The function of the alula in avian flight

The alula is a small structure located at the joint between the hand-wing and arm-wing of birds and is known to be used in slow flight with high angles of attack such as landing. It is assumed to function similarly to a leading-edge slat that increases lift and delays stall. However, in spite of its universal presence in flying birds and the wide acceptance of stall delay as its main function, how the alula delays the stall and aids the flight of birds remains unclear. Here, we investigated the function of alula on the aerodynamic performance of avian wings based on data from flight tasks and wind-tunnel experiments. With the alula, the birds performed steeper descending flights with greater changes in body orientation. Force measurements revealed that the alula increases the lift and often delays the stall. Digital particle image velocimetry showed that these effects are caused by the streamwise vortex, formed at the tip of the alula, that induces strong downwash and suppresses the flow separation over the wing surface. This is the first experimental evidence that the alula functions as a vortex generator that increases the lift force and enhances manoeuvrability in flights at high angles of attack.open1

Protein trafficking through the endosomal system prepares intracellular parasites for a home invasion

Toxoplasma (toxoplasmosis) and Plasmodium (malaria) use unique secretory organelles for migration, cell invasion, manipulation of host cell functions, and cell egress. In particular, the apical secretory micronemes and rhoptries of apicomplexan parasites are essential for successful host infection. New findings reveal that the contents of these organelles, which are transported through the endoplasmic reticulum (ER) and Golgi, also require the parasite endosome-like system to access their respective organelles. In this review, we discuss recent findings that demonstrate that these parasites reduced their endosomal system and modified classical regulators of this pathway for the biogenesis of apical organelles

Toxoplasma gondii-Induced Activation of EGFR Prevents Autophagy Protein-Mediated Killing of the Parasite

Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome-lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3(+) structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival

VgrG and PAAR Proteins Define Distinct Versions of a Functional Type VI Secretion System

The Type VI secretion system (T6SS) is widespread among bacterial pathogens and acts as an effective weapon against competitor bacteria and eukaryotic hosts by delivering toxic effector proteins directly into target cells. The T6SS utilises a bacteriophage-like contractile machinery to expel a puncturing device based on a tube of Hcp topped with a VgrG spike, which can be extended by a final tip from a PAAR domain-containing protein. Effector proteins are believed to be delivered by specifically associating with particular Hcp, VgrG or PAAR proteins, either covalently ('specialised') or non-covalently ('cargo' effectors). Here we used the T6SS of the opportunistic pathogen Serratia marcescens, together with integratecd genetic, proteomic and biochemical approaches, to elucidate the role of specific VgrG and PAAR homologues in T6SS function and effector specificity, revealing new aspects and unexpected subtleties in effector delivery by the T6SS. We identified effectors, both cargo and specialised, absolutely dependent on a particular VgrG for delivery to target cells, and discovered that other cargo effectors can show a preference for a particular VgrG. The presence of at least one PAAR protein was found to be essential for T6SS function, consistent with designation as a 'core' T6SS component. We showed that specific VgrG-PAAR combinations are required to assemble a functional T6SS and that the three distinct VgrG-PAAR assemblies in S. marcescens exhibit distinct effector specificity and efficiency. Unexpectedly, we discovered that two different PAAR-containing Rhs proteins can functionally pair with the same VgrG protein. Showing that accessory EagR proteins are involved in these interactions, native VgrG-Rhs-EagR complexes were isolated and specific interactions between EagR and cognate Rhs proteins identified. This study defines an essential yet flexible role for PAAR proteins in the T6SS and highlights the existence of distinct versions of the machinery with differential effector specificity and efficiency of target cell delivery

Identification of the Microsporidian Encephalitozoon cuniculi as a New Target of the IFNγ-Inducible IRG Resistance System

The IRG system of IFNγ-inducible GTPases constitutes a powerful resistance mechanism in mice against Toxoplasma gondii and two Chlamydia strains but not against many other bacteria and protozoa. Why only T. gondii and Chlamydia? We hypothesized that unusual features of the entry mechanisms and intracellular replicative niches of these two organisms, neither of which resembles a phagosome, might hint at a common principle. We examined another unicellular parasitic organism of mammals, member of an early-diverging group of Fungi, that bypasses the phagocytic mechanism when it enters the host cell: the microsporidian Encephalitozoon cuniculi. Consistent with the known susceptibility of IFNγ-deficient mice to E. cuniculi infection, we found that IFNγ treatment suppresses meront development and spore formation in mouse fibroblasts in vitro, and that this effect is mediated by IRG proteins. The process resembles that previously described in T. gondii and Chlamydia resistance. Effector (GKS subfamily) IRG proteins accumulate at the parasitophorous vacuole of E. cuniculi and the meronts are eliminated. The suppression of E. cuniculi growth by IFNγ is completely reversed in cells lacking regulatory (GMS subfamily) IRG proteins, cells that effectively lack all IRG function. In addition IFNγ-induced cells infected with E. cuniculi die by necrosis as previously shown for IFNγ-induced cells resisting T. gondii infection. Thus the IRG resistance system provides cell-autonomous immunity to specific parasites from three kingdoms of life: protozoa, bacteria and fungi. The phylogenetic divergence of the three organisms whose vacuoles are now known to be involved in IRG-mediated immunity and the non-phagosomal character of the vacuoles themselves strongly suggests that the IRG system is triggered not by the presence of specific parasite components but rather by absence of specific host components on the vacuolar membrane.Grants from the Deutsche Forschungsgemeinschaft: SFB635, 670, 680, SPP1399

Evaluation of fast atmospheric dispersion models in a regular street network

The need to balance computational speed and simulation accuracy is a key challenge in designing atmospheric dispersion models that can be used in scenarios where near real-time hazard predictions are needed. This challenge is aggravated in cities, where models need to have some degree of building-awareness, alongside the ability to capture effects of dominant urban flow processes. We use a combination of high-resolution large-eddy simulation (LES) and wind-tunnel data of flow and dispersion in an idealised, equal-height urban canopy to highlight important dispersion processes and evaluate how these are reproduced by representatives of the most prevalent modelling approaches: (i) a Gaussian plume model, (ii) a Lagrangian stochastic model and (iii) street-network dispersion models. Concentration data from the LES, validated against the wind-tunnel data, were averaged over the volumes of streets in order to provide a high-fidelity reference suitable for evaluating the different models on the same footing. For the particular combination of forcing wind direction and source location studied here, the strongest deviations from the LES reference were associated with mean over-predictions of concentrations by approximately a factor of 2 and with a relative scatter larger than a factor of 4 of the mean, corresponding to cases where the mean plume centreline also deviated significantly from the LES. This was linked to low accuracy of the underlying flow models/parameters that resulted in a misrepresentation of pollutant channelling along streets and of the uneven plume branching observed in intersections. The agreement of model predictions with the LES (which explicitly resolves the turbulent flow and dispersion processes) greatly improved by increasing the accuracy of building-induced modifications of the driving flow field. When provided with a limited set of representative velocity parameters, the comparatively simple street-network models performed equally well or better compared to the Lagrangian model run on full 3D wind fields. The study showed that street-network models capture the dominant building-induced dispersion processes in the canopy layer through parametrisations of horizontal advection and vertical exchange processes at scales of practical interest. At the same time, computational costs and computing times associated with the network approach are ideally suited for emergency-response applications

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Lichen response to ammonia deposition defines the footprint of a penguin rookery

Ammonia volatilized from penguin rookeries is a major nitrogen source in Antarctic coastal terrestrial ecosystems. However, the spatial extent of ammonia dispersion from rookeries and its impacts have not been quantified previously. We measured ammonia concentration in air and lichen ecophysiological response variables proximate to an Adèlie penguin rookery at Cape Hallett, northern Victoria Land. Ammonia emitted from the rookery was 15N-enriched (δ15N value +6.9) and concentrations in air ranged from 36–75 µg m−3 at the rookery centre to 0.05 µg m−3 at a distance of 15.3 km. δ15N values and rates of phosphomonoesterase (PME) activity in the lichens Usnea sphacelata and Umbilicaria decussata were strongly negatively related to distance from the rookery and PME activity was positively related to thallus N:P mass ratio. In contrast, the lichen Xanthomendoza borealis, which is largely restricted to within an area 0.5 km from the rookery perimeter, had high N, P and 15N concentrations but low PME activity suggesting that nutrient scavenging capacity is suppressed in highly eutrophicated sites. An ammonia dispersion model indicates that ammonia concentrations sufficient to significantly elevate PME activity and δ15N values (≥0.1 µg NH3 m−3) occurred over c. 40–300 km2 surrounding the rookery suggesting that penguin rookeries potentially can generate large spatial impact zones. In a general linear model NH3 concentration and lichen species identity were found to account for 72 % of variation in the putative proportion of lichen thallus N originating from penguin derived NH3. The results provide evidence of large scale impact of N transfer from a marine to an N-limited terrestrial ecosystem

Constrained pre-equalization accounting for multi-path fading emulated using large RC networks: applications to wireless and photonics communications

Multi-path propagation is modelled assuming a multi-layer RC network with randomly allocated resistors and capacitors to represent the transmission medium. Due to frequency-selective attenuation, the waveforms associated with each propagation path incur path-dependent distortion. A pre-equalization procedure that takes into account the capabilities of the transmission source as well as the transmission properties of the medium is developed. The problem is cast within a Mixed Integer Linear Programming optimization framework that uses the developed nominal RC network model, with the excitation waveform customized to optimize signal fidelity from the transmitter to the receiver. The objective is to match a Gaussian pulse input accounting for frequency regions where there would be pronounced fading. Simulations are carried out with different network realizations in order to evaluate the sensitivity of the solution with respect to changes in the transmission medium mimicking the multi-path propagation. The proposed approach is of relevance where equalization techniques are difficult to implement. Applications are discussed within the context of emergent communication modalities across the EM spectrum such as light percolation as well as emergent indoor communications assuming various modulation protocols or UWB schemes as well as within the context of space division multiplexing

Ligand-Induced Movements of Inner Transmembrane Helices of Glut1 Revealed by Chemical Cross-Linking of Di-Cysteine Mutants

The relative orientation and proximity of the pseudo-symmetrical inner transmembrane helical pairs 5/8 and 2/11 of Glut1 were analyzed by chemical cross-linking of di-cysteine mutants. Thirteen functional di-cysteine mutants were created from a C-less Glut1 reporter construct containing cysteine substitutions in helices 5 and 8 or helices 2 and 11. The mutants were expressed in Xenopus oocytes and the sensitivity of each mutant to intramolecular cross-linking by two homobifunctional thiol-specific reagents was ascertained by protease cleavage followed by immunoblot analysis. Five of 9 mutants with cysteine residues predicted to lie in close proximity to each other were susceptible to cross-linking by one or both reagents. None of 4 mutants with cysteine substitutions predicted to lie on opposite faces of their respective helices was susceptible to cross-linking. Additionally, the cross-linking of a di-cysteine pair (A70C/M420C, helices 2/11) predicted to lie near the exoplasmic face of the membrane was stimulated by ethylidene glucose, a non-transported glucose analog that preferentially binds to the exofacial substrate-binding site, suggesting that the binding of this ligand stimulates the closure of helices at the exoplasmic face of the membrane. In contrast, the cross-linking of a second di-cysteine pair (T158C/L325, helices 5/8), predicted to lie near the cytoplasmic face of the membrane, was stimulated by cytochalasin B, a glucose transport inhibitor that competitively inhibits substrate efflux, suggesting that this compound recruits the transporter to a conformational state in which closure of inner helices occurs at the cytoplasmic face of the membrane. This observation provides a structural explanation for the competitive inhibition of substrate efflux by cytochalasin B. These data indicate that the binding of competitive inhibitors of glucose efflux or influx induce occluded states in the transporter in which substrate is excluded from the exofacial or endofacial binding site