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Inguinal hernia (IH) after radical prostatectomy (RP) is a complication that impairs quality of life; however, the factors contributing to IH after RP remain unclear. Therefore, we herein attempted to identify the factors responsible for the development of IH after RP.We reviewed 622 patients who underwent laparoscopic or robot-assisted laparoscopic RP at our hospital between December 2011 and April 2020. The total fat area and visceral fat area were calculated at the level of the umbilicus using computed tomography, and the subcutaneous fat area (SFA) was calculated by subtracting the visceral fat area from the total fat area. The psoas muscle area was measured at the third lumbar vertebrae level using computed tomography to calculate the psoas muscle mass index, which is used in sarcopenia as an index of muscle mass. We investigated the risk factors for IH after laparoscopic or robot-assisted laparoscopic RP.IH developed in 88 patients (16.7%). Fifty-seven of these patients underwent hernia repair at our hospital, and 56 (98.2%) had indirect hernias. A multivariate analysis identified SFA (odds ratios: 0.383, p 0.001) as an independent predictor for the development of IH. Two-year IH-free survival rates were 77.3% in the small SFA group (SFA 123 cmSubcutaneous fat was associated with the development of IH, particularly indirect IH, after laparoscopic or robot-assisted laparoscopic RP. An indirect IH prevention technique needs to be considered, particularly for patients with less subcutaneous fat.

Purpose To evaluate the high-resolution CT (HRCT) findings of pulmonary infections in patients with hematologic malignancy and compare them between patients with or without hematopoietic stem cell transplantation (HSCT). Materials and methods A total of 128 patients with hematologic malignancy and pulmonary infection were included in this study. The diagnoses of the patients consisted of bacterial pneumonia (37 non-HSCT cases and 14 HSCT cases), pneumocystis pneumonia (PCP) (29 non-HSCT cases and 11 HSCT cases), and fungal infection other than PCP (20 non-HSCT cases and 17 HSCT cases). Two chest radiologists retrospectively evaluated the HRCT criteria and compared them using chi-squared tests and a multiple logistic regression analysis. Results According to the multiple logistic regression analysis, nodules were an indicator in HSCT patients with PCP (p = 0.025; odds ratio, 5.8; 95% confidence interval, 1.2–26.6). The centrilobular distribution of nodules was the most frequent (n = 4, 36%) in HSCT patients with PCP. A mosaic pattern was an indicator of PCP in both HSCT and non-HSCT patients. There were no significant differences in other infections. Conclusion The mosaic pattern could be an indicator of PCP in both HSCT and non-HSCT patients. Nodules with centrilobular distribution might be relatively frequent HRCT findings of PCP in HSCT patients.

Volatile organic compounds (VOCs), CO2, temperature, and humidity in a private room in a care facility for the elderly were measured and the behavior of a resident and staff were recorded in order to clarify the effects of the resident’s behavior, especially defecation, on indoor air quality. Average indoor concentrations of total VOCs (in μg m-3) in summer, autumn, and winter were 40.9, 16.7, and 18.8, respectively. Average indoor concentrations of CO2 in summer, autumn, and winter were 813, 761, and 1144 ppm, respectively, revealing a tendency for the concentrations of CO2 to be higher in winter, in contrast to the VOC concentration. The concentrations of VOCs and CO2 were 1.1 to 1.5 times higher when the resident was present in the room than when the resident was absent. This result suggests that one of the main sources of VOC and CO2 emissions in indoor air was the resident. Acetic acid, 1-butanol, propanoic acid, hexanoic acid, and phenol, which are contained in human sweat, exhaled air, and excrement, were the predominant VOCs in the air of the room regardless of the season, and these five components accounted for more than 90% of the total VOCs. The concentrations of these components were higher when the resident was present in the room, suggesting that the resident was the main source of these components. Based on the changes in the VOC and CO2 concentrations over time and the records of the resident and the staff, it was noted that VOC concentrations decreased, in some cases, before and after diaper changes. Our research suggests that certain aspects of the behavior of residents can be inferred by monitoring changes in indoor air quality.

Background Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis. Methods Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood. Expected outcome Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs. Trial registration The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021.

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39-) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39- T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.

The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC). A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed. Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9 months, 95% confidence interval, CI 4.1–19.8, p = 0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p = 0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14–0.99, p = 0.047). The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

Clarifying the influences of paleoclimate changes on the disjunct distribution formation of plants allows a historical and mechanical understanding of current vegetation and biodiversity. This study investigated the influences of paleoclimate changes on the present disjunct distribution formation of Pinus koraiensis (Korean pine) using species distribution modeling. A species distribution model (SDM) was built using maximum entropy principle algorithms (MaxEnt), data from 152 occurrences of the species, and four bioclimatic variables at 2.5 arcminute (approximately 5 km) spatial resolution. The simulation revealed the excellent fit of the MaxEnt model performance, with an area under the curve (AUC) value of 0.922 and continuous Boyce index (BCI) value of 0.925 with fivefold cross-validation. The most important climatic factor was the minimum temperature of the coldest month. Suitable habitats for the species ranged between − 30.1 and − 4.1 °C. Projected suitable habitats under the Last Glacial Maximum (approximately 22,000 years ago [ka BP]: LGM) period showed wide distributions in eastern China, the southern part of the Korean Peninsula, and the Japanese Archipelago. After the mid-Holocene (approximately 6 ka BP), the suitable habitats expanded northwards in continental regions and retreated from both north and southwest of Japan. This eventually formed disjunct suitable habitats in central Japan. An increase in temperature after the LGM period caused the migration of P. koraiensis toward new, suitable habitats in continental Northeast Asia, while species in the Japanese Archipelago retreated, forming the present disjunct distributions.

To evaluate the association between a sign and visceral pleural invasion (VPI) of peripheral non–small-cell lung cancer (NSCLC) that does not appear touching the pleural surface. A total of 221 consecutive patients with NSCLC that did not appear touching the pleural surface, ≤ 3 cm in solid tumor diameter, and was surgically resected between January 2009 and December 2015 were included. We focused on the flat distortion of the tumor caused by an arch-shaped linear tag between the tumor and the pleura on CT and named it a bridge tag sign. We evaluated the associations between the clinicopathological features of the tumor, including the bridge tag sign, and VPI. We also evaluated the associations between histopathological findings and the bridge tag sign. The utility of the bridge tag sign in the diagnosis of VPI was statistically assessed. The bridge tag sign was observed in 48 (20.8%) patients. VPI was positive in 9 (4.1%) patients; among these, the bridge tag sign was positive in 8 patients. In multivariate analysis, a bridge tag sign was significantly associated with VPI. The bridge tag sign was associated with longer contact length of the pleura with the tumor and trapezoid type pleural retraction. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the bridge tag sign in the diagnosis of VPI were 88.9%, 83.5%, 83.7%, 18.6%, and 99.4%, respectively. A bridge tag sign on CT might improve the accuracy of the prediction of VPI. • We present the bridge tag sign which is defined as a flat distortion of an NSCLC tumor by an arch-shaped linear tag between the tumor and chest wall or interlobar fissure. • The bridge tag sign was an independent predictive factor for visceral pleural invasion. • The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the bridge tag sign in the diagnosis of visceral pleural invasion were 88.9%, 83.5%, 83.7%, 18.6%, and 99.4%, respectively.

The salvage treatments for biochemical recurrence (BCR) include local external beam radiation therapy (RT) and systemic androgen-deprivation therapy (ADT). We reviewed patients who underwent radical prostatectomy (RP) and developed BCR at three institutions. After excluding patients whose nadir prostate-specific antigen (PSA) was higher than 0.2 ng/mL, those who received neoadjuvant/adjuvant therapy, and those whose BCR was not treated until their PSA exceeded 4.0 ng/mL, the remaining 335 patients comprised the cohort of this study. Salvage RT and ADT were performed for 154 and 181 patients, respectively. After the failure of salvage RT, all patients received subsequent ADT. The starting point of this study was the timing of BCR and the endpoint was the development of castration-resistant prostate cancer (CRPC). During the mean follow-up period of 8.5 years after BCR, CRPC was observed in 13 patients administered RT and 24 patients administered ADT. Kaplan–Meier curves demonstrated no significant difference in CRPC-free survival between the RT and ADT groups (10-year CRPC-free survival 89.9 vs. 86.3%, p = 0.199). On the other hand, we found a significant difference in CRPC-free survival between the RT and ADT groups in 50 high-risk patients with two risk factors of Grade Group ≥ 4 and PSA-doubling time

Intravesical bacillus Calmette–Guerin (BCG) is the standard of care for bladder carcinoma in situ (CIS). The response to BCG therapy against CIS is generally assessed by random bladder biopsy (RBB). In this study, we examined the necessity of routine RBB after BCG therapy. We retrospectively identified 102 patients who were initially diagnosed with CIS with or without papillary tumor and received subsequent 6–8-week BCG therapy. Thereafter, all patients underwent voiding cytology analysis, cystoscopy, and RBB to evaluate the effects of BCG therapy. We evaluated the association between clinical parameters (voiding cytology and cystoscopy findings) and the final pathological results by RBB specimens. According to the pathological results of RBB, 30 (29%) patients had BCG-unresponsive disease (remaining urothelial carcinoma was confirmed pathologically) and 20 were diagnosed with CIS. Positive/suspicious voiding cytology and positive cystoscopy findings were well observed in patients who had BCG-unresponsive disease compared with their counterparts (p = 0.116, and p

To clarify the emissions of volatile organic compounds (VOCs) from hen rearing in Japan, we collected air samples from inside a hen shed for the four seasons in 2019 and analyzed 34 VOCs in the air samples by gas chromatography-mass spectrometry and high performance liquid chromatography. The temperature and humidity inside and outside of the shed were monitored simultaneously during each sampling campaign. The average concentrations of VOCs in the shed ranged from 150 to 427 μg m-3, the concentrations being higher in summer and lower in winter. Acetone, dimethyl sulfide, 2-butanone, 2-pentanone, and acetic acid were dominant throughout all the seasons and these five compounds accounted for 70-89% of the total VOCs. The reactivity of each VOC with hydroxyl radical was also calculated and dimethyl sulfide was found to be the most reactive VOC, accounting for 84-94% of the total hydroxyl radical reactivity. The emission rate (ER) for the total VOCs (μg h-1 kg-1) was 602 in winter, 7,900 in spring, 46,500 in summer and 37,600 in autumn, respectively. Acetone, dimethyl sulfide, 2-butanone, 3-pentanone and acetic acid had higher ERs throughout all the seasons, and these five components accounted for 70-90% of the ERs for the total VOCs. The ERs of the VOCs increased exponentially in accord with temperature increases inside the shed, indicating that the ERs of the VOCs depended on the ambient temperature. The annual VOC emission from one hen and from the hen shed was calculated to be 405 g y-1 and 121 kg y-1, respectively.

To evaluate the oncological feasibility of pure laparoscopic radical nephroureterectomy (p-LRNU) for upper tract urothelial carcinoma (UTUC) compared with conventional LRNU (c-LRNU) using a propensity-adjusted multi-institutional collaboration dataset. Among the 503 UTUC patients who underwent RNU, we identified 219 who underwent c-LRNU (laparoscopic nephrectomy with open bladder cuff resection) and 72 who underwent p-LRNU (dissecting the kidney, ureter, and bladder cuff under complete laparoscopy). We adopted a propensity score (PS) matching method to achieve homogeneity with respect to patient backgrounds. PS matching-adjusted Cox-regression analysis was performed to evaluate the risk factors that influenced oncological outcomes. Sixty-eight p-LRNU and 68 c-LRNU patients were matched. Overall, 51 (37.0%) developed intravesical recurrence (IVR), 21 (15.4%) had disease recurrence, and 20 (14.7%) died. Patients who underwent p-LRNU had a significantly shorter operation time and less blood loss than those who underwent c-LRNU. Although no significant differences in 3-year recurrence-free survival were found between the two methods, atypical recurrence sites were observed in the p-LRNU group, including the brain, sigmoid colon, vagina, and peritoneum. Regarding IVR, the 3-year IVR-free survival rate was 41.8% in the p-LRNU group, which was significantly lower than that in the c-LRNU group (66.6%, p = 0.004). Multivariate analysis demonstrated that a history of bladder cancer, ureteral cancer, and p-LRNU were independent risk factors for subsequent IVR. Although p-LRNU is less invasive, the current technique may increase the incidence of atypical disease recurrence and subsequent IVR due to extravesical and intravesical tumor dissemination.

In the course of taxonomic studies on Zingiberaceae in Myanmar, a new species of Curcuma assignable to subgenus Ecomatae was discovered in Htamanthi Wildlife Sanctuary, Sagaing Region, northwestern Myanmar. It is described and illustrated here as Curcuma stolonifera. This new species differs from other species in subgenus Ecomatae Skornick. & Sida f. in having a combination of the following characters; long creeping rhizomes, an oblong-lanceolate lamina with reddish midrib, a small number of green bracts, a central inflorescence, pale whitish yellow flowers, and a short slightly L-shaped anther with a curved spur.

Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an increase in asymptomatic prostate-specific antigen (PSA). We previously reported the “optimal PSA follow-up schedule after RP”. The aim of this study was to confirm the usefulness and safety of that follow-up schedule in another cohort. We retrospectively reviewed the clinicopathological data of 798 consecutive patients who underwent radical prostatectomy between 2009 and 2017. We examined all PSA values measured during follow-up. Furthermore, we estimated the PSA value when we observed the “optimal PSA follow-up schedule” at each timing in the virtual follow-up. BCR was defined as an elevation of PSA to greater than 0.2 ng/ml, and the ideal PSA range for detection of BCR was regarded to be 0.2–0.4 ng/ml. During the mean follow-up period of 5.8 years, BCR occurred in 115 (14.9%) patients and the frequency of virtual follow-up was significantly lower than the actual frequency. However, overlooking of BCR (detecting BCR when PSA exceeded 0.4 ng/ml) was observed in 17 patients, which is higher than the actual frequency of overlooking (12 patients). Therefore, we modified the follow-up schedule, which could achieve the lower follow-up frequency and a limited number of overlooking of BCR (7 patients). This external validation study revealed that the "modified optimal PSA follow-up schedule after RP" can reduce the frequency of PSA measurement with a limited risk of overlooking BCR.

Cancer stem cells (CSCs) have tumour initiation, self-renewal, and long-term tumour repopulation properties, and it is postulated that differentiated somatic cells can be reprogrammed to CSCs by oncogenic signals. We previously showed that oncogenic HRASV12 conferred tumour initiation capacity in tumour suppressor p53-deficient (p53−/−) primary mouse embryonic fibroblasts (MEFs) through transcription factor NF-κB-mediated enhancement of glucose uptake; however, the underlying mechanisms of RAS oncogene-induced CSC reprogramming have not been elucidated. Here, we found that the expression of the reprogramming factor SOX2 was induced by HRASV12 in p53−/− MEFs. Moreover, gene knockout studies revealed that SOX2 is an essential factor for the generation of CSCs by HRASV12 in mouse and human fibroblasts. We demonstrated that HRASV12-induced cyclin-dependent kinase 1 (CDK1) activity and subsequent enhancement of protein O-GlcNAcylation were required for SOX2 induction and CSC generation in these fibroblasts and cancer cell lines containing RAS mutations. Moreover, the CDK inhibitor dinaciclib and O-GlcNAcylation inhibitor OSMI1 reduced the number of CSCs derived from these cells. Taken together, our results reveal a signalling pathway and mechanism for CSC generation by oncogenic RAS and suggest the possibility that this signalling pathway is a therapeutic target for CSCs.

To clarify the nature and characteristics of volatile organic compounds (VOCs) emitted from dairy cattle within a cattle shed located in Chiba, Japan, air samples were collected and analyzed for the four seasons in 2017-2018. Thirty-four VOCs were determined by gas chromatography-mass spectrometry and high performance liquid chromatography. In addition, air temperature and relative humidity inside and outside of the shed were monitored during each sampling campaign to estimate the ventilation rate of the shed. The average concentrations of total VOCs (μg m-3) in the shed in each season were 50.5 (spring), 128.4 (summer), 168.8 (autumn), and 199.5 (winter). Ketones were always the most dominant components followed by alcohols and volatile fatty acids (VFAs). The sum of ketones, alcohols, and VFAs accounted for more than 80% of the total VOCs in all seasons. Acetone, 3-pentanone, 1-butanol, and acetic acid were the major components regardless of the season, accounting for more than 60% of the total VOCs. The average emission rates of total VOCs from the shed (μg h-1 kg-1) were calculated to be 623 (spring), 1520 (summer), 585 (autumn) and 469 (winter). The emission rates of almost all the VOCs except alcohols increased exponentially with increase of air temperature in the shed. The ranges of the emission rates for each class of chemical (μg h-1 kg-1) were 39-170 (VFAs), 247-913 (ketones), 65-134 (alcohols), 40-122 (phenols), 10-122 (aldehydes), 4.17-22.3 (sulfur compounds), and 0.0067-0.74 (indoles). Furthermore, the annual emissions of VOCs for a single dairy cattle and for the cattle shed were estimated to be 5.5 kg and 44 kg, respectively

To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation.The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA 0.2 ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) 6 months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death.During the mean follow-up period of 8.3 years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA 1.0 ng/mL, PSA 1.0-4.0, and PSA 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA 4.0 ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10 years from the timing of BCR.Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months when their life expectancy is within 10 years.

The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS). Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4–17.5) and 29.4 (95% CI 25.5–33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4–4.2, p = 0.001). The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

The aims of this study were to compare the high-resolution computed tomography (HRCT) findings of pulmonary infections in immunocompromised patients and to assess the usefulness of HRCT in the differential diagnosis of these infections. A total of 345 immunocompromised patients with pulmonary infections were included in this study. The diagnoses of the patients consisted of bacterial pneumonia (123 cases), pneumocystis pneumonia (PCP) (105 cases), fungal pneumonia (80 cases), tuberculosis (15 cases), cytomegalovirus pneumonia (11 cases), and septic embolism (11 cases). Two chest radiologists retrospectively evaluated the computed tomography (CT) images, which consisted of 22 findings including ground-glass attenuation, consolidation, nodules, and thickening of the bronchial wall and interlobular septum. Associations between the CT criteria and infections were investigated using χ2 test; multiple logistic regression analyses were conducted to identify the significant indicator for each infection. The area under the curve (AUC) of each model was calculated. Bronchial wall thickening was a significant indicator for bacterial pneumonia (p = 0.002; odds ratio [OR], 2.341; 95% confidence interval [CI], 1.378–3.978). The presence of a mosaic pattern and the absence of nodules were significant indicators for PCP (p

Single cell analysis has gained attention as a means to investigate the heterogeneity of cells and amplify a cell with desired characteristics. However, obtaining a single cell from a large number of cells remains difficult because preparation of single-cell samples relies on conventional techniques such as pipetting that are labor intensive. In this study, we developed a system combining a 0.6-mm thin glass microfluidic device and machine vision approach to isolate single Euglena gracilis cells, as a model of microorganism with mobility, in a small/thin glass chamber. A single E. gracilis cell in a chamber was cultured for 4 days to monitor its multiplication. With this system, we successfully simplified preparation of single cells of interest and determined that it is possible to combine it with other analytical techniques to observe single cells continuously.

Tumour-promoting inflammation is a hallmark of cancer, and chronic inflammatory disease increases the risk of cancer. In this context, MYD88, a downstream signalling molecule of Toll-like receptors that initiates inflammatory signalling cascades, has a critical role in tumour development in mice and its gene mutation was found in human cancers. In inflammation-induced colon cancer, tumour suppressor p53 mutations have also been detected with high frequency as early events. However, the molecular mechanism of MYD88-induced cancer development is poorly understood. Here, we demonstrated that MYD88 induced the protein accumulation of the transcription factor HIF-1α through NF-κB in p53-deficient cells. HIF-1α accumulation was not caused by enhanced protein stability but by NF-κB-mediated transcriptional activation, the enhanced translation of HIF-1α and JNK activation. In contrast, MYD88-induced mRNA expressions of HIF-1α and HIF-1-target genes were attenuated in the presence of p53. Furthermore, constitutively active forms of MYD88 induced tumour-initiating cell (TIC) generation in p53-deficient cells, as determined by tumour xenografts in nude mice. TIC generating activity was diminished by the suppression of NF-κB or HIF-1α. These results indicate that MYD88 signals induce the generation of TICs through the NF-κB-HIF-1α activation cascade in p53-deficient cells and suggest this molecular mechanism underlies inflammation-induced cancer development.

Creation of a seabed map is a significant task for various activities including safe navigation of vessels, commercial fishing and securing sea-mined resources. Conventionally, search machines including autonomous underwater vehicles or sonar systems have been used for this purpose. Here, we propose a completely different approach to improve the seabed map by using benthic (sting and electric) rays as agents which may explore the seabed by their autonomous behavior without precise control and possibly add extra information such as biota. For the first step to realize this concept, the detail behavior of the benthic rays must be analyzed. In this study, we used a system with a large water tank (10 m × 5 m × 6 m height) to measure the movement patterns of the benthic rays. We confirmed that it was feasible to optically trace the 2D and 3D movement of a sting and an electric ray and that the speed of the rays indicated whether they were skimming slowly over the bottom surface or swimming. Then, we investigated feasibility for measuring the sea bottom features using two electric rays equipped with small pingers (acoustic transmitters) and receivers on a boat. We confirmed tracing of the movements of the rays over the sea bottom for more than 90 min at 1 s time resolution. Since we can know whether rays are skimming slowly over the bottom surface or swimming in water from the speed, this would be applicable to mapping the sea bottom depth. This is the first step to investigate the feasibility of mapping the seabed using a benthic creature.

Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is associated with induction of chemotaxis and degranulation of neutrophils. IL-8 is overexpressed in many tumors, including colon and lung cancer, and recent studies demonstrated essential roles for IL-8 in tumor progression within the tumor microenvironment. However, the molecular mechanism underlying the functions of IL-8 in tumor progression is unclear. In this study, we found that IL-8 is overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and is required for CSC properties, including tumor-initiating abilities. These findings suggest that IL-8 plays an essential role in the development of CSCs. We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose-6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein O-GlcNAcylation. We demonstrated that these events are required for the generation and maintenance CSC-like characteristics of colon and lung cancer cells. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O-GlcNAcylation is required for generation and maintenance of CSCs of colon and lung cancer cells and suggests this regulatory pathway as a candidate therapeutic target of CSCs.

Native forests on oceanic islands are among the most threatened ecosystems. The forests formed on Sekimon uplifted limestone in Haha-jima Island (Ogasawara Islands) have not yet been destroyed by human activities and remain as primary forests harboring several narrow endemic endangered plants. In this paper, we described the plant species diversity, community structure, and status of invasion by alien plants in the mesic forests of Sekimon. The Sekimon forest was characterized by low tree diversity (37 species), high stem density (1731 ha−1), and high basal area (63.9 m2 ha−1), comparing with natural forests in world islands. The forests were dominated in the number of stems by the sub-tree Ardisia sieboldii followed by the trees Pisonia umbellifera and Elaeocarpus photiniifolius. The invasive tree Bischofia javanica ranked fourth for basal area and third for the number of stems (DBH ≥ 10 cm), and its distribution expanded, especially near a past plantation site. Surveys of forest floor vegetation revealed that species richness of vascular plants was 109 species and that many alien plants had already invaded the forests. Despite the low species richness of alien (16% for vascular flora and 8% for trees), the high frequency of aliens on the forest floor suggests that they have colonized successfully in the Sekimon forest. Extrapolation analysis based on the rarefaction curves predicted that the vascular plants in the Sekimon (25 ha) accounted for 135 species (29.9% of the vascular flora of the Ogasawara Islands) and endemic plants were 85 species (62.0%). The fact that the 39 vascular species recorded in our plots were listed in Japanese Red List suggests that the Sekimon forest should be conserved as a sanctuary of biodiversity. Because alien plants are invading the forests without apparent anthropogenic disturbance, immediate action to eradicate these invaders is highly needed.

In the realm of stationary energy storage, a plurality of candidate chemistries continues to vie for acceptance, among them the Na–NiCl2 displacement battery, which has eluded widespread adoption owing to the fragility of the β″-Al2O3 membrane. Here we report a porous electronically conductive membrane, which achieves chemical selectivity by preferred faradaic reaction instead of by regulated ionic conduction. Fitted with a porous membrane of TiN, a displacement cell comprising a liquid Pb positive electrode, a liquid Li–Pb negative electrode and a molten-salt electrolyte of PbCl2 dissolved in LiCl–KCl eutectic was cycled at a current density of 150 mA cm−2 at a temperature of 410 °C and exhibited a coulombic efficiency of 92% and a round-trip energy efficiency of 71%. As an indication of industrial scalability, we show comparable performance in a cell fitted with a faradaic membrane fashioned out of porous metal. Molten-salt batteries such as Na–NiCl2 are promising candidates for grid storage, but suffer from fragility of ion-selective ceramic membranes. Here the authors report the operation of a Li–Pb||PbCl2 battery fitted with a robust TiN mesh membrane that functions by protective faradaic reaction.

Intratumoral heterogeneity is a critical factor when diagnosing and treating patients with cancer. Marked differences in the genetic and epigenetic backgrounds of cancer cells have been revealed by advances in genome sequencing, yet little is known about the phenotypic landscape and the spatial distribution of intratumoral heterogeneity within solid tumours. Here, we show that three-dimensional light-sheet microscopy of cleared solid tumours can identify unique patterns of phenotypic heterogeneity, in the epithelial-to-mesenchymal transition and in angiogenesis, at single-cell resolution in whole formalin-fixed paraffin-embedded (FFPE) biopsy samples. We also show that cleared FFPE samples can be re-embedded in paraffin after examination for future use, and that our tumour-phenotyping pipeline can determine tumour stage and stratify patient prognosis from clinical samples with higher accuracy than current diagnostic methods, thus facilitating the design of more efficient cancer therapies. A method that identifies patterns of tumour heterogeneity in intact biopsy samples using 3D light-sheet microscopy stratifies patients by tumour stage.

There has been an increasing number of studies on species extinction because of global warming based on estimations of changes in species distributions. Life cycle impact assessment methods do not have a biodiversity damage factor for global warming that uses the extinction risk index. In this study, a method for determining the extinction risks of individual species per unit CO2 emission was proposed and test calculations of the extinction risks of 216 species of Japanese vascular plants were performed. We also examined the possibility of determining local and global extinction risk factors using this method. This method uses the Expected Increase in the Number of Extinction Species (EINES), which is defined as the inverse of the time to extinction, as the extinction risk index. Procedures for determining the extinction risks of individual species per unit CO2 emission (EINES/species/kg) are as follows. First, based on the base scenario of CO2 emission, a niche-based species distribution model is used to estimate species distribution areas in 2000 and 2100 and calculate the distribution area decrease over 100 years. The number of years before the zero distribution area is then determined by assuming that the decrease is constant. Extinction risk is defined as the inverse of this time. The final step is to determine the extinction risk at specific CO2 emissions in addition to the base emission scenario and divide the difference in the extinction risk by the additional amount of CO2 emissions. The distribution areas of 216 species of Japanese vascular plants having southern distribution limits were estimated to decrease by 40–85% in 100 years. The accuracy of the estimation was sufficient according to the value of area under the curve (AUC). Considering climate models and migration conditions, the extinction risk per unit CO2 emission was estimated between −0.6 × 10−18 and 4.7 × 10−18 (EINES/species/kg). We converted the normalization values of the extinction risk of Japan for the 216 species to compare impact of land use changes and waste processing with that of global warming on the species. We found that global warming has smaller impact compared with land use changes and larger impact compared with waste processing. A method for estimating the extinction risks of species per unit CO2 emission was proposed, and it can be used to determine the local and global extinction risk factors of CO2.

The reduction of plasticity with age has been shown by many previous papers in animal experiments. This issue can be studied in humans because several non-invasive brain stimulation techniques induce synaptic plasticity in the human brain. We investigated the influence of individuals' age on the responder rate of the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS). The participants were 107 healthy volunteers: 53 older participants (Mean ± SD 65.0 ± 1.5 years) and 54 younger participants (37.2 ± 8.7). The quadripulse stimulation with 5-ms inter-pulse interval (QPS5) was applied over the primary motor cortex (M1). We measured motor evoked potentials (MEPs) before QPS, and at five time points after QPS for up to 25 min. In each participant, average MEP amplitude (size) ratios were quantified. We first classified participants as responders and non-responders simply by comparing the size ratio with 1.0 for consistency with previous studies, then as "significant responders", "non-responders", and "opposite responders" for more detailed analysis by comparing the size ratio with the mean and standard deviation of the MEP size ratios of the sham condition. The degree of LTP-like effects induced by QPS5 was significantly smaller in the older group compared to the younger group. Also, the rates of responders and significant responders were lower in the older group (58 and 47%, respectively) compared to the younger group (80 and 76%, respectively). The age of the participants significantly affected the LTP-like effect induced by QPS5, which suggests that brain plasticity decreases with age.

Limiting the magnitude of climate change via stringent greenhouse gas (GHG) mitigation is necessary to prevent further biodiversity loss. However, some strategies to mitigate GHG emission involve greater land-based mitigation efforts, which may cause biodiversity loss from land-use changes. Here we estimate how climate and land-based mitigation efforts interact with global biodiversity by using an integrated assessment model framework to project potential habitat for five major taxonomic groups. We find that stringent GHG mitigation can generally bring a net benefit to global biodiversity even if land-based mitigation is adopted. This trend is strengthened in the latter half of this century. In contrast, some regions projected to experience much growth in land-based mitigation efforts (i.e., Europe and Oceania) are expected to suffer biodiversity loss. Our results support the enactment of stringent GHG mitigation policies in terms of biodiversity. To conserve local biodiversity, however, these policies must be carefully designed in conjunction with land-use regulations and societal transformation in order to minimize the conversion of natural habitats., Greenhouse gas mitigation can involve land-use changes that alter the habitat available for wildlife. Here, Ohashi et al. perform an integrated assessment showing that climate mitigation can be beneficial for global biodiversity but may entail local biodiversity losses where land-based mitigation is implemented.

Transcription factor GLI1 is an effecter of Hedgehog (HH) signalling and activated in a broad spectrum of cancers. However, the role of the HH-GLI1 pathway in cancer and the activation mechanism of GLI1 in HH signalling after dissociation from its inhibitor, SUFU, are not fully understood. Here, we found that GLI1 associated with the methylosome protein 50 (MEP50)/protein arginine methyltransferase 5 (PRMT5) complex and was methylated. Association of MEP50/PRMT5 with GLI1 was enhanced and expression of MEP50 and PRMT5 was activated by HH signals, suggesting their role in positive feedback regulation. Methylated GLI1 lost its ability to bind ubiquitin ligase ITCH/NUMB, resulting in nuclear accumulation and activation of GLI1. Moreover, protein expression of GLI1 was enhanced by MEP50/PRMT5 and expression of MEP50, PRMT5, and GLI1 target genes was upregulated in HH-expressing cancers. These results suggest that MEP50/PRMT5 is important for HH signal-induced GLI1 activation, especially in cancers., Yoshinori Abe et al. find that the Hedgehog (HH) signalling effector GLI1 is methylated by and associates with the MEP50/PRMT5 methyltransferase complex upon HH activation. They find that this complex plays a key role in positive feedback regulation of HH signalling in cancer.

Apprehension over exhaustion of fossil fuels and global warming, due to increasing amounts of CO2, has generated a lot of attention for the subject of renewable energy. Renewable energy has an intermittency problem and its output fluctuates depending on natural conditions. Biohydrogen is one of the promising renewable energy sources. Hydrogen produced by photosynthetic bacteria depends on the intensity of light irradiation and also fluctuates with the daily variation of sunlight. The co-culture system of dark-fermentative and photosynthetic bacteria is one solution for reducing the dependency of hydrogen production on light intensity. Because these two strains of bacteria have different processes of hydrogen production, it is possible to combine different outputs so far as the co-culture system works well. This study performed hydrogen production by the co-culture system composed of agar gels embedded with both dark-fermentative bacteria, Clostridium butyricum MIYAIRI, and photosynthetic bacteria, Rhodobacter sphaeroides RV, under a fluctuating light-irradiation. The time-course of hydrogen production was determined for the different conditions of co-culture in the mixing ratios of the two bacterial strains and light-irradiation patterns. As a result, the co-culture system succeeded in producing hydrogen exceeding that in the case of a single culture system and improved its stability against light fluctuation. Hydrogen production by the co-culture system would be applicable to the reduction of intermittency in renewable energies.

Renewable energy is regarded as a clean energy source but has some problems, one of which is intermittency. To reduce this, the time-delay of hydrogen production by photosynthetic bacteria can be effective. In this study, we qualitatively evaluated the time-delay of hydrogen production by photosynthetic bacteria under various irradiation conditions, and we also quantitatively evaluated it by fitting the experimental data and the hydrogen production model with a genetic algorithm. As a result of model fitting, we found that the relationship between the lengths of the optimized time-delay of hydrogen production by photosynthetic bacteria and the amount of light irradiation is linear. And we also found that the time-delay of hydrogen production by photosynthetic bacteria had an upper limit under low light intensity. We have suggested the existence of an energy store mechanism in photosynthetic bacteria.

In recent years, world climate change and global warming have been big issues. One of the solutions is to use renewable energies; however, renewable energies have an intermittent nature. In the case of photovoltaic arrays, the intermittency is mainly caused by fluctuating irradiation from sunlight due to clouds. In this study, biohydrogen production from photosynthetic bacteria was focused for the use of fluctuating sunlight irradiation. Previous researches have revealed some characteristics of biohydrogen production, and these results enable one to expect that photosynthetic bacteria have fluctuating light tolerance of biohydrogen production, in which the bacteria are able to produce biohydrogen continuously under fluctuating light irradiation. There have been quite a few studies to evaluate time-course changes of biohydrogen production under fluctuating irradiation, and therefore time-course evaluations have been performed. A 10-min light/dark illumination pattern was set for the fluctuating irradiation and the magnitude of the fluctuation was used to evaluate the fluctuation of the hydrogen production rate and irradiation light. The results indicated that the fluctuation was 0.22 times smaller through the photosynthetic bacteria. The results of this study indicate that photosynthetic bacteria have fluctuating light tolerance. Biohydrogen production, having fluctuating light tolerance, would be useful for realistic use of sunlight energy as renewable energy.

We built a classification tree (CT) model to estimate climatic factors controllingthe cold temperate coniferous forest (CTCF) distributions in Yunnan provinceand to predict its potential habitats under the current and future climates, using seven climate change scenarios, projected over the years of 2070-2099. The accurate CT model on CTCFs showed that minimum temperature of coldest month (TMW) was the overwhelmingly potent factor among the six climate variables.The areas of TMW

We demonstrated that our previously developed gas-phase fluoroalkylsilane patterning method was applicable to polydimethylsiloxane (PDMS) and we compared the stability of patterned proteins and cultured cells between PDMS and glass surfaces. The shapes of the protein patterns were stable on both glass and PDMS surfaces for more than 1 week. The cell patterns were stable on glass surfaces for 1 week, while those on PDMS collapsed within a few days. These results indicated that our method was applicable to PDMS, although, compared with glass, PDMS has an unsolved issue for its application to long-term patterning of cells.

Assessing suitable climate conditions to regenerate trees over a large area is of great importance to investigate potential impacts of climate change. In this study, we developed a size-based species distribution model (SBSDM) to assess spatiotemporal changes in the tree regeneration niche separately from the growth niche in adults. Siebold’s beech (Fagus crenata) was selected as the target species. We projected (1) areas where adult and juvenile potential habitats (PHs) overlapped, (2)only-adult PHs, (3) only-juvenile PHs, and (4) non-habitats for 2080–2099 using the SBSDM, a distribution dataset from the Phytosociological Releve Database of Japan, and a future climatic dataset from 24 general circulation models (GCMs). We also projected juvenile PHs for all decades between 2011 and 2099 using four representative GCMs to assess potential lost decades of the regeneration niche. The SBSDM provided sufficient projections of adult and juvenile tree distributions as well as their niche differences under the current climate. Overlapping areas and only-adult PHs were projected to decrease by the end of this century. An increase in only-juvenile PHs was projected to occur in snowy regions, with juvenile PHs starting to decrease in warm and less snowy regions. Furthermore, juvenile PHs are expected to decrease widely around 2060 as well as at the end of this century due to considerable rapid warming around those times. We conclude that regeneration of F. crenata will start to decline in 2060, but snowy conditions will postpone the timing of the regeneration loss, causing an increase in only-juvenile PHs.

To elucidate what kinds of lesions tend to be overlooked or misinterpreted and why they were overlooked or misinterpreted on chest radiographs in the diagnosis of community-acquired pneumonia (CAP) by comparing radiographic findings with HRCT findings. In 129 patients with CAP (107 bacterial and 22 atypical) and 105 healthy subjects, the chest radiographic findings were correlated with the HRCT findings. The diagnostic accuracy of each chest radiographic finding was evaluated by comparing it with the HRCT finding. The false negative rate of radiographic interpretation tended to be higher for nodules and thickening of the bronchial wall, especially in patients with atypical pneumonia. The most frequent reason for false negative interpretations of nodules and bronchial wall thickening was the overlapping of these findings with airspace consolidation or ground-glass opacity (GGO). Thin lesions were the most frequent reasons for the false negative interpretation of airspace consolidation and GGO. The chest radiographic interpretations of GGO and airspace consolidation were influenced by the thickness of lesions, and those of nodules and thickening of bronchial walls were influenced by coexisting GGO and airspace consolidation and may contribute to a misinterpretation of these lesions and an incorrect diagnosis of CAP.

Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.

In this paper, we report the development and demonstration of a method to fabricate an all-glass microfluidic cell culturing device without circulation flow. On-chip microfluidic cell culturing is an indispensable technique for cellular replacement therapies and experimental cell biology. Polydimethylsiloxane (PDMS) have become a popular material for fabricating microfluidic cell culture devices because it is a transparent, biocompatible, deformable, easy-to-mold, and gas-permeable. However, PDMS is also a chemically and physically unstable material. For example, PDMS undergoes aging easily even in room temperature conditions. Therefore, it is difficult to control long term experimental culturing conditions. On the other hand, glass is expected to be stable not only in physically but also chemically even in the presence of organic solvents. However, cell culturing still requires substance exchanges such as gases and nutrients, and so on, which cannot be done in a closed space of a glass device without circulation flow that may influence cell behavior. Thus, we introduce a filter structure with micropores onto a glass device to improve permeability to the cell culture space. Normally, it is extremely difficult to fabricate a filter structure on a normal glass plate by using a conventional fabrication method. Here, we demonstrated a method for fabricating an all-glass microfluidic cell culturing device having filters structure. The function of this all-glass culturing device was confirmed by culturing HeLa, fibroblast and ES cells. Compared with the closed glass devices without a filter structure, the numbers of cells in our device increased and embryonic bodies (EBs) were formed. This method offers a new tool in microfluidic cell culture technology for biological analysis and it expands the field of microfluidic cell culture.

Background Alzheimer’s disease (AD)-linked β-amyloid (Aβ) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on Aβ accumulation and tau pathology are incompletely understood. Methods MVB size and Aβ fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent microscopy. MVB-dysfunction, modelled by expression of dominant negative VPS4A (dnVPS4A), was analysed by biochemical methods and exosome isolation. Results Here we show that AD transgenic neurons have enlarged MVBs compared to wild type neurons. Uptake of exogenous Aβ also leads to enlarged MVBs in wild type neurons and generates fibril-like structures in endocytic vesicles. With time fibrillar oligomers/fibrils can extend out of the endocytic vesicles and are eventually detectable extracellularly. Further, endosomal sorting complexes required for transport (ESCRT) components were found associated with amyloid plaques in AD transgenic mice. The phenotypes previously reported in AD transgenic neurons, with net increased intracellular levels and reduced secretion of Aβ, were mimicked by blocking recycling of ESCRT-III by dnVPS4A. DnVPS4A further resembled AD pathology by increasing tau phosphorylation at serine 396 and increasing markers of autophagy. Conclusions We demonstrate that Aβ leads to MVB enlargement and that amyloid fibres can form within the endocytic pathway of neurons. These results are consistent with the scenario of the endosome-lysosome system representing the site of initiation of Aβ aggregation. In turn, a dominant negative form of the CHMP2B-interacting protein VPS4A, which alters MVBs, leads to accumulation and aggregation of Aβ as well as tau phosphorylation, mimicking the cellular changes in AD. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0203-y) contains supplementary material, which is available to authorized users.

To evaluate the high-resolution CT (HRCT) features of peripherally located small cell lung cancer (SCLC). We retrospectively reviewed the HRCT findings of 33 patients with peripherally located SCLC measuring 30 mm or less. The shape and marginal and internal characteristics of the nodules were evaluated. We also assessed the differences in these HRCT findings associated with the differences in the stages of disease. In 10 surgically treated cases, the HRCT-pathological correlations were evaluated. The findings of a well-defined margin (97.0 %), lobulation (78.8 %), thickening of the bronchovascular bundle (BVB) (57.6 %) and inhomogeneous enhancement (64.0 %) were common. A vermiform/branching and polygonal shape were observed in 33.3 and 21.2 % of cases, respectively. Air bronchograms (15.2 %) and marginal ground-glass opacity (GGO) (3.0 %) were less common findings. The vermiform/branching shape and thickening of the BVB were more frequently observed in non-stage I than in stage I tumors. The pathologic findings showed expansive tumor growth along the lymphatics and minimal necrosis between the tumor nests. A non-round shape and thickening of the BVB were common, while marginal GGO and air bronchogram were less common in small-sized, peripherally located SCLC. Furthermore, the vermiform/branching shape and thickening of the BVB suggested relatively advanced disease.

The objective of this study was to assess the impact of climate change on keystone subalpine conifers, Tsuga diversifolia and Abies veitchii, incorporating the uncertainties of general circulation models (GCMs) for spatial conservation planning in Japan. Potential habitats for T. diversifolia and A. veitchii under current and 20 GCMs in 2080–2100 were predicted using generalized additive models. We counted the number of GCMs under which current potential habitat was predicted to lose by a spatial unit and used them as indices of vulnerability and prediction uncertainty. Gaps between protected areas and potential habitats under the future climates were identified. Reasonably accurate models revealed that T. diversifolia and A. veitchii require cool and wet summers with low winter precipitation. Only less than 1 % of current potential habitats for the species were predicted to be sustainable with low GCMs-related uncertainties. Most of these certainly sustainable habitats were designated as protected areas. Of current potential habitats for T. diversifolia and A. veitchii, 88 and 97 % were predicted to be non-habitats under future climates with low GCMs-related uncertainties. These certainly vulnerable habitats included the southern and low elevated northern range limits of the species, of which 70 % were designated as protected areas. These results suggest that subalpine conifers are vulnerable to the climate change irrespective of GCMs variation. Strengthening of monitoring may be necessary, especially at unprotected and certainly vulnerable habitats in lower subalpine areas where influences of the climate change will appear first. Active management including assisted regeneration may be necessary for preserving the vulnerable and genetically endemic populations.

Ecosystem vulnerability to climate change remains elusive in the species-rich Taiwan-Japan archipelago. We predicted potential habitats (PHs) of ten dominant evergreen broad-leaved tree species by using the current and twenty potential climate change scenarios using generalised additive models. The presence/absence records of each species, extracted from vegetation database, were used as response variables. Four climatic and one spatial variables were used as explanatory variables. The results showed that the interaction terms of spatial variable, indicating historical range shifts or species interactions, restricted the distribution of all the target species as much as that by the each climatic variable. The PHs of all the target species were predicted to consistently increase, and in particular, to expand northward and upward to the cool temperate zone. However, the PHs were predicted to decrease within the range of 23.6–38.1 % in the Ryukyu Islands for Castanopsis sieboldii and Elaeocarpus japonica, respectively, and within the range of 32.4–42.3 % in Taiwan for Camellia japonica and Distylium racemosum, respectively. These findings suggest that the four species will be vulnerable at the southern range limits; however, the remaining six species will potentially increase within the PH areas in the future at all regions.

This study used Langmuir-Schaefer (LS) method to produce thermo-responsive poly(N-isopropylacrylamide) (PIPAAm) modified surface. Block copolymer composed of polystyrene (PSt) and PIPAAm was synthesized by RAFT polymerization. PSt-block-PIPAAm (St-IP) with various chemical compositions was dropped on an air-water interface and formed Langmuir film by compression. Then, the Langmuir film changing a density was transferred on a hydrophobic modified glass substrate to produce St-IP transferred surface (St-IP LS surface). From the observation of atomic force microscope images, a nanostructure was observed on the transference of Langmuir films. Cell adhesion and detachment were also evaluated on the LS surfaces in response to temperature. Cell adhesion on LS surfaces at 37 °C was controlled by changing the chemical compositions and densities. After reducing temperature to 20 °C, adhering cells rapidly detached themselves with lower Am and higher composition of PIPAAm. Our method should be proved novel insights for investigating cell adhesion and detachment on thermo-responsive surfaces.

Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach., Nrf2 is a transcriptional activator of oxidative stress response genes. Here the authors show that Nrf2 binds to promoters of proinflammatory genes and interferes with their transcriptional upregulation in LPS-stimulated macrophages independently of its role in regulation of reactive oxygen species.

Endosomal sorting required for transport (ESCRT) complexes orchestrate endo-lysosomal sorting of ubiquitinated proteins, multivesicular body formation and autophagic degradation. Defects in the ESCRT pathway have been implicated in many neurodegenerative diseases, but the underlying molecular mechanisms that link them to neurodegeneration remain unknown. In this study, we showed that forebrain-specific ablation of ESCRT-0/Hrs induced marked hippocampal neuronal cell loss accompanied by the accumulation of ubiquitinated proteins, including α-synuclein, TDP-43 and huntingtin as well as the autophagic substrate SQSTM1/p62. Consistent with this, silencing of Hrs in cultured cells not only led to α-synuclein and TDP-43 accumulation in addition to impaired autophagic flux but also suppressed cell viability through the induction of ER stress followed by the activation of JNK and RIPK1, a key regulator of necroptosis. Moreover, necrostatin-1, a specific inhibitor of RIPK1 and pan-caspase inhibitors partially reduced the neurotoxicity in the Hrs-silenced cells. Altogether, these findings suggest that the disruption of ESCRT-0/Hrs in the nervous system compromises autophagic/lysosomal degradation of neurodegenerative disease-related proteins, which thereby triggers ER stress-mediated apoptotic and necroptotic cell death.

Under some pathological conditions in brain, a large amount of superoxide anion (O2 −) is produced, causing various cellular damages. Among three isozymes of superoxide dismutase (SOD), extracellular (EC)-SOD should play a role to detoxify O2 − in extracellular space; however, a little is known about EC-SOD in brain. Although dopamine (DA) stored in the synaptic vesicle is stable, the excess leaked DA is spontaneously oxidized to yield O2 − and reactive DA quinones, causing damages of dopaminergic neurons. In the present study, we examined the effects of DA on SOD expression in cultured rat cortical astrocytes. By means of RT-PCR, all mRNA of three isozymes of SOD could be detected; however, only EC-SOD was increased by DA exposure for 24 h, dose-dependently. The expression of EC-SOD protein and the cell-surface SOD activity in astrocytes also increased with 100 μM DA exposure. The increase of EC-SOD mRNA by DA was inhibited by a DA transporter inhibitor, GBR12909, whereas it was not changed by DA receptor antagonists, SKF-83566 (D1) and haloperidol (D2). Furthermore, a monoamine oxidase inhibitor, pargyline, and antioxidants, N-acetyl-l-cysteine and glutathione, also did not affect the DA-induced expression of EC-SOD mRNA. On the other hand, an inhibitor of nuclear factor kappaB (NF-κB), ammonium pyrrolidine-1-carbodithioate, suppressed the DA-induced expression of EC-SOD mRNA. These results suggest that DA incorporated into the cells caused the induction of EC-SOD mRNA followed by the enhancements of EC-SOD protein level and the enzyme activity, and that NF-κB activation is involved in the mechanisms of the EC-SOD induction. The regulation of EC-SOD in astrocytes surrounding dopaminergic neurons may contribute to the defensive mechanism against oxidative stress in brain.