Magnesium sensing via LFA-1 regulates CD8+ T cell effector function.

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.

Enhanced magnetic modulation of surface plasmon polaritons on hyperbolic metasurfaces.

In this Letter we demonstrate a fundamentally new, to the best of our knowledge, concept to enhance the magnetic modulation of the surface plasmon polaritons (SPPs) by using hybrid magneto-plasmonic structures consisting of hyperbolic plasmonic metasurfaces and magnetic dielectric substrates. Our results show that the magnetic modulation of SPPs in the proposed structures can be an order of magnitude stronger than in the hybrid metal-ferromagnet multilayer structures conventionally used in active magneto-plasmonics. We believe that this effect will allow for the further miniaturization of magneto-plasmonic devices.

Hyperbolic plasmonics with anisotropic gain-loss metasurfaces.

In this Letter, a fundamentally new concept of realization of hyperbolic plasmonic metasurfaces by anisotropic gain-loss competition is proposed, and the possibility of highly directional propagation and amplification of surface plasmon polaritons is predicted. A simple realistic configuration of such a metasurface represents the periodic array of lossy metallic slabs embedded in the gain matrix. Our results may pave the way for numerous applications ranging from integrated and highly directional quantum light emitters to nonlinear-optical frequency converters.

Spider toxin inhibits gating pore currents underlying periodic paralysis.

Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3-S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.

De novo sequencing, assembly and functional annotation of Armillaria borealis genome.

BACKGROUND: Massive forest decline has been observed almost everywhere as a result of negative anthropogenic and climatic effects, which can interact with pests, fungi and other phytopathogens and aggravate their effects. Climatic changes can weaken trees and make fungi, such as Armillaria more destructive. Armillaria borealis (Marxm. & Korhonen) is a fungus from the Physalacriaceae family (Basidiomycota) widely distributed in Eurasia, including Siberia and the Far East. Species from this genus cause the root white rot disease that weakens and often kills woody plants. However, little is known about ecological behavior and genetics of A. borealis. According to field research data, A. borealis is less pathogenic than A. ostoyae, and its aggressive behavior is quite rare. Mainly A. borealis behaves as a secondary pathogen killing trees already weakened by other factors. However, changing environment might cause unpredictable effects in fungus behavior. RESULTS: The de novo genome assembly and annotation were performed for the A. borealis species for the first time and presented in this study. The A. borealis genome assembly contained ~ 68 Mbp and was comparable with ~ 60 and ~ 79.5 Mbp for the A. ostoyae and A. mellea genomes, respectively. The N50 for contigs equaled 50,544 bp. Functional annotation analysis revealed 21,969 protein coding genes and provided data for further comparative analysis. Repetitive sequences were also identified. The main focus for further study and comparative analysis will be on the enzymes and regulatory factors associated with pathogenicity. CONCLUSIONS: Pathogenic fungi such as Armillaria are currently one of the main problems in forest conservation. A comprehensive study of these species and their pathogenicity is of great importance and needs good genomic resources. The assembled genome of A. borealis presented in this study is of sufficiently good quality for further detailed comparative study on the composition of enzymes in other Armillaria species. There is also a fundamental problem with the identification and classification of species of the Armillaria genus, where the study of repetitive sequences in the genomes of basidiomycetes and their comparative analysis will help us identify more accurately taxonomy of these species and reveal their evolutionary relationships.

Siberian larch (Larix sibirica Ledeb.) mitochondrial genome assembled using both short and long nucleotide sequence reads is currently the largest known mitogenome.

BACKGROUND: Plant mitochondrial genomes (mitogenomes) can be structurally complex while their size can vary from ~ 222 Kbp in Brassica napus to 11.3 Mbp in Silene conica. To date, in comparison with the number of plant species, only a few plant mitogenomes have been sequenced and released, particularly for conifers (the Pinaceae family). Conifers cover an ancient group of land plants that includes about 600 species, and which are of great ecological and economical value. Among them, Siberian larch (Larix sibirica Ledeb.) represents one of the keystone species in Siberian boreal forests. Yet, despite its importance for evolutionary and population studies, the mitogenome of Siberian larch has not yet been assembled and studied. RESULTS: Two sources of DNA sequences were used to search for mitochondrial DNA (mtDNA) sequences: mtDNA enriched samples and nucleotide reads generated in the de novo whole genome sequencing project, respectively. The assembly of the Siberian larch mitogenome contained nine contigs, with the shortest and the largest contigs being 24,767 bp and 4,008,762 bp, respectively. The total size of the genome was estimated at 11.7 Mbp. In total, 40 protein-coding, 34 tRNA, and 3 rRNA genes and numerous repetitive elements (REs) were annotated in this mitogenome. In total, 864 C-to-U RNA editing sites were found for 38 out of 40 protein-coding genes. The immense size of this genome, currently the largest reported, can be partly explained by variable numbers of mobile genetic elements, and introns, but unlikely by plasmid-related sequences. We found few plasmid-like insertions representing only 0.11% of the entire Siberian larch mitogenome. CONCLUSIONS: Our study showed that the size of the Siberian larch mitogenome is much larger than in other so far studied Gymnosperms, and in the same range as for the annual flowering plant Silene conica (11.3 Mbp). Similar to other species, the Siberian larch mitogenome contains relatively few genes, and despite its huge size, the repeated and low complexity regions cover only 14.46% of the mitogenome sequence.

Stepwise large genome assembly approach: a case of Siberian larch (Larix sibirica Ledeb).

BACKGROUND: De novo assembling of large genomes, such as in conifers (~ 12-30 Gbp), which also consist of ~ 80% of repetitive DNA, is a very complex and computationally intense endeavor. One of the main problems in assembling such genomes lays in computing limitations of nucleotide sequence assembly programs (DNA assemblers). As a rule, modern assemblers are usually designed to assemble genomes with a length not exceeding the length of the human genome (3.24 Gbp). Most assemblers cannot handle the amount of input sequence data required to provide sufficient coverage needed for a high-quality assembly. RESULTS: An original stepwise method of de novo assembly by parts (sets), which allows to bypass the limitations of modern assemblers associated with a huge amount of data being processed, is presented in this paper. The results of numerical assembling experiments conducted using the model plant Arabidopsis thaliana, Prunus persica (peach) and four most popular assemblers, ABySS, SOAPdenovo, SPAdes, and CLC Assembly Cell, showed the validity and effectiveness of the proposed stepwise assembling method. CONCLUSION: Using the new stepwise de novo assembling method presented in the paper, the genome of Siberian larch, Larix sibirica Ledeb. (12.34 Gbp) was completely assembled de novo by the CLC Assembly Cell assembler. It is the first genome assembly for larch species in addition to only five other conifer genomes sequenced and assembled for Picea abies, Picea glauca, Pinus taeda, Pinus lambertiana, and Pseudotsuga menziesii var. menziesii.

Mobile genetic elements explain size variation in the mitochondrial genomes of four closely-related Armillaria species.

BACKGROUND: Species in the genus Armillaria (fungi, basidiomycota) are well-known as saprophytes and pathogens on plants. Many of them cause white-rot root disease in diverse woody plants worldwide. Mitochondrial genomes (mitogenomes) are widely used in evolutionary and population studies, but despite the importance and wide distribution of Armillaria, the complete mitogenomes have not previously been reported for this genus. Meanwhile, the well-supported phylogeny of Armillaria species provides an excellent framework in which to study variation in mitogenomes and how they have evolved over time. RESULTS: Here we completely sequenced, assembled, and annotated the circular mitogenomes of four species: A. borealis, A. gallica, A. sinapina, and A. solidipes (116,443, 98,896, 103,563, and 122,167 bp, respectively). The variation in mitogenome size can be explained by variable numbers of mobile genetic elements, introns, and plasmid-related sequences. Most Armillaria introns contained open reading frames (ORFs) that are related to homing endonucleases of the LAGLIDADG and GIY-YIG families. Insertions of mobile elements were also evident as fragments of plasmid-related sequences in Armillaria mitogenomes. We also found several truncated gene duplications in all four mitogenomes. CONCLUSIONS: Our study showed that fungal mitogenomes have a high degree of variation in size, gene content, and genomic organization even among closely related species of Armillara. We suggest that mobile genetic elements invading introns and intergenic sequences in the Armillaria mitogenomes have played a significant role in shaping their genome structure. The mitogenome changes we describe here are consistent with widely accepted phylogenetic relationships among the four species.

Plasmon mediated inverse Faraday effect in a graphene-dielectric-metal structure.

This Letter shows the features of inverse Faraday effect (IFE) in a graphene-dielectric-metal (GDM) structure. The constants of propagation and attenuation of the surface plasmon-polariton modes are calculated. The effective magnetic field induced by surface plasmon modes in the dielectric due to the IFE is estimated to reach above 1 tesla. The possibility to control the distribution of the magnetic field by chemical potential of graphene is shown. The concept of strain-driven control of the IFE in the structure has been proposed and investigated.

De novo assembling and primary analysis of genome and transcriptome of gray whale Eschrichtius robustus.

BACKGROUND: Gray whale, Eschrichtius robustus (E. robustus), is a single member of the family Eschrichtiidae, which is considered to be the most primitive in the class Cetacea. Gray whale is often described as a "living fossil". It is adapted to extreme marine conditions and has a high life expectancy (77 years). The assembly of a gray whale genome and transcriptome will allow to carry out further studies of whale evolution, longevity, and resistance to extreme environment. RESULTS: In this work, we report the first de novo assembly and primary analysis of the E. robustus genome and transcriptome based on kidney and liver samples. The presented draft genome assembly is complete by 55% in terms of a total genome length, but only by 24% in terms of the BUSCO complete gene groups, although 10,895 genes were identified. Transcriptome annotation and comparison with other whale species revealed robust expression of DNA repair and hypoxia-response genes, which is expected for whales. CONCLUSIONS: This preliminary study of the gray whale genome and transcriptome provides new data to better understand the whale evolution and the mechanisms of their adaptation to the hypoxic conditions.

A young source for the Hawaiian plume.

Recycling of oceanic crust through subduction, mantle upwelling, and remelting in mantle plumes is a widely accepted mechanism to explain ocean island volcanism. The timescale of this recycling is important to our understanding of mantle circulation rates. Correlations of uranogenic lead isotopes in lavas from ocean islands such as Hawaii or Iceland, when interpreted as model isochrons, have yielded source differentiation ages between 1 and 2.5 billion years (Gyr). However, if such correlations are produced by mixing of unrelated mantle components they will have no direct age significance. Re-Os decay model ages take into account the mixing of sources with different histories, but they depend on the assumed initial Re/Os ratio of the subducted crust, which is poorly constrained because of the high mobility of rhenium during subduction. Here we report the first data on (87)Sr/(86)Sr ratios for 138 melt inclusions in olivine phenocrysts from lavas of Mauna Loa shield volcano, Hawaii, indicating enormous mantle source heterogeneity. We show that highly radiogenic strontium in severely rubidium-depleted melt inclusions matches the isotopic composition of 200-650-Myr-old sea water. We infer that such sea water must have contaminated the Mauna Loa source rock, before subduction, imparting a unique 'time stamp' on this source. Small amounts of seawater-derived strontium in plume sources may be common but can be identified clearly only in ultra-depleted melts originating from generally highly (incompatible-element) depleted source components. The presence of 200-650-Myr-old oceanic crust in the source of Hawaiian lavas implies a timescale of general mantle circulation with an average rate of about 2 (±1) cm yr(-1), much faster than previously thought.

Linking mantle plumes, large igneous provinces and environmental catastrophes.

Large igneous provinces (LIPs) are known for their rapid production of enormous volumes of magma (up to several million cubic kilometres in less than a million years), for marked thinning of the lithosphere, often ending with a continental break-up, and for their links to global environmental catastrophes. Despite the importance of LIPs, controversy surrounds even the basic idea that they form through melting in the heads of thermal mantle plumes. The Permo-Triassic Siberian Traps--the type example and the largest continental LIP--is located on thick cratonic lithosphere and was synchronous with the largest known mass-extinction event. However, there is no evidence of pre-magmatic uplift or of a large lithospheric stretching, as predicted above a plume head. Moreover, estimates of magmatic CO(2) degassing from the Siberian Traps are considered insufficient to trigger climatic crises, leading to the hypothesis that the release of thermogenic gases from the sediment pile caused the mass extinction. Here we present petrological evidence for a large amount (15 wt%) of dense recycled oceanic crust in the head of the plume and develop a thermomechanical model that predicts no pre-magmatic uplift and requires no lithospheric extension. The model implies extensive plume melting and heterogeneous erosion of the thick cratonic lithosphere over the course of a few hundred thousand years. The model suggests that massive degassing of CO(2) and HCl, mostly from the recycled crust in the plume head, could alone trigger a mass extinction and predicts it happening before the main volcanic phase, in agreement with stratigraphic and geochronological data for the Siberian Traps and other LIPs.

Giant Faraday Rotation of High-Order Plasmonic Modes in Graphene-Covered Nanowires.

Plasmonic Faraday rotation in nanowires manifests itself in the rotation of the spatial intensity distribution of high-order surface plasmon polariton (SPP) modes around the nanowire axis. Here we predict theoretically the giant Faraday rotation for SPPs propagating on graphene-coated magneto-optically active nanowires. Upon the reversal of the external magnetic field pointing along the nanowire axis some high-order plasmonic modes may be rotated by up to ∼100° on the length scale of about 500 nm at mid-infrared frequencies. Tuning the carrier concentration in graphene by chemical doping or gate voltage allows for controlling SPP-properties and notably the rotation angle of high-order azimuthal modes. Our results open the door to novel plasmonic applications ranging from nanowire-based Faraday isolators to the magnetic control in quantum-optical applications.

Plasmonically induced magnetic field in graphene-coated nanowires.

In this Letter, we investigate a magnetic field induced by guiding plasmonic modes in graphene-coated nanowire via an inverse Faraday effect. Magnetic field distribution for different plasmonic modes has been calculated. It has been shown that a magnetic field has a vortex-like distribution for some plasmonic modes. The possibility of producing magnetic field distribution that rotates along the nanowire axis and periodically depends on azimuthal angle has been demonstrated.

Magnetic field control of plasmon polaritons in graphene-covered gyrotropic planar waveguide.

In this Letter, we report about magnetic field switching of plasmon polaritons propagating into a planar gyrotropic waveguide covered by two graphene layers at a deeply subwavelength scale. It is shown that applying an external magnetic field may lead to energy redistribution between two waveguide surfaces. The effect value resonantly depends on the relation between waveguide size and exciting light wavelength. A change in chemical potential of graphene layers may be used for tuning the phase shift between plasmon polaritons at near-resonant wavelengths. Evident effect may be observed at low magnetic fields (less than one tesla) for wavelengths about microns on a scale of tens of nanometers. Such an effect may be used for plasmonics, photonics. and optoelectronics devices, as well as sensing applications.

Influence of graphene coating on speckle-pattern rotation of light in gyrotropic optical fiber.

In the present work, change in speckle-pattern of linearly polarized light passed through graphene-covered optical fiber placed in external magnetic field is investigated. The possibility of magnetic speckle-pattern rotation suppression and inverse speckle-pattern rotation effect is shown. This effect can be controlled by a chemical potential of graphene layer, which can be changed easily by a gate voltage, for example. For quartz optical fiber at wavelength 0.633 µm, core diameter 9 µm, and fiber length 5 cm, an inverse rotation value of 17° is reached at chemical potential of graphene layer about 1 eV and magnetic field strength 30 kOe. Results of the work may be useful for different magneto-optics, opto-electronics, and photonics applications.

A structural and mutagenic blueprint for molecular recognition of strychnine and d-tubocurarine by different cys-loop receptors.

Cys-loop receptors (CLR) are pentameric ligand-gated ion channels that mediate fast excitatory or inhibitory transmission in the nervous system. Strychnine and d-tubocurarine (d-TC) are neurotoxins that have been highly instrumental in decades of research on glycine receptors (GlyR) and nicotinic acetylcholine receptors (nAChR), respectively. In this study we addressed the question how the molecular recognition of strychnine and d-TC occurs with high affinity and yet low specificity towards diverse CLR family members. X-ray crystal structures of the complexes with AChBP, a well-described structural homolog of the extracellular domain of the nAChRs, revealed that strychnine and d-TC adopt multiple occupancies and different ligand orientations, stabilizing the homopentameric protein in an asymmetric state. This introduces a new level of structural diversity in CLRs. Unlike protein and peptide neurotoxins, strychnine and d-TC form a limited number of contacts in the binding pocket of AChBP, offering an explanation for their low selectivity. Based on the ligand interactions observed in strychnine- and d-TC-AChBP complexes we performed alanine-scanning mutagenesis in the binding pocket of the human α1 GlyR and α7 nAChR and showed the functional relevance of these residues in conferring high potency of strychnine and d-TC, respectively. Our results demonstrate that a limited number of ligand interactions in the binding pocket together with an energetic stabilization of the extracellular domain are key to the poor selective recognition of strychnine and d-TC by CLRs as diverse as the GlyR, nAChR, and 5-HT(3)R.

The Earth's missing lead may not be in the core.

Relative to the CI chondrite class of meteorites (widely thought to be the 'building blocks' of the terrestrial planets), the Earth is depleted in volatile elements. For most elements this depletion is thought to be a solar nebular signature, as chondrites show depletions qualitatively similar to that of the Earth. On the other hand, as lead is a volatile element, some Pb may also have been lost after accretion. The unique (206)Pb/(204)Pb and (207)Pb/(204)Pb ratios of the Earth's mantle suggest that some lead was lost about 50 to 130 Myr after Solar System formation. This has commonly been explained by lead lost via the segregation of a sulphide melt to the Earth's core, which assumes that lead has an affinity towards sulphide. Some models, however, have reconciled the Earth's lead deficit with volatilization. Whichever model is preferred, the broad coincidence of U-Pb model ages with the age of the Moon suggests that lead loss may be related to the Moon-forming impact. Here we report partitioning experiments in metal-sulphide-silicate systems. We show that lead is neither siderophile nor chalcophile enough to explain the high U/Pb ratio of the Earth's mantle as being a result of lead pumping to the core. The Earth may have accreted from initially volatile-depleted material, some lead may have been lost to degassing following the Moon-forming giant impact, or a hidden reservoir exists in the deep mantle with lead isotope compositions complementary to upper-mantle values; it is unlikely though that the missing lead resides in the core.

A metabolic dependency of EBV can be targeted to hinder B cell transformation.

After infection of B cells, Epstein-Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates nicotinamide adenine dinucleotide (NAD) de novo biosynthesis by driving expression of the metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match adenosine triphosphate (ATP) production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is therefore a druggable metabolic vulnerability of EBV-driven B cell transformation, opening therapeutic possibilities for EBV-related diseases.

Metal saturation in the upper mantle.

The oxygen fugacity f(O2)of the Earth's mantle is one of the fundamental variables in mantle petrology. Through ferric-ferrous iron and carbon-hydrogen-oxygen equilibria, f(O2) influences the pressure-temperature positions of mantle solidi and compositions of small-degree mantle melts. Among other parameters, f(O2) affects the water storage capacity and rheology of the mantle. The uppermost mantle, as represented by samples and partial melts, is sufficiently oxidized to sustain volatiles, such as H2O and CO2, as well as carbonatitic melts, but it is not known whether the shallow mantle is representative of the entire upper mantle. Using high-pressure experiments, we show here that large parts of the asthenosphere are likely to be metal-saturated. We found that pyroxene and garnet synthesized at >7 GPa in equilibrium with metallic Fe can incorporate sufficient ferric iron that the mantle at >250 km depth is so reduced that an (Fe,Ni)-metal phase may be stable. Our results indicate that the oxidized nature of the upper mantle can no longer be regarded as being representative for the Earth's upper mantle as a whole and instead that oxidation is a shallow phenomenon restricted to an upper veneer only about 250 km in thickness.