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A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans
Get PDFThe sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in approximately 0.4% of present-day Britons, where they are associated with heightened pain sensitivity.journal articl
Visualizing Nudivirus Assembly and Egress
Get PDFEnveloped viruses hijack cellular membranes in order to provide the necessary material for virion assembly. In particular, viruses that replicate and assemble inside the nucleus have developed special approaches to modify the nuclear landscape for their advantage. We used electron microscopy to investigate cellular changes occurring during nudivirus infection and we characterized a unique mechanism for assembly, packaging, and transport of new virions across the nuclear membrane and through the cytoplasm. Our three-dimensional reconstructions describe the complex remodeling of the nuclear membrane necessary to release vesicle-associated viruses into the cytoplasm. This is the first report of nuclear morphological reconfigurations that occur during nudiviral infection.journal articl
Cryo-EM structure of human Cx31.3/GJC3 connexin hemichannel
Get PDFConnexin family proteins assemble into hexameric channels called hemichannels/connexons, which function as transmembrane channels or dock together to form gap junction intercellular channels (GJIChs). We determined the cryo-electron microscopy structures of human connexin 31.3 (Cx31.3)/GJC3 hemichannels in the presence and absence of calcium ions and with a hearing-loss mutation R15G at 2.3-, 2.5-, and 2.6-A resolutions, respectively. Compared with available structures of GJICh in open conformation, Cx31.3 hemichannel shows substantial structural changes of highly conserved regions in the connexin family, including opening of calcium ion-binding tunnels, reorganization of salt-bridge networks, exposure of lipid-binding sites, and collocation of amino-terminal helices at the cytoplasmic entrance. We also found that the hemichannel has a pore with a diameter of ~8 A and selectively transports chloride ions. Our study provides structural insights into the permeant selectivity of Cx31.3 hemichannel.journal articl
Quantum oscillations with magnetic hysteresis observed in CeTe3 thin films
Get PDFWe have performed magnetotransport measurements in CeTe3 thin films down to 0.2K. It is known that CeTe3 has two magnetic transitions at TN 1 approximate to 3K and TN 2 approximate to 1K. A clear Shubnikov-de-Haas (SdH) oscillation was observed at 4K, demonstrating the strong two-dimensional nature in this material. Below
TN 2, the SdH oscillation has two frequencies, indicating that the Fermi surface could be slightly modulated due to the second magnetic transition. We also observed a magnetic hysteresis in the SdH oscillation below TN 1. Specifically, there is a unique spike in the magnetoresistance at B approximate to 0.6T only when the magnetic field is swept from a high enough field (more than 2T) to zero field.journal articl
Tip‐Induced Inversion of the Chirality of a Molecule's Adsorption Potential Probed by the Switching Directionality
Get PDFThe switching behavior of surface-supported molecular units excited by current, light, or mechanical forces is determined by the shape of the adsorption potential. The ability to tailor the energy landscape in which a molecule resides at a surface gives the possibility of imposing a desired response, which is of paramount importance for the realization of molecular electronic units. Here, by means of scanning tunneling microscopy, a triazatruxene (TAT) molecule on Ag(111) is studied, which shows a switching behavior characterized by transitions of the molecule between three states, and which is attributed to three energetically degenerate bonding configurations. Upon tunneling current injection, the system can be excited and continuously driven, showing a switching directionality close to 100%. Two surface enantiomers of TAT show opposite switching directions pointing at the chirality of the energy landscape of the adsorption potential as a key ingredient for directional switching. Further, it is shown that by tuning the tunneling parameters, the symmetry of the adsorption potential can be controllably adjusted, leading to a suppression of the directionality or an inversion of the switching direction. The findings represent a molecule-surface model system exhibiting unprecedented control of the shape of its adsorption potential.journal articl
Nucleosome positioning stability is a modulator of germline mutation rate variation across the human genome
Get PDFNucleosome organization has been suggested to affect local mutation rates in the genome. However, the lack of de novo mutation and high-resolution nucleosome data has limited the investigation of this hypothesis. Additionally, analyses using indirect mutation rate measurements have yielded contradictory and potentially confounding results. Here, we combine data on >300,000 human de novo mutations with high-resolution nucleosome maps and find substantially elevated mutation rates around translationally stable ('strong') nucleosomes. We show that the mutational mechanisms affected by strong nucleosomes are low-fidelity replication, insufficient mismatch repair and increased double-strand breaks. Strong nucleosomes preferentially locate within young SINE/LINE transposons, suggesting that when subject to increased mutation rates, transposons are then more rapidly inactivated. Depletion of strong nucleosomes in older transposons suggests frequent positioning changes during evolution. The findings have important implications for human genetics and genome evolution.journal articl
Somatodendritic consistency check for temporal feature segmentation
Get PDFThe brain identifies potentially salient features within continuous information streams to process hierarchical temporal events. This requires the compression of information streams, for which effective computational principles are yet to be explored. Backpropagating action potentials can induce synaptic plasticity in the dendrites of cortical pyramidal neurons. By analogy with this effect, we model a self-supervising process that increases the similarity between dendritic and somatic activities where the somatic activity is normalized by a running average. We further show that a family of networks composed of the two-compartment neurons performs a surprisingly wide variety of complex unsupervised learning tasks, including chunking of temporal sequences and the source separation of mixed correlated signals. Common methods applicable to these temporal feature analyses were previously unknown. Our results suggest the powerful ability of neural networks with dendrites to analyze temporal features. This simple neuron model may also be potentially useful in neural engineering applications.journal articl
Polycyclic aromatic chains on metals and insulating layers by repetitive [3+2] cycloadditions
Get PDFThe vast potential of organic materials for electronic, optoelectronic and spintronic devices entails substantial interest in the fabrication of pi-conjugated systems with tailored functionality directly at insulating interfaces. On-surface fabrication of such materials on non-metal surfaces remains to be demonstrated with high yield and selectivity. Here we present the synthesis of polyaromatic chains on metallic substrates, insulating layers, and in the solid state. Scanning probe microscopy shows the formation of azaullazine repeating units on Au(111), Ag(111), and h-BN/Cu(111), stemming from intermolecular homo-coupling via cycloaddition reactions of CN-substituted polycyclic aromatic azomethine ylide (PAMY) intermediates followed by subsequent dehydrogenation. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry demonstrates that the reaction also takes place in the solid state in the absence of any catalyst. Such intermolecular cycloaddition reactions are promising methods for direct synthesis of regioregular polyaromatic polymers on arbitrary insulating surfaces.journal articl
Proof‐of‐concept modular fluid handling prototype integrated with microfluidic biochemical assay modules for point‐of‐care testing
Get PDFLarge populations around the world suffer from numerous but treatable health issues, caused by either lifestyle choices or environmental factors. Over the past decades, point-of-care testing kits have been developed to circumvent the reliance on laboratories, by allowing users to perform preliminary health or environmental testing from the privacy of their homes. However, these kits heavily rely on the precision of the user to perform the procedures, leading to increased variability in final assessments. To eliminate user-induced errors, we present an integrated, completely sealed, and disposable point-of-care testing prototype that exploits the benefits of microfluidics and 3D-printing fabrication techniques. The palm-sized modular prototype consists of a manually operated fluid handling device that allows precise mixing, filtration, and delivery of fluids to an on-board microfluidic assay unit for subsequent detection of specific biochemical analytes, with a minimized risk of contamination.journal articl
