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Biogenic Mn oxides are reactive and ubiquitous in many Earth surface environments, yet their role in radionuclide sequestration at U mill-tailings sites still require an improved understanding at the nano- and molecular-scales. This study concerns the uptake of Ba, utilized as a safe and chemically appropriate surrogate for radioactive Ra, by biogenic Mn oxides produced by a fungal species, Coprinopsis urticicola, isolated from the mine water of the Ningyo-toge U mine, Okayama, Japan. The biogenic Mn oxides were identified as birnessite nanocrystals O binding to the newly overlying MnO6 layer during coprecipitation. Static desorption experiments for 7 days reveal that the steady-state release rate of adsorbed Ba is ∼1.4 times faster than that of the coprecipitated Ba, when the Ba concentration in the initial loading solution was ∼10–8 mol/L, indicating that the release of intercalated (coprecipitation) Ba to solution is retarded. The present study demonstrates the importance of fungus-generated Mn oxides as an efficient absorber of Ba2+, and likely Ra2+, among soil compounds in U mill-tailings. This may be applicable to other contaminated sites due to the ubiquitous occurrence of fungi in the environment.

In the present work, the multiple-indicator dilution (MID) technique was used to investigate the kinetic mechanisms by which nickel (Ni2+) affects the calcium (Ca2+) transport in intact rat liver. 45Ca2+ and extra- and intracellular space indicators were injected in livers perfused with 1 mM Ni2+, and the outflow profiles were analyzed by a mathematical model. For comparative purposes, the effects of norepinephrine were measured. The influence of Ni2+ on the cytosolic Ca2+ concentration ([Ca2+]c) in human hepatoma Huh7 cells and on liver glycogen catabolism, a biological response sensitive to cellular Ca2+, was also evaluated. The estimated transfer coefficients of 45Ca2+ transport indicated two mechanisms by which Ni2+ increases the [Ca2+]c in liver under steady-state conditions: (1) an increase in the net efflux of Ca2+ from intracellular Ca2+ stores due to a stimulus of Ca2+ efflux to the cytosolic space along with a diminution of Ca2+ re-entry into the cellular Ca2+ stores; (2) a decrease in Ca2+ efflux from the cytosolic space to vascular space, minimizing Ca2+ loss. Glycogen catabolism activated by Ni2+ was transient contrasting with the sustained activation induced by norepinephrine. Ni2+ caused a partial reduction in the norepinephrine-induced stimulation in the [Ca2+]c in Huh7 cells. Our data revealed that the kinetic parameters of Ca2+ transport modified by Ni2+ in intact liver are similar to those modified by norepinephrine in its first minutes of action, but the membrane receptors or Ca2+ transporters affected by Ni2+ seem to be distinct from those known to be modulated by norepinephrine. Graphic abstract: [Figure not available: see fulltext.]

Background Lichen sclerosus (LS) is an acquired inflammatory mucocutaneous disease affecting the anogenital area, characterized histologically by hyalinosis and thickened vessel walls in the dermis. The presence of serum autoantibodies against extracellular matrix protein 1 (ECM1) in LS patients may suggest its involvement in disease pathogenesis. Objective To examine if reduced ECM1 production by dermal fibroblasts contributes to the pathogenic features of LS. Methods Gene expression in ECM1 knockdown human dermal fibroblasts was analyzed by cDNA microarray. Functional enrichment for genes involved in cellular functions was conducted. Protein expression was analyzed by ELISA and confocal laser scanning microscopy using LS skin. Results Microarray analysis identified 3,035 differentially expressed genes in ECM1 knockdown cells, wherein 1,471 were upregulated genes related exclusively to cell adhesion, proliferation, apoptosis, intracellular signaling, and extracellular matrix organization. Further narrowing with criteria specific for localization and function of ECM1 identified 48 upregulated genes identified to have structural, fibrogenic, and carcinogenic properties. Of these, laminin-332 and collagen-IV displayed altered immunolabeling within the basement membrane zone (BMZ) and dermal vessels in LS skin, similar to that of collagen-VII, which exhibited unchanged transcription levels in ECM1-knockdown fibroblasts. Collagen-VII bound to recombinant ECM1 in a solid-phase immunoassay and colocalized with ECM1 in the skin BMZ. Further, ECM1-knockdown fibroblasts exhibited a marked delay in cell migration and gel contraction. Conclusion In the absence of ECM1 expression in fibroblasts there is selective dysregulation and disassembly of structural and extracellular matrix molecules, which may result in microstructural abnormalities reminiscent of LS.

Patients with adipsic hypernatremia present with chronic hypernatremia because of defects in thirst sensation and dysregulated salt appetite, without demonstrable hypothalamic structural lesions. The involvement of autoantibodies directed against the sodium channel, Na(x) in the subfornical organ (SFO) has recently been reported. However, the pathophysiology of water and electrolyte imbalance underlying the disease has yet to be elucidated. We describe the case of a 5-year-old boy who complained of headaches and vomiting that gradually worsened. Brain magnetic resonance imaging detected no abnormal lesions. Blood laboratory testing revealed a serum sodium (Na) concentration of 152 mmol/L and a serum osmolarity of 312 mOsm/L. His body weight had slightly decreased, and his thirst sensation was absent. His plasma vasopressin concentration was 0.9 pg/mL, despite the high serum osmolarity. He was encouraged to drink water, and oral 1-deamino-8-D-arginine-vasopressin was administered. When serum sodium concentrations were normalized, plasma vasopressin concentrations were apparently normal and ranged from 0.8 to 2.0 pg/mL. He did not present with polyuria at any time. Immunohistochemical study using mouse brain sections and the patient’s serum revealed the deposition of human immunoglobulin G (IgG) antibody in the mouse SFO. In conclusion, our observations suggested that water and electrolyte imbalance in adipsic hypernatremia is characterized by a certain amount of vasopressin release regardless of serum sodium concentrations with no response to hyperosmolarity.

The amphibian populations have faced a drastic decline over the past decades. This decline has been associated with the presence of contaminants in the environment, among other environmental stressors. The present study tested the responses following the exposure to lithium (2.5 mg L−1) and selenium (10μg L−1), both isolated and as a mixture, on the metabolic status of the tail muscle of premetamorphic American bullfrog (Lithobates catesbeianus) through the assessment of the total protein content, mobilization of glucose and triglycerides, and the activity of lactate dehydrogenase (LDH). The exposure followed a 21-day assay with two sampling periods (on the 7th and 21st day after the onset of exposure) to evaluate the effects over time. The group exposed to the mixture presented a statistically decreased LDH activity (P 0.05). The total protein content did not show any statistical difference in the treated groups throughout the experiment (P > 0.05). The presented results highlight the importance of the assessment of mixtures that can occur in the environment, since the combination of contaminants may elicit distinct toxicity compared with the effects triggered by the chemicals isolated.

Objective We assessed the effect of canagliflozin, an sodium-glucose co-transporter type-2 inhibitor, on hepatic steatosis using three imaging modalities: magnetic resonance imaging (MRI), computed tomography, and transient elastography. We further determined factors associated with improving hepatic steatosis by canagliflozin among patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods We conducted a six-month prospective single-arm study between August 2015 and June 2017. The primary outcome was the change in hepatic steatosis assessed using the hepatic proton density fat fraction (PDFF) on MRI before and after treatment with canagliflozin. The secondary outcomes were changes in measures of glucose metabolism, including the hepatic glucose uptake on fluorodeoxyglucose-positron emission tomography, and the inflammation and volumes of visceral and subcutaneous adipose tissue and skeletal muscle. Patients Nine patients with type 2 diabetes and NAFLD completed this study. All participants received canagliflozin at a dose of 100 mg daily. Results Canagliflozin caused a significant reduction in hepatic PDFF from baseline [median 20.6% (interquartile range 11.7%, 29.8%)] after 6 months [10.6% (5.4%, 22.6%), p=0.008]. Canagliflozin also significantly reduced the body weight, glycated hemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hs-CRP), and volumes of adipose tissue and skeletal muscle (all p

Ferrihydrite, a hydrous ferric oxide, is ubiquitous in silica-rich mine drainage sites, although some uncertaity remains concerning its nanoscale texture and colloidal properties such as its association with amorphous silica and reactions with contaminant metals. To understand the mechanisms of natural attenuation of contaminants governed by ferrihydrite and amorphous silica aggregations, mine tailings material from the Ningyo-toge uranium deposit, Japan, has been investigated in detail utilizing many traditional solution and mass spectroscopy methods, as well as synchrotron-based methods the latest in FIB- and analytic TEM-based technologies. At this site, the past mining activity results in slightly acidic mine drainage and the contamination of a mill tailings pond with relatively high concentrations of toxic elements, including U, As, and Ra. We have systematically investigated the geochemistry of water, colloids, and sediments from the groundwater draining the former mine site (now remediated), down gradient to the mill tailings pond where the water pH remains ∼6.2. Groundwater with 0.18 mg/L dissolved oxygen (DO) is oxygenated rapidly to levels of 1.65 mg/L DO when exposed to the atmosphere along this flow path. Dissolved Fe2+ is oxidized instantly to form ferrihydrite nanoparticle aggregates > 200 nm in diameter, adsorbing ∼67% of the total As (3.36 µmol/L) in solution. For solutions and particles/aggregates passing through 200-nm filters, ∼17% of the 1.17 µmol/L As is sorbed on these smaller ferrihydrite aggregates. Simultaneously, varying amounts of amorphous silica with particle sizes as small as several nanometers were observed to adsorb onto ferrihydrite aggregates. Arsenic is present predominantly as arsenate, As(V), and preferentially adsorbs to ferrihydrite within these ferrihydrite–amorphous silica aggregates. Arsenate adsorption is not inhibited by silica adsoption on ferrihydrite when the Si/Fe composition is ∼0.25. Uranium is also adsorbed onto aggregates of colloids. After 24 h of static exposure to the ambient atmosphere, the zeta potential of the aggregate that formed in oxygenated water decreases from −16 to −24 mV, near the zeta potential of pure silica, potentially leading to increased colloidal stability. Some large-sized aggregates are deposited at the bottom of the collecting well and slowly adsorb minor amounts of Mn (1.45 wt.%); other aggregates are transported to the mill tailings pond downsteam, where the water is further oxidized (DO = 3.09 mg/L), and deposited onto the sediment together with birnessite, a hydrated Mn-oxide that appears to be biogenic in this case. During sedimentation, associations of amorphous silica within the aggregate play a key role in retaining the ferrihydrite structure that adsorbs toxic elements such as As. Consequently, the mechanism of natural attenuation at the nanoscale constrained by the chemical and physical properties of ferrihydrite–amorphous silica aggregates is of critical importance in the Ningyo-toge mill tailing site. It is shown that it is also important in other mine drainage and mill tailings sites due to the ubiquitous and dominant occurrence of both Si and Fe in these types of settings.

Ti-Pd alloy catalysts were developed for the cross β-arylmethylation between arylmethylalcohols and different primary alcohols via a hydrogen autotransfer mechanism. The alloy catalysts could be reused multiple times without the need for pre-activation. Analysis of the reaction solution by inductively coupled plasma atomic absorption spectroscopy indicated that only a minimal amount of Ti and no Pd was leached from the catalyst.

Homologous genes for the peptidoglycan precursor flippase MurJ, and peptidoglycan hydrolases: lytic transglycosylase MltB, and DD-carboxypeptidase VanY are required for chloroplast division in the moss Physcomitrella patens. The moss Physcomitrella patens is used as a model plant to study plastid peptidoglycan biosynthesis. In bacteria, MurJ flippase transports peptidoglycan precursors from the cytoplasm to the periplasm. In this study, we identified a MurJ homolog (PpMurJ) in the P. patens genome. Bacteria employ peptidoglycan degradation and recycling pathways for cell division. We also searched the P. patens genome for genes homologous to bacterial peptidoglycan hydrolases and identified genes homologous for the lytic transglycosylase mltB, N-acetylglucosaminidase nagZ, and LD-carboxypeptidase ldcA in addition to a putative DD-carboxypeptidase vanY reported previously. Moreover, we found a ß-lactamase-like gene (Pplactamase). GFP fusion proteins with either PpMltB or PpVanY were detected in the chloroplasts, whereas fusion proteins with PpNagZ, PpLdcA, or Pplactamase localized in the cytoplasm. Experiments seeking PpMurJ-GFP fusion proteins failed. PpMurJ gene disruption in P. patens resulted in the appearance of macrochloroplasts in protonemal cells. Compared with the numbers of chloroplasts in wild-type plants (38.9 ± 4.9), PpMltB knockout and PpVanY knockout had lower numbers of chloroplasts (14.3 ± 6.7 and 28.1 ± 5.9, respectively). No differences in chloroplast numbers were observed after PpNagZ, PpLdcA, or Pplactamase single-knockout. Chloroplast numbers in PpMltB/PpVanY double-knockout cells were similar to those in PpMltB single-knockout cells. Zymogram analysis of the recombinant PpMltB protein revealed its peptidoglycan hydrolase activity. Our results imply that PpMurJ, PpMltB and PpVanY play a critical role in chloroplast division in the moss P. patens.

Aims/Introduction Tofogliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3‐year prospective observational post‐marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J‐STEP/LT]). Materials and Methods This surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward. Results Of 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion‐related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were −0.68 ± 1.34% (n = 6,158, P, Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term was a 3‐year, prospective, observational and post‐marketing study of patients who received tofogliflozin, a sodium–glucose cotransporter 2 inhibitor, in usual clinical practice in Japan. There were no unprecedented adverse drug reactions. Reductions from baseline in HbA1c and bodyweight were maintained over the observation period.

Background We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen. Patients and Methods Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m2/day), doxorubicin (10 mg/m2/day), and vincristine (0.4 mg/m2/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m2/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert’s formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6. Results In 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed Conclusion The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.

Aims/Introduction Tofogliflozin is a potent and highly selective sodium–glucose cotransporter 2 inhibitor, and is currently used to treat patients with type 2 diabetes mellitus. We designed a 3‐year study of tofogliflozin in patients with type 2 diabetes mellitus to evaluate the safety and effectiveness in routine clinical practice. The 3‐ and 12‐month interim analysis showed tofogliflozin was well‐tolerated, safe and clinically effective. Here, we report the results of the 24‐month interim analysis. Materials and Methods This is a 3‐year prospective, observational and multicenter post‐marketing study (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term). Results Of the 6,897 patients enrolled, 6,712 and 6,461 patients were analyzed for the safety and effectiveness of tofogliflozin, respectively. During the 24‐month observation period, the incidence rates of adverse drug reactions (ADRs) and serious adverse drug reactions were 11.25 and 1.21%, respectively. As to adverse drug reactions of special interest, the incidence rates of hypoglycemia, polyuria/pollakiuria, volume depletion‐related events, urinary tract infections and genital infection were 0.83, 1.28, 1.46, 1.18 and 1.62%, respectively. Renal disorders, and cardiovascular and cerebrovascular disorders occurred in 0.63 and 0.76% of the patients, respectively. Glycated hemoglobin A1c and bodyweight decreased significantly by −0.70% (P, Significant safety concerns have not been observed and clinical benefit including a long‐term reduction in glycated hemoglobin A1c over a 104‐week (24 months) observation period with weight loss was suggested in this 24‐month interim analysis of the 3‐year Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term study in routine clinical practice.

Although intermediate filaments (IFs) are biochemically and immunologically suggested to exist in plant cells, there are few molecular genetic studies related to the proteins that form these structures. In this study, Arabidopsis AT3G05270 was selected as a candidate gene for a protein constituting IF in plant cells. The protein encoded by AT3G05270 has a large α-helix as well as the IF protein motif indispensable for maintaining the structures of IF. Moreover, fluorescence signals of this protein fused with GFP exhibited cytoskeleton-like filamentous structures in plant cells. Thus, we named the protein encoded by AT3G05270 as Intermediate Filament Motif Protein 1 (IFMoP1). The structures composed of IFMoP1 and their localizations were examined in IFMoP1-GFP-expressing tobacco BY-2 cells whose cell cycle was synchronized using aphidicolin, a DNA synthesis inhibitor, and propyzamide, a microtubule-disrupting agent. The IFMoP1-GFP signals were present at the spindles and phragmoplasts in the mitotic phase. In addition, the frequency of cells with cytoskeleton-like filamentous structures composed of IFMoP1-GFP increased with the increase in cells that completed cell division, and then decreased after several hours. In terms of the relationship in intracellular localization between IFMoP1 and microtubules, the filamentous structures composed of IFMoP1 were present independently of microtubules during interphase. In living cells, these filamentous structures moved along with the nucleus. IFMoP1 co-localized with spindle and phragmoplast microtubules during mitosis, as well as with a part of the cortical microtubules in interphase.

Aims/Introduction This subanalysis aimed to assess the safety and effectiveness of tofogliflozin by using data from the Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly to categorize elderly Japanese patients with type 2 diabetes mellitus by the number of concomitant oral antidiabetic drugs (OADs) and insulin use at baseline. Materials and Methods Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly is a 1‐year prospective, observational and multicenter post‐marketing study that enrolled all patients with type 2 diabetes mellitus aged ≥65 years who started tofogliflozin during the first 3 months after its launch in May 2014 in Japan. Results The safety and effectiveness analysis sets included 1,497 and 1,422 patients, respectively. Overall, 18.10 and 2.20% of the patients experienced adverse drug reactions (ADRs) and serious ADRs, respectively. ADRs of special interest in the total, 0 OAD, one OAD, two OADs, three or more OADs and insulin groups occurred in 12.22, 10.04, 12.35, 13.32, 11.27 and 14.91% of patients, respectively. Volume depletion‐related events were the most frequently observed ADRs of special interest. Hypoglycemia occurred in 1.07% of patients. Overall, glycated hemoglobin and bodyweight were significantly decreased, but the estimated glomerular filtration rate was not significantly changed. Conclusions Our finding suggests that tofogliflozin could be safely and effectively used in elderly Japanese patients with type 2 diabetes mellitus, irrespective of the number of OADs and the use of insulin., This subanalysis suggests that tofogliflozin could be safely and effectively used in elderly Japanese patients with type 2 diabetes mellitus in a real‐world clinical setting irrespective of the numbers of oral antidiabetic drugs and insulin use.

The foaming of an A1050 precursor was performed using only the frictional heat generated during the traversing of a friction stir processing (FSP) tool on a steel plate. In this study, the experimental conditions during FSP were optimized for relatively high melting point A1050 precursor. For tool traversing speeds of 10 mm/min and 20 mm/min, the A1050 precursor was successfully foamed, where the precursor gradually foamed during the traversing of the tool. However, too much heat was generated, which resulted in excess heat input, in the case of tool traversing speed of 10 mm/min, whereas there was less excess heat input in the case of tool traversing speed of 20 mm/min. Large pores were observed owing to the coalescence of pores, which may have induced the release of gas from the top surface of the Al foam during foaming, decreasing the porosity of the obtained Al foam. In the case of tool traversing speed of 30 mm/min, the latter half of the Al foam was sufficiently foamed and fine pores were observed, although the first half of the precursor was not foamed. Moreover, it was indicated that a uniform temperature distribution during FSP is necessary to obtain uniform pore structures, which may be achieved by gradually increasing the tool traversing speed. The use of a steel plate with lower thermal conductivity was effective for foaming the precursor, which may introduce too much heat into the precursor with less heat diffusion.

Rolled sheets may turn up or down after passing the roll gap. The curling occurs under asymmetric conditions, e.g., different roll speeds, diameters, frictions, etc. Even under apparently symmetric conditions, the curling incidentally occurs in hot rolling. In this study, low carbon sheets with controlled upper and lower oxide scale were hot-rolled with 15% reduction in thickness. The rolled sheets always curled toward the side with thin oxide scale and that severe curling occurred when upper and lower oxide scales deformed differently. It is concluded that surface oxide scale is a hidden factor to cause curling in hot steel rolling.

Sake and shochu are traditional alcoholic beverages in Japan. Sake is a fermented beverage made from rice, whereas shochu is a distilled liquor made from rice, barley, sweet potato, or other raw materials. The various types of shochu have characteristic flavours derived from their main fermentation material. A common feature of sake- and shochu-making is the use of koji—a substance made by culturing Aspergillus spp. on rice or other grains—as an enzyme source instead of malt. During fermentation, enzymes from koji hydrolyse starch and the resulting glucose is simultaneously fermented by yeast. This fermentation style, as well as the low water content in the fermentation mash and the characteristics of sake and shochu yeast, produces a high concentration of alcohol after fermentation. As a result, shochu is made through a single distillation. These two liquors have an important place in the consumption of alcoholic beverages in Japan; their exports are still small but increasing.

BackgroundSystemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by myofibroblasts. Myofibroblasts may be derived from epithelial and endothelial precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that can disrupt the differentiation of dermal fibroblasts into myofibroblasts. This compound was originally generated as a curcumin derivative. MethodsIn this study, we investigated the effect of LG283 on inhibiting fibrosis and vascular injury. The action of LG283 on TGF-β-dependent fibrogenic activity, epithelial mesenchymal transition (EMT), and endothelial cell mesenchymal transition (EndoMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model.ResultsLG283 suppressed TGF-β-induced ECM expression, Smad3 phosphorylation, and expression of transcription factors responsible for the mesenchymal transition, Snail 1 and 2, in cultured human dermal fibroblasts. LG283 was also found to block EMT and EndoMT in cultured human epithelial cells and endothelial cells, respectively. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and vascular injury without affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of phosphorylated Smad3 in the bleomycin-injected skin. Increased expression of Snail 1 and 2 were reduced by LG283 treatment in the mouse model. ConclusionsThe LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-β/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for treatment of SSc. Furthermore, the screening of EMT and/or EndoMT regulatory compounds may be an attractive approach for SSc therapy.

Calcium molybdate nanoparticles were synthesized using a liposome based on egg phosphatidylcholine and cholesterol. The molybdate ion was encapsulated into the liposome, and then a calcium chloride...

In this report, micropatterns of (3-aminopropyl)trimethoxysilane (APTMS) were developed on hydrophilic and hydrophobic surfaces after patterning using 172 nm vacuum ultraviolet (VUV) photolithography. Self-assembled monolayers (SAMs) formed on Si substrates through UV hydrosilylation of 1-hexadecene (HD) and 10-undecenoic acid (UDA) were used as hydrophilic and hydrophobic surfaces, respectively. For templating the HD- and UDA-SAMs, the VUV light was exposed to HD- and UDA-SAMs from the slits of photomasks in atmospheric and evacuated environments, respectively. Various oxygenated groups were generated at the exposed domains of HD-SAM, while the COOH groups were trimmed from the irradiated domains of UDA-SAM. The APTMS molecules were immobilized on the domains that were terminated by oxygenated groups after chemical vapor deposition (CVD). The thicknesses of the developed APTMS micropatterns increased significantly by raising the CVD temperature and in the presence of ambient air in the CVD Teflon container as well. The increase in thicknesses was ascribed to the formation of APTMS multilayers, which were mediated by H3N+ ions. Also, the developed APTMS micropatterns on the UDA-SAM patterned by VUV light irradiation in a high-vacuum environment (HV-VUV) were thicker than those on the VUV/(O) patterned HD-SAM due to the presence of inactive oxygenated groups at the surface of VUV/(O)-terminated domains of HD-SAM such as COO-C and C-O-C groups. The presence of water or ambient air facilitated the silane coupling between the silyl groups with the oxygenated and amino groups The combination of VUV photolithography and the CVD method with control of the conditions would enable us to control the thicknesses and shapes of the developed APTMS micropatterns. These findings illustrate the applicability of VUV photolithography for templating hydrophobic and hydrophobic surfaces toward the development of organosilane architectures, which can be feasible for several applications.

Background We established an adipogenic progenitor cell line derived from mature adipocytes and named these cells dedifferentiated fat (DFAT) cells, which have been shown to have characteristics very similar to those of mesenchymal stem cells (MSCs). The potential application of DFAT cells to support cell-based therapies for regenerative and immunosuppressive therapies has been suggested. The present study was designed to address beneficial ways that DFAT implantation can be used clinically as immunosuppressive therapy to treat immunological glomerulonephritis. Methods We evaluated distribution of DFAT cells after intravenous injection through the tail vein in Wistar rats. We examined effects of allogenic implantation of DFAT cells on BrdU incorporation into kidney from rats with monoclonal antibody (mAb) 1-22-3-induced glomerulonephritis. We compared effects of allogenic and autogenic implantations of DFAT cells on excretion of urinary protein, renal function, and glomerular and nephrotubular injuries in these rats, and serum levels of tumor necrosis factor-stimulated gene-6 (TSG-6), and expression of TSG-6 mRNA in kidney. Results The allogenic implantations of DFAT cells trapped in lung improved excretion of urinary protein and renal function, and significantly suppressed glomerular and nephrotubular injuries in the rats with mAb1-22-3-induced glomerulonephritis compared with the autogenic implantations. The allogenic implantation of DFAT cells increased serum levels of TSG-6 especially in mAb 1-22-3-induced glomerulonephritis and significantly increased the expression of TSG-6 mRNA in kidney compared to the autogenic implantation. Conclusion These findings suggest that allogenic implantation of DFAT cells could be clinically useful immunosuppressive therapy for immunological glomerulonephritis.

Human T-cell leukemia virus type 1 (HTLV-1) infects target cells primarily through cell-to-cell routes. Here, we provide evidence that cellular protein M-Sec plays a critical role in this process. When purified and briefly cultured, CD4+ T cells of HTLV-1 carriers, but not of HTLV-1- individuals, expressed M-Sec. The viral protein Tax was revealed to mediate M-Sec induction. Knockdown or pharmacological inhibition of M-Sec reduced viral infection in multiple co-culture conditions. Furthermore, M-Sec knockdown reduced the number of proviral copies in the tissues of a mouse model of HTLV-1 infection. Phenotypically, M-Sec knockdown or inhibition reduced not only plasma membrane protrusions and migratory activity of cells, but also large clusters of Gag, a viral structural protein required for the formation of viral particles. Taken together, these results suggest that M-Sec induced by Tax mediates an efficient cell-to-cell viral infection, which is likely due to enhanced membrane protrusions, cell migration, and the clustering of Gag., Author summary In the present study, we identified the cellular protein M-Sec as a host factor necessary for de novo infection of human T-cell leukemia virus type 1 (HTLV-1), the causative retrovirus of an aggressive blood cancer known as adult T-cell leukemia/lymphoma. The inhibition or knockdown of M-Sec in infected cells resulted in a reduced viral infection in several culture models and a mouse model. We recently demonstrated a similar role of M-Sec in macrophages infected with another human retrovirus HIV-1, but it has been generally thought that M-Sec is not related to HTLV-1 infection because of the lack of its expression in CD4+ T cells, the major target of HTLV-1. In this study, we revealed that CD4+ T cells of HTLV-1 asymptomatic carriers, but not those of HTLV-1- individuals, expressed M-Sec, and that the viral protein Tax mediated the induction of M-Sec. Thus, M-Sec is a new and useful tool for further understanding the process of HTLV-1 transmission.

The accumulation of glycosaminoglycans (GAGs) in bone and cartilage leads to progressive damage in cartilage that, in turn, reduces bone growth by the destruction of the growth plate, incomplete ossification, and growth imbalance. The mechanisms of pathophysiology related to bone metabolism in mucopolysaccharidoses (MPS) include impaired chondrocyte function and the failure of endochondral ossification, which leads to the release of inflammatory cytokines via the activation of Toll-like receptors by GAGs. Although improvements in the daily living of patients with MPS have been achieved with enzyme replacement, treatment for the bone disorder is limited. There is an increasing need to identify biomarkers related to bone and cartilage to evaluate the progressive status and to monitor the treatment of MPS. Recently, new analysis methods, such as proteomic analysis, have identified new biomarkers in MPS. This review summarizes advances in clinical bone metabolism and bone biomarkers.

Purpose Occupational exposure to antineoplastic drugs in hospital settings is recognized to be hazardous, and as such environmental decontamination including degradation and inactivation of such drugs is recommended. To data, although various agents such as oxidants have been reported to be useful for decontamination, simpler, safer, and more convenient methods are required. In this study, the degradation and inactivation efficacy of ozone water, which has newly been introduced for decontamination of antineoplastic drugs in spills, was investigated for formulations of gemcitabine, irinotecan, and paclitaxel. Methods Antineoplastic formulations (medicinal ingredient: ∼1.5 μmol) were mixed with 50 mL of ozone water (>4 mg/L). The reactions were monitored by high-performance liquid chromatography, and the degradation mixtures were analyzed by 1H nuclear magnetic resonance spectroscopy in order to obtain the structural information of the degradation products. The formulations of gemcitabine and irinotecan and those degradation mixtures were evaluated for their mutagenicity using the Ames test and cytotoxicity against human cancer cells. Results gemcitabine and irinotecan were found to be readily degraded by the ozone treatment, and their active sites were suggested to be degraded. In contrast, paclitaxel was hard to be decomposed, possibly owing to the consumption of ozone by the polyoxyethylene castor oil added as a pharmaceutical additive of the formulation. No significant mutagenic changes of Salmonella typhimurium strains used for the Ames test were observed for the samples within the concentration ranges examined. The ozone treatment showed obvious increases in cell viability for gemcitabine formulation, and mild increases for irinotecan formulation. Conclusions Ozone water was shown to be effective as a decomposition agent for the antineoplastic drug formulations examined, although the efficacy depends on the chemical structures of the drugs and the pharmaceutical additives. It was also suggested that ozone treatment has a tendency to decrease the toxicity of the antineoplastic drug formulations. As such, further studies are required in order to clarify the effects and application limitations of ozone water.

The use of genetically modified (GM) mesenchymal stromal cells (MSCs) and preconditioned MSCs (pMSCs) may provide further opportunities to improve the outcome of core decompression (CD) for the treatment of early-stage osteonecrosis of the femoral head (ONFH). GM interleukin-4 (IL4) over-expressing MSCs (IL4-MSCs), platelet-derived growth factor (PDGF)-BB over-expressing MSCs (PDGF-BB-MSCs), and IL4-PDGF-BB co-over-expressing MSCs (IL4-PDGF-BB-MSCs) and their respective pMSCs were used in this in vitro study and compared with respect to cell proliferation and osteogenic differentiation. IL4-MSCs, PDGF-BB-MSCs, IL4-PDGF-BB-MSCs, and each pMSC treatment significantly increased cell proliferation compared to the MSC group alone. The percentage of Alizarin red-stained area in the IL4-MSC and IL4-pMSC groups was significantly lower than in the MSC group. However, the percentage of Alizarin red-stained area in the PDGF-BB-MSC group was significantly higher than in the MSC and PDGF-BB-pMSC groups. The percentage of Alizarin red-stained area in the IL4-PDGF-BB-pMSC was significantly higher than in the IL4-PDGF-BB-MSC group. There were no significant differences in the percentage of Alizarin red-stained area between the MSC and IL4-PDGF-BB-pMSC groups. The use of PDGF-BB-MSCs or IL4-PDGF-BB-pMSCs increased cell proliferation. Furthermore, PDGF-BB-MSCs promoted osteogenic differentiation. The addition of GM MSCs may provide a useful supplementary cell-based therapy to CD for treatment of ONFH.

Hospital preparations are frequently prepared in Japanese hospitals when ready-made formulations to meet patients' needs are unavailable. Although the quality of hospital preparations have to be ensured for efficacy and safety, such quality evaluation tends to be insufficient mainly due to lack of manpower and experimental environments in hospitals. In this paper, we investigated the applicability of quantitative (q)NMR spectroscopy to the quality control of diclofenac gargles as examples of hospital preparations, as it has various merits for the quantitative analysis of mixtures in solutions. Diclofenac gargles are composed of diclofenac, tranexamic acid, and lidocaine, and are used for the pain relief of stomatitis induced by cancer chemotherapy. Aliquots of the gargles, which were prepared five times, were mixed with dimethylsulfone as an internal standard, followed by qNMR measurements. Water signal suppression was achieved using a pulse program, water suppression enhanced through T1 effects, because the pulse program was superior to other ones such as presaturation and one-dimensional nuclear Overhauser effect spectroscopy in terms of quantitativeness. Concentrations of the three medicinal ingredients were simultaneously determined based on the signals selected by considering the spectral separation and the quantitativeness. Consequently, the gargles were found to be prepared with constant quality, and were stable at room temperature for at least four weeks. qNMR is considered to be potentially useful for the quality control of various hospital preparations because of minimal sample pretreatments, lack of need of calibration curves, and its comprehensive detection abilities.

Neonatal screening (NS) for methylmalonic acidemia uses propionylcarnitine (C3) as a primary index, which is insufficiently sensitive at detecting methylmalonic acidemia caused by defects in the adenosylcobalamin synthesis pathway. Moreover, homocystinuria from cystathionine β-synthase deficiency is screened by detecting hypermethioninemia, but methionine levels decrease in homocystinuria caused by defects in homocysteine remethylation. To establish NS detection of methylmalonic acidemia and homocystinuria of these subtypes, we evaluated the utility of indices (1) C3 ≥ 3.6 μmol/L and C3/acetylcarnitine (C2) ≥ 0.23, (2) C3/methionine ≥ 0.25, and (3) methionine &lt, 10 μmol/L, by retrospectively applying them to NS data of 59,207 newborns. We found positive results in 116 subjects for index (1), 37 for (2), and 15 for (3). Second-tier tests revealed that for index 1, methylmalonate (MMA) was elevated in two cases, and MMA and total homocysteine (tHcy) were elevated in two cases, for index 2 that MMA was elevated in one case, and for index 3 that tHcy was elevated in one case. Though data were anonymized, two cases identified by index 1 had been diagnosed with maternal vitamin B12 deficiency during NS. Methylene tetrahydrofolate reductase deficiency was confirmed for the case identified by index 3, which was examined because an elder sibling was affected by the same disease. Based on these data, a prospective NS study is underway.

Dietary palmitic acid (PA) promotes liver fibrosis in patients with nonalcoholic steatohepatitis (NASH). Herein, we clarified the intestinal absorption kinetics of dietary PA and effect of trans-portal PA on the activation of hepatic stellate cells (HSCs) involved in liver fibrosis in NASH. Blood PA levels after meals were significantly increased in patients with NASH compared to those in the control. Expression of genes associated with fat absorption and chylomicron formation, such as CD36 and MTP, was significantly increased in the intestine of NASH model rats compared with that in the controls. Plasma levels of glucagon-like peptide-2, involved in the upregulation of CD36 expression, were elevated in NASH rats compared with those in the controls. Furthermore, portal PA levels after meals in NASH rats were significantly higher than those in control and nonalcoholic fatty liver rats. Moreover, PA injection into the portal vein to the liver in control rats increased the mRNA levels associated with the activation of HSCs. Increased intestinal absorption of diet-derived PA was observed in NASH. Thus, the rapid increase in PA levels via the portal vein to the liver may activate HSCs and affect the development of liver fibrosis in NASH.

OBJECTIVE To assess the preclinical efficacy and mechanism of action of an anti-CX3 CL1 monoclonal antibody (mAb) in systemic sclerosis (SSc). METHODS Cultured human dermal fibroblasts were used to evaluate the direct effect of anti-CX3 CL1 mAb on fibroblasts. In addition, bleomycin-induced and growth factor-induced models of SSc were used to investigate the effect of anti-CX3 CL1 mAb on leukocyte infiltration, collagen deposition, and vascular damage in the skin. RESULTS Anti-CX3 CL1 mAb treatment significantly inhibited Smad3 phosphorylation (P < 0.05) and expression of type I collagen and fibronectin 1 (P < 0.01) in dermal fibroblasts stimulated with transforming growth factor β1 (TGFβ1). In the bleomycin model, daily subcutaneous bleomycin injection increased serum CX3 CL1 levels (P < 0.05) and augmented lesional CX3 CL1 expression. Simultaneous administration of anti-CX3 CL1 mAb or CX3 CR1 deficiency significantly suppressed the dermal thickness, collagen content, and capillary loss caused by bleomycin (P < 0.05). Injection of bleomycin induced expression of pSmad3 and TGFβ1 in the skin, which was inhibited by anti-CX3 CL1 mAb. Further, the dermal infiltration of CX3 CR1+ cells, macrophages (inflammatory and alternatively activated [M2-like] subsets), and CD3+ cells significantly decreased following anti-CX3 CL1 mAb therapy (P < 0.05), as did the enhanced skin expression of fibrogenic molecules, such as thymic stromal lymphopoietin and secreted phosphoprotein 1 (P < 0.05). However, the treatment did not significantly reduce established skin fibrosis. In the second model, simultaneous anti-mCX3 CL1 mAb therapy significantly diminished the skin fibrosis induced by serial subcutaneous injection of TGFβ and connective tissue growth factor (P < 0.01). CONCLUSION Anti-CX3 CL1 mAb therapy may be a novel approach for treating early skin fibrosis in inflammation-driven fibrotic skin disorders such as SSc.

In this work, graphene oxide (GO) monolayers were immobilized on a hydrogen terminated silicon (H-Si) substrate by applying 4-vinylaniline (VAn) molecules as the intermediate linkers. Surface prope...

Palladium (Pd) clusters on zirconia (ZrO2) and single Pd atoms on ceria (CeO2) exhibited high catalytic activity and selectivity for decarbonylation of furfural to furan without additives in the liquid phase. To study the active size of Pd and changes in chemical states or structures during the reaction, in-situ X-ray absorption fine structure (XAFS) measurements were conducted. The size of Pd clusters consisting of less than 10 Pd atoms was maintained on ZrO2 during the reaction. In contrast, single Pd atoms were aggregated during heating and only Pd clusters consisting of 13 atoms were present after the reaction. According to the in-situ XAFS results, the size of Pd particles did not gradually increase to Pd13 clusters. Instead, Pd13 clusters were partly formed from the beginning of the reaction, and the proportion of Pd13 clusters increased with time while keeping the size of Pd13 clusters. This result suggests that a single Pd atom is inactive, but Pd clusters are active for decarbonylation. Ab-initio calculation revealed that ZrO2 (1 1 1) surface had lower adsorption and migration energies than CeO2 (1 1 1), implying that Pd was easily diffused on the surface and stabilized as small Pd clusters.

Following identification of radioactive Cs microparticles (CsMPs) in aerosol samples from the Fukushima Daiichi Nuclear Power Plant (FDNPP), numerous reports on CsMPs have been published. This pape...

Aims/Introduction The present study analysis was carried out to evaluate the safety and efficacy of tofogliflozin, a sodium–glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus in real‐world clinical practice. Materials and Methods This was a 3‐year non‐interventional observational study of patients with type 2 diabetes mellitus newly administered tofogliflozin who were uncontrolled on current therapy. We carried out a 12‐week interim analysis of tofogliflozin as part of 3‐year post‐marketing surveillance study. The incidence of adverse drug reactions was evaluated as a safety end‐point. As efficacy end‐points, glycated hemoglobin and bodyweight were evaluated. Results A total of 6,897 patients were enrolled. Tofogliflozin significantly reduced mean changes from baseline glycated hemoglobin (−0.63%, P

The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (AR T878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.

OBJECTIVE Precise monthly achievement rates for reaching guideline targets for HbA1c, blood pressure (BP), and lipid levels remain unknown. We evaluated achievement rates on a monthly basis in persons with type 2 diabetes mellitus (T2DM) and explored related factors. RESEARCH DESIGN AND METHODS This retrospective study initially analyzed data on 104,601 persons with T2DM throughout Japan. Patients whose HbA1c, BP, and LDL cholesterol were measured ≥12 times during a 24-month period were included. We evaluated monthly achievement rates. Achieved targets were defined as HbA1c RESULTS A total of 4,678 patients were analyzed. The achievement rates of all ABC, HbA1c, BP, and LDL cholesterol were lowest in winter, with those for systolic BP (SBP) being particularly low (all ABC, summer 15.6%, winter 9.6%; HbA1c, 53.1%, 48.9%; SBP, 56.6%, 40.9%; LDL cholesterol, 50.8%, 47.2%). In winter, age ≥65 years (odds ratio 0.47 [95% CI 0.34–0.63]) was independently related to decreased achievement rates for SBP, BMI ≥25 kg/m2 (BMI 25–30 kg/m2, 0.45 [0.29–0.70]; BMI ≥30 kg/m2, 0.35 [0.22–0.57]), and diabetes duration ≥10 years (0.53 [0.37–0.76]) were independently related to lower achievement rates for HbA1c. Insulin use and sulfonylurea use were independently associated with the decreased all ABC achievement rates in both summer and winter. CONCLUSIONS The all ABC achievement rate for guideline targets changed on a monthly basis. Seasonal variations in the all ABC achievement rate should be considered when managing T2DM in ordinary clinical practices.

Aluminum (Al) foam does not recover to its initial shape once it absorbs shock energy and deforms. In this study, the refoaming of deformed A6061 Al foam was attempted. Closed-cell Al foam fabricated by a precursor foaming process was reproduced to obtain a similar closed-cell Al foam by subjecting it to the precursor foaming process again. It was found that only slight refoaming of the precursor was observed for a cold-compressed Al foam. It is considered that the low density of the precursor causes the release of the generated gases from the cracks and pores of the precursor. In contrast, sufficient refoaming of a cold-compressed precursor can be achieved by conducting spark plasma sintering (SPS). Initial Al foams with porosity of approximately 80% and closed-cell pore structures can be reproduced with similar porosity and pore structures. From these results, it was found that not all the blowing agent in the precursor was used during the initial foaming, and some of the blowing agent remained in the foamed Al foam without decomposition. Therefore, the successful reproduction of the Al foam was due to the remaining blowing agent in the initial Al foam.

In metal forming processes, electrical contact resistance between the workpiece and a tool could give useful information on the contact state of the two surfaces. However, measurement during rolling is difficult because rolls rotate at high speed. In this study, two titanium sheets were cold-rolled in parallel. A closed circuit was composed of the two sheets, one roll and a power source. Difference in electrical potentials between the two sheets was measured to estimate the contact resistance. It is found that the contact resistance decreases with reduction in thickness and that it depends on lubrication and surface conditions of the rolls.

Formation of precise and high-resolution silica micropatterns on polymer substrates is of importance in surface structuring for flexible device fabrication of optics, microelectronic, and biotechnology. To achieve that, substrates modified with affinity-patterns serve as a strategy for site-selective deposition. In the present paper, vacuum ultraviolet (VUV) treatment is utilized to achieve spatially-controlled surface functionalization on a cyclo-olefin polymer (COP) substrate. An organosilane, 2, 4, 6, 8-tetramethylcyclotetrasiloxane (TMCTS), preferentially deposits on the functionalized regions. Well-defined patterns of TMCTS are formed with a minimum feature of ∼500 nm. The secondary VUV/(O)-treatment converts TMCTS into SiOx, meanwhile etches the bare COP surface, forming patterned SiOx/COP microstructures with an average height of ∼150 nm. The resulting SiOx patterns retain a good copy of TMCTS patterns, which are also consistent with the patterns of photomask used in polymer affinity-patterning. The high quality SiOx patterns are of interests in microdevice fabrication, and the hydrophilicity contrast and adjustable heights reveal their potential application as a “stamp” for microcontact printing (μCP) techniques.

d-amino acid-containing proteins have been found in several human tissues, and the spontaneous accumulation of d-amino acids in proteins is thought to be involved in age-dependent diseases including dementia. Tau, a microtubule-associated protein, is a major component of neurofibrillary tangles in Alzheimer's disease. Site-specific amino acid D-isomerization in Tau has been observed in the brains of patients with Alzheimer's disease. Here, we conducted amino acid D-isomerization at specific sites in microtubule-binding repeat peptides of Tau (Tau R2 and R3) and examined the effects on Tau structure and fibril formation. Our results demonstrate that amino acid D-isomerization in Tau R2 peptides decreased the rates of β-sheet transition and fibril formation compared with those of the wild-type peptide composed of all l-amino acids. In contrast, Tau R3 peptides that had undergone amino acid D-isomerization at either Asp314, Ser316, or Ser324 showed increased rates of β-sheet transition and fibril formation compared with those of the wild-type Tau R3 peptide.