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This study examines the critical interaction between seasonal precipitation variability and forest maturity in determining ion deposition patterns in rehabilitated forest ecosystems. This research was conducted in rehabilitated forest sites in Bintulu, Sarawak, Malaysia that had ecologically similar plant distribution, species, and age in each planting area. This facilitated the standardization of rainfall deposition in the different study plots which streamlined the study of these specific facets of ecosystem dynamics. The goal is to understand how seasonal changes and the age of the forest influence the chemical composition of the flux that relates to the movement and deposition of nutrients through the forest ecosystem. This flux is a key factor in the health of the forest ecosystem and nutrient cycling. Using ion exchange resin (IER) samplers, we accurately measured and compared the deposition of different ions (Ca 2+ , Na + , Fe 2+ , Cu 2+ , NO 3 - , NH 4 + and SO 4 2- ) across different seasons and forest ages. The deposition of Ca 2+ and NH₄ + was significantly lower in the low-precipitation season than in the high-precipitation season in all forest stands, regardless of the year they were established (1996, 1999, 2002, 2005, and 2009). In contrast, ions such as Na + , Fe 2+ , Cu 2+ , NO 3 - and SO 4 2- showed no clear seasonal fluctuations. In addition, the study shows that through-fall in forest stands from 2002, 2005 and 2009 had higher concentrations of Ca 2+ in both seasons than in 1996 and 1999. Interestingly, forest stands from 2009 and 2002 had elevated levels of Na + and SO₄ 2- in seasons with low precipitation, while stands from 1996 had higher levels in seasons with high precipitation. Our results emphasize the crucial role of precipitation amount and canopy age in determining ion deposition in forest ecosystems. By demonstrating the significant influence of precipitation seasonality and forest maturity on the chemical composition of throughfall, this study contributes to a deeper understanding of nutrient dynamics in developing forest landscapes and provides valuable insights for ecological restoration measures., Competing Interests: The author declares that there is no conflict of interest., (© 2024 The Author(s). Plant‐Environment Interactions published by New Phytologist Foundation and John Wiley & Sons Ltd.)

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Elevated nitrogen (N) deposition due to intensified emissions of NH 3 and NO x is a global problem with profound consequences on living organisms and the environment. Although N emission rates are currently considered to be high in East Asia, reports on the current N deposition level and composition are still limited, especially in northeastern China, where official N deposition monitoring sites are unavailable. This limits our understanding of the spatio-temporal N deposition patterns and their influencing factors at regional to continental scales. Here, we used data collected mostly during 2019 at 38 sites, comprising 7 sites in northeastern China and 31 EANET (Acid Deposition Monitoring Network in East Asia) sites in middle and east Russia, Mongolia, central and southern China, South Korea and Japan to explore the spatial-seasonal variations and drivers of ammonium and nitrate deposition across the Northeast Asia. Total bulk inorganic N (TIN) deposition was 3.7-24.5 kg N ha -1 yr -1 and NH 4 + -N/NO 3 - -N ratio in the TIN was 0.8-2.8 in northeastern China. The bulk/wet TIN deposition averaged 7.5 kg N ha -1 yr -1 (predominantly in the form of ammonium-N: NH 4 + -N/NO 3 - -N = 1.4) over the Northeast Asia region, with the highest rates being observed in northeastern China (11.6), as well as central and southern China (10.7), followed by east Russia, South Korea and Japan (5.6), and the lowest in middle Russia and Mongolia (1.5). This regional bulk/wet TIN deposition level is about twice of the wet TIN deposition level in Europe and the United States. The TIN deposition in summer and spring was 45-467% higher than in autumn and winter. Out of the ten land uses considered, only agricultural and urban land uses significantly positively correlated with NH 4 + -N and NO 3 - -N deposition rates across all monitored sites. This study suggests that the ongoing agricultural and urban expansions are likely to enhance N deposition and its associated effects across global ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N -alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including C log P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10 -6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.

As black carbon (BC) particles can be deposited on the leaf surfaces, urban greening is considered to be effective in purifying urban air. However, little information on the seasonal variations in the amount of BC particles deposited on the leaf surfaces (BC amount on the leaves) is available in Japanese urban greening tree species. Therefore, we investigated seasonal variations in the BC amount on the leaves of evergreen ( Quercus glauca , Quercus myrsinaefolia , Osmanthus fragrans and Ilex rotunda ) and deciduous ( Zelkova serrata , Styrax japonica , Magnolia kobus , Cornus kousa and Cornus florida ) broad-leaved tree species. The BC amount on the leaves tended to increase from April for different periods, and then reached a saturated state in the tree species, excluding M. kobus . In the 4 evergreen broad-leaved trees, the seasonal variation was positively correlated with the atmospheric concentration of BC particle. In the 5 deciduous broad-leaved trees, the seasonal variation was negatively and positively correlated with the water-repellence (water droplet contact angle) and the amount of epicuticular wax on the leaf surface, respectively. Therefore, the BC amounts on the leaves of evergreen and deciduous broad-leaved urban tree species are considered to be mainly regulated by environmental factors and leaf surface characteristics, respectively.

To select urban greening tree species suitable for the purification of the atmosphere polluted by black carbon (BC) particles, it is necessary to clarify the determinants of the amount of BC particles deposited on the tree leaves. In the present study, we investigated the relationship between the amount of BC particles that were deposited from the atmosphere and firmly adhered to the leaf epicuticular wax, and leaf surface traits in seedlings of nine tree species grown for two years under natural conditions (Fuchu, Tokyo, Japan). There was a significant interspecific difference in the maximum amount of BC particles deposited on the leaf surface, and the order was as follows: Ilex rotunda > Cornus florida > Osmanthus fragrans > Cornus kousa > Quercus glauca ≒ Quercus myrsinifolia > Magnolia kobus ≒ Zelkova serrata ≒ Styrax japonicus . In the nine tree species, significant highly positive correlations were observed between the amount of BC particles deposited on the leaf surface, and the hydrophobicity of leaf epicuticular wax determined by its chemical composition. Therefore, we concluded that the hydrophobicity of leaf epicuticular wax is an important determinant of the amount of BC particles deposited on the leaf surface of urban greening tree species.

Spatial variations in sulfur (S) and nitrogen (N) deposition have changed in East and Southeast Asia in recent decades. Nevertheless, in this region, including the tropics, regional-scale assessments of the long-term risk of acidification and eutrophication (N saturation) for terrestrial ecosystems using a critical load approach have not been updated since 2001. To evaluate future risks, maps of critical loads and exceedances were updated using recently acquired spatial datasets of soil properties, soil minerals, climate, tree plantations, and the annual S and N depositions estimated using the Community Multiscale Air Quality (CMAQ) model. The resulting maps were verified using data on long-term trends in soil pH and nitrate concentration in surface water acquired by the Acid Deposition Monitoring Network in East Asia (EANET). It was found that N deposition exceeded the critical load for eutrophication not only in East Asia but also in some parts of the tropical monsoon and humid regions in Southeast Asia, whereas S deposition partly exceeded the critical load for soil acidification in China and small parts of the tropical monsoon region. The high-risk areas for eutrophication coincided well with the EANET sites, where the increase in nitrate concentration in the surface water was significant over the last 20 years. Hence, the estimated map of the critical load exceedance for eutrophication is more plausible for assessing the risk in East and Southeast Asia than that for acidification, although the critical load exceedance for acidification would be sufficiently significant as an updated risk map based on the latest input values. This update also suggests that increased N deposition around megacities, water discharge, and tree plantations may play an important role in the spatial variability of eutrophication risks in the tropics of Southeast Asia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Although it is an integral part of global change, most of the research addressing the effects of climate change on forests have overlooked the role of environmental pollution. Similarly, most studies investigating the effects of air pollutants on forests have generally neglected the impacts of climate change. We review the current knowledge on combined air pollution and climate change effects on global forest ecosystems and identify several key research priorities as a roadmap for the future. Specifically, we recommend (1) the establishment of much denser array of monitoring sites, particularly in the South Hemisphere; (2) further integration of ground and satellite monitoring; (3) generation of flux-based standards and critical levels taking into account the sensitivity of dominant forest tree species; (4) long-term monitoring of N, S, P cycles and base cations deposition together at global scale; (5) intensification of experimental studies, addressing the combined effects of different abiotic factors on forests by assuring a better representation of taxonomic and functional diversity across the ~73,000 tree species on Earth; (6) more experimental focus on phenomics and genomics; (7) improved knowledge on key processes regulating the dynamics of radionuclides in forest systems; and (8) development of models integrating air pollution and climate change data from long-term monitoring programs., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Scientific and public interest in acid deposition and its ecological impacts have increased throughout 1990s in East Asia (Northeast and Southeast Asia). After being established in 2001, the Acid Deposition Monitoring Network in East Asia (EANET) celebrates the 20th anniversary in 2021, and is now being expanded in scope reflecting the shifting social concern from acid deposition to broader air quality and climate change in recent years. This paper reviews the past 30 years of development of scientific research and policy related to acid deposition in East Asia. Since the onset of the twenty-first century, East Asia has had the highest SO 2 and NO x emissions in the world by continents, with substantial economic developmental inequality among countries. An overview of studies on sulfur and nitrogen deposition, the acidification of inland water and forest soil, and forest decline reveal that although limited acidification of inland water and forest soils have been documented, no decline in the populations of fish and other aquatic biota has been reported in East Asia. After a review of policy-oriented modeling studies on source receptor relationships and the critical loads of sulfur and nitrogen in East Asia, the history of EANET and its success and challenges are discussed. Finally, the importance of epistemic communities as the interface between science and policy in the region is discussed. Regional governance and cooperation are essential for reducing the emission of greenhouse gases, especially short-lived climate pollutants and atmospheric pollutants to realize the co-benefits of global climate change mitigation and improved air quality., (© 2022. The Author(s) under exclusive licence to Royal Swedish Academy of Sciences.)

Air pollution and atmospheric deposition have adverse effects on tree and forest health. We reviewed studies on tree and forest decline in Northeast and Southeast Asia, Siberia, and the Russian Far East (hereafter referred to as East Asia). This included studies published in domestic journals and languages. We identified information about the locations, causes, periods, and tree species exhibiting decline. Past air pollution was also reviewed. Most East Asian countries show declining trends in SO 2 concentration in recent years, although Mongolia and Russia show increasing trends. Ozone (O 3 ) concentrations are stable or gradually increasing in the East Asia region, with high maxima. Wet nitrogen (N) deposition was high in China and tropical countries, but low in Russia. The decline of trees and forests primarily occurred in the mid-latitudes of Japan, Korea, China, and Russia. Long-term large N deposition resulted in the N saturation phenomenon in Japan and China, but no clear forest health response was observed. Thereafter, forest decline symptoms, suspected to be caused by O 3 , were observed in Japan and China. In East Russia, tree decline occurred around industrial centers in Siberia. Haze events have been increasing in tropical and boreal forests, and particulate matter inhibits photosynthesis. In recent years, chronically high O 3 concentrations, in conjunction with climate change, are likely have adverse effects on tree physiology. The effects of air pollution and related factors on tree decline are summarized. Recently, the effects of air pollution on tree decline have not been apparent under the changing climate, however, monitoring air pollution is indispensable for identifying the cause of tree decline. Further economic growth is projected in Southeast Asia and therefore, the monitoring network should be expanded to tropical and boreal forest zones. Countermeasures such as restoring urban trees and rural forests are important for ensuring future ecosystem services., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

High emissions of air pollutants from Northeast Asia are strongly influenced by air quality as well as by ecosystems. This study investigated the spatiotemporal variations in the sulfur isotopic ratio (δ 34 S) in atmospheric deposition at eleven monitoring stations in Japan from 2011 to 2016 and estimated the amount of transboundary transported anthropogenic sulfate (TRB) deposition using mass balance calculations. The δ 34 S of sulfate in precipitation ranged from -0.42 to +22.7‰. Sea salt (SS), TRB, and domestic anthropogenic sources (DOM) were the dominant sources of sulfate deposition in Japan. TRB sulfate deposition was largest on the Sea of Japan side, with an annual average value of 1.5 ± 0.3-6.9 ± 0.5 mg m -2  d -1 (36-44%), followed by Mt. Happo (4.5 ± 0.1 mg m -2  d -1 ; 88%), the Pacific Ocean side (1.5 ± 0.8, 4.3 ± 0.9 mg m -2  d -1 ; 24-50%), and the remote islands in the North Pacific Ocean (1.1 ± 0.2, 2.0 ± 0.8 mg m -2  d -1 ; 19-32%). TRB sulfate deposition on the Sea of Japan side was 2-12 times higher in winter and 1-2 times higher in summer than that of DOM. In contrast, TRB sulfate deposition on the Pacific Ocean side was 1.5-3 times higher in summer than in winter due to high precipitation levels. In Tokyo, the annual contribution from DOM sulfate deposition is approximately three times higher than that from TRB. Annual TRB sulfate deposition is lowest at Ogasawara at 1.1 ± 0.2 mg m -2  d -1 , and the annual oceanic DMS contribution to sulfate deposition is high, accounting for 1.3 mg m -2  d -1 (20 ± 6%). The contribution of Asian dust was estimated to be 1-5.2 mg m -2  d -1 (3-6%), which occurred in a single Asian dust event on the Sea of Japan side., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion-positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer., (©2018 American Association for Cancer Research.)

FGFR2 gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors FGFR2 amplification. We established single-cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor. To screen the genetic alterations acquired in AZD-R, we ran a comparative genomic hybridization assay and found an amplification of Chr7q34 region. The chromosomal breakpoints were located between the 12th and the 13th exon of jumonji C domain containing histone demethylase 1 homolog D ( JHDM1D ) and between the 3rd and the 4th exon of BRAF We sequenced cDNA of the AZD-R clones and found fusion kinase JHDM1D-BRAF , which has previously been identified in primary ovarian cancer. Because JHDM1D-BRAF fusion lacks a RAS-binding domain, the dimerization of JHDM1D-BRAF was enhanced. A cell growth inhibition assay using MEK inhibitors and RAF-dimer inhibitors indicated the dependence of AZD-R clones for growth on the MAPK pathway. Our data provide a clinical rationale for using a MEK or RAF dimer inhibitor to treat FGFR2 -amplified gastric cancer patients who have acquired resistance through the JHDN1D-BRAF fusion. Mol Cancer Ther; 17(10); 2217-25. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (ERK) gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers., (©2015 American Association for Cancer Research.)

The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations., (©2014 American Association for Cancer Research.)

During lymphatic development, Prox1 plays central roles in the differentiation of blood vascular endothelial cells (BECs) into lymphatic endothelial cells (LECs), and subsequently in the maturation and maintenance of lymphatic vessels. However, the molecular mechanisms by which Prox1 elicits these functions remain to be elucidated. Here, we identified FoxC2 and angiopoietin-2 (Ang2), which play important roles in the maturation of lymphatic vessels, as novel targets of Prox1 in mouse embryonic-stem-cell-derived endothelial cells (MESECs). Furthermore, we found that expression of HoxD8 was significantly induced by Prox1 in MESECs, a finding confirmed in human umbilical vein endothelial cells (HUVECs) and human dermal LECs (HDLECs). In mouse embryos, HoxD8 expression was significantly higher in LECs than in BECs. In a model of inflammatory lymphangiogenesis, diameters of lymphatic vessels of the diaphragm were increased by adenovirally transduced HoxD8. We also found that HoxD8 induces Ang2 expression in HDLECs and HUVECs. Moreover, we found that HoxD8 induces Prox1 expression in HUVECs and that knockdown of HoxD8 reduces this expression in HDLECs, suggesting that Prox1 expression in LECs is maintained by HoxD8. These findings indicate that transcriptional networks of Prox1 and HoxD8 play important roles in the maturation and maintenance of lymphatic vessels.

Vascular endothelial growth factor receptor 2 (VEGFR2) plays crucial roles in vasculogenesis, a process involving cell proliferation, migration and differentiation. However, the molecular mechanism by which VEGFR2 signaling directs vascular endothelial differentiation of VEGFR2(+) mesodermal progenitors is not well understood. In this study, we examined the signal transduction pathway downstream of VEGFR2 for endothelial differentiation using an in vitro differentiation system of mouse embryonic stem-cell-derived VEGFR2(+) cells. Using chimeric receptors composed of VEGFR2 and VEGFR3, the third member of the VEGFR family, we found that signaling through tyrosine 1175 (Y1175, corresponding to mouse Y1173) of VEGFR2 is crucial for two processes of endothelial differentiation: endothelial specification of VEGFR2(+) progenitors, and subsequent survival of endothelial cells (ECs). Furthermore, we found that phospholipase Cgamma1 (PLCgamma1), which interacts with VEGFR2 through phosphorylated Y1175, is an inducer of endothelial specification. In contrast to VEGFR2, VEGFR3 does not transmit a signal for endothelial differentiation of VEGFR2(+) cells. We found that VEGFR3 does not activate PLCgamma1, although VEGFR3 has the ability to support endothelial cell survival. Taken together, these findings indicate that VEGFR2-PLCgamma1 signal relay gives rise to the unique function of VEGFR2, thus enabling endothelial differentiation from vascular progenitors.

Vascular endothelial growth factor receptor 2 (VEGFR2) transmits signals of crucial importance to vasculogenesis, including proliferation, migration, and differentiation of vascular progenitor cells. Embryonic stem cell-derived VEGFR2(+) mesodermal cells differentiate into mural lineage in the presence of platelet derived growth factor (PDGF)-BB or serum but into endothelial lineage in response to VEGF-A. We found that inhibition of H-Ras function by a farnesyltransferase inhibitor or a knockdown technique results in selective suppression of VEGF-A-induced endothelial specification. Experiments with ex vivo whole-embryo culture as well as analysis of H-ras(-/-) mice also supported this conclusion. Furthermore, expression of a constitutively active H-Ras[G12V] in VEGFR2(+) progenitor cells resulted in endothelial differentiation through the extracellular signal-related kinase (Erk) pathway. Both VEGF-A and PDGF-BB activated Ras in VEGFR2(+) progenitor cells 5 min after treatment. However, VEGF-A, but not PDGF-BB, activated Ras 6-9 h after treatment, preceding the induction of endothelial markers. VEGF-A thus activates temporally distinct Ras-Erk signaling to direct endothelial specification of VEGFR2(+) vascular progenitor cells.

The seasonal changes in throughfall (TF) and stemflow (SF) chemistry and the canopy interactions of K+ and N compounds were studied in a Japanese cedar forest near the Sea of Japan. The fluxes of most ions, including non-sea-salt SO4(2-), from TF, SF, and rainfall showed distinct seasonal trends, increasing from autumn to winter, owing to the seasonal west wind, while the fluxes of NH4+ and K+ ions from TF+SF might have a large effect of canopy interactions. The contact angle (CA) of water droplets on leaves decreased with leaf aging, suggesting that surface wettability increases with leaf age. The K+ concentration in TF was negatively correlated with the CA of 1-year-old leaves, while the NH4+ concentration was positively correlated with the CA. The net fluxes of NH4+ and NO3(-) from TF were positively correlated with the CA. The increase in wettability may accelerate leaching of K+ or uptake of NH4+.

Background: The findings of magnetic resonance imaging (MRI) have not been studied systematically in patients with osteoarthritis (OA). The objective here was to compare MRI findings with radiological findings in patients with knee pain and to identify factors that influence the progression of OA of the knee., Methods: Of 212 patients with knee pain and MRI of the knee joint, 161 patients were selected for the study after exclusion of cases of trauma and other arthritides. MRI was used to evaluate the presence and degree of bone bruise, hydrarthrosis, and injuries to the cruciate ligament and meniscus. Bone bruise was classified into four types, and hydrarthrosis into four grades. Radiologically, OA progression in the femorotibial and patellofemoral joints was analyzed according to the Kellgren-Lawrence classification. Age was divided into four groups based on distribution quartiles. Logistic regression analysis and a generalized linear model with Poisson regression were used to analyze correlations among these factors., Results: Bone bruise was present in 87 cases, hydrarthrosis in 100, cruciate ligament injury in 20, and meniscus injury in 98. The presence of bone bruise was not related to age, cruciate ligament injury, meniscus injury, nor to OA of the patellofemoral joint, but was related to hydrarthrosis and to OA of the femorotibial joint. Femorotibial OA was much more strongly associated with bone bruise than with hydrarthrosis. Furthermore, analyzing the relation between the types of bone bruise and the degree of hydrarthrosis using a generalized linear model with Poisson regression, there was a positive correlation between the grade of bone bruise and the amount of hydrarthrosis., Conclusions: A factor associated with the degree of osteoarthritis of the knee is bone bruise observed on MRI. The degree of hydrarthrosis is related to the grade of bone bruise, but is not linked to the degree of osteoarthritis.

Transforming growth factor-beta (TGF-beta) signaling is controlled by a variety of regulators that target either signaling receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF-beta signaling mainly through targeting the signaling receptors, whereas SnoN and c-Ski repress signaling at the transcriptional level through inactivation of Smad complexes. We previously found that Arkadia is a positive regulator of TGF-beta signaling that induces ubiquitin-dependent degradation of Smad7 through its C-terminal RING domain. We report here that Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. Arkadia interacts with SnoN and c-Ski in their free forms as well as in the forms bound to Smad proteins, and constitutively down-regulates levels of their expression. Arkadia thus appears to effectively enhance TGF-beta signaling through simultaneous down-regulation of two distinct types of negative regulators, Smad7 and SnoN/c-Ski, and may play an important role in determining the intensity of TGF-beta family signaling in target cells.