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We examined the association between texture features using three-dimensional (3D) io-dine density histogram on delayed phase of dual-energy CT (DECT) and expression of programmed death-ligand 1 (PD-L1) using immunostaining methods in non-small cell lung cancer. Consecutive 37 patients were scanned by DECT. Unenhanced and enhanced (3 min delay) images were obtained. 3D texture analysis was performed for each nodule to obtain 7 features (max, min, median, mean, standard deviation, skewness, and kurtosis) from iodine density mapping and extracellular volume (ECV). A pathologist evaluated a tumor proportion score (TPS, %) using PD-L1 immunostaining: PD-L1 high (TPS ≥ 50%) and low or negative expression (TPS < 50%). Associations between PD-L1 expression and each 8 parameter were evaluated using logistic regression analysis. The multivariate logistic regression analysis revealed that skewness and ECV were independent indicators associated with high PD-L1 expression (skewness: odds ratio [OR]  7.1 [95% CI 1.1, 45.6], p = 0.039; ECV: OR 6.6 [95% CI 1.1, 38.4], p = 0.037). In the receiver-operating characteristic analysis, the area under the curve of the combination of skewness and ECV was 0.83 (95% CI 0.67, 0.93) with sensitivity of 64% and specificity of 96%. Skewness from 3D iodine density histogram and ECV on dual energy CT were significant factors for predicting PD-L1 expression., (© 2024. The Author(s).)

Weather conditions influence the incidence of cardiovascular disease. However, few studies have investigated the association between weather temperature and humidity and cerebrovascular disease hospitalizations in a super-aging society. We included 606,807 consecutive patients with cerebrovascular disease admitted to Japanese acute-care hospitals between 2015 and 2019. The primary outcome was the number of cerebrovascular disease hospitalizations per day. Multilevel mixed-effects linear regression models were used to estimate the association of mean temperature and humidity, 1 day before hospital admission, with cerebrovascular disease hospitalizations, after adjusting for air pollution, hospital, and patient demographics. Lower mean temperatures and humidity < 70% or humidity ≧ 70% are associated with an increased incidence of cerebrovascular disease hospitalization (coefficient, - 1.442 [- 1.473 to - 1.411] per °C, p < 0.001, coefficient, - 0.084 [- 0.112 to - 0.056] per%, p < 0.001, and coefficient, 0.136 [0.103 to 0.168] per %, p < 0.001, respectively). Lower mean temperatures and extremely lower or higher humidity are associated with an increased incidence of cerebrovascular disease hospitalization in a super-aging society., (© 2023. The Author(s).)

Dipeptidyl-peptidase-4 inhibitors (DPP4i) have been the most used antidiabetic medications worldwide due to their good safety profiles and tolerability with a low risk of hypoglycemia, however, large cardiovascular outcome trials (CVOTs) have not shown any significant the prognostic superiority. On the contrary, since observational studies have suggested the effects of DPP4i are enhanced some populations, such as Asians and those who without overweight, their prognostic benefit is still under debate. The aim of this study was thus to assess the prognostic impact of DPP4i in patients with both diabetes and coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) through the insulin-like growth factor-1 (IGF-1) axis, a substrate of DPP4. This single-center analysis involved consecutive Japanese diabetic patients who underwent PCI for the first time between 2008 and 2018 (n = 885). Primary and secondary endpoints were set as cardiovascular (CV) death and the composite of CV death, non-fatal myocardial infarction and ischemic stroke (3P-MACE). Serum levels of IGF-1 and its main binding protein (insulin-like growth factor binding protein-3: IGFBP-3) were measured. In consequences, unadjusted Kaplan-Meier analyses revealed reduced incidences of CV-death and 3P-MACE by DPP4i, which was particularly enhanced in patients who were not overweight (BMI ≤ 25). Multivariate Cox hazard analyses consistently indicated reduced risks of CV death by DPP4i at PCI (hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.16-0.82, p = 0.01) and 3P-MACE (HR 0.47, 95% CI 0.25-0.84, p = 0.01), respectively. Moreover, elevated IGF-1 activity indicated by the IGF-1/IGFBP-3 ratio was associated with decreased risks of both endpoints and it was significantly higher in patients with DPP4i (p < 0.0001). In conclusion, the findings of the present study indicate beneficial effects of DPP4i to improve outcomes in Japanese diabetic patients following PCI, which might be mediated by DPP4-IGF-1 axis., (© 2022. The Author(s).)

Weather conditions affect the incidence of acute myocardial infarction (AMI). However, little is known on the association of weather temperature and humidity with AMI hospitalizations in a super-aging society. This study sought to examine this association. We included 87,911 consecutive patients with AMI admitted to Japanese acute-care hospitals between April 1, 2012 and March 31, 2015. The primary outcome was the number of AMI hospitalizations per day. Multilevel mixed-effects linear regression models were used to estimate the association of the average temperature and humidity, 1 day before hospital admission, with AMI hospitalizations, after adjusting for weather, hospital, and patient demographics.Lower temperature and humidity were associated with an increased number of AMI hospitalizations (coefficient - 0.500 [- 0.524 to - 0.474] per °C change, p < 0.001 and coefficient - 0.012 [- 0.023 to - 0.001] per % change, p = 0.039, respectively). The effects of temperature and humidity on AMI hospitalization did not differ by age and sex (all interaction p > 0.05), but differed by season. However, higher temperatures in spring (coefficient 0.089 [0.025 to 0.152] per °C change, p = 0.010) and higher humidity in autumn (coefficient 0.144 [0.121 to 0.166] per % change, p < 0.001) were risk factors for AMI hospitalization. Increased average temperatures and humidity, 1 day before hospitalization, are associated with a decreased number of AMI hospitalizations., (© 2021. The Author(s).)

Gpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with currently no established physiological role in vivo. We characterized Gpr19 expression in the suprachiasmatic nucleus (SCN), the locus of the master circadian clock in the brain, and determined its role in the context of the circadian rhythm regulation. We found that Gpr19 is mainly expressed in the dorsal part of the SCN, with its expression fluctuating in a circadian fashion. A conserved cAMP-responsive element in the Gpr19 promoter was able to produce circadian transcription in the SCN. Gpr19 -/- mice exhibited a prolonged circadian period and a delayed initiation of daily locomotor activity. Gpr19 deficiency caused the downregulation of several genes that normally peak during the night, including Bmal1 and Gpr176. In response to light exposure at night, Gpr19 -/- mice had a reduced capacity for light-induced phase-delays, but not for phase-advances. This defect was accompanied by reduced response of c-Fos expression in the dorsal region of the SCN, while apparently normal in the ventral area of the SCN, in Gpr19 -/- mice. Thus, our data demonstrate that Gpr19 is an SCN-enriched orphan GPCR with a distinct role in circadian regulation and may provide a potential target option for modulating the circadian clock., (© 2021. The Author(s).)

To investigate the prevalence of nodular pulmonary ossifications (POs) in patients with honeycombing on ultra-high-resolution CT (UHRCT) and to compare the detectability of nodular POs between images reconstructed using the ultra-high-resolution setting (UHR-setting) and those using the conventional setting (C-setting) on UHRCT. Twenty patients with honeycombing in the lung were evaluated retrospectively. All patients underwent non-contrast-enhanced UHRCT. Images were reconstructed with UHR-setting (matrix, 2048 × 2048; slice thickness, 0.25 mm) and with C-setting (matrix size, 512 × 512; slice thickness, 0.5 mm). Two chest radiologists independently recorded the number of nodular POs (< 4 mm diameter) in each lung lobes. Each lobe was classified as one of the following five categories according to the number of POs: C0, none; C1, 1-4 POs; C2, 5-9 POs; C3, 10-49 POs; and C4, ≥ 50 POs. The maximum CT values of the POs were measured and compared between the two settings. PO categories were significantly higher with UHR-setting than with C-setting (p < 0.001). Maximum CT values were significantly higher with UHR-setting than with C-setting (p < 0.001). Nodular POs were seen in 80% or more of patients with honeycombing and more easily detected in images reconstructed with UHR-setting than in those with C-setting., (© 2021. The Author(s).)

This retrospective study was performed to classify diabetic macular edema (DME) based on the localization and area of the fluid and to investigate the relationship of the classification with visual acuity (VA). The fluid was visualized using en face optical coherence tomography (OCT) images constructed using swept-source OCT. A total of 128 eyes with DME were included. The retina was segmented into: Segment 1, mainly comprising the inner nuclear layer and outer plexiform layer, including Henle's fiber layer; and Segment 2, mainly comprising the outer nuclear layer. DME was classified as: foveal cystoid space at Segment 1 and no fluid at Segment 2 (n = 24), parafoveal cystoid space at Segment 1 and no fluid at Segment 2 (n = 25), parafoveal cystoid space at Segment 1 and diffuse fluid at Segment 2 (n = 16), diffuse fluid at both segments (n = 37), and diffuse fluid at both segments with subretinal fluid (n = 26). Eyes with diffuse fluid at Segment 2 showed significantly poorer VA, higher ellipsoid zone disruption rates, and greater central subfield thickness than did those without fluid at Segment 2 (P < 0.001 for all). These results indicate the importance of the localization and area of the fluid for VA in DME.

Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs' therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia-reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-β1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.

This retrospective study investigated foveal and perifoveal retinal sensitivities using microperimetry before and after surgery for rhegmatogenous retinal detachment (RRD). Consecutive patients with RRD who underwent vitrectomy or scleral buckling were included. Comprehensive ophthalmological examinations, including microperimetry and swept-source optical coherence tomography, were performed before and 6 months after surgery. Pre- and postoperative retinal sensitivities at the fovea and 4 perifoveal measurement points farthest from the fixation point, both vertically and horizontally (superior, inferior, nasal, and temporal) were examined. A total of 34 foveal and 136 perifoveal measurement points in 34 eyes of 34 patients were evaluated. The postoperative retinal sensitivity was significantly higher than the preoperative value at foveal and perifoveal points with (P < 0.001 for both) and without (fovea: P = 0.005, perifovea: P < 0.001) RRD. The postoperative retinal sensitivity was significantly lower at foveal (P < 0.01) and perifoveal (P < 0.001) points with preoperative RRD than at points without preoperative RRD; furthermore, it was significantly better at points with ellipsoid zone (Ez) continuity than at points with Ez discontinuity (fovea: P < 0.01, perifovea: P < 0.001). RRD deteriorates retinal sensitivity, regardless of its presence or absence at the measurement point before surgery. Postoperative Ez continuity is important for good postoperative retinal sensitivity.

Globally many children are living with grandparents, and it has been suggested that grandparent co-residence may be associated with dental caries in infants and toddlers possibly through passive parenting style, accompanied by children's cariogenic behaviors such as feeding sugary sweets. However, little is known about this association in schoolchildren, adjusted for socioeconomic status. Therefore, this study investigates the association between grandparent co-residence, socioeconomic status, and dental caries among schoolchildren. All caregivers of first-grade children (age 6-7 years) in Adachi City, Tokyo, were administered a questionnaire about children's grandparent co-residence status and oral health-related behaviors, and responses were linked with dental examination records conducted by school dentists (N = 3,578). Multilevel Poisson regression analysis was applied to examine the association between grandparent co-residence, socioeconomic status, and dental caries status for each individual tooth, adjusting for potential covariates. The percentage of dental caries experience was higher among children living with grandparents (48.9%) than among children living without grandparents (44.0%). The risk for caries, however, did not differ according to grandparent co-residence status when tooth type, child's age and sex, and parental socio-economic status and structure were adjusted (PR, 1.13; 95%CI, 0.90, 1.42). The association between grandparent co-residence and dental caries among early school-aged children in urban Japan was confounded by socioeconomic status.

Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4 + T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORγ. Here, we present the crystal structure of a novel RORγ inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 Å shift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORγ-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders.

Renal fibrosis is a histological manifestation that occurs in almost every type of chronic kidney disease. Histone variant H3.3 and its chaperone, histone cell cycle regulation defective homolog A (HIRA), serve as epigenetic marks that regulate transcriptional activity. In this study, we assessed the roles of histone H3.3 and HIRA in unilateral ureteral-obstruction (UUO) mice. In UUO mice, the levels of histone H3.3 and HIRA were significantly upregulated in the kidneys. These upregulated levels were decreased by a TGF-β1 neutralizing antibody. TGF-β1 induced histone H3.3 and HIRA expression in vitro via a Smad3-dependent pathway in normal rat kidney (NRK)-52E cells. Additionally, knockdown of HIRA expression decreased histone H3.3 expression and fibrogenesis in NRK-52E cells after TGF-β1 stimulation. Chromatin immunoprecipitation analysis revealed that promoters of fibrosis-related genes were immunoprecipitated with both histone H3.3 and HIRA in NRK-52E cells. Lastly, in human kidney biopsies from patients diagnosed with IgA nephropathy, histone H3.3 and HIRA immunostaining correlated positively with areas of fibrosis and estimated glomerular filtration rate. In conclusion, TGF-β1 induces expression of histone H3.3 and HIRA, which regulates expression of fibrosis-related genes.

Anion channelrhodopsin-2 (ACR2) was recently identified from the cryptophyte algae Guillardia theta and has become a focus of interest in part because of its novel light-gated anion channel activity and its extremely high neural silencing activity. In this study, we tried to express ACR2 in Escherichia coli cells as a recombinant protein. The E. coli cells expressing ACR2 showed an increase in pH upon blue-light illumination in the presence of monovalent anions and the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP), indicating an inward anion channel activity. Then, taking advantage of the E. coli expression system, we performed alanine-scanning mutagenesis on conserved basic amino acid residues. One of them, R84A, showed strong signals compared with the wild-type, indicating an inhibitory role of R84 on Cl - transportation. The signal was strongly enhanced in R84E, whereas R84K was less effective than the wild-type (i.e., R84). These results suggest that the positive charge at position 84 is critical for the inhibition. Thus we succeeded in functional expression of ACR2 in E. coli and found the inhibitory role of R84 during the anion transportation., Competing Interests: The authors declare no competing financial interests.

Piperonal-catabolizing microorganisms were isolated from soil, the one (strain CT39-3) exhibiting the highest activity being identified as Burkholderia sp. The piperonal-converting enzyme involved in the initial step of piperonal metabolism was purified from strain CT39-3. Gene cloning of the enzyme and a homology search revealed that the enzyme belongs to the xanthine oxidase family, which comprises molybdoenzymes containing a molybdopterin cytosine dinucleotide cofactor. We found that the piperonal-converting enzyme acts on piperonal in the presence of O 2 , leading to formation of piperonylic acid and H 2 O 2 . The growth of strain CT39-3 was inhibited by higher concentrations of piperonal in the culture medium. Together with this finding, the broad substrate specificity of this enzyme for various aldehydes suggests that it would play an important role in the defense mechanism against antimicrobial compounds derived from plant species.