Tissue Determinants of Human NK Cell Development, Function, and Residence.

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT

VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications

Voltage-Dependent Anion selective Channels (VDAC) are pore-forming mitochondrial outer membrane proteins. In mammals VDAC3, the least characterized isoform, presents a set of cysteines predicted to be exposed toward the intermembrane space. We find that cysteines in VDAC3 can stay in different oxidation states. This was preliminary observed when, in our experimental conditions, completely lacking any reducing agent, VDAC3 presented a pattern of slightly different electrophoretic mobilities. This observation holds true both for rat liver mitochondrial VDAC3 and for recombinant and refolded human VDAC3. Mass spectroscopy revealed that cysteines 2 and 8 can form a disulfide bridge in native VDAC3. Single or combined site-directed mutagenesis of cysteines 2, 8 and 122 showed that the protein mobility in SDS-PAGE is influenced by the presence of cysteine and by the redox status. In addition, cysteines 2, 8 and 122 are involved in the stability control of the pore as shown by electrophysiology, complementation assays and chemico-physical characterization. Furthermore, a positive correlation between the pore conductance of the mutants and their ability to complement the growth of porin-less yeast mutant cells was found. Our work provides evidence for a complex oxidation pattern of a mitochondrial protein not directly involved in electron transport. The most likely biological meaning of this behavior is to buffer the ROS load and keep track of the redox level in the intermembrane space, eventually signaling it through conformational change

A 2-D π–π dimer model system to investigate structure-charge transfer relationships in rubrene

© The Royal Society of Chemistry 2019Rubrene (5,6,11,12-tetraphenyltetracene) is undoubtedly one of the best performing organic charge transfer mediating materials, with experimentally determined mobilities up to 40 cm2 V−1 s−1. Consequently, there has been increasing interest by means of crystal engineering in trying to generate rubrene-based materials with analogous or even superior conducting properties. Often, experimental measurements are carried out in thin film architectures of these materials, where measured properties can be detrimentally impacted by device manufacture rather than intrinsic charge transfer properties of the material. The latter results in discarding potential good performers. To address these concerns, we report a two-dimensional model system that will allow researchers to predict charge transfer properties of their materials solely requiring the coordinates of the π–π stacking motifs. We envisaged this study to be of significant interest to the increasingly large community of materials scientists devoted to the realisation of improved organic charge mediating materials and particularly to those engaged in exploiting rubrene-based architectures.Peer reviewedFinal Accepted Versio

Membrane Sigma-Models and Quantization of Non-Geometric Flux Backgrounds

We develop quantization techniques for describing the nonassociative geometry probed by closed strings in flat non-geometric R-flux backgrounds M. Starting from a suitable Courant sigma-model on an open membrane with target space M, regarded as a topological sector of closed string dynamics in R-space, we derive a twisted Poisson sigma-model on the boundary of the membrane whose target space is the cotangent bundle T^*M and whose quasi-Poisson structure coincides with those previously proposed. We argue that from the membrane perspective the path integral over multivalued closed string fields in Q-space is equivalent to integrating over open strings in R-space. The corresponding boundary correlation functions reproduce Kontsevich's deformation quantization formula for the twisted Poisson manifolds. For constant R-flux, we derive closed formulas for the corresponding nonassociative star product and its associator, and compare them with previous proposals for a 3-product of fields on R-space. We develop various versions of the Seiberg-Witten map which relate our nonassociative star products to associative ones and add fluctuations to the R-flux background. We show that the Kontsevich formula coincides with the star product obtained by quantizing the dual of a Lie 2-algebra via convolution in an integrating Lie 2-group associated to the T-dual doubled geometry, and hence clarify the relation to the twisted convolution products for topological nonassociative torus bundles. We further demonstrate how our approach leads to a consistent quantization of Nambu-Poisson 3-brackets.Comment: 52 pages; v2: references adde

Kinesin Is an Evolutionarily Fine-Tuned Molecular Ratchet-and-Pawl Device of Decisively Locked Direction

Conventional kinesin is a dimeric motor protein that transports membranous organelles toward the plus-end of microtubules (MTs). Individual kinesin dimers show steadfast directionality and hundreds of consecutive steps, yetthe detailed physical mechanism remains unclear. Here we compute free energies for the entire dimer-MT system for all possible interacting configurations by taking full account of molecular details. Employing merely first principles and several measured binding and barrier energies, the system-level analysis reveals insurmountable energy gaps between configurations, asymmetric ground state caused by mechanically lifted configurational degeneracy, and forbidden transitions ensuring coordination between both motor domains for alternating catalysis. This wealth of physical effects converts a kinesin dimer into a molecular ratchet-and-pawl device, which determinedly locks the dimer's movement into the MT plus-end and ensures consecutive steps in hand-over-hand gait.Under a certain range of extreme loads, however, the ratchet-and-pawl device becomes defective but not entirely abolished to allow consecutive back-steps. This study yielded quantitative evidence that kinesin's multiple molecular properties have been evolutionarily adapted to fine-tune the ratchet-and-pawl device so as to ensure the motor's distinguished performance.Comment: 10 printed page

Biological, ecological, conservation and legal information for all species and subspecies of Australian bird

We introduce a dataset of biological, ecological, conservation and legal information for every species and subspecies of Australian bird, 2056 taxa or populations in total. Version 1 contains 230 fields grouped under the following headings: Taxonomy & nomenclature, Phylogeny, Australian population status, Conservation status, Legal status, Distribution, Morphology, Habitat, Food, Behaviour, Breeding, Mobility and Climate metrics. It is envisaged that the dataset will be updated periodically with new data for existing fields and the addition of new fields. The dataset has already had, and will continue to have applications in Australian and international ornithology, especially those that require standard information for a large number of taxa

Self-Consistent Electron-Nucleus Cusp Correction for Molecular Orbitals

We describe a method for imposing the correct electron-nucleus (e-n) cusp in molecular orbitals expanded as a linear combination of (cuspless) Gaussian basis functions. Enforcing the e-n cusp in trial wave functions is an important asset in quantum Monte Carlo calculations as it significantly reduces the variance of the local energy during the Monte Carlo sampling. In the method presented here, the Gaussian basis set is augmented with a small number of Slater basis functions. Note that, unlike other e-n cusp correction schemes, the presence of the Slater function is not limited to the vicinity of the nuclei. Both the coefficients of these cuspless Gaussian and cusp-correcting Slater basis functions may be self-consistently optimized by diagonalization of an orbital-dependent effective Fock operator. Illustrative examples are reported for atoms (\ce{H}, \ce{He} and \ce{Ne}) as well as for a small molecular system (\ce{BeH2}). For the simple case of the \ce{He} atom, we observe that, with respect to the cuspless version, the variance is reduced by one order of magnitude by applying our cusp-corrected scheme.Comment: 23 pages, 5 figure

Selection for Replicases in Protocells

PMCID: PMC3649988This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Mapping spaces and automorphism groups of toric noncommutative spaces

We develop a sheaf theory approach to toric noncommutative geometry which allows us to formalize the concept of mapping spaces between two toric noncommutative spaces. As an application we study the 'internalized' automorphism group of a toric noncommutative space and show that its Lie algebra has an elementary description in terms of braided derivations