Role of the DELSEED Loop in Torque Transmission of F1-ATPase

AbstractF1-ATPase is an ATP-driven rotary motor that generates torque at the interface between the catalytic β-subunits and the rotor γ-subunit. The β-subunit inwardly rotates the C-terminal domain upon nucleotide binding/dissociation; hence, the region of the C-terminal domain that is in direct contact with γ—termed the DELSEED loop—is thought to play a critical role in torque transmission. We substituted all the DELSEED loop residues with alanine to diminish specific DELSEED loop-γ interactions and with glycine to disrupt the loop structure. All the mutants rotated unidirectionally with kinetic parameters comparable to those of the wild-type F1, suggesting that the specific interactions between DELSEED loop and γ is not involved in cooperative interplays between the catalytic β-subunits. Glycine substitution mutants generated half the torque of the wild-type F1, whereas the alanine mutant generated comparable torque. Fluctuation analyses of the glycine/alanine mutants revealed that the γ-subunit was less tightly held in the α3β3-stator ring of the glycine mutant than in the wild-type F1 and the alanine mutant. Molecular dynamics simulation showed that the DELSEED loop was disordered by the glycine substitution, whereas it formed an α-helix in the alanine mutant. Our results emphasize the importance of loop rigidity for efficient torque transmissions

Site-specific DNA oxidation by a dinuclear copper complex containing a photoisomerizable azobenzene ligand

A dinuclear copper complex possessing an azobenzene backbone (Cu^[II]_[2]1) was synthesized and its affinity towards DNA was investigated and found to be dependent on the trans–cis isomeric forms. Upon exposure to UV light at 365 nm the trans form of the complex (Cu^[II]_[2]trans-1) underwent photoisomerization into the cis-isomer (Cu^[II]_[2]cis-1), which reverted to the original trans-form on exposure to visible light at 420 nm. Both thetrans and cis isomers exhibited moderate DNA cleavage activity toward plasmid duplex DNA in the presence of a reducing agent 3-mercaptopropionic acid (MPA) suggesting that the Cu^[I] species could activate molecular oxygen to form a reactive oxygen species in situ. Interestingly, the isomeric copper complexes showed different site-specificities in the oxidation of an oligodeoxynucleotide having single-strand–double-helix junctions in the sequence. The trans isomer Cu^[I]_[2]trans-1 induced oxidation at the consecutive deoxyguanosine site (GG) near the junction; on the other hand, such site-specificity was not observed in the case of Cu^[I]_[2]cis-1

Gemcitabine and S-1 Combination Chemotherapy in Patients with Advanced Biliary Tract Cancer: A Retrospective Study

Background:The aim of this study was to investigate the efficacy and safety of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. Patients and Methods: A retrospective study was performed on 15 consecutive patients. Gemcitabine was administered intravenously at 1,000 mg/m2 on days 8 and 15. Oral S-1 (60 mg/m2 in 2 divided doses) was given daily for the first 2 weeks, followed by 1 week of rest. This 3-week course of treatment was repeated. The primary endpoint was response rate, and the secondary endpoints were overall survival, progression-free survival, and safety. Results: The overall response rate was 26.7%, and the disease control rate was 73.4%. The overall survival was 12.0 months (95% CI, 9.5–14.5 months), and the progression-free survival was 8.0 months (95% CI, 4.3–11.7 months). Adverse events of grade 3 or 4 occurred in 33.3%, and the major grade 3/4 toxicities were anemia (20.0%), leukopenia (13.3%), and anorexia (13.3%). Conclusion:Gemcitabine and S-1 combination chemotherapy is effective and safe in patients with advanced biliary tract cancer

Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells

RUNX3 is a tumor suppressor for a variety of cancers. RUNX3 suppresses the canonical Wnt signaling pathway by binding to the TCF4/β-catenin complex, resulting in the inhibition of binding of the complex to the Wnt target gene promoter. Here, we confirmed that RUNX3 suppressed Wnt signaling activity in several gastric cancer cell lines; however, we found that RUNX3 increased the Wnt signaling activity in KatoIII and SNU668 gastric cancer cells. Notably, RUNX3 expression increased the ratio of the Wnt signaling-high population in the KatoIII cells. although the maximum Wnt activation level of individual cells was similar to that in the control. As found previously, RUNX3 also binds to TCF4 and β-catenin in KatoIII cells, suggesting that these molecules form a ternary complex. Moreover, the ChIP analyses revealed that TCF4, β-catenin and RUNX3 bind the promoter region of the Wnt target genes, Axin2 and c-Myc, and the occupancy of TCF4 and β-catenin in these promoter regions is increased by the RUNX3 expression. These results suggest that RUNX3 stabilizes the TCF4/β-catenin complex on the Wnt target gene promoter in KatoIII cells, leading to activation of Wnt signaling. Although RUNX3 increased the Wnt signaling activity, its expression resulted in suppression of tumorigenesis of KatoIII cells, indicating that RUNX3 plays a tumor-suppressing role in KatoIII cells through a Wnt-independent mechanism. These results indicate that RUNX3 can either suppress or activate the Wnt signaling pathway through its binding to the TCF4/β-catenin complex by cell context-dependent mechanisms. © 2014 The Authors

Questionnaire survey on the continuity of home oxygen therapy after a disaster with power outages

AbstractBackgroundAfter the Great East Japan Earthquake, oxygen-dependent patients in areas experiencing power outages could not continue home oxygen therapy (HOT) without oxygen cylinders. The purpose of this study was to examine use of oxygen cylinders in areas experiencing power outages and the effects of HOT interruption on patients' health.MethodsQuestionnaires were mailed to 1106 oxygen-dependent patients and HOT-prescribing physicians in Akita, near the disaster-stricken area. We investigated patients' actions when unable to use an oxygen concentrator and classified the patients based on oxygen cylinder use. Patients who experienced an interruption of or reduction in oxygen flow rate by their own judgment were assigned to the “interruption” and “reduction” groups, respectively; those who maintained their usual flow rate were assigned to the “continuation” group. Differences were tested using analysis of variance and the χ2 tests.ResultsIn total, 599 patients responded to the questionnaire. Oxygen cylinders were supplied to 574 patients (95.8%) before their oxygen cylinders were depleted. Comparison of the continuation (n=356), reduction (n=64), and interruption (n=154) groups showed significant differences in family structure (p=0.004), underlying disease (p=0.014), oxygen flow rate (p<0.001), situation regarding use (p<0.001), knowledge of HOT (p<0.001), and anxiety about oxygen supply (p<0.001). There were no differences in changes in physical condition.ConclusionsMost patients could receive oxygen cylinders after the disaster. Some patients discontinued their usual oxygen therapy, but their overall health status was not affected

Regional Carbon Fluxes from Land Use and Land Cover Change in Asia, 1980-2009

We present a synthesis of the land-atmosphere carbon flux from land use and land cover change (LULCC) in Asia using multiple data sources and paying particular attention to deforestation and forest regrowth fluxes. The data sources are quasi-independent and include the U.N. Food and Agriculture Organization-Forest Resource Assessment (FAO-FRA 2015; country-level inventory estimates), the Emission Database for Global Atmospheric Research (EDGARv4.3), the 'Houghton' bookkeeping model that incorporates FAO-FRA data, an ensemble of 8 state-of-the-art Dynamic Global Vegetation Models (DGVM), and 2 recently published independent studies using primarily remote sensing techniques. The estimates are aggregated spatially to Southeast, East, and South Asia and temporally for three decades, 1980&#8211;1989, 1990-1999 and 2000-2009. Since 1980, net carbon emissions from LULCC in Asia were responsible for 20%-40% of global LULCC emissions, with emissions from Southeast Asia alone accounting for 15%-25% of global LULCC emissions during the same period. In the 2000s and for all Asia, three estimates (FAO-FRA, DGVM, Houghton) were in agreement of a net source of carbon to the atmosphere, with mean estimates ranging between 0.24 to 0.41 Pg C yr?1, whereas EDGARv4.3 suggested a net carbon sink of ?0.17 Pg C yr?1. Three of 4 estimates suggest that LULCC carbon emissions declined by at least 34% in the preceding decade (1990-2000). Spread in the estimates is due to the inclusion of different flux components and their treatments, showing the importance to include emissions from carbon rich peatlands and land management, such as shifting cultivation and wood harvesting, which appear to be consistently underreported