIV. Based on these results, STIKO recommends that LAIV should be used preferentially for influenza vaccination of at-risk children aged 2-6 years. In children and adolescents aged 7-17 years, either LAIV or TIV may be used without specific preference. Possible contraindications and the vaccinee's and his/her guardians' preferences should be taken into account.

Background paper to the revised recommendation for hepatitis B vaccination of persons at particular risk and for hepatitis B postexposure prophylaxis in Germany.

The German Standing Committee on Vaccination (Ständige Impfkommission, STIKO) recommends vaccinating risk groups against hepatitis B and gives advice for postexposure prophylaxis. STIKO has recently revised this recommendation, focusing on: (i) classification of risk groups, (ii) duration of protection after primary immunization, and (iii) anti-HBs threshold that defines successful hepatitis B vaccination. Orientating literature reviews were performed for the first objective. Examples of population subgroups at increased risk were identified and classified into three indication groups. Systematic reviews on the duration of vaccine-induced protection identified one randomized controlled trial (RCT) and nine cohort studies. When applying the grading of recommendation, assessment, development, and evaluation (GRADE) methodology, evidence from RCTs was considered of very low quality regarding the question of whether hepatitis B can be prevented for 15 years after successful primary vaccination (anti-HBs ≥ 10 IU/l) with a vaccine efficacy of 96 % against chronic hepatitis, 89 % against HBsAg positivity, and 73 % against isolated anti-HBc positivity. However, seven cohort studies showed that no cases of clinical hepatitis B or HBsAg positivity occurred during a maximum follow-up period of 10 years in settings comparable to the situation in Germany when anti-HBs ≥ 10 IU/l was used to indicate vaccination success. Less than 1 % of vaccinated study participants had isolated anti-HBc positivity. GRADE assessment of two cohort studies revealed that evidence of very low quality exists that the use of anti-HBs ≥ 100 IU/l to measure vaccination success leads to a lower frequency of anti-HBc positivity during follow-up than the use of anti-HBs ≥ 10 IU/l. The recommendation was revised according to this evidence.

Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains.

There is accumulating evidence that lateral assemblies (rafts) of sphingolipids and cholesterol form platforms that serve to support numerous cellular events in membrane traffic and signal transduction. Raft membrane microdomains are thought to function by preferentially associating with specific proteins while excluding others. The basic forces driving raft formation are lipid interactions which are, per se, weak and transient. Sphingolipid rafts should therefore be considered to be dynamic structures in which cholesterol plays an important role as a linker. Caveolins influence these dynamics by forming stabilized raft domains in intracellular membranes as well as at the plasma membrane. Recent data suggest that clustering of raft components could regulate raft dynamics and therefore represents an important feature in the function of these membrane microdomains.

[The pandemic influenza virus H1N1/2009: a review of the molecular biology, phylogeny, history of reassortments, and parameters of host switching]. / Das pandemische H1N1-Influenzavirus/2009: Eine Übersicht zur Molekularbiologie, Phylogenie, Reassortierungsgeschichte und den Parametern des Wirtswechsels.

The generation of pandemic influenza A viruses of the previous century as well as that of the current influenza A/H1N1/2009 pandemic appear to be governed and preceded by reassortment events in other mammalian species. So far, it could not be shown that transmission of avian influenza viruses to humans will directly cause a pandemic. Zoonotic transmissions of avian and also of porcine influenza viruses of diverse subtypes have been repeatedly described. However, these events did not lead to further spread and establishment of these viruses. This is in contrast to the current A/H1N1/2009 viruses which already have started to outcompete seasonal human influenza viruses. The actual molecular key factors required for a successful exchange of genome segments between different influenza virus strains and which factors foster the consecutive spread of certain reassortant viruses in the human population remain to be pinpointed. It has been elucidated so far that newly introduced genome segments need to be compatible with both the remaining original segments and the human hosts.

Selective accumulation of raft-associated membrane protein LAT in T cell receptor signaling assemblies.

Activation of T cell antigen receptor (TCR) induces tyrosine phosphorylations that mediate the assembly of signaling protein complexes. Moreover, cholesterol-sphingolipid raft membrane domains have been implicated to play a role in TCR signal transduction. Here, we studied the assembly of TCR with signal transduction proteins and raft markers in plasma membrane subdomains of Jurkat T leukemic cells. We employed a novel method to immunoisolate plasma membrane subfragments that were highly concentrated in activated TCR-CD3 complexes and associated signaling proteins. We found that the raft transmembrane protein linker for activation of T cells (LAT), but not a palmitoylation-deficient non-raft LAT mutant, strongly accumulated in TCR-enriched immunoisolates in a tyrosine phosphorylation-dependent manner. In contrast, other raft-associated molecules, including protein tyrosine kinases Lck and Fyn, GM1, and cholesterol, were not highly concentrated in TCR-enriched plasma membrane immunoisolates. Many downstream signaling proteins coisolated with the TCR/LAT-enriched plasma membrane fragments, suggesting that LAT/TCR assemblies form a structural scaffold for TCR signal transduction proteins. Our results indicate that TCR signaling assemblies in plasma membrane subdomains, rather than generally concentrating raft-associated membrane proteins and lipids, form by a selective protein-mediated anchoring of the raft membrane protein LAT in vicinity of TCR.

The subcellular distribution of early endosomes is affected by the annexin II2p11(2) complex.

The tyrosine kinase substrate annexin II is a member of a multigene family of Ca2+ and lipid-binding proteins which have been implicated in a number of membrane-related events. We have analyzed the subcellular distribution of annexin II in relation to other cellular components in normal and specifically manipulated MDCK cells. In a polarized monolayer of MDCK cells annexin II and its cellular ligand p11 are restricted almost exclusively to the cortical regions of the cells which also contain peripheral early endosomes. Treatment of the polarized cells with low Ca2+ medium leads to a disintegration of the cortical cytoskeleton and a translocation of both, the annexin II2p11(2) complex and early endosomes, to the cytoplasm. A similar translocation which is however specific for the annexin II2p11(2) complex and early endosomes and does not affect other elements of the cell cortex is observed in cells expressing a trans-dominant annexin II-p11 mutant. This chimeric mutant protein causes the aggregation of endogenous annexin II and p11 and the simultaneous detachment of early endosomes from the cell periphery resulting in the binding of the early endosomes but no other components of the endocytotic or biosynthetic pathways to the annexin II/p11 aggregates. The specificity of this effect argues for the association of the annexin II2p11(2) complex with early endosomes and suggests that this association contributes to establish the peripheral localization of early endosomal structures.

Induction of caveolae in the apical plasma membrane of Madin-Darby canine kidney cells.

In this paper, we have analyzed the behavior of antibody cross-linked raft-associated proteins on the surface of MDCK cells. We observed that cross-linking of membrane proteins gave different results depending on whether cross-linking occurred on the apical or basolateral plasma membrane. Whereas antibody cross-linking induced the formation of large clusters on the basolateral membrane, resembling those observed on the surface of fibroblasts (Harder, T., P. Scheiffele, P. Verkade, and K. Simons. 1998. J. Cell Biol. 929-942), only small ( approximately 100 nm) clusters formed on the apical plasma membrane. Cross-linked apical raft proteins e.g., GPI-anchored placental alkaline phosphatase (PLAP), influenza hemagglutinin, and gp114 coclustered and were internalized slowly ( approximately 10% after 60 min). Endocytosis occurred through surface invaginations that corresponded in size to caveolae and were labeled with caveolin-1 antibodies. Upon cholesterol depletion the internalization of PLAP was completely inhibited. In contrast, when a non-raft protein, the mutant LDL receptor LDLR-CT22, was cross-linked, it was excluded from the clusters of raft proteins and was rapidly internalized via clathrin-coated pits. Since caveolae are normally present on the basolateral membrane but lacking from the apical side, our data demonstrate that antibody cross-linking induced the formation of caveolae, which slowly internalized cross-linked clusters of raft-associated proteins.

Lipid domain structure of the plasma membrane revealed by patching of membrane components.

Lateral assemblies of glycolipids and cholesterol, "rafts," have been implicated to play a role in cellular processes like membrane sorting, signal transduction, and cell adhesion. We studied the structure of raft domains in the plasma membrane of non-polarized cells. Overexpressed plasma membrane markers were evenly distributed in the plasma membrane. We compared the patching behavior of pairs of raft markers (defined by insolubility in Triton X-100) with pairs of raft/non-raft markers. For this purpose we cross-linked glycosyl-phosphatidylinositol (GPI)-anchored proteins placental alkaline phosphatase (PLAP), Thy-1, influenza virus hemagglutinin (HA), and the raft lipid ganglioside GM1 using antibodies and/or cholera toxin. The patches of these raft markers overlapped extensively in BHK cells as well as in Jurkat T-lymphoma cells. Importantly, patches of GPI-anchored PLAP accumulated src-like protein tyrosine kinase fyn, which is thought to be anchored in the cytoplasmic leaflet of raft domains. In contrast patched raft components and patches of transferrin receptor as a non-raft marker were sharply separated. Taken together, our data strongly suggest that coalescence of cross-linked raft elements is mediated by their common lipid environments, whereas separation of raft and non-raft patches is caused by the immiscibility of different lipid phases. This view is supported by the finding that cholesterol depletion abrogated segregation. Our results are consistent with the view that raft domains in the plasma membrane of non-polarized cells are normally small and highly dispersed but that raft size can be modulated by oligomerization of raft components.

Analysis of CD44-containing lipid rafts: Recruitment of annexin II and stabilization by the actin cytoskeleton.

CD44, the major cell surface receptor for hyaluronic acid (HA), was shown to localize to detergent-resistant cholesterol-rich microdomains, called lipid rafts, in fibroblasts and blood cells. Here, we have investigated the molecular environment of CD44 within the plane of the basolateral membrane of polarized mammary epithelial cells. We show that CD44 partitions into lipid rafts that contain annexin II at their cytoplasmic face. Both CD44 and annexin II were released from these lipid rafts by sequestration of plasma membrane cholesterol. Partition of annexin II and CD44 to the same type of lipid rafts was demonstrated by cross-linking experiments in living cells. First, when CD44 was clustered at the cell surface by anti-CD44 antibodies, annexin II was recruited into the cytoplasmic leaflet of CD44 clusters. Second, the formation of intracellular, submembranous annexin II-p11 aggregates caused by expression of a trans-dominant mutant of annexin II resulted in coclustering of CD44. Moreover, a frequent redirection of actin bundles to these clusters was observed. These basolateral CD44/annexin II-lipid raft complexes were stabilized by addition of GTPgammaS or phalloidin in a semipermeabilized and cholesterol-depleted cell system. The low lateral mobility of CD44 in the plasma membrane, as assessed with fluorescent recovery after photobleaching (FRAP), was dependent on the presence of plasma membrane cholesterol and an intact actin cytoskeleton. Disruption of the actin cytoskeleton dramatically increased the fraction of CD44 which could be recovered from the light detergent-insoluble membrane fraction. Taken together, our data indicate that in mammary epithelial cells the vast majority of CD44 interacts with annexin II in lipid rafts in a cholesterol-dependent manner. These CD44-containing lipid microdomains interact with the underlying actin cytoskeleton.

Rapid molecular subtyping by reverse transcription polymerase chain reaction of the neuraminidase gene of avian influenza A viruses.

Accurate identification of hemagglutinin (HA) and neuraminidase (NA) subtypes of influenza A viruses is an integral part of monitoring programs targeting avian influenza viruses (AIV). Use of highly sensitive molecular screening methods such as pan influenza-specific real-time RT-PCR (rRT-PCR) yields an increasing number of samples which are positive for AIV RNA but negative by virus isolation and, therefore, require molecular, instead of serological, subtyping. We developed specific RT-PCR assays for all known nine AIV NA subtypes. Validation using 43 reference isolates from different animal species revealed good performance characteristics regarding sensitivity and specificity. On basis of serial tenfold dilution series of reference isolates a benchmark value of C(t) 32 in an M gene-specific rRT-PCR became evident below which all nine NA subtypes were readily detectable by the subtype-specific RT-PCRs. For subtypes N1, N2, N4 and N6 detection was extended to dilutions with C(t) values of up to 35. Diagnostic applicability of the whole set of conventional NA-specific RT-PCRs was evaluated by analysis of 119 different diagnostic samples from wild birds which proved to be positive for AIV by M gene-specific rRT-PCR. Diagnostic sensitivity and specificity was confirmed by sequencing NA amplicons from 41 field isolates generated from this set and by NA inhibition assays. A universal molecular HA/NA subtyping algorithm for rRT-PCR positive avian influenza virus monitoring samples is proposed which may complement classical serological subtyping of influenza A virus isolates.

Virological monitoring of white storks (Ciconia ciconia) for avian influenza.

Between 2003 and 2008, more than 600 white stork (Ciconia ciconia) nestlings in the German federal state of Brandenburg were ringed and examined for influenza A viruses. With the spread of highly pathogenic avian influenza virus (HPAIV) of subtype H5N1 among wild birds in Germany in spring 2006, dead wild birds, including 88 white storks, were tested for infection with HPAIV. Furthermore, fresh fecal samples were examined by RT-PCR to monitor the occurrence of HPAIV in adult storks. While the monitoring of nestlings and adult white storks failed to yield evidence of influenza A virus infections in these birds, two storks found dead in April 2006 in the same location tested positive for HPAIV H5N1. Sequence analysis revealed that the virus isolated from one of the storks belonged to clade 2.2, which was commonly found in wild birds in the north of Germany and other European countries during the epidemic in 2006. Despite these two cases, white storks seemed to serve as neither a vector nor as a reservoir for HPAIV in Germany. The risk of white storks transmitting HPAIV to domestic poultry and humans is low.