Equation of states for dense ice up to 80 GPa at low-temperature conditions.

We have measured the lattice volume of ice VIII in different pressure-temperature pathways and found that the volume depends on the pathway, implying that deviatoric stress makes the volume larger. Dense ice is in the ice VIII phase with the molar volume of 6.56 cm3 and in a high-pressure phase with the molar volume of 6.45 cm3 at 10 K where the pressure can be estimated as 57.0 ± 3.4 and 60.4 ± 3.6 GPa, respectively, based on the third-order Birch-Murnaghan equation with parameters determined in this study (K0 = 30.8 ± 1.3 GPa and K'0 = 3.7 ± 0.1 with V0 fixed to 12.030 cm3).

Electronic structure of dense solid oxygen from insulator to metal investigated with X-ray Raman scattering.

Electronic structures of dense solid oxygen have been investigated up to 140 GPa with oxygen K-edge X-ray Raman scattering spectroscopy with the help of ab initio calculations based on density functional theory with semilocal metageneralized gradient approximation and nonlocal van der Waals density functionals. The present study demonstrates that the transition energies (Pi*, Sigma*, and the continuum) increase with compression, and the slopes of the pressure dependences then change at 94 GPa. The change in the slopes indicates that the electronic structure changes at the metallic transition. The change in the Pi* and Sigma* bands implies metallic characteristics of dense solid oxygen not only in the crystal a-b plane but also parallel to the c axis. The pressure evolution of the spectra also changes at ∼40 GPa. The experimental results are qualitatively reproduced in the calculations, indicating that dense solid oxygen transforms from insulator to metal via the semimetallic transition.

Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis.

Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called "leaky gut". Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.

Platelet hyperaggregability is associated with decreased ADAMTS13 activity and enhanced endotoxemia in patients with acute cholangitis.

AIM: Insufficient ADAMTS13 activity (ADAMTS13:AC) leads to increased levels of unusually large von Willebrand factor (VWF) multimers and causes microcirculatory disturbance and multiple organ failure (MOF). Endotoxin (Et) triggers the activation of coagulation and cytokine cascades, leading to MOF in severe inflammatory response syndrome. Here, we investigated the potential role of endotoxemia-related ADAMTS13 in acute cholangitis. METHODS: Twenty-four patients with acute cholangitis, including 7 with severe acute cholangitis, were recruited in this study. The levels of ADAMTS13:AC, VWF antigen (VWF:Ag), interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in each patient were determined by enzyme-linked immunosorbent assay, whereas Et levels were determined by Et activity assay (EAA) analysis. RESULTS: The ADAMTS13:AC and VWF:Ag levels were significantly lower and higher, respectively, in patients with acute cholangitis than in controls. The EAA levels were higher in patients with acute cholangitis than in controls, and were inversely correlated with that of ADAMTS13:AC. Patients with severe acute cholangitis had significantly lower ADAMTS13:AC and higher VWF:Ag levels than those with mild to moderate cholangitis. Notably, ADMTS13:AC was directly correlated with platelet counts and inversely correlated with IL-6 levels, and the VWF:Ag/ADAMTS13:AC ratio was directly correlated with IL-8 and TNF-α levels. CONCLUSIONS: Imbalance of ADAMTS13:AC and VWF:Ag levels might be associated with severe acute cholangitis, reflecting platelet hyperaggregability. Severe acute cholangitis has severe pathophysiological features and is complicated by endotoxemia and MOF. Notably, this is the first report indicating an association between the levels of ADAMTS13:AC and VWF:Ag and those of EAA and cytokines in acute cholangitis.

Biocommunication between Plants and Pollinating Insects through Fluorescence of Pollen and Anthers.

Flowering plants attract pollinators via various stimuli such as odor, color, and shape. Factors determining the foraging behavior of pollinators remain a major theme in ecological and evolutionary research, although the floral traits and cognitive ability of pollinators have been investigated for centuries. Here we show that the autofluorescence emitted from pollen and anthers under UV irradiation may act as another attractant for flower-visiting insects. We have identified fluorescent compounds from pollen and anthers of five plant species as hydroxycinnamoyl derivatives. The fluorescent compounds are also shown to quench UV energy and exhibit antioxidant activity, indicating a function as protectants of pollen genes from UV-induced damage. A two-choice assay using honeybees in the field demonstrated that they perceived the blue fluorescence emitted from the fluorescent compounds and were attracted to it. This result suggested that the fluorescence from pollen and anthers serves as a visual cue to attract pollinators under sunlight.

Treatment for cirrhotic ascites.

Common complications of decompensated liver cirrhosis are esophageal varices, hepatic encephalopathy and ascites. After the onset of complications, the prognosis worsens. In patients with ascites, the 5-year mortality rate is 44%. Furthermore, hyponatremia, spontaneous bacterial translocation and hepatorenal syndrome also greatly worsen the prognosis. Effective treatment of cirrhotic ascites improves the quality of life and survival rate. Recently, the newly produced diuretic, tolvaptan (vasopressin V2 receptor antagonist), was reported to be effective in the treatment of refractory ascites in liver cirrhosis; however, there has not been an associated positive effect on the prognosis. There are various types of treatment for ascites, such as large-volume paracenteses, a cell-free and concentrated ascites reinfusion therapy, a transjugular intrahepatic portosystemic shunt, and a peritoneo-venous shunt. Although they improve the prognosis, liver transplantation remains the ultimate form of treatment. The present article discusses the therapeutic management of cirrhotic ascites.

Predictive parameter of tolvaptan effectiveness in cirrhotic ascites.

AIMS: The efficacy of the vasopressin V2 receptor antagonist tolvaptan for difficult-to-treat cirrhotic ascites has recently been reported. However, its effect is variable among patients. This study aimed to clarify the predictive factors for obtaining a good response to tolvaptan in patients with difficult-to-treat ascites. METHODS: Data were collected from 50 patients with liver cirrhosis having ascites (hepatitis B, n = 1; hepatitis C, n = 22; alcoholism, n = 11; and others, n = 16) after treatment with tolvaptan (3.75-7.5 mg/day) in addition to conventional diuretics. A follow-up assessment was carried out after 7-day tolvaptan treatment for all patients. RESULTS: After an uneventful 7-day tolvaptan treatment, 18 patients (36.0%) lost more than 2 kg of their body weight (responders). Twenty-six patients (52.0%) showed an increase in urine volume (>300 mL) on day 2. Tolvaptan was also effective for patients with pleural effusion, portal vein thrombosis, and hepatocellular carcinoma. Basal blood urea nitrogen (BUN) levels, plasma renin activity, and aldosterone levels were significantly higher in the poor responders (<2 kg weight loss), who were considered to be in the relative vascular underfilling state, than in the responders. Basal BUN was extracted as a predictive factor of responsiveness by multivariate logistic regression analysis. CONCLUSIONS: Tolvaptan is useful and safe for the treatment of cirrhotic ascites. This report showed that BUN will predict the response of tolvaptan even when measured before tolvaptan treatment.

Computer Simulation and Field Experiment for Downlink Multiuser MIMO in Mobile WiMAX System.

The transmission performance for a downlink mobile WiMAX system with multiuser multiple-input multiple-output (MU-MIMO) systems in a computer simulation and field experiment is described. In computer simulation, a MU-MIMO transmission system can be realized by using the block diagonalization (BD) algorithm, and each user can receive signals without any signal interference from other users. The bit error rate (BER) performance and channel capacity in accordance with modulation schemes and the number of streams were simulated in a spatially correlated multipath fading environment. Furthermore, we propose a method for evaluating the transmission performance for this downlink mobile WiMAX system in this environment by using the computer simulation. In the field experiment, the received power and downlink throughput in the UDP layer were measured on an experimental mobile WiMAX system developed in Azumino City in Japan. In comparison with the simulated and experimented results, the measured maximum throughput performance in the downlink had almost the same performance as the simulated throughput. It was confirmed that the experimental mobile WiMAX system for MU-MIMO transmission successfully increased the total channel capacity of the system.

Differential expression of drug uptake and efflux transporters in Japanese patients with hepatocellular carcinoma.

Targeted chemotherapy for hepatocellular carcinoma (HCC) is impaired by intrinsic and/or acquired drug resistance. Because drugs used in HCC therapy (e.g., anthracyclines or the tyrosine kinase inhibitor sorafenib) are substrates of uptake and/or efflux transporters, variable expression of these transporters at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. In this study, the variability of expression of uptake transporters [organic cation transporter (OCT) 1 and OCT3] and efflux transporters [multidrug resistance 1 (MDR1)/P-glycoprotein, multidrug resistance protein (MRP) 1, MRP2, and breast cancer resistance protein (BCRP)], selected for their implication in transporting drugs used in HCC therapy, was investigated. HCC and corresponding nontumor tissue samples were collected from 24 Japanese patients at the time of surgery. Protein expression was determined by immunohistochemistry. Expression data were correlated with clinicopathological characteristics and patients' outcome (median follow-up, 53 months). Generally, expression was highly variable among individual tumor samples. Yet median expression of OCT1, OCT3, and MDR1 in HCC was significantly lower (1.4-, 2.7-, and 2-fold, respectively) than in nontumor tissue, while expression of MRP2 persisted and BCRP showed a trend of increased levels in HCC. Patients with low BCRP expression had significantly shorter overall and recurrence-free survival times. Results suggest different expression patterns of drug transporters in HCC, which are associated only in part with clinicopathological characteristics. Detailed information on expression of drug transporters in HCC may be promising for individualization and optimization of drug therapy for liver cancer.

Open-labeled randomized controlled trial to compare diuretic therapy with recombinant human serum albumin and diuretic therapy for therapeutic treatment of ascites in patients with advanced liver cirrhosis: An exploratory trial.

AIM: There have been only a few trials demonstrating additional effects of human serum albumin (HSA) on diuretic therapy in patients with cirrhotic ascites. We aimed to evaluate the safety and efficacy of recombinant HSA, KD-294, treatment in patients with cirrhotic ascites. METHODS: The inclusion criteria were patients 20-75 years of age, with cirrhotic ascites and a serum albumin concentration of less than 3.0 g/dL. Eighty-five patients were registered and 71 patients underwent randomization. Enrolled patients received oral spironolactone at 50 mg/day and i.v. furosemide at 20 mg/day in addition to low-sodium diet. They were divided randomly into a KD-294 treatment group (n = 35) or non-treatment control group (n = 36). Patients in the KD-294 group received KD-294 at 25 g/day for up to 5 days and those in the control group continued the diuretic therapy. They were followed up for 5 weeks. RESULTS: KD-294 was well tolerated. A correlation between the increases in serum albumin and decreases in bodyweight was not shown. However, changes of plasma renin concentration (PRC) showed a significant decrease in the KD-294 group compared with the control group. As a result of this exploratory analysis, patients with high PRC showed a significant correlation between increases in serum albumin and decreases in bodyweight. CONCLUSION: The present data do not show efficacy in all patients with cirrhotic ascites, however, they suggest that additional effects of HSA on diuretic therapy are expected in high PRC patients.

Tuberculous peritonitis during pegylated interferon plus ribavirin combination therapy in a patient with chronic hepatitis C.

A woman in her 70s with fever and abdominal distension was referred to our hospital for investigation. She had just finished a course of pegylated interferon and ribavirin combination therapy for chronic hepatitis C. Abdominal computed tomography revealed peritoneal thickening and ascites. QuantiFERON(®)-TB Gold was positive, ascitic adenosine deaminase was high, and fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed diffuse accumulation in the peritoneum. Although these findings suggested tuberculous peritonitis, we did not detect Mycobacterium tuberculosis in any bacterial cultures, ascites, or other specimens. However, laparoscopic peritoneal biopsy demonstrated a large number of miliary white nodules in the parietal and visceral peritonea. Pathological examination of these nodules revealed epidermoid granuloma with giant Langhans' cells and caseous necrosis. Finally, the diagnosed of tuberculous peritonitis was established. It is important to consider tuberculosis in patients presenting with new symptoms while receiving interferon therapy.

Large-aperture refractive lenses for momentum-resolved spectroscopy with hard X-rays.

One-dimensional kinoform and prism refractive lenses with large aperture and high transmittance at 22 keV have been investigated. A 12.0 µm focus size (full width at half-maximum) and an effective aperture of 0.85 mm, at a focal length of 705 mm and 21.747 keV, were achieved.

Direct renin inhibitor, aliskiren, attenuates the progression of non-alcoholic steatohepatitis in the rat model.

AIM: Renin is a rate-limiting enzyme of the renin-angiotensin system (RAS), and several reports have shown that renin plays an important role in several pathological processes. Although RAS is known to play a pivotal role in the progression of non-alcoholic steatohepatitis (NASH), the role of renin is still obscure. The aim of the current study was to examine the effect of the clinically used direct renin inhibitor (DRI), aliskiren, on the progression of NASH in a rat model. METHODS: The effects of DRI on the choline-deficient L-amino acid-defined (CDAA) diet-induced rat NASH model was examined in conjunction with the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which are known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. RESULTS: DRI exerted a marked inhibitory effect against liver fibrosis development and glutathione-S-transferase placental form (GST-P) positive preneoplastic lesions along with suppression of the Ac-HSC and neovascularization in a dose-dependent manner. DRI also inhibited the hepatic expressions of transforming growth factor-beta 1 (TGF-beta 1), angiotensin-II (AT-II) and vascular endothelial growth factor (VEGF). These results indicated that renin played a pivotal role in the liver fibrosis development and hepatocarcinogenesis of NASH. CONCLUSION: Because DRI is already widely used in the clinical practice with safety, this drug may represent a potential new strategy against the progression of NASH in the future.

Dual blockade of angiotensin-II and aldosterone suppresses the progression of a non-diabetic rat model of steatohepatitis.

AIM: Both angiotensin-II (AT-II) and aldosterone (Ald) play pivotal roles in the pathogenesis of diseases in several organs including the liver. We previously reported that suppression of AT-II and Ald with angiotensin-converting enzyme inhibitor (ACE-I) and selective Ald blocker (SAB), respectively, attenuated the rat liver fibrogenesis and hepatocarcinogenesis. The aim of our current study was to elucidate the combined effects of ACE-I and SAB in the progression of a non-diabetic rat model of steatohepatitis, and the possible mechanisms involved. METHODS: In the choline-deficient L-amino acid-defined (CDAA) diet-induced model, the effects of ACE-I and SAB on liver fibrosis development and hepatocarcinogenesis were elucidated, especially in conjunction with neovascularization. RESULTS: Treatment with both ACE-I and SAB suppressed the development of liver fibrosis and glutathione-S-transferase placental form (GST-P) positive pre-neoplastic lesions. The combined treatment with both agents exerted more inhibitory effects as compared with either a single agent along with suppression of the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which play important roles in these processes. Our in vitro study showed that AT-II type 1 receptor blocker (ARB) and SAB inhibited Ac-HSC proliferation and in vitro angiogenesis along with suppression of the in vivo studies. CONCLUSION: Dual blockade of AT-II and Ald suppresses the progression of a non-diabetic rat model of steatohepatitis. Because both agents are widely and safely used in clinical practice, this combination therapy could be an effective new strategy against steatohepatitis in the future.

Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis.

BACKGROUND AND AIM: The innate immune system, including toll-like receptor-4 (TLR4) signaling cascade and angiotensin-II (AT-II) play important roles in the progression of liver fibrosis development; the cross talk between TLR4 and AT-II has not been elucidated yet. The aim of the current study was to elucidate the effect of AT-II type 1 receptor blocker (ARB), on the liver fibrosis development, especially in conjunction with the interaction of TLR4 and AT-II in the rat model of non-alcoholic steatohepatitis. METHODS: Fischer 344 rats were fed a choline-deficient, L-amino-acid-defined diet for 8 weeks and the effects of losartan were elucidated in conjunction with activated hepatic stellate cells (Ac-HSC) activation, TLR4, nuclear factor-κB (NF-κB), and transforming growth factor-ß (TGF-ß) expressions. In vitro study was carried out to elucidate the effect of AT-II on several indices including TLR4, myeloid differentiation factor 88, NF-κB, and TGF-ß expressions in the rat HSC. RESULTS: ARB markedly inhibited liver fibrosis development along with suppression of the number of Ac-HSC and TGF-ß. These inhibitory effects of ARB were almost in parallel with suppression of the hepatic TLR4 and NF-κB expressions. This in vitro study showed that AT-II significantly augmented the TLR4 expression in a dose- and time-dependent manner via AT-II type 1 receptor in the Ac-HSC. AT-II also augmented the lipopolysaccharide-induced myeloid differentiation factor 88 (MyD88), NF-κB, and TGF-ß and these increments were attenuated by treatment with ARB. CONCLUSIONS: These studies indicated that the cross talk between TLR4 signaling cascade and AT-II plays a pivotal role in liver fibrosis development in non-alcoholic steatohepatitis.

The effect of inflammatory cytokines in alcoholic liver disease.

Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-α and IFN-γ, induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro- and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation.

Density deficit of Earth's core revealed by a multimegabar primary pressure scale.

An accurate pressure scale is a fundamental requirement to understand planetary interiors. Here, we establish a primary pressure scale extending to the multimegabar pressures of Earth's core, by combined measurement of the acoustic velocities and the density from a rhenium sample in a diamond anvil cell using inelastic x-ray scattering and x-ray diffraction. Our scale agrees well with previous primary scales and shock Hugoniots in each experimental pressure range and reveals that previous scales have overestimated laboratory pressures by at least 20% at 230 gigapascals. It suggests that the light element content in Earth's inner core (the density deficit relative to iron) is likely to be double what was previously estimated, or Earth's inner core temperature is much higher than expected, or some combination thereof.

Competing charge-density wave instabilities in the kagome metal ScV6Sn6.

Owing to its unique geometry, the kagome lattice hosts various many-body quantum states including frustrated magnetism, superconductivity, and charge-density waves (CDWs). In this work, using inelastic X-ray scattering, we discover a dynamic short-range [Formula: see text] CDW that is dominant in the kagome metal ScV6Sn6 above TCDW ≈ 91 K, competing with the [Formula: see text] CDW that orders below TCDW. The competing CDW instabilities lead to an unusual CDW formation process, with the most pronounced phonon softening and the static CDW occurring at different wavevectors. First-principles calculations indicate that the [Formula: see text] CDW is energetically favored, while a wavevector-dependent electron-phonon coupling (EPC) promotes the [Formula: see text] CDW as the ground state, and leads to enhanced electron scattering above TCDW. These findings underscore EPC-driven correlated many-body physics in ScV6Sn6 and motivate studies of emergent quantum phases in the strong EPC regime.

Innate immune reactivity of the ileum-liver axis in nonalcoholic steatohepatitis.

BACKGROUND: Over-proliferation and bacterial translocation of Gram-negative bacilli within the intestinal flora, and increased portal venous levels of endotoxins, are involved in nonalcoholic steatohepatitis (NASH). AIM: To evaluate the innate immune response in the small intestine and liver using the rat NASH model. METHODS: We produced the NASH model by administering a choline-deficient amino acid-defined diet to F344 rats. We analyzed the serum and liver tissue to assess the effects of innate immune reactivity in this NASH model. RESULTS: Significant increases were detected in serum ALT levels and in the portal venous serum and whole-liver levels of TNF-α and IFN-γ in the NASH group. Strong Sirius red staining and TNF-α immune staining were seen in the NASH group, and real-time PCR revealed significantly increased expression of TNF-α and TLR4 mRNA in the NASH group. Higher TNF-α levels were detected in the Kupffer cells isolated culture supernatant in the NASH group than in the control group. Immune staining of the ileal tissue specimens resulted in greater staining of TNF-α, TLR4, and macrophage/dendritic cells, mainly in the submucosa, in the NASH group than in the control group. CONCLUSIONS: In the small intestine and liver of the rat NASH model, the possibility that enhancement of the innate immune response, mediated by the TLR4 signal, led to increased production of TNF-α was suggested. This interaction between the small intestine and liver may be involved in the onset and progression of NASH.

Sound velocity of hexagonal close-packed iron to the Earth's inner core pressure.

Here we determine the compressional and shear wave velocities (vp and vs) of hexagonal close-packed iron, a candidate for the main constituent of the Earth's inner core, to pressures above 300 gigapascals using a newly designed diamond anvil cell and inelastic X-ray scattering combined with X-ray diffraction. The present results reveal that the vp and vs of the Preliminary reference Earth model (PREM) inner core are 4(±2)% and 36(±17)% slower than those of the pure iron, respectively at the centre of the core. The density and sound velocity of the PREM inner core can be explained by addition of 3(±1) wt% silicon and 3(±2) wt% sulphur to iron‒5 wt% nickel alloy. Our suggested inner core composition is consistent with the existing outer core model with oxygen, as the growth of the inner core may have created a secular enrichment of the element in the outer core.