vol.17 奥付・裏表紙

protein atomic structure predicted using homology modelin

Loss-of-Function Mutations in Rab Escort Protein 1 (REP-1) Affect Intracellular Transport in Fibroblasts and Monocytes of Choroideremia Patients

BACKGROUND: Choroideremia (CHM) is a progressive X-linked retinopathy caused by mutations in the CHM gene, which encodes Rab escort protein-1 (REP-1), an escort protein involved in the prenylation of Rabs. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis and secretion in peripheral cells of CHM patients. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate this hypothesis, intracellular vesicle transport, lysosomal acidification and rates of proteolytic degradation were studied in monocytes (CD14+ fraction) and primary skin fibroblasts from the nine age-matched controls and thirteen CHM patients carrying 10 different loss-of-function mutations. With the use of pHrodo BioParticles conjugated with E. coli, collagen I coated FluoSpheres beads and fluorescent DQ ovalbumin with BODYPY FL dye, we demonstrated for the first time that lysosomal pH was increased in monocytes of CHM patients and, as a consequence, the rates of proteolytic degradation were slowed. Microarray analysis of gene expression revealed that some genes involved in the immune response, small GTPase regulation, transcription, cell adhesion and the regulation of exocytosis were significantly up and down regulated in cells from CHM patients compared to controls. Finally, CHM fibroblasts secreted significantly lower levels of cytokine/growth factors such as macrophage chemoattractant protein-1 (MCP-1), pigment epithelial derived factor (PEDF), tumor necrosis factor (TNF) alpha, fibroblast growth factor (FGF) beta and interleukin (lL)-8. CONCLUSIONS/SIGNIFICANCE: We demonstrated for the first time that peripheral cells of CHM patients had increased pH levels in lysosomes, reduced rates of proteolytic degradation and altered secretion of cytokines. Peripheral cells from CHM patients expose characteristics that were not previously recognized and could used as an alternative models to study the effects of different mutations in the REP-1 gene on mechanism of CHM development in human population

Sputtered NbN Films for Ultrahigh Performance Superconducting Nanowire Single-Photon Detectors

Nowadays ultrahigh performance superconducting nanowire single-photon detectors are the key elements in a variety of devices from biological research to quantum communications and computing. Accurate tuning of superconducting material properties is a powerful resource for fabricating single-photon detectors with a desired properties. Here, we report on the major theoretical relations between ultrathin niobium nitride (NbN) films properties and superconducting nanowire single-photon detectors characteristics, as well as ultrathin NbN films properties dependence on reactive magnetron sputtering recipes. Based on this study we formulate the exact requirements to ultrathin NbN films for ultrahigh performance superconducting nanowire single-photon detectors. Then, we experimentally study ultrathin NbN films properties (morphology, crystalline structure, critical temperature, sheet resistance) on silicon, sapphire, silicon dioxide and silicon nitride substrates sputtered with various recipes. We demonstrate ultrathin NbN films (obtained with more than 100 films deposition) with a wide range of critical temperature from 2.5 to 12.1 K and sheet resistance from 285 to 2000 ~$\Omega$/sq, as well as investigate a sheet resistance evolution over for more than 40\% within two years. Finally, we found out that one should use ultrathin NbN films with specific critical temperature near 9 K and sheet resistance of 400 ~$\Omega$/sq for ultrahigh performance SNSPD.Comment: The following article has been submitted to APL Materials. After it is published, it will be found at https://pubs.aip.org/aip/apm. Copyright 2023 Author(s). This article is distributed under a Creative Commons Attribution (CC BY) Licens

Papillorenal Syndrome-Causing Missense Mutations in PAX2/Pax2 Result in Hypomorphic Alleles in Mouse and Human

Papillorenal syndrome (PRS, also known as renal-coloboma syndrome) is an autosomal dominant disease characterized by potentially-blinding congenital optic nerve excavation and congenital kidney abnormalities. Many patients with PRS have mutations in the paired box transcription factor gene, PAX2. Although most mutations in PAX2 are predicted to result in complete loss of one allele's function, three missense mutations have been reported, raising the possibility that more subtle alterations in PAX2 function may be disease-causing. To date, the molecular behaviors of these mutations have not been explored. We describe a novel mouse model of PRS due to a missense mutation in a highly-conserved threonine residue in the paired domain of Pax2 (p.T74A) that recapitulates the ocular and kidney findings of patients. This mutation is in the Pax2 paired domain at the same location as two human missense mutations. We show that all three missense mutations disrupt potentially critical hydrogen bonds in atomic models and result in reduced Pax2 transactivation, but do not affect nuclear localization, steady state mRNA levels, or the ability of Pax2 to bind its DNA consensus sequence. Moreover, these mutations show reduced steady-state levels of Pax2 protein in vitro and (for p.T74A) in vivo, likely by reducing protein stability. These results suggest that hypomorphic alleles of PAX2/Pax2 can lead to significant disease in humans and mice

βB1-Crystallin: Thermodynamic Profiles of Molecular Interactions

β-Crystallins are structural proteins maintaining eye lens transparency and opacification. Previous work demonstrated that dimerization of both βA3 and βB2 crystallins (βA3 and βB2) involves endothermic enthalpy of association (∼8 kcal/mol) mediated by hydrophobic interactions.Thermodynamic profiles of the associations of dimeric βA3 and βB1 and tetrameric βB1/βA3 were measured using sedimentation equilibrium. The homo- and heteromolecular associations of βB1 crystallin are dominated by exothermic enthalpy (-13.3 and -24.5 kcal/mol, respectively).Global thermodynamics of βB1 interactions suggest a role in the formation of stable protein complexes in the lens via specific van der Waals contacts, hydrogen bonds and salt bridges whereas those β-crystallins which associate by predominately hydrophobic forces participate in a weaker protein associations

Near-Earth plasma sheet boundary dynamics during substorm dipolarization.

We report on the large-scale evolution of dipolarization in the near-Earth plasma sheet during an intense (AL ~ -1000 nT) substorm on August 10, 2016, when multiple spacecraft at radial distances between 4 and 15 R E were present in the night-side magnetosphere. This global dipolarization consisted of multiple short-timescale (a couple of minutes) B z disturbances detected by spacecraft distributed over 9 MLT, consistent with the large-scale substorm current wedge observed by ground-based magnetometers. The four spacecraft of the Magnetospheric Multiscale were located in the southern hemisphere plasma sheet and observed fast flow disturbances associated with this dipolarization. The high-time-resolution measurements from MMS enable us to detect the rapid motion of the field structures and flow disturbances separately. A distinct pattern of the flow and field disturbance near the plasma boundaries was found. We suggest that a vortex motion created around the localized flows resulted in another field-aligned current system at the off-equatorial side of the BBF-associated R1/R2 systems, as was predicted by the MHD simulation of a localized reconnection jet. The observations by GOES and Geotail, which were located in the opposite hemisphere and local time, support this view. We demonstrate that the processes of both Earthward flow braking and of accumulated magnetic flux evolving tailward also control the dynamics in the boundary region of the near-Earth plasma sheet.Graphical AbstractMultispacecraft observations of dipolarization (left panel). Magnetic field component normal to the current sheet (BZ) observed in the night side magnetosphere are plotted from post-midnight to premidnight region: a GOES 13, b Van Allen Probe-A, c GOES 14, d GOES 15, e MMS3, g Geotail, h Cluster 1, together with f a combined product of energy spectra of electrons from MMS1 and MMS3 and i auroral electrojet indices. Spacecraft location in the GSM X-Y plane (upper right panel). Colorcoded By disturbances around the reconnection jets from the MHD simulation of the reconnection by Birn and Hesse (1996) (lower right panel). MMS and GOES 14-15 observed disturbances similar to those at the location indicated by arrows

Climate shapes the spatiotemporal variation in color morph diversity and composition across the distribution range of Chrysomela lapponica leaf beetle

Color polymorphism offers rich opportunities for studying the eco-evolutionary mechanisms that drive the adaptations of local populations to heterogeneous and changing environments. We explored the color morph diversity and composition in a Chrysomela lapponica leaf beetle across its entire distribution range to test the hypothesis that environmental and climatic variables shape spatiotemporal variation in the phenotypic structure of a polymorphic species. We obtained information on 13 617 specimens of this beetle from museums, private collections, and websites. These specimens (collected from 1830-2020) originated from 959 localities spanning 33 degrees latitude, 178 degrees longitude, and 4200 m altitude. We classified the beetles into five color morphs and searched for environmental factors that could explain the variation in the level of polymorphism (quantified by the Shannon diversity index) and in the relative frequencies of individual color morphs. The highest level of polymorphism was found at high latitudes and altitudes. The color morphs differed in their climatic requirements; composition of colour morphs was independent of the geographic distance that separated populations but changed with collection year, longitude, mean July temperature and between-year temperature fluctuations. The proportion of melanic beetles, in line with the thermal melanism hypothesis, increased with increasing latitude and altitude and decreased with increasing climate seasonality. Melanic morph frequencies also declined during the past century, but only at high latitudes and altitudes where recent climate warming was especially strong. The observed patterns suggest that color polymorphism is especially advantageous for populations inhabiting unpredictable environments, presumably due to the different climatic requirements of coexisting color morphs