Gradual crossover in molecular organization of stable liquid H2O at moderately high pressure and temperature

Using the literature raw data of the speed of sound and the specific volume, the isothermal compressibility, κT, a second derivative thermodynamic quantity of G, was evaluated for liquid H2O in the pressure range up to 350 MPa and the temperature to 50 ºC. We then obtained its pressure derivative, dκT/dp, a third derivative numerically without using a fitting function to the κT data. On taking yet another p-derivative at a fixed T graphically without resorting to any fitting function, the resulting d2κT/dp2, a fourth derivative, showed a weak but clear step anomaly, with the onset of the step named point X and its end point Y. In analogy with another third and fourth derivative pair in binary aqueous solutions of glycerol, dαp/dxGly and d2αp/dxGly2, at 0.1 MPa (αp is the thermal expansivity and xGly the mole fraction of solute glycerol) in our recent publication [J. Solution Chem. 43, 663-674 (2014); DOI:10.1007/s10953-013-0122-7], we argue that there is a gradual crossover in the molecular organization of pure H2O from a low to a high p-regions starting at point X and ending at Y at a fixed T. The crossover takes place gradually spanning for about 100 MPa at a fixed temperature. The extrapolated temperature to zero p seems to be about 70 – 80 °C for points X and 90 – 110 °C for Y. Furthermore, the mid-points of X and Y seem to extrapolate to the triple point of liquid, ice Ih and ice III. Recalling that the zero xGly extrapolation of point X and Y for binary aqueous glycerol at 0.1 MPa gives about the same T values respectively, we suggest that at zero pressure the region below about 70 °C the hydrogen bond network is bond-percolated, while above about 90 ºC there is no hydrogen bond network. Implication of these findings is discussed

Analysis of a city‐wide COVID‐19 prevention strategy for aged‐care facilities during third and fifth waves of COVID‐19 in Kyoto City, Kyoto, Japan

[Background] During the third wave of the COVID-19 pandemic at the end of 2020, clusters occurred frequently in aged-care facilities (ACFs), which put pressure on the medical field in Japan. Based on this experience, Kyoto University and Kyoto City collaborated to promote a citywide COVID-19 prevention strategy to prevent the spread of COVID-19 within ACFs. The aim of this study was to clarify the effect of the prevention strategy among ACFs in Kyoto City during the third and fifth waves of the pandemic. [Methods] During the study period, the following measures were adopted as the prevention strategy in all ACFs: (1) active polymerase chain reaction (PCR) mass testing and facility-wide testing when a single case was identified, (2) implementation of strategies to prevent transmission within a facility, and (3) vaccination program for ACFs. [Results] Of the 1, 144 facilities subjected to the mass testing, 71.0% participated in the whole program including active PCR testing. The remainder participated in the rest of the programs. The prevalence of ACF-related COVID-19 cases among total COVID-19 cases in Kyoto City decreased from 7.9% in the third wave to 4.1% in the fourth wave and 2.1% in the fifth wave. The incidence of clusters and proportion of severe elderly cases also decreased during the study period. [Conclusions] A city-wide multidisciplinary effort including PCR mass testing and a vaccination program in cooperation with a university and local administrative office successfully reduced the clusters and transmission in ACFs in Kyoto City, Japan

Clonal Expansion of Multidrug-Resistant <i>Streptococcus dysgalactiae</i> Subspecies <i>equisimilis</i> Causing Bacteremia, Japan, 2005–2021

Incidence of Streptococcus dysgalactiae subspecies equisimilis (SDSE) bacteremia is increasing in the Kyoto-Shiga region of Japan. We retrospectively analyzed clinical features of SDSE bacteremia and conducted comparative genomic analyses of isolates collected from 146 bacteremia episodes among 133 patients during 2005-2021. Of those patients, 7.7% required vasopressor support, and 7.0% died while in the hospital. The prevalence of isolates resistant to erythromycin, minocycline, and clindamycin increased from 8.6% during 2005-2017 to 21.6% during 2018-2021. Our genomic analysis demonstrated that sequence type 525 and clonal complex 25 were predominant in SDSE isolates collected during 2018-2021. In addition, those isolates had acquired 2 antimicrobial-resistance genes, ermB and tetM, via Tn916-like integrative and conjugative elements (ICEs). Phylogenetic analysis revealed clonal distribution of Tn916-like ICEs in SDSE isolates. Our findings suggest that Tn916-like ICEs contributed to the emergence and recent increase of multidrug-resistant SDSE bacteremia in this region of Japan

Response Rate Is Associated with Prolonged Survival in Patients with Advanced Non-small Cell Lung Cancer Treated with Gefitinib or Erlotinib

Introduction:Gaining a higher response rate (RR) has usually been determined as a primary end point in phase II trials evaluating the efficacy of new molecular targeted drugs. However, a relationship between clinical response and survival benefit has not been well studied in the patients treated with molecular targeted agents.Methods:Prospective trials of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) monotherapy in non-small cell lung cancer were extracted from MEDLINE, EMBASE, and the annual meetings in 2007 of the American Society of Clinical Oncology, European Cancer Conference, and World Conference on Lung Cancer.Correlation between clinical response and survival was examined using linear regression analysis. We also tried to compare the significance of RR as surrogate markers for survival with that of disease control rate (DCR) by calculating the area under their receiver operating characteristic (ROC) curves.Results:We identified 24 phase II trials and 4 phase III trials with a total of 6171 patients and 30 treatment arms, including 22 arms for the gefitinib group and 8 arms for the erlotinib group. Both RR and DCR strongly correlated with median survival time (MST; p < 0.0001 and p = 0.003, respectively). In an ROC analysis, the area under the ROC curve predicting MST prolongation by RR was 0.918, which was higher than the area under the ROC curve by DCR.Conclusions:We found a significant relationship between RR and MST in clinical trials with EGFR-TKIs. RR could be an independent surrogate marker for MST in the current response criteria in the clinical trials of EGFR-TKIs

Multiplexed Molecular Profiling of Lung Cancer Using Pleural Effusion

Introduction:Pleural effusion is frequently observed in patients with advanced lung cancer. Although effusion can be obtained less invasively and repeatedly, its use in multiplexed molecular profiling has not been fully investigated.Methods:Between July 2011 and April 2013, pleural effusion samples were obtained from patients with lung cancer at Shizuoka Cancer Center. They were analyzed for EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 mutations, EGFR, MET, FGFR1, FGFR2, and PIK3CA amplifications, and ALK, ROS1, and RET fusion genes using pyrosequensing and/or capillary electrophoresis, quantitative reverse-transcriptase polymerase chain reaction, and reverse-transcriptase polymerase chain reaction, respectively.Results:One hundred and two samples from 84 patients were analyzed. Adenocarcinoma was the most common histological subtype (82%). Genetic abnormalities were detected in 42% of patients. The most common abnormality was EGFR mutation (29%), followed by EML4-ALK rearrangement (5%), KRAS mutation, and EGFR amplification (4%, each). Concordance rates between pleural effusion and matched formalin-fixed, paraffin-embedded samples were 88%. Among 11 patients who provided samples at multiple time points, changes in molecular profile over the course of treatment were observed in five patients.Conclusions:The use of pleural effusion for multiplexed molecular testing and real-time monitoring in lung cancer was demonstrated

KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels

KUS121は新規の心不全治療薬となる --Ca2+負荷なしに血行動態を改善--. 京都大学プレスリリース. 2023-12-15.[Aims] As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models. [Methods and results] Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca²⁺ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors. [Conclusions] KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF

Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis

マイクロRNA-33bの阻害は非アルコール性脂肪肝炎を改善する --核酸医薬による治療応用へ--. 京都大学プレスリリース. 2023-06-13.Nonalcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma in their advanced stages; however, there are currently no approved therapies. Here, we show that microRNA (miR)-33b in hepatocytes is critical for the development of NASH. miR-33b is located in the intron of sterol regulatory element–binding transcription factor 1 and is abundantly expressed in humans, but absent in rodents. miR-33b knock-in (KI) mice, which have a miR-33b sequence in the same intron of sterol regulatory element–binding transcription factor 1 as humans and express miR-33b similar to humans, exhibit NASH under high-fat diet feeding. This condition is ameliorated by hepatocyte-specific miR-33b deficiency but unaffected by macrophage-specific miR-33b deficiency. Anti-miR-33b oligonucleotide improves the phenotype of NASH in miR-33b KI mice fed a Gubra Amylin NASH diet, which induces miR-33b and worsens NASH more than a high-fat diet. Anti-miR-33b treatment reduces hepatic free cholesterol and triglyceride accumulation through up-regulation of the lipid metabolism–related target genes. Furthermore, it decreases the expression of fibrosis marker genes in cultured hepatic stellate cells. Thus, inhibition of miR-33b using nucleic acid medicine is a promising treatment for NASH

Measurement of low-energy antiproton detection efficiency in BESS below 1 GeV

An accelerator experiment was performed using a low-energy antiproton beam to measure antiproton detection efficiency of BESS, a balloon-borne spectrometer with a superconducting solenoid. Measured efficiencies showed good agreement with calculated ones derived from the BESS Monte Carlo simulation based on GEANT/GHEISHA. With detailed verification of the BESS simulation, the relative systematic error of detection efficiency derived from the BESS simulation has been determined to be $\pm$5%, compared with the previous estimation of $\pm$15% which was the dominant uncertainty for measurements of cosmic-ray antiproton flux.Comment: 13 pages, 7 figure

MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons

Recent reports, including ours, have indicated that microRNA (miR)-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here, we show that SPAST, which encodes a microtubule-severing protein called SPASTIN, was a novel target gene of miR-33 in human. Actually, the miR-33 binding site in the SPAST 3′-UTR is conserved not in mice but in mid to large mammals, and it is impossible to clarify the role of miR-33 on SPAST in mice. We demonstrated that inhibition of miR-33a, a major form of miR-33 in human neurons, via locked nucleic acid (LNA)-anti-miR ameliorated the pathological phenotype in hereditary spastic paraplegia (HSP)-SPG4 patient induced pluripotent stem cell (iPSC)-derived cortical neurons. Thus, miR-33a can be a potential therapeutic target for the treatment of HSP-SPG4

Precise Measurement of Cosmic-Ray Proton and Helium Spectra with the BESS Spectrometer

We report cosmic-ray proton and helium spectra in energy ranges of 1 to 120 GeV and 1 to 54 GeV/nucleon, respectively, measured by a balloon flight of the BESS spectrometer in 1998. The magnetic-rigidity of the cosmic-rays was reliably determined by highly precise measurement of the circular track in a uniform solenoidal magnetic field of 1 Tesla. Those spectra were determined within overall uncertainties of +-5 % for protons and +- 10 % for helium nuclei including statistical and systematic errors.Comment: 12 pages, 4 figure