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Conventional demand-prediction methods predominantly rely on past user behaviors to predict regular future transportation demands using acquired user preference data. Nevertheless, predicting unforeseen travel demands arising from bad weather or emergency events remains challenging owing to the absence of data on such future contingencies. This study introduces a method to predict travel demand by leveraging search history data, which potentially signal unforeseen travel requirements. We elucidate the correlation between the search count and integrated circuit (IC) card usage on an aggregate level. Subsequently, we propose a two-stage analytical technique to estimate the number of IC card usages based on route-search counts. Our findings demonstrate that the proposed model has superior accuracy, and the route-search count plays a pivotal role in predicting the number of IC card usages, especially unforeseen shifts in demand. [ABSTRACT FROM AUTHOR]

Simple Summary: A number of agents, including immune checkpoint inhibitors, have become available for the treatment of hepatocellular carcinoma, but the objective response rate of these drugs is currently only 30% to 40%. Therefore, the identification of new predictive biomarkers and an increased knowledge of the mechanisms of response or resistance to systemic chemotherapies are required. In the systemic drug treatment of hepatocellular carcinoma, only the tyrosine kinase inhibitor (TKI) sorafenib was available for a period. This was followed by the development of regorafenib as a second-line treatment after sorafenib, and then lenvatinib, a new TKI, proved non-inferiority to sorafenib and became available as a first-line treatment. Subsequently, cabozantinib, another TKI, was introduced as a second-line treatment, along with ramucirumab, the only drug proven to be predictive of therapeutic efficacy when AFP levels are >400 ng/mL. It is an anti-VEGF receptor antibody. More recently, immune checkpoint inhibitors have become the mainstay of systemic therapy and can now be used as a first-line standard treatment for HCC. However, the objective response rate for these drugs is currently only 30% to 40%, and there is a high incidence of side effects. Additionally, there are no practical biomarkers to predict their therapeutic effects. Therefore, this review provides an overview of extensive research conducted on potential HCC biomarkers from blood, tissue, or imaging information that can be used in practice to predict the therapeutic efficacy of systemic therapy before its initiation. [ABSTRACT FROM AUTHOR]

Background: Redness of the facial skin is an important cosmetic concern. Although qualitative and quantitative modifications of sebum on the skin surface are major pathogenic factors of chronic inflammatory skin conditions, the relationship between skin redness, sebum, and mild inflammation on the cheeks of healthy subjects remains elusive. Aims: We aimed to explore the correlation between cheek redness and sebum and inflammatory cytokines in the stratum corneum (SC) of healthy subjects. We also examined the effects of representative sebum lipids on the gene expression of inflammatory cytokines in cultured keratinocytes. Patients/Methods: This study included 198 healthy participants. Skin sebum was analyzed using flow injection analysis, and skin redness was assessed using a spectrophotometer. Inflammatory cytokines in tape‐stripped SC were measured using enzyme‐linked immunosorbent assay. Results: Cheek redness parameters positively correlated with the amount of skin sebum and the proportion of monounsaturated free fatty acids (C16:1 and C18:1) in the sebum. They also positively correlated with the interleukin (IL)‐36γ/IL‐37 ratio in the SC. Among the representative sebum lipids examined, oleic acid (C18:1, cis‐9) dose‐ and time‐dependently regulated the mRNA expression of IL‐36γ and IL‐37 in cultured keratinocytes, and this effect was attenuated by the N‐methyl‐D‐aspartate (NMDA)‐type glutamate receptor antagonist, MK801. Conclusions: Skin surface sebum may be related to cheek redness in healthy subjects, and oleic acid‐induced IL‐36γ through NMDA‐type glutamate receptors may be a link between them. Our study provides a possible skincare strategy for mitigating unfavorable increase in skin redness by targeting the facial skin sebum, particularly oleic acid. [ABSTRACT FROM AUTHOR]

Simple Summary: We evaluated the effectiveness of antlerless sika deer culling on sika deer population dynamics, based on the population trends in response to spatial variation of antlerless proportion in imposed culls. Deer populations tended to decrease in areas of higher antlerless culling, while they increased in areas of lower antlerless culling, suggesting that a high proportion of antlerless culling can effectively decrease the deer population. Because increasing large herbivore populations have caused environmental damage around the world, antlerless-biased culling could be a crucial measure to manage overabundant populations of herbivores. Increasing populations of large herbivores have caused environmental damage around the world, and it is necessary to improve population management strategies. Culling is a traditional management method. Antlerless deer proportions, consisting of adult female deer and fawn in Cervidae in wildlife statistics, are directly related to population increases; thus, the culling-based removal of individuals from habitats and the removal of these antlerless individuals by game hunting and nuisance control might be effective approaches for reducing population sizes. We evaluated the effectiveness of antlerless culling on 17-year density trends in the sika deer (Cervus nippon) population across an area of 1175 km2 in Fukuoka Prefecture (Japan). In 11 out of 47 grids (area measuring 5 by 5 km), the densities of sika deer tended to decline; meanwhile, in the remaining 36 grids, the densities increased. These density trends were explained by changes in the proportion of antlerless culling, as the densities declined with increasing proportions of antlerless deer. The results affirm the theory that antlerless culling is effective in population management; it is posited that antlerless-biased culling could be a crucial measure in managing overabundant populations of herbivores, contributing to more effective conservation of forest environments. [ABSTRACT FROM AUTHOR]

Lenvatinib is an approved therapy for advanced hepatocellular carcinoma (HCC). Recently, immune checkpoint inhibitors have been approved as frontline chemotherapies for HCC, and the tumor immune microenvironment (TIME) has been demonstrated to significantly affect HCC treatment. The neutrophil-to-lymphocyte ratio (NLR) is associated with the TIME, and the dynamics of the NLR are associated with prognosis or treatment efficacy in various cancer types. The present study investigated the dynamics of the TIME using the NLR in 101 patients with HCC treated with lenvatinib. Immunostaining for CD8+ tumor-infiltrating lymphocytes (TILs) was also performed in 9 patients who underwent liver tumor biopsy prior to subsequent chemotherapy for progression or discontinuation due to adverse events on lenvatinib treatment. The NLR values measured at the start of treatment (SOT), after 1 month of treatment and after 3 months of treatment were 2.78±2.20, 2.61±1.86 and 2.66±2.36, respectively (P=0.733). Among the patients with no reduction in the initial dose, there was no significant difference between the NLR after 1 month (2.34±0.25) and that at the SOT (2.86±2.33) (P=0.613). In patients who achieved a complete or partial response, the NLR at the time of the best tumor response was 1.65±0.56, which was significantly lower than that at the SOT (2.05±0.78) (P=0.023). In patients who did not respond to lenvatinib, the NLR at the time of disease progression was 3.68±3.19, which was significantly higher than that at the SOT (2.78±1.79) (P=0.043). Overall, 5 out of the 6 patients who did not respond to lenvatinib had low CD8+ TIL counts at disease progression. Although the present study included a limited number of patients, the NLR was associated with the therapeutic effects of lenvatinib. These findings suggest the potential of lenvatinib as an immunomodulator. [ABSTRACT FROM AUTHOR]

The population dynamics of mosquitoes in temperate regions are not as well understood as those in tropical and subtropical regions, despite concerns that vector-borne diseases may be prevalent in future climates. Aedes albopictus, a vector mosquito in temperate regions, undergoes egg diapause while overwintering. To assess the prevalence of mosquito-borne diseases in the future, this study aimed to simulate and predict mosquito population dynamics under estimated future climatic conditions. In this study, we tailored the physiology-based climate-driven mosquito population (PCMP) model for temperate mosquitoes to incorporate egg diapauses for overwintering. We also investigated how the incorporation of the effect of rainfall on larval carrying capacity (into a model) changes the population dynamics of this species under future climate conditions. The PCMP model was constructed to simulate mosquito population dynamics, and the parameters of egg diapause and rainfall effects were estimated for each model to fit the observed data in Tokyo. We applied the global climate model data to the PCMP model and observed an increase in the mosquito population under future climate conditions. By applying the PCMP models (with or without the rainfall effect on the carrying capacity of the A. albopictus), our projections indicated that mosquito population dynamics in the future could experience changes in the patterns of their active season and population abundance. According to our results, the peak population number simulated using the highest CO2 emission scenario, while incorporating the rainfall effect on the carrying capacity, was approximately 1.35 times larger than that predicted using the model that did not consider the rainfall effect. This implies that the inclusion of rainfall effects on mosquito population dynamics has a major impact on the risk assessments of mosquito-borne diseases in the future. [ABSTRACT FROM AUTHOR]

Non-invasive acquisition of mRNA data from the skin can be extremely useful for understanding skin physiology and diseases. Inspired by the holocrine process, in which the sebaceous glands secrete cell contents into the sebum, we focused on the possible presence of mRNAs in skin surface lipids (SSLs). We found that measurable levels of human mRNAs exist in SSLs, where the sebum protects them from degradation by RNases. The AmpliSeq transcriptome analysis was modified to measure SSL-RNA levels, and our results revealed that the SSL-RNAs predominantly comprised mRNAs derived from sebaceous glands, the epidermis, and hair follicles. Analysis of SSL-RNAs non-invasively collected from patients with atopic dermatitis revealed increased expression of inflammation-related genes and decreased expression of terminal differentiation-related genes, consistent with the results of previous reports. Further, we found that lipid synthesis-related genes were downregulated in the sebaceous glands of patients with atopic dermatitis. These results indicate that the analysis of SSL-RNAs is a promising strategy to understand the pathophysiology of skin diseases. Inoue et al develop a non-invasive method of analyzing human skin mRNA using RNA in skin surface lipids collected with oil-blotting films. The authors outline the validation of this methodology and describe an application to determine transcriptome in skin surface lipids in patients with atopic dermatitis versus healthy skin. [ABSTRACT FROM AUTHOR]

Background & Aims: Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) is a rare neuroendocrine neoplasm (NEN) comprising dual neuroendocrine and non-neuroendocrine components. Although the coexistence pattern of neuroendocrine and non-neuroendocrine components in definitive MiNEN is thought to overlap, there may be a coexistent pattern of both components, such as superficial carcinoma adjacent to NEN. The present study evaluated the histopathological findings of the coexistence pattern of superficial carcinomas adjacent to NENs in the esophagogastrointestinal tract. Methods: From 2000 to 2019, 35 serial NEN resections of the esophagus (n = 9), stomach (n = 3), and large intestine (n = 23), respectively, were performed at Gunma University Hospital. Borderline areas between NEN and resident superficial epithelium were observed in the 35 serial NEN cases as well as two additional cases from affiliated hospitals. Results: Among the 35 serial NEN samples, squamous cell carcinomatous/dysplastic components were identified 77.8% (7/9 cases) of esophageal NENs, and adenocarcinomatous areas were seen in 66.7% (2/3 cases) of gastric NENs and 26% (6/23 cases) of colorectal NENs. Thus, all superficial carcinomatous components adjacent to NENs were observed as squamous cell carcinoma/dysplasia in esophagus and adenocarcinoma in stomach and large intestine, which showed histological characteristics as the resident epithelial pattern in each organ. Conclusions: These findings suggested a potential "paratransformation" or "bystander effect" in resident epithelium by NENs. Thus, "bystander carcinogenesis" could be a pathogenic mechanism of resident epithelium transformation adjacent to NENs in the esophagogastrointestinal tract. [ABSTRACT FROM AUTHOR]

Previous studies have reported that hepatocellular carcinoma (HCC) harboring WNT/β-catenin mutations exhibits iso-high intensity by gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-MRI, i.e. EOB-MRI) during the hepatobiliary phase (HBP), thus indicating that EOB-MRI may help clinicians identify an immune exclusion class, which might not respond to treatment with immune checkpoint inhibitors. The present study analyzed the effi- cacy of lenvatinib for HCC with iso-high intensity during the HBP of EOB-MRI. Overall, 52 patients who underwent EOB-MRI for 140 HCC nodules were classified into iso-high-intensity and low-intensity groups during the HBP of EOB-MRI. The clinical and histological characteristics, and different responses to treatment of both groups were analyzed. The expression levels of β-catenin and glutamine synthetase, indicative of WNT/β-catenin mutations, were enhanced in the HCC with iso-high-intensity group. Nine patients had iso-high intensity, whereas 43 patients had low intensity. Tumor size was larger, and the levels of antagonist-II or vitamin K absence were higher in the iso-high-intensity group. Furthermore, 3/9 patients in the iso-high-intensity group had objective responses compared with 13/43 patients in the low-intensity group. Disease control was observed in 5/9 patients in the iso-high-intensity group and 26/43 patients in the low-intensity group. Median overall survival was 29.8 months for the iso-high-intensity group compared with 20.8 months for the low-intensity group. In the iso-high-intensity group, the median progression-free survival rate was 6.7 months compared with 5.6 months in the low-intensity group. No differences in best percentage change from baseline tumor size were observed in either group. Although few patients were included in this study, the present findings suggested that the efficacy of lenvatinib was unaffected by signal intensity during the HBP of EOB-MRI. [ABSTRACT FROM AUTHOR]

Ultraconserved regions (UCRs) are 481 genomic sequences with 100% identity across humans, rats, and mice. Increasing evidence suggests that non-coding RNAs transcribed from UCRs are involved in various diseases, especially cancers. The human transformer 2β gene (TRA2B) encodes a UCR (uc.138) that spans exon 2 and its neighboring introns. TRA2B4 RNA is the only transcript that contains the whole exon 2 among five spliced TRA2B RNA variants (TRA2B1-5). TRA2B4 is upregulated in colon cancer cell lines, although it is not translated to Tra2β protein because of its nuclear retention. Nevertheless, the clinical significance and biological functions of uc.138 in colon cancer cells remain unclear. In this study, RNA in situ hybridization showed that TRA2B4 was predominantly overexpressed in the nucleus of colon adenocarcinoma and adenoma. Overexpression of TRA2B4 in colon cancer HCT116 cells promoted cell proliferation by changing the expression of G2/M-related cell cycle regulators. Moreover, TRA2B4 increased migration and cell viability in a uc.138 sequence-dependent manner. TRA2B4 significantly enhanced tumorigenesis in vivo. Taken together, uc.138 encoded in TRA2B4 plays an oncogenic role in tumor progression and may become a potential biomarker and therapeutic target in colon cancer. [ABSTRACT FROM AUTHOR]

Meflin (Islr) expression has gained attention as a marker for mesenchymal stem cells, but its function remains largely unexplored. Here, we report the generation of Meflin-CreERT2 mice with CreERT2 inserted under the Meflin gene promoter to label Meflin-expressing cells genetically, thereby enabling their lineages to be traced. We found that in adult mice, Meflin-expressing lineage cells were present in adipose tissue stroma and had differentiated into mature adipocytes. These cells constituted Crown-like structures in the adipose tissue of mice after high-fat diet loading. Cold stimulation led to the differentiation of Meflin-expressing lineage cells into beige adipocytes. Thus, the Meflin-CreERT2 mouse line is a useful new tool for visualizing and tracking the lineage of Meflin-expressing cells. [ABSTRACT FROM AUTHOR]

To realize next-generation capacitor materials with novel absorption properties under unconventionally severe conditions, the present study estimates the Maxwell-Wagner relaxation via investigation on (Ta+Ga) co-doped rutile-type TiO 2 ceramics with changing the nominal proportions of penta-/tri-valent dopants and sintering temperatures. The key roles of Ta and Ga on resistivities in grains and grain boundaries are clarified by carefully discussing the temperature- and frequency-dependence of permittivity, Cole-Cole plots, and activation energies. It is deduced that a mean free path of charge carriers in grains is longer for a Ta-doped sample than (Ta+Ga) co-doped ones, while Ga-rich samples are more resistive. High-temperature sintering tends to result in less resistive samples due to the generation of oxygen vacancies or more active donor-like defects like Ta5+ and Ti3+ ions. For ideal Maxwell-Wagner properties on rutile-type TiO 2 , it is promising to optimize the conductive-core/insulative-shell structure by manufacturing Ta-rich grains and Ga-rich grain boundaries with low-temperature sintering. • The Maxwell-Wagner behavior of (Ta+Ga)-doped TiO 2 ceramics was systematically investigated. • Ratio of donor-like Ta and acceptor-like Ga are critical on electrical conduction and insulation. • Conductive-core/insulative-shell structure is promising for "dielectric absorbers." [ABSTRACT FROM AUTHOR]

Recombinant human soluble thrombomodulin alpha (rhTM) has been developed as an anticoagulant with anti-inflammatory activity. Notably, acetaminophen (APAP) -induced liver disease (AILI) is caused by direct metabolite-induced hepatotoxicity as well as hepatic hyper-coagulation. To evaluate the utility of anticoagulant for the treatment of AILI, rhTM was administered in a mouse AILI model and liver damage was analyzed. AILI was induced in 8-week-old mice by intraperitoneal injection of APAP. rhTM (20 mg/kg) or placebo was injected at the same time as APAP administration. Serum alanine aminotransferase, fibrin degradation products and high-mobility group box 1 levels were significantly decreased in the rhTM-treated group compared with the control group. Furthermore, rhTM reduced the necrotic area and fibrin deposition in liver sections. rhTM suppressed the mRNA expression of heme oxygenase-1, plasminogen activator inhibitor type-1, tissue factors, and inflammatory cytokines compared with the control group. rhTM did not change the hepatic GSH content at 2 h after APAP injection, but restored them at 4 h after the insult. rhTM ameliorated liver damage in mice with AILI, probably via the improvement in liver perfusion induced by it's anticoagulant acitivity, which can lead to the suppression of secondary liver damage. [ABSTRACT FROM AUTHOR]

Current antiviral therapies cannot achieve eradication of hepatitis B virus (HBV) and can reduce but not eliminate the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV infection. The present study aimed to identify the risk factors for HCC development by analyzing nucleoside analogue (NA)-treated patients as a retrospective cohort using fibrosis-4 index (FIB-4 index) as a non-invasive fibrosis marker. A total of 260 patients with HBV receiving NAs without a history of HCC between January 2001 and January 2021 were included in the present study. The incidence of HCC in patients with HBV during NA therapy and the factors contributing to HCC occurrence were identified using clinical characteristics and blood test results. Among the 260 patients, 40 patients (15.4%) developed HCC. Univariate and multivariate analysis showed that age [hazard ratio (HR), 1.03; P=0.045], male sex (HR, 3.14; P<0.01) and FIB-4 index at 6 months after NA treatment <1.95 (HR, 4.35; P<0.01) correlated with the incidence of HCC. The cumulative incidence of HCC in patients with FIB-4 index at 6 months after NA treatment >1.95 was significantly higher compared with that in patients with FIB-4 index ≤1.95 (P<0.01). Multivariate analysis in patients in which serum α-fetoprotein (AFP) level at 6 months after NA treatment was measured showed that FIB-4 index >1.95 (HR, 8.27; P=0.014) and serum AFP level >4 ng/ml (HR, 4.26; P=0.033) contributed to HCC occurrence. FIB-4 index at 6 months after NA treatment and serum AFP levels at 6 months after NA treatment were predictors for the development of HCC in patients with HBV during NA treatment. Further study of hepatocarcinogenesis during NA with a longer follow-up period and larger numbers of participants is required. [ABSTRACT FROM AUTHOR]

Atezolizumab plus bevacizumab and lenvatinib are approved frontline therapies for advanced hepatocellular carcinoma (HCC). Patients with advanced HCC continue to have a poor prognosis despite these therapeutic choices. Previous studies have reported CD8+ tumor-infiltrating lymphocytes (TILs) as a biomarker to predict responsiveness to systemic chemotherapy. The present study investigated whether evaluating CD8+ TILs by immunohistochemistry staining of liver tumor biopsy tissues could help predict the response of patients with HCC to atezolizumab plus bevacizumab and lenvatinib. In total, 39 patients with HCC who underwent liver tumor biopsy were classified into high and low CD8+ TILs groups and were then divided by therapy type. The clinical responses to treatment in both groups were evaluated for each therapy. There were 12 patients with high-level CD8+ TILs and 12 patients with low-level CD8+ TILs among those who received atezolizumab plus bevacizumab. An improved response rate was observed in the high-level group compared with the low-level group. The high-level CD8+ TILs group had a significantly longer median progression-free survival compared with the low-level group. Among the patients with HCC who received lenvatinib, five had high-level CD8+ TILs and 10 had low-level CD8+ TILs. There were no differences in response rate or progression-free survival between these groups. Although the present study included only a limited number of patients, the findings suggested that CD8+ TILs could be a biomarker for predicting response to systemic chemotherapy in HCC. [ABSTRACT FROM AUTHOR]

Symptomatic cerebral vasospasm after subarachnoid hemorrhage (SAH) is a significant cause of delayed cerebral ischemia that leads to poor outcomes. Selective intra-arterial administration of fasudil hydrochloride (IAF) has been adopted for its vasodilatory effect on spasm arteries to prevent delayed cerebral ischemia. However, its effect on clinical outcomes and predictive factors for good recovery are not fully understood. This study aimed to investigate the outcomes of selective IAF and identify predictive factors for good outcomes in patients with cerebral vasospasm after SAH.A retrospective study of 36 patients with cerebral vasospasm following SAH who underwent selective IAF at our institution between January 2014 and May 2022 was conducted. We evaluated the improvements in neurological findings before and after selective IAF. Statistical analyses were performed to determine factors associated with good outcomes.Selective IAF improved the neurological findings in 26 patients (72.2%). Pre-therapeutic absence of cerebral infarction in more than 1/3 of the spasm artery perfusion area was significantly associated with an improvement in neurological findings (p < 0.0001). Furthermore, there was a tendency for a good outcome when the age was younger (p = 0.093), and the spasm was limited to peripheral vessels (p = 0.065).Our study indicates that selective IAF has a promising effect in improving symptomatic vasospasm, except when a large cerebral infarction exists in the spasm artery perfusion area. Early consideration of selective IAF could be recommended once patients experience symptomatic cerebral vasospasm after SAH. [ABSTRACT FROM AUTHOR]

Genome integrity can be threatened by various endogenous or exogenous events. To counteract these stressors, the DNA damage response network contributes to the prevention and/or repair of genomic DNA damage and serves an essential function in cellular survival. DNA binding proteins are involved in this network. Recently, several RNA-binding proteins (RBPs) that are recruited to DNA damage sites have been shown to be direct players in the prevention or repair of DNA damage. In addition, non-coding RNAs, themselves, are involved in the RNA-mediated DNA repair system. Furthermore, RNA modification such as m6A methylation might also contribute to the ultraviolet-responsive DNA damage response. Accumulating evidence suggests that RNA metabolism is more deeply involved in diverse cellular functions than previously expected, and is also intricately associated with the maintenance of genome integrity. In this review, we highlight the roles of RBPs in the maintenance of genome integrity. [ABSTRACT FROM AUTHOR]

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase that phosphorylates and activates the apoptotic program through interaction with diverse downstream targets including tumor suppressor p53. HIPK2 is activated by genotoxic stimuli and modulates cell fate following DNA damage. The DNA damage response (DDR) is triggered by DNA lesions or chromatin alterations. The DDR regulates DNA repair, cell cycle checkpoint activation, and apoptosis to restore genome integrity and cellular homeostasis. Maintenance of the DDR is essential to prevent development of diseases caused by genomic instability, including cancer, defects of development, and neurodegenerative disorders. Recent studies reveal a novel HIPK2-mediated pathway for DDR through interaction with chromatin remodeling factor homeodomain protein 1γ. In this review, we will highlight the molecular mechanisms of HIPK2 and show its functions as a crucial DDR regulator. [ABSTRACT FROM AUTHOR]

Inflammatory angiogenesis is a critical process in tumor progression and other diseases. The inflammatory cytokine IL-1 promotes angiogenesis, tumor growth, and metastasis, but its mechanisms remain unclear. We examined the association between IL-1-induced angiogenesis and cell inflammation. IL-1 induced neovascularization in the mouse cornea at rates comparable to those of VEGF. Neutrophil infiltration occurred on day 2. Macrophage infiltration occurred on days 4 and 6. The anti-Gr-1 Ab-induced depletion of infiltrating neutrophils did not affect IL-1- or VEGF-induced angiogenesis. The former was reduced in monocyte chemoattractant protein-1-deficient (MCP-1-/-) mice compared with wild-type mice. After day 4, clodronate liposomes, which kill macrophages, reduced IL-1-induced angiogenesis and partially inhibited VEGF-induced angiogenesis. Infiltrating macrophages near the IL-1-induced neovasculature were COX-2 positive. Lewis lung carcinoma cells expressing IL-1 (LLC/IL-1) developed neovasculature with macrophage infiltration and enhanced tumor growth in wild-type but not MCP-1-/- mice. A COX-2 inhibitor reduced tumor growth, angiogenesis, and macrophage infiltration in LLC/IL-1. Thus, macrophage involvement might be a prerequisite for IL-1-induced neovascularization and tumor progression. [ABSTRACT FROM AUTHOR]

In multiple myeloma (MM), the interaction between myeloma cells and bone marrow microenvironment has an important role in the pathogenesis of MM. We first examined the inducing effect of myeloma cells on migration of human umbilical vein vascular endothelial cells (HUVECs). Five myeloma cell lines produced varying amounts of VEGF, and migration of HUVECs was induced by coculture with myeloma cells. We next examined the inhibitory effect of a novel synthetic retinoid Am80 (Tamibarotene) on both myeloma cells and HUVECs. Am80 is specific for the retinoic-acid receptor-a/ß, and has therapeutic effects in all-trans retinoic acid resistant acute promyelocytic leukemia. Am80 slightly inhibited the growth of both myeloma cells and HUVECs, and remarkably inhibited the growth of HUVECs stimulated by VEGF. Am80 showed little growth inhibition of bone marrow stromal cells (BMSCs), but it markedly inhibited migration of HUVECs by cocultured myeloma cells. Am80 inhibited VEGF-induced phosphorylation of VEGF receptor. In addition, VEGF-induced formation of tube-like structures in vitro and neovascularization in mouse corneas were significantly inhibited by Am80. These findings clearly demonstrate that Am80 is a potential inhibitor of angiogenesis caused by the interaction between vascular endothelial cells and myeloma cells, and might be a useful therapeutic agent against MM.Leukemia (2005) 19, 901-909. doi:10.1038/sj.leu.2403754 Published online 21 April 2005 [ABSTRACT FROM AUTHOR]

The sound produced by a dental air turbine handpiece (dental drill) can markedly influence the sound environment in a dental clinic. Indeed, many patients report that the sound of a dental drill elicits an unpleasant feeling. Although several manufacturers have attempted to reduce the sound pressure levels produced by dental drills during idling based on ISO 14457, the sound emitted by such drills under active drilling conditions may negatively influence the dental clinic sound environment. The physical metrics related to the unpleasant impressions associated with dental drill sounds have not been determined. In the present study, psychological measurements of dental drill sounds were conducted with the aim of facilitating improvement of the sound environment at dental clinics. Specifically, we examined the impressions elicited by the sounds of 12 types of dental drills in idling and drilling conditions using a semantic differential. The analysis revealed that the impressions of dental drill sounds varied considerably between idling and drilling conditions and among the examined drills. This finding suggests that measuring the sound of a dental drill in idling conditions alone may be insufficient for evaluating the effects of the sound. We related the results of the psychological evaluations to those of measurements of the physical metrics of equivalent continuous A-weighted sound pressure levels (LAeq) and sharpness. Factor analysis indicated that impressions of the dental drill sounds consisted of two factors: “metallic and unpleasant” and “powerful”. LAeq had a strong relationship with “powerful impression”, calculated sharpness was positively related to “metallic impression”, and “unpleasant impression” was predicted by the combination of both LAeq and calculated sharpness. The present analyses indicate that, in addition to a reduction in sound pressure level, refining the frequency components of dental drill sounds is important for creating a comfortable sound environment in dental clinics. [ABSTRACT FROM AUTHOR]

ARL-17477 is a selective neuronal nitric oxide synthase (NOS1) inhibitor that has been used in many preclinical studies since its initial discovery in the 1990s. In the present study, we demonstrate that ARL-17477 exhibits a NOS1-independent pharmacological activity that involves inhibition of the autophagy-lysosomal system and prevents cancer growth in vitro and in vivo. Initially, we screened a chemical compound library for potential anticancer agents, and identified ARL-17477 with micromolar anticancer activity against a wide spectrum of cancers, preferentially affecting cancer stem-like cells and KRAS-mutant cancer cells. Interestingly, ARL-17477 also affected NOS1-knockout cells, suggesting the existence of a NOS1-independent anticancer mechanism. Analysis of cell signals and death markers revealed that LC3B-II, p62, and GABARAP-II protein levels were significantly increased by ARL-17477. Furthermore, ARL-17477 had a chemical structure similar to that of chloroquine, suggesting the inhibition of autophagic flux at the level of lysosomal fusion as an underlying anticancer mechanism. Consistently, ARL-17477 induced lysosomal membrane permeabilization, impaired protein aggregate clearance, and activated transcription factor EB and lysosomal biogenesis. Furthermore, in vivo ARL-17477 inhibited the tumor growth of KRAS-mutant cancer. Thus, ARL-17477 is a dual inhibitor of NOS1 and the autophagy-lysosomal system that could potentially be used as a cancer therapeutic. [ABSTRACT FROM AUTHOR]

Atezolizumab plus bevacizumab therapy has high response rates in patients with advanced hepatocellular carcinoma (HCC). It has been reported that HCC with immune exclusion associated with the signal activation of WNT/β-catenin is resistant to immune checkpoint inhibitors; however, to the best of our knowledge, the effectiveness of atezolizumab plus bevacizumab for HCC with WNT/β-catenin signal activation has not been reported. The present study aimed to analyze the efficacy of atezolizumab plus bevacizumab for HCC with WNT/β-catenin signal activation. A total of 24 patients who underwent liver tumor biopsy for HCC were classified into WNT/β-catenin signal activation and inactivation groups according to the expression levels of β-catenin and glutamine synthetase, which are indicative of WNT/β-catenin signal activation. The differences in the clinical responses to treatment between the groups were analyzed. A total of 15 patients had HCC with WNT/β-catenin signal activation, whereas 9 patients had HCC with WNT/β-catenin signal inactivation. There were no significant differences between both groups regarding objective responses (P=0.519) and disease control (P=0.586). In the WNT/β-catenin signal activation group, the median progression-free survival rate was 6.9 months compared with 6.2 months in the WNT/β-catenin signal inactivation group (P=0.674). Although a small number of patients was included in the present study, the present findings suggested that the efficacy of atezolizumab plus bevacizumab might be unaffected by WNT/β-catenin signal activation. [ABSTRACT FROM AUTHOR]

Homeodomain-interacting protein kinase 2 (HIPK2) is a potential tumor suppressor that has a crucial role in the DNA damage response (DDR) by regulating cell-cycle checkpoint activation and apoptosis. However, it is unclear whether HIPK2 exerts distinct roles in DNA damage repair. The aim of this study was to identify novel target molecule(s) of HIPK2, which mediates HIPK2-dependent DNA damage repair. HIPK2-knockdown human colon cancer cells (HCT116) or hipk1/hipk2 double-deficient mouse embryonic fibroblasts could not remove histone H2A.X phosphorylated at Ser139 (γH2A.X) after irradiation with a sublethal dose (10 J/m2) of ultraviolet (UV)-C, resulting in apoptosis. Knockdown of HIPK2 in p53-null HCT116 cells similarly promoted the UV-C-induced γH2A.X accumulation and apoptosis. Proteomic analysis of HIPK2-associated proteins using liquid chromatography-tandem mass spectrometry identified heterochromatin protein 1γ (HP1γ) as a novel target for HIPK2. Immunoprecipitation experiments with HCT116 cells expressing FLAG-tagged HIPK2 and one of the HA-tagged HP1 family members demonstrated that HIPK2 specifically associated with HP1γ, but not with HP1α or HP1β, through its chromo-shadow domain. Mutation of the HP1box motif (883-PTVSV-887) within HIPK2 abolished the association. HP1γ knockdown also enhanced accumulation of γH2A.X and apoptosis after sublethal UV-C irradiation. In vitro kinase assay demonstrated an HP1γ-phosphorylating activity of HIPK2. Sublethal UV-C irradiation phosphorylated HP1γ. This phosphorylation was absent in endogenous HIPK2-silenced cells with HIPK2 3'UTR siRNA. Overexpression of FLAG-HIPK2, but not the HP1box-mutated or kinase-dead HIPK2 mutant, in the HIPK2-silenced cells increased HP1γ binding to trimethylated (Lys9) histone H3 (H3K9me3), rescued the UV-C-induced phosphorylation of HP1γ, triggered release of HP1γ from histone H3K9me3 and suppressed γH2A.X accumulation. Our results suggest that HIPK2-dependent phosphorylation of HP1γ may participate in the regulation of dynamic interaction between HP1γ and histone H3K9me3 to promote DNA damage repair. This HIPK2/HP1γ pathway may uncover a new functional aspect of HIPK2 as a tumor suppressor. [ABSTRACT FROM AUTHOR]

RNA-binding proteins and microRNAs are potent post-transcriptional regulators of gene expression. Human transformer 2β (Tra2β) is a serine/arginine-rich-like protein splicing factor and is now implicated to have wide-ranging roles in gene expression as an RNA-binding protein. RNA immunoprecipitation (RIP) with an anti-Tra2β antibody and microarray analysis identified a subset of Tra2β-associated mRNAs in HCT116 human colon cancer cells, many of which encoded cell death-related proteins including Bcl-2 (B-cell CLL/lymphoma 2). Tra2β knockdown in HCT116 cells decreased Bcl-2 expression and induced apoptosis. Tra2β knockdown accelerated the decay of BCL2α mRNA that encodes Bcl-2 and full-length 3′ UTR, while it did not affect the stability of BCL2β mRNA having a short, alternatively spliced 3′ UTR different from BCL2α 3′ UTR. RIP assays with anti-Tra2β and anti-Argonaute 2 antibodies, respectively, showed that Tra2β bound to BCL2α 3′ UTR, and that Tra2β knockdown facilitated association of miR-204 with BCL2α 3′ UTR. The consensus sequence (GAA) for Tra2β-binding lies within the miR-204-binding site of BCL2 3′ UTR. Mutation of the consensus sequence canceled the binding of Tra2β to BCL2 3′ UTR without disrupting miR-204-binding to BCL2 3′ UTR. Transfection of an anti-miR-204 or introduction of three-point mutations into the miR-204-binding site increased BCL2 mRNA and Bcl-2 protein levels. Inversely, transfection of precursor miR-204 reduced their levels. Experiments with Tra2β-silenced or overexpressed cells revealed that Tra2β antagonized the effects of miR-204 and upregulated Bcl-2 expression. Furthermore, TRA2β mRNA expression was significantly upregulated in 22 colon cancer tissues compared with paired normal tissues and positively correlated with BCL2 mRNA expression. Tra2β knockdown in human lung adenocarcinoma cells (A549) increased their sensitivity to anticancer drugs. Taken together, our findings suggest that Tra2β regulates apoptosis by modulating Bcl-2 expression through its competition with miR-204. This novel function may have a crucial role in tumor growth. [ABSTRACT FROM AUTHOR]

RNA interference (RNAi) has emerged as a powerful tool for studying target identification and holds promise for the development of therapeutic gene silencing. Recent advances in RNAi delivery and target selection provide remarkable opportunities for translational medical research. The induction of RNAi relies on small silencing RNAs, which affect specific messenger RNA (mRNA) degradation. Two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications. Lung cancer is still the leading cause of cancer death worldwide, for which novel therapeutic strategies are critically needed. Recently, we have reported a novel platform (PnkRNA™ and nkRNA®) to promote naked RNAi approaches through inhalation without delivery vehicles in lung cancer xenograft models. We suggest that a new class of RNAi therapeutic agent and local drug delivery system could also offer a promising RNAi-based strategy for clinical applications in cancer therapy. In this article, we show recent strategies for an RNAi delivery system and suggest the possible clinical usefulness of RNAi-based therapeutics for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Adoptive cell transfer (ACT) is a type of personalized immunotherapy in which expanded immune cells are administered to patients with cancer. However, single-cell populations, such as killer T cells, dendritic cells, natural killer (NK) cells, and NKT (NKT) cells, have been generally used, and their effectiveness remains limited. Here, we established a novel culture method via CD3/CD161 co-stimulation and successfully expanded CD3+/CD4+ helper T cells, CD3+/CD8+ cytotoxic T cells (CTLs), CD3−/CD56+ NK cells, CD3+/CD1d+ NKT cells, CD3+/CD56+ NKT cells, CD3+/TCRγδ+ T cells, and CD3−/CD11c+/HLA-DR+ dendritic cells in peripheral blood mononuclear cells from healthy donors; their respective numbers were 155.5, 1132.5, 5.7, 117.0, 659.2, 325.6, and 6.8 times higher than those before expansion. These mixed immune cells showed strong cytotoxicity against cancer cell lines Capan-1 and SW480. Moreover, both CD3+/CD8+ CTLs and CD3+/CD56+ NKT cells killed tumor cells in cell contact-dependent and -independent manners via granzyme B and interferon-γ/TNF-α, respectively. Furthermore, the cytotoxicity of the mixed cells was significantly superior to that of CTLs or NKTs alone. A bet-hedging CTL-NKT circuitry is one potential mechanism underlying this cooperative cytotoxicity. Collectively, CD3/CD161 co-stimulation may be a promising culture method to expand multiple, distinct immune cell populations for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related deaths. Biomarkers for lung cancer have raised great expectations in their clinical applications for early diagnosis, survival, and therapeutic responses. MicroRNAs (miRNAs), a family of short endogenous noncoding RNAs, play critical roles in cell growth, differentiation, and the development of various types of cancers. Current studies have shown that miRNAs are present in the extracellular spaces, packaged into various membrane-bound vesicles. Tumor-specific circulating miRNAs have been developed as early diagnostic biomarkers for lung cancer. Remarkably, some studies have succeeded in discovering circulating miRNAs with prognostic or predictive significance. Extracellular vesicles (EVs), such as exosomes and microvesicles, are recognized as novel tools for cell-cell communication and as biomarkers for various diseases. Their vesicle composition and miRNA content have the ability to transfer biological information to recipient cells and play an important role in cancer metastasis and prognosis.This review provides an in-depth summary of current findings on circulating miRNAs in lung cancer patients used as diagnostic biomarkers.We also discuss the role of EV miRNAs in cell-cell communication and explore the effectiveness of these contents as predictive biomarkers for cancer malignancy. [ABSTRACT FROM AUTHOR]

The baiu rainband is a summer rainband stretching from eastern China through Japan toward the northwestern Pacific. The climatological termination of the baiu rainband is investigated using the Japanese 25-yr Reanalysis (JRA-25), a stand-alone atmospheric general circulation model (GCM) forced with observed sea surface temperature (SST) and an atmosphere-ocean GCM (AOGCM). The baiu rainband over the North Pacific abruptly shifts northward and weakens substantially in early July in the atmospheric GCM (AGCM), too early compared to observations (late July). The midtroposphere westerly jet and its thermal advection explain this meridional shift of the baiu rainband, but the ocean surface evaporation modulates the precipitation intensity. In AGCM, deep convection in the subtropical northwestern Pacific sets in prematurely, displacing the westerly jet northward over the cold ocean surface earlier than in observations. The suppressed surface evaporation over the cold ocean suppresses precipitation even though the midtropospheric warm advection and vertically integrated moisture convergence are similar to those before the westerly jet's northward shift. As a result, the baiu rainband abruptly weakens after the northward shift in JRA-25 and AGCM. In AOGCM, cold SST biases in the subtropics inhibit deep convection, delaying the poleward excursion of the westerly jet. As a result, the upward motion induced by both the strong westerly jet and the rainband persist over the northwestern Pacific through summer in the AOGCM. The results indicate that the westerly jet and the ocean evaporation underneath are important for the baiu rainband, the latter suggesting an oceanic effect on this important phenomenon. [ABSTRACT FROM AUTHOR]

Abstract: The band gap and disordered structure in Li8GeN4 (lattice constant: 9.622Å) are studied by optical absorption, photoacoustic spectroscopy, X-ray diffraction, and Raman scattering spectroscopy. Li8GeN4 is a semiconductor with the band gap of 2.61eV, suggesting the transition from the N-2p valence band to the conduction band mainly consisting of Ge-4s and/or -4p orbitals. A broad Raman peak is observed at 530cm−1, indicating the homogenously random distribution of Li and Ge atoms. A possible distribution of Li and Ge is proposed. Li8GeN4 crystallizes in a superstructure of eight face-centered N sublattices. In each sublattice, one Li and one Ge atoms are randomly and diagonally occupied at two tetrahedral sites next to N, while six Li atoms reside at the other six tetrahedral sites next to N. The possible locations of one remaining Li atom are also discussed. [Copyright &y& Elsevier]

The article discusses isolation of invertebrate (i)-type lysozyme from Meretrix lusoria, scientific name of common orient clam to determine structure and functional relationships of invertebrate lysozymes. Topics discussed include determination of amino acid sequence of two isozymes, lytic activities of lysozyme and examination of hen-egg lysozyme (HFL). It also mentions that effect of sodium chloride (NaCl) on lytic and chitinase activity.

The predictability of explosive cyclones over the northwestern Pacific region is investigated using an ensemble reanalysis dataset. Explosive cyclones are categorized into two types according to whether the region of the most rapid development is in the Sea of Okhotsk or Sea of Japan (OJ) or in the northwestern Pacific Ocean (PO). Cyclone-relative composite analyses are performed for analysis increments (the differences between the analysis and the 6-h forecast) and ensemble spreads (the standard deviations of ensemble members of the analysis or first guess) at the time of the maximum deepening rate. The increment composite shows that the OJ explosive cyclone center is forecast too far north compared to the analyzed center, whereas the PO explosive cyclone is forecast shallower than the analyzed center. To understand the cause of these biases, a diagnosis of the increment using the Zwack-Okossi (Z-O) development equation is conducted. The results suggest that the increment characteristics of both the OJ and PO explosive cyclones are associated with the most important cyclone development mechanisms. The OJ explosive cyclone forecast error is related to a deeper upper trough, whereas the PO explosive cyclone error is related to weaker latent heat release in the model. A diagnosis of the spread utilizing the Z-O development equation clarifies the mechanism underlying the uncertainty in the modeled sea level pressure. For OJ explosive cyclones, the spread of adiabatic warming causes substantial sea level pressure spreading southwest of the center of the cyclones. For PO explosive cyclones, the latent heat release causes substantial sea level pressure spreading around the cyclone center. [ABSTRACT FROM AUTHOR]

To evaluate the structure-function relationships of invertebrate lysozymes, a new invertebrate-type (i-type) lysozyme was isolated from the common orient clam ( Meretrix lusoria) and the tertiary structure of this enzyme was determined. Comparison of the tertiary structure of this enzyme with those of chicken and Venerupi philippinarum lysozymes revealed that the location of the side chain of the second catalytic residue, an aspartic acid, and the N-acetylglucosamine trimer bound at subsites A- C were different. Furthermore, the amino acid electrostatically interacting with Asp30 in V. philippinarum lysozyme, Lys108, was substituted by Gly in M. lusoria lysozyme and no other possible amino acid that could contribute to this interaction was found in M. lusoria lysozyme. It therefore seems that the substitutions of the amino acids at the interface of the V. philippinarum lysozyme dimer are likely to change the oligomeric state of the M. lusoria lysozyme. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play key roles in regulation of cellular processes in response to changes in environment. In this study, we examined alterations in miRNA profiles in peripheral blood from 25 male medical students two months and two days before the National Examination for Medical Practitioners. Blood obtained one month after the examination were used as baseline controls. Levels of seven miRNAs (miR-16, -20b, -26b, -29a, -126, -144 and -144*) were significantly elevated during the pre-examination period in association with significant down-regulation of their target mRNAs (WNT4, CCM2, MAK, and FGFR1 mRNAs) two days before the examination. State anxiety assessed two months before the examination was positively and negatively correlated with miR-16 and its target WNT4 mRNA levels, respectively. Fold changes in miR-16 levels from two days before to one month after the examination were inversely correlated with those in WNT4 mRNA levels over the same time points. We also confirmed the interaction between miR-16 and WNT4 3′UTR in HEK293T cells overexpressing FLAG-tagged WNT4 3′UTR and miR-16. Thus, a distinct group of miRNAs in periheral blood may participate in the integrated response to chronic academic stress in healthy young men. [ABSTRACT FROM AUTHOR]

Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate many processes of cellular metabolism, including transcriptional control, translational control, mRNA processing and localization. Nuclear factor 90 (NF90), one of the DSRBPs, is abundantly expressed in vertebrate tissue and participates in many aspects of RNA metabolism. NF90 was originally purified as a component of a DNA binding complex which binds to the antigen recognition response element 2 in the interleukin 2 promoter. Recent studies have provided us with interesting insights into its possible physiological roles in RNA metabolism, including transcription, degradation, and translation. In addition, it was shown that NF90 regulates microRNA expression. In this review, we try to focus on the function of NF90 in posttranscriptional gene regulation and microRNA biogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Soil liquefaction is a devastating geotechnical phenomenon associated with earthquakes that causes failure of foundations, soil embankments and dams, especially in cities built on young alluvial deposits. Therefore, the ability to predict liquefaction potential is important and valuable for seismic hazard assessment. The conventional approach to evaluating liquefaction potential at any given point is through the use of borehole data. The liquefaction potentials within sedimentary basins vary over short distances with local soil properties. The purpose of this paper is to evaluate liquefaction potentials at unsampled locations where borehole data are not available based on the measured liquefaction potentials at selected borehole locations. The application and the importance of the geostatistical analytical technique (kriging method) for the estimation of liquefaction potential at unsampled locations are shown. The data set consists of liquefaction potential values measured at 86 randomly distributed boreholes in Saitama City, Japan. With the use of calculated liquefaction potentials at sampled locations, the experimental semivariograms were constructed. The experimental variogram characterizes the spatial variability of the calculated liquefaction potential. To interpolate the liquefaction potential over the entire area, the ordinary kriging spherical model was applied. In applying the kriging method, both isotropic and anisotropic models were used; however, the anisotropic model exhibited a better fit for interpolating sedimentary deposits. The interpolated liquefaction potentials are validated with the measured liquefaction potentials of an independently collected second set of 41 boreholes. The interpolated liquefaction potentials show strong concurrence with the measured values. [Copyright &y& Elsevier]

Objective--To examine the distribution of water in hoof wall specimens of horses via nuclear magnetic resonance (NMR) microscopy and determine changes in water distribution during hydration. Sample--4 hoof wall specimens (2 obtained from the dorsum and 1 each obtained from the lateral quarter and lateral heel regions) of the stratum medium of healthy hooves of 1 horse. Procedures--Equine hoof wall specimens were examined via NMR microscopy. Proton density-weighted 3-D images were acquired. Changes during water absorption were assessed on sequential images. Results--The inner zone of the stratum medium had higher signals than did the outer zone. Areas of high signal intensity were evident in transverse images; these corresponded to the distribution of horn tubules. During water absorption, the increase in signal intensity started at the bottom of a specimen and extended to the upper region; it maintained the localization pattern observed before hydration. The relationship between the local maximal signals in areas corresponding to the horn tubules and minimal signal intensities in areas corresponding to the intertubular horn was similar and maintained approximately a linear distribution. Conclusions and Clinical Relevance--Based on the premise that signal intensity reflects water content, hydration in the equine hoof wall during water absorption occurred concurrently in the tubules and intertubular horn, and there was maintenance of the original water gradients. This technique can be applied for the assessment of pathophysiologic changes in the hoof wall on the basis of its hydration properties. [ABSTRACT FROM AUTHOR]

To illuminate brittle and ductile fracturing of magma, we investigated bubble expansion and fracturing in two contrasting fluids: a Maxwell‐type viscoelastic fluid and a Bingham‐type yield‐strength fluid. Measurements of the complex shear modulus, G′ + iG″ (i is the imaginary unit), under small‐strain oscillation showed that both fluids are elastic (G′ > G″) with similar rigidity. Viscous behavior (G′ < G″) appeared at lower frequency in the Maxwell fluid but at larger strain in the Bingham fluid. When we injected air into the Maxwell fluid, bubbles expanded viscously at low flux, fractured in a brittle manner at high flux, and behaved transitionally at intermediate flux. In contrast, we observed no fracturing in the Bingham fluid. This demonstrates that the G′ > G″ condition is insufficient to infer that brittle fracturing can occur. Brittle fracturing of the Maxwell fluid occurred not at a critical strain rate but under decreasing strain rate and increasing stress. Plain Language Summary: The flow‐to‐fracture transition of magma is an essential process controlling eruption explosivity. This transition has been explained based on the linear Maxwell viscoelastic model: magma can flow slowly but breaks in a brittle manner under rapid deformation. The Bingham model represents another type of fluid‐solid transition: a material flows under a sufficiently large force but behaves elastically below this force. The present study investigates bubble growth and fracture by air injection in Maxwell‐type and Bingham‐type fluids, both having similar elasticity. We demonstrate that brittle fracture occurs in the Maxwell fluid at high air flux but never in the Bingham fluid. Detailed observations of the deformation until brittle fracture reveals a stress increase and strain rate decrease. The fracture onset is not determined by the critical strain rate, contrary to conventional brittle fragmentation criteria widely used in volcanology. These results will help improve brittle‐ductile transition models for complex fluids in volcanic eruptions. Key Points: Rapid air injection generated brittle fracture in a Maxwell fluid but not in a Bingham fluid, although they have similar elasticityThe observation of elasticity in small‐amplitude oscillation tests is not sufficient to infer that the fluid can fractureThe strain rate around a bubble decreased toward fracture, contrary to the conventional critical strain‐rate fracture criterion [ABSTRACT FROM AUTHOR]

A variety of 3-substituted benzisoxazoles were reduced with hydrogen using the chiral ruthenium catalyst, {RuCl(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl. The ruthenium-catalyzed hydrogenation proceeded in high yield in the presence of an acylating agent, affording α-substituted o-hydroxybenzylamines with up to 57% ee. In the catalytic transformation, the N-O bond of the benzisoxazole substrate is reductively cleaved by the ruthenium complex under the hydrogenation conditions. The C-N double bond of the resulting imine is saturated stereoselectively through the PhTRAP-ruthenium catalysis. The hydrogenation produces chiral primary amines, which may work as catalytic poisons, however, the amino group of the hydrogenation product is rapidly acylated when the reaction is conducted in the presence of an appropriate acylating agent, such as Boc2O or Cbz-OSu. [ABSTRACT FROM AUTHOR]

The lymph transports tissue-resident dendritic cells (DCs) to regional lymph nodes (LNs), having important roles in immune function. The biological effects on tissue inflammation following lymphatic flow obstruction in vivo, however, are not fully known. In this study, we investigated the role of the lymphatic system in contact hypersensitivity (CHS) responses using k-cyclin transgenic (kCYC+/−) mice, which demonstrate severe lymphatic dysfunction. kCYC+/− mice showed enhanced ear swelling to both DNFB and FITC, as well as stronger irritant responses to croton oil compared with wild-type littermates. Consistently, challenged ears of kCYC+/− mice exhibited massive infiltrates of inflammatory cells. In contrast, DC migration to regional LNs, drainage of cell-free antigen to LNs, antigen-specific IFN-γ production, and lymphocyte proliferation were impaired during the sensitization phase of CHS in kCYC+/− mice. Transfer experiments using lymphocytes from sensitized mice and real-time PCR analysis of cytokine expression using challenged ear revealed that ear swelling was enhanced because of impaired lymphatic flow. Collectively, we conclude that insufficient lymphatic drainage augments apparent inflammation to topically applied allergens and irritants. The findings add insight into the clinical problem of allergic and irritant contact dermatitis that commonly occurs in humans with peripheral edema of the lower legs. [ABSTRACT FROM AUTHOR]

Electrokinetic phenomena are believed to be the most likely origin of electromagnetic signals preceding or accompanying earthquakes. The intensity of the source current due to the electrokinetic phenomena is determined by the fluid flux and the electrokinetic coupling coefficient called streaming current coefficient; therefore, how the coefficient changes before rupture is essential. Here, we show how the electrokinetic coefficients change during the rock deformation experiment up to failure. The streaming current coefficient did not increase before failure, but continued to decrease up to failure, which is explained in terms of the elastic closure of capillary. On the other hand, the streaming potential coefficient, which is the product of the streaming current coefficient and bulk resistivity of the rock, increased at the onset of dilatancy. It may be due to change in bulk resistivity. Our result indicates that the zeta potential of the newly created surface does not change so much from that of the preexisting fluid rock interface. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder. [ABSTRACT FROM AUTHOR]

The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC. [ABSTRACT FROM AUTHOR]

The precipitation response to sea surface temperature (SST) gradients associated with the Gulf Stream is investigated using an atmospheric general circulation model. Forced by observed SST, the model simulates a narrow band of precipitation, surface convergence, and evaporation that closely follows the Gulf Stream, much like satellite observations. Such a Gulf Stream rainband disappears in the model when the SST front is removed by horizontally smoothing SST. The analysis herein shows that it is convective precipitation that is sensitive to SST gradients. The Gulf Stream anchors a convective rainband by creating surface wind convergence and intensifying surface evaporation on the warmer flank. Deep convection develops near the Gulf Stream in summer when the atmosphere is conditionally unstable. As a result, a narrow band of upward velocity develops above the Gulf Stream throughout the troposphere in summer, while it is limited to the lower troposphere in other seasons. [ABSTRACT FROM AUTHOR]

RNA-binding proteins (RBPs) and microRNAs (miRNAs) are potent post-transcriptional regulators of gene expression. Here, we show that the RBP HuR reduced c-Myc expression by associating with the c-Myc 3′ untranslated region (UTR) next to a miRNA let-7-binding site. Lowering HuR or let-7 levels relieved the translational repression of c-Myc. Unexpectedly, HuR and let-7 repressed c-Myc through an interdependent mechanism, as let-7 required HuR to reduce c-Myc expression and HuR required let-7 to inhibit c-Myc expression. Our findings suggest a regulatory paradigm wherein HuR inhibits c-Myc expression by recruiting let-7-loaded RISC (RNA miRNA-induced silencing complex) to the c-Myc 3'UTR. [ABSTRACT FROM AUTHOR]

We previously observed that nitric oxide (NO) exposure increases the stability of mRNAs encoding heme oxygenase 1 (HO-1) and TIEG-1 in human and mouse fibroblasts. Here, we have used microarrays to look broadly for changes in mRNA stability in response to NO treatment. Using human IMR-90 and mouse NIH 3T3 fibroblasts treated with actinomycin D to block de novo transcription, microarray analysis suggested that the stability of the majority of mRNAs was unaffected. Among the mRNAs that were stabilized by NO treatment, seven transcripts were found in both IMR-90 and NIH 3T3 cells (CHIC2, GADD45B, HO-1, PTGS2, RGS2, TIEG, and ID3) and were chosen for further analysis. All seven mRNAs showed at least one hit of a signature motif for the stabilizing RNA-binding protein (RBP) HuR; accordingly, ribonucleoprotein immunoprecipitation analysis revealed that all seven mRNAs associated with HuR. In keeping with a functional role of HuR in the response to NO, a measurable fraction of HuR increased in the cytoplasm following NO treatment. However, among the seven transcripts, only HO-1 mRNA showed a robust increase in the level of its association with HuR following NO treatment. In turn, HO-1 mRNA and protein levels were significantly reduced when HuR levels were silenced in IMR-90 cells, and they were elevated when HuR was overexpressed. In sum, our results indicate that NO stabilizes mRNA subsets in fibroblasts, identify HuR as an RBP implicated in the NO response, reveal that HuR alone is insufficient for stabilizing several mRNAs by NO, and show that HO-1 induction by NO is regulated by HuR. [ABSTRACT FROM AUTHOR]

Phytic acid acts as the major storage form of phosphorus in plant seeds and is poorly digested by monogastric animals. The degradation of phytic acid in animal diets is necessary to overcome both environmental and nutritional issues. The enzyme 1d- myo-inositol 3-phosphate [Ins(3)P1] synthase (EC 5.5.1.4) catalyses the first step of myo-inositol biosynthesis and directs phytic acid biosynthesis in seeds. The rice Ins(3)P1 synthase gene ( RINO1) is highly expressed in developing seed embryos and in the aleurone layer, where phytic acid is synthesized and stored. In rice seeds, 18-kDa oleosin (Ole18) is expressed in a seed-specific manner, and its transcripts are restricted to the embryo and the aleurone layer. Therefore, to effectively suppress phytic acid biosynthesis, antisense RINO1 cDNA was expressed under the control of the Ole18 promoter, directing the same spatial pattern in seeds as RINO1 in transgenic rice plants. The generated transgenic rice plants showed strong ‘low phytic acid’ (lpa) phenotypes, in which seed phytic acid was reduced by 68% and free available phosphate was concomitantly increased. No negative effects on seed weight, germination or plant growth were observed. The available phosphate levels of the stable transgenic plants surpassed those of currently available rice lpa mutants. [ABSTRACT FROM AUTHOR]

The Gulf Stream transports large amounts of heat from the tropics to middle and high latitudes, and thereby affects weather phenomena such as cyclogenesis and low cloud formation. But its climatic influence, on monthly and longer timescales, remains poorly understood. In particular, it is unclear how the warm current affects the free atmosphere above the marine atmospheric boundary layer. Here we consider the Gulf Stream’s influence on the troposphere, using a combination of operational weather analyses, satellite observations and an atmospheric general circulation model. Our results reveal that the Gulf Stream affects the entire troposphere. In the marine boundary layer, atmospheric pressure adjustments to sharp sea surface temperature gradients lead to surface wind convergence, which anchors a narrow band of precipitation along the Gulf Stream. In this rain band, upward motion and cloud formation extend into the upper troposphere, as corroborated by the frequent occurrence of very low cloud-top temperatures. These mechanisms provide a pathway by which the Gulf Stream can affect the atmosphere locally, and possibly also in remote regions by forcing planetary waves. The identification of this pathway may have implications for our understanding of the processes involved in climate change, because the Gulf Stream is the upper limb of the Atlantic meridional overturning circulation, which has varied in strength in the past and is predicted to weaken in response to human-induced global warming in the future. [ABSTRACT FROM AUTHOR]

Numerical simulations of six explosively developing extratropical cyclones in the northwestern Pacific Ocean region are conducted using a regional mesoscale numerical model [the fifth-generation Pennsylvania State University–National Center for Atmospheric Research Mesoscale Model (MM5)]. Cyclones are categorized according to the locations where they form and develop: Okhotsk–Japan Sea (OJ) cyclones originate over the eastern Asian continent and develop over the Sea of Japan or the Sea of Okhotsk, Pacific Ocean–land (PO–L) cyclones also form over the Asian continent and develop over the northwestern Pacific Ocean, and Pacific Ocean–ocean (PO–O) cyclones form and develop over the northwestern Pacific Ocean. Two cases (the most extreme and normal deepening rate cases for each cyclone type) are selected and simulated. Simulations show that the extreme cyclone of each type is characterized by a different mesoscale structure and evolutionary path, which strongly reflect the larger-scale environment: an OJ cyclone has the smallest deepening rates, associated with a distinct upper-level shortwave trough, a clear lower-level cold front, and a precipitation area that is far from the cyclone center; a PO–L cyclone has moderate deepening rates with high propagation speeds under zonally stretched upper-level jets; and a PO–O cyclone has the strongest deepening rates associated with large amounts of precipitation near its center. Sensitivity experiments involving the latent heat release associated with water vapor condensation show that PO–O cyclones rarely develop without a release of latent heat and their structures are drastically different from the control runs, while OJ cyclones exhibit almost the same developments and have similar structures to the control runs. These tendencies can be seen in both extreme and normal deepening rate cases. These results reveal that the importance of latent heat release to explosive cyclone development varies among the cyclone types, as is reflected by the cyclone origin, frontal structure, moisture distribution, and jet stream configuration. [ABSTRACT FROM AUTHOR]

An HTS magnet for a Superconducting Maglev, consisting of four persistent current HTS coils, was developed. The HTS coils are installed in a cryostat, and cooled to approximately 15 K by conduction cooling, using two sets of two-stage GM type pulse tube cryocoolers. The HTS magnet is operated in a persistent current mode at a rated magneto-motive force of 750 kA. The running tests were executed on the Yamanashi Maglev Test Line, with a top speed of 553 km/h achieved on December 2, 2005. The test result demonstrated that the HTS coils generated no excessive vibration or heat load. [ABSTRACT FROM AUTHOR]