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In this study, we examined the pharmacokinetics of nifedipine and investigated the maternal and foetal background factors that prolong pregnancy in pregnant women undergoing long-term tocolysis. This prospective observational study included 38 pregnant women hospitalised for threatened preterm labour and treated with nifedipine extended-release tablets in combination with an intravenous ritodrine infusion. Maternal plasma nifedipine concentrations were determined using high-performance liquid chromatography. All patients were administered 20 or 40 mg/dose of nifedipine every 6 h at the time of blood sampling. The plasma trough concentration (C trough ) was 22.6 ± 17.3 ng/mL, the maximum plasma concentration (C max ) was 30.9 ± 15.3 ng/mL and the time to maximum concentration (T max ) was 1.70 ± 1.10 h, as determined using noncompartmental analysis (NCA). The area under the curve for drug concentration (AUC tau ) was 152.3 ± 91.8 mg/L・h, and oral clearance (CL/F) was 0.17 ± 0.08 L/h. Using logistic regression analyses, we identified the factors that predicted term delivery from 37 weeks to <42 weeks of gestation. Gestational age at admission and the AUC tau of nifedipine can predict term delivery. The AUC tau of nifedipine is a valuable regulatory predictor of term delivery in pregnant women undergoing long-term tocolysis., (© 2023 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Protein-ligand interactions in crowded cellular environments play a crucial role in biological functions. The crowded environment can perturb the overall protein structure and local conformation, thereby influencing the binding pathway of protein-ligand reactions within the cellular milieu. Therefore, a detailed understanding of the local conformation is crucial for elucidating the intricacies of protein-ligand interactions in crowded cellular environments. In this study, we investigated the feasibility of induced circular dichroism (ICD) using 8-anilinonaphthalene-1-sulfonic acid (ANS) for local conformational analysis at the binding site in a crowding environment. Bovine serum albumin (BSA) concentration-dependent measurements were performed to assess the feasibility of ANS-ICD for analyzing protein interior binding sites. The results showed distinct changes in the ANS-ICD spectra of BSA solutions, indicating their potential for analyzing the internal conformation of proteins. Moreover, temperature-dependent measurements were performed in dilute and crowding environments, revealing distinct denaturation pathways of BSA binding sites. Principal component analysis of ANS-ICD spectral changes revealed lower temperature pre-denaturation in the crowded solution than that in the diluted solution, suggesting destabilization of binding sites owing to self-crowding repulsive interactions. The established ANS-ICD method can provide valuable conformational insights into protein-ligand interactions in crowded cellular environments., (© 2023 Wiley-VCH GmbH.)

Industry-academia Collaboration is an academic activity within academia(educational institutions such as universities, research institutes, etc.)formed to research and develop new technologies, create new businesses and knowledge, and recruit outsourcing human resources. There is a collaboration between an industry(a private company, a group that engages in broad commercial activities and links research and development directly to economic activity)and academia. Amidst the dramatic changes in the environment surrounding the goals of research and development of new technologies and the creation of new businesses, there are changes in what academia can do complementarily. We will outline the changes and current situation, including the efforts of the Tohoku University Hospital.

Background: The primary objective of this study was to examine risk factors for toddler's hypertension., Methods: Subjects of this study were children and parents participating in a national birth cohort study in Japan, the Japan Environment and Children's Study. We measured the children's blood pressure (BP) at 2 and 4 years old. We obtained children's and parents' backgrounds from the questionnaire. We investigated the factors that affect BP elevation., Results: Within 4988 participants, the mean systolic BP at 2 years old was 91.2 mmHg for boys and 90.0 mmHg for girls. The mean systolic BP at 4 years old was 93.8 mmHg for boys and 93.1 mmHg for girls. Parental smoking was associated with elevated values of BP at 2 and 4 years old. Obesity, gestational hypertension, and parental lower education were associated with elevated values of BP at 4 years old. Hypertensive group had a significantly higher obesity rate. The mother's lower education and parental smoking were involved in hypertensive groups., Conclusion: Parental smoking had a significant effect on BP even in early toddlers. We emphasize the importance of avoiding second-hand smoking from early infancy to prevent future lifestyle-related illnesses including hypertension., Impact: The mean systolic BP at 2 years old was 91.2 mmHg for boys and 90.0 mmHg for girls. The mean systolic BP at 4 years old was 93.8 mmHg for boys and 93.1 mmHg for girls. Obesity, parental smoking, and lower education were associated with hypertension at 4 years old. Parental smoking was associated with hypertension at 2 and 4 years old. We emphasize the importance of avoiding second-hand smoking from early infancy., (© 2023. The Author(s).)

Background: This study aimed to establish a systematic method for diagnosing atrioventricular nodal reentrant tachycardia (AVNRT) with a bystander concealed nodoventricular pathway (cNVP)., Methods: We analyzed 13 cases of AVNRT with a bystander cNVP, 11 connected to the slow pathway (cNVP-SP) and two to the fast pathway (cNVP-FP), along with two cases of cNVP-related orthodromic reciprocating tachycardia (ORT)., Results: The diagnostic process was summarized in three steps. Step 1 was identification of the presence of an accessory pathway by resetting the tachycardia with delay (n = 9) and termination without atrial capture ( n  = 4) immediately after delivery of a His-refractory premature ventricular contraction (PVC). Step 2 was exclusion of ORT by atrio-His block during the tachycardia ( n  = 4), disappearance of the reset phenomenon after the early PVC ( n  = 7), or dissociation of His from the tachycardia during ventricular overdrive pacing (n = 1). Moreover, tachycardia reset/termination without the atrial capture ( n  = 2/2) 1 cycle after the His-refractory PVC was specifically diagnostic. Exceptionally, the disappearance of the reset phenomenon was also observed in the two cNVP-ORTs. Step 3 was verification of the AVN as the cNVP insertion site, evidenced by an atrial reset/block preceding the His reset/block in fast-slow AVNRT with a cNVP-SP and slow-fast AVNRT with a cNVP-FP or His reset preceding the atrial reset in slow-fast AVNRT with a cNVP-SP., Conclusion: AVNRT with a bystander cNVP can be diagnosed in the three steps with few exceptions. Notably, tachycardia reset/termination without atrial capture one cycle after delivery of a His-refractory PVC is specifically diagnostic., Competing Interests: The authors have no conflict of interest to declare., (© 2023 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background: The timing of primary teeth eruption is a visible indicator of infant physical growth other than body weight or height. It also reflects neurological integrity and development as well as nutrition, socioeconomic state, or underlying diseases. Therefore, the timing of primary teeth eruption is one of the major concerns for parents in health checkups for infants and children. However, the detailed developmental timing of teeth eruption differs depending on the survey methodology, country, or generation. We hypothesized that the timing of primary teeth eruption differs between the medical checkup by dentists and the daily records by parents., Methods: We conducted a questionnaire survey on the date of eruption of primary teeth as an adjunct study among Miyagi Regional Center participants in the Japan Environment and Children's Study (JECS), a large-scale birth cohort study. A total of 1695 responses (3793 participants) were analyzed., Results: The median ages of eruption were 7.1 months (male) and 7.6 months (female) for mandibular primary central incisors, 8.7 months (male) and 9.2 months (female) for maxillary primary central incisors, 10.0 months (male) and 10.3 months (female) for maxillary primary lateral incisors, and 10.4 months (male) and 10.8 months (female) for mandibular primary lateral incisors, which were earlier than the reported timings based on dental check-ups. Comparing the eruption time of preterm and term infants, the eruption time was earlier in preterm infants in the corrected ages., Conclusions: The eruption timing observed and described by the parents is earlier than that examined by dentists at regular check-ups. In addition to examining the primary teeth eruption of full-term birth children, we also examined that of preterm birth children because of the increasing number of premature births. To the best of our knowledge, this is the first report from a large cohort study to clarify the eruption time of primary teeth monitored by parents.

Aims: Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH., Methods: This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death., Results: The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 ( P  = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P  = .009)., Conclusions: The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chida-Nagai, Masaki, Maeda, Sasaki, Sato, Muneuchi, Ochiai, Murayama, Tahara, Shiono, Shinozuka, Kono, Machida, Toyooka, Sugimoto, Nakamura, Akagi, Kondo, Kasahara, Kotani, Koizumi, Oda, Harada, Nakajima, Murata, Nagata, Yatsunami, Kobayashi, Matsunaga, Inoue, Yamagishi, Nakagawa, Ohtani, Yamamoto, Ito, Hokosaki, Kuwahara, Masutani, Nomura, Wada, Sawada, Abiko, Takahashi, Ishikawa, Okada, Naitoh, Toda, Ando, Masuzawa, Hoshino, Kawada, Nomura, Ueno, Ohashi, Tachibana, Cao, Ueda, Yanagi, Koide, Mitsushita, Higashi, Minosaki, Hayashi, Okamoto, Kuraishi, Ehara, Ishida, Horigome, Murakami, Takei, Ishii, Harada, Hirata, Maeda, Tatebe, Ota, Hayabuchi, Sakazaki, Sasaki, Hirono, Suzuki, Yasuda, Takeda, Sawai, Miyaji, Kitagawa, Nakai, Kakimoto, Agematsu, Manabe and Saiki.)

Competing Interests: None

Solute carrier 12 (Slc12) is a family of electroneutral cation-coupled chloride (Cl - ) cotransporters. Na + /K + /2Cl - (Nkcc) and Na + /Cl - cotransporters (Ncc) belong to the Nkcc/Ncc subfamily. Human and mouse possess one gene for the Na + /Cl - cotransporter ( ncc gene: slc12a3 ), whereas teleost fishes possess multiple ncc genes, slc12a3 ( ncc1 ) and slc12a10 ( ncc2 ), in addition to their species-specific paralogs. Amphibians and squamates have two ncc genes: slc12a3 ( ncc1 ) and ncc3 . However, the evolutionary relationship between slc12a10 and ncc3 remains unresolved, and the presence of slc12a10 ( ncc2 ) in mammals has not been clarified. Synteny and phylogenetic analyses of vertebrate genome databases showed that ncc3 is the ortholog of slc12a10 , and slc12a10 is present in most ray-finned fishes, coelacanths, amphibians, reptiles, and a few mammals (e.g., platypus and horse) but pseudogenized or deleted in birds, most mammals, and some ray-finned fishes (pufferfishes). This shows that slc12a10 is widely present among bony vertebrates and pseudogenized or deleted independently in multiple lineages. Notably, as compared with some fish that show varied slc12a10 tissue expression profile, spotted gar, African clawed frog, red-eared slider turtle, and horse express slc12a10 in the ovaries or premature gonads. In horse tissues, an unexpectedly large number of splicing variants for Slc12a10 have been cloned, many of which encode truncated forms of Slc12a10, suggesting that the functional constraints of horse slc12a10 are weakened, which may be in the process of becoming a pseudogene. Our results elaborate on the evolution of Nkcc/Ncc subfamily of Slc12 in vertebrates. NEW & NOTEWORTHY slc12a10 is not a fish-specific gene and is present in a few mammals (e.g., platypus and horse), non-avian reptiles, amphibians, but was pseudogenized or deleted in most mammals (e.g., human, mouse, cat, cow, and rhinoceros), birds, and some ray-finned fishes (pufferfishes).

Background: Postpartum smoking relapse is a serious public health concern. Previous studies have identified several risk factors for postpartum smoking relapse; however, very little is known about the predictors of early postpartum smoking relapse. This study aimed to determine postpartum smoking relapse status and its associated risk factors at 1 month postpartum among Japanese women., Methods: Data were obtained from 93,851 mothers with live births in an ongoing birth cohort study, the Japan Environment and Children's Study. Data on smoking status and confounding variables were collected using self-administered questionnaires and medical record transcripts. Self-administered questionnaires were administered during the first trimester, second/third trimester, and 1 month after delivery. A multiple logistic regression analysis was performed., Results: Among the 14,326 mothers who smoked during pregnancy, 10,917 (76.2%) quit smoking during pregnancy. Subsequently, 617 (5.7%) of the mothers who had quit relapsed smoking at 1 month postpartum. Maternal age (≤24, ≥35), maternal education (≤12 years), parity (≥Second), feeding method (Formula milk), partner smoking status during pregnancy (Smoker), number of cigarettes per day before the cessation of smoking (≥11), maternal alcohol consumption at 1-month postpartum (Drinker), postpartum depression (EPDS score ≥9), and spending time at the parents' home after delivery (≥14 days) were associated with smoking relapse., Conclusions: A certain number of mothers relapsed even 1 month postpartum. Besides mother's alcohol and smoking habit before pregnancy, breastfeeding and partner smoking are important factors in early postpartum smoking relapse in Japan.

Objective: To examine the relationship between timing of smoking cessation during pregnancy and anthropometric indices of newborns., Methods: Mothers and neonates enrolled in the JECS (Japan Environment and Children's Study), a nationwide birth cohort study, were examined. Patients with full-term neonates were included in the analysis, and 73,025 mother-neonate pairs with complete data were identified. The mothers were classified into six groups according to smoking status during pregnancy (nonsmokers [Q1, n=44,198]; ex-smokers who quit before pregnancy [Q2, n=16,461]; ex-smokers who quit in the first trimester [Q3, n=8,948]; ex-smokers who quit in the second trimester [Q4, n=498]; ex-smokers who quit in the third trimester [Q5, n=651]; and smokers who smoked throughout pregnancy [Q6, n=2,269)]). Data on smoking were based on questionnaires administered in the first, second, or third trimester and 1 month after delivery. The primary outcomes were birth weight, height, and head circumference., Results: Compared with nonsmokers (Q1), no adverse outcomes were observed for ex-smokers who quit before pregnancy (Q2). The mean adjusted weights of male and female neonates were 135 g and 125 g lower, respectively, in Q6 participants than in Q1 participants. Comparing Q1 and Q6 participants, height was 0.6 cm and 0.7 cm smaller for male and female neonates, respectively. Head circumference in neonates of Q6 participants was 0.3 cm and 0.3 cm smaller for male and female neonates, respectively, than that in Q1 participants. Across all three measures, smoking cessation in the first and second trimester reduced the differential in outcomes between nonsmokers and individuals who smoked throughout pregnancy., Conclusion: Smoking during pregnancy is associated with reduced newborn birth weight, height, and head circumference. Earlier smoking cessation during pregnancy reduces the adverse effects of smoking on fetal growth., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Kawasaki disease (KD) is a systemic vasculitis syndrome that mostly affects children under 4 years old. Among the reported KD cases, only 1% were over 10 years old. We herein report 2 cases of adult-onset KD (AKD) in 19- and 17-year-old boys diagnosed with a persistent fever and cervical lymphadenitis. Both patients showed cardiac complications, such as coronary artery dilation and myocarditis. Repeated intravenous immunoglobulin therapy was effective in the 19-year-old, while plasma exchange therapy was needed for the 17-year-old, with no sequelae noted at discharge. KD should be considered as a differential diagnosis for persistent fever in adults.

The molecular crowding effect on ligand-protein interactions, which plays several crucial roles in life processes, has been investigated using various models by adding crowding agents to mimic the intracellular environment. Several studies evaluating this effect have focused on the ligand-protein binding reaction of well-structured binding sites with rigid conformations. However, the crowding effect on flexible binding sites is not well-understood, especially in terms of the conformations. In this work, to elucidate the detailed molecular mechanism underlying the ligand-protein interactions with flexible binding sites on a protein surface, we studied the interaction between the basic protrusion of Escherichia coli ribonuclease HI (RNase HI) and 8-anilinonaphthalene-1-sulfonic acid (ANS). The RNase HI concentration-dependent measurement of ANS fluorescence combined with the multivariate analysis and the fluorescence vibronic structure analysis revealed an increase in the heterogeneous species with an increase in the protein concentration, which is a different behavior from that of proteins with rigid binding sites. This result indicates that ANS molecules bind to the additional binding sites because of the destabilization of the main sites by the excluded volume effect in a crowded environment. The fluorescence vibronic structure analysis yields a detailed molecular picture, indicating that the main species of ANS can have a distorted structure. On the other hand, some ANS molecules move to the minor binding sites of a different microenvironment to secure a stabilized structure. These spectroscopic analyses may show a hypothesis, suggesting that the decrease in the Δ G difference between the main and minor sites due to destabilization of the main binding site could lower the potential barrier between them, inducing the dispersion of binding pathways.

The application of proton transfer ionization reaction mass spectrometry (PTR MS) combined with microscale supercritical fluid extraction (SFE) and supercritical fluid chromatography (SFC) aiming to quantitate single-cell fatty acid analysis levels was investigated. Using a microscale extraction vessel, the obtained low limits of quantitation (LLOQs) of arachidonic acid and arachidic acid were 1.2 and 2.7 fmol, respectively, by using less than 1 µL of sample on stainless steel frit. A series of phthalate, vitamin K 1 , and α-tocopherol were also tested, and the LLOQ was less than one femtomole for phthalate and 35 and 13 fmol for vitamin K 1 and α-tocopherol, respectively. A microliter portion of SFE extracts was introduced into the SFC column by split injection, improving the reproducibility of the chromatography and separation efficiency. The method in the present study has great potential to quantitate lipophilic molecules on the nanogram scale of a sample without complex preparation procedures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Noonan syndrome (NS) is a congenital disease with characteristic facial features as well as heart disease, short stature and thoracic abnormalities. More than eighty per cent of patients with NS show several cardiac disorders including pulmonary valvular stenosis, hypertrophic cardiomyopathy (HCM) and/or atrial septal defects. HCM is a serious cardiac comorbidity in patients with NS, especially in those who are diagnosed within 6 months of age with congestive heart failure. Arrhythmia with or without HCM in NS is a rare comorbidity with a complicated clinical course and poor prognosis.In this manuscript, we present the case of a male infant with NS with RAF1 gene mutation, who showed various types of arrhythmias. He developed life-threatening heart failure and uncontrollable arrhythmias. We attempted several antiarrhythmic agents and finally controlled the arrhythmias to establish a normal sinus rhythm with a combination of amiodarone and flecainide., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Induced mutation is a viable breeding strategy that is widely utilized in the development of elite plant varieties. We aimed to improve a variety of edamame by constructing novel mutant populations using the ethyl methanesulfonate in soybeans ( Glycine max (L.) Merr.). In the M 2 population, the flowering stage showed a considerable standard deviation compared to the wild type, confirming that the mutant populations had the expected DNA mutations. To identify the DNA mutations in the mutant populations, we used the targeting induced local lesions in genomes (TILLING) method, which is a reverse genetic method, to search for soybean flowering-related gene mutants. A total of 30 mutants from E1 , E3 , E4 , and PhyA1 genes, which are known to be highly effective genes, or their homologous gene for flowering and maturation found in soybean quantitative trait locus analyses were isolated from our TILLING screening. Among these mutants, there were eleven nonsynonymous substitution mutants, one nonsense mutant, and two single nucleotide deletion mutants that could be expected to reduce or eliminate gene function. The e1 , e3 , and e4 mutants obtained in this study flowered considerably earlier than the wild type. In particular, the e1 mutant with a nonsynonymous substitution flowered approximately 1 month after sowing regardless of the sowing date, and its harvest date was approximately 1 month earlier than that of the wild type. Mutations identified using the TILLING method could not only be used as gel-based DNA markers with the same manipulation method, but the mutations could also be detected as DNA markers by the high-resolution melting method. These results indicate that mutations achieved without chromosome modification by crossbreeding are effective for early and practical improvement of superior varieties and that efficient selection of mutants by reverse genetics is an effective method for the identification of genetic modifications. The edamame mutant populations developed in this study are believed to possess various useful alleles which may be applicable in the search for mutations that lead to improved edamame yield and eating quality beyond the flowering stage.

Background: Tardigrades are microscopic animals that are capable of tolerating extreme environments by entering a desiccated state of suspended animation known as anhydrobiosis. While antioxidative stress proteins, antiapoptotic pathways and tardigrade-specific intrinsically disordered proteins have been implicated in the anhydrobiotic machinery, conservation of these mechanisms is not universal within the phylum Tardigrada, suggesting the existence of overlooked components., Results: Here, we show that a novel Mn-dependent peroxidase is an important factor in tardigrade anhydrobiosis. Through time-series transcriptome analysis of Ramazzottius varieornatus specimens exposed to ultraviolet light and comparison with anhydrobiosis entry, we first identified several novel gene families without similarity to existing sequences that are induced rapidly after stress exposure. Among these, a single gene family with multiple orthologs that is highly conserved within the phylum Tardigrada and enhances oxidative stress tolerance when expressed in human cells was identified. Crystallographic study of this protein suggested Zn or Mn binding at the active site, and we further confirmed that this protein has Mn-dependent peroxidase activity in vitro., Conclusions: Our results demonstrated novel mechanisms for coping with oxidative stress that may be a fundamental mechanism of anhydrobiosis in tardigrades. Furthermore, localization of these sets of proteins mainly in the Golgi apparatus suggests an indispensable role of the Golgi stress response in desiccation tolerance., (© 2022. The Author(s).)

Proton-transfer-reaction (PTR) mass spectrometry (MS), a widely used method for detecting trace-levels of volatile organic compounds in gaseous samples, can also be used for the analysis of small non-volatile molecules by using supercritical fluid as a transporter for the molecules. Supercritical fluid extraction (SFE) is a method that permits lipophilic compounds to be rapidly and selectively extracted from complex matrices. The combination of the high sensitivity of PTR MS with the SFE is a potentially novel method for analyzing small molecules in a single cell, particularly for the analysis of lipophilic compounds. We preliminarily evaluated this method for analyzing the components of a single HeLa cell that is fixed on a stainless steel frit and is then directly introduces the SFE extracts into the PTR MS. A total of 200/91 ions were observed in positive/negative ion mode time-of-flight mass spectra, and the masses of 11/10 ions could be matched to chemical formulae obtained from the LipidMaps lipids structure database. Using various authentic lipophilic samples, the method could be used to detect free fatty acids in the sub-femtomole to femtomole order in the negative ion mode, the femtomole to sub-picomole order for fat-soluble vitamins, and the picomole order for poly aromatic hydrocarbons in both the positive and negative ion mode., (Copyright © 2022 Toshinobu Hondo, Chihiro Ota, Kohta Nakatani, Yumi Miyake, Hiroshi Furutani, Takeshi Bamba, and Michisato Toyoda.)

Background: Recent advancements in a 3-dimensional mapping system allow for the assessment of detailed conduction properties during sinus rhythm and thus the establishment of a strategy targeting functionally abnormal regions in scar-related ventricular tachycardia (VT). We hypothesized that a rotational activation pattern (RAP) observed in maps during baseline rhythm was associated with the critical location of VT., Methods: We retrospectively examined the pattern of wavefront propagation during sinus rhythm in patients with scar-related VT. The prevalence and features of the RAP on critical VT circuits were analyzed. RAP was defined as >90° of inward curvature directly above or at the edge of the slow conductive areas., Results: Forty-five VTs in 37 patients (66±15 years old, 89% male, 27% ischemic heart disease) were evaluated. High-density substrate mapping during sinus rhythm (median, 2524 points) was performed using the CARTO3 system before VT induction. Critical sites for reentry were identified by direct termination by radiofrequency catheter ablation in 21 VTs or by pace mapping in 12 VTs. Among them, RAP was present in 70% of the 33 VTs. Four VTs had no RAP at the critical sites during sinus rhythm, but it became visible in the mappings with different wavefront directions. Six VTs, in which intramural or epicardial isthmus was suspected, were rendered noninducible by radiofrequency catheter ablation to the endocardial surface without RAP. RAP had a sensitivity and specificity of 70% and 89%, respectively, for predicting the elements in the critical zone for VT., Conclusions: The critical zone of VT appears to correspond to an area characterized by the RAP with slow conduction during sinus rhythm, which facilitates targeting areas specific for reentry. However, this may not be applicable to intramural VT substrates and might be affected by the direction of wavefront propagation to the scar during mapping. Graphic Abstract: A graphic abstract is available for this article.

We have developed a rapid and sensitive analytical method for α-tocopherol and its oxidative products by combining online hyphenation of supercritical fluid extraction-supercritical fluid chromatography (SFC) with proton transfer reaction (PTR) ionization mass spectrometry (MS). α-Tocopherol is a well-known antioxidant that plays a vital role in the antioxidant defense system in plant cells. However, studies on the cellular mechanisms of α-tocopherol have been limited owing to the lack of a rapid analytical method, which limits the comparison of plant cells incubated in various conditions. Additionally, complex sample preparation and long chromatography separation times are required. Moreover, the majority of the involved molecules are a combination of isomers, which must be separated before applying tandem MS. α-Tocopherol produces the α-tocopheroxyl radical in the first step of its antioxidant function; another ion with the same mass may also be generated from the source. SFC separation effectively distinguished the observed ions from their oxidative products in the sample and those produced during the ionization reaction process. This method enabled the measurement of α-tocopherol and its oxidative products such as α-tocopheroxyl radical and α-tocopheryl quinone in approximately 3 min per sample, including the time required for sample preparation., (Copyright © 2022 Chihiro Ota, Toshinobu Hondo, Yumi Miyake, Hiroshi Furutani, and Michisato Toyoda.)

Streptococcus thermophilus bacteria, which are widely used as fermented starter for dairy production, exert various beneficial health effects. Nevertheless, even though pro-longevity effects of various probiotics have been reported, no report has described Streptococcus thermophilus effects on longevity. This study was conducted to evaluate Streptococcus thermophilus effects on lifespan extension and to elucidate the Streptococcus thermophilus -mediated longevity mechanism using Caenorhabditis elegans worms as a model animal. They were fed standard food ( Escherichia coli OP50) or Streptococcus thermophilus from the young adult stage. Feeding with Streptococcus thermophilus , compared to Escherichia coli OP50, to Caenorhabditis elegans extend the lifespan, reduced lipofuscin accumulation, and maintain vigorous locomotion. Feeding with Streptococcus thermophilus did not alter the worm growth curve or the offspring number, indicating that the Streptococcus thermophilus -mediated lifespan extension is not attributable to caloric restriction. The qRT-PCR data showed that Streptococcus thermophilus increased the expression of daf-16 and some of its downstream antioxidant genes. Furthermore, the pro-longevity effects of Streptococcus thermophilus were decreased in loss-of-function mutant of daf-16 . Results show that Streptococcus thermophilus extends the lifespan of Caenorhabditis elegans through DAF-16-mediated antioxidant pathway activation., Competing Interests: YK is a salaried employee of the Mill Souhonsha Company Limited. This does not alter our adherence to JCBN policies on sharing data and materials. YN received scholarship funds from EA Pharma Co. Ltd. and Taiyo Kagaku Co., Ltd.; a collaboration research funds from Taiyo Kagaku Co., Ltd. and Mill Souhonsha Co. Ltd.; and received lecture fees by Mylan EPD Co., Takeda Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd., EA Pharma Co. Ltd., Otsuka Pharmaceutical Co. Ltd., and Miyarisan Pharmaceutical Co. Ltd. The present research was partly supported by these funds. Neither the funding agency nor any outside organization has participated in the study design or have any competing interests. These companies had final approval of the manuscript. The other authors have no conflict of interest to disclose., (Copyright © 2022 JCBN.)

Femtosecond time-resolved transient absorption spectroscopy was performed for a nonfluorescent solvatochromic dye, phenol blue, N -(4-dimethylaminophenyl)-1,4-benzoquinoneimine, which exhibits ultrafast nonradiative decay due to its flexible molecular structure. By exciting the molecule in ethanol (EtOH) solution with two excitation wavelengths located at shorter- and longer-wavelength sides of the visible absorption band, we observed ultrafast nonradiative decay from the excited state, followed by spectral evolution in the ground state. The nonradiative decay in the subpicosecond range creates a vibrationally hot ground state with the lifetime in the picosecond range. Subsequently, a tautomer that absorbs at shorter wavelengths is produced from the hot state, which causes a red shift of the ground-state bleach (GSB). The tautomerization presumably involves twisting of the benzoquinoneimine moiety induced by the breaking of the hydrogen bond (H-bond) between the solute and the solvent molecules. The recombination of the H-bond occurs with a time constant of ∼30 ps, and the system returns to its original state. We also observed low-frequency coherent wavepacket oscillations that modulate the GSB with dephasing times similar to the excited-state lifetime.

To establish appropriate ex vivo models for a glaucomatous trabecular meshwork (TM), two-dimensional (2D) and three-dimensional (3D) cultures of human trabecular meshwork cells (HTM) were prepared in the presence of 250 nM dexamethasone (DEX) or 5 ng/mL TGFβ2, and characterized by the following analyses; transendothelial electrical resistance (TEER) measurements, FITC dextran permeability, scanning electron microscopy and the expression of the extracellular matrix (ECM) including collagen (COL)1, 4 and 6, and fibronectin (FN), α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase (TIMP)1-4, and matrix metalloproteinase (MMP)2, 9 and 14. DEX and TGFβ2 both caused a significant increase or decrease in the TEER values and FITC dextran permeability. During the 3D spheroid culture, DEX or TGFβ2 induced a mild and significant down-sizing and an increase in stiffness, respectively. TGFβ2 induced a significant up-regulation of COL1 and 4, FN, α-SMA, and MMP 2 and 14 (2D) or COL1 and 6, and TIMP2 and 3 (3D), and DEX induced a significant up-regulation of FN (3D) and TIMP4 (2D and 3D). The findings presented herein indicate that DEX or TGFβ2 resulted in mild and severe down-sized and stiff 3D HTM spheroids, respectively, thus making them viable in vitro HTM models for steroid-induced and primary open angle glaucoma., (© 2021. The Author(s).)

The self-face advantage has been demonstrated not only at the supraliminal level, but also at the subliminal level. However, it remains unclear whether subliminal self-face processing involves the same neural networks as those for supraliminal self-face processing. Here, we show that the ventral tegmental area, a center of the dopamine reward pathway, exhibited greater activation to subliminal presentations of the self-face than those of the others' faces, whereas subliminal presentations of the others' faces induced activation in the amygdala, which generally responds to unfamiliar information. This self-other difference in brain response was consistently observed even when the facial configuration was modified without changing the shape of the facial parts. The present findings suggest that the dopamine reward pathway is involved in automatic self-advantage in face processing, and the subliminal self-other facial discrimination does not depend on information of the precise facial configuration., (© The Author(s) 2021. Published by Oxford University Press.)

A pan-ROCK-inhibitor, ripasudil (Rip), and a ROCK2 inhibitor, KD025, were used To study the effects of Rho-associated coiled-coil containing protein kinase (ROCK)1 and 2 on two-dimensional (2D) and three-dimensional (3D) cultures of a TGFβ2-treated human trabecular meshwork (HTM) cells. In the presence of 5 ng/mL TGFβ2, the effects of these inhibitors were characterized by transendothelial electrical resistance (TEER), FITC-dextran permeability, and the size and stiffness of 3D sphenoids, the expression of extracellular matrix (ECM) including collagen1, 4 and 6, and fibronectin, α-smooth muscle actin, a tissue inhibitor of metalloproteinase (TIMP)1-4, and matrix metalloproteinase (MMP)2, 9 and 14. TGFβ2 caused a significant increase in the TEER values, and decrease in FITC-dextran permeability, as well as a decrease in the sizes and stiffness of the 3D sphenoids. In the presence of ROCK inhibitors, the TGFβ2-induced effects of the TEER and FITC-dextran permeability were inhibited, especially by KD025. Rip induced a significant increase in sizes and a decrease in the stiffness of the TGFβ2-treated 3D sphenoids, although the effects of KD025 were weaker. Gene expressions of most of the ECMs, TIMP2 and MMP9 of 2D and 3D HTM cells were significantly up-regulated by TGFβ2. Those were significantly and differently modulated by Rip or KD025., (© 2021. The Author(s).)

Proton-transfer-reaction (PTR) mass spectrometry (MS) is capable of detecting trace-level volatile organic compounds (VOCs) in gaseous samples in real time. Therefore, PTR-MS has become a popular method in many different study areas. Most of the currently reported PTR-MS applications are designed to determine volatile compounds. However, the method might be applicable for nonvolatile organic compound detection. Supercritical fluid chromatography (SFC) has been studied in the last 5 decades. This approach has high separation efficiency and predictable retention behavior, making separation optimization easy. Atmospheric ionization techniques, such as atmospheric chemical ionization (APCI) and electrospray ionization (ESI), are the most studied SFC-MS interfaces. These processes require the addition of makeup solvents to prevent precipitation or crystallization of the solute while depressurizing the mobile phase. In contrast, the PTR process is carried out in a vacuum; supercritical carbon dioxide may release solute into the PTR flow tube without a phase transition as long as it is maintained above a critical temperature. Therefore, this might constitute yet another use for the SFC-MS interface. Caffeine and a few other nonpolar compounds in supercritical carbon dioxide were successfully detected with time-of-flight MS without adding solvent by using preliminarily assembled supercritical flow injection and supercritical fluid extraction (SFE)-PTR interfaces.

Beauty filters, while often employed for retouching photos to appear more attractive on social media, when used in excess cause images to give a distorted impression. The neural mechanisms underlying this change in facial attractiveness according to beauty retouching level remain unknown. The present study used functional magnetic resonance imaging in women as they viewed photos of their own face or unknown faces that had been retouched at three levels: no, mild, and extreme. The activity in the nucleus accumbens (NA) exhibited a positive correlation with facial attractiveness, whereas amygdala activity showed a negative correlation with attractiveness. Even though the participants rated others' faces as more attractive than their own, the NA showed increased activity only for their mildly retouched own face and the amygdala exhibited greater activation in the others' faces condition than the own face condition. Moreover, amygdala activity was greater for extremely retouched faces than for unretouched or mildly retouched faces for both conditions. Frontotemporal and cortical midline areas showed greater activation for one's own than others' faces, but such self-related activation was absent when extremely retouched. These results suggest that neural activity dynamically switches between the NA and amygdala according to perceived attractiveness of one's face.

8-Anilino-1-naphthalenesulfonic acid (ANS) is used as a hydrophobic fluorescence probe due to its high intensity in hydrophobic environments, and also as a microenvironment probe because of its unique ability to exhibit peak shift and intensity change depending on the surrounding solvent environment. The difference in fluorescence can not only be caused by the microenvironment but can also be affected by the binding affinity, which is represented by the binding constant ( K ). However, the overall binding process considering the binding constant is not fully understood, which requires the ANS fluorescence binding mechanism to be examined. In this study, to reveal the rate-limiting step of the ANS-protein binding process, protein concentration-dependent measurements of the ANS fluorescence of lysozyme and bovine serum albumin were performed, and the binding constants were analyzed. The results suggest that the main factor of the binding process is the microenvironment at the binding site, which restricts the attached ANS molecule, rather than the attractive diffusion-limited association. The molecular mechanism of ANS-protein binding will help us to interpret the molecular motions of ANS molecules at the binding site in detail, especially with respect to an equilibrium perspective.

Recent advances in 3D bioprinting allow for generating intricate structures with dimensions relevant for human tissue, but suitable bioinks for producing translationally relevant tissue with complex geometries remain unidentified. Here, a tissue-specific hybrid bioink is described, composed of a natural polymer, alginate, reinforced with extracellular matrix derived from decellularized tissue (rECM). rECM has rheological and gelation properties beneficial for 3D bioprinting while retaining biologically inductive properties supporting tissue maturation ex vivo and in vivo. These bioinks are shear thinning, resist cell sedimentation, improve viability of multiple cell types, and enhance mechanical stability in hydrogels derived from them. 3D printed constructs generated from rECM bioinks suppress the foreign body response, are pro-angiogenic and support recipient-derived de novo blood vessel formation across the entire graft thickness in a murine model of transplant immunosuppression. Their proof-of-principle for generating human tissue is demonstrated by 3D bioprinting human airways composed of regionally specified primary human airway epithelial progenitor and smooth muscle cells. Airway lumens remained patent with viable cells for one month in vitro with evidence of differentiation into mature epithelial cell types found in native human airways. rECM bioinks are a promising new approach for generating functional human tissue using 3D bioprinting., (© 2020 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

The effect of salt on the electrostatic interaction of a protein is an important issue, because addition of salt affects protein stability and association/aggregation. Although adding salt is a generally recognized strategy to improve protein stability, this improvement does not necessarily occur. The lack of an effect upon the addition of salt was previously confirmed for the tenth fibronectin type III domain from human fibronectin (FN3) by thermal stability analysis. However, the detailed molecular mechanism is unknown. In the present study, by employing the negatively charged carboxyl triad on the surface of FN3 as a case study, the molecular mechanism of the inefficient NaCl effect on protein stability was experimentally addressed using spectroscopic methods. Complementary analysis using Raman spectroscopy and 8-anilino-1-naphthalenesulfonic acid fluorescence revealed the three-phase behavior of the salt-protein interaction between NaCl and FN3 over a wide salt concentration range from 100 mM to 4.0 M, suggesting that the Na + -specific binding to the negatively charged carboxyl triad causes a local conformational change around the binding site with an accompanying structural change in the overall protein, which contributes to the protein's structural destabilization. This spectroscopic evidence clarifies the molecular understanding of the inefficiency of salt to improve protein stability. The findings will inform the optimization of formulation conditions.

To elucidate molecular pharmacology of Rho-associated coiled-coil containing protein kinase inhibitors (ROCK-i, Ripasudil and Y27632) on their efficiency for aqueous outflow, 2D or 3D cultures of a human trabecular meshwork (HTM) were prepared in the presence of TGFβ2. Those were examined by transendothelial electrical resistance (TEER, 2D), electronic microscopy (EM, 2D and 3D), expression of the extracellular matrix (ECM) including collagen1 (COL1), COL4 and COL6, and fibronectin (FN) by immunolabeling and/or quantitative PCR (3D), and solidity of 3D organoids by a micro-squeezer. TGFβ2 significantly increased the TEER values in 2D cultures, and the ECM expression indicated that the 3D organoids assumed a more densely packed shape. ROCK-i greatly reduced the TGFβ2-induced enhancement of TEER and the immunolabeled ECM expression of the 3D organoids. In contrast, the mRNA expression of COL1 was increased, and those of COL4 and FN were unchanged. EM revealed that TGFβ2 caused the HTM cells to become more compact and abundant ECM deposits within the 3D organoids were observed. These were significantly inhibited by ROCK-i. The dense solids caused by the presence of TGFβ2 were significantly suppressed by ROCK-i. Current study indicates that ROCK-i cause beneficial effects toward the spatial configuration of TGFβ2-induced HTM 3D organoids.

Wnt/β-catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/β-catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/β-catenin responsive progenitor cells and the potential impact of Wnt/β-catenin signaling on adult distal lung epithelial progenitor cell function in emphysema are poorly understood. Here, we used TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/β-catenin signaling in lung organoid formation. We identified an organoid-forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/β-catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. Endogenous Wnt/β-catenin activity was required for the initiation of multiple subtypes of distal lung organoids derived from the Wnt low epithelial progenitors. Further ectopic Wnt/β-catenin activation specifically led to an increase in alveolar organoid number; however, the subsequent proliferation of alveolar epithelial cells in the organoids did not require constitutive Wnt/β-catenin signaling. Distal lung epithelial progenitor cells derived from the mouse model of elastase-induced emphysema exhibited reduced organoid forming capacity. This was rescued by Wnt/β-catenin signal activation, which largely increased the number of alveolar organoids. Together, our study reveals a novel mechanism of lung epithelial progenitor cell activation in homeostasis and emphysema., (©2020 The Authors. Stem Cells published by Wiley Periodicals LLC on behalf of AlphaMed Press 2020.)

Mirogabalin is a novel drug for alleviating peripheral neuropathic pain, available since April 2019 in Japan. Since cancer pain was not included as an outcome in clinical trials for product approval, there have been no reports on its effectiveness or safety for treating cancer pain. The purpose of this study was to evaluate the effectiveness and safety of mirogabalin for patients with cancer pain. During the 5 months from April to August 2019, our palliative care team prescribed mirogabalin to 34 patients who had not achieved effective analgesia even after opioid titration. Effectiveness was defined as(1)reduction in persistent pain of 50% or more on the numeric rating scale(NRS); or(2)reduction in the frequency of rescue medicine of 50% or more for breakthrough pain. Based on this definition, the rate of effectiveness of mirogabalin was 88.2%. Two patients experienced mild side effects in the central nervous system. However, these effects did not result in discontinuation of the medication. The results of the study showed that mirogabalin can be used effectively and safely for cancer pain relief.

A cavity-filling mutation at a hydrophobic cavity is a useful method for increasing protein stability. This method, however, sometimes destabilizes the protein because of the accompanying structural changes by the steric hindrance around the cavity. Thus, detailed knowledge of unfavorable structural changes is important for a comprehensive understanding of the cavity-filling mutation. In the present study, by employing the cavity-filling mutant of Escherichia coli RNase HI as a case study, the structural change induced by the substitution of Phe for Ala 52 (Ala52Phe) was analyzed in detail using Raman spectroscopy. In previous studies, the thermodynamic result apparently indicated a small decrease in Δ G (destabilization) by the mutation. In the present study, Raman differential spectra show a clear structural difference between wild-type E. coli RNase HI and Ala52Phe. Consequently, the direct signature of the conformational strains around the protein cavity is readily acquired, leading to further understanding of the trade-off relationship between the cavity-filling and incidental steric hindrance.

Human clinical specimens are a valuable source of tissue-resident stem cells, but such cells need to be collected immediately after tissue collection. To extend the timescale for collection from fresh human samples, we developed a new extracellular fluid (ECF)-type preservation solution based on a high-sodium and low-potassium solution containing low-molecular-weight dextran and glucose, which is used for preservation of organs for transplantation. In this study, we compared the preservation of tissue-resident stem cells using our ECF solution with that using three other solutions: PBS, Dulbecco's modified Eagle's medium and Euro-Collins solution. These solutions represent a common buffer, a common culture medium and a benchmark organ-preservation solution, respectively. Lung tissues were removed from mice and preserved for 72 h under low-temperature conditions. Of the solutions tested, only preservation in the ECF-type solution could maintain the proliferation and differentiation capacity of mouse lung tissue-resident stem cells. In addition, the ECF solution could preserve the viability and proliferation of human alveolar epithelial progenitor cells when stored for more than 7 days at 4 °C. The mean viability of human alveolar type II cells at 2, 5, 8 and 14 days of low-temperature preservation was 90.9%, 84.8%, 85.7% and 66.3%, respectively, with no significant differences up to 8 days. Overall, our findings show that use of our ECF-type preservation solution may maintain the viability and function of tissue-resident stem cells. Use of this preservation solution may facilitate the investigation of currently unobtainable human tissue specimens for human stem cell biology., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

The molecular behaviors of proteins under crowding conditions are crucial for understanding the protein actions in intracellular environments. Under a crowded environment, the distance between protein molecules is almost the same size as the molecular level, thus, both the excluded volume effect and short ranged soft chemical interaction on protein surface could induce the complicated influence on the protein behavior cooperatively. Recently, various kinds of analytical approaches from macroscopic to microscopic aspects have been made to evaluate the crowding effect. The method, however, has not been established to evaluate the surface specific interactions on protein surface. In this study, the analytical method to evaluate the crowding effect has been suggested by using a charge-transfer fluorescence probe, ANS. By employing the unique property of ANS attaching to charged residues on the surface of lysozyme, the crowding effect was focused, while the case was compared as a reference, in which ANS is confined in hydrophobic pockets of BSA. Consequently, the surface specific changes of fluorescence spectra were readily observed under the crowded environment, whereas the fluorescence spectra of ANS in protein inside did not change. This result suggests the fluorescence spectra of ANS binding to protein surface have the capability to estimate the crowding effect of proteins., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

PHACES syndrome is an uncommon neurocutaneous disorder first identified in 1996. Patients with PHACES syndrome often require surgical treatment for their anomalies, including intracranial vasculopathy, coarctation/interruption of the aorta, intracardiac defects, glaucoma/cataract and sternal defects. Risk factors associated with the symptoms of intraoperative/perioperative management include ischaemic stroke due to the cerebral vasculopathy, airway obstruction due to the subglottic/tracheal haemangiomas and massive bleeding due to the large haemangiomas. Recently, propranolol is considered as first-line therapy for patients with infantile haemangiomas (IHs). However, until now, there have been no reported cases of PHACES syndrome treated by propranolol to reduce the surgical risks associated with IH. In this report, we describe a case of a 14-month-old Japanese girl with PHACES syndrome treated by propranolol for IH before surgical closure of the ventricular septum defect. Oral administration of propranolol was effective in decreasing the size of IH, leading to the uneventful perioperative course., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The existence of atypical fast-slow (F/S) atrioventricular (AV) nodal reentrant tachycardias (NRT) using slow pathway (SP) variants connected to the right atrial (RA) inferolateral (inf) free wall (FW) along the tricuspid annulus (TA), has been neither confirmed nor precisely characterized. Methods and Results: We studied 7 patients (mean age, 48±16 years; 5 men) with F/S-AVNRT with long RP intervals and an earliest atrial activation at the RA inf-FW along the TA (inf-F/S-AVNRT). AV reentrant tachycardia was excluded on observation of the transition zone criteria in all 7 patients. Atrial tachycardia was excluded on the observation of a V-A-V activation sequence after the induction or entrainment of the tachycardia from the right ventricle in all. During the tachycardia, low-frequency, fractionated potentials (LP) preceding the local atrial electrogram were recorded near the site of the earliest atrial activation in 6 patients. Observations of conduction delay and block of the LP during ventricular entrainment or ablation of the tachycardia indicated that LP reflect retrograde activation via the inf-SP. Retrograde SP conduction was interrupted at the site of earliest atrial activation in 3 patients, and in the right posterior septum in 4 patients. Conclusions: inf-F/S-AVNRT are distinct supraventricular tachycardia incorporating an SP variant connected to the RA inf-FW along the TA in the retrograde direction, which were eliminated by ablation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019, THE JAPANESE CIRCULATION SOCIETY.)

For photosynthetic organisms that nourish the earth's biosphere, chlorophylls (Chls) are the major pigments utilized for light harvesting and primary charge separation. Although Chl molecules are effective photosensitizers, they are inevitably phototoxic to living organisms due to the facile generation of highly oxidative singlet oxygen ( 1 O 2 ) through triplet energy transfer from their photoexcited states to oxygen molecules. Such phototoxicity of Chls is a major problem for translucent microbes that feed on photosynthetic algae. Recently, it has been reported that the metabolic conversion of Chls-a/b to 13 2 ,17 3 -cyclopheophorbide-a/b enols (cPPB-a/bEs) is the detoxification mechanism for algivorous protists. cPPB-a/bEs are colored π-conjugated cyclic tetrapyrroles but are nonfluorescent due to efficient nonradiative decay. In this study, femtosecond time-resolved transient absorption spectroscopy was applied to cPPB-aE with the aim of understanding its quenching mechanism. As a result, we have captured the ultrafast generation of an intermediate state (∼140 fs) that leads to the rapid internal conversion to the ground state (∼450 fs).

At present, there are few reports that have clarified the effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPSV23) against all-cause pneumonia or pneumococcal pneumonia in community-acquired pneumonia (CAP) in older individuals in Japan. We conducted a hospital-based matched case-control study to investigate separately the preventive effects of PPSV23 and trivalent influenza vaccine (TIV) on all-cause CAP and pneumococcal CAP in older individuals in Japan. Cases were individuals aged 65 years or older who were newly diagnosed with CAP from October 2010 to September 2014. Two control patients with a different disease (one respiratory medicine and one non-respiratory medicine) matched for sex, age, date of outpatient visit, and medical institution were selected for each case. Odds ratios (ORs) and 95% confidence intervals (CIs) of PPSV23 and TIV for the occurrence of all-cause CAP and pneumococcal CAP were calculated using conditional and unconditional logistic regression models. The analysis included 161 cases and 308 controls from the 4-year period. The adjusted OR for the occurrence of all-cause CAP was 0.76 (95%CI = 0.44-1.32) with PPSV23 vaccination and 0.79 (95%CI = 0.50-1.25) with TIV vaccination compared with unvaccinated individuals. When the outcome index was restricted to pneumococcal CAP, the adjusted OR significantly decreased to 0.23 (95%CI = 0.08-0.66) with PPSV23 vaccination, but not with TIV vaccination (adjusted OR = 0.65, 95%CI = 0.31-1.36). PPSV23 vaccination is likely effective in reducing incidence of pneumococcal CAP in older individuals, although its preventive effect for all-cause CAP has not been achieved.

Background: In patients undergoing breast-conserving surgery and having positive sentinel lymph nodes (SLNs), the ACOSOG Z0011 trial showed equivalent loco-regional outcomes for patients receiving SLN dissection (SLND) alone and those receiving axillary lymph node dissection (ALND). We conducted a prospective single-arm study to confirm the applicability of the Z0011 criteria to Japanese patients with breast cancer., Methods: Patients meeting the Z0011 inclusion criteria and providing consent to receive no additional ALND were prospectively enrolled at the Osaka International Cancer Institute from April 2012 to December 2016. Cumulative incidence of loco-regional recurrence was estimated and compared to that of the Z0011 study., Results: Among a total of 881 patients who underwent breast-conserving surgery, 189 fulfilling the Z0011 criteria were enrolled and eligible for the subsequent analysis. Adjuvant chemotherapy was given to 113 (59.8%) patients, adjuvant hormone therapy to 170 (89.9%), and whole breast irradiation to 183 (96.8%). The frequency of tumors with positive lymphovascular invasion (p < 0.0001) and macrometastases in SLNs (p < 0.0001) were significantly higher in our study than in the Z0011 study. At the median follow-up of 36 months (range 10-64 months), only 2 of 189 patients (1.1%) experienced loco-regional recurrence. The 5-year cumulative rate of loco-regional recurrences was 1.3% (95% CI 0-3.1%), and the 3-year distant DFS rate was 96.8% (95% CI 94.0-99.6%)., Conclusions: Our prospective study showed that it is feasible to apply the Z0011 strategy to Japanese patients with clinically node-negative breast cancer undergoing breast-conserving surgery with planned whole breast irradiation.