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The variable shape function enables attitude and orbit control by actively changing the shape of a spacecraft on orbit. In order to demonstrate this function on orbit, we developed the "HIBARI" satellite equipped with drivable solar array paddles and demonstrated the world's first in-orbit variable shape attitude control in FY2021. The present study first compares the behavior of the paddle drive on the ground and on orbit to evaluate its performance. In addition, attitude change angle data from paddle drive on orbit is used for comparison with analytical values and evaluation control performance. [ABSTRACT FROM AUTHOR]

This paper discusses an indoor positioning technique aimed at human-centric services such as pedestrian navigation or service robots. The method is called "CEPHEID" and uses a light flickering pattern as an environmental fingerprint. The authors found that each lighting fixture has unique and distinguishable flickering characteristics. In this paper, CEPHEID is introduced as a "classifier" and its validity is shown based on experimental results. Additionally, an approach for improving the positional precision is proposed. The classifier and regressor are combined to create a zone-classified regressor model for CEPHEID. The basic performance of this concept is also tested using an experiment. [ABSTRACT FROM AUTHOR]

Entireleaf morning glory (Ipomoea hederacea Jacq. var. integriuscula A. Gray) is a difficult-to-control weed that causes severe yield loss in soybean (Glycine max L.). It invades fields from the field margins and contributes to maintenance of the populations in the fields. This study aimed to determine the optimal period to control the populations in field margins effectively. We identified the naturally emerging plants in field margins and adjacent fields. We recorded the number of invading vines and the timing of flowering and fruiting of several cohorts (each cohort comprised a group of individuals that emerged within a certain time frame). The main seed-producing cohort on the field margins was a cohort that emerged from early August to mid-September and flowered and fruited after mid-September. The weed formed seed banks in the field margins, maintained by repeated depletion and accumulation during the emergence and seed production stages. The weed control rate by weed management practices was higher in field margins (100%) than in the fields (76%). In conclusion, the entireleaf morning glory populations were maintained by specific cohorts in field margins and weed management practices from early August to mid-September can effectively reduce its population size in the field margins. [ABSTRACT FROM AUTHOR]

Spontaneous esophageal perforation in Boerhaave's syndrome results in significant morbidity and mortality. The gold standard treatment for this disease is thoracotomy and laparotomy because it can be a life-saving procedure that can be performed in emergencies; however, minimally invasive surgery has recently been reported. This report describes three cases of Boerhaave's syndrome that were treated using laparoscopic transhiatal suture and omental patch. One patient recovered uneventfully and was discharged from the hospital after 12 days. The other 2 patients had postoperative complications, such as minor leakage and remnant abscess (Clavien-Dindo Grade II), but were discharged from the hospital after 17 days and 30 days, respectively. In the case of Boerhaave's syndrome with localized mediastinal collections, a good clinical course can be obtained by laparoscopic transhiatal esophageal repair to avoid surgical invasion due to thoracotomy. [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT) is a neurodevelopmental disorder with X-linked dominant inheritance caused mainly by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The effects of various Mecp2 mutations have been extensively assessed in mouse models, but none adequately mimic the symptoms and pathological changes of RTT. In this study, we assessed the effects of Mecp2 gene deletion on female rats (Mecp2+/−) and found severe impairments in social behavior [at 8 weeks (w), 12 w, and 23 w of age], motor function [at 16 w and 26 w], and spatial cognition [at 29 w] as well as lower plasma insulin-like growth factor (but not brain-derived neurotrophic factor) and markedly reduced acetylcholine (30%–50%) in multiple brain regions compared to female Mecp2+/+ rats [at 29 w]. Alternatively, changes in brain monoamine levels were relatively small, in contrast to reports on mouse Mecp2 mutants. Female Mecp2-deficient rats express phenotypes resembling RTT and so may provide a robust model for future research on RTT pathobiology and treatment. [ABSTRACT FROM AUTHOR]

Purpose: Medication discontinuation for patients with Alzheimer's dementia (AD) influences treatment efficacy. This study aimed to evaluate the effect of psychoeducational intervention (PI) on donepezil retention rates and identify the factors associated with donepezil continuation in patients with AD. Patients and Methods: One hundred and seventeen patients with AD were randomly allocated to the PI (n = 58) or standard care (SC; n = 59) groups. All patients were prescribed donepezil for 48 weeks. Primary endpoints were the 48-week donepezil retention rate and the reasons for donepezil discontinuation in the PI and SC groups. The secondary endpoint was the predictive factors, among the baseline clinical variables, for donepezil continuation in all patients. Results: The donepezil retention rate was 62.1% (36/58) in the PI group and 66.1% (39/59) in the SC group. The most common reason for discontinuation in both groups was adverse events (PI, 12.1%; SC, 10.2%). Logistic regression analysis revealed that the results of the pentagon copying test in the Mini-Mental State Examination administered at baseline was a significant predictor of donepezil continuation for all patients in both the groups (odds ratio: 0.359; 95% confidence interval: 0.154– 0.839). Conclusion: There was no significant difference between the PI and SC groups concerning donepezil retention rate in patients with AD. Our results demonstrate that the pentagon copying test can significantly predict donepezil continuation in patients with AD, indicating that impaired visuospatial and executive functions may reflect medication discontinuation. Trial Registration: UMIN-CTR:UMIN000012617. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization has set a goal of hepatitis C virus (HCV) elimination by the year 2030. However, no regions in Japan have succeeded in eradicating HCV. Micro-elimination is an approach to attain hepatitis C eradication in which national eradication goals are applied to specific populations so that viral treatment and control efforts can move forward quickly and efficiently. In order to eradicate HCV from Japan, this study aims to achieve HCV micro-elimination in the town of Nagawa. Methods and design: The Nagawa Project is an ongoing, prospective, multiple-institution, observational study running from April 1, 2021, to March 31, 2024. All residents of Nagawa town, excluding those under 20 years of age, not consenting to the study, or unable to undergo health check-ups due to nursing care needs, will be included. If found to be HCV antibody-positive, the participant will be recommended to see a doctor in consideration of MAC-2 binding protein glycosylation isomer values. Then, the participant will undergo serum HCV RNA measurement with the real-time polymerase chain reaction by an attending physician. If the participant is HCV RNA-positive, he or she will be referred to a hepatologist for further evaluation. In the case of a definitive diagnosis of chronic hepatitis C, direct acting antiviral treatment will be initiated. Through this process, HCV will be systematically micro-eliminated from the region. Discussion: The Nagawa Project will reveal the prevalence of chronic HCV in addition to the HCV eradication rate in Nagawa town towards achieving HCV micro-elimination. Trial registration: This study is performed by Shinshu University School of Medicine and was registered as UMIN 000044114 on May 6, 2021. [ABSTRACT FROM AUTHOR]

Decreasing the transfer of radioactive cesium (RCs) from soil to crops has been important since the deposition of RCs in agricultural soil owing to the Fukushima nuclear power plant accident of 2011. We investigated the genotypic variation in RCs accumulation in 234 and 198 hexaploid wheat (Triticum spp.) varieties in an affected field in 2012 and 2013, respectively. The effects of soil exchangeable potassium (ExK) content to RCs accumulation in wheat varieties were also evaluated. A test field showed fourfold differences in soil ExK contents based on location, and the wheat varieties grown in areas with lower soil ExK contents tended to have higher grain RCs concentrations. RCs concentrations of shoots, when corrected by the soil ExK content, were positively significantly correlated between years, and RCs concentrations of shoots were significantly correlated with the grain RCs concentration corrected by the soil ExK content. These results indicated that there were genotypic variations in RCs accumulation. The grain to shoot ratio of RCs also showed significant genotypic variation. Wheat varieties with low RCs accumulations were identified. They could contribute to the research and breeding of low RCs accumulating wheat and to agricultural production in the area affected by RCs deposition. [ABSTRACT FROM AUTHOR]

Arc temperature measurement by optical emission spectroscopy in a gas circuit breaker (GCB) has been of great interest to improve the interruption performance. In this article, emission spectra were observed by using the actual self-blast GCB apparatus. Under the large current condition of 50-kA root-mean-square (rms), a strong continuous spectrum was observed. On the contrary, S+ line emission spectra, which have been widely used for arc temperature evaluation, were not observed under the large current condition. Thus, the gas temperature was evaluated by assuming that the continuous spectrum was a black-body radiation spectrum. The gas temperature at the stagnation point decreased gradually, while that at the nozzle throat decreased suddenly by about 1 ms before current zero. Absorption spectra of the C2 radical generated by the ablation of a nozzle material were also observed in the continuous spectrum. Then, the C2 density was roughly evaluated by the intensity of C2 absorption spectra. It was confirmed that the gas temperature decreased with a decrease of C2 density, which indicates that SF6 gas blow to the arc plasma reduces the gas temperature. [ABSTRACT FROM AUTHOR]

Thermal-cyclic atomic layer etching of Co blanket film and a fine pattern by plasma oxidation and organometallization were investigated. To obtain a smoothly etched surface and self-limiting etching, a two-step temperature-etching process was used. Co was first oxidized using O2 plasma at a low temperature of 25 °C. Then, the Co oxide formed in the first step was organometallized with acetylacetone (acacH) and sublimed at a high temperature of 210 °C, which is appropriate for organometallization and sublimation. The etched amount per cycle was 0.6 nm. This value is the same as the saturated oxidation amount. The root-mean-square roughness after 20-cycle etching was 0.53 nm, and an atomically smooth etched surface was obtained. From the x-ray photoelectron spectroscopy (XPS) analysis, the oxidation state of Co oxide with a 530-eV O1s peak was dominant for organometallization with acacH. As the temperature increased, the O1s XPS peak of the Co oxide shifted lower to 529 eV and formed a columnar-shaped oxide. However, with acacH, oxide was organometallized when the O1s peak was at 530 eV. [ABSTRACT FROM AUTHOR]

Abstract: This study was conducted to test our hypothesis that intramuscular fat (IMF) accumulation increases in pigs fed on a low lysine diet during the dark period than those fed on the same diet during the light period. Using barrows aged 6 weeks, we monitored whether serum glucose and insulin levels were affected by light conditions. Two diets with different levels of lysine, 0.78% (LL diet) and 1.37% (control diet) were prepared. Eight pigs were fed on the diet during the light period, while the remaining pigs were fed during the dark period. The pigs were fed either the LL diet or the control diet. Although IMF contents of Longissimus dorsi (LD) muscle were higher in the pigs fed on a LL diet (p < .05), the light conditions had no effect. Low dietary lysine caused reduction in serum glucose levels (p < .05) and serum insulin levels (p = .0613). However, they were also unaffected by the lighting conditions. To gain further insights, we determined the messenger RNA levels of insulin receptor, insulin receptor substrate 1, acetyl CoA carboxylase, and fatty acid synthase in LD and Rhomboideus muscles and in the liver. [ABSTRACT FROM AUTHOR]

Taste is a crucial factor of meat quality, and amino acids are important taste-active components in meat. Here, the effects of dietary lysine (Lys) content on taste-active components in meat, especially free glutamate (Glu), were investigated. Twenty-eight-day-old broilers ( Gallus gallus) were fed diets with graded Lys content of 90% or 100% of the recommended Lys requirement, (according to the National Research Council, ) for 10 days. Free amino acid content in meat and sensory scores of meat soup were estimated. Free Glu content, the main taste-active component of meat, was significantly increased by a reduction of dietary Lys. Compared with the Lys 100% group (control), free Glu concentrations of meat were increased by 35.7% in the Lys 90% group ( P < 0.05). In addition, free glycine, valine, isoleucine, leucine, histidine and threonine concentrations of meat were significantly increased in the Lys 90% group ( P < 0.05). Sensory evaluation of meat soup made from the Lys 100% and 90% groups indicated different meat tastes. Sensory scores of taste intensity, umami and kokumi tastes were significantly higher in the Lys 90% group. These results suggest that a reduction of dietary lysine increased free glutamate content in meat and improved its taste. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examines the effect of low level of threonine and lysine amino acids on the accumulation of fat in porcine muscle. It mentions several methods including enzyme linked immunosorbent assay, statistical analysis and food content analysis which are used as the research methodologies. The result reveals that the accumulation of fat in porcine muscle is not affected by the dietary threonine levels.

The major taste active component, glutamate (Glu), improves the taste of meat. In this study, we investigated the effect of a short-term high-protein (HCP) diet on the intramuscular free Glu content to improve the taste of meat. Furthermore, we elucidated how the muscle free Glu content was controlled by the HCP diet. Chicks (14 days old) were fed the control diet or HCP diet for 10 days. Plasma and muscle free amino acid concentrations, and activity and messenger RNA (mRNA) expression of muscle enzymes related to Glu metabolism were determined. Muscle free Glu content was increased ( P < 0.01) by 51%. Activity and mRNA expression of glutaminase (GA), which is one of the major Glu-related enzymes, were significantly decreased ( P < 0.05) in the HCP group because of feedback inhibition. The mRNA expression of lysine α-ketoglutarate reductase (LKR), which is the enzyme involved in lysine (Lys) degradation and Glu production, was significantly increased ( P < 0.001) in the HCP group. These results suggest that short-term dietary HCP feeding is an effective treatment for improving the taste of meat. Furthermore, our results suggest that the free Glu content in muscle is regulated by GA and LKR. [ABSTRACT FROM AUTHOR]

Postoperative cerebrospinal fluid (CSF) leakage is one of the most common and aggravating complications in transsphenoidal surgery. Although primary closure of the fistula would be the most desirable solution for an intraoperatively encountered CSF leak, it is difficult to achieve in such a deep and narrow operative field. In this article, the authors report endonasal endoscopic applications of no-penetrating titanium clips to repair a CSF fistula following tumor removal. The AnastoClip Vessel Closure System (VCS; LeMaitre Vascular, Boston, MA) was used for closure of a CSF fistula in endonasal transsphenoidal surgery. In all four patients, CSF leakage was successfully obliterated primarily with two to five clips. There was no postoperative CSF rhinorrhea or complications related to the use of the VCS. Metal artifact by the clips on postoperative images was tolerable. Primary closure of the fistula using the VCS was an effective strategy to prevent postoperative CSF leakage in transsphenoidal surgery. Future application can be expanded to reconstruction of the skull base dura via endonasal skull base approaches. [ABSTRACT FROM AUTHOR]

Granulocyte-colony-stimulating factor(G-CSF) has been reported to improve cardiac function after myocardial infarction (MI). However, whether postinfarct acute effect of G-CSF is mediated through the same signaling pathways as those of ischemic postconditioning is still unclear. We examined the postinfarct acute effect of G-CSF on myocardial infarct size and its precise molecular mechanism. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Rabbits were intravenously injected 10 μg/kg of G-CSF (G-CSF group), saline (control group) immediately after reperfusion. The wortmannin+G-CSF, PD98059+G-CSF, Nω-nitro-L-arginine methyl ester (L-NAME) + G-CSF, and 5-HD+G-CSF groups were respectively injected with wortmannin(0.6mg/kg), PD98059(0.3mg/kg), L-NAME(10mg/kg) and 5-HD(5mg/kg), 5 min before G-CSF administration. Myocardial infarct size was calculated as a percentage of the risk area of the left ventricle. Western blot analysis was performed to examine the signals such as Akt, ERK, eNOS, p70S6K and GSK3β in the ischemic myocardium after 48 hours of reperfusion. The infarct size was significantly smaller in the G-CSF group (26.7±2.7%) than in the control group (42.3±4.6%). The infarct size-reducing effect of G-CSF was completely blocked by wortmannin(44.7±4.8%), PD98059(38.3±3.9%), L-NAME (42.1±4.2%) and 5-HD (42.5±1.7%). Wortmannin, PD98059, L-NAME or 5HD alone did not affect the infarct size. Western blotting showed higher myocardial expression of phospho-Akt, phospho-ERK, phosho-eNOS, phosho-p70S6K and phosho-GSK3β at 10 min and 48 hours after reperfusion in the G-CSF group than in the control group. In conclusion, postreperfusion G-CSF administration reduces myocardial infarct size via activation of PI3K-Akt and ERK prosurvival signaling pathways and their down stream targets eNOS, p70S6K, GSK3β and mitochondrial KATP channels. [ABSTRACT FROM AUTHOR]

Abstract: Here we describe the interaction of phosphorylated ∼40kDa protein with phosphorylated Akt which is a serine/threonine kinase resulting from increased blood glucose in rat cardiac muscle. Mass spectrometry analysis revealed that this protein was glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Furthermore, increase in Akt and GAPDH phosporylation and induction of their association were both observed after insulin stimulation in the H9c2 cell line derived from embryonic rat ventricle. Moreover, the activation of GAPDH was upregulated when the GAPDH phosphorylation was increased. Our data suggest that GAPDH phosphorylation and association with Akt by insulin treatment have some bearing on the enhancement of GAPDH activity. Structured summary: MINT-7891324, MINT-7891304, MINT-7891314: GAPDH (uniprotkb:P04797) physically interacts (MI:0915) with Akt (uniprotkb:P47196) by anti bait coimmunoprecipitation (MI:0006) [Copyright &y& Elsevier]

The behavior of particles that are reflected in a turbo molecular pump is investigated by measuring particle trajectories and the number of particles that fall on a wafer in a plasma etching apparatus. Some scattered particles collide with the wafer at high velocity, which damage fine patterns of the photoresist on the wafer. Particle contamination can be reduced by supplying carrier gas to form a down-flow when the etching plasma is not discharged. During plasma discharge, the number of particles that fall on the wafer decreases because particles are trapped near the plasma-sheath boundary. The down-flow gas reduces particle contamination by 90% through the etching sequence, including wafer transfer. [ABSTRACT FROM AUTHOR]

Site-directed mutagenesis guided by evolutionary trace analysis revealed that substitution of V179 and W183 within a cluster of evolutionarily important residues on the surface of the fourth transmembrane domain of the β1-adrenergic receptor (β1AR) significantly reduced the propensity of the receptor to self-assemble into homodimers as assessed by bioluminescence resonance energy transfer in living cells. These results suggest that mutation of V179 and W183 result in conformational changes that reduce homodimerization either directly by interfering with the dimerization interface or indirectly by causing local misfolding that result in reduced self-assembly. However, the mutations did not cause a general misfolding of the β1AR as they did not prevent heterodimerization with the β2AR. The homodimerization-compromised mutants were significantly retained in the endoplasmic reticulum (ER) and could not be properly matured and trafficked to the cell surface. Lipophilic β-adrenergic ligands acted as pharmacological chaperones by restoring both dimerization and plasma membrane trafficking of the ER-retained dimerization-compromised β1AR mutants. These results clearly indicate that homodimerization occurs early in the biosynthetic process in the ER and that pharmacological chaperones can promote both dimerization and cell surface targeting, most likely by stabilizing receptor conformations compatible with the two processes. [ABSTRACT FROM AUTHOR]

Yasuda S, Kobayashi H, Iwasa M, Kawamura I, Sumi 5, Narentuoya B, Yamaki T, Ushikoshi H, Nishigaki K, Nagashima K, Takemura G, Fujiwara T, Fujiwara H, Minatoguchi S. Antidiabetic drug pioglitazone protects the heart via activation of PPAR--y receptors, P13kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction. Am J Physiol Heart Circ Physiol 296: H1558-H1565, 2009. First published March 13, 2009; doi: 10.1 152/ajpheart.00712.2008.4-The insulin-sensitizing drug pioglitazone has been reported to be protective against myocardial infarction. However, its precise mechanism is unclear. Rabbits underwent 30 mm of coronary occlusion followed by 48 h of reperfusion. Rabbits were assigned randomly to nine groups (n = 10 in each): the control group (fed a normal diet), pioglitazone group (fed diets containing 1 mg kg[sup-1]∙ day[sup-1] pioglitazone), pioglitazone + 5hydroxydecanoic acid (HI)) group [fed the pioglitazone diet + 5 mg/kg iv 5-HD, a mitochondrial ATP-sensitive K[sup+] (KATp) channel blocker], pioglitazone + GW9662 group [fed the pioglitazone diet + 2 mg/kg iv GW9662, a peroxisome proliferator activated receptor (PPAR)-γ antagonist], GW9662 group (fed a normal diet + iv GW9662), pioglitazone + wortmannin group [fed the pioglitazone diet + 0.6 mg/kg iv wortmannin, a phosphatidylinositol (PI)3-kinase inhibitor], wortmannin group (fed a normal diet + iv wortmannin), pioglitazone + nitro-L-arginirie methyl ester (L-NAME) group [fed the pioglitazone diet + 10 mg/kg iv LNAME, a nitric oxide synthase (NOS) inhibitor], and L-NAME group (fed a normal diet + iv L-NAME). All groups were fed the diets for 7 days. The risk area and nonrisk area of the left ventricle (LV) were separated by Evans blue dye, and the infarct area was determined by triphenyltetrazolium chloride staining. The infarct size was calculated as a percentage of the LV risk area. Western blotting was performed to assess levels of Akt and phospho-Akt and phospho-endothelial NOS (eNpS) in the myocardium following reperfusion. The infarct size was significantly smaller in the pioglitazone group (21 ± 2%) than in the control group (43 ± 3%). This effect was abolished by GW9662 (42 ± 3%), wortmannin (40 ± 3%), or L-NAME (42 ± 7%) but not by 5-HI) (24 ± 5%). Western blotting showed higher levels of phospho-Akt and phospho-eNOS in the pipglitazone group. Pioglitazone reduces the myocardial infarct size via activation of PPAR-γ, PI3-kinase, Akt, and eNOS pathways, but not via opening the mitochondrial KATP channel. Pioglitazone may be a novel strategy for the treatment of diabetes mellitus with coronary artery disease. [ABSTRACT FROM AUTHOR]

Abstract: Many different physical characteristics of goldfish (Carassius auratus auratus), such as celestial and telescopic eyes, fancy but uncontrollable shapes of tail fin, an unfittingly fat body, and loss of dorsal fins, provide us with a unique opportunity of studying artificial selection on phenotypic changes on the basis of molecular evolution. The aim of the present study is to elucidate the evolutionary origin and history of goldfish, taking into account the different characteristics of goldfish and human culture. Collecting 44 samples of a variety of goldfish from Japan and China as well as common and Crucian carps, we determined the nucleotide sequences for a substantial portion of mitochondrial genome including eight gene regions (D-loop, 12SrRNA, 16SrRNA, ND1, ND2, COI, ND5 and Cyt b) of approximately 11,180 bps. We, then, constructed phylogenetic trees for a total of 78 fishes, adding the 19 sequence data available in the international DNA database DDBJ/EMBL/GenBank to our 59 sequence data determined. From the phylogenetic trees obtained, we found that Japanese goldfish are not relative to Japanese Crucian carp (Carassius auratus langsdorfi) and that all the goldfish examined were originated from one of the two groups of the Chinese Crucian carp “Gibelio” (Carassius auratus gibelio). Moreover, we found that the process of artificial selection began from losing the dorsal fin followed by diversification of other characters such as eyes. This is supported by our further observations that the improvement of celestial and telescope eyes took place independently at different times, implying that goldfish was imposed by strong artificial selection only to meet diversified needs of human preferences in a unsystematic way. [Copyright &y& Elsevier]

Abstract: Measurements of the performance decay for a proton exchange membrane fuel cell (PEMFC) and the observation of water droplets were simultaneously carried out for 4000h under degradation conditions of low humidity and high CO concentration. An optical cell was designed for observation of water droplets and measurement of the transition points. It was found that as the performance decayed with time, the transition point to a two-phase flow moved toward the cathode exit for conditions of both low humidity and high CO concentration. Performance data showed that under these conditions, there was no pinhole in the membrane or significant mass transport loss observed. It was supposed that the deactivation of electrodes occurred at the cathode inlet and the anode outlet under low humidity and high CO concentration, and that this caused the decay in performance and observed change of the transition point at the cathode. The change of the transition point was computed using a two-dimensional cell model. Performance decay, such as oxygen gain and the cell over-potential, was simulated by changing the value of the exchange current densities of the cathode and anode. Comparison with the experimental results shows good agreement for the total duration of cell operation. [Copyright &y& Elsevier]

Characterizes the linear plasmid of strain RHA1 of the polychlorinated biphenyl degrading bacteria Rhodococcus. Distribution and localization of the degradative genes on the plasmids; Terminal structure of the pRHL2 plasmid; Association of proteins with the plasmid termini; Frequency of genetic translocation.

Classically, G protein-coupled receptors (GPCRs) promote signaling at the plasma membrane through activation of heterotrimeric Gαβγ proteins, followed by the recruitment of GPCR kinases and βarrestin (βarr) to initiate receptor desensitization and internalization. However, studies demonstrated that some GPCRs continue to signal from internalized compartments, with distinct cellular responses. Both βarr and Gβγ contribute to such non-canonical endosomal G protein signaling, but their specific roles and contributions remain poorly understood. Here, we demonstrate that the vasopressin V2 receptor (V2R)–βarr complex scaffolds Gβγ at the plasma membrane through a direct interaction with βarr, enabling its transport to endosomes. Gβγ subsequently potentiates Gαs endosomal translocation, presumably to regenerate an endosomal pool of heterotrimeric Gs. This work shines light on the mechanism underlying G protein subunits translocation from the plasma membrane to the endosomes and provides a basis for understanding the role of βarr in mediating sustained G protein signaling. A V2R–βarrestin–Gβγ complex forms at the plasma membrane and translocates to endosomes. This sheds light on G protein subunit translocation and βarr's role in sustained signaling. [ABSTRACT FROM AUTHOR]

Simple Summary: The manifestation of Takotsubo Syndrome (TTS) may be different in males and females based on past reports and our clinical research. However, the gender differences in TTS are unknown because patients with TTS are predominantly female. TTS is common in females; however, approximately 10–20% of males have TTS and it has been reported that in-hospital complications mostly occur in males. TTS in males is often caused by physical stress and often develops in the hospital or during hospitalization. TTS in males is associated with severe cardiac complications, which may require careful observations and interventions. Regarding the pathogenic mechanism of TTS, it has been reported that decreased estrogen levels, common in postmenopausal females, are involved in the pathogenic mechanism. Moreover, the pathological findings and gene expression were different in males and females. From these results, it can be considered that the mechanism of the onset of TTS may be different between males and females. Most patients with Takotsubo Syndrome (TTS) are postmenopausal females. TTS in males is rare and gender differences have not been sufficiently investigated. Therefore, we investigated gender differences in TTS. TTS in males and females is often triggered by physical and emotional stress, respectively. Heart failure, a severe in-hospital complication, requires greater mechanical respiratory support in males. Fatal arrhythmias such as ventricular tachycardia and ventricular fibrillation and in-hospital mortality rates are higher in males. The white blood cell (WBC) count has been shown to be higher in males than in females with cardiovascular death compared with non-cardiovascular death. Therefore, the WBC count, a simple marker, may reflect severe TTS. Decreased estrogen levels, common in postmenopausal females, are a pathogenic mechanism of TTS. Females have a more significant increase in the extracellular matrix-receptor interaction than males. Moreover, the pathological findings after hematoxylin–eosin staining were different in males and females. Males had more severe complications than females in the acute phase of TTS; thus, more careful observations and interventions are likely required. From these results, it can be considered that the mechanism of the onset of TTS may be different between males and females. Therefore, it is necessary to fully understand the gender differences in order to more effectively manage TTS. [ABSTRACT FROM AUTHOR]

Background Geriatric assessments (GAs) used to evaluate various aspects in elderly patients have recently been introduced for their usefulness in predicting toxicities of cancer treatments and subsequent patient prognoses. Utilizing GAs to decide on treatment policies has been recommended. However, there are few reports on the relationship between Geriatric 8 (G8), a screening tool for GA, and treatment outcomes of elderly patients with de novo acute myeloid leukemia (AML) who received low-dose chemotherapy (LDC). Patients and Methods We reviewed 47 patients aged≥70 years who were newly diagnosed with de novo AML (except for acute promyelocytic leukemia) and received LDC as an initial treatment at our hospital between April 2012 and June 2018. We divided them into two groups (high: N = 11, low: N = 36) according to G8 scores (cutoff: 14 points) at the time of diagnosis and retrospectively analyzed the differences in clinical features and treatment outcomes. Results Statistically significant differences in age (median, 73 vs. 79 years, p = 0.009) were observed between the two groups. The proportions of sex, median white blood cell and bone marrow blast counts, and percentages of patients with unfavorable cytogenetic abnormalities did not differ significantly between groups. The most frequent initial LDC in both groups was low-dose cytarabine combined with acrarubicine. The complete remission rate and overall survival at two years were significantly higher in the G8 high-score group than those in the low-score group (72.7% vs. 19.4%; p = 0.002 and 55.6% vs. 11.0%; p < 0.001), respectively. Early death from fatal infections, bleeding, and disease progression were frequently observed in the G8 low-score group (0.0% vs. 11.1%). Conclusion Our data suggest that G8 scores can predict treatment outcomes in elderly patients with de novo AML who received LDC. [ABSTRACT FROM AUTHOR]

Geriatric assessments (GAs) used to evaluate various aspects in elderly patients have recently been introduced for their usefulness in predicting toxicities of cancer treatments and subsequent patient prognoses. Utilizing GAs to decide on treatment policies has been recommended. However, there are few reports on the relationship between Geriatric 8 (G8), a screening tool for GA, and treatment outcomes of elderly patients with de novo acute myeloid leukemia (AML) who received low-dose chemotherapy (LDC). We reviewed 47 patients aged≥70 years who were newly diagnosed with de novo AML (except for acute promyelocytic leukemia) and received LDC as an initial treatment at our hospital between April 2012 and June 2018. We divided them into two groups (high: N = 11, low: N = 36) according to G8 scores (cutoff: 14 points) at the time of diagnosis and retrospectively analyzed the differences in clinical features and treatment outcomes. Statistically significant differences in age (median, 73 vs. 79 years, p = 0.009) were observed between the two groups. The proportions of sex, median white blood cell and bone marrow blast counts, and percentages of patients with unfavorable cytogenetic abnormalities did not differ significantly between groups. The most frequent initial LDC in both groups was low-dose cytarabine combined with acrarubicine. The complete remission rate and overall survival at two years were significantly higher in the G8 high-score group than those in the low-score group (72.7% vs. 19.4%; p = 0.002 and 55.6% vs. 11.0%; p < 0.001), respectively. Early death from fatal infections, bleeding, and disease progression were frequently observed in the G8 low-score group (0.0% vs. 11.1%). Our data suggest that G8 scores can predict treatment outcomes in elderly patients with de novo AML who received LDC. [ABSTRACT FROM AUTHOR]

Natural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. No significant associations of KIR/HLA pairs were detected in terms of liver cirrhosis development. The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) [30.8% vs. 14.9%, odds ratio (OR) 2.53, P = 0.015]. The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusion, this study indicated remarkable associations of KIR/HLA with HCC development (KIR2DS3) and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients, although the number of cases was insufficient for statistical purposes. Additional multi-center analyses of larger groups are needed to clarify whether KIR/HLA pairs play a role in HBV patient status. [ABSTRACT FROM AUTHOR]

Mutations of receptor tyrosine kinases (RTKs) are associated with the development of many cancers by modifying receptor signaling and contributing to drug resistance in clinical settings. We present enhanced bystander bioluminescence resonance energy transfer-based biosensors providing new insights into RTK biology and pharmacology critical for the development of more effective RTK-targeting drugs. Distinct SH2-specific effector biosensors allow for real-time and spatiotemporal monitoring of signal transduction pathways engaged upon RTK activation. Using EGFR as a model, we demonstrate the capacity of these biosensors to differentiate unique signaling signatures, with EGF and Epiregulin ligands displaying differences in efficacy, potency, and responses within different cellular compartments. We further demonstrate that EGFR single point mutations found in Glioblastoma or non-small cell lung cancer, impact the constitutive activity of EGFR and response to tyrosine kinase inhibitor. The BRET-based biosensors are compatible with microscopy, and more importantly characterize the next generation of therapeutics directed against RTKs. BRET-based biosensors allow the quantitative live-cell monitoring of RTKmediated signaling, revealing ligand-specific spatiotemporal and mutation-specific signaling biases, advancing the understanding of RTK functional selectivity. [ABSTRACT FROM AUTHOR]

This retrospective study aimed to determine the optimal cutoff values of the Dry Eye-Related Quality-of-Life Score (DEQS) questionnaire for diagnosing dry eye disease (DED) and classifying DED severities. Participants completed the DEQS questionnaire, the Japanese version of the Ocular Surface Disease Index (J-OSDI) questionnaire, and DED examinations. DED was diagnosed according to the 2016 Asia Dry Eye Society diagnostic criteria based on DED symptoms (J-OSDI ≥ 13 points) and tear film breakup time ≤ 5 s. Receiver operating characteristic (ROC) analysis was used to calculate the optimal cutoff values of the DEQS summary score for detecting DED and grading its severity. Among 427 patients, 296 (69.3%) and 131 (30.7%) were diagnosed with DED and non-DED, respectively. ROC analysis determined an optimal cutoff value of 15.0 points for DED diagnosis, with 83.5% sensitivity, 87.0% specificity, and an area under the curve of 0.915. The positive and negative predictive values for DEQS ≥ 15.0 points were 93.6% and 69.9%, respectively. DEQS cutoff values of 15.0, 20.0, and 26.8 points could be accepted for severity classification of DED subjective symptoms in clinical use and represent mild, moderate, and severe DED, respectively. Conclusively, the optimal cutoff values of DEQS enable DED detection and subjective symptom severity classification. [ABSTRACT FROM AUTHOR]

Bivalent ligands are composed of two pharmacophores connected by a spacer of variable size. These ligands are able to simultaneously recognize two binding sites, for example in a G protein-coupled receptor heterodimer, resulting in enhanced binding affinity. Taking advantage of previously described heterobivalent dopamine-neurotensin receptor ligands, we demonstrate specific interactions between dopamine D3 (D3R) and neurotensin receptor 1 (NTSR1), two receptors with expression in overlapping brain areas that are associated with neuropsychiatric diseases and addiction. Bivalent ligand binding to D3R-NTSR1 dimers results in picomolar binding affinity and high selectivity compared to the binding to monomeric receptors. Specificity of the ligands for the D3R-NTSR1 receptor pair over D2R-NTSR1 dimers can be achieved by a careful choice of the linker length. Bivalent ligands enhance and stabilize the receptor-receptor interaction leading to NTSR1-controlled internalization of D3R into endosomes via recruitment of β-arrestin, highlighting a potential mechanism for dimer-specific receptor trafficking and signalling. Budzinski et al use bivalent ligands, BRET assays and radioligand competition to demonstrate a specific interaction between two receptors associated with neuropsychiatric diseases and addiction, dopamine D3 (D3R) and neurotensin receptor 1. They show that the bivalent ligands promote endosomal trafficking of D3R, suggesting a potential role for dimerization in vivo. [ABSTRACT FROM AUTHOR]

Various gene alterations related to acute leukemia are reported to be involved in drug resistance. We investigated idarubicin (IDR) resistance using exome nuclear DNA analyses of the human acute leukemia cell line MOLT-3 and the derived IDR-resistant cell line MOLT-3/IDR. We detected mutations in MOLT-3/IDR and MOLT-3 using both Genome Analysis Toolkit (GATK) and SnpEff program. We found 8839 genes with specific mutations in MOLT-3/IDR and 1162 genes with accompanying amino acid mutations. The 1162 genes were identified by exome analysis of polymerase-related genes using Kyoto Encyclopedia of Genes and Genomes (KEGG) and, among these, we identified genes with amino acid changes. In resistant strains, LIG and helicase plurality genes showed amino-acid-related changes. An amino acid mutation was also confirmed in polymerase-associated genes. Gene ontology (GO) enrichment testing was performed, and lipid-related genes were selected from the results. Fluorescent activated cell sorting (FACS) was used to determine whether IDR permeability was significantly different in MOLT-3/IDR and MOLT-3. The results showed that an IDR concentration of 0.5 μg/mL resulted in slow permeability in MOLT-3/IDR. This slow IDR permeability may be due to the effects of amino acid changes in polymerase- and lipid-associated genes. [ABSTRACT FROM AUTHOR]

We examined the impact of 5-aminolevulinic acid (5-ALA) and sodium-ferrous-citrate supplementation on aerobic capacity and redox balance through a placebo-controlled, double-blind trial. Fourteen healthy volunteers were randomly assigned to Pla + ALA (4-week placebo followed by 4-week 5-ALA supplementation) or ALA + Pla (4-week 5-ALA supplement followed by a 4-week placebo) group and administered 5-ALA (25 mg/day) or placebo once daily. The participants underwent submaximal incremental cycling tests at weeks 0, 2, 4, 6, and 8. In the cycling test at week 0, individual load-intensity stages required for blood lactate levels >2 mmol/L (lactate threshold, LT) and 4 mmol/L (onset of blood lactate accumulation, OBLA) were determined. The heart rate (HR), blood lactate (La), and oxidative stress markers (diacron reactive oxygen metabolite, d-ROMs; biological antioxidant potential, BAP) were measured at resting, LT, and OBLA states in each cycling test. Marker values were not significantly different between the groups. HR, La, and d-ROMs at resting, LT, and OBLA states were not significantly different among the conditions. BAP and BAP/d-ROMs ratios were significantly different in the OBLA state at week 4 of the 5-ALA group compared with that of the placebo group (p < 0.05). In conclusion, 5-ALA supplementation might improve redox balance during high-intensity aerobic exercise. [ABSTRACT FROM AUTHOR]

Neurally mediated syncope (NMS) is associated with a sudden loss of consciousness. However, the diagnostic tools and measures for prognosis management are limited. To overcome these limitations, the differences in the binding energies of Giα-protein-coupled receptors to the Glu9 and Glu12 residues on the α2B-AR gene were elucidated through the analysis of α2B-AR gene polymorphism. The suppression of the activity of adenylate cyclase (AC), which is involved in vasoconstriction, may be related to the onset of NMS. The head-up tilt (HUT) test results indicated differences in systolic blood pressure (SBP) and AC activity between patients with vasodepressor (VT)-NMS and healthy volunteers. Patients with VT-NMS had increased AC activity and decreased SBP. Conversely, in healthy volunteers, no changes in AC activity or SBP were found. These findings suggest that a high SBP and elevated AC activity at rest are likely to cause syncope. A high incidence of cardiovascular events is found in patients with negative HUT test results, highlighting the importance of investigating the cause of syncope in cases where the HUT test results are negative. Overall, our results may provide a means of assessing the risk of NMS development within healthy populations and underscore the importance of subsequent treatments for NMS. [ABSTRACT FROM AUTHOR]

The coronavirus disease (COVID-19) pandemic has emphasized the paucity of non-contact and non-invasive methods for the objective evaluation of dry eye disease (DED). However, robust evidence to support the implementation of mHealth- and app-based biometrics for clinical use is lacking. This study aimed to evaluate the reliability and validity of app-based maximum blink interval (MBI) measurements using DryEyeRhythm and equivalent traditional techniques in providing an accessible and convenient diagnosis. In this single-center, prospective, cross-sectional, observational study, 83 participants, including 57 with DED, had measurements recorded including slit-lamp-based, app-based, and visually confirmed MBI. Internal consistency and reliability were assessed using Cronbach's alpha and intraclass correlation coefficients. Discriminant and concurrent validity were assessed by comparing the MBIs from the DED and non-DED groups and Pearson's tests for each platform pair. Bland–Altman analysis was performed to assess the agreement between platforms. App-based MBI showed good Cronbach's alpha coefficient, intraclass correlation coefficient, and Pearson correlation coefficient values, compared with visually confirmed MBI. The DED group had significantly shorter app-based MBIs, compared with the non-DED group. Bland–Altman analysis revealed minimal biases between the app-based and visually confirmed MBIs. Our findings indicate that DryEyeRhythm is a reliable and valid tool that can be used for non-invasive and non-contact collection of MBI measurements, which can assist in accessible DED detection and management. [ABSTRACT FROM AUTHOR]

Simple Summary: Serum C-reactive protein (CRP) is an established biomarker for acute inflammation and has been identified as a prognostic indicator for hepatocellular carcinoma (HCC). It is especially important to verify the utility of CRP in HCC patients treated with lenvatinib because the benefits of lenvatinib vary greatly depending on each case. We retrospectively analyzed 125 HCC patients who received lenvatinib treatment at six centers. The low-CRP (<0.5 mg/dL) group exhibited significantly longer overall survival (OS) than the high-CRP (0.5≥ mg/dL) group (22.9 vs. 7.8 months, p < 0.001). In addition, time-to-treatment failure (TTF) was significantly longer in the low-CRP group (8.5 vs. 4.4 months, p = 0.007). In conclusion, baseline serum CRP level was identified as a useful prognostic factor in HCC patients receiving lenvatinib treatment. Background: Serum C-reactive protein (CRP) is an established biomarker for acute inflammation and has been identified as a prognostic indicator for hepatocellular carcinoma (HCC). However, the significance of the serum CRP level, specifically in HCC patients treated with lenvatinib, remains unclear. Methods: We retrospectively analyzed 125 HCC patients who received lenvatinib treatment at six centers. Clinical characteristics were assessed to identify clinical associations between serum CRP and HCC prognosis. Results: The median overall serum CRP level was 0.29 mg/dL. The cohort was divided into two groups: the low-CRP group with a serum CRP < 0.5 mg/dL and the high-CRP group with a serum CRP ≥ 0.5 mg/dL. The low-CRP group exhibited significantly longer overall survival (OS) than the high-CRP group (22.9 vs. 7.8 months, p < 0.001). No significant difference was observed for progression-free survival (PFS) between the high- and low-CRP groups (9.8 vs. 8.4 months, p = 0.411), while time-to-treatment failure (TTF) was significantly longer in the low-CRP group (8.5 vs. 4.4 months, p = 0.007). The discontinuation rate due to poor performance status was significantly higher in the high-CRP group (p < 0.001). Conclusion: A baseline serum CRP level exceeding 0.5 mg/dL was identified as an unfavorable prognostic factor in HCC patients receiving lenvatinib treatment. [ABSTRACT FROM AUTHOR]

Shoseiryuto (SST) (Xiao-Qing-Long-Tang in Chinese) is an effective treatment for respiratory diseases, such as bronchial asthma and allergic rhinitis, but its effects on the bronchial tight-junction (TJ) barrier have not been clarified. This study aimed to evaluate the effect of SST on TJ-barrier function in human bronchial epithelial (16HBE) cells. The 16HBE cells were cultured in a culture medium without (control) and with SST in the absence and presence of bacterial endotoxin lipopolysaccharide (LPS) in transwell chambers. Transepithelial electrical resistance (TEER) and sodium fluorescein (Na-F) permeability of the cultured-cell monolayer were measured as TJ integrity markers. In addition, immunofluorescence staining and quantitative real-time polymerase chain reaction analysis were used to measure the expression of the TJ protein, occludin. SST increased TEER and decreased Na-F permeability of the 16HBE cell monolayers. Furthermore, SST increased both occludin mRNA and immunostained protein expressions, suggesting that SST has the effect of directly promoting epithelial TJ-barrier function. LPS decreased TEER, increased Na-F permeability, and decreased both occludin mRNA and protein expression. LPS-induced barrier dysfunction was completely blocked by pre/co- and posttreatment with SST. These results suggest that SST has protective and therapeutic effects against LPS-induced TJ-barrier damage. To our knowledge, these are the first results to demonstrate the protective and therapeutic effects conferred by TJ-barrier promoting, which may be a novel mechanism contributing to the efficacy of SST for respiratory diseases. [ABSTRACT FROM AUTHOR]

The coronavirus disease (COVID-19) pandemic has emphasized the paucity of non-contact and non-invasive methods for the objective evaluation of dry eye disease (DED). However, robust evidence to support the implementation of mHealth- and app-based biometrics for clinical use is lacking. This study aimed to evaluate the reliability and validity of app-based maximum blink interval (MBI) measurements using DryEyeRhythm and equivalent traditional techniques in providing an accessible and convenient diagnosis. In this single-center, prospective, cross-sectional, observational study, 83 participants, including 57 with DED, had measurements recorded including slit-lamp-based, app-based, and visually confirmed MBI. Internal consistency and reliability were assessed using Cronbach's alpha and intraclass correlation coefficients. Discriminant and concurrent validity were assessed by comparing the MBIs from the DED and non-DED groups and Pearson's tests for each platform pair. Bland–Altman analysis was performed to assess the agreement between platforms. App-based MBI showed good Cronbach's alpha coefficient, intraclass correlation coefficient, and Pearson correlation coefficient values, compared with visually confirmed MBI. The DED group had significantly shorter app-based MBIs, compared with the non-DED group. Bland–Altman analysis revealed minimal biases between the app-based and visually confirmed MBIs. Our findings indicate that DryEyeRhythm is a reliable and valid tool that can be used for non-invasive and non-contact collection of MBI measurements, which can assist in accessible DED detection and management. [ABSTRACT FROM AUTHOR]

Background: Hay fever is a common allergic disease, with an estimated worldwide prevalence of 14.4% and a variety of symptoms. This study assessed the minimal clinically important difference (MCID) of nasal symptom score (NSS), non‐nasal symptom score (NNSS), and total symptoms score (TSS) for app‐based hay‐fever monitoring. Methods: MCIDs were calculated based on the data from a previous large‐scale, crowdsourced, cross‐sectional study using AllerSearch, an in‐house smartphone application. MCIDs were determined with anchor‐based and distribution‐based methods. The face scale score of the Japanese Allergic Conjunctival Disease Standard Quality of Life Questionnaire Domain III and the daily stress level due to hay fever were used as anchors for determining MCIDs. The MCID estimates were summarized as MCID ranges. Results: A total of 7590 participants were included in the analysis (mean age: 35.3 years, 57.1% women). The anchor‐based method produced a range of MCID values (median, interquartile range) for NSS (2.0, 1.5–2.1), NNSS (1.0, 0.9–1.2), and TSS (2.9, 2.4–3.3). The distribution‐based method produced two MCIDs (based on half a standard deviation, based on a standard error of measurement) for NSS (2.0, 1.8), NNSS (1.3, 1.2), and TSS (3.0, 2.3). The final suggested MCID ranges for NSS, NNSS, and TSS were 1.8–2.1, 1.2–1.3, and 2.4–3.3, respectively. Conclusions: MCID ranges for app‐based hay‐fever symptom assessment were obtained from the data collected through a smartphone application, AllerSearch. These estimates may be useful for monitoring the subjective symptoms of Japanese patients with hay fever through mobile platforms. [ABSTRACT FROM AUTHOR]

Local recurrence after colorectal liver metastasis (CRLM) resection severely affects survival; however, the required surgical margin width remains controversial. This study investigated the impact of KRAS status on surgical margin width and local recurrence rate (LRR) post-CRLM resection. Overall, 146 resected CRLMs with KRAS status (wild-type KRAS (wtKRAS): 98, KRAS mutant (mKRAS): 48) were included. The LRR for each group, R1 (margin positive) and R0 (margin negative), was analyzed by KRAS status. R0 was further stratified into Ra (margin ≥ 5 mm) and Rb (margin < 5 mm). Patients with local recurrence had significantly worse 5-year overall survival than those without local recurrence (p = 0.0036). The mKRAS LRR was significantly higher than wtKRAS LRR (p = 0.0145). R1 resection resulted in significantly higher LRRs than R0 resection for both wtKRAS and mKRAS (p = 0.0068 and p = 0.0204, respectively), and while no significant difference was observed in the Ra and Rb LRR with wtKRAS, the Rb LRR with mKRAS (33.3%) was significantly higher than Ra LRR (5.9%) (p = 0.0289). Thus, R0 resection is sufficient for CRLM with wtKRAS; however, CRLM with mKRAS requires resection with a margin of at least 5 mm to prevent local recurrence. [ABSTRACT FROM AUTHOR]

Muscle fiber composition is associated with physical performance, with endurance athletes having a high proportion of slow-twitch muscle fibers compared to power athletes. Approximately 45% of muscle fiber composition is heritable, however, single nucleotide polymorphisms (SNP) underlying inter-individual differences in muscle fiber types remain largely unknown. Based on three whole genome SNP datasets, we have shown that the rs236448 A allele located near the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene was associated with an increased proportion of slow-twitch muscle fibers in Russian (n = 151; p = 0.039), Finnish (n = 287; p = 0.03), and Japanese (n = 207; p = 0.008) cohorts (meta-analysis: p = 7.9 × 10−5. Furthermore, the frequency of the rs236448 A allele was significantly higher in Russian (p = 0.045) and Japanese (p = 0.038) elite endurance athletes compared to ethnically matched power athletes. On the contrary, the C allele was associated with a greater proportion of fast-twitch muscle fibers and a predisposition to power sports. CDKN1A participates in cell cycle regulation and is suppressed by the miR-208b, which has a prominent role in the activation of the slow myofiber gene program. Bioinformatic analysis revealed that the rs236448 C allele was associated with increased CDKN1A expression in whole blood (p = 8.5 × 10−15) and with greater appendicular lean mass (p = 1.2 × 10−5), whereas the A allele was associated with longer durations of exercise (p = 0.044) reported amongst the UK Biobank cohort. Furthermore, the expression of CDKN1A increased in response to strength (p < 0.0001) or sprint (p = 0.00035) training. Accordingly, we found that CDKN1A expression is significantly (p = 0.002) higher in the m. vastus lateralis of strength athletes compared to endurance athletes and is positively correlated with the percentage of fast-twitch muscle fibers (p = 0.018). In conclusion, our data suggest that the CDKN1A rs236448 SNP may be implicated in the determination of muscle fiber composition and may affect athletic performance. [ABSTRACT FROM AUTHOR]

Among several secreted glycoproteins belonging to the thrombospondin family, thrombospondin 2 (TSP2) is involved in various functions, including collagen/fibrin formation. Liver/serum TSP2 levels have been correlated to liver fibrosis stage and disease activity in nonalcoholic fatty liver disease. This study investigated whether serum TSP2 was associated with clinicopathological features in hepatitis C virus (HCV)-infected patients as well. A total of 350 patients with HCV who had undergone liver biopsy were retrospectively enrolled and divided into a discovery cohort (n = 270) and a validation cohort (n = 80). In the discovery cohort, serum TSP2 levels were moderately correlated with both liver fibrosis stage (r = 0.426, P < 0.0001) and activity grade (r = 0.435, P < 0.0001). The area under the receiver operating characteristic curve of TSP2 for predicting severe fibrosis (≥ F3) was 0.78 and comparable to or better than those of autotaxin (0.78), FIB-4 index (0.78), and APRI (0.76). The discovery cohort findings were closely replicated in the validation cohort. Moreover, comprehensive liver genetic analysis of HCV-infected patients confirmed that the expression of the THBS2 gene encoding TSP2 was significantly higher in severely fibrotic F4 than in F1 patients. Circulating TSP2 levels may reflect the severity of hepatic fibrosis/inflammation in HCV-infected patients. [ABSTRACT FROM AUTHOR]

We investigated and characterized the prevalence of dry eye disease (DED) in Parkinson's disease (PD). PubMed and EMBASE databases were searched for relevant studies between January 1, 1979 and March 10, 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Study-specific estimates were combined using the DerSimonian–Laird random-effects model. Prevalence of subjective DED symptoms in patients with PD and mean differences in blink rate, corneal thickness, tear film breakup time, and tear secretion volume on Schirmer test I were compared to those in controls. Of 383 studies, 13 (1519 patients with PD) and 12 were included in qualitative and quantitative syntheses, respectively. Meta-analysis revealed a 61.1% prevalence of subjective DED symptoms in PD and that, compared with controls, patients with PD had significantly lower blink rate, thinner corneal thickness, shorter tear film breakup time, and lower tear secretion volumes on Schirmer test I, without and with anesthesia. [ABSTRACT FROM AUTHOR]

Inchinkoto (ICKT), a traditional herbal medicine that is often used as a hepatoprotective drug in Japan, has pharmacological properties that include antioxidant, anti-inflammatory, and choleretic actions. Genipin is a metabolite of geniposide and the most abundant ingredient of ICKT; furthermore, it is considered to be the active substance responsible for its pharmacological properties in the liver. Drugs with such pharmacological characteristics are expected to prevent intestinal barrier dysfunction, which causes inflammatory bowel diseases (IBDs). However, no studies have investigated the effects of ICKT on the intestinal epithelial barrier. Therefore, we investigated the activity of ICKT in intestinal tight junctions by using cultured Caco-2 cell monolayers. The action of the compound on tight junctions was examined by measuring transepithelial electrical resistance (TEER) and sodium fluorescein (Na-F) permeability in the presence or absence of lipopolysaccharide (LPS). Moreover, the expression of the tight junction protein claudin-1 was assessed by using immunofluorescent staining. ICKT and genipin increased TEER and decreased Na-F permeability, which was suggestive of enhanced intestinal epithelial barrier function. Moreover, they prevented the LPS-induced destruction of the barrier, i.e., a decrease in TEER and an increase in Na-F permeability. Immunofluorescence staining revealed a high claudin-1 expression level on the cell surface, whereas exposure to LPS downregulated claudin-1. In turn, ICKT and genipin prevented the LPS-mediated reduction of claudin-1. These results suggest that ICKT enhances intestinal epithelial barrier function by upregulating claudin-1. Furthermore, genipin contributed to these effects. ICKT may be a promising medicine for the prevention and treatment of diseases associated with intestinal barrier disruption, such as IBD, obesity, and metabolic disorders. [ABSTRACT FROM AUTHOR]

Background: Skeletal muscle fiber type distribution has implications for human health, muscle function, and performance. This knowledge has been gathered using labor-intensive and costly methodology that limited these studies. Here, we present a method based on muscle tissue RNA sequencing data (totRNAseq) to estimate the distribution of skeletal muscle fiber types from frozen human samples, allowing for a larger number of individuals to be tested. Methods: By using single-nuclei RNA sequencing (snRNAseq) data as a reference, cluster expression signatures were produced by averaging gene expression of cluster gene markers and then applying these to totRNAseq data and inferring muscle fiber nuclei type via linear matrix decomposition. This estimate was then compared with fiber type distribution measured by ATPase staining or myosin heavy chain protein isoform distribution of 62 muscle samples in two independent cohorts (n = 39 and 22). Results: The correlation between the sequencing-based method and the other two were rATPas = 0.44 [0.13–0.67], [95% CI], and rmyosin = 0.83 [0.61–0.93], with p = 5.70 × 10–3 and 2.00 × 10–6, respectively. The deconvolution inference of fiber type composition was accurate even for very low totRNAseq sequencing depths, i.e., down to an average of ~ 10,000 paired-end reads. Conclusions: This new method (https://github.com/OlaHanssonLab/PredictFiberType) consequently allows for measurement of fiber type distribution of a larger number of samples using totRNAseq in a cost and labor-efficient way. It is now feasible to study the association between fiber type distribution and e.g. health outcomes in large well-powered studies. [ABSTRACT FROM AUTHOR]

The new duty hour (DH) limit for doctors in Japan will begin in 2024, setting the maximum DHs for postgraduate residents at approximately 80 h weekly. To set appropriate limits, understanding the association between DHs and psychological health is necessary. Thus, we assessed the relationship between residents' psychological health and DHs. We conducted a cross-sectional study involving examinees of the General Medicine In-training Examination 2020. Mental health outcomes were measured dichotomously using the Patient Health Questionnaire-2 for depression and Mini-Z 2.0, for burnout, stress, and satisfaction. Weekly DHs were measured in seven categories at 10-h intervals. The prevalence ratios (PRs) between the DH categories were estimated for each outcome. Of the 6045 residents who provided data on DHs and psychological outcomes, 37.3% showed signs of depression, 21.6% experienced burn out, and 39.2% were highly stressed. In contrast, 62.3% were highly satisfied with their training. Proportions of burnout were higher among residents in Category 6 (≥ 90 and < 100 h; PR 1.36; 95% CI 1.11–1.66) and Category 7 (≥ 100 h; PR 1.36; 95% CI 1.10–1.68) compared with residents in Category 3 (≥ 60 and < 70 h; reference). The results partially support the weekly 80-h DH limit in terms of resident well-being. [ABSTRACT FROM AUTHOR]

Simple Summary: We performed mutation analysis of ribonucleic acid sequencing (RNA-seq) and whole mitochondrial genome data from tissues collected from metastatic lesions of a male patient in his 60s with metastatic renal cell carcinoma. We confirmed the common mutation sites of a mitochondrial gene containing the T3394Y, R11,807G, and G15,438R sites. Pathway analysis, using RNA-seq data, confirmed the common mutant pathway between renal cell carcinoma and metastatic adrenal carcinoma as cytokine–cytokine receptor (CCR) interaction. However, no common nuclear gene mutations were identified. The two similar sequences suggest that mtDNA-mutation-driven metastasis to the adrenal gland may affect CCR interactions and cause cancer cells to thrive. This study aimed to clarify whether genetic mutations participate in renal cell carcinoma (RCC) metastasis to the adrenal gland (AG). Our study analyzed whole mitochondrial gene and ribonucleic acid sequencing (RNA-seq) data from a male patient in his 60s with metastatic RCC. We confirmed common mutation sites in the mitochondrial gene and carried out Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis using RNA-seq data for RCC and adrenal carcinoma. Furthermore, we confirmed the common mutation sites of mitochondrial genes in which the T3394Y (p.H30Y) site transitioned from histidine (His.; H) to tyrosine (Tyr.; Y) in the NADH dehydrogenase subunit 1 (ND1) gene. The R11,807G (p.T350A) site transitioned from threonine (Thr.; T) to alanine (Ala.; A). Additionally, the G15,438R or A (p.G231D) site transitioned from glycine (Gly.; G) to aspartic acid (Asp.; D) in cytochrome b (CYTB). Furthermore, pathway analysis, using RNA-seq, confirmed the common mutant pathway between RCC and adrenal carcinoma as cytokine–cytokine receptor (CCR) interaction. Confirmation of the original mutation sites suggests that transfer to AG may be related to the CCR interaction. Thus, during metastasis to the AG, mitochondria DNA mutation may represent the initial origin of the metastasis, followed by the likely mutation of the nuclear genes. [ABSTRACT FROM AUTHOR]

The halogen bond has been widely used as an important supramolecular tool in various research areas. However, there are relatively few studies on halogen bonding related to molecular chirality. 3-(2-Halophenyl)quinazoline-4-thione derivatives have stable atropisomeric structures due to the rotational restriction around an N-C single bond. In X-ray single crystal structures of the racemic and optically pure N-C axially chiral quinazoline-4-thiones, we found that different types of intermolecular halogen bonds (C=S⋯X) are formed. That is, in the racemic crystals, the intermolecular halogen bond between the ortho-halogen atom and sulfur atom was found to be oriented in a periplanar conformation toward the thiocarbonyl plane, leading to a syndiotactic zig-zag array. On the other hand, the halogen bond in the enantiomerically pure crystals was oriented orthogonally toward the thiocarbonyl plane, resulting in the formation of a homochiral dimer. These results indicate that the corresponding racemic and optically pure forms in chiral molecules are expected to display different halogen bonding properties, respectively, and should be separately studied as different chemical entities. [ABSTRACT FROM AUTHOR]