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ABSTRACT Objective Methods Results Conclusion To investigate the association between dental attendance with periodontal care and the risk of dialysis initiation in patients with type 2 diabetes mellitus (T2D).This retrospective cohort study used data from the Japan Medical Data Center (JMDC) claims database (January 2015 to August 2022). Patients with T2D, aged 40–74, were included. Dental attendance with periodontal care and initiation of dialysis were used as the exposure and outcome variables, respectively. We fitted the Cox proportional hazards model, including potential confounders, to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs).Among 99,273 participants (mean age = 54.4 years [SD = 7.8], male = 71.9%), the incidence rate of dialysis initiation was 0.92 per 1000 person‐years. After adjusting for all covariates, those with periodontal care (HR = 0.68 [95%CI = 0.51–0.91] for ≥ 1 time/year and HR = 0.56 [95%CI = 0.41–0.77] for ≥ 1 time/6 months) had a significantly lower risk of dialysis initiation compared to those without dental attendance.Periodontal disease care in patients with T2D is associated with a reduced risk of dialysis initiation by 32%–44%. This suggests that integrating periodontal care into diabetes management may help prevent the progression of diabetic nephropathy and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Fishes of the genus Rhinogobius (Gobiidae) display paternal care of their nests, constructed beneath stones. Rhinogobius flumineus often coexist with larger Rhinogobius congeners (hence, stronger competitors for the nest site). To understand how R. flumineus reproduce successfully with the presence of a potential nest site competitor, nest-use characteristics of R. flumineus and Rhinogobius nagoyae were investigated in two rivers in southern central Honshu, Japan: one site with both species in sympatry and the other site with R. flumineus in allopatry. Analyses of nest stone, egg clutch, and male body sizes demonstrated that reproductive success, namely the number of eggs deposited, increased with male body size in both species and was positively correlated with nest stone size only in R. nagoyae. The pattern that R. flumineus males are less insistent on using large stones for nesting may partly explain the coexistence mechanism of the two species. [ABSTRACT FROM AUTHOR]

The Vesical Imaging-Reporting and Data System (VI-RADS) is a standard magnetic resonance imaging (MRI) and diagnostic method for muscle-invasive bladder cancer that was published in 2018. Several studies have demonstrated that VI-RADS has high diagnostic power and reproducibility. However, reading VI-RADS requires a certain amount of expertise, and radiologists need to be aware of the various pitfalls. MRI of the bladder includes T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced imaging (DCEI). T2WI is excellent for understanding anatomy. DWI and DCEI show high contrast between the tumor and normal anatomical structures and are suitable for staging local tumors. Bladder tumors are classified into five categories according to their size and morphology and their positional relationship to the bladder wall based on the VI-RADS diagnostic criteria. If the T2WI, DWI, and DCEI categories are the same, the category is the VI-RADS category. If the categories do not match, the DWI category is the VI-RADS category. If image quality of DWI is not evaluable, the DCEI category is the final category. In many cases, DWI is dominant, but this does not mean that T2WI and DCEI can be omitted from the reading of the bladder. In this educational review, typical and atypical teaching cases are demonstrated, and how to resolve misdiagnosis and the limitations of VI-RADS are discussed. The most important aspect of VI-RADS reading is to practice multiparametric reading with a solid understanding of the characteristics and role of each sequence and an awareness of the various pitfalls. [ABSTRACT FROM AUTHOR]

Background: Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a cancer stem cell (CSC) marker of colorectal cancer and may be a CSC marker of other cancer types. Few studies have been conducted on LGR5 expression in extrahepatic cholangiocarcinoma (ECC). Methods: We analyzed LGR5 expression using RNAscope, a highly sensitive RNA in situ hybridization technique. Fifty-three ECCs were selected from the medical archives at Shinshu University Hospital and analyzed using a tissue microarray. LGR5 expression levels were divided into expression and no expression groups. LGR5 expression and clinicopathological characteristics were analyzed. Results: Among 25 cases, no LGR5-positive dots were identified. Among 28 cases, some LGR5-positive dots were observed in carcinoma cells, together with a wide range of LGR5-positive cells. LGR5 expression was conspicuous in glandular duct formations. Well- to moderately differentiated types showed significantly higher LGR5 expression than the poorly differentiated type (p = 0.0268). LGR5 expression was associated with good overall survival (p = 0.0219) and good disease-free survival (DFS) (p = 0.0228). High LGR5 expression was associated with well- to moderately-differentiated types, indicating a favorable prognosis. In terms of DFS, multivariate analysis showed that high LGR5 expression was an independent favorable prognostic factor (p = 0.0397). Conclusions: These findings suggest that LGR5 is a promising, novel prognostic marker. [ABSTRACT FROM AUTHOR]

Astrocytes, the major non-dividing glial cells in the central nervous system, exhibit hyperactivation in Alzheimer’s disease (AD), leading to neuroinflammation and cognitive impairments. P2Y1- receptor (P2Y1R) in AD brain has been pointed out some contribution to AD pathogenesis, therefore, this study aims to elucidate how astrocytic P2Y1R affects the progression of AD and explore its potential as a new target for AD therapy. In this study, we performed the two-steps verification to assess P2Y1R inhibition in AD progression: P2Y1R-KO AD mice and AD mice treated with astrocyte-specific P2Y1R gene knockdown by using shRNAs for P2Y1R in adeno-associated virus vector. Histochemistry was conducted for the assessment of amyloid-beta accumulation, neuroinflammation and blood brain barrier function. Expression of inflammatory cytokines was evaluated by qPCR after the separation of astrocytes. Cognitive function was assessed through the Morris water maze, Y maze, and contextual fear conditioning tests. P2Y1R inhibition not only by gene knockout but also by astrocyte-specific knockdown reduced amyloid-beta accumulation, glial neuroinflammation, blood brain barrier dysfunction, and cognitive impairment in an AD mice model. Reduced neuroinflammation by astrocytic P2Y1R silencing in AD was further confirmed by the reduction of IL-6 gene expression after the separation of astrocytes from AD mouse brain, which may relate to the amelioration of blood brain barrier as well as cognitive functions. Our results clearly note that P2Y1R in astrocyte contributes to the progression of AD pathology through the acceleration of neuroinflammation, and one-time gene therapy for silencing astrocytic P2Y1R may offer a new therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Background: Secondary healthcare data use has been increasing in the dental research field. The validity of the number of remaining teeth assessed from Japanese dental claims data has been reported in several studies, but has not been tested in the general population in Japan. Objectives: To evaluate the validity of the number of remaining teeth assessed from Japanese dental claims data and assess its predictability against subsequent health deterioration. Methods: We used the claims data of residents of a municipality that implemented oral health screening programs. Using the number of teeth in the screening records as the reference standard, we assessed the validity of the claims-based number of teeth by calculating the mean differences. In addition, we assessed the association between the claims-based number of teeth and pneumococcal disease (PD) or Alzheimer's disease (AD) in adults aged ≥65 years using Cox proportional hazards analyses. Results: Of the 10,154 participants, the mean number of teeth assessed from the claims data was 20.9, that in the screening records was 20.5, and their mean difference was 0.5. During the 3-year follow-up, PD or AD onset was observed in 10.4% (3,212/30,838) and 5.3% (1,589/30,207) of participants, respectively. Compared with participants with ≥20 teeth, those with 1–9 teeth had a 1.29 (95% confidence interval [CI]: 1.17–1.43) or 1.19 (95% CI: 1.04–1.36) times higher risk of developing PD or AD, respectively. Conclusion: High validity of the claims-based number of teeth was observed. In addition, the claims-based number of teeth was associated with the risk of PD and AD. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) extends throughout a cell and plays a critical role in maintaining cellular homeostasis. Changes in ER shape could provide a clue to explore the mechanisms that underlie the fate determination of neurons after axon injury because the ER drastically changes its morphology under neuronal stress to maintain cellular homeostasis and recover from damage. Because of their tiny structures and richness in the soma, the detailed morphology of the ER and its dynamics have not been well analysed. In this study, the focused ion beam/scanning electron microscopy (FIB/SEM) analysis was performed to explore the ultra-structures of the ER in the somata of motor neuron with axon regenerative injury models. In normal motor neurons, ER in the somata is abundantly localised near the perinucleus and represents lamella-like structures. After injury, analysis of the ER volume and ER branching points indicated a collapse of the normal distribution and a transformation from lamella-like structures to mesh-like structures. Furthermore, accompanied by ER accumulation near the plasma membrane (PM), the contact between the ER and PM (ER-PM contacts) significantly increased after injury. The accumulation of extended-synaptotagmin 1 (E-Syt1), a tethering protein of the ER and PM that regulates Ca2+-dependent lipid transfer, was also identified by immunohistochemistry and quantitative Real-time PCR after injury. These morphological alterations of ER and the increase in ER-PM contacts may be crucial events that occur in motor neurons as a resilient response for the survival after axonal injury. [ABSTRACT FROM AUTHOR]

Hakutsurunishiki is a sake rice cultivar bred using Yamadabo (seed parent) and Wataribune 2 (pollen parent), equivalent to a Yamadanishiki sibling. This study evaluated the structural characteristics of the Hakutsurunishiki rice grain that contribute to the brewing characteristics of daiginjo-shu , via a comparison with Yamadanishiki. Hakutsurunishiki brown rice was a little heavy and had a large white core. Observing a cross-section of white rice after soaking revealed that the rice grain structure of Hakutsurunishiki was different from that of Yamadanishiki. Hakutsurunishiki white rice showed fewer voids than Yamadanishiki , promoting a slower water absorption rate. Glucose distribution in rice koji obtained by mass spectrometry imaging showed that Hakutsurunishiki rice koji , like Yamadanishiki , is tsuki-haze type, suggesting that its grain structure is suitable for making rice koji for daiginjo-shu. With these observations, we were able to clarify the structural characteristics of Hakutsurunishiki rice grain. [ABSTRACT FROM AUTHOR]

The lack of functional vascular system in stem cell-derived cerebral organoids (COs) limits their utility in modeling developmental processes and disease pathologies. Unlike other organs, brain vascularization is poorly understood, which makes it particularly difficult to mimic in vitro. Although several attempts have been made to vascularize COs, complete vascularization leading to functional capillary network development has only been achieved via transplantation into a mouse brain. Understanding the cues governing neurovascular communication is therefore imperative for establishing an efficient in vitro system for vascularized cerebral organoids that can emulate human brain development. Here, we used a multidisciplinary approach combining microfluidics, organoids, and transcriptomics to identify molecular changes in angiogenic programs that impede the successful in vitro vascularization of human induced pluripotent stem cell (iPSC)-derived COs. First, we established a microfluidic cerebral organoid (CO)-vascular bed (VB) co-culture system and conducted transcriptome analysis on the outermost cell layer of COs cultured on the preformed VB. Results revealed coordinated regulation of multiple pro-angiogenic factors and their downstream targets. The VEGF-HIF1A-AKT network was identified as a central pathway involved in the angiogenic response of cerebral organoids to the preformed VB. Among the 324 regulated genes associated with angiogenesis, six transcripts represented significantly regulated growth factors with the capacity to influence angiogenic activity during co-culture. Subsequent on-chip experiments demonstrated the angiogenic and vasculogenic potential of cysteine-rich angiogenic inducer 61 (CYR61) and hepatoma-derived growth factor (HDGF) as potential enhancers of organoid vascularization. Our study provides the first global analysis of cerebral organoid response to three-dimensional microvasculature for in vitro vascularization. [ABSTRACT FROM AUTHOR]

Background: Bivalent COVID-19 vaccines have been implemented worldwide since the booster vaccination campaigns of autumn of 2022, but little is known about their effectiveness. Thus, this study holistically evaluated the effectiveness of bivalent vaccines against infection in older adults in Japan. Methods: We adopted the test-negative design using COVID-19 test data of individuals, aged ≥ 65 years, residing in three municipalities in Japan, who underwent tests in medical institutions between October 1 and December 30, 2022. Logistic regression analyses were conducted to estimate the odds of testing positive according to vaccination status. Vaccine effectiveness was defined as (1 − odds ratio) × 100%. Results: A total of 3,908 positive and 16,090 negative results were included in the analyses. Receiving a bivalent dose in addition to ≥ 2 monovalent doses was 33.6% (95% confidence interval [CI]: 20.8, 44.3%) more effective than receiving no vaccination, and 18.2% (95% CI: 9.4, 26.0%) more effective than receiving ≥ 2 monovalent doses but not receiving a bivalent vaccination. In addition, the effectiveness peaked at 14–20 days after administration and then gradually declined over time. Furthermore, a bivalent booster dose provided 18.6% (95% CI: 9.9, 26.5%) additional protection among those vaccinated with ≥ 2 monovalent doses, in the absence of a previous infection history. However, we did not find sufficient evidence of effectiveness of bivalent vaccines among previously infected older adults. Conclusions: Bivalent vaccines are effective against COVID-19 infections among older adults without a history of infection. [ABSTRACT FROM AUTHOR]

Russia's 2022 invasion of Ukraine has sent shockwaves across the international community, not least the international investment community and the arbitration world. A flurry of disputes has arisen not only in connection to harm to the interests of foreign investors in Ukraine and Russia but also in relation to sanctions – including asset freezing measures – imposed by many western and aligned states. This article outlines the typology of arising cases, and discusses the principal arguments, outcomes and challenges of means of redress (typically, arbitration) that appear to be at play. [ABSTRACT FROM AUTHOR]

At the time of writing, the war in Ukraine was the subject of ICJ proceedings in the Allegations of Genocide case. As the case title suggests, however, the key issue before the ICJ is not Russia's use of force, but the question of genocide. Restrictions on its jurisdiction have led to the ICJ facing a serious dilemma between, on the one hand, having to meet unprecedented high levels of expectation and political pressure to stop Russia's military action and, on the other, inherent legal constraints in maintaining its judicial character. This article elucidates how the ICJ has overcome procedural hurdles, including the requirements for provisional measures and intervention, to reach conclusions in favour of Ukraine. It also highlights the procedural challenges arising from the acrobatic reasoning adopted by the ICJ in the present case. [ABSTRACT FROM AUTHOR]

Background: The influence of psychosocial factors on differentiating between melancholic depression (MEL) and non-melancholic depression (NMEL) remains unclear. In this study, we aimed to investigate the interrelationship between dysfunctional parenting, personality traits, stressful life events, and the diagnosis of MEL and NMEL among patients with major depressive disorder (MDD). Methods: Ninety-eight patients with MDD completed the following self-administered questionnaires: the Parental Bonding Instrument (PBI) for dysfunctional parenting, the short version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) for affective temperaments, and the Life Experiences Survey (LES) for stressful life events. The data were analyzed using single and multiple regression analyses and path analysis. Results: Dysfunctional parenting did not have a significant direct effect on MEL. However, paternal care had a significant indirect effect on MEL through depressive temperament. The total indirect effect of paternal care on MEL was significant (indirect path coefficient = 0.161, p <0.05). In other words, low levels of paternal care were associated with the development of NMEL via increased depressive temperament. None of the paths from paternal care to MEL via negative change scores of the LES were significant. Limitations: This study used cross-sectional data, so the possibility that current depressive status may affect the assessment of LES and TEMPS-A cannot be ruled out. Conclusions: We found that low levels of paternal care did not directly affect the development of NMEL, but affected the development of NMEL through the mediation of depressive temperament rather than stressful life events. [ABSTRACT FROM AUTHOR]

Aim: The risk of falls owing to simultaneous use of multiple hypnotics has not been clarified. The aim of this study was to assess the association between the simultaneous use of 2 hypnotics and the occurrence of falls in hospitalized patients. Methods: A matched case-control study was conducted at Tokyo Medical University Hospital in Tokyo, Japan, utilizing data from medical records. Cases were 434 hospitalized patients who experienced falls during their hospital stay between January 2016 and December 2016, and controls were 434 hospitalized patients without falls, individually matched by age, sex, and clinical department. The outcome was the occurrence of an in-hospital fall. The associations between the use of 1 hypnotic and falls, and between the use of 2 hypnotics and falls were assessed by conditional logistic regression analyses. The main multivariable conditional logistic regression model was adjusted for potential risk factors, including the use of other classes of psychotropics (antipsychotics, antidepressants, and anxiolytics), in addition to patient characteristics. Results: The main multivariable conditional logistic regression analyses showed that the simultaneous use of 2 hypnotics (odds ratio [OR] = 2.986; 95% confidence interval [CI], 1.041–8.567), but not the use of a single hypnotic (OR = 1.252; 95% CI, 0.843–1.859), was significantly associated with an increased OR of falls. Conclusion: The simultaneous use of 2 hypnotics is a risk factor for falls among hospitalized patients, whereas the use of a single hypnotic may not. [ABSTRACT FROM AUTHOR]

• This is the first multi-region community-based test-negative study in Japan. • High real-world effectiveness of COVID-19 vaccines against infection was observed. • The vaccines effectiveness at ≥14 days after the second dose was found to be ≥80%. Although the effectiveness of coronavirus disease 2019 (COVID-19) vaccines is a crucial public health concern, evidence from Western Pacific countries is limited, including Japan. This study aimed to estimate the COVID-19 vaccines effectiveness (VE) against infection during the Delta variant predominance (July–September 2021) in Japan. We performed a test-negative study using COVID-19 test data of ≥20-year-old residents in four municipalities who were tested in medical institutions between July 1 and September 30, 2021. We extracted COVID-19 test data from healthcare claims data, and the vaccination status at the testing date was ascertained using the Vaccination Record System data. Confirmed positive cases were identified using data from the national system for COVID-19, Health Center Real-time Information-sharing System on COVID-19. Logistic regression analyses were conducted to estimate the odds of testing positive according to vaccination status. VE was calculated as (1 − odds ratio) × 100%. This study included 530 positive and 15,650 negative results. Adjusted manufacturer-unspecified VE was 4.1% (95% confidence interval [CI], −36.5–32.6) at 0–13 days after the first dose, 45.2% (95% CI, 13.4–65.3) at ≥14 days after the first dose, 85.2% (95% CI, 69.9–92.7) at 0–13 days after the second dose, and 79.6% (95% CI, 72.6–84.8) at ≥14 days after the second dose. In addition, the VE after the second dose was highest at 14–34 days after the dose (VE, 89.1%; 95% CI, 80.5–93.9). High real-world effectiveness of COVID-19 vaccines, especially two doses, against infection during the Delta variant predominance in Japan was confirmed. [ABSTRACT FROM AUTHOR]

Morphological analysis of organelles is one of the important clues for understanding the cellular conditions and mechanisms occurring in cells. In particular, nanoscale information within crowded intracellular organelles of tissues provide more direct implications when compared to analyses of cells in culture or isolation. However, there are some difficulties in detecting individual shape using light microscopy, including super-resolution microscopy. Transmission electron microscopy (TEM), wherein the ultrastructure can be imaged at the membrane level, cannot determine the whole structure, and analyze it quantitatively. Volume EM, such as focused ion beam/scanning electron microscopy (FIB/SEM), can be a powerful tool to explore the details of three-dimensional ultrastructures even within a certain volume, and to measure several parameters from them. In this review, the advantages of FIB/SEM analysis in organelle studies are highlighted along with the introduction of mitochondrial analysis in injured motor neurons. This would aid in understanding the morphological details of mitochondria, especially those distributed in the cell bodies as well as in the axon initial segment (AIS) in mouse tissues. These regions have not been explored thus far due to the difficulties encountered in accessing their images by conditional microscopies. Some mechanisms of nerve regeneration have also been discussed with reference to the obtained findings. Finally, future perspectives on FIB/SEM are introduced. The combination of biochemical and genetic understanding of organelle structures and a nanoscale understanding of their three-dimensional distribution and morphology will help to match achievements in genomics and structural biology. [ABSTRACT FROM AUTHOR]

Background: Although various new drugs have been developed for neurological diseases, many diseases have no effective treatment or only inadequate efficacy. Here we introduce some examples of effective Kampo treatment. Key Findings: (1) Parasomnia in the elderly is preceded by the onset of diffuse Lewy body disease, with symptoms such as nightmares and loud screaming in the middle of the night. Keishikaryukotsuboreito (KSTRB), indicated in the classics for treating parasomnia, was effective in alleviating the symptoms. KSTRB is also used for enuresis that persists into adulthood. (2) Chronic subdural hematomas (CSDHs), treated by hematoma removal with burr‐hole surgery, recur at a rate of up to 20%. Goreisan (GRS) reduces hematoma volume and prevents postoperative CSDH recurrence. Homogeneous CSDH was most responsive to GRS in preventing recurrence. (3) Migraine frequently interferes with daily life. Keishibukuryogan (KBG), which alleviates blood stasis, was effective for patients with both menstruation‐associated migraine and scintillating scotomas. (4) Many traditional herbal medicines are listed in the Korean Medicine Clinical Practice Guideline for Stroke in Korea. Chunghyuldan, a related formula of Orengedokuto (OGT), is mainly used to prevent stroke. Conclusion: Kampo medicine is being applied in new and effective ways to treat various neurological diseases. Hopefully, more clinicians will recognize the usefulness of such Kampo medicines and utilize them in their daily practice. [ABSTRACT FROM AUTHOR]

Background: Nephrectomy is a curative treatment for localized renal cell carcinoma (RCC), but patients with poor prognostic features may experience relapse. Understanding the prognostic impact of programmed death-ligand 1 (PD-L1) expression in patients who underwent nephrectomy for RCC may aid in future development of adjuvant therapy. Methods: Of 770 surgical specimens collected from Japanese patients enrolled in the ARCHERY study, only samples obtained from patients with recurrent RCC after nephrectomy were examined for this secondary analysis. Patients were categorized into low- and high-risk groups based on clinical stage and Fuhrman grade. Time to recurrence (TTR) and overall survival (OS) were analyzed. Results: Both TTR and OS were shorter in patients with PD-L1-positive than -negative tumors (median TTR 12.1 vs. 21.9 months [HR 1.46, 95% CI 1.17, 1.81]; median OS, 75.8 vs. 97.7 months [HR 1.32, 95% CI 1.00, 1.75]). TTR and OS were shorter in high-risk patients with PD-L1-positive than -negative tumors (median TTR 7.6 vs. 15.3 months [HR 1.49, 95% CI 1.11, 2.00]; median OS, 55.2 vs. 83.5 months [HR 1.53, 95% CI 1.06, 2.21]) but not in low-risk patients. Conclusions: This ARCHERY secondary analysis suggests that PD-L1 expression may play a role in predicting OS and risk of recurrence in high-risk patients with localized RCC. Clinical Trial Registration: UMIN000034131. [ABSTRACT FROM AUTHOR]

Introduction: The growing use of heated tobacco products (HTPs) has raised concerns about secondhand aerosol (SHA) from HTPs, but few studies have been reported on it. This study aimed to investigate the trends in SHA exposure and their socioeconomic inequalities in Japan.Methods: The prevalence of SHA exposure from 2017 to 2020 was estimated using longitudinal internet survey data of 5221 participants, aged 20-69 years in 2017 (baseline), with adjustments using inverse probability weighting for "being a participant in an internet survey". Multivariable modified Poisson regression models were applied to examine the association between socioeconomic status (ie, educational attainment and equivalent income) at baseline and SHA exposure in 2020 with adjustments for sex and age.Results: The estimated prevalence of SHA exposure has consistently increased from 4.5% in 2017 to 10.8% in 2020. Lower educational attainment was associated with a higher risk of SHA exposure (p for trend = 0.010). The covariate-adjusted risks of SHA exposure in participants with a low-education and middle-education level were 1.57 and 1.34 times higher, respectively, than in those with a high-education level. However, significant differences in risks of SHA exposure between participants with low-, middle-, and high-income levels were not observed. Meanwhile, participants with a low-education and middle-education level also had 1.87 and 1.61 times higher risks of secondhand smoke (SHS) exposure from combustible cigarettes than those with a high-education level, respectively.Conclusions: Our study revealed a rapid increase in SHA exposure and the existence of educational inequalities in both SHA and SHS exposure.Implications: Using longitudinal internet cohort survey data, we found that the prevalence of exposure to secondhand aerosol (SHA) from heated tobacco products (HTPs) rapidly increased to 10.8% in 2020 in Japan. Furthermore, people with lower educational attainment were at higher risk of SHA exposure, suggesting that extensive educational interventions may be necessary to inform the public that although emissions from HTPs contain significantly lesser amounts of harmful and potentially harmful constituents and these compounds than cigarette smoke, they are not harmless and still entail risks, and its long-term effects are unknown. Therefore, future extensive monitoring of SHA exposure is needed. [ABSTRACT FROM AUTHOR]

To enhance the bioavailability of carrier-free drug nanoparticles (NP) and extend their application on the fluorescence imaging of cancer cells, the design and functionalization of NP surfaces are crucial. In this study, the surface of podophyllotoxin dimeric prodrug nanoparticles (PPTD-NP) was functionalized with PEG-BODIPY FL conjugate (PB@PPTD-NP). PB@PPTD-NP shows superior dispersion stability in biological media compared to the previously reported PPTD-NP. Furthermore, thanks to the superior fluorescence property of BODIPY FL, PB@PPTD-NP inside cancer cells can be visualized by fluorescence microscopy. These results demonstrate the potential of surface functionalization for enhancing the application of NP in cancer treatment and diagnosis. [ABSTRACT FROM AUTHOR]

SUMMARY: Bud dormancy helps woody perennials survive winter and activate robust plant development in the spring. For apple (Malus × domestica), short‐term chilling induces bud dormancy in autumn, then prolonged chilling leads to dormancy release and a shift to a quiescent state in winter, with subsequent warm periods promoting bud break in spring. Epigenetic regulation contributes to seasonal responses such as vernalization. However, how histone modifications integrate seasonal cues and internal signals during bud dormancy in woody perennials remains largely unknown. Here, we show that H3K4me3 plays a key role in establishing permissive chromatin states during bud dormancy and bud break in apple. The global changes in gene expression strongly correlated with changes in H3K4me3, but not H3K27me3. High expression of DORMANCY‐ASSOCIATED MADS‐box (DAM) genes, key regulators of dormancy, in autumn was associated with high H3K4me3 levels. In addition, known DAM/SHORT VEGETATIVE PHASE (SVP) target genes significantly overlapped with H3K4me3‐modified genes as bud dormancy progressed. These data suggest that H3K4me3 contributes to the central dormancy circuit, consisting of DAM/SVP and abscisic acid (ABA), in autumn. In winter, the lower expression and H3K4me3 levels at DAMs and gibberellin metabolism genes control chilling‐induced release of dormancy. Warming conditions in spring facilitate the expression of genes related to phytohormones, the cell cycle, and cell wall modification by increasing H3K4me3 toward bud break. Our study also revealed that activation of auxin and repression of ABA sensitivity in spring are conditioned at least partly through temperature‐mediated epigenetic regulation in winter. Significance Statement: The active histone methylation mark H3K4me3 underpins the changes in expression of genes involved in metabolic pathways involving phytohormones, the cell cycle, and cell wall modification during bud dormancy and break in apple. This research uncovers an epigenetic mechanism that establishes a permissive chromatin state at critical regulators underlying floral bud dormancy progression and bud break in perennials. [ABSTRACT FROM AUTHOR]

Background: Organizing pneumonia (OP) is a rare manifestation of systemic lupus erythematosus (SLE). It has been described in very few case reports. Purpose and Methods: We encountered OP in three patients with SLE in 1 year; two manifested OP as an initial presentation of SLE, while the third manifested OP when SLE relapsed. To elucidate the clinical features and outcomes of OP in patients with SLE, we screened the PubMed database for cases diagnosed with OP either at or after the diagnosis of SLE; the search was restricted to articles that were published after 1990, when OP became widely recognized. Results: We identified 15 cases of OP in patients with SLE. Thus, we analyzed a total of 18 cases (including our three). OP developed at the initial diagnosis of SLE in 15 cases and at relapse of SLE in three cases. In most cases, the disease activity of SLE was moderate or high. In all cases, OP was accompanied by other extrapulmonary symptoms of SLE, namely, fever (77.8%), cutaneous manifestations (61.1%), arthralgia/arthritis (50%), and lupus nephritis (33.3%). Steroid monotherapy or increasing the dose of the steroids was effective in seven cases (38.8%); however, steroid monotherapy was ineffective and led to death due to respiratory failure in two cases (11.1%). Combination therapies of steroids with hydroxychloroquine, azathioprine, tacrolimus, mycophenolate mofetil, intravenous pulse cyclophosphamide therapy, and belimumab were effective in seven cases (38.8%). Conclusions: Based on the review of previously reported and our cases, we concluded that OP is an important pulmonary manifestation of SLE. Clinicians should be aware of it as it may require intensive immunosuppressive therapy either at or after the diagnosis of SLE. [ABSTRACT FROM AUTHOR]

Since the clinical outcome of patients with sarcoidosis is still unpredictable, a good prognostic biomarker is necessary. Autotaxin (ATX) and phosphatidylserine-specific phospholipase A1 (PS-PLA1) function as main enzymes to produce lysophospholipids (LPLs), and these enzymes are attracting attention as useful biomarkers for several chronic inflammatory diseases. Here, we investigated the relationships between LPLs-producing enzymes and the disease activity of sarcoidosis. In total, 157 patients with sarcoidosis (active state, 51%) were consecutively enrolled. Using plasma or urine specimens, we measured the values of LPLs-producing enzymes. Urine ATX (U-ATX) levels were significantly lower in the active state compared to those in the inactive state, while the plasma ATX (P-ATX) and PS-PLA1 levels showed no significant difference between these two states. Concerning the comparison with existing clinical biomarkers for sarcoidosis, U-ATX showed a weak negative correlation to ACE, P-ATX a weak positive correlation to both ACE and sIL-2R, and PS-PLA1 a weak positive one to sIL-2R. Notably, only the U-ATX levels inversely fluctuated depending on the status of disease activity whether OCS had been used or not. These findings suggest that U-ATX is likely to be a novel and useful molecule for assessing the disease activity of sarcoidosis. [ABSTRACT FROM AUTHOR]

For assessing a cancer treatment, and for detecting and characterizing cancer, Diffusion-weighted imaging (DWI) is commonly used. The key in DWI's use extracranially has been due to the emergence of of high-gradient amplitude and multichannel coils, parallelimaging, and echo-planar imaging. The benefit has been fewer motion artefacts and high-quality prostate images.Recently, new techniques have been developed to improve the signal-to-noise ratio of DWI with fewer artefacts, allowing an increase in spatial resolution. For apparent diffusion coefficient quantification, non-Gaussian diffusion models have been proposed as additional tools for prostate cancer detection and evaluation of its aggressiveness. More recently, radiomics and machine learning for prostate magnetic resonance imaging have emerged as novel techniques for the non-invasive characterisation of prostate cancer. This review presents recent developments in prostate DWI and discusses its potential use in clinical practice. [ABSTRACT FROM AUTHOR]

High b-value diffusion-weighted imaging (hDWI) with a b-value of 2000 s/mm2 provides insufficient image contrast between benign and malignant tissues and an overlap of apparent diffusion coefficient (ADC) between Gleason grades (GG) in prostate cancer (PC). We compared image quality, PC detectability, and discrimination ability for PC aggressiveness between ultra-high b-value DWI (uhDWI) of 3000 s/mm2 and hDWI. The subjects were 49 patients with PC who underwent 3T multiparametric MRI. Single-shot echo-planar DWI was acquired with b-values of 0, 2000, and 3000 s/mm2. Anatomical distortion of prostate (AD), signal intensity of benign prostate (PSI), and lesion conspicuity score (LCS) were assessed using a 4-point scale; and signal-to-noise ratio, contrast-to-noise ratio, and mean ADC (×10–3 mm2/s) of lesion (lADC) and surrounding benign region (bADC) were measured. PSI was significantly lower in uhDWI than in hDWI (p < 0.001). AD, LCS, signal-to-noise ratio, and contrast-to-noise ratio were comparable between uhDWI and hDWI (all p > 0.05). In contrast, lADC was significantly lower than bADC in both uhDWI and hDWI (both p < 0.001). In comparison of lADC between tumors of ≤GG2 and those of ≥GG3, both uhDWI and hDWI showed significant difference (p = 0.007 and p = 0.021, respectively). AUC for separating tumors of ≤GG2 from those of ≥GG3 was 0.731 in hDWI and 0.699 in uhDWI (p = 0.161). uhDWI suppressed background signal better than hDWI, but did not contribute to increased diagnostic performance in PC. Compared with hDWI, uhDWI could not contribute to increased diagnostic performance in PC. [ABSTRACT FROM AUTHOR]

Background: Prostate apparent diffusion coefficient (ADC) values calculated from diffusion-weighted imaging have been used for evaluating prostate cancer (PCa) aggressiveness. However, the way of measuring ADC values has varied depending on the study. Purpose: To investigate inter- and intra-reader variability and diagnostic performance of three kinds of shaped 2D regions of interests (ROIs) for tumor ADC measurements in PCa. Material and Methods: Seventy-four patients with PCa undergoing 3-T MRI before surgery were included. Histologic findings from radical prostatectomy specimens were reviewed to define each patient's dominant tumor. Three readers independently measured the tumor ADCs using three different ROI methods: freehand, large-circle, and small-circles ROIs. Readers repeated measurements after 3 weeks. Bland-Altman analysis was performed to evaluate the inter- and intra-reader variability. Receiver Operating Characteristic analysis was used for assessment of tumor aggressiveness for PCa. Results: For intra-reader and inter-reader variability, the mean coefficient of repeatability for freehand ROIs, large-circle ROIs, and small-circles ROIs were as follows: 13.7%, 12.4%, and 11.5%; 9.4%, 9.7%, and 9.5%. For differentiating Gleason score (GS) = 3 + 3 from GS ≥ 3 + 4 tumors, the area under the curves were 0.90 for freehand ROIs, 0.89 for large-circle ROIs, and 0.94 small-circles ROIs (p = 0.31). Conclusion: The variations in ROI method did not have a major influence on intra-reader or inter-reader reproducibility or diagnostic performance for prostate ADC measurements. [ABSTRACT FROM AUTHOR]

Background: In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan. Methods: Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints. Results: The Japanese subgroup comprised 94 patients (pembrolizumab–axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6–37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab–axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab–axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab–axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab–axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred. Conclusions: Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population. [ABSTRACT FROM AUTHOR]

Magnetic drug delivery system (MDDS) is a technique to effectively accumulate drugs, which are combined with ferromagnetic particles, into the affected area using magnetic force control. This study intends to apply MDDS for immunotherapy by enhancing immune responses by a surface treatment of a ferromagnetic particle. The objective of this study is to give the adjuvant effect to a ferromagnetic particle by the surface treatment with alum, which is known as one of the common adjuvants that activates inflammasome pathway. First, magnetite was prepared as a ferromagnetic particle and coated with alum. Alum-coated magnetite increased the expression of caspase-1, which is an activated indicator of inflammasome, in the culture of human monocyte cell (THP-1 cell). To evaluate the potential of the surface coated particles, the particles were subcutaneously injected to mice with a peptide vaccine. As a result, the antibody titer was increased by the surface coated particles as assessed by ELISA. Although a magnetic force has not yet applied in this study, the administration experiment to mice using magnetic force control is our next step. In conclusion, we modified the immune response to magnetite by coating the surface with alum. This can lead to a clinical application for vaccine therapy in future. [ABSTRACT FROM AUTHOR]

The identification of cancer subtypes is important for the understanding of tumor heterogeneity. In recent years, numerous computational methods have been proposed for this problem based on the multi-omics data of patients. It is widely accepted that different cancer subtypes are induced by different molecular regulatory networks. However, only a few incorporate the differences between their molecular systems into the identification processes. In this study, we present a novel method to identify cancer subtypes based on patient-specific molecular systems. Our method realizes this by quantifying patient-specific gene networks, which are estimated from their transcriptome data, and by clustering their quantified networks. Comprehensive analyses of The Cancer Genome Atlas (TCGA) datasets applied to our method confirmed that they were able to identify more clinically meaningful cancer subtypes than the existing subtypes and found that the identified subtypes comprised different molecular features. Our findings also show that the proposed method can identify the novel cancer subtypes even with single omics data, which cannot otherwise be captured by existing methods using multi-omics data. [ABSTRACT FROM AUTHOR]

Hydrogen atoms and hydration water molecules in proteins are indispensable for many biochemical processes, especially enzymatic catalysis. The locations of hydrogen atoms in proteins are usually predicted based on X-ray structures, but it is still very difficult to know the ionization states of the catalytic residues, the hydration structure of the protein, and the characteristics of hydrogen-bonding interactions. Neutron crystallography allows the direct observation of hydrogen atoms that play crucial roles in molecular recognition and the catalytic reactions of enzymes. In this review, we present the current status of neutron crystallography in structural biology and recent neutron structural analyses of three enzymes: ascorbate peroxidase, the main protease of severe acute respiratory syndrome coronavirus 2, and copper-containing nitrite reductase. • Neutron crystallography can observe hydrogen atoms directly, which play essential roles in enzyme catalyzed reactions. • Ferric ascorbate peroxidase has a possible proton transfer pathway from ascorbate to the heme iron via arginines and waters. • Protonation states in the catalytic dyad of severe acute respiratory syndrome coronavirus 2 main protease are observed. • Electron transfer via a hydrogen-bond jump and a hydroxide ion ligation in copper-containing nitrite reductase are clarified. [ABSTRACT FROM AUTHOR]

Aim: We have previously reported the therapeutic benefits of kamikihito for managing cancer‐related fatigue (CRF) in patients with hormone‐sensitive prostate cancer. Now, due to the routine use of enzalutamide and similar agents for treating castration‐resistant prostate cancer (CRPC), managing enzalutamide‐related fatigue is imperative. Here, we objectively evaluated the effectiveness of kamikihito on fatigue in CRPC patients receiving enzalutamide. Methods: Kamikihito was administered for 12 weeks to 11 patients receiving enzalutamide. We measured the changes in the levels of fatigue (using the Chalder Fatigue Scale (CFS)), depression (using the Center for Epidemiologic Studies Depression Scale (CES‐D)), oxidative stress (by measuring derivatives of reactive oxygen metabolites (d‐ROMs) and biological antioxidant potential (BAP) levels), various cytokines, insomnia (using actigraphy), and in‐vivo metabolites (by metabolomics analysis). Results: Kamikihito improved CFS and CES‐D scores, thus improving fatigue and depression in enzalutamide‐treated patients; however, it did not improve oxidative stress levels. Further, actigraphy showed prolongation of sleeping time, while the levels of various cytokines showed no change. Metabolomics analysis confirmed decrease in lipids and increase in amino acids that correlated with improvement in fatigue. Conclusion: Kamikihito corrected the abnormalities in lipid metabolism, which may have improved the production of amino acids, leading to reduced CRF in CRPC patients receiving enzalutamide. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is structurally and functionally distinct from other regions of the axon, yet alterations in the milieu of the AIS after brain injury have not been well characterized. In this study, we have examined extracellular and intracellular changes in the AIS after hypoglossal nerve injury. Microglial adhesions to the AIS were rarely observed in healthy controls, whereas microglial adhesions to the AIS became apparent in the axonal injury model. Regarding intra‐AIS morphology, we focused on mitochondria because mitochondrial flow into the injured axon appears critical for axonal regeneration. To visualize mitochondria specifically in injured axons, we used Atf3:BAC transgenic mice whose mitochondria were labeled with GFP in response to nerve injury. These mice clearly showed mitochondrial localization in the AIS after nerve injury. To precisely confirm the light microscopic observations, we performed three‐dimensional ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM). Although the healthy AIS was not surrounded by microglia, tight microglial adhesions with thick processes adhering to the AIS were observed after injury. FIB/SEM simultaneously allowed the observation of mitochondrial localization in the AIS. In the AIS of non‐injured neurons, few mitochondria were observed, whereas mitochondria were abundantly localized in the cell body, axon hillock, and axon. Intriguingly, in the injured AIS, numerous mitochondria were observed throughout the AIS. Taken together, axonal injury changes the extracellular glial environment surrounding the AIS and intracellular mitochondrial localization in the AIS. These changes would be crucial responses, perhaps for injured neurons to regenerate after axonal injury. [ABSTRACT FROM AUTHOR]

To compare diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MR imaging (DCE-MRI) for characterization of prostate cancer (PC). 104 PC patients who underwent prostate multiparametric MRI at 3T including DWI and DCE-MRI before MRI-guided biopsy or radical prostatectomy. Apparent diffusion coefficient (ADC) with histogram analysis (mean, 0–25th percentile, skewness, and kurtosis), intravoxel incoherent motion model including D and f ; stretched exponential model including distributed diffusion coefficient (DDC) and a ; and permeability parameters including Ktrans, K ep , and V e were obtained from a region of interest placed on the dominant tumor of each patient. ADC mean , ADC 0 – 25 , D , DDC , and V e were significantly lower and K ep was significantly higher in GS ≥ 3 + 4 tumors (n = 89) than in GS = 3 + 3 tumors (n = 15), and also in GS ≥ 4 + 3 tumors (n = 57) than in GS ≤ 3 + 4 tumors (n = 47) (P < 0.001 to P = 0.040). f was significantly lower in GS ≥ 4 + 3 tumors than in GS ≤ 3 + 4 tumors (P = 0.022), but there was no significant difference between GS = 3 + 3 tumors and GS ≥ 3 + 4 tumors, or between the remaining metrics in both comparisons. In metrics with area under the curve (AUC) >0.80, there was a significant difference in AUC between ADC 0 – 25 and D , and DDC for separating GS ≤ 3 + 4 tumors from GS ≥ 4 + 3 tumors (P = 0.040 and P = 0.022, respectively). There were no significant differences between metrics with AUC > 0.80 for separating GS = 3 + 3 tumors from GS ≥ 3 + 4 tumors. ADC 0 – 25 had the highest correlation with Gleason grade (ρ = −0.625, P < 0.001). DWI and DCE-MRI showed no apparent clinical superiority of non-Gaussian models or permeability MRI over the mono-exponential model for assessment of tumor aggressiveness in PC. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is structurally and functionally distinct from other regions of the axon, yet alterations in the milieu of the AIS after brain injury have not been well characterized. In this study, we have examined extracellular and intracellular changes in the AIS after hypoglossal nerve injury. Microglial adhesions to the AIS were rarely observed in healthy controls, whereas microglial adhesions to the AIS became apparent in the axonal injury model. Regarding intra‐AIS morphology, we focused on mitochondria because mitochondrial flow into the injured axon appears critical for axonal regeneration. To visualize mitochondria specifically in injured axons, we used Atf3:BAC transgenic mice whose mitochondria were labeled with GFP in response to nerve injury. These mice clearly showed mitochondrial localization in the AIS after nerve injury. To precisely confirm the light microscopic observations, we performed three‐dimensional ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM). Although the healthy AIS was not surrounded by microglia, tight microglial adhesions with thick processes adhering to the AIS were observed after injury. FIB/SEM simultaneously allowed the observation of mitochondrial localization in the AIS. In the AIS of non‐injured neurons, few mitochondria were observed, whereas mitochondria were abundantly localized in the cell body, axon hillock, and axon. Intriguingly, in the injured AIS, numerous mitochondria were observed throughout the AIS. Taken together, axonal injury changes the extracellular glial environment surrounding the AIS and intracellular mitochondrial localization in the AIS. These changes would be crucial responses, perhaps for injured neurons to regenerate after axonal injury. [ABSTRACT FROM AUTHOR]

Long-term measurement of cloud condensation nuclei (CCN) is essential to assess the role of seasonally varying aerosol sources and underlying synoptical meteorological conditions in aerosol-cloud interactions. However, long-term measurement of CCN is limited over the Indian region and globally. This study provides first-ever long-term observations of CCN concentrations at different supersaturation (SS) values ranging from 0.2 to 1.0% using a CCN counter from a rural location of Gadanki, India (13.5°N, 79.2°E, and 375 m AMSL) during October 2019–August 2023. The total CCN concentration (N CCN) was the highest during pre-monsoon season (2847 ± 1148 #/cc), followed by winter (2463 ± 1066 #/cc), post-monsoon (2124 ± 1145 #/cc), and monsoon (1099 ± 740 #/cc) at 0.4% SS. Diurnal variations in N CCN showed bi-modal distribution with a relatively weak peak at around 8:00 h (Local time, LT) and a substantial rise at about 20 h LT. However, a systematic increase in N CCN was observed during the daytime in all the seasons except for the monsoon. The two peaks in diurnal variation of N CCN were associated with CCN of sizes less than 2 μm. The peak diameter of the mono-modal size distribution of CCN shifted towards the higher SS, implying the growth of small aerosols and available CCN. The broad peak indicates that most aerosol particles over Gadanki grow at the SS of 0.4%. Estimates of the k-parameter (Twomey's empirical fit) show the aerosols over Gadanki are relatively more hygroscopic during the monsoon than in winter, with their respective k-values of 0.7 and 0.4. Further, the diurnal variation in the k-parameter suggests significant variability in hygroscopicity within a day during monsoon and winter. Comparison with other locations suggests the CCN concentrations over Gadanki lies between those of polluted urban, coastal, and high-altitude stations. • Long-term observations of CCN reported from a rural location Gadanki (13.5° N, 79.2° E and 375 m AMSL) in India. • Highest CCN concentrations found in pre-monsoon were associated with forest fires. • Small size aerosols growth leads to observed two peaks in diurnal variation of CCN. • Majority of aerosol particles over Gadanki grow to CCN at 0.4% super saturation. • Although lowest in concentration, aerosols are more hygroscopic during the monsoon. [ABSTRACT FROM AUTHOR]

This paper presents the fabrication and evaluation of a total cross-tied (TCT) Si module designed to mitigate the partial shading effect, which is known to reduce the output performance of vehicle-integrated photovoltaic (VIPV) modules. The TCT module, consisting of 27 Si solar cells interconnected both vertically and horizontally, demonstrated an 18.8 % decrease in output power when one cell was shaded. In contrast, the output of the series-parallel (SP) Si module decreased by 31.6 % under the same shading condition. Comparative analysis of the output performances of TCT, SP, and single-string commercial modules under three driving conditions revealed that increasing the number of strings helped alleviate the impact of partial shading. Notably, the TCT module configuration showed a positive impact on mitigating the partial shading effect. [ABSTRACT FROM AUTHOR]

The International Convention on the Elimination of All Forms of Racial Discrimination (ICERD) contains the inter-State communication procedure within which the Committee on the Elimination of Racial Discrimination (CERD) received the following three communications in 2018: Qatar v Saudi Arabia , Qatar v the United Arab Emirates , and Palestine v Israel. In these cases, CERD characterized this procedure as relating to collective enforcement, analogous to the inter-State application procedure within the order/regime of the European Court of Human Rights (ECtHR). However, unlike the European Convention on Human Rights (ECHR), ICERD does not refer to 'collective enforcement', but merely contains ad hoc conciliation, that is a bilateral means for reaching a mutually agreed solution to a dispute. This article aims, rather critically, to assess whether, and to which extent, it is justified to view the CERD ad hoc conciliation procedure as a means of collective enforcement. [ABSTRACT FROM AUTHOR]

An acquired dysregulation of airway secretion is likely involved in the pathophysiology of chronic bronchitis and chronic obstructive pulmonary disease (COPD). Nowadays, it is widely known that several kinds of long-acting bronchodilators reduce the frequency of COPD exacerbations. However, limited data are available concerning the complementary additive effects on airflow obstruction. Using an optical method and a selective pH indicator, we succeeded in evaluating the gland secretion rate and the pH in swine tracheal membrane. A physiologically relevant concentration of acetylcholine (ACh) 100 nM induced a gradual increase in the amount of gland secretion. Lipopolysaccharides (LPS) accelerated the ACh-induced secretory responses up to around threefold and lowered the pH level significantly. Long-acting β2-agonists (LABAs) including indacaterol (IND), formoterol, and salmeterol restored the LPS-induced changes in both the hypersecretion and acidification. The subsequent addition of the long-acting muscarine antagonist, glycopyrronium, further increased the pH values. Two different inhibitors for cystic fibrosis transmembrane conductance regulator (CFTR), NPPB and CFTRinh172, abolished the IND-mediated pH normalization in the presence of both ACh and ACh + LPS. Both immunofluorescence staining and western blotting analysis revealed that LPS downregulated the abundant expression of CFTR protein. However, IND did not restore the LPS-induced decrease in CFTR expression on Calu-3 cells. These findings suggest that the activation of cAMP-dependent HCO3− secretion through CFTR would be partly involved in the IND-mediated pH normalization in gland secretion and may be suitable for the maintenance of airway defense against exacerbating factors including LPS. [ABSTRACT FROM AUTHOR]

Shiga toxin (Stx) is a major virulence factor of enterohemorrhagic Escherichia coli, which causes fatal systemic complications. Here, we identified a tetravalent peptide that inhibited Stx by targeting its receptor-binding, B-subunit pentamer through a multivalent interaction. A monomeric peptide with the same motif, however, did not bind to the B-subunit pentamer. Instead, the monomer inhibited cytotoxicity with remarkable potency by binding to the catalytic A-subunit. An X-ray crystal structure analysis to 1.6 Å resolution revealed that the monomeric peptide fully occupied the catalytic cavity, interacting with Glu167 and Arg170, both of which are essential for catalytic activity. Thus, the peptide motif demonstrated potent inhibition of two functionally distinct subunits of Stx. Watanabe-Takahashi, Tamada, Senda et al. identify a tetravalent peptide that inhibits Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli, by targeting its receptor-binding. On the other hand, a monomeric peptide containing the same motif occupies the Stx catalytic cavity, suggesting that this peptide motif can inhibit two subunits of Stx. [ABSTRACT FROM AUTHOR]

It is well established that serotonergic fibers distribute throughout the brain. Abnormal densities or patterns of serotonergic fibers have been implicated in neuropsychiatric disorders. Although many classical studies have examined the distribution pattern of serotonergic fibers, most of them were either limited to specific brain areas or had limitations in demonstrating the fine axonal morphology. In this study, we utilize male mice expressing green fluorescence protein under the serotonin transporter (SERT) promoter to map the topography of serotonergic fibers across the rostro‐caudal extent of each brain area. We demonstrate previously unreported regional density and fine‐grained anatomy of serotonergic fibers. Our findings include: (a) SERT fibers distribute abundantly in the thalamic nuclei close to the midline and dorsolateral areas, in most of the hypothalamic nuclei with few exceptions such as the median eminence and arcuate nuclei, and within the basal amygdaloid complex and lateral septal nuclei, (b) the source fibers of innervation of the hippocampus traverse through the septal nuclei before reaching its destination, (c) unique, filamentous type of straight terminal fibers within the nucleus accumbens, (d) laminar pattern of innervation in the hippocampus, olfactory bulb and cortex with heterogenicity in innervation density among the layers, (e) cortical labeling density gradually decreases rostro‐caudally, (f) fibers traverse and distribute mostly within the gray matter, leaving the white fiber bundles uninnervated, and (g) most of the highly labeled nuclei and cortical areas have predominant anatomical connection to limbic structures. In conclusion, we provide novel, regionally specific insights on the distribution map of serotonergic fibers using transgenic mouse. [ABSTRACT FROM AUTHOR]

Purpose: Melancholia has recently been re-evaluated, because patients with major depressive disorder (MDD) were found to be heterogeneous. However, the DSM-5 criteria for melancholia (DSM-MEL) have been criticized, because of the difficulty in clearly distinguishing between melancholic and non-melancholic depression using DSM-MEL. Psychomotor disturbance (PMD) is one of the most important, as well as one of the only measurable symptoms of melancholia. Parker et al developed the CORE measure, which assesses PMD as a behavioral characteristic. The aim of our study was to objectively identify the subjective symptoms of melancholia by analyzing the symptoms associated with PMD. Patients and Methods: A total of 106 participants with MDD were examined by psychiatrists. Multiple regression analysis was performed in which the total CORE score was the dependent variable, and items of the DSM-MEL and historically suggested melancholic features were independent variables. Results: The following five independent variables were able to predict the total CORE score: 1) feelings of having lost feeling, 2) depressive delusions, 3) perplexity, 4) indecisiveness, and 5) no aggression against others. These five variables were more strongly associated with the total CORE score than the DSM-MEL. Limitation: The major limitation of this study was that when choosing non-DSM melancholic signs and symptoms, we did not comprehensively evaluate and select the symptoms but chose items that are clinically important. Conclusion: We identified five subjective symptoms that were associated with PMD. These five symptoms may be clinically useful as diagnostic criteria for melancholia. [ABSTRACT FROM AUTHOR]

The thermoelectric properties of Heusler-type Fe2–xV1+xAl1–ySiy and Fe2–xV1+x–yTiyAl alloys have been investigated to clarify which off-stoichiometric alloy, i.e., V-rich (x>0) or V-poor (x<0), is more effective in enhancing the Seebeck coefficient when doped by Si and Ti, while retaining a low electrical resistivity. Large Seebeck coefficients of –182 μV/K and 110 μV/K at 300K are obtained for n-type Fe1.95V1.05Al0.97Si0.03 and p-type Fe2.04V0.93Ti0.03Al, respectively. When the Seebeck coefficient is plotted as a function of valence electron concentration (VEC), the VEC dependence for the doped off-stoichiometric alloys falls on characteristic curves depending on the off-stoichiometric composition x. It is concluded that a larger Seebeck coefficient with a negative sign can be obtained for the V-rich alloys rather than the V-poor alloys, whilst good p-type materials are always derived from the V-poor alloys. Substantial enhancements in the Seebeck coefficient for the off-stoichiometric alloys could be achieved by a favorable modification in the electronic structure around the Fermi level through the antisite V or Fe defect formation. [ABSTRACT FROM AUTHOR]

Beet necrotic yellow vein virus (BNYVV) generally has a four‐segmented positive‐sense RNA genome (RNAs 1–4), but some European and most Asian strains have an additional segment, RNA5. This study examined the effect of RNA5 and RNA3 on different sugar beet cultivars using a Polymyxa‐mediated inoculation system under field and laboratory conditions. In field tests, the degree of sugar yield served as an index for assessing the virulence of BNYVV strains. Japanese A‐II type isolates without RNA5 caused mostly 15%–90% sugar yield reductions, depending on the susceptibility of sugar beet cultivars, whereas the isolates with RNA5 induced more than 90% yield losses in the seven susceptible cultivars, but small yield losses in one Rz1‐resistant and Rizor cultivars. However, a laboratory‐produced isolate containing RNA5 but lacking RNA3 caused higher yield losses in Rizor than in susceptible plants, and induced scab‐like symptoms on the root surface of both susceptible and resistant plants. In laboratory tests, A‐II type isolates without RNA5 had low viral RNA accumulation levels in roots of Rizor and Rz1‐resistant plants at early stages of infection, but in the presence of RNA5, viral RNA3 accumulation levels increased remarkably. This increased RNA3 accumulation was not observed in roots of the WB42 accession with the Rz2 gene. In contrast, the presence of RNA3 did not affect RNA5 accumulation levels. Collectively, this study demonstrated that RNA5 is involved in the development of scab‐like symptoms and the enhancement of RNA3 accumulation, and suggests these characteristics of RNA5 are associated with Rz1‐resistance breaking. [ABSTRACT FROM AUTHOR]

Previously, we showed that cryo fixation of adult mouse brain tissue gave a truer representation of brain ultrastructure in comparison with a standard chemical fixation method (Korogod et al., 2015). Extracellular space matched physiological measurements, there were larger numbers of docked vesicles and less glial coverage of synapses and blood capillaries. Here, using the same preservation approaches, we compared the morphology of dendritic spines. We show that the length of the spine and the volume of its head is unchanged; however, the spine neck width is thinner by more than 30% after cryo fixation. In addition, the weak correlation between spine neck width and head volume seen after chemical fixation was not present in cryo-fixed spines. Our data suggest that spine neck geometry is independent of the spine head volume, with cryo fixation showing enhanced spine head compartmentalization and a higher predicted electrical resistance between spine head and parent dendrite. [ABSTRACT FROM AUTHOR]

To evaluate the influence of cholecystectomy on the flow dynamic pattern of bile in the extrahepatic bile duct by using cine-dynamic MRCP with spatially-selective inversion-recovery (IR) pulse non-invasively. 56 patients with cholecystectomy and 48 control subjects without cholecystectomy who underwent cine-dynamic MRCP with spatially-selective IR pulse at 1.5 T or 3 T (TR/TE, 4000 msec/500 msec; echo train spacing, 6.5 msec; echo train length, 172; section thickness, 50 mm; matrix, 320 × 320; field of view, 320 × 320 mm; bandwidth, 488 Hz; and inversion time, 2200 msec). In cine-dynamic MRCP, IR pulse with 20 mm width was placed on the common bile duct (CBD) to evaluate the movement of bile (antegrade and reversed bile flow). Cine-dynamic MRCP imaging was scanned every 15 s (imaging, 4 s; rest, 11 s) during 5 min to acquire a series of single-shot images (a total of 20 images). The frequency that antegrade or reversed bile flow was observed in the extrahepatic bile duct, and 5-point grading score based on the moving distance of antegrade or reversed bile flow were compared between the groups. Both groups were compared using the χ2 and Mann-Whitney U tests (P < 0.05 considered significant). Antegrade bile flow was observed more frequently in the cholecystectomy group than in the non-cholecystectomy group (5.1 times vs. 2.8 times, P = 0.008). Mean grading score of antegrade bile flow was significantly greater in the cholecystectomy group than in the non-cholecystectomy group (mean grade, 0.33 vs 0.21; P = 0.014). Regarding reversed bile flow, there were no significant differences in the frequency and grading score between cholecystectomy group and non-cholecystectomy group. Antegrade bile flow was observed more frequently and predominantly in patients after cholecystectomy in cine-dynamic MRCP with spatially-selective IR pulse while reversed bile flow was observed equivalently. [ABSTRACT FROM AUTHOR]

Most flowering plants are visited by various pollinator insects. To understand floral specialization for pollinators, the relative importance of different flower visitors to the focal plant species should be revealed. In the present study, we observed the insects that visited the orchid Platanthera hologlottis throughout the day and night using interval timer photography to reveal the relative importance of diurnal and nocturnal flower visitors. We observed visitation by both diurnal (e.g. the butterfly Ochlodes ochraceus) and nocturnal (e.g. the moth Thysanoplusia intermixta) insects and examined their relative contribution to fruit production and pollinarium removal experimentally. Results showed that the fitness was higher in flowers visited by nocturnal insects than in those visited by diurnal insects. These results suggest that the floral traits of P. hologlottis may be specialized for nocturnal flower visitors rather than diurnal flower visitors. [ABSTRACT FROM AUTHOR]