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Non-invasive biomarkers will enable widespread screening and early diagnosis of Alzheimer's disease (AD). We hypothesized that the considerable loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD. We examined urine dicarboxylic acids (DCA) of carbon length 3-10 to reflect products of oxidative damage and energy generation or balance that may account for changes in brain function in AD. Mean C4-C5 DCAs were lower and mean C7-C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4-C5 DCAs were lower and mean C7-C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of early AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aβ42, while C7-C10 DCAs negatively correlated with CSF Aβ42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7-C10 DCAs with hippocampal volume (p < 0.01), which was not found in the occipital volume. Urine measures of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau. These data suggest that urine measures of increased lipoxidation and dysfunctional energy balance reflect early AD pathology from brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness or monitor the efficacy of therapies in clinical trials.

Objectives: To describe inpatient and outpatient cardiac rehabilitation (CR) utilization patterns over time and by subgroups among patients admitted for acute heart failure (AHF) in Japan., Background: Cardiac rehabilitation (CR) is a crucial secondary prevention strategy for patients with heart failure. While the number of older patients with AHF continues to rise, trends in inpatient and outpatient CR participation following AHF in Japan have not been described to date., Methods: We conducted a retrospective cohort study of adult patients hospitalized for AHF in Japan between April 2008 and December 2020. Using data from the Medical Data Vision database, we measured trends in inpatient and outpatient CR participation following AHF. Descriptive analyses and summary statistics for AHF patients by CR participation status were reported., Results: The analytic cohort included 88,052 patients. Among these patients, 37,810 (42.9%) participated in inpatient and/or outpatient CR. Of those, 36,431 (96.4%) participated in inpatient CR only and 1,277 (3.4%) participated in both inpatient and outpatient CR. Rates of inpatient CR rose more than 6-fold over the study period, from 9% in 2009 to 55% in 2020, whereas rates of outpatient CR were consistently low., Conclusions: The rate of inpatient CR participation among AHF patients in Japan rose dramatically over a 12-year period, whereas outpatient CR following AHF was vastly underutilized. Further study is needed to assess the clinical effectiveness of inpatient CR and to create infrastructure and incentives to support and encourage outpatient CR., Competing Interests: Soko Setoguchi and Junghyun Kim received consultancy fees from Bristol Myers Squibb. Jenny Jiang and Sophie Shen are employees of Bristol Myers Squibb, and Junghyun Kim was an employee of Rutgers University when the research was conducted. The study was funded by Bristol Myers Squibb, NJ, USA (CV013-030). This does not alter our adherence to PLOS ONE policies on sharing data and materials. The datasets analyzed during the current study are not publicly available due to licensing agreement with Medical Data Vision Co., Ltd., (Copyright: © 2023 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

China has been fully implementing the policy of the cultural and tourism industrial integration since 2018. However, the value-added benefits of this policy are not prominent, and the relationship between industrial integration and the value added to the tourism value chain was seldom addressed by researchers. In the context of China's high-quality development, it is necessary to conduct the impact of the integration of cultural and tourism industries on the value added to tourism value chain. This paper proposed four theoretical hypotheses and the corresponding econometric models based on the panel data from 2013 to 2020 in China's Jiangsu Province. According to empirical results, the integration of cultural and tourism industries is spatially unbalanced, with notable imbalances between the south and the north. This paper identified a new connection between cultural and tourism integration and the tourism value chain. It is found that the integration of cultural and tourism industries can enhance the value added to tourism value chain either directly or indirectly through the information technology, with the direct effect being positively moderated by tourism agglomeration. Moreover, this paper may overturn how people generally think about the integration between cultural and tourism industries. It reveals a single-threshold effect that only when the integration of cultural and tourism industries reached a high level will it exert a positive effect. To be more specific, not all Chinese cities are suitable for implementing cultural and tourism integration, because the integration is likely to be ineffective in regions where the cultural industry is substantially less developed than the tourism industry., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zeng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The spatial layout of the coastal forts defense system of the Ming Dynasty of China has been studied in a relatively comprehensive way. Nonetheless, ancient defense mechanisms have not been fully revealed. Previous studies have focused more on the macro and meso levels. Studies into its microscopic construction mechanism need to be enhanced. This research attempts to quantify and validate the rationality of the ancient microscopic defense mechanism, using the ancient defense mechanism of Pu Zhuang Suo-Fort in Zhejiang Province as an instance. This study concentrates on the distribution of firepower strength beyond the walls of coastal defense forts, as well as the effect of wall height on firepower defense capabilities. There is a specific firepower attenuation area near the walls due to the firing blind area in the coastal forts defense system. And the construction of the moat plays an additive role in its defensive capability. Meanwhile, the height of the fort wall will also affect the range of the firing blind zone under Yangmacheng. In theory, there is a reasonable height range of the wall and a proper position of the moat. This height range can meet both good economy and defensive capabilities. In turn, the position of the moats and the height of the walls can verify the rationality of the construction mechanism of the coastal forts' defense system., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Shen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background/objectives: Most of the studies on functional outcomes in pediatric survivors of cancers and bone marrow failure disorders have been conducted in North American, European, and Oceanian populations, with few studies having been performed in China. The objective of this study was to evaluate psychosocial outcomes in a cohort of Chinese pediatric survivors diagnosed with cancer or conditions requiring hematopoietic stem cell transplantation (HSCT), and to identify clinical and behavioral factors associated with adverse psychosocial outcomes., Methods: This was a cross-sectional survey study. We recruited pediatric survivors of cancer or inherited disorder requiring HSCT at ≤18 years old and were ≥6 months post-treatment. Parents completed the St. Jude Children's Research Hospital After Completion of Therapy questionnaire to report their child's emotional functioning, social functioning, attention/concentration and behavior. Multivariable general linear modeling was used to identify clinical, treatment and behavioral factors associated with psychosocial outcomes, adjusting for sex, age and cancer diagnoses., Results: Ninety-five pediatric survivors were recruited (62.1% male; mean [standard deviation] age 9.7 [3.4] years; 4.1 [2.6] years post-diagnosis). They were diagnosed with bone marrow failure disorders (23.2%), hematological malignancies (45.3%) or solid tumors (23.2%). Compared with survivors with no current health problems, those with more than one current health problem performed worse in emotional functioning (Estimate = 2.42, SE = 0.88, P = 0.008) and social functioning (Estimate = 2.90, SE = 1.64, P = 0.03). Higher pain interference was significantly associated with worse emotional functioning (Estimate = 0.19, SE = 0.08, P = 0.03) and attention functioning (Estimate = 0.26, SE = 0.11, P = 0.03). Compared with survivors who reported less sleep problems, those who had more sleep problems demonstrated poorer emotional functioning (Estimate = 0.30, SE = 0.08, P = 0.001). Survivors who had a longer duration of screen usage per day reported more impairment on attention and behavior functioning than those who had a shorter duration of screen usage per day (both P<0.5)., Conclusion: Survivors who were diagnosed at a younger age or had unaddressed/untreated health problems may require additional psychological evaluation. The implementation of psychosocial assessments during routine long-term follow-up care may help to identify high-risk patients during the early phase of survivorship. Rehabilitation interventions should address modifiable behavioral factors (e.g. sleep habits, screen time and chronic pain)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Cai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In this article, we investigate the chronological change of settlements of the Lower Xiajiadian (LXJD) culture in northeast China. On the basis of excavation data, two types of settlements can be identified based on the methods of site construction: earthen (rammed earth/mudbrick) settlements and stone-constructed settlements. After integrating and reanalyzing all published 14C radiocarbon data of different LXJD sites, we argue that there is a clear chronological difference between these two types of settlements. It is revealed by the OxCal model that settlements built with earthen structures are generally earlier than those constructed with stones, and the changes in settlement spatial distribution and constructive material largely happened after 1500 BC. By means of correlation analysis with other related archaeological evidence, we suggest that the underlying social dynamics that contributed to LXJD settlement changes can be explored through multiple prospects., Competing Interests: The authors have declared that no competing interests exist.

Cadherins control intercellular adhesion in most metazoans. In vertebrates, intercellular adhesion differs considerably between cadherins of type-I and type-II, predominantly due to their different extracellular regions. Yet, intercellular adhesion critically depends on actomyosin contractility, in which the role of the cadherin extracellular region is unclear. Here, we dissect the roles of the Extracellular Cadherin (EC) Ig-like domains by expressing chimeric E-cadherin with E-cadherin and cadherin-7 Ig-like domains in cells naturally devoid of cadherins. Using cell-cell separation, cortical tension measurement, tissue stretching and migration assays, we show that distinct EC repeats in the extracellular region of cadherins differentially modulate epithelial sheet integrity, cell-cell separation forces, and cell cortical tension with the Cdc42 pathway, which further differentially regulate epithelial tensile strength, ductility, and ultimately collective migration. Interestingly, dissipative processes rather than static adhesion energy mostly dominate cell-cell separation forces. We provide a framework for the emergence of epithelial phenotypes from cell mechanical properties dependent on EC outside-in signaling., Competing Interests: The authors have declared that no competing interests exist.

Traditional dose-finding designs are substantially inefficient for targeted agents and cancer immunotherapies by failing to incorporate efficacy signals, mild and moderate adverse events, and late, cumulative toxicities. However, the lack of user-friendly software is a barrier to the practical use of the novel phase I designs, despite their demonstrated superiority of traditional 3+3 designs. To overcome these barriers, we present an R package, phase1RMD, which provides a comprehensive implementation of novel designs with repeated toxicity measures and early efficacy. A novel phase I repeated measures design that used a continuous toxicity score from multiple treatment cycles was implemented. Furthermore, in studies where preliminary efficacy is evaluated, an adaptive, multi-stage design to identify the most efficacious dose with acceptable toxicity was demonstrated. Functions are provided to recommend the next dose based on the data collected in a phase I trial, as well as to assess trial characteristics given design parameters via simulations. The repeated measure designs accurately estimated both the magnitude and direction of toxicity trends in late treatment cycles, and allocated more patients at therapeutic doses. The R package for implementing these designs is available from the Comprehensive R Archive Network. To our best knowledge, this is the first software that implement novel phase I dose-finding designs that simultaneously accounts for the multiple-grade toxicity events over multiple treatment cycles and a continuous early efficacy outcome. With the software published on CRAN, we will pursue the implementation of these designs in phase I trials in real-life settings., Competing Interests: The authors have read the journal’s policy and have the following competing interests: YD is an employee of Eli Lilly and Company; RQ is an employee of Janssen Research & Development, LLC (owned by Johnson & Johnson); and SS is an employee of DermBiont. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

The development of China's manufacturing industry has received global attention. However, research on the distribution pattern, changes, and driving forces of the manufacturing industry has been limited by the accessibility of data. This study proposes a method for classifying based on natural language processing. A case study was conducted employing this method, hotspot detection and driving force analysis, wherein the driving forces industrial development during the "13th Five-Year plan" period in Jiangsu province were determined. The main conclusions of the empirical case study are as follows. 1) Through the acquisition of Amap's point-of-interest (POI, a special point location that commonly used in modern automotive navigation systems.) data, an industry type classification algorithm based on the natural language processing of POI names is proposed, with Jiangsu Province serving as an example. The empirical test shows that the accuracy was 95%, and the kappa coefficient was 0.872. 2) The seven types of manufacturing industries including the pulp and paper (PP) industry, metallurgical chemical (MC) industry, pharmaceutical manufacturing (PM) industry, machinery and electronics (ME) industry, wood furniture (WF) industry, textile clothing (TC) industry, and agricultural and food product processing (AF) industry are drawn through a 1 km× 1km projection grid. The evolution map of the spatial pattern and the density field hotspots are also drawn. 3) After analyzing the driving forces of the changes in the number of manufacturing industries mentioned above, we found that manufacturing base, distance from town, population, GDP per capita, distance from the railway station were the significant driving factors of changes in the manufacturing industries mentioned above. The results of this research can help guide the development of manufacturing industries, maximize the advantages of regional factors and conditions, and provide insight into how the spatial layout of the manufacturing industry could be optimized., Competing Interests: The authors have declared that no competing interests exist.

Resilience is important for people to maintain mental health after negative life-events. However, its longitudinal psychological and social predictors are poorly revealed. Based on the ecological system theory model, the current study aimed to determine the longitudinal temporal mechanism underlying the development of early-adulthood resilience using long-term (early-life trauma and personality), medium-term and short-term (life-events, social support, and depression) psychosocial predictors. A total of 505 university students were recruited at baseline (T1), 433 of whom took part in a three-year longitudinal investigation (T2). The results showed that at T1 and T2, the resilience scores of individuals were identically high (72.98 and 73.21, respectively). Pearson correlation analysis showed that early-adulthood resilience was negatively correlated with early-life trauma, psychoticism and neuroticism, depression, ad life-events, and positively correlated with extraversion, social-support, and resilience. Regression and structural equation models showed that extraversion had a direct positive effect on T1 resilience through the mediation of T1 life-events, depression, and social-support, while childhood emotional neglect (EN) had indirect negative effect and extraversion had direct positive effect on T2 resilience through the mediation of T1 resilience, and T2 depression and social-support. In conclusion, this study is among the first to reveal the longitudinal temporal process of the development of early-adulthood resilience using remote and adjacent psychosocial predictors. The findings confirm that childhood EN and extraversion have a remote impact on early-adulthood resilience through recent and current depression and social-support. Our results imply that early-life trauma does not hinder the development of early-adulthood resilience in a linear trend., Competing Interests: The authors have declared that no competing interests exist.

Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) was recently identified as a tick-borne pathogen that threat to human health. Since 2010, many countries including China, South Korea, and Japan have reported Human SFTS caused by SFTSV infection. The glycoprotein encoded by the SFTSV M gene is the major antigenic component on the viral surface, and responsible for the viral entry, which makes it an important viral antigen and a clinical diagnostic target. The present study aimed to map linear B cell epitopes (BCEs) on the N-terminal glycoprotein (Gn) from SFTSV strain WCH/97/HN/China/2011 using the modified biosynthetic peptide method. Five fine epitopes (E1, 196FSQSEFPD203; E2, 232GHSHKII238; E3, 256VCYKEGTGPC265; E4, 285FCKVAG290, and E5, 316SYGGM320) were identified using the rabbit antisera. Western blot analysis showed that all the five epitopes interacted with the positive serum of sheep that had been naturally infected with SFTSV. Three-dimensional structural modeling analysis showed that all identified BCEs were located on the surface of the SFTSV-Gn and contained flexible loops. The sequence alignment revealed high conservation of the identified BCEs among 13 SFTSV strains from different lineage. These mapped epitopes will escalate the understanding of the epitope distribution and pathogenic mechanism of SFTSV, and could provide a basis for the development of a SFTSV multi-epitope detection antigen., Competing Interests: The authors have declared that no competing interests exist.

Autism Spectrum Disorder (ASD) is a heterogeneous disorder that is often accompanied with many co-morbidities. Recent genetic studies have identified various pathways from hundreds of candidate risk genes with varying levels of association to ASD. However, it is unknown which pathways are specific to the core symptoms or which are shared by the co-morbidities. We hypothesised that critical ASD candidates should appear widely across different scoring systems, and that comorbidity pathways should be constituted by genes expressed in the relevant tissues. We analysed the Simons Foundation for Autism Research Initiative (SFARI) database and four independently published scoring systems and identified 292 overlapping genes. We examined their mRNA expression using the Genotype-Tissue Expression (GTEx) database and validated protein expression levels using the human protein atlas (HPA) dataset. This led to clustering of the overlapping ASD genes into 2 groups; one with 91 genes primarily expressed in the central nervous system (CNS geneset) and another with 201 genes expressed in both CNS and peripheral tissues (CNS+PT geneset). Bioinformatic analyses showed a high enrichment of CNS development and synaptic transmission in the CNS geneset, and an enrichment of synapse, chromatin remodelling, gene regulation and endocrine signalling in the CNS+PT geneset. Calcium signalling and the glutamatergic synapse were found to be highly interconnected among pathways in the combined geneset. Our analyses demonstrate that 2/3 of ASD genes are expressed beyond the brain, which may impact peripheral function and involve in ASD co-morbidities, and relevant pathways may be explored for the treatment of ASD co-morbidities., Competing Interests: The authors have declared that no competing interests exist.

Plant landscapes are fundamental components of the green space of urban parks and are often dynamic, changing throughout the year. Winter is a season with poor plant landscape effects in urban park green spaces. However, plant community landscapes in the winter in urban park green spaces could be further optimized. Here, we conducted scenic beauty estimation (SBE) of the landscape factors in 29 winter plant communities in four typical urban parks in Yangzhou, China using partial correlation analysis and multiple linear regression. The standard SBE values of the 29 plant communities ranged from -0.981 to 1.209. Complex plant community landscapes with abundant plant species, beautiful plant community morphology and obvious seasonal changes generally received high scenic beauty scores. Six landscape factors, including the diversity of plant species, the proportion of evergreen tree species, the morphological characteristics of plants, the ground cover rate, the overall sense of harmony and the color composition, greatly influenced the scenic beauty of the plant landscape in the winter. Generally, the results of this study provide insight into how the plant community landscape in urban parks could be improved., Competing Interests: The authors have declared that no competing interests exist.

The antibacterial effects of quaternary ammonium resins (QARs) have been reported for decades, but there are few practical applications because of limited improvements in bactericidal capacity and the absence of an efficient antibacterial-indicating parameter. An in-situ determination method of surficial N+ groups for QARs, defined as surficial N+ charge density, was first established to merely quantify the exposed surficial quaternary ammonium groups (QAs). The mechanism of the new method depends on the tetraphenylboron sodium standard solution (TS), which is a colloidal solution with high steric hindrance, making it difficult to permeate into QARs and further react with the inner QAs. The results showed that the antibacterial efficacy of QARs correlates with the surficial N+ charge density with R2 > 0.95 (R2 of 0.97 for Escherichia coli, R2 of 0.96 for Staphylococcus aureus) but not with the strong-base group exchange capacity or zeta potential. Furthermore, the surficial N+ charge density was demonstrated efficient to indicate the antibacterial capacities against both gram-negative and gram-positive bacteria for commercial QARs, including acrylic, styrene and pyridine resin skeletons, especially for the QARs with similar skeletons and similar QAs. Based on the finding that the bactericidal groups merely involve the surficial QAs of QARs, this study proposes a new direction for improving the antibacterial capacity by enriching the surficial QAs and enhancing the bactericidal property of these surficial QAs, and provides a practicable synthesis with two-step quaternization., Competing Interests: The authors have declared that no competing interests exist.

The AINTEGUMENTA-like (AIL) proteins, which belong to the AP2 family, play important roles in regulating the growth and development of plant organs. The AIL family has not yet been comprehensively studied in rapeseed (Brassica napus), an allotetraploid and model organism for the study of polyploid evolution. In the present study, 99 AIL family genes were identified and characterized from B. rapa, B. oleracea, B. napus, B. juncea, and B. nigra using a comprehensive genome-wide study, including analyses of phylogeny, gene structure, chromosomal localization, and expression pattern. Using a phylogenetic analysis, the AIL genes were divided into eight groups, which were closely related to the eight AtAIL genes, and which shared highly conserved structural features within the same subfamily. The non-synonymous/synonymous substitution ratios of the paralogs and orthologs were less than 1, suggesting that the AIL genes mainly experienced purifying selection during evolution. In addition, the RNA sequencing data and qRT-PCR analysis revealed that the B. napus AIL genes exhibited organ- and developmental stage-specific expression patterns. Certain genes were highly expressed in the developing seeds (BnaAIL1, BnaAIL2, BnaAIL5, and BnaAIL6), the roots (BnaANT, BnaAIL5, and BnaAIL6), and the stem (BnaAIL7B). Our results provide valuable information for further functional analysis of the AIL family in B. napus and related Brassica species., Competing Interests: The authors have declared that no competing interests exist.

Guertu virus (GTV) is a tick-borne phleboviruses (TBPVs) which belongs to the genus Banyangvirus in the family of Phenuiviridae. In vitro and in vivo studies of GTV demonstrated that it was able to infect animal and human cell lines and could cause pathological lesions in mice. Glycoproteins (GP, including Gn and Gc) on the surface of Guertu virus (GTV) could bind to receptors on host cells and induce protective immunity in the host, but knowledge is now lacking on the information of B cell epitopes (BCEs) present on GTV-GP protein. The aim of this study was to identify all BCEs on Gn of the GTV DXM strain using rabbit pAbs against GTV-Gn. Seven fine BCEs and two antigenic peptides (APs) from nine reactive 16mer-peptides were identified, which are EGn1 (2PIICEGLTHS11), EGn2 (135CSQDSGT141), EGn3 (165IP EDVF170), EGn4 (169VFQEL K174), EGn5 (187IDGILFN193), EGn6 (223QTKWIQ228), EGn7 (237CHKDGIGPC245), AP-8 (299GVRVRPKCYGFSRMMA314) and AP-9 (355CASH FCSSAESGKKNT370), of which six of mapped BCEs were recognized by the IgG-positive sheep serum obtained from sheep GTV-infected naturally. Multiple sequence alignments (MSA) based on each mapped BCE motif identified that the most of identified BCEs and APs are highly conserved among 10 SFTSV strains from different countries and lineages that share relatively close evolutionary relationships with GTV. The fine epitope mapping of the GTV-Gn would provide basic data with which to explore the GTV-Gn antigen structure and pathogenic mechanisms, and it could lay the foundation for the design and development of a GTV multi-epitope peptide vaccine and detection antigen., Competing Interests: The authors have declared that no competing interests exist.

Background: Few studies have reported the clinical characteristics and outcomes of young adult patients diagnosed with hepatocellular carcinoma (HCC). This study aimed to formulate a nomogram to predict the prognosis of young adult HCC patients., Methods: Young adult patients diagnosed with HCC from 2004 to 2015 were screened from the Surveillance, Epidemiology, and End Results (SEER) database. Based on the multivariate analysis results, a nomogram was constructed. The concordance index (c-index) and calibration were used to assess the predictive performance of the nomogram. The clinical benefit was measured by using decision curve analysis (DCA)., Results: The mean follow-up time of the patients was 25.0±34.0 months. Gender, race, AFP level, Edmondson-Steiner classification, treatment and TNM stage were selected as independent prognostic factors and integrated into the nomogram. The c-indexes of the two sets were 0.786 and 0.775, respectively. The calibration curves showed good agreement between the nomogram-predicted probability and the actual observations. Furthermore, the DCA indicated that the nomogram had positive net benefits compared with the conventional staging system., Conclusions: The nomogram could accurately predict the prognosis of young adult HCC patients., Competing Interests: The authors have declared that no competing interests exist.

Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is an airborne fungal disease which always destructs leaf and leads to stagnation of grain filling, decreasing of kernel weight, thin seed and yield loss. Winter wheat Huixianhong is a special germplasm with special characteristics of tolerance or resistance against stripe rust. In order to understand the effect on Huixianhong from stripe rust, we designed two kinds of treatment, inoculation of stripe rust fungi (IH) and artificial immune by bactericide (CK) to study the dynamic of disease process, the grain filling and the thousand-kernel weight (TKW). Our results showed that the incubation period of Hongxinahui was 13.5 days. The prevalence increased from 32.9% at 15 days after jointing to 80.0% at 9 days after booting, and reached to 97.0% at the heading stage. The infection type (IT) was 7 to 9 at the beginning of anthesis. The severity, leaf withered area ratio and disease index at the 15th day after anthesis were 67.17%, 98.17% and 0.6717, respectively. The IH maximum increasing rate of leaf necrosis and chlorosis area was from heading beginning stage to anthesis beginning stage, which increased from 18.66 mm2·d-1 to 21.04 mm2·d-1. The maximum rate of grain filling was 1.25 mg·d-1 at the 18th day after anthesis, which was earlier than that of CK by 3.3 days. The IH thousand-kernel weight Loss (TKWL) was more than that of CK by 6.19%, the stage of heading and amature were 3.0 days and 4.5 days earlier than CK, respectively. The stripe rust infection seriously destructed the photosynthetic function of leaf at the earlier stage of grain filling, i.e. at the beginning of anthesis, which led to the most important biomass loss and the grain filling rate decrease. As far as stripe rust is concerned, Huixianhong is a high susceptible, easily been infected, seriously showing symptoms and most quickly epidemic type but can successfully complete grain filling in high quality. It is a very useful germplasm for creating and selecting special breeding materials against stripe rust., Competing Interests: The authors have declared that no competing interests exist.

Oxyplax ochracea (Moore) is a pest that causes severe damage to a wide range of crops, forests and fruit trees. The complete genome sequence of Oxyplax ochracea nucleopolyhedrovirus (OxocNPV) was determined using a Roche 454 pyrosequencing system. OxocNPV has a double-stranded DNA (dsDNA) genome of 113,971 bp with a G+C content of 31.1%. One hundred and twenty-four putative open reading frames (ORFs) encoding proteins of >50 amino acids in length and with minimal overlapping were predicted, which covered 92% of the whole genome. Six baculoviral typical homologous regions (hrs) were identified. Phylogenetic analysis and gene parity plot analysis showed that OxocNPV belongs to clade "a" of Group I alphabaculoviruses, and it seems to be close to the most recent common ancestor of Group I alphabaculoviruses. Three unique ORFs (with no homologs in the National Center for Biotechnology Information database) were identified. Interestingly, OxocNPV lacks three auxiliary genes (lef7, ie-2 and pcna) related to viral DNA replication and RNA transcription. In addition, OxocNPV has significantly different sequences for several genes (including ie1 and odv-e66) in comparison with those of other baculoviruses. However, three dimensional structure prediction showed that OxocNPV ODV-E66 contain the conserved catalytic residues, implying that it might possess polysaccharide lyase activity as AcMNPV ODV-E66. All these unique features suggest that OxocNPV represents a novel species of the Group I alphabaculovirus lineage.

This study visualized and analyzed the developing trends and hot topics in natural disaster research. 19694 natural disaster-related articles (January 1900 to June 2015) are indexed in the Web of Science database. The first step in this study is using complex networks to visualize and analyze these articles. CiteSpace and Gephi were employed to generate a countries collaboration network and a disciplines collaboration network, and then attached hot topics to countries and disciplines, respectively. The results show that USA, China, and Italy are the three major contributors to natural disaster research. "Prediction model", "social vulnerability", and "landslide inventory map" are three hot topics in recent years. They have attracted attention not only from large countries like China but also from small countries like Panama and Turkey. Comparing two hybrid networks provides details of natural disaster research. Scientists from USA and China use image data to research earthquakes. Indonesia and Germany collaboratively study tsunamis in the Indian Ocean. However, Indonesian studies focus on modeling and simulations, while German research focuses on early warning technology. This study also introduces an activity index (AI) and an attractive index (AAI) to generate time evolution trajectories of some major countries from 2000 to 2013 and evaluate their trends and performance. Four patterns of evolution are visible during this 14-year period. China and India show steadily rising contributions and impacts, USA and England show relatively decreasing research efforts and impacts, Japan and Australia show fluctuating activities and stable attraction, and Spain and Germany show fluctuating activities and increasing impacts.

Objective: To explore the different influences of walking, running and stair activity on knee articular cartilage with T1 rho and T2 mapping sequences., Materials and Methods: MRI (3.0-T) scans of the right knee were performed in twenty-three young healthy adults immediately after 30 minutes of rest, walking, running and stair activity respectively. Articular cartilage was quantitatively assessed based on T1 rho and T2 relaxation times. Analysis of variance for random block design data, bonferroni test and paired samples t tests were performed to estimate the different influences of physiological activities on articular cartilage., Results: T1 rho and T2 values had reductions after physiological activities in all regions of articular cartilage. T1 rho and T2 values were decreased more after running than walking. T1 rho and T2 values were decreased more after stair activity than running, except for femoral cartilage. The superficial layer of patella cartilage had higher reduction rates than the deep layer. The T1 rho and T2 values of articular cartilage were reduced in the following order: patellofemoral cartilage> medial tibiofemoral cartilage> lateral tibiofemoral cartilage. Patellofemoral cartilage experienced reductions in the following order: lateral part> middle part> medial part. Tibiofemoral cartilage had reductions in the following order: posterior part> middle part> anterior part., Conclusions: T1 rho and T2 mapping sequences can quantitatively reflect the different influences of physiological activities on knee articular cartilage. Fluid shifts, collagen fiber deformation, spatial heterogeneity, inherent differences in material properties and tissue stiffness have close relationship with cartilage loading characteristics.

The ovary is the main regulator of female fertility. Granulosa cell dysfunction may be involved in various reproductive endocrine disorders. Here we investigated the effect of insulin resistance on the metabolism and function of ovarian granulosa cells, and dissected the functional status of the mitogen-activated protein kinase signaling pathway in these cells. Our data showed that dexamethasone-induced insulin resistance in mouse granulosa cells reduced insulin sensitivity, accompanied with an increase in phosphorylation of p44/42 mitogen-activated protein kinase. Furthermore, up-regulation of cytochrome P450 subfamily 17 and testosterone and down-regulation of progesterone were observed in insulin-resistant mouse granulosa cells. Inhibition of p44/42 mitogen-activated protein kinase after induction of insulin resistance in mouse granulosa cells decreased phosphorylation of p44/42 mitogen-activated protein kinase, downregulated cytochrome P450 subfamily 17 and lowered progesterone production. This insulin resistance cell model can successfully demonstrate certain mechanisms such as hyperandrogenism, which may inspire a new strategy for treating reproductive endocrine disorders by regulating cell signaling pathways.

Background: Atrial fibrillation (AF) is a mechanistically heterogeneous disorder, and the ability to identify sub-phenotypes ("endophenotypes") of AF would assist in the delivery of personalized medicine. We used the clinical response to pulmonary vein isolation (PVI) to identify a sub-group of patients with non-PV mediated AF and sought to define the clinical associations., Methods: Subjects enrolled in the Vanderbilt AF Ablation Registry who underwent a repeat AF ablation due to arrhythmia recurrence were analyzed on the basis of PV reconnection. Subjects who had no PV reconnection were defined as "non-PV mediated AF". A comparison group of subjects were identified who had AF that was treated with PVI-only and experienced no arrhythmia recurrence >12 months. They were considered a group enriched for "PV-mediated AF". Univariate and multivariable binary logistic regression analysis was performed to investigate clinical associations between the PV and non-PV mediated AF groups., Results: Two hundred and twenty nine subjects underwent repeat AF ablation and thirty three (14%) had no PV reconnection. They were compared with 91 subjects identified as having PV-mediated AF. Subjects with non-PV mediated AF were older (64 years [IQR 60,71] vs. 60 [52,67], P = 0.01), more likely to have non-paroxysmal AF (82% [N = 27] vs. 35% [N = 32], P<0.001), and had a larger left atrium (LA) (4.2cm [3.6,4.8] vs. 4.0 [3.3,4.4], P = 0.04). In univariate analysis, age (per decade: OR 1.56 [95% CI: 1.04 to 2.33], P = 0.03), LA size (per cm: OR 1.8 [1.06 to 3.21], P = 0.03) and non-paroxysmal AF (OR 8.3 [3.10 to 22.19], P<0.001) were all significantly associated with non-PV mediated AF. However, in multivariable analysis only non-paroxysmal AF was independently associated with non-PV mediated AF (OR 7.47 [95% CI 2.62 to 21.29], P<0.001), when adjusted for age (per decade: OR 1.25 [0.81 to 1.94], P = 0.31), male gender (OR 0.48 [0.18 to 1.28], P = 0.14), and LA size (per 1cm: 1.24 [0.65 to 2.33], P = 0.52)., Conclusions: Non-paroxysmal AF was the only clinical variable found to be independently associated with non-PV mediated AF. We demonstrated that analysis of AF ablation outcomes data can serve as a tool to successfully identify a sub-phenotype of subjects who have non-PV mediated AF., Clinical Trial Registration: ClinicalTrials.gov ID # NCT02404415.

The aim of our study was to determine the impact of genetic polymorphisms in the caspase (CASP) genes on prognosis of hepatocellular carcinoma (HCC). We genotyped 7 potentially functional polymorphisms in CASP3, CASP7, CASP8, CASP9, CASP10 genes in 362 HCC patients of receiving surgical resection of HCC tumor. The associations of genotype and haplotype with overall survival (OS) and disease free survival (DFS) were analyzed by using the Cox proportional hazards model. We found that the CASP9 rs4645981 C allele was significantly associated with positive effect on DFS (P = 0.011 and 0.016 for CT+CC vs. TT in univariate and multivariate analysis, respectively), CT genotype was associated with a better OS of HCC than the TT genotype both in univariate and multivariate analysis (P = 0.048 and 0.041, respectively). Moreover, the CASP3 rs2705897 GT genotype showed marginally significant association with decreased OS and DFS, compared with the GG genotype. One haplotype TT/TG in CASP3 (constructed by rs12108497 T>C and rs2705897 T>G) was significantly associated with decreased OS and DFS, compared to the common haplotype TT/TT both in univariate analysis (P = 0.021 and 0.026, respectively) and multivariate analysis (P = 0.025 and 0.030, respectively). The haplotype GT/GT in CASP9 (constructed by rs4645978 A>G and rs4645981 C>T) was significantly associated with decreased DFS both in univariate and multivariate analysis (P = 0.012 and 0.010, respectively). In conclusion, the CASP9 rs4645981 polymorphism, CASP3 and CASP9 haplotypes may be useful prognosis markers for HCC patients with surgical resection of tumor.

Purpose: Corticosteroids are efficient anti-inflammation treatments. However, there are still arguments on whether it should be used in keratitis. This study was to observe the effect of corticosteroids on keratocytes both in normal condition and inflammation status in vitro., Methods: Rat keratocytes were cultured and used for examination. 10 μg/ml lipopolysaccharide (LPS) was used to establish the inflammatory keratocyte cell model, and prednisolone acetate (PA), dexamethasone (Dex) and fluorometholone (Flu) were used as corticosteroids treatments. 5 d-growth curve and cell viabilities were assayed by CCK8, and cell morphologies and migration rate were studied. TNF-α, IL-6 and IL-1β levels were examined by ELISA. Western blotting was used to quantified type VI collagen (Col VI) and matrix metalloproteinase 9 (MMP9) expressions, and immunofluorescence staining assays of Col I and Col VI were carried out., Results: In normal condition, proliferation and migration of keratocytes were slightly influenced in PA, Dex and Flu groups. The secretion of Col I and Col VI was suppressed and MMP9 expression increased in corticosteroids groups. But no significant difference was seen in TNF-α, IL-6 and IL-1β expression levels. In inflammatory status, TNF-α, IL-6 and MMP9 levels increased in LPS group, while they significantly decreased in corticosteroids groups. Although keratocytes viabilities and migration were slightly affected in 24 h, no significant differences were seen between LPS group and corticosteroids groups in 5-d proliferation. Col I and Col VI secretion in LPS-keratocytes was maintained with corticosteroids treatments., Conclusions: Corticosteroids showed lightly effects on keratocytes proliferation and migration, but it successfully decreased TNF-α, IL-6 level and maintained the secretion of and Col I and Col VI, while suppressed the expression of MMP9 in LPS-induced keratocytes. PA was suggested to use in early stage of keratitis clinical treatment.

Mutations in the UBQLN2 gene, which encodes a member of the ubiquitin-like protein family (ubiquilin-2), have been identified in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (FTD). We analyzed mutations in the UBQLN2 gene in a Chinese cohort of 515 patients with sporadic ALS (sALS). A novel missense mutation (p.M392V) was detected in one sALS patient. The p.M392V mutation substitutes a highly conserved residue, has not been reported in the population databases, and previously, at the same residue, a missense mutation p.M392I was detected in two Turkey ALS patients and was considered to be pathogenic, so the M392V is a variant of uncertain significance (VOUS) for ALS. We also found a deletion mutation (p.P500&#95;G502del), which seems to be benign. In conclusion, our data suggest that mutations in the UBQLN2 gene are rare in Chinese sALS patients., Competing Interests: The authors have declared that no competing interests exist.

The recently-introduced Orbitrap Fusion mass spectrometry permits various types of MS2 acquisition methods. To date, these different MS2 strategies and the optimal data interpretation approach for each have not been adequately evaluated. This study comprehensively investigated the four MS2 strategies: HCD-OT (higher-energy-collisional-dissociation with Orbitrap detection), HCD-IT (HCD with ion trap, IT), CID-IT (collision-induced-dissociation with IT) and CID-OT on Orbitrap Fusion. To achieve extensive comparison and identify the optimal data interpretation method for each technique, several search engines (SEQUEST and Mascot) and post-processing methods (score-based, PeptideProphet, and Percolator) were assessed for all techniques for the analysis of a human cell proteome. It was found that divergent conclusions could be made from the same dataset when different data interpretation approaches were used and therefore requiring a relatively fair comparison among techniques. Percolator was chosen for comparison of techniques because it performs the best among all search engines and MS2 strategies. For the analysis of human cell proteome using individual MS2 strategies, the highest number of identifications was achieved by HCD-OT, followed by HCD-IT and CID-IT. Based on these results, we concluded that a relatively fair platform for data interpretation is necessary to avoid divergent conclusions from the same dataset, and HCD-OT and HCD-IT may be preferable for protein/peptide identification using Orbitrap Fusion.

This article presents an improved Filtering Facepiece Respirator (FFR) designed to increase the comfort of wearers during low-moderate work. The improved FFR aims to lower the deadspace temperature and CO2 level by an active ventilation fan. The reversing modeling is used to build the 3D geometric model of this FFR; the Computational Fluid Dynamics (CFD) simulation is then introduced to investigate the flow field. Based on the simulation result, the ventilation fan of the improved FFR can fit the flow field well when placed in the proper blowing orientation; streamlines from this fan show a cup-shape distribution and are perfectly matched to the shape of the FFR and human face when the fan blowing inward. In the deadspace of the improved FFR, the CO2 volume fraction is controlled by the optimized flow field. In addition, an experimental prototype of the improved FFR has been tested to validate the simulation. A wireless temperature sensor is used to detect the temperature variation inside the prototype FFR, deadspace temperature is lowered by 2 K compared to the normal FFR without a fan. An infrared camera (IRC) method is used to elucidate the temperature distribution on the prototype FFR's outside surface and the wearer's face, surface temperature is lowered notably. Both inside and outside temperature results from the simulation are in agreement with experimental results. Therefore, adding an inward-blowing fan on the outer surface of an N95 FFR is a feasible approach to reducing the deadspace CO2 concentration and improve temperature comfort.

Background: Tuberculosis is a major public health problem especially in developing countries, the comparative efficacy and safety of fluroquinolones (FQs) for adult patients with newly diagnosed, sputum-positive tuberculosis remains controversial. We aimed to investigate the benefits and risks of FQs-containing (addition/substitution) regimens in this population., Methods: A network meta-analysis was performed to compare FQs (C: ciprofloxacin; O: ofloxacin; Lo: levofloxacin; M: moxifloxacin; G: gatifloxacin) addition/substitution regimen with standard HRZE regimen (ie isoniazid, rifampicin, pyrazinamide and ethambutol) in newly diagnosed, sputum-positive tuberculosis. Medline, Embase and Cochrane Central Register of Controlled Trials were systematically searched, randomized trials with duration longer than 8 weeks were included. The primary outcome was week-8 sputum negativity, and secondary outcomes included treatment failure, serious adverse events and death from all cause., Results: Twelve studies comprising 6465 participants were included in the network meta-analysis. Löwenstein-Jensen culture method showed that HRZEM (OR 4.96, 95% CI 2.83-8.67), MRZE (OR 1.48, 95% CI 1.19-1.84) and HRZM (OR 1.32, 95% CI 1.08-1.62) had more sputum conversion than HRZE by the eighth week, whereas HRC (OR 0.39, 95% CI 0.19-0.77) and HRZO (OR 0.47, 95% CI 0.24-0.92) were worse than HRZE. Moxifloxacin-containing regimens showed more conversion than HRZE by liquid method at the end of two months. But by the end of treatment, FQs-containing regimens didn't show superiority than HRZE on treatment failure. There were no significant differences between any regimens on other outcomes like serious adverse events and all-cause death., Conclusion: This comprehensive network meta-analysis showed that compared with HRZE, moxifloxacin-containing regimens could significantly increase sputum conversion by the eighth week for patients with newly diagnosed pulmonary tuberculosis while HRC and HRZO regimens were inferior. But all the FQs-containing regimens did not show superiority in other outcomes (such as treatment failure, serious adverse events and all-cause death). Thus, HRZE is still an effective regimen for this population. Although moxifloxacin-containing regimens have deomonstrated their potential, FQs-containing regimens should be used with great caution to avoid widespread FQs-resistance worldwide.

Objectives: The contribution of ultrasound-assisted thoracic paravertebral block to postoperative analgesia remains unclear. We compared the effect of a combination of ultrasound assisted-thoracic paravertebral block and propofol general anesthesia with opioid and sevoflurane general anesthesia on volatile anesthetic, propofol and opioid consumption, and postoperative pain in patients having breast cancer surgery., Methods: Patients undergoing breast cancer surgery were randomly assigned to ultrasound-assisted paravertebral block with propofol general anesthesia (PPA group, n = 121) or fentanyl with sevoflurane general anesthesia (GA group, n = 126). Volatile anesthetic, propofol and opioid consumption, and postoperative pain intensity were compared between the groups using noninferiority and superiority tests., Results: Patients in the PPA group required less sevoflurane than those in the GA group (median [interquartile range] of 0 [0, 0] vs. 0.4 [0.3, 0.6] minimum alveolar concentration [MAC]-hours), less intraoperative fentanyl requirements (100 [50, 100] vs. 250 [200, 300]μg,), less intense postoperative pain (median visual analog scale score 2 [1, 3.5] vs. 3 [2, 4.5]), but more propofol (median 529 [424, 672] vs. 100 [100, 130] mg). Noninferiority was detected for all four outcomes; one-tailed superiority tests for each outcome were highly significant at P<0.001 in the expected directions., Conclusions: The combination of propofol anesthesia with ultrasound-assisted paravertebral block reduces intraoperative volatile anesthetic and opioid requirements, and results in less post operative pain in patients undergoing breast cancer surgery., Trial Registration: ClinicalTrial.gov NCT00418457.

A novel avian influenza A H7N9-subtype virus emerged in China in 2013 and threatened global public health. Commercial kits that specifically detect avian influenza A (H7N9) virus RNA are urgently required to prepare for the emergence and potential pandemic of this novel influenza virus. The safety and effectiveness of three commercial molecular diagnostic assays were evaluated using a quality-control panel and clinical specimens collected from over 90 patients with confirmed avian influenza A (H7N9) virus infections. The analytical performance evaluation showed that diverse influenza H7N9 viruses can be detected with high within- and between-lot reproducibility and without cross-reactivity to other influenza viruses (H1N1 pdm09, seasonal H1N1, H3N2, H5N1 and influenza B). The detection limit of all the commercial assays was 2.83 Log10 copies/μl [0.7 Log10TCID50/mL of avian influenza A (H7N9) virus strain A/Zhejiang/DTID-ZJU01/2013], which is comparable to the method recommended by the World Health Organization (WHO). In addition, using a WHO-Chinese National Influenza Center (CNIC) method as a reference for clinical evaluation, positive agreement of more than 98% was determined for all of the commercial kits, while negative agreement of more than 99% was observed. In conclusion, our findings provide comprehensive evidence for the high performance of three commercial diagnostic assays and suggest the application of these assays as rapid and effective diagnostic tools for avian influenza A (H7N9) virus in the routine clinical practice of medical laboratories.

The aim of this study was to evaluate the effects of hydrofluoric (HF) acid, acetic acid, and citric acid treatments on the physical properties and structure of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) at ambient temperature. In total, 110 bar-shaped zirconia specimens were randomly assigned to 11 groups. The specimens in the control group (C) received no surface treatment, while those in the Cage group were hydrothermally aged at 134°C and 0.2 MPa for 20 h. Ten specimens each were immersed at ambient temperature in 5% and 40% HF acid for 2 h (40HF0), 1 day (5HF1, 40HF1), and 5 days (5HF5, 40HF5), while 10 each were immersed at ambient temperature in 10% acetic acid and 20% citric acid for 7 (AC7, CI7) and 14 days (AC14, CI14). X-ray diffraction (XRD) was used to quantitatively estimate the monoclinic phase. Furthermore, flexural strength, surface roughness, and surface Vickers hardness were measured after treatment. Scanning electron microscopy (SEM) was used to characterize the surface morphology. The Cage group specimens exhibited an increased monoclinic phase and flexural strength. Furthermore, 40% HF acid immersion decreased the flexural strength and surface hardness and deteriorated the surface finish, while 5% HF acid immersion only decreased the surface hardness. All the HF acid-immersed specimens showed an etched surface texture on SEM observations, while the other groups did not. These findings suggest that the treatment of Y-TZP with 40% HF acid at ambient temperature causes potential damage, while treatment with 5% HF acid, acetic acid, and citric acid is safe.

Baculoviruses generally produce two progeny phenotypes--the budded virus (BV) and the occlusion-derived virus (ODV)--and the intricate mechanisms that regulate the temporal synthesis of the two phenotypes are critical for the virus replication cycle, which are far from being clearly understood. FP25K was reported to be responsible for the regulation of BV/ODV, and the mutations within result in a decrease of normal ODVs formation and an increase of BVs production. In this study, we demonstrated that the increase of BV titer in an fp25k knockout recombinant (fp25k-negative) was a result of higher infectivity of BVs rather than an increased production of BVs. The constitution of the major structural proteins and genome of parental and fp25k-negative BVs were analyzed. The results showed that the integrity of the majority of DNA packaged into the fp25k-negative BVs was intact; i.e., the genomic DNA of fp25k-negative BV had better transformation and transfection efficiency than that of the parental virus, indicating more intact genomes in the virions. Although the analysis of proteins associated with BVs revealed that more envelope protein GP64 were incorporated into the fp25k-negative BVs, subsequent experiments suggested that overexpression of GP64 did not improve the titer of BVs. Thus, we conclude that the main reason for higher infectivity of BVs is due to better genome integrity, which benefits from the deletion of fp25k resulting in increased stability of the genome and produce a higher proportion of infectious BVs. FP25K acts as a negative factor for the infectivity of BV.

Background: Colorectal cancer is common. Polyunsaturated fatty acids (PUFAs) exert growth-inhibitory and pro-apoptotic effects on colon cancer cells. Metabolites of PUFAs such as prostaglandins (PGs), leukotrienes (LTs) and lipoxins (LXs) play a significant role in colon cancer., Methods: Human colon cancer LoVo and RKO cells were cultured with different concentration of PUFAs and 5-fluorouracil (5-FU) in vitro. Cell morphological changes, fatty acid composition, formation of PGE2, LTB4 and LXA4 and expression of COX-2, ALOX5, PGD synthase (PGDS), microsomal prostaglandin E synthase (mPGES) were assessed in LoVo and RKO cells when supplemented with PUFAs and 5-FU., Results: PUFAs and 5-FU inhibited growth of LoVo and RKO cells to the same extent at the doses used and produced significant alterations in their shape. As expected, higher concentrations of supplemented PUFAs were noted in the cells compared to control. LA, GLA, AA, ALA and EPA supplementation to LoVo cells suppressed production of PGE2, LTB4,and ALOX5, mPGES expression, but enhanced that of LXA4; whereas DHA enhanced PGE2 and LXA4 synthesis but decreased LTB4 formation and COX-2, ALOX5, mPGES expression. In contrast, 5-FU enhanced formation of PGE2, LTB4 and mPGES expression, but suppressed LXA4 synthesis and COX-2 expression. PGE2, LTB4 synthesis and ALOX5 expression was suppressed by LA, GLA, ALA and DHA; whereas AA, EPA and 5-FU enhanced PGE2 but paradoxically AA decreased and EPA and 5-FU enhanced LTB4 synthesis in RKO cells. All the PUFAs tested enhanced, while 5-FU decreased LXA4 formation in RKO cells; whereas GLA, AA, and 5-FU augmented while LA, ALA, EPA and DHA enhanced COX-2 expression in RKO cells., Conclusions: Tumoricidal action of PUFAs on colorectal LoVo and RKO cancer cells in vitro was associated with increased formation of LXA4, decreased synthesis of PGE2 and LTB4 and suppressed expression of COX-2, ALOX5, mPGES, whereas 5-FU produced contrasting actions on these indices.

Background: Physical performance is reported to have various beneficial effects on human health, especially in older individuals. Although such effects are associated with body mass index (BMI), the relationship between BMI and physical performance has not been clarified., Design: We conducted a cross-sectional study of 966 suburb-dwelling Tianjin individuals aged ≥ 60 years (average age 67.5±6.02, men 435, women 531). Mobility, balance, and muscle strength were assessed by walking speed, timed up-and-go test (TUGT), and grip strength, respectively. The subjects were categorized into three groups based on BMI (kg/m2) as follows: normal weight, 18.5 ≤ BMI ≤ 23.9; overweight, 24.0 ≤ BMI ≤ 27.9; and obese, BMI ≥ 28.0., Result: After adjusting for all other variables, relative grip strength decreased when BMI increased in both men and women (P for trend <0.001 and <0.001, respectively). BMI may be negatively associated with TUGT performance in the women only. There was no apparent association between walking speed and BMI in either sex, but after adjusting for age, walking speed was faster when BMI increased in women (P for trend= 0.0162)., Conclusion: This study suggests that in older individuals, higher BMI is associated with poor muscle strength in both sexes.

USP21 is a ubiquitin specific protease that catalyzes protein deubiquitination, however the identification of its physiological substrates remains challenging. USP21 is known to deubiquitinate transcription factor GATA3 and death-domain kinase RIPK1 in vitro, however the in vivo settings where this regulation plays a biologically significant role remain unknown. In order to determine whether USP21 is an essential and non-redundant regulator of GATA3 or RIPK1 activity in vivo, we characterized Usp21-deficient mice, focusing on mouse viability and development, hematopoietic stem cell function, and lymphocyte differentiation. The Usp21-knockout mice were found to be viable and fertile, with no significant dysmorphology, in contrast to the GATA3 and RIPK1 knockout lines that exhibit embryonic or perinatal lethality. Loss of USP21 also had no effect on hematopoietic stem cell function, lymphocyte development, or the responses of antigen presenting cells to TLR and TNFR stimulation. GATA3 levels in hematopoietic stem cells or T lymphocytes remained unchanged. We observed that aged Usp21-knockout mice exhibited spontaneous T cell activation, however this was not linked to altered GATA3 levels in the affected cells. The contrast in the phenotype of the Usp21-knockout line with the previously characterized GATA3 and RIPK1 knockout mice strongly indicates that USP21 is redundant for the regulation of GATA3 and RIPK1 activity during mouse development, in hematopoietic stem cells, and in lymphocyte differentiation. The Usp21-deficient mouse line characterized in this study may serve as a useful tool for the future characterization of USP21 physiological functions.

Objective: To determine whether a relationship exists between performance-based physical assessments and pre-diabetes/diabetes in an older Chinese population., Methods: Our study population comprised 976 subjects (mean ± SD age: 67.6±6.0 years; 44.5% men) from the Hangu area of Tianjin, China. Diabetes was defined by self-reporting of a physician's diagnosis, or a fasting plasma glucose level ≥126 mg/dL; and pre-diabetes was defined as a fasting plasma glucose level ≥100 mg/dL and <126 mg/dL., Results: When all other variables were adjusted for, men needing longer to finish a Timed Up and Go Test and a decreased usual walking speed had higher odds of pre-diabetes (P for trend = 0.007 and 0.008, respectively) and diabetes (P for trend = 0.012 and 0.014, respectively). However, women needing longer to finish the test and a decreased usual walking speed had a higher odds of diabetes (P for trend = 0.020 and 0.034, respectively) but not of pre-diabetes. There was no apparent association between grip strength and pre-diabetes/diabetes in both sexes., Conclusions: In this study, poor lower extremity function was associated with pre-diabetes/diabetes in older people.

This study utilized magnetic resonance imaging (MRI) to monitor the real-time status of the urinary bladder in normal and diseased states following cyclophosphamide (CYP)-induced cystitis, and also examined the role of the phosphoinositide 3-kinase (PI3K) pathway in the regulation of urinary bladder hypertrophy in vivo. Our results showed that under MRI visualization the urinary bladder wall was significantly thickened at 8 h and 48 h post CYP injection. The intravesical volume of the urinary bladder was also markedly reduced. Treatment of the cystitis animals with a specific PI3K inhibitor LY294002 reduced cystitis-induced bladder wall thickening and enlarged the intravesical volumes. To confirm the MRI results, we performed H&E stain postmortem and examined the levels of type I collagen by real-time PCR and western blot. Inhibition of the PI3K in vivo reduced the levels of type I collagen mRNA and protein in the urinary bladder ultimately attenuating cystitis-induced bladder hypertrophy. The bladder mass calculated according to MRI data was consistent to the bladder weight measured ex vivo under each drug treatment. MRI results also showed that the urinary bladder from animals with cystitis demonstrated high magnetic signal intensity indicating considerable inflammation of the urinary bladder when compared to normal animals. This was confirmed by examination of the pro-inflammatory factors showing that interleukin (IL)-1α, IL-6 and tumor necrosis factor (TNF)α levels in the urinary bladder were increased with cystitis. Our results suggest that MRI can be a useful technique in tracing bladder anatomy and examining bladder hypertrophy in vivo during disease development and the PI3K pathway has a critical role in regulating bladder hypertrophy during cystitis.

Purpose: To develop a tri-modality image fusion method for better target delineation in image-guided radiotherapy for patients with brain tumors., Methods: A new method of tri-modality image fusion was developed, which can fuse and display all image sets in one panel and one operation. And a feasibility study in gross tumor volume (GTV) delineation using data from three patients with brain tumors was conducted, which included images of simulation CT, MRI, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) examinations before radiotherapy. Tri-modality image fusion was implemented after image registrations of CT+PET and CT+MRI, and the transparency weight of each modality could be adjusted and set by users. Three radiation oncologists delineated GTVs for all patients using dual-modality (MRI/CT) and tri-modality (MRI/CT/PET) image fusion respectively. Inter-observer variation was assessed by the coefficient of variation (COV), the average distance between surface and centroid (ADSC), and the local standard deviation (SDlocal). Analysis of COV was also performed to evaluate intra-observer volume variation., Results: The inter-observer variation analysis showed that, the mean COV was 0.14(± 0.09) and 0.07(± 0.01) for dual-modality and tri-modality respectively; the standard deviation of ADSC was significantly reduced (p<0.05) with tri-modality; SDlocal averaged over median GTV surface was reduced in patient 2 (from 0.57 cm to 0.39 cm) and patient 3 (from 0.42 cm to 0.36 cm) with the new method. The intra-observer volume variation was also significantly reduced (p = 0.00) with the tri-modality method as compared with using the dual-modality method., Conclusion: With the new tri-modality image fusion method smaller inter- and intra-observer variation in GTV definition for the brain tumors can be achieved, which improves the consistency and accuracy for target delineation in individualized radiotherapy.

Background and Objective: Sodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect., Research Design and Methods: We induced diabetes using a low dose streptozotocin protocol in 7-8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice)., Results: Diabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups., Conclusion: Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.

Proteins that are post-translationally adducted with 2-(ω-carboxyethyl)pyrrole (CEP) have been proposed to play a pathogenic role in age-related macular degeneration, by inducing angiogenesis in a Toll Like Receptor 2 (TLR2)-dependent manner. We have investigated the involvement of CEP adducts in angiogenesis and TLR activation, to assess the therapeutic potential of inhibiting CEP adducts and TLR2 for ocular angiogenesis. As tool reagents, several CEP-adducted proteins and peptides were synthetically generated by published methodology and adduction was confirmed by NMR and LC-MS/MS analyses. Structural studies showed significant changes in secondary structure in CEP-adducted proteins but not the untreated proteins. Similar structural changes were also observed in the treated unadducted proteins, which were treated by the same adduction method except for one critical step required to form the CEP group. Thus some structural changes were unrelated to CEP groups and were artificially induced by the synthesis method. In biological studies, the CEP-adducted proteins and peptides failed to activate TLR2 in cell-based assays and in an in vivo TLR2-mediated retinal leukocyte infiltration model. Neither CEP adducts nor TLR agonists were able to induce angiogenesis in a tube formation assay. In vivo, treatment of animals with CEP-adducted protein had no effect on laser-induced choroidal neovascularization. Furthermore, in vivo inactivation of TLR2 by deficiency in Myeloid Differentiation factor 88 (Myd88) had no effect on abrasion-induced corneal neovascularization. Thus the CEP-TLR2 axis, which is implicated in other wound angiogenesis models, does not appear to play a pathological role in a corneal wound angiogenesis model. Collectively, our data do not support the mechanism of action of CEP adducts in TLR2-mediated angiogenesis proposed by others.

Background: Epidemiological studies have reported conflicting results regarding maternal parity and the risk of congenital heart defects (CHDs). However, a meta-analysis of the association between maternal parity and CHDs in offspring has not been conducted., Methods: We searched MEDLINE and EMBASE for articles catalogued between their inception and March 8, 2014; we identified relevant published studies that assessed the association between maternal parity and CHD risk. Two authors independently assessed the eligibility of the retrieved articles and extracted data from them. Study-specific relative risk estimates were pooled by random-effects or fixed-effects models. From the 11272 references, a total of 16 case-control studies and 3 cohort studies were enrolled in this meta-analysis., Results: The overall relative risk of CHD in parous versus nulliparous women was 1.01 (95% CI, 0.97-1.06; Q = 32.34; P = 0.006; I2 = 53.6%). Furthermore, we observed a significant association between the highest versus lowest parity number, with an overall RR = 1.20 (95% CI, 1.10-1.31; (Q = 74.61, P<0.001, I2 = 82.6%). A dose-response analysis also indicated a positive effect of maternal parity on CHD risk, and the overall increase in relative risk per one live birth was 1.06 (95% CI, 1.02-1.09); Q = 68.09; P<0.001; I2 = 80.9%). We conducted stratified and meta-regression analyses to identify the origin of the heterogeneity among studies. A Galbraith plot was created to graphically assess the sources of heterogeneity., Conclusion: In summary, this meta-analysis provided a robust estimate of the positive association between maternal parity and risk of CHD.

Chloroplast formation is associated with embryo development and seedling growth. However, the relationship between chloroplast differentiation and embryo development remains unclear. Five FtsHi genes that encode proteins with high similarity to FtsH proteins, but lack Zn2+-binding motifs, are present in the Arabidopsis genome. In this study, we showed that T-DNA insertion mutations in the Arabidopsis FtsHi4 gene resulted in embryo arrest at the globular-to-heart-shaped transition stage. Transmission electron microscopic analyses revealed abnormal plastid differentiation with a severe defect in thylakoid formation in the mutant embryos. Immunocytological studies demonstrated that FtsHi4 localized in chloroplasts as a thylakoid membrane-associated protein, supporting its essential role in thylakoid membrane formation. We further showed that FtsHi4 forms protein complexes, and that there was a significant reduction in the accumulation of D2 and PsbO (two photosystem II proteins) in mutant ovules. The role of FtsHi4 in chloroplast development was confirmed using an RNA-interfering approach. Additionally, mutations in other FtsHi genes including FtsHi1, FtsHi2, and FtsHi5 caused phenotypic abnormalities similar to ftshi4 with respect to plastid differentiation during embryogenesis. Taken together, our data suggest that FtsHi4, together with FtsHi1, FtsHi2, and FtsHi5 are essential for chloroplast development in Arabidopsis.

Objective: Triple-negative breast cancer (TNBC) is an aggressive but heterogeneous subtype of breast cancer. This study aimed to identify and validate a prognostic signature for TNBC patients to improve prognostic capability and to guide individualized treatment., Methods: We retrospectively analyzed the prognostic performance of clinicopathological characteristics and miRNAs in a training set of 58 patients with invasive ductal TNBC diagnosed between 2002 and 2012. A prediction model was developed based on independent clinicopathological and miRNA covariates. The prognostic value of the model was further validated in a separate set of 41 TNBC patients diagnosed between 2007 and 2008., Results: Only lymph node status was marginally significantly associated with poor prognosis of TNBC (P = 0.054), whereas other clinicopathological factors, including age, tumor size, histological grade, lymphovascular invasion, P53 status, Ki-67 index, and type of surgery, were not. The expression levels of miR-27b-3p, miR-107, and miR-103a-3p were significantly elevated in the metastatic group compared with the disease-free group (P value: 0.008, 0.005, and 0.050, respectively). The Cox proportional hazards regression analysis revealed that lymph node status and miR-27b-3p were independent predictors of poor prognosis (P value: 0.012 and 0.027, respectively). A logistic regression model was developed based on these two independent covariates, and the prognostic value of the model was subsequently confirmed in a separate validation set. The two different risk groups, which were stratified according to the model, showed significant differences in the rates of distant metastasis and breast cancer-related death not only in the training set (P value: 0.001 and 0.040, respectively) but also in the validation set (P value: 0.013 and 0.012, respectively)., Conclusion: This model based on miRNA and node status covariates may be used to stratify TNBC patients into different prognostic subgroups for potentially individualized therapy.