Showing papers by "Kyushu University published in 2006"
TL;DR: It is suggested that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.
Abstract: Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.
2,451 citations
TL;DR: A surprisingly simple rule is described that is a good approximation for all graphs that are analysed, including cycles, spatial lattices, random regular graphs, random graphs and scale-free networks: natural selection favours cooperation if the benefit of the altruistic act, b, exceeds the average number of neighbours, k, which means b/c > k.
Abstract: The evolution and maintenance of cooperative behaviour take some explaining. Cooperative groups can be undermined by ‘cheaters’ who selfishly exploit common resources, and a large body of theory predicts that cheats will usually displace cooperators. But a possible explanation of why cheats don't always prosper emerges from competition experiments between strains of yeast that act as cooperators and cheaters, competing for glucose and utilizing it either efficiently or ‘selfishly’. The results show that both strategies can coexist, because both are associated with costs and benefits. There is a cost to cheating; in this instance the production of fewer offspring than the opposition. A graphic — really — demonstration that natural selection can favour cooperation comes in a study by Ohtsuki et al. of the evolutionary dynamics of structured ‘virtual’ populations formed of points on a graph. Cooperation is favoured if the benefit of the altruistic act divided by the cost exceeds the average number of neighbours. So cooperation can evolve as a consequence of this ‘social viscosity’ even in the absence of reputation effects or strategic complexity. Natural selection generally favours cooperation if the benefit of the altruistic act divided by the cost exceeds the average number of neighbours, indicating that cooperation can evolve as a consequence of ‘social viscosity’, even in the absence of reputation effects or strategic complexity. A fundamental aspect of all biological systems is cooperation. Cooperative interactions are required for many levels of biological organization ranging from single cells to groups of animals1,2,3,4. Human society is based to a large extent on mechanisms that promote cooperation5,6,7. It is well known that in unstructured populations, natural selection favours defectors over cooperators. There is much current interest, however, in studying evolutionary games in structured populations and on graphs8,9,10,11,12,13,14,15,16,17. These efforts recognize the fact that who-meets-whom is not random, but determined by spatial relationships or social networks18,19,20,21,22,23,24. Here we describe a surprisingly simple rule that is a good approximation for all graphs that we have analysed, including cycles, spatial lattices, random regular graphs, random graphs and scale-free networks25,26: natural selection favours cooperation, if the benefit of the altruistic act, b, divided by the cost, c, exceeds the average number of neighbours, k, which means b/c > k. In this case, cooperation can evolve as a consequence of ‘social viscosity’ even in the absence of reputation effects or strategic complexity.
1,942 citations
TL;DR: Ovarian-type stroma has been proposed as a requisite to distinguish MCN from IPMN, and some other distinct features to characterize IPMN and MCN have been identified, but there remain ambiguities between the two diseases.
1,912 citations
TL;DR: A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.
Abstract: A driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs), the activities of which are controlled by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors. Two ubiquitin ligases, the SKP1-CUL1-F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), are responsible for the specific ubiquitylation of many of these regulators. Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.
1,365 citations
TL;DR: In this article, an overview of recent achievements and new trends in the production of bulk ultrafine-grained (UFG) materials using severe plastic deformation (SPD) is presented.
Abstract: This overview highlights very recent achievements and new trends in one of the most active and developing fields in modern materials science: the production of bulk ultrafine-grained (UFG) materials using severe plastic deformation (SPD). The article also summarizes the chronology of early work in SPD processing and presents clear and definitive descriptions of the terminology currently in use in this research area. Special attention is given to the principles of the various SPD processing techniques as well as the major structural features and unique properties of bulk UFG materials that underlie their prospects for widespread practical utilization.
1,345 citations
TL;DR: PEG-modified gold nanoparticles showed a nearly neutral surface, and had little cytotoxicity in vitro, following intravenous injection into mice, whereas most of gold was detected in the liver in the case of original gold nanorods stabilized with CTAB.
1,133 citations
TL;DR: It is shown that IL-27 receptor–deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response.
Abstract: Studies have focused on the events that influence the development of interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize TH-17 cell effector responses. Here we show that IL-27 receptor–deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development TH-17 cells induced by IL-6 and transforming growth factor-β, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of TH-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.
965 citations
Donald E. Brownlee1, Peter Tsou2, Jérôme Aléon3, Conel M. O'd. Alexander4 +182 more•Institutions (57)
TL;DR: The Stardust spacecraft collected thousands of particles from comet 81P/Wild 2 and returned them to Earth for laboratory study, and preliminary examination shows that the nonvolatile portion of the comet is an unequilibrated assortment of materials that have both presolar and solar system origin.
Abstract: The Stardust spacecraft collected thousands of particles from comet 81P/Wild 2 and returned them to Earth for laboratory study. The preliminary examination of these samples shows that the nonvolatile portion of the comet is an unequilibrated assortment of materials that have both presolar and solar system origin. The comet contains an abundance of silicate grains that are much larger than predictions of interstellar grain models, and many of these are high-temperature minerals that appear to have formed in the inner regions of the solar nebula. Their presence in a comet proves that the formation of the solar system included mixing on the grandest scales.
886 citations
TL;DR: It is suggested that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury.
Abstract: In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoterenhancer (Nes-Stat3 –/– , Nes-Socs3 –/– ). Reactive astrocytes in Nes-Stat3 –/– mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3 –/– mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury. Because the regenerative capability of the mammalian CNS is poor, limited functional recovery occurs during the chronic phase of SCI. At the subacute phase of SCI, however, gradual functional recovery is observed to some extent in both rodents and humans (except in cases of complete paralysis). The mechanism behind this functional recovery remains unclear. Here, we investigated this issue by focusing on the action of reactive astrocytes in a mouse model of SCI. To interpret the process of paralysis improvement in the subacute phase, we examined serial histological sections of contused spinal cords and followed motor function for 6 weeks after injury in wild-type mice and found that the area of neural cell loss gradually enlarged in a rostral-caudal direction within a few days after SCI (acute phase) and a portion of Hu-expressing neurons were positive for cleaved caspase-3, indicating that the secondary injury process lasted for several days in this model (Supplementary Fig. 1 online) during which we observed limited functional recovery (Fig. 1a). Astrocytes surrounding the lesion underwent a typical change of hypertrophy, process extension and increased expression of intermediate filaments such as GFAP and Nestin by 7 d after SCI (Fig. 1b), characteristic of ‘reactive astrocytes.’ Notably, these astrocytes eventually migrated centripetally to the lesion
834 citations
TL;DR: M mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ‐dependent manner through proteolytic cleavage of Mgm1, the yeast homolog of O PA1.
Abstract: The dynamin-like GTPase OPA1, a causal gene product of human dominant optic atrophy, functions in mitochondrial fusion and inner membrane remodeling. It has several splice variants and even a single variant is found as several processed forms, although their functional significance is unknown. In yeast, mitochondrial rhomboid protease regulates mitochondrial function and morphology through proteolytic cleavage of Mgm1, the yeast homolog of OPA1. We demonstrate that OPA1 variants are synthesized with a bipartite-type mitochondrial targeting sequence. During import, the matrix-targeting signal is removed and processed forms (L-isoforms) are anchored to the inner membrane in type I topology. L-isoforms undergo further processing in the matrix to produce S-isoforms. Knockdown of OPA1 induced mitochondrial fragmentation, whose network morphology was recovered by expression of L-isoform but not S-isoform, indicating that only L-isoform is fusion-competent. Dissipation of membrane potential, expression of m-AAA protease paraplegin, or induction of apoptosis stimulated this processing along with the mitochondrial fragmentation. Thus, mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ-dependent manner.
810 citations
TL;DR: The daily human intake of BPA is <1 microg/kg body weight/day on the basis of several studies, and whether these doses can have an adverse endocrine disruptive effect on humans, especially fetuses, needs to be studied carefully.
Tokyo Medical and Dental University1, Shinshu University2, Tohoku University3, Kyushu University4, Hokkaido University5, Gifu University6, Fujita Health University7, RMIT University8, Tokyo Kasei University9, Kyorin University10, National Defense Medical College11, Kōchi University12, University of Washington13, Ludwig Maximilian University of Munich14, Boston Children's Hospital15, University of Toyama16
TL;DR: It is demonstrated that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially fromTyk2 function in mice.
Utrecht University1, Yale University2, Rice University3, Purdue University4, Alfred Wegener Institute for Polar and Marine Research5, Stockholm University6, University of Rhode Island7, Brown University8, United States Geological Survey9, University of Bordeaux10, Aix-Marseille University11, Centre national de la recherche scientifique12, Yamagata University13, University College London14, Norwegian Polar Institute15, Boston University16, British Geological Survey17, University of Michigan18, Kyushu University19, University of Southampton20, University of Aberdeen21, University of Padua22, Japan Agency for Marine-Earth Science and Technology23, James Madison University24, University of Tsukuba25, Tohoku University26, National Institute of Advanced Industrial Science and Technology27, Hokkaido University28
TL;DR: It is shown that sea surface temperatures near the North Pole increased from ∼18 °C to over 23°C during this event, which suggests that higher-than-modern greenhouse gas concentrations must have operated in conjunction with other feedback mechanisms—perhaps polar stratospheric clouds or hurricane-induced ocean mixing—to amplify early Palaeogene polar temperatures.
Abstract: The Palaeocene/Eocene thermal maximum, ~55 million years ago, was a brief period of widespread, extreme climatic warming1, 2, 3, that was associated with massive atmospheric greenhouse gas input4. Although aspects of the resulting environmental changes are well documented at low latitudes, no data were available to quantify simultaneous changes in the Arctic region. Here we identify the Palaeocene/Eocene thermal maximum in a marine sedimentary sequence obtained during the Arctic Coring Expedition5. We show that sea surface temperatures near the North Pole increased from ~18 °C to over 23 °C during this event. Such warm values imply the absence of ice and thus exclude the influence of ice-albedo feedbacks on this Arctic warming. At the same time, sea level rose while anoxic and euxinic conditions developed in the ocean's bottom waters and photic zone, respectively. Increasing temperature and sea level match expectations based on palaeoclimate model simulations6, but the absolute polar temperatures that we derive before, during and after the event are more than 10 °C warmer than those model-predicted. This suggests that higher-than-modern greenhouse gas concentrations must have operated in conjunction with other feedback mechanisms—perhaps polar stratospheric clouds7 or hurricane-induced ocean mixing8—to amplify early Palaeogene polar temperatures.
United States Naval Research Laboratory1, Brookhaven National Laboratory2, Space Sciences Laboratory3, Kingsborough Community College4, University of Münster5, Michigan State University6, Osaka University7, Jet Propulsion Laboratory8, Lawrence Livermore National Laboratory9, Kobe University10, European Synchrotron Radiation Facility11, Washington University in St. Louis12, University of Chicago13, École normale supérieure de Lyon14, University of New Mexico15, Kyushu University16, University of Tokyo17, University of Washington18, Lawrence Berkeley National Laboratory19, University of Jena20, University of Hawaii21, American Museum of Natural History22, Case Western Reserve University23, University of Hyogo24, United States Geological Survey25, Imperial College London26, State University of New York System27, Open University28, Stanford University29
TL;DR: The bulk of the comet 81P/Wild 2 samples returned to Earth by the Stardust spacecraft appear to be weakly constructed mixtures of nanometer-scale grains, with occasional much larger ferromagnesian silicates, Fe-Ni sulfides,Fe-Ni metal, and accessory phases.
Abstract: The bulk of the comet 81P/Wild 2 (hereafter Wild 2) samples returned to Earth by the Stardust spacecraft appear to be weakly constructed mixtures of nanometer-scale grains, with occasional much larger (over 1 micrometer) ferromagnesian silicates, Fe-Ni sulfides, Fe-Ni metal, and accessory phases. The very wide range of olivine and low-Ca pyroxene compositions in comet Wild 2 requires a wide range of formation conditions, probably reflecting very different formation locations in the protoplanetary disk. The restricted compositional ranges of Fe-Ni sulfides, the wide range for silicates, and the absence of hydrous phases indicate that comet Wild 2 experienced little or no aqueous alteration. Less abundant Wild 2 materials include a refractory particle, whose presence appears to require radial transport in the early protoplanetary disk.
TL;DR: In this paper, a harmonized estimate for the aerosol di- rect radiative forcing (RF) under all-sky conditions is derived from the difference of two model simulations with prescribed aerosol emissions, one for present-day and one for pre-industrial conditions.
Abstract: Nine different global models with detailed aerosol modules have independently produced instantaneous direct radiative forcing due to anthropogenic aerosols. The an- thropogenic impact is derived from the difference of two model simulations with prescribed aerosol emissions, one for present-day and one for pre-industrial conditions. The differ- ence in the solar energy budget at the top of the atmosphere (ToA) yields a new harmonized estimate for the aerosol di- rect radiative forcing (RF) under all-sky conditions. On a global annual basis RF is 0.22Wm 2 , ranging from +0.04 to 0.41Wm 2 , with a standard deviation of ±0.16Wm 2 . Anthropogenic nitrate and dust are not included in this esti- mate. No model shows a significant positive all-sky RF. The corresponding clear-sky RF is 0.68Wm 2 . The cloud-sky RF was derived based on all-sky and clear-sky RF and mod- elled cloud cover. It was significantly different from zero and ranged between 0.16 and +0.34Wm 2 . A sensitivity anal- ysis shows that the total aerosol RF is influenced by consid- erable diversity in simulated residence times, mass extinction coefficients and most importantly forcing efficiencies (forc- ing per unit optical depth). The clear-sky forcing efficiency (forcing per unit optical depth) has diversity comparable to that for the all-sky/ clear-sky forcing ratio. While the di- versity in clear-sky forcing efficiency is impacted by factors such as aerosol absorption, size, and surface albedo, we can show that the all-sky/clear-sky forcing ratio is important be- cause all-sky forcing estimates require proper representation of cloud fields and the correct relative altitude placement be- tween absorbing aerosol and clouds. The analysis of the sul- phate RF shows that long sulphate residence times are com- pensated by low mass extinction coefficients and vice versa. This is explained by more sulphate particle humidity growth and thus higher extinction in those models where short-lived sulphate is present at lower altitude and vice versa. Solar atmospheric forcing within the atmospheric column is esti- mated at +0.82±0.17Wm 2 . The local annual average max- ima of atmospheric forcing exceed +5Wm 2 confirming the regional character of aerosol impacts on climate. The annual average surface forcing is 1.02±0.23Wm 2 . With the cur- rent uncertainties in the modelling of the radiative forcing due to the direct aerosol effect we show here that an estimate from one model is not sufficient but a combination of several model estimates is necessary to provide a mean and to ex- plore the uncertainty.
TL;DR: It is concluded that Socs3 is an essential negative regulator of IL-23 signaling, inhibition of which constrains the generation of Th17 differentiation.
Abstract: Suppressor of cytokine signaling (Socs) 3 is a cytokine-inducible inhibitor with critical but selective cell-specific effects. We show that deficiency of Socs3 in T cells had minimal effects on differentiation of T cells to the T helper (Th) 1 or Th2 subsets; accordingly, Socs3 had no effect on IL-12-dependent signal transducer and activator of transcription (Stat) 4 phosphorylation or IL-4-dependent Stat6 phosphorylation. By contrast, Socs3 was found to be a major regulator of IL-23-mediated Stat3 phosphorylation and Th17 generation, and Stat3 directly binds to the IL-17A and IL-17F promoters. We conclude that Socs3 is an essential negative regulator of IL-23 signaling, inhibition of which constrains the generation of Th17 differentiation.
TL;DR: The OABSS, the sum score of four symptoms (daytime frequency, nighttime frequency, urgency, and urgency incontinence), has been developed and validated and may be a useful tool for research and clinical practice.
TL;DR: It is demonstrated that cancers of the gastrointestinal system do contain SP cells that show some characteristics of so‐called stem cells.
Abstract: A subset of stem cells, termed "side population" (SP) cells, has been identified and characterized in several mammalian tissues and cell lines. However, SP cells have never been identified or isolated from gastrointestinal cancers. We used flow cytometry and the DNA-binding dye Hoechst 33342 to isolate SP cells from various human gastrointestinal system cancer cell lines. Fifteen of sixteen cancer cell lines from the gastrointestinal system contained 0.3%-2.2% SP cells. Next, we used an oligonucleotide microarray to analyze differentially expressed genes between SP and non-SP cells of hepatoma HuH7. The expression of GATA6, which is associated with embryonic development and hepatocytic differentiation, was significantly upregulated in HuH7 SP cells. The expression of ABCG2, ABCB1, and CEACAM6, which are associated with chemoresistance, was also significantly increased in SP cells. In addition, some epithelial markers and mesenchymal markers were overexpressed in SP cells. Reverse transcription-polymerase chain reaction and immunocytochemical staining validated these results and suggested a multilineage potential for HuH7 SP cells. In hepatoma HuH7 and colorectal SW480 cell lines, SP cells showed evidence for self-renewal, generating both SP and non-SP cells. Finally, chemoresistance to anticancer agents, including doxorubicin, 5-fluorouracil, and gemcitabine, were compared between HuH7 SP and non-SP cells using an ATP bioluminescence assay. The HuH7 SP cells expressed a higher resistance to doxorubicin, 5-fluorouracil, and gemcitabine compared with non-SP cells. These findings demonstrate that cancers of the gastrointestinal system do contain SP cells that show some characteristics of so-called stem cells.
Kansai Medical University1, Shinshu University2, Tokyo Metropolitan Komagome Hospital3, Nagoya University4, Showa University5, Kōchi University6, Nagoya City University7, Kyushu University8, Fujita Health University9, Tohoku University10, Juntendo University11, Chiba University12, Kyorin University13, University of Occupational and Environmental Health Japan14
TL;DR: The accumulation of many AIP cases shows that the concept of AIP has changed slightly to include extrapancreatic lesions and associated disorders, which suggests that the current diagnostic criteria are becoming inadequate.
Abstract: In 1961, Sarles et al.1 asked the following question regarding the particular cases of pancreatitis with hypergammaglobulinemia: “Chronic inflammatory sclerosis of the pancreas—an autoimmune pancreatic disease?” As similar cases were rarely observed, a relationship between such pancreatitis and autoimmunity was viewed skeptically during the following several decades. In 1992, Toki et al.2 have reported 4 cases with unusual diffuse irregular narrowing of the main pancreatic duct and diffuse enlargement of the entire pancreas due to lymphocyte infiltration. In 1995, Japanese investigators3 firstly proposed a concept of “autoimmune pancreatitis (AIP)”, in which the patients showed diffusely enlarged pancreas, narrowing pancreatogram, increased serum IgG, presence of autoantibodies, fibrotic changes with lymphocytic infiltration and steroidal efficacy. Thereafter, many AIP cases have been reported from Japan, and AIP has been accepted as a new clinical entity.4,5 The histopathological findings of AIP show massive infiltration of lymphoplasmacytes with fibrosis, which is consistent with lymphoplasmacytic sclerosing pancreatitis (LPSP).6 Many Japanese investigators have paid great attention to AIP, especially with regard to its unique pancreatic images,2 IgG4,7 disease-associated autoantibodies,8 extrapancreatic lesions,6,9–14 and steroidal efficacy.14,15
Currently in Japan, diagnosis of AIP is based on the “diagnostic criteria 2002 of autoimmune pancreatitis”16 proposed by the Japan Pancreas Society. However, the accumulation of many AIP cases shows that the concept of AIP has changed slightly to include extrapancreatic lesions and associated disorders, which suggests that the current diagnostic criteria are becoming inadequate.
In 2003, the Research Committee of Intractable Diseases of the Pancreas, supported by the Japanese Ministry of Health, Labour and Welfare (Chairman, M. Otsuki), began to review the current diagnostic criteria in light of recently acquired information and knowledge. The team organized a working group (WG), consisting of the team members and researchers specializing in autoimmune pancreatitis, to develop a proposal for the revision of the current diagnostic criteria. On 7 October 2005 and 22 April 2006, the Research Committee of Intractable Diseases of the Pancreas and the Japan Pancreas Society jointly held open forums to discuss the proposed amendments.
This report describes the background of the proposed amendments and the final proposal for the revised version of the clinical diagnostic criteria of AIP.
University of Rhode Island1, Stockholm University2, Utrecht University3, Brown University4, United States Geological Survey5, Rice University6, University of Bordeaux7, Centre national de la recherche scientifique8, Yamagata University9, University College London10, Norwegian Polar Institute11, Boston University12, British Geological Survey13, University of Michigan14, Kyushu University15, National Oceanography Centre16, University of Aberdeen17, University of Padua18, Japan Agency for Marine-Earth Science and Technology19, James Madison University20, Nagoya University21, Tohoku University22, Hokkaido University23, Leibniz Institute of Marine Sciences24, Paul Scherrer Institute25, University of Bergen26
TL;DR: This record of the Neogene reveals cooling of the Arctic that was synchronous with the expansion of Greenland ice and East Antarctic ice and supporting arguments for bipolar symmetry in climate change.
Abstract: The history of the Arctic Ocean during the Cenozoic era (0–65 million years ago) is largely unknown from direct evidence. Here we present a Cenozoic palaeoceanographic record constructed from >400 m of sediment core from a recent drilling expedition to the Lomonosov ridge in the Arctic Ocean. Our record shows a palaeoenvironmental transition from a warm ‘greenhouse’ world, during the late Palaeocene and early Eocene epochs, to a colder ‘icehouse’ world influenced by sea ice and icebergs from the middle Eocene epoch to the present. For the most recent ~14 Myr, we find sedimentation rates of 1–2 cm per thousand years, in stark contrast to the substantially lower rates proposed in earlier studies; this record of the Neogene reveals cooling of the Arctic that was synchronous with the expansion of Greenland ice (~3.2 Myr ago) and East Antarctic ice (~14 Myr ago). We find evidence for the first occurrence of ice-rafted debris in the middle Eocene epoch (~45 Myr ago), some 35 Myr earlier than previously thought; fresh surface waters were present at ~49 Myr ago, before the onset of ice-rafted debris. Also, the temperatures of surface waters during the Palaeocene/Eocene thermal maximum (~55 Myr ago) appear to have been substantially warmer than previously estimated. The revised timing of the earliest Arctic cooling events coincides with those from Antarctica, supporting arguments for bipolar symmetry in climate change.
TL;DR: The p16INK4a /Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cδ (PKCδ) in human senescent cells, uncover an unexpected role for the p16ink4a–Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.
Abstract: The p16(INK4a) cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb in cellular senescence. Here, we show that the p16(INK4a) /Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cdelta (PKCdelta) in human senescent cells. Importantly, once activated by ROS, PKCdelta promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKCdelta signalling. Sustained activation of ROS-PKCdelta signalling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis, in human senescent cells. This irreversible cytokinetic block is likely to act as a second barrier to cellular immortalization ensuring stable cell-cycle arrest in human senescent cells. These results uncover an unexpected role for the p16(INK4a)-Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.
TL;DR: It is suggested that CD11c+ LPCs, via TLR5, detect and are used by pathogenic bacteria in the intestinal lumen, as suggested in Tlr5−/− mice.
Abstract: Toll-like receptors (TLRs) recognize distinct microbial components and induce innate immune responses. TLR5 is triggered by bacterial flagellin. Here we generated Tlr5-/- mice and assessed TLR5 function in vivo. Unlike other TLRs, TLR5 was not expressed on conventional dendritic cells or macrophages. In contrast, TLR5 was expressed mainly on intestinal CD11c+ lamina propria cells (LPCs). CD11c+ LPCs detected pathogenic bacteria and secreted proinflammatory cytokines in a TLR5-dependent way. However, CD11c+ LPCs do not express TLR4 and did not secrete proinflammatory cytokines after exposure to a commensal bacterium. Notably, transport of pathogenic Salmonella typhimurium from the intestinal tract to mesenteric lymph nodes was impaired in Tlr5-/- mice. These data suggest that CD11c+ LPCs, via TLR5, detect and are used by pathogenic bacteria in the intestinal lumen.
TL;DR: A differential equation is derived which describes how the average frequency of each strategy on the graph changes over time, and is a replicator equation with a transformed payoff matrix, which results in a transformation of the payoff matrix.
TL;DR: The extraction using a chloroform phase containing PC was found to be a convenient way of replacing the CTAB with alternative capping agents such as PC, and the PC-passivated NRs showed low cytotoxicity in comparison with twice-centrifuged NRs.
Abstract: Hexadecyltrimethylammonium bromide (CTAB), which is necessary for the preparation of gold nanorods (NRs), was extracted from a NR solution into a chloroform phase containing phosphatidylcholine (PC). After three extractions, the zeta potential of the NRs remained positive, but its magnitude decreased from +67 ± 1 to +15 ± 1 mV. Transmission electron microscopy and energy-dispersive X-ray analysis indicated that the NRs were passivated with PC. The PC layer on the NR surface contributed to the prevention of NR aggregation. The PC-passivated NRs showed low cytotoxicity in comparison with twice-centrifuged NRs. It was shown that a negligible amount of CTAB was dispersed in the NR solution after the extraction. The extraction using a chloroform phase containing PC was found to be a convenient way of replacing the CTAB with alternative capping agents such as PC. This is a key technique for preparing functional NRs that can have practical applications.
TL;DR: In this article, the authors demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory active ulcerative colitis (UC) patients.
Abstract: Background and aims: Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies. Methods: Patients with refractory active UC were randomly assigned to a high trough concentration (10–15 ng/ml) group (HT group) (n = 21), low trough concentration (5–10 ng/ml) group (LT group) (n = 22), or placebo group (n = 20). Patients received an initial oral dose of 0.05 mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10 week open label extension. Results: An improvement in DAI score (⩾4 points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p Conclusions: Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC. The optimal target range appears to be 10–15 ng/ml in terms of efficacy with two week therapy.
TL;DR: It is shown here that the N‐terminal 100 amino acids of human Cdt1 are recognized for proteolysis by two distinct E3 ubiquitin ligases during S–G2 phases, which are essential for DDB1‐Cul4‐mediated proteolyses and following ultraviolet‐irradiation.
Abstract: Replication licensing is carefully regulated to restrict replication to once in a cell cycle. In higher eukaryotes, regulation of the licensing factor Cdt1 by proteolysis and Geminin is essential to prevent re-replication. We show here that the N-terminal 100 amino acids of human Cdt1 are recognized for proteolysis by two distinct E3 ubiquitin ligases during S–G2 phases. Six highly conserved amino acids within the 10 first amino acids of Cdt1 are essential for DDB1-Cul4-mediated proteolysis. This region is also involved in proteolysis following DNA damage. The second E3 is SCF-Skp2, which recognizes the Cy-motif-mediated Cyclin E/A-cyclin-dependent kinase-phosphorylated region. Consistently, in HeLa cells cosilenced of Skp2 and Cul4, Cdt1 remained stable in S–G2 phases. The Cul4-containing E3 is active during ongoing replication, while SCF-Skp2 operates both in S and G2 phases. PCNA binds to Cdt1 through the six conserved N-terminal amino acids. PCNA is essential for Cul4- but not Skp2-directed degradation during DNA replication and following ultraviolet-irradiation. Our data unravel multiple distinct pathways regulating Cdt1 to block re-replication.
TL;DR: This study identifies a genomic duplication that causes adult-onset autosomal dominant leukodystrophy, the first human disease attributable to mutations in the gene encoding lamin B1, and raises the possibility that lamination B may be a link to the autoimmune attack that occurs in multiple sclerosis.
Abstract: Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, with a phenotype similar to chronic progressive multiple sclerosis. In this study, we identify a genomic duplication that causes ADLD. Affected individuals carry an extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD. Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells overexpressed this protein. This is the first human disease attributable to mutations in the gene encoding lamin B1. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis.
TL;DR: Data suggest that DAG‐induced Ca2+ signaling pathway through TRPC3 and TRPC6 is essential for Ang II‐induced NFAT activation and cardiac hypertrophy.
Abstract: Angiotensin (Ang) II participates in the pathogenesis of heart failure through induction of cardiac hypertrophy. Ang II-induced hypertrophic growth of cardiomyocytes is mediated by nuclear factor of activated T cells (NFAT), a Ca2+-responsive transcriptional factor. It is believed that phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP3) is responsible for Ca2+ increase that is necessary for NFAT activation. However, we demonstrate that PLC-mediated production of diacylglycerol (DAG) but not IP3 is essential for Ang II-induced NFAT activation in rat cardiac myocytes. NFAT activation and hypertrophic responses by Ang II stimulation required the enhanced frequency of Ca2+ oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca2+ channel. Patch clamp recordings from single myocytes revealed that Ang II activated DAG-sensitive TRPC-like currents. Among DAG-activating TRPC channels (TRPC3, TRPC6, and TRPC7), the activities of TRPC3 and TRPC6 channels correlated with Ang II-induced NFAT activation and hypertrophic responses. These data suggest that DAG-induced Ca2+ signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy.
TL;DR: A photo-hydrogen-evolving molecular device has been found to serve as the first effective model of a "molecular device" which evolves molecular hydrogen from water in the presence of a sacrificial electron donor (EDTA) under the visible-light illumination.
Abstract: A photo-hydrogen-evolving molecular device made up of a tris(2,2'-bipyridine)ruthenium(II) derivative and a dichloro(2,2'-bipyridine)platinum(II) derivative has been found to serve as the first effective model of a "molecular device" which evolves molecular hydrogen from water in the presence of a sacrificial electron donor (EDTA), under the visible-light illumination.
TL;DR: The keys to the success in indirect reciprocity are to be nice (maintenance of cooperation among themselves), retaliatory (detection of defectors, punishment, and justification of punishment), apologetic, and forgiving.