Human monogenic obesity syndromes, including Bardet-Biedl syndrome (BBS), implicate neuronal primary cilia in regulation of energy homeostasis. Cilia in hypothalamic neurons have been hypothesized to ...sense and regulate systemic energy status, but the molecular mechanism of this signaling remains unknown. Here, we report a comprehensive localization screen of 42 G-protein-coupled receptors (GPCR) revealing seven ciliary GPCRs, including the neuropeptide Y (NPY) receptors NPY2R and NPY5R. We show that mice modeling BBS disease or obese tubby mice fail to localize NPY2R to cilia in the hypothalamus and that BBS mutant mice fail to activate c-fos or decrease food intake in response to the NPY2R ligand PYY3-36. We find that cells with ciliary NPY2R show augmented PYY3-36-dependent cAMP signaling. Our data demonstrate that ciliary targeting of NPY receptors is important for controlling energy balance in mammals, revealing a physiologically defined ligand-receptor pathway signaling within neuronal cilia.
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•A screen of 42 GPCRs shows that NPY2R, NPY5R, and five other GPCRs are ciliary•Obese BBS or tubby mice fail to localize NPY2R to cilia in the hypothalamus•BBS mice fail to decrease food intake in response to the NPY2R ligand PYY3-36•Cells with ciliary NPY2R show augmented ligand-dependent cAMP signaling
Primary cilia in hypothalamic neurons have been hypothesized to sense and regulate systemic energy status, but the molecular mechanisms underlying this signaling remain unknown. Here, Loktev and Jackson report a localization screen of 42 GPCRs and find that NPY2R, NPY5R, and five other GPCRs are ciliary. Using mouse models of ciliopathies, they show that trafficking of NPY2R to the neuronal cilia via the Bardet-Biedl syndrome and Tubby pathways regulates food intake. They demonstrate that ciliary localization of NPY2R augments ligand-dependent cAMP signaling.
Rotaviruses (RVs) are the leading cause of severe gastroenteritis in young children, accounting for half a million deaths annually worldwide. RV encodes non-structural protein 1 (NSP1), a ...well-characterized interferon (IFN) antagonist, which facilitates virus replication by mediating the degradation of host antiviral factors including IRF3 and β-TrCP. Here, we utilized six human and animal RV NSP1s as baits and performed tandem-affinity purification coupled with high-resolution mass spectrometry to comprehensively characterize NSP1-host protein interaction network. Multiple Cullin-RING ubiquitin ligase (CRL) complexes were identified. Importantly, inhibition of cullin-3 (Cul3) or RING-box protein 1 (Rbx1), by siRNA silencing or chemical perturbation, significantly impairs strain-specific NSP1-mediated β-TrCP degradation. Mechanistically, we demonstrate that NSP1 localizes to the Golgi with the host Cul3-Rbx1 CRL complex, which targets β-TrCP and NSP1 for co-destruction at the proteasome. Our study uncovers a novel mechanism that RV employs to promote β-TrCP turnover and provides molecular insights into virus-mediated innate immunity inhibition.
High fraction of the surface atoms considerably enhances the influence of size and shape on the magnetic and electronic properties of nanoparticles. Shape effects in ferromagnetic nanoparticles are ...well understood and allow us to set and control the parameters of a sample that affect its magnetic anisotropy during production. In the present paper we study the shape effects in the other widely used magnetic materials – antiferromagnets, – which possess vanishingly small or zero macroscopic magnetization. We take into account the difference between the surface and bulk magnetic anisotropy of a nanoparticle and show that the effective magnetic anisotropy depends on the particle shape and crystallographic orientation of its faces. The corresponding shape-induced contribution to the magnetic anisotropy energy is proportional to the particle volume, depends on magnetostriction, and can cause formation of equilibrium domain structure. Crystallographic orientation of the nanoparticle surface determines the type of domain structure. The proposed model allows us to predict the magnetic properties of antiferromagnetic nanoparticles depending on their shape and treatment.
•We demonstrate that the shape effects in antiferromagnetic nanoparticles stem from the difference of surface and bulk magnetic properties combined with strong magnetoelastic coupling.•We predict shape-induced anisotropy in antiferromagnetic particles with large aspect ratio.•We predict different types of domain structures depending on the orientation of the particle faces.
Square-octagon lattice underlies the description of a family of two-dimensional materials such as tetragraphene. In the present paper we show that the tight-binding model of square-octagon lattice ...contains both conventional and high-order van Hove points. In particular, the spectrum of the model contains flat lines along some directions composed of high-order saddle points. Their role is analyzed by calculating the orbital susceptibility of electrons. We find that the presence of van Hove singularities (VHS) of different kinds in the density of states leads to strong responses: paramagnetic for ordinary singularities and more complicated for high-order singularities. It is shown that at doping level of high-order VHS the orbital susceptibility as a function of hoppings ratio α reveals the dia- to paramagnetic phase transition at α ≈ 0.94 . This is due to the competition of paramagnetic contribution of high-order VHS and diamagnetic contribution of Dirac cones. The results for the tight-binding model are compared with the low-energy effective pseudospin-1 model near the three band touching point.
A promising approach to the development of new means for preventing infection caused by tick-borne encephalitis virus can be DNA vaccines encoding polyepitope T-cell immunogens. A DNA vaccine ...pVAX-AG4-ub encoding an artificial polyepitope immunogen that includes cytotoxic and T-helper epitopes from the NS1, NS3, NS5, and E proteins of the tick-borne encephalitis virus has been obtained. The developed construct ensured the synthesis of the corresponding mRNAs in transfected eukaryotic cells. Immunization of mice with pVAX-AG4-ub induced the formation of a virus-specific T-cell response providing 50% protection from lethal infection with the virus.
Field-induced magnetic quantum phase transitions in the Van Vleck paramagnet with easy-plane single-ion anisotropy and competing Ising exchange between ions with the spin S=1 have been studied ...theoretically. The description was made by minimizing the Lagrange function at zero temperature (Т=0) and the free energy at T≠0. Stable and unstable solutions of equations corresponding to the case ψ0=|0〉 asymptotically transform into those following from the Lagrange function at Т=0. First-order phase transitions from the Van Vleck paramagnet state into the ferromagnet one were found to take place at a sufficiently high single-ion anisotropy. The entropy of such a magnet was shown to grow with its magnetization, as it occurs for antiferromagnets. At the point of quantum phase transition, the entropy has a jump, which magnitude depends on the ratio between the Ising exchange and anisotropy constants, as well as on the temperature. The described magnetic phase transition was supposed to be accompanied by the magnetocaloric effect. In the case when the Ising exchange dominates over the single-ion anisotropy, the magnetization reversal of ferromagnetic state by an external field was shown to be a phase transition of the first kind, which does not belong to orientational ones and which should be regarded as a quantum order-order phase transition.
•Consistent theory is proposed for the phase transition description at T=0 and T≠0.•We receive phase H–T diagram of Van Vleck paramagnet with quantum phase transitions.•Van Vleck paramagnet with S=1 and Ising exchange has a hysteresis loop as ferromagnet.•The entropy change in Van Vleck system is similar to that at antiferromagnets magnetization.•We show that quantum phase transition is followed by magnetocaloric effect.
Several human diseases in Europe are caused by viruses transmitted by tick bite. These viruses belong to the genus Flavivirus, and include tick-borne encephalitis virus, Omsk haemorrhagic fever ...virus, louping ill virus, Powassan virus, Nairovirus (Crimean-Congo haemorrhagic fever virus) and Coltivirus (Eyach virus). All of these viruses cause more or less severe neurological diseases, and some are also responsible for haemorrhagic fever. The epidemiology, clinical picture and methods for diagnosis are detailed in this review. Most of these viral pathogens are classified as Biosafety Level 3 or 4 agents, and therefore some of them have been classified in Categories A–C of potential bioterrorism agents by the Centers for Disease Control and Prevention. Their ability to cause severe disease in man means that these viruses, as well as any clinical samples suspected of containing them, must be handled with specific and stringent precautions.
The PBX1 homeodomain transcription factor is converted by t(1;19) chromosomal translocations in acute leukemia into the chimeric E2A-PBX1 oncoprotein. Fusion with E2A confers potent transcriptional ...activation and constitutive nuclear localization, bypassing the need for dimerization with protein partners that normally stabilize and regulate import of PBX1 into the nucleus, but the mechanisms underlying its oncogenic activation are incompletely defined. We demonstrate here that E2A-PBX1 self-associates through the PBX1 PBC-B domain of the chimeric protein to form higher-order oligomers in t(1;19) human leukemia cells, and that this property is required for oncogenic activity. Structural and functional studies indicate that self-association facilitates the binding of E2A-PBX1 to DNA. Mutants unable to self-associate are transformation defective, however their oncogenic activity is rescued by the synthetic oligomerization domain of FKBP, which confers conditional transformation properties on E2A-PBX1. In contrast to self-association, PBX1 protein domains that mediate interactions with HOX DNA-binding partners are dispensable. These studies suggest that oligomeric self-association may compensate for the inability of monomeric E2A-PBX1 to stably bind DNA and circumvents protein interactions that otherwise modulate PBX1 stability, nuclear localization, DNA binding, and transcriptional activity. The unique dependence on self-association for E2A-PBX1 oncogenic activity suggests potential approaches for mechanism-based targeted therapies.
The tick-borne encephalitis virus (TBEV) strain C11-13 (GenBank acc. no. OQ565596) of the Siberian genotype was previously isolated from the brain of a deceased person. TBEV C11-13 variants obtained ...at passages 3 and 8 in SPEV cells were inoculated into the brains of white mice for subsequent passages. Full genome sequences of all virus variants were analyzed by high-throughput sequencing. A total of 41 single nucleotide substitutions were found to occur mainly in the genes for the nonstructural proteins NS3 and NS5 (GenBank MF043953, OP902894, and OP902895), and 12 amino acid substitutions were identified in the deduced protein sequences. Reverse nucleotide and amino acid substitutions were detected after three passages through mouse brains. The substitutions restored the primary structures that were characteristic of the isolate C11-13 from a human patient and changed during the eight subsequent passages in SPEV cells. In addition, the 3′-untranslated region (3′-UTR) of the viral genome increased by 306 nt. The Y3 and Y2 3'-UTR elements were found to contain imperfect L and R repeats, which were probably associated with inhibition of cellular XRN1 RNase and thus involved in the formation of subgenomic flaviviral RNAs (sfRNAs). All TBEV variants showed high-level reproduction in both cell cultures and mouse brains. The genomic changes that occurred during successive passages of TBEV are most likely due to its significant genetic variability, which ensures its efficient reproduction in various hosts and its broad distribution in various climatic zones.
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