Showing papers by "Hokkaido University published in 2012"

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Global assessment of experimental climate warming on tundra vegetation: heterogeneity over space and time.

Abstract: 35 Abstract Understanding the sensitivity of tundra vegetation to climate warming is critical to forecasting future biodiversity and vegetation feedbacks to climate. In situ warming experiments accelerate climate change on a small scale to forecast responses of local plant communities. Limitations of this approach include the apparent site-specificity of results and uncertainty about the power of short-term studies to anticipate longer term change. We address these issues with a synthesis of 61 experimental warming studies, of up to 20 years duration, in tundra sites worldwide. The response of plant groups to warming often differed with ambient summer temperature, soil moisture and experimental duration. Shrubs increased with warming only where ambient temperature was high, whereas graminoids increased primarily in the coldest study sites. Linear increases in effect size over time were frequently observed. There was little indication of saturating or accelerating effects, as would be predicted if negative or positive vegetation feedbacks were common. These results indicate that tundra vegetation exhibits strong regional variation in response to warming, and that in vulnerable regions, cumulative effects of long-term warming on tundra vegetation - and associated ecosystem consequences - have the potential to be much greater than we have observed to date.

Plot-scale evidence of tundra vegetation change and links to recent summer warming.

Abstract: Temperature is increasing at unprecedented rates across most of the tundra biome(1). Remote-sensing data indicate that contemporary climate warming has already resulted in increased productivity ov ...

A III–V nanowire channel on silicon for high-performance vertical transistors

Abstract: The fabrication of transistors using vertical, six-sided core–multishell indium gallium arsenide nanowires with an all-surrounding gate on a silicon substrate combines the advantages of a three-dimensional gate architecture with the high electron mobility of the III–V nanowires, drastically enhancing the on-state current and transconductance. In the continuing drive to improve and miniaturize transistors, the microelectronics industry has recently adopted three-dimensional electronic gate structures. Another way of improving transistors is to use semiconductor materials with higher electron mobility than silicon, although this presents significant fabrication challenges. Katsuhiro Tomioka et al. combine the two approaches; they grow, with high precision, vertical, six-sided core–multishell indium gallium arsenide nanowires with an all-surrounding gate on a silicon substrate. The resulting devices demonstrate superior transistor performance with excellent on/off switching behaviour and fast operation. Silicon transistors are expected to have new gate architectures, channel materials and switching mechanisms in ten years’ time1,2,3,4. The trend in transistor scaling has already led to a change in gate structure from two dimensions to three, used in fin field-effect transistors, to avoid problems inherent in miniaturization such as high off-state leakage current and the short-channel effect. At present, planar and fin architectures using III–V materials, specifically InGaAs, are being explored as alternative fast channels on silicon5,6,7,8,9 because of their high electron mobility and high-quality interface with gate dielectrics10. The idea of surrounding-gate transistors11, in which the gate is wrapped around a nanowire channel to provide the best possible electrostatic gate control, using InGaAs channels on silicon, however, has been less well investigated12,13 because of difficulties in integrating free-standing InGaAs nanostructures on silicon. Here we report the position-controlled growth of vertical InGaAs nanowires on silicon without any buffering technique and demonstrate surrounding-gate transistors using InGaAs nanowires and InGaAs/InP/InAlAs/InGaAs core–multishell nanowires as channels. Surrounding-gate transistors using core–multishell nanowire channels with a six-sided, high-electron-mobility transistor structure greatly enhance the on-state current and transconductance while keeping good gate controllability. These devices provide a route to making vertically oriented transistors for the next generation of field-effect transistors and may be useful as building blocks for wireless networks on silicon platforms.

Carbon Nanofibers Prepared via Electrospinning

Abstract: Carbon nanofibers prepared via electrospinning and following carbonization are summarized by focusing on the structure and properties in relation to their applications, after a brief review of electrospinning of some polymers. Carbon precursors, pore structure control, improvement in electrical conductivity,and metal loading into carbon nanofibers via electrospinning are discussed from the viewpoint of structure and texture control of carbon.

Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1

Abstract: The mechanisms by which tumor microenvironments modulate nucleic acid-mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor-associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids.

Alkali‐Metal‐Promoted Pt/TiO2 Opens a More Efficient Pathway to Formaldehyde Oxidation at Ambient Temperatures

Abstract: Formaldehyde is emitted from building and furnishing materials and consumer products, and is known to cause irritation of eyes and respiratory tract, headache, pneumonia, and even cancer. It is a dominant indoor air pollutant, especially in developing countries, and significant efforts have gone into indoor HCHO purification to meet environmental regulations and human health needs. Removal of HCHO by adsorbents has been investigated extensively using potassium permanganate, activated carbon, aluminum oxide, and some ceramic materials. Sorbent effectiveness is typically limited by low adsorption capacities. Catalytic oxidation is the most effective technology for volatile organic compound (VOC) abatement because VOCs can be oxidized to CO2 over certain catalysts at much lower temperatures than in thermal oxidation. Supported noble metal catalysts (Pt, Pd, Rh, Au, Ag) or metal oxide catalysts (Ni, Cu, Cr, Mn) have been used for the catalytic oxidation of VOCs. Complete oxidation of HCHO over catalysts occurs above 150 8C on clean and oxidized films of Ni, Pd, and Al and over silver–cerium composite oxide, above 100 8C over Ag/MnOx-CeO2 [18] and Au/CeO2, [19] and above 85 8C over Pd-Mn/Al2O3 [17] and Au/FeOx. As catalytic oxidation at even lower temperatures is desirable for indoor air purification, the development of a catalyst for total HCHOoxidation at room temperature is of great interest. In our recent study, 1% Pt/TiO2 catalyst was shown to be effective for HCHO oxidation at room temperature, achieving 100% conversion of d= 100 ppm HCHO to CO2 and H2O at a gas hourly space velocity (GHSV) of 50000 h . However, we also observed that this type catalyst is not as active as needed for practical applications, and deactivates with time-on-stream. Herein, we report a novel alkali-metal-promoted Pt/TiO2 catalyst for the ambient destruction of HCHO. We show that the addition of alkali-metal ions (such as Li, Na, and K) to Pt/TiO2 catalyst stabilized an atomically dispersed PtO(OH)x–alkali-metal species on the catalyst surface and also opened a new low-temperature reaction pathway, significantly promoting the activity for the HCHO oxidation by activating H2O and catalyzing the facile reaction between surface OH and formate species to total oxidation products. Figure 1a shows the HCHO conversion to CO2 as a function of temperature over the x% Na-1% Pt/TiO2 (x= 0, 1, and 2) samples at a GHSVof 120000 h 1 andHCHO inlet of d= 600 ppm. All gas streams were humidified to a RH of around 50%. Before each activity test, the samples were reduced in H2 at 300 8C for 30 min. The sodium-free catalyst had low activity for the HCHO oxidation reaction, with HCHO conversion being only about 19% at 15 8C. With 1% Na addition, the HCHO conversion reached 96% at 15 8C and 100% at 40 8C. With 2% Na addition, 100% HCHO conversion to CO2 and H2O was measured at 15 8C. The effect of Na addition on the surface reducibility was examined by H2 temperature-programmed reduction (TPR; Figure 1b). The amounts of H2 consumption were about the same over all the samples, but the addition of Na shifted the reduction peak to lower temperatures, that is, from 2 8C for 1% Pt/TiO2 to 6 8C for 1% Na-1% Pt/TiO2 and 11 8C for 2% Na-1% Pt/ TiO2. Thus, the sample reducibility correlates with the sample activity. The most active 2% Na-promoted sample had excellent stability as checked by long isothermal tests. For example, at a GHSV of 300000 h 1 and with the same other reaction conditions, approximately 80% HCHO conversion was maintained over a 72 h-long test (Figure 1a, inset). Li and K were equally effective promoters to Na and imparted the same high activity and stability to the Pt species (Supporting Information, Figure S1). Water vapor and oxygen effects on the activity of Na-Pt/TiO2 are important (Supporting Information, Figures S2,S3). Deionized-water washing of the samples was performed to check the alkali-metal and Pt interaction.While most of the Na was removed from the Nacontaining catalysts, a residual amount remained (Supporting Information, Table S1). Activity test results (Supporting Information, Figure S1) showed that the washed catalyst had identical activity for HCHO [*] C. Zhang, F. Liu, Y. Liu, Prof. H. He Research Center for Eco-Environmental Sciences Chinese Academy of Sciences Shuangqing Road 18, Beijing, 100085 (China) E-mail: honghe@rcees.ac.cn

Atg9 vesicles are an important membrane source during early steps of autophagosome formation.

Abstract: During the process of autophagy, cytoplasmic materials are sequestered by double-membrane structures, the autophagosomes, and then transported to a lytic compartment to be degraded One of the most fundamental questions about autophagy involves the origin of the autophagosomal membranes In this study, we focus on the intracellular dynamics of Atg9, a multispanning membrane protein essential for autophagosome formation in yeast We found that the vast majority of Atg9 existed on cytoplasmic mobile vesicles (designated Atg9 vesicles) that were derived from the Golgi apparatus in a process involving Atg23 and Atg27 We also found that only a few Atg9 vesicles were required for a single round of autophagosome formation During starvation, several Atg9 vesicles assembled individually into the preautophagosomal structure, and eventually, they are incorporated into the autophagosomal outer membrane Our findings provide conclusive linkage between the cytoplasmic Atg9 vesicles and autophagosomal membranes and offer new insight into the requirement for Atg9 vesicles at the early step of autophagosome formation

Discovery of Small-Scale Spiral Structures in the Disk of SAO 206462 (HD 135344B): Implications for the Physical State of the Disk from Spiral Density Wave Theory

Abstract: We present high-resolution, H-band, imaging observations, collected with Subaru/HiCIAO, of the scattered light from the transitional disk around SAO 206462 (HD 135344B). Although previous sub-mm imagery suggested the existence of the dust-depleted cavity at r approximates 46 AU, our observations reveal the presence of scattered light components as close as 0".2 (approx 28 AU) from the star. Moreover, we have discovered two small-scale spiral structures lying within 0".5 (approx 70 AU). We present models for the spiral structures using the spiral density wave theory, and derive a disk aspect ratio of h approx 0.1, which is consistent with previous sub-mm observations. This model can potentially give estimates of the temperature and rotation profiles of the disk based on dynamical processes, independently from sub-mm observations. It also predicts the evolution of the spiral structures, which can be observable on timescales of 10-20 years, providing conclusive tests of the model. While we cannot uniquely identify the origin of these spirals, planets embedded in the disk may be capable of exciting the observed morphology. Assuming that this is the case, we can make predictions on the locations and, possibly, the masses of the unseen planets. Such planets may be detected by future multi-wavelengths observations.

Tree height integrated into pantropical forest biomass estimates

Abstract: . Aboveground tropical tree biomass and carbon storage estimates commonly ignore tree height (H). We estimate the effect of incorporating H on tropics-wide forest biomass estimates in 327 plots across four continents using 42 656 H and diameter measurements and harvested trees from 20 sites to answer the following questions: 1. What is the best H-model form and geographic unit to include in biomass models to minimise site-level uncertainty in estimates of destructive biomass? 2. To what extent does including H estimates derived in (1) reduce uncertainty in biomass estimates across all 327 plots? 3. What effect does accounting for H have on plot- and continental-scale forest biomass estimates? The mean relative error in biomass estimates of destructively harvested trees when including H (mean 0.06), was half that when excluding H (mean 0.13). Power- and Weibull-H models provided the greatest reduction in uncertainty, with regional Weibull-H models preferred because they reduce uncertainty in smaller-diameter classes (≤40 cm D) that store about one-third of biomass per hectare in most forests. Propagating the relationships from destructively harvested tree biomass to each of the 327 plots from across the tropics shows that including H reduces errors from 41.8 Mg ha−1 (range 6.6 to 112.4) to 8.0 Mg ha−1 (−2.5 to 23.0). For all plots, aboveground live biomass was −52.2 Mg ha−1 (−82.0 to −20.3 bootstrapped 95% CI), or 13%, lower when including H estimates, with the greatest relative reductions in estimated biomass in forests of the Brazilian Shield, east Africa, and Australia, and relatively little change in the Guiana Shield, central Africa and southeast Asia. Appreciably different stand structure was observed among regions across the tropical continents, with some storing significantly more biomass in small diameter stems, which affects selection of the best height models to reduce uncertainty and biomass reductions due to H. After accounting for variation in H, total biomass per hectare is greatest in Australia, the Guiana Shield, Asia, central and east Africa, and lowest in east-central Amazonia, W. Africa, W. Amazonia, and the Brazilian Shield (descending order). Thus, if tropical forests span 1668 million km2 and store 285 Pg C (estimate including H), then applying our regional relationships implies that carbon storage is overestimated by 35 Pg C (31–39 bootstrapped 95% CI) if H is ignored, assuming that the sampled plots are an unbiased statistical representation of all tropical forest in terms of biomass and height factors. Our results show that tree H is an important allometric factor that needs to be included in future forest biomass estimates to reduce error in estimates of tropical carbon stocks and emissions due to deforestation.

Using optical vortex to control the chirality of twisted metal nanostructures.

Abstract: We discovered for the first time that light can twist metal to control the chirality of metal nanostructures (hereafter, chiral metal nanoneedles). The helicity of optical vortices is transferred to the constituent elements of the irradiated material (mostly melted material), resulting in the formation of chiral metal nanoneedles. The chirality of these nanoneedles could be controlled by just changing the sign of the helicity of the optical vortex. The tip curvature of these chiral nanoneedles was measured to be <40 nm, which is less than 1/25th of the laser wavelength (1064 nm). Such chiral metal nanoneedles will enable us to selectively distinguish the chirality and optical activity of molecules and chemical composites on a nanoscale and they will provide chiral selectivity for nanoscale imaging systems (e.g., atomic force microscopes), chemical reactions on plasmonic nanostructures, and planar metamaterials.

Rapid coagulation of porous dust aggregates outside the snow line: a pathway to successful icy planetesimal formation

Abstract: Rapid orbital drift of macroscopic dust particles is one of the major obstacles to planetesimal formation in protoplanetary disks. We re-examine this problem by considering the porosity evolution of dust aggregates. We apply a porosity model based on recent N-body simulations of aggregate collisions, which allows us to study the porosity change upon collision for a wide range of impact energies. As a first step, we neglect collisional fragmentation and instead focus on dust evolution outside the snow line, where the fragmentation has been suggested to be less significant than inside the snow line because of the high sticking efficiency of icy particles. We show that dust particles can evolve into highly porous aggregates (with internal densities of much less than 0.1 g cm–3) even if collisional compression is taken into account. We also show that the high porosity triggers significant acceleration in collisional growth. This acceleration is a natural consequence of the particles' aerodynamical properties at low Knudsen numbers, i.e., at particle radii larger than the mean free path of the gas molecules. Thanks to this rapid growth, the highly porous aggregates are found to overcome the radial drift barrier at orbital radii less than 10 AU (assuming the minimum-mass solar nebula model). This suggests that, if collisional fragmentation is truly insignificant, formation of icy planetesimals is possible via direct collisional growth of submicron-sized icy particles.

Release probability of hippocampal glutamatergic terminals scales with the size of the active zone

Abstract: Using functional and morphological analysis, this study demonstrates that in CA3 pyramidal cell recurrent axon terminals, the release probability and the number of voltage-gated calcium channels are linearly correlated with the size of the active zone.

Highly Stable Water Splitting on Oxynitride TaON Photoanode System under Visible Light Irradiation

Abstract: Highly stable photoelectrochemical water splitting is demonstrated for the first time on a tantalum oxynitride (TaON) photoanode under visible light irradiation. Highly dispersed CoOx nanoparticles on the TaON photoanode efficiently scavenge photogenerated holes and effectively suppress self-oxidative deactivation of the TaON surface, resulting in a stable photocurrent. The use of highly dispersed CoOx cocatalyst on TaON together with phosphate solutions significantly increased the photocurrent due to the formation of a cobalt/phosphate phase. This enabled us to stably split water into H2 and O2 under visible light irradiation at a relatively low applied bias (0.6 V vs Pt counter electrode).

Positional cloning and characterization reveal the molecular basis for soybean maturity locus E1 that regulates photoperiodic flowering.

Abstract: The complex and coordinated regulation of flowering has high ecological and agricultural significance The maturity locus E1 has a large impact on flowering time in soybean, but the molecular basis for the E1 locus is largely unknown Through positional cloning, we delimited the E1 locus to a 174-kb region containing an intron-free gene (E1) The E1 protein contains a putative bipartite nuclear localization signal and a region distantly related to B3 domain In the recessive allele, a nonsynonymous substitution occurred in the putative nuclear localization signal, leading to the loss of localization specificity of the E1 protein and earlier flowering The early-flowering phenotype was consistently observed in three ethylmethanesulfonate-induced mutants and two natural mutations that harbored a premature stop codon or a deletion of the entire E1 gene E1 expression was significantly suppressed under short-day conditions and showed a bimodal diurnal pattern under long-day conditions, suggesting its response to photoperiod and its dominant effect induced by long day length When a functional E1 gene was transformed into the early-flowering cultivar Kariyutaka with low E1 expression, transgenic plants carrying exogenous E1 displayed late flowering Furthermore, the transcript abundance of E1 was negatively correlated with that of GmFT2a and GmFT5a, homologues of FLOWERING LOCUS T that promote flowering These findings demonstrated the key role of E1 in repressing flowering and delaying maturity in soybean The molecular identification of the maturity locus E1 will contribute to our understanding of the molecular mechanisms by which a short-day plant regulates flowering time and maturity

Analytical Expression of Average Power-Coupling Coefficients for Estimating Intercore Crosstalk in Multicore Fibers

Abstract: In order to realize fast and accurate estimation of intercore crosstalk in bent multicore fibers (MCFs), an analytical expression of the average power-coupling coefficient (PCC) based on an exponential autocorrelation function is, for the first time, derived, resulting in no need for heavy numerical computations. It is revealed that, when the bending radius is large and the correlation length is large, the average PCC is inversely proportional to the correlation length and to the square of the propagation constant difference Δβmn between core m and core n, and when the bending radius is small and the correlation length is large, the average PCC is proportional to the bending radius and is independent of the correlation length. When the correlation length is small, on the other hand, the average PCC is proportional to the correlation length and is independent of the bending radius. For homogeneous MCFs (Δβmn = 0) with small bending radius, the average PCC coincides with the mean crosstalk increase per unit length derived from the coupled-mode theory of Hayashi et al. that is proportional to the bending radius. Average crosstalk values calculated by using the analytical expression derived here are in excellent agreement with those of numerical solutions of coupled-power equations, irrespective of the values of bending radius and correlation length.

Enhancement in Aerobic Alcohol Oxidation Catalysis of Au25 Clusters by Single Pd Atom Doping

Abstract: Au25 and Pd1Au24 clusters on multiwalled carbon nanotubes were developed via adsorption of Au25(SC12H25)18 and Pd1Au24(SC12H25)18, respectively, on the nanotubes, followed by calcination. Comparison of their catalysis for the aerobic oxidation of benzyl alcohol showed that single Pd atom doping significantly improved the catalytic performance of Au25 for the first time.

1.01-Pb/s (12 SDM/222 WDM/456 Gb/s) Crosstalk-managed Transmission with 91.4-b/s/Hz Aggregate Spectral Efficiency

Abstract: (40-Word Limit): We demonstrate 1.01-Pb/s transmission over 52 km with the highest aggregate spectral efficiency of 91.4 b/s/Hz by using low-crosstalk one-ring-structured 12-core fiber. Our multi-core fiber and compact fan-in/fan-out devices are designed to support high-order modulation formats up to 32-QAM in SDM transmission.

A Cenozoic record of the equatorial Pacific carbonate compensation depth

Abstract: Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.

Very long-chain fatty acids: elongation, physiology and related disorders

Abstract: Very long-chain fatty acids (VLCFAs) are fatty acids (FAs) with a chain-length of ≥22 carbons. Mammals have a variety of VLCFAs differing in chain-length and the number of double bonds. Each VLCFA exhibits certain functions, for example in skin barrier formation, liver homeostasis, myelin maintenance, spermatogenesis, retinal function and anti-inflammation. These functions are elicited not by free VLCFAs themselves, but through their influences as components of membrane lipids (sphingolipids and glycerophospholipids) or precursors of inflammation-resolving lipid mediators. VLCFAs are synthesized by endoplasmic reticulum membrane-embedded enzymes through a four-step cycle. The most important enzymes determining the tissue distribution of VLCFAs are FA elongases, which catalyze the first, rate-limiting step of the FA elongation cycle. Mammals have seven elongases (ELOVL1-7), each exhibiting a characteristic substrate specificity. Several inherited disorders are caused by mutations in genes involved in VLCFA synthesis or degradation. In this review, I describe the molecular mechanism of FA elongation and the responsible enzymes in mammals and yeast, as well as VLCFA-related disorders in human.

Human mitotic chromosomes consist predominantly of irregularly folded nucleosome fibres without a 30-nm chromatin structure

Abstract: How a long strand of genomic DNA is compacted into a mitotic chromosome remains one of the basic questions in biology. The nucleosome fibre, in which DNA is wrapped around core histones, has long been assumed to be folded into a 30-nm chromatin fibre and further hierarchical regular structures to form mitotic chromosomes, although the actual existence of these regular structures is controversial. Here, we show that human mitotic HeLa chromosomes are mainly composed of irregularly folded nucleosome fibres rather than 30-nm chromatin fibres. Our comprehensive and quantitative study using cryo-electron microscopy and synchrotron X-ray scattering resolved the long-standing contradictions regarding the existence of 30-nm chromatin structures and detected no regular structure >11 nm. Our finding suggests that the mitotic chromosome consists of irregularly arranged nucleosome fibres, with a fractal nature, which permits a more dynamic and flexible genome organization than would be allowed by static regular structures.

Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease

Abstract: Rationale: Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes.Objectives: To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity.Methods: A total of 279 eligible patients with COPD (stages I–IV: 26, 45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient.Measurements and Main Results: Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was −32 ± 24 (SD) ml/yr (n = 261). We classified the subjects of less than the ...

The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice

Abstract: The bioactive lysophospholipid mediator sphingosine-1-phosphate (S1P) promotes the egress of newly formed T cells from the thymus and the release of immature B cells from the bone marrow. It has remained unclear, however, where and how S1P is released. Here, we show that in mice, the S1P transporter spinster homolog 2 (Spns2) is responsible for the egress of mature T cells and immature B cells from the thymus and bone marrow, respectively. Global Spns2-KO mice exhibited marked accumulation of mature T cells in thymi and decreased numbers of peripheral T cells in blood and secondary lymphoid organs. Mature recirculating B cells were reduced in frequency in the bone marrow as well as in blood and secondary lymphoid organs. Bone marrow reconstitution studies revealed that Spns2 was not involved in S1P release from blood cells and suggested a role for Spns2 in other cells. Consistent with these data, endothelia-specific deletion of Spns2 resulted in defects of lymphocyte egress similar to those observed in the global Spns2-KO mice. These data suggest that Spns2 functions in ECs to establish the S1P gradient required for T and B cells to egress from their respective primary lymphoid organs. Furthermore, Spns2 could be a therapeutic target for a broad array of inflammatory and autoimmune diseases.

Definitions and outcome measures for bullous pemphigoid: Recommendations by an international panel of experts

Abstract: Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial

Abstract: Summary Background Treatments that confer survival benefit are needed in patients with heavily pretreated metastatic colorectal cancer. The aim of this trial was to investigate the efficacy and safety of TAS-102—a novel oral nucleoside antitumour agent. Methods Between August 25, 2009, and April 12, 2010, we undertook a multicentre, double-blind, randomised, placebo-controlled phase 2 trial in Japan. Eligible patients were 20 years or older; had confirmed colorectal adenocarcinoma; had a treatment history of two or more regimens of standard chemotherapy; and were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin. Patients had to be able to take oral drugs; have measurable lesions; have an Eastern Cooperative Oncology Group performance status of between 0 and 2; and have adequate bone-marrow, hepatic, and renal functions within 7 days of enrolment. Patients were randomly assigned (2:1) to either TAS-102 (35 mg/m 2 given orally twice a day in a 28-day cycle [2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period]) or placebo; all patients received best supportive care. Randomisation was done with minimisation methods, with performance status as the allocation factor. The randomisation sequence was generated with a validated computer system by an independent team from the trial sponsor. Investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety analyses were done in the per-protocol population. The study is in progress and is registered with Japan Pharmaceutical Information Center, number JapicCTI-090880. Findings 112 patients allocated to TAS-102 and 57 allocated to placebo made up the intention-to-treat population. Median follow-up was 11·3 months (IQR 10·7–14·0). Median overall survival was 9·0 months (95% CI 7·3–11·3) in the TAS-102 group and 6·6 months (4·9–8·0) in the placebo group (hazard ratio for death 0·56, 80% CI 0·44–0·71, 95% CI 0·39–0·81; p=0·0011). 57 (50%) of 113 patients given TAS-102 in the safety population had neutropenia of grade 3 or 4, 32 (28%) leucopenia, and 19 (17%) anaemia. No patient given placebo had grade 3 or worse neutropenia or leucopenia; three (5%) of 57 had grade 3 or worse anaemia. Serious adverse events occurred in 21 (19%) patients in the TAS-102 group and in five (9%) in the placebo group. No treatment-related deaths occurred. Interpretation TAS-102 has promising efficacy and a manageable safety profile in patients with metastatic colorectal cancer who are refractory or intolerant to standard chemotherapies. Funding Taiho Pharmaceutical.

Incubation period as part of the case definition of severe respiratory illness caused by a novel coronavirus.

Abstract: Non-specific symptoms of acute respiratory viral infections make it difficult for many countries without ongoing transmission of a novel coronavirus to rule out other possibilities including influenza before isolating imported febrile individuals with a possible exposure history. The incubation period helps differential diagnosis, and up to two days is suggestive of influenza. It is worth including the incubation period in the case definition of novel coronavirus infection.

Comprehensive IR study on acid/base properties of metal oxides

Abstract: Acid/base properties (type, strength, number) of a wide range of metal oxides were studied by IR (infra-red) spectroscopy. Ammonia, pyridine and CD3CN were used as probe molecules for acidity measurement. CO2, CHCl3, benzaldehyde and nitrobenzene were used for basicity measurement. Pyridine for the nature and number of acid sites, CD3CN for the strength of acid sites, CHCl3 for the strength of basic sites and nitrobenzene for the number of basic sites were found to be suitable probes. The absorption coefficients of pyridine for acidic sites and nitrobenzene for basic sites, estimated for various metal oxides by IR coupled with mass spectrometry, were within ±10% of the average value, which indicates that the integrated molar extinction coefficients could be used for semi-quantification of acid/base sites of various oxides samples. The comprehensive IR results in this study will be available to characterize properties of Lewis and Bronsted acid sites and basic sites on metal oxides by a simple IR experiment.