6 The predominant literature on NRH is in the form of case reports or small case series and there are

only few reports of portal pressure measurements in this condition. In the current issue of the Journal, Bissonnette et al.8 reported hemodynamic measurements, including HVPG, in 21 patients and portal vein pressure gradient (PVPG, portal vein pressure – inferior vena cava pressure) in 12 patients with NRH. The causes of NRH in these patients included oxaliplatin chemotherapy, treatment with purine antagonists, liver transplantation, hematological and rheumatological conditions, and HIV infection. selleck screening library Fifteen out of 21 patients with varices/ascites had HVPG less than 10 mm Hg suggesting a pre-sinusoidal portal hypertension, which was confirmed by a portal vein pressure higher than 12 mm Hg in all 12 patients. Though the majority of patients (15/21) had a pre-sinusoidal component, six patients did have higher HVPG (more

than 10 mm Hg) suggesting sinusoidal portal hypertension.8 These data by Julien et al. thus suggest that both components of portal hypertension (pre-sinusoidal and sinusoidal) occur in patients with NRH. The pre-sinusoidal portal hypertension is related to the well-described vasculopathy (obliterative portal venopathy), while the sinusoidal portal hypertension is probably attributable to sinusoidal obstruction because of compression by regenerative nodules.8 Even though data are sparse, Tofacitinib other studies in patients with NRH have also suggested a mixed type of portal hypertension (pre-sinusoidal and sinusoidal).

Methocarbamol In one of the case reports, a 47-year-old woman with NRH who underwent HVPG before and after splenectomy had a marked difference between WHVP and FHVP with little difference between portal venous pressure and WHVP; these findings indicated that portal hypertension in NRH was primarily sinusoidal.9 Similar data were shown by two other studies, one another single case report and the other a series of 13 cases.4,10 On the other hand, in a relatively large number of biopsy-proven cases of NRH (n = 14), Arvanitaki and Adler5 suggested that portal hypertension in patients with NRH was pre-sinusoidal. The clinical manifestations included splenomegaly, esophageal varices and variceal bleeding.5 In another recent study, 26 patients receiving 6-thioguanine for inflammatory bowel disease were evaluated with HVPG and liver biopsy.11 Six out of 24 patients (25%) with adequate liver tissue on histology had evidence of NRH. Of six patients with NRH, three had elevated (> 5 mm Hg) HVPG, two with HVPG > 10 mm Hg, whereas three others had HVPG < 5 mm Hg in spite of having clinical manifestations of portal hypertension.

Moreover, the spongy bone of juvenile skulls is organized in such a way that reflects radial growth of the bone, which indicates rapid growth (Francillon-Vieillot et al., 1990: p. 512). Rather than deflecting concussive

forces from the brain cavity, this radial organization would have more likely directed them into the brain cavity (Goodwin & Horner, 2004). Maryanska et al. (2004) recently renewed the argument for mechanical agonistic RO4929097 behavior, but their analysis had no control for ontogeny or sexual dimorphism, so there is no support for assigning male status to larger and thicker domes as they did. Moreover, the knobs and spikes that ornamented some pachycephalosaur skulls (such

as Stygimoloch) would not have been visible until the heads were lowered, www.selleckchem.com/products/cb-839.html and in any case could not have been involved in combat (Goodwin, Rosner & Johnson, 1998). For these reasons a function in combat for both the domes and ornamentation is implausible. Moreover, there is now evidence that Stygimoloch was a subadult form of Pachycephalosaurus, which has somewhat less extreme spikes than Stygimoloch, thus casting doubt on the functional interpretation (Horner & Goodwin, 2009). Weishampel’s (1981, 1997) study of Parasaurolophus described above was Mannose-binding protein-associated serine protease the first example of an explicit test of a hypothesis that a particular structure functioned in communication.

As noted, this function may apply to this genus, but it has not been proposed and tested for other lambeosaurines until recently, when Evans, Ridgely & Witmer (2009) examined Lambeosaurus, Corythosaurus and Hypacrosaurus. They showed, as Weishampel (1981) had done using Lophorhothon, that the ear region was capable of hearing the low-frequency sounds that Weishampel calculated might have been produced by the resonating crests of these hadrosaurs. However, phylogenetic analysis of lambeosaurines (Horner, Weishampel & Forster, 2004) shows no apparent trends in selection for improvement of the features related to this function (Fig. 4), and Evans et al. (2009) noted that Hypacrosaurus altispinus had a particularly derived and convoluted nasal chamber. Only two kinds of dinosaurian structures have been proposed as thermoregulatory structures. The first is the plates of stegosaurs. Main et al. (2005) showed that the explanation hypothesized for stegosaurs (Buffrenil et al., 1986) could not be completely eliminated for Stegosaurus itself but was unlikely to apply to related taxa, so there was no evidence of the evolution of a functional adaptation in the group.

We examined GS-1101 concentration whether IFN treatment would reduce HCC incidence in CHB patients when compared with untreated patients. Methods: We conducted a retrospective cohort study of in hepatitis B e antigen (HBeAg) positive 295 Japanese patients who received

conventional IFN alpha (IFN group), and 391 untreated e-positive patients (control group). The IFN group comprised patients recruited from 1988 to 2011 and treated with IFN in our institute, and the control group patients from 1973 to 1999. Patients in IFN group received conventional 3-12 MU IFN alpha (lymphoblastoid or recombinant). The duration and regimens of treatment

were 16-72 weeks (daily for 4 weeks followed by 2 or 3 times a week, or 2 or 3 times a week from the beginning). Responders (RP) were defined as normalized alanine aminotransferase, HBeAg loss, and low HBV DNA (< 5 log copies/mL) at 6 months after the end of IFN treatment (EOT). Patients treated with nucleos(t)ide analogues (NA) after IFN were defined as non-responders (NR). Primary outcome is HCC incidence for 10 years. Results: The response find more rates at 6 months after EOT were 15.6% (46/295) in the IFN group. During follow-ups of 9.2 years in the www.selleck.co.jp/products/erastin.html IFN group and 9.9 years in the control group, 22 patients (7.5%) in the IFN group had developed HCC (81/10,000 person-years) compared with 62 patients (15.9%) in the control group (159/10,000 person-years). Propensity score (PS) matching eliminated the baseline differences of the two cohorts, resulting in a matched sample size of 119 patients in each cohort. The cumulative

HCC incidence rates at 5- and 10-year were 2.7% and 15.9% for the PS-matched IFN, and 13.9% and 25.3% for the control group, respectively (P = 0.055). No patients with RP had developed HCC. Patients in the IFN group were divided into three groups (RP, NR-NA, and NR-noTx). Multivariate Cox regression analysis, adjusted for known HCC risk factors and PS quartiles, showed that patients in the RP or NR-NA group were less likely to develop HCC than those in the control group (hazard ratio (HR): 0.36; 95% CI: 0.16 to 0.84; P = 0.017). The beneficial effect was not observed in the NR-noTx group (HR: 0.71; 95% CI: 0.35 to 1.47). Conclusion: IFN treatment marginally reduced HCC in CHB patients. The treatment effect was greater in the IFN responders compared with the control group. There was no benefit about the reduction of HCC incidence in IFN NRs. Disclosures: Norio Akuta – Patent Held/Filed: SRL. Inc.

e., fitness) of the variants. Conclusion: Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination

therapy. (HEPATOLOGY 2011) The hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a multifunctional protein with key roles in HCV replication. NS5A has also been implicated in the modulation of cellular signaling pathways.1, 2 Because it is required in vivo and in vitro for viral replication and has no known human homologs, NS5A provides an attractive click here target for therapeutic intervention.3 BMS-790052 is a potent HCV

NS5A replication complex inhibitor, with 50% effective concentration (EC50) values of 9 and 50 pM against genotype 1b and 1a replicons, respectively.4, 5 It is also potent against live virus (genotype 2a, JFH-1), with an EC50 of ∼28 pM.4 BMS-790052 has broad genotype coverage, with EC50 values ranging from pM to low nM for replicons with NS5A sequences derived Kinase Inhibitor Library supplier from genotype 2a, 3a, 4a, and 5a.4 Proof of concept for BMS-790052 has been achieved clinically, where its exceptional in vitro potency translated to an in vivo effect in a single-ascending dose study.4 In this study, marked HCV RNA decline (∼2.9 log10) was needed for detection of resistant variants, suggesting that the variants were likely present as preexisting minor quasi species and were uncovered by the efficient suppression of wild-type

virus.4 However, the ability of BMS-790052 to further suppress viral replication with continuous dosing could not be assessed in the single-ascending PTK6 dose study. In addition, analysis of specimens from the single-ascending dose study did not reveal whether the resistance detected clinically correlates with resistance observed in the in vitro replicon system. In the multiple-ascending dose (MAD) study reported here, a total of 24 chronically infected patients (4 active patients per cohort) were treated with BMS-790052 at 1, 10, 30, 60, and 100 mg once-daily or 30 mg twice-daily for 14 days. The treated patients generally experienced rapid, marked viral load declines. However, HCV RNA remained detectable in all genotype 1a–infected patients, and viral breakthrough was observed during the course of treatment in the majority of these patients. In contrast, viral breakthrough was observed less often in patients infected with HCV genotype 1b, and, in several patients, HCV RNA dropped below the level of quantitation (<25 IU/mL).

e., fitness) of the variants. Conclusion: Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination

therapy. (HEPATOLOGY 2011) The hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a multifunctional protein with key roles in HCV replication. NS5A has also been implicated in the modulation of cellular signaling pathways.1, 2 Because it is required in vivo and in vitro for viral replication and has no known human homologs, NS5A provides an attractive check details target for therapeutic intervention.3 BMS-790052 is a potent HCV

NS5A replication complex inhibitor, with 50% effective concentration (EC50) values of 9 and 50 pM against genotype 1b and 1a replicons, respectively.4, 5 It is also potent against live virus (genotype 2a, JFH-1), with an EC50 of ∼28 pM.4 BMS-790052 has broad genotype coverage, with EC50 values ranging from pM to low nM for replicons with NS5A sequences derived Tanespimycin from genotype 2a, 3a, 4a, and 5a.4 Proof of concept for BMS-790052 has been achieved clinically, where its exceptional in vitro potency translated to an in vivo effect in a single-ascending dose study.4 In this study, marked HCV RNA decline (∼2.9 log10) was needed for detection of resistant variants, suggesting that the variants were likely present as preexisting minor quasi species and were uncovered by the efficient suppression of wild-type

virus.4 However, the ability of BMS-790052 to further suppress viral replication with continuous dosing could not be assessed in the single-ascending Janus kinase (JAK) dose study. In addition, analysis of specimens from the single-ascending dose study did not reveal whether the resistance detected clinically correlates with resistance observed in the in vitro replicon system. In the multiple-ascending dose (MAD) study reported here, a total of 24 chronically infected patients (4 active patients per cohort) were treated with BMS-790052 at 1, 10, 30, 60, and 100 mg once-daily or 30 mg twice-daily for 14 days. The treated patients generally experienced rapid, marked viral load declines. However, HCV RNA remained detectable in all genotype 1a–infected patients, and viral breakthrough was observed during the course of treatment in the majority of these patients. In contrast, viral breakthrough was observed less often in patients infected with HCV genotype 1b, and, in several patients, HCV RNA dropped below the level of quantitation (<25 IU/mL).

As this occurred in several repeated experiments, the hepatocytes were not investigated further. The movement of procaspase-9 into check details and out of the nuclei appeared to occur in an organized manner. Whether this transport depended on the assembly of microtubules was tested by the microtubule-disrupting agent vinblastine. Ten μM vinblastine was added to the cell culture medium 4 hours after the isolation of hepatocytes (Fig. 3B). Its addition prevented the transport of procaspase-9

into cell nuclei. Therefore, procaspase-9 is transported along the microtubules from the cytoplasm to the nuclei. The mitochondrial morphology changed over time in cultured hepatocytes (Fig. 4A). The same types of changes were observed when the mitochondria were labeled by a MitoTracker, fluorescently labeled Tim23 (an integral mitochondrial inner membrane protein) and by fluorescently labeled streptavidin, which specifically labels mitochondria by binding

to biotinylated proteins of mitochondrial matrix.21 Mitochondria were labeled by streptavidin in this study because the strengths of streptavidin fluorescent signals did not vary during the incubation time of primary hepatocytes. selleckchem Mitochondria appeared circular in liver slices and in freshly isolated cells for up to 8 hours. They appeared dispersed after 24 hours postisolation (Fig. 4A), whereas mitochondria formed longer tubules after 3 days in culture. It seemed that mitochondrial fission predominated immediately after the isolation of primary hepatocytes. As in the case of the nuclear shift of procaspase-9, the fission of mitochondria was reversible too. Despite the

changes in mitochondrial morphology, there was neither Cyt-c leakage from dispersed mitochondria nor was there a decrease in MMP (Fig. 4B). The ratio between the potentials of the energized mitochondria and when MMP was dissipated by FCCP was statistically higher at 1 day of hepatocyte culture compared to immediately after isolation (P = 3 × 10−7, unpaired two-tailed Student’s t test). The difference between the MMPs of hepatocytes immediately after isolation and Phospholipase D1 those cultured for 1 day is relatively small and could be due to the presence of some cells that were damaged during isolation in the sample that was assayed immediately thereafter. The change in cellular location of Bax may be another feature of early apoptosis. We localized Bax to the cytoplasm of hepatocytes in rat liver sections (Fig. 5A). In contrast, only minor amounts of it were cytoplasmic, whereas most of it was in the nuclei of the primary hepatocytes cultured for 24 hours. Bax remained predominantly in the nuclei throughout the culturing of primary hepatocytes; it shifted to cytosol and mitochondria whenever apoptosis was induced by STS. The antibody used for labeling of Bax detected a single band of 22 kDa (Fig. 5B). This proves that Bax was labeled specifically.

Apart from CD causes that can be the result of multiple issues, including the etiology of cirrhosis, mentioned by the authors,1 Helicobacter pylori infection (Hp-I) appears to be a common denominator PI3K inhibitor associated with CD-related falls and fractures and liver cirrhosis.2-4 In this respect, we reported that Hp-I is frequently detected in neurodegenerative diseases including CD and Alzheimer’s disease (AD) and Hp eradication may positively influence AD manifestations at 2- and 5-year clinical endpoints,2 thereby supporting a role for this common infection in the pathobiology of the disease. Others also found that AD patients infected by Hp tended to be more cognitively impaired, and patients with dementia

have a higher risk of falls and fractures3;

Hp-I may also be responsible for osteoporosis. Moreover, hepatitis B (HBV) and C (HCV) are among the commonest causes of liver cirrhosis worldwide4, 5 and Hp-I is strongly associated with HBV- and HCV-related cirrhosis in Europe (Italy); Hp-I is more common in cirrhosis patients with hepatic encephalopathy (HE) than in those without,5 and HE is not a fully reversible condition. Summarizing the aforementioned data, Hp may be involved in the pathophysiology of cirrhosis-related CD by several mechanisms,4 such as the release of proinflammatory and vasoactive substances, involved through blood-brain barrier (BBB) disruption, in a number of vascular disorders including AD, which can lead to long-term neurologic deficits; promoting platelet-leukocyte aggregation Selleck Lenvatinib proposed to play pathophysiologic roles in AD and liver fibrosis; producing reactive oxygen

metabolites involved in the AD Erastin solubility dmso pathophysiology and complications of cirrhosis; or influencing the apoptotic process, an important form of cell death in AD and cirrhosis. Finally, activated monocytes (possibly infected with Hp due to defective autophagy resulting in Hp replication in autophagic vesicles) might also enter the brain due to BBB disruption contributing to cirrhosis-related CD development associated with falls and fractures.3 Jannis Kountouras M.D., Ph.D.*, Christos Zavos M.D., Ph.D.*, Georgia Deretzi M.D., Ph.D.*, Elizabeth Vardaka Ph.D.*, Marina Boziki M.D.*, Emmanouel Gavalas M.D.*, George Kouklakis M.D., Ph.D.*, Panagiotis Katsinelos M.D., Ph.D.*, Ioannis Venizelos M.D., Ph.D.*, Christina Nikolaidou M.D.*, Stergios A. Polyzos M.D., Ph.D.*, Evaggelia Giartza-Taxidou M.D., Ph.D.*, * Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece. “
“If I have seen a little further it is by standing on the shoulders of giants—Isaac Newton (1676) The vision of the American Association for the Study of Liver Diseases (AASLD) is to prevent and cure liver disease. The journal HEPATOLOGY is a critical tool that the society uses to pursue its vision. By every standard, the journal has been highly successful in this regard.

Eradication rate differences did not reach statistical significance. The most common adverse event, bad taste, occurred in all groups, but more frequently in groups OAC-P (34%) and OAB-C-F (32%), than OAB-M-F (14%) (p < .05). Adverse symptoms score were 0.88 ± 2.05 in group OAB-M-F, 1.15 ± 1.40 in group OAC-P, and 1.87 ± 1.62 in group OAB-C-F. Conclusion:  Furazolidone can replace clarithromycin in H. pylori eradication regimens because of lack of development of resistance and very low cost. "
“Helicobacter pylori infection is a substantial public health problem and plays etiological role in the pathogenesis of many gastroduodenal disorders. The addition of ecabet sodium is proven to improve

the efficacy of the standard triple therapy. Our aim was to assess the efficacy and safety of ecabet Poziotinib chemical structure sodium–containing quadruple therapy versus 10-day bismuth-containing quadruple therapy for H. pylori learn more eradication. We did a randomized, open-label, phase IV

trial in four cities (eight sites) in China, comparing the efficacy and safety of 10-days ecabet sodium–containing versus bismuth-containing quadruple therapy in adults with H. pylori infection. Eligible patients were randomly assigned treatment and monitored H. pylori eradication by negative [13C]/[14C] urea breath test 28 days after the treatment as the primary outcome. Symptoms improvement and side effects were the secondary outcome. A total of 311 H. pylori-positive subjects were enrolled: 155 were assigned ecabet

sodium quadruple therapy and 156 bismuth quadruple therapy. The eradication rates with ecabet sodium–containing and bismuth-containing quadruple regimens were 68.4% (106/155) and 68.0% (106/156) p = .9339 intention-to-treat (ITT) and 75.4% (104/138) and 77.0% (104/135) p = .7453 per-protocol (PP), respectively. The eradication rates for the ecabet sodium quadruple regimen differed significantly between cities (e.g., 81.2% ITT and 89.6% PP in Shanghai and 50% ITT and 53.5% PP in Xi’an). The symptom improvements and safety profiles were also similar for both treatments. Neither 10-day Ecabet sodium–containing quadruple therapy or 10-day bismuth-containing quadruple therapy can be recommended as empiric therapy in cities with high antibiotic resistance rate of China. Anacetrapib “
“Background:  Th immune response plays an important role in Helicobacter pylori (H. pylori) infection. Tim-1 and Tim-3 are expressed on terminally differentiated Th2 and Th1 cells, respectively, and participate in the regulation of Th immune response. Until now, the role of Tim in H. pylori infection remains unclear. Materials and Methods:  (1) Lymphocytes isolated from the spleen of BALB/c mice were co-cultured with different concentrations of viable H. pylori. Alternatively, mice were challenged by viable H. pylori to set up the H. pylori infection model. (2) The expression of Tim-1 and Tim-3 on mRNA level in lymphocytes or spleen of mice was determined by RT-PCR.

marsci.uga.edu/fidoplankter. “
“Microalgal strains for algal biofuels production in outdoor ponds will need to have high net growth rates under diverse environmental conditions. A small,

variable salinity pond in the San Elijo Lagoon estuary in southern California was chosen to serve as a model pond due to its routinely high chlorophyll content. Profiles of microalgal assemblages from water samples collected from April 2011 to January 2012 were obtained by constructing 18S rDNA environmental clone libraries. Pond assemblages were found to be dominated by green algae Picochlorum sp. and Picocystis sp. throughout the year. Pigment analysis suggested that the two species contributed most of the chlorophyll a of the pond, which ranged from 21.9 to 664.3 μg · L−1 with the Picocystis contribution Tanespimycin mouse increasing at higher salinities. However, changes of temperature, learn more salinity or irradiance may have enabled a bloom of the diatom Chaetoceros sp. in June 2011. Isolates of these microalgae were obtained and their growth rates characterized as a function of temperature and salinity. Chaetoceros

sp. had the highest growth rate over the temperature test range while it showed the most sensitivity to high salinity. All three strains showed the presence of lipid bodies during nitrogen starvation, suggesting they have potential as future biofuels strains. “
“Inorganic carbon uptake by Alexandrium catenella

estimated from incorporation of 13C labelled bicarbonate (an estimate of carbon gain by autotrophy) was compared to increases in particulate carbon (PC) that integrate all processes leading to carbon gain by cells (autotrophy, heterotrophy, mixotrophy). During blooms of A. catenella in the field, the 13C tracer technique could account for only 47% (range 29%–59%) of the increase in PC in conventional 24 h incubations. From dilution experiments, the ratio of PC increases cAMP to bicarbonate uptake was related significantly and positively to the grazing rate, indicating that dissolved organic carbon contributes to growth as a direct function of grazing activity. In addition, as grazing rate increases, the contribution of dissolved inorganic carbon uptake to carbon-based growth decreases in a linear way (from 56% to 33% of total C acquisition) and the contribution of non autotrophic processes increases (from 54% to 67%). Thus, grazing appears to closely control the balance between autotrophic and non autotrophic processes leading to carbon acquisition by natural populations of A. catenella. “
“Resource allocation and translocation are fundamental physiological functions for autotrophs. The mobilization and use of resources drive population dynamics by regulating growth and recovery of individuals, but also influences ecosystem-level processes such as primary productivity and carbon cycling.

IL-22R1 has been classically thought to be expressed exclusively in epithelial AZD5363 cells.1-3 Interestingly, our study demonstrates the detection of high levels of IL-22R1 mRNA and protein expression in quiescent and activated primary mHSCs, primary hHSCs, and the human HSC cell line, LX2. HSCs are thought to originate from mesodermal mesothelial cells/submesothelial cells19

and differ from hepatocytes and biliary epithelial cells, which are derived from the embryonic endoderm. Additionally, the expression of IL-22R1 was reported on colonic subepithelial myofibroblasts.20 Therefore, there is evidence that, in addition to epithelial cells, some nonepithelial cells, such as quiescent HSCs, activated HSCs/myofibroblasts, subepithelial myofibroblasts, and skin fibroblasts, also express IL-22R1. Upon binding to IL-22R1 and IL-10R2,

IL-22 promotes epithelial cell (e.g., hepatocyte) proliferation and survival.4 In the present article, we have demonstrated that IL-22 also promotes HSC survival, but induces HSC senescence, rather than Poziotinib price stimulating HSC proliferation. Our study shows that the overexpression of IL-22 by either gene targeting (i.e., transgenic) or the exogenous administration of Ad-IL-22 increased the number of senescent HSCs within the fibrotic scars of the livers of CCl4-treated mice. Furthermore, we show that IL-22 challenge modulates the expression of “senescence-associated secretory phenotype” genes10 by up-regulating proinflammatory genes and MMP-9 and by down-regulating TIMP1/2 genes in the liver Clomifene in vivo and in cultured HSCs in vitro. Finally,

in vitro IL-22 treatment increased SA-β-Gal activity and the expression of the cellular senescence-associated genes, p53 and p21. The up-regulation of these genes likely contributes to IL-22-mediated HSC senescence, because the p53-p21 axis is known to inhibit the cell cycle.21-23 Our study also provided evidence suggesting that the IL-22-dependent up-regulation of p53 and p21 is mediated through STAT3 and SOCS3, resulting in HSC senescence. Although there is no evidence suggesting that STAT3 directly promotes cellular senescence, several STAT3 downstream target genes have been shown to induce cellular senescence, including p53, p21, and the SOCS family.18, 21-24 Our data in this article showed that the deletion of STAT3 abolished the IL-22-mediated induction of p53, p21, and HSC senescence, whereas the overexpression of caSTAT3 promoted HSC senescence (Fig. 6). This suggests that STAT3 plays an important role in IL-22-mediated HSC senescence through the induction of p53 and p21. SOCS3 is an important feedback suppressor for STAT3 activation during normal cytokine signaling. Our results support another aspect of SOCS3 function, in that SOCS3 directly binds to p53, thus enhancing the expression of p53 protein and p53 target genes. The deletion of SOCS3 abolished the IL-22-mediated induction of p53 and p53-regulated genes (Fig. 7).