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Summary: Background: Cooking practice has transitioned from use of solid fuels to use of clean fuels, with addition of better ventilation facilities. However, the change in mortality risk associated with such a transition remains unclear. Methods: The China Kadoorie Biobank (CKB) Study enrolled participants (aged 30–79 years) from ten areas across China; we chose to study participants from five urban areas where transition from use of solid fuels to clean fuels for cooking was prevalent. Participants who reported regular cooking (weekly or more frequently) at baseline were categorised as persistent clean fuel users, previous solid fuel users, or persistent solid fuel users, according to self-reported fuel use histories. All-cause and cardiopulmonary mortality were identified through linkage to China's Disease Surveillance Point system and local mortality records. Findings: Between June 24, 2004, and July 15, 2008, 226 186 participants living in five urban areas of China were enrolled in the CKB Study. Among 171 677 participants who reported cooking regularly (weekly or more frequently), 75 785 (44%) were persistent clean fuel users, 80 511 (47%) were previous solid fuel users, and 15 381 (9%) were persistent solid fuel users. During a mean of 9·8 (SD 1·7) years of follow-up, 10 831 deaths were documented, including 3819 cardiovascular deaths and 761 respiratory deaths. Compared with persistent clean fuel users, persistent solid fuel users had significantly higher risks of all-cause mortality (hazard ratio [HR] 1·19, 95% CI 1·10–1·28), cardiovascular mortality (1·24, 1·10–1·39), and respiratory mortality (1·43, 1·10–1·85). The excess risk of all-cause and cardiopulmonary mortality fell by more than 60% in 5 years after cessation of solid fuel use and continued to decrease afterwards. Use of ventilation was associated with lower all-cause mortality risk, even among persistent clean fuel users (HR 0·78, 0·69–0·89). Interpretation: Solid fuel use for cooking is associated with a higher risk of mortality, and cessation of solid fuel use cuts excess mortality risks swiftly and substantially within 5 years. Ventilation use also lowers the risk of mortality, even among people who persistently use clean fuels. It is of prime importance for both policy makers and the public to accelerate the transition from solid fuels to clean fuels and promote efficient ventilation to minimise further adverse health effects. Funding: National Natural Science Foundation of China, Wellcome Trust, and Kadoorie Charitable Foundation.

The terrestrial ecosystem productivity (hereafter, TEP) is a key index of global carbon cycles and a fundamental constraint of carbon sequestration capacity, and also an important measure of ecosystem services and food security. However, the TEP has been significantly affected by the long-lasting droughts. Identifying the spatial relationship between droughts and the TEP is crucial for enhancing ecosystem services in China. Here the net primary production (hereafter, NPP) derived from the Carnegie-Ames-Stanford Approach model (CASA-NPP) and two drought indices, namely the Standard Precipitation Index (hereafter, SPI) and the Standard Precipitation Evaporation Index (hereafter, SPEI), are used to examine the spatial relationship between droughts and the NPP in China for the period of 1982–2012. Our main results have shown that: (1) China’s annual NPP has increased slowly from 3.82 to 4.35 PgC per year (hereafter, PgC/yr), while droughts have become much severer from 1982 to 2012; (2) on the 3-month timescale, the NPP in arid and semi-arid ecosystems has decreased at a rate of 1.28 TgC per month with per “unit” decrease in the drought index (indicating drier conditions). (3) Overall, the NPP in China has increased 5.71 TgC per month with per “unit” increase in the drought index (indicating wetter conditions); the contribution of this NPP increase is mainly from forests and farmlands; (4) the SPEI is a relatively more effective and sensitive index in representing China’s droughts. In southern China, the lagging period for the NPP response to droughts is about 3-month, while a 6-month lagging period is found in the arid and semi-arid ecosystems in northern China.

Summary: Although the functional roles of long noncoding RNAs (lncRNAs) have been increasingly identified, few lncRNAs that control the naïve state of embryonic stem cells (ESCs) are known. Here, we report a naïve-state-associated lncRNA, LincU, which is intrinsically activated by Nanog in mESCs. LincU-deficient mESCs exhibit a primed-like pluripotent state and potentiate the transition from the naïve state to the primed state, whereas ectopic LincU expression maintains mESCs in the naïve state. Mechanistically, we demonstrate that LincU binds and stabilizes the DUSP9 protein, an ERK-specific phosphatase, and then constitutively inhibits the ERK1/2 signaling pathway, which critically contributes to maintenance of the naïve state. Importantly, we reveal the functional role of LincU to be evolutionarily conserved in human. Therefore, our findings unveil LincU as a conserved lncRNA that intrinsically restricts MAPK/ERK activity and maintains the naïve state of ESCs. : Kang and colleagues report a naïve-state-associated long noncoding RNA (LincU), which is directly regulated by Nanog and stabilizes the ERK-specific phosphatase DUSP9 by protecting it from ubiquitin-proteasome mediated degradation to maintain the naïve state of mESCs. Moreover, LincU is functionally conserved in human ESCs. Keywords: naïve state, embryonic stem cells, lincRNA, DUSP9, MAPK signaling

Abstract Background TREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined. Methods Potential binding of oligomeric amyloid-β 1–42 (oAβ1–42) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ1–42 to activate TREM2 signaling pathways was examined by analyzing the phosphorylation of Syk and Akt in primary microglia as well as TREM2-mediated signaling in a reporter cell system. Lastly, the functional outcome of oAβ1–42-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ1–42-bearing brain areas in vivo. Results We found that oAβ1–42 bound to TREM2 with high affinity and activated TREM2-dependent signaling pathway. Neither monomeric nor scrambled Aβ bound to TREM2 supporting a specific interaction between oAβ and TREM2. The disease-associated mutations of TREM2 reduced its binding affinity to oAβ1–42. Furthermore, we identified several positively charged amino acids within residues 31–91 of TREM2 that were crucial for its interaction with oAβ1–42. Importantly, oAβ1–42 promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner. Conclusions Our data establish a critical link between oAβ1–42, a major pathological component of AD, and TREM2, a strong genetic risk factor for AD expressed in microglia, and suggest that such interaction contributes to the pathogenic events in AD by modulating microglial responses.

With the rapid development of cooperative detection technology, target fusion detection with regard of LEO satellites can be realized by means of their diverse observation configurations. However, the existing constant false alarm ratio (CFAR) detection research rarely involves the space-based target fusion detection theory. In this paper, a novel multi-source fusion detection method based on LEO satellites is presented. Firstly, the pre-compensation function is constructed by employing the range and Doppler history of the cell where the antenna beam center is pointed. As a result, not only is the Doppler band broadening problem caused by the high-speed movement of the satellite platform, but the Doppler frequency rate (DFR) offset issue resulted from different observation configurations are alleviated synchronously. Then, the theoretical upper and lower limits of DFR are designed to achieve the effective clutter suppression and the accurate target echo fusion. Finally, the CFAR detection threshold based on the exponential weighted likelihood ratio is derived, which effectively increases the contrast ratio between the target cell and other background cells, and thus to provide an effective multi-source fusion detection method for LEO-based satellite constellation. Simulation results verify the effectiveness of the proposed algorithm.

Fruit abscission is triggered by multiple changes in endogenous components of the fruit, including energy metabolism. However, it is still unknown how the core energy metabolism pathways are modified during fruit abscission. Here, we investigated the relationship between carbon starvation-induced fruitlet abscission and energy metabolism changes in litchi. The fruitlet abscission of litchi ‘Feizixiao’ was induced sharply by girdling plus defoliation (GPD), a carbon stress treatment. Using liquid chromatography tandem mass spectrometry (LC-MS/MS) targeted metabolomics analysis, we identified a total of 21 metabolites involved in glycolysis, TCA cycle and oxidative phosphorylation pathways. Among them, the content of most metabolites in glycolysis pathways and TCA cycles was reduced, and the activity of corresponding metabolic enzymes such as ATP-dependent phosphofructokinase (ATP-PFK), pyruvate kinase (PK), citrate synthase (CS), succinate thiokinase (SAT), and NAD-dependent malate dehydrogenase (NAD-MDH) was decreased. Consistently, we further showed that the expression of the relative genes (LcPFK2, LcPK2, LcPK4, LcCS1, LcCS2, LcSAT, LcMDH1 and LcMDH2) was also significantly down-regulated. In contrast, the level of ATP, an important metabolite in the oxidative phosphorylation pathway, was elevated in parallel with both higher activity of H+-ATPase and the increased expression level of LcH+-ATPase1. In conclusion, our findings suggest that carbon starvation can induce fruitlet abscission in litchi probably by energy depletion that mediated through both the suppression of the glycolysis pathway and TCA cycle and the enhancement of the oxidative phosphorylation pathway.

Worldwide, silage is considered the main component in dairy animal diets; however, this portion is mainly dominated by corn silage, which raises availability challenges in some agricultural production systems. The present study evaluated a partial replacement of corn silage with forage rape silage (FRS) and its effect on feed intake, nutrient digestibility, rumen fermentation, milk production, and blood metabolites in buffalo. Thirty-six lactating buffaloes were randomly assigned to four different groups, according to supplementation of FRS (only corn silage, FRS0) or with 15% (FRS15), 25% (FRS25), and 35% (FRS35) of forage rape silage instead of corn silage. The results showed that, compared to corn silage, forage rape silage has a lower carbohydrate but a higher protein concentration. The buffalo intake of dry matter and organic matter were improved linearly with the FRS increasing in the diet. The apparent total-tract digestibility (ATTD) of dry matter, organic matter, nitrogen, neutral detergent fiber, and acid detergent fiber also increased by the FRS supplementation compared with FRS0. Conversely, FRS supplementation decreased the propionic, butyric, and valeric acid contents and increased the acetic:propionic ratio and microbial protein content. Furthermore, FRS inclusion led to a significantly higher milk urea and non-fat milk solid content, higher blood glucose, total globulins, blood urea nitrogen, and lower blood high-density lipoprotein. These results suggested that FRS has high a nutritional value and digestibility, is a good feed resource, and showed favorable effects when supplemented with dairy buffalo ration.

To get an insight into the residual sodium content of Al–Mg alloys, three types of sodium-containing fluxes were introduced into the melt with different magnesium content. The increment, existing form and distribution of sodium in Al–Mg alloys with different magnesium content were analyzed. The results show that the influence of different sodium salts on the increment of sodium in Al–10Mg alloy is significantly different. The NaF raised the sodium level in Al–10Mg alloy to the highest extent, Na3AlF6 coming second, and NaCl did not have an obvious influence. The magnesium element in the aluminum melt was found to be the key factor leading to the increment of sodium level. After the salt fluxing treatment of aluminum alloy with different magnesium content, this increment would be proportional to the content of magnesium. EDS mapping indicates the sodium introduced by the fluxes was distributed in the form of Na-rich particles in Al–Mg alloys and preferentially located near Al3Mg2(β) phase in the situation of high magnesium content.

Background/Purpose: To compare the clinical efficacy and safety of nemonoxacin with levofloxacin in treating community-acquired pneumonia (CAP) in a Phase II clinical trial. Methods: One hundred ninety-two patients with CAP were randomized to receive oral nemonoxacin (500 mg or 750 mg) or levofloxacin (500 mg) once daily for 7â10 days. Clinical and bacteriological responses were determined at the test of cure (TOC) visit in the full analysis set (FAS). Results: The clinical cure rate of nemonoxacin (500 mg), nemonoxacin (750 mg), and levofloxacin (500 mg) was 93.3%, 87.3%, and 88.5%, respectively, in the FAS (n = 168), and 93.0%, 93.9%, and 88.9%, respectively in the per protocol set (n = 152). At the TOC visit, nemonoxacin at 500 mg and 750 mg was proven to be noninferior to levofloxacin at 500 mg in the FAS in terms of clinical efficacy. The overall bacteriological success rate was 83.3% in both nemonoxacin groups and 80.0% in the levofloxacin 500 mg group in the bacteriological FAS. The comprehensive efficacy rate was comparable among the three groups (87.5% for the nemonoxacin 500 mg group, 93.8% for the nemonoxacin 750 mg group, and 81.3% for the levofloxacin 500 mg group). Most drug-related adverse events were mild and transient, mainly gastrointestinal symptoms such as nausea and vomiting, transient neutropenia, and elevated liver enzymes. No drug-related serious adverse events occurred. Conclusion: Either 500 mg or 750 mg of oral nemonoxacin taken once daily for 7â10 days demonstrated high clinical and bacteriological success rates in Chinese adult patients with CAP. Nemonoxacin at 500 mg once daily for 7â10 days is recommended for future Phase III clinical trials.ClinicalTrials.gov identifier: NCT01537250. Keywords: clinical trial, community-acquired pneumonia, efficacy, nenomoxacin, safety

Abstract RNA sequencing has been extensively used to study specific gene expression patterns to discover potential key genes related to complex traits of interest in animals. Of note, a new regulatory mechanism builds a large-scale regulatory network among transcriptome, where lncRNAs act as competing endogenous RNAs (ceRNAs) to sponge miRNAs to regulate the expression of miRNA target genes post-transcriptionally. In this study, we sequenced the cDNA and sRNA libraries of nine liver samples from three Holstein cows during dry period, early lactation, and peak of lactation with HiSeq platform. As a result, we identified 665 genes, 57 miRNAs and 33 lncRNAs that displayed differential expression patterns across periods. Subsequently, a total of 41ceRNA pairs (lncRNA-mRNA) sharing 11 miRNAs were constructed including 30 differentially expressed genes. Importantly, 12 among them were presented in our large metabolic networks, and predicted to influence the lipid metabolism through insulin, PI3K-Akt, MAPK, AMPK, mTOR, and PPAR signaling pathways, thus, these genes were considered as the most promising candidates for milk fat formation. To our knowledge, this is first investigation to profile the ceRNA regulatory networks of liver transcriptome that could affect milk fat synthesis in bovine, providing a new view of the regulatory mechanism of RNAs.

Previous research regarding Holstein cows has mainly focused on increasing milk yield. However, in order to maximize the economical profits of Holstein cattle farming, it is necessary to fully take advantage of Holstein bulls to produce high-grade beef. The present study aims to investigate different transcriptomic profiling of Holstein bulls and steers, via high-throughput RNA-sequencing (RNA-seq). The growth and beef quality traits of Holstein steers and bulls were characterized via assessment of weight, rib eye area, marbling score, shear force and intramuscular fat percentage of the longissimus lumborum (LL) muscle. The results indicated that castration improved the meat quality, yet reduced the meat yield. Subsequently, RNA-seq of the LL muscle from Holstein steers and bulls revealed a total of 56 differentially expressed genes (DEGs). We performed the functional enrichment analysis in Gene Ontology (GO) annotations of the DEGs using GOseq R package software and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using KOBAS tool. Through the integrated analysis of DEGs with reported QTLs and SNPs, seven promising candidate genes potentially affecting the beef quality of LL muscle following castration were discovered, including muscle structural protein coding genes (MYH1, MYH4, MYH10) and functional protein coding genes (GADL1, CYP2R1, EEPD1, SHISA3). Among them, MYH10, GADL1, CYP2R1, EEPD1 and SHISA3 were novel candidate genes associated with beef quality traits. Notably, EEPD1 was associated with both meat quality and reproduction traits, thus indicating its overlapping role in responding to hormone change, and subsequently inducing beef quality improvement. Our findings provide a complete dataset of gene expression profile of LL in Holstein bulls and steers, and will aid in understanding how castration influence meat yield and quality.

Thorium (Th) is an associated ore of rare earth metals that is radioactive and harmful to the environment, but it is also a potential nuclear fuel replacement for uranium. The separation of Th from rare earth elements (REEs) is of great importance in environmental governance and clean-energy development. In this work, a monolithic cerium (Ce) doped silica aerogel-like with flexibility was synthesized using a low consumption and rapid technique, and it was used in a continuous solid-phase extraction as an adsorbent for the selective separation of Th/REEs. The batch adsorption experiments showed that the adsorption efficiency of Th(IV) can be up to 96% when abnormally high levels of metal ions (20 ppm) exist. Under the same conditions, the adsorption efficiency of REEs is at a near-zero level, which demonstrates the great selective separation of Th/REEs for the aerogel-like. The results also indicated that Th(IV) could desorb from the adsorbent in weak acidic media, which is friendly to the environment. Therefore, the material has application prospects for the separation of Th/REEs and removal of radioactive contamination from the environment. Keywords: Silica aerogel-like monoliths, Selective adsorption, Rare earth, Thorium, Monazite

Abstract Advanced interface materials made from petrochemical resources have been extensively investigated for organic solar cells (OSCs) over the past decades. These interface materials have demonstrated excellent performances in OSC devices. However, the limited resources, high‐cost, and non‐ecofriendly nature of petrochemical‐based interface materials restrict their commercial applications. Here, a facile and effective approach to prepare cellulose and its derivatives as a cathode interface layer for OSCs with enhanced performance from rice straw of agroforestry residues is demonstrated. By employing this carboxymethyl cellulose sodium (CMC) into OSCs, a highly efficient inverted OSC is constructed, and a power conversion efficiency (PCE) of 12.01% is realized using poly[(2,6‐(4,8‐bis(5‐(2‐ethyl‐hexyl)‐thiophen‐2‐yl)‐benzo[1,2‐b:4,5‐b′] dithiophene))‐alt‐(5,5‐(1′,3′‐di‐2‐thienyl‐5′,7‐bis(2‐ethylhexyl)benzo[1′,2′‐c: 4′,5′‐c′]dithiophene‐4,8‐dione): 3,9‐bis(2‐methylene‐((3‐(1, 1‐dicyanomethylene)‐6/7‐methyl)‐indanone))‐5,5,11,11‐tetrakis(4‐hexylphenyl)‐dithieno[2,3‐d: 2′,3′‐d′]‐s‐indaceno[1,2‐b: 5, 6‐b′]dithiophene as the active layer, which shows over 9.4% improvement in PCE compared to that of a device without the CMC layer (PCE = 10.98%), especially the enhancement in short‐circuit current. The improved current densities and PCEs are attributed to the reduced work function, enhanced absorption, and improved interfacial contact by using CMC and ZnO as co‐interface. This approach of fabricating interface materials from biorenewable sources for OSCs is simple, scalable, and cost‐effective, representing a promising direction for the development of smart interface and green electronics.

Abstract Background Pediatric myelodysplastic syndromes (MDS) display clonal genomic instability that can lead to acquisition of other hematological disorders, usually by loss of heterozygosity. Immunodeficiency caused by uniparental disomy (UPD) has not previously been reported. Methods We investigated a 13‐year‐old boy who suffered from recurrent infections and pancytopenia for 1 year. Both the comet assay and chromosome breakage analysis were normal, but the bone marrow showed evidence of dysplasia characteristic of MDS. With his normal sister as donor, he underwent failed hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) followed by successful HSCT with myeloablative conditioning (MAC). We used single nucleotide polymorphism (SNP) array, targeted gene panel, and whole exome sequencing to investigate the etiology of his disease. Results The molecular analyses revealed multiple regions of homozygosity, one region encompassing a homozygous missense variant of recombination activating gene 1 (RAG1) which was previously associated with severe immunodeficiency in infancy. This RAG1 mutation was heterozygous in the proband’s fingernail DNA, but was changed to homozygous in the proband’s marrow by somatic acquisition of UPD event. No other pathogenic driver mutation for MDS‐related genes was identified. Conclusion The hematological phenotype, somatic genomic instability, and response to HSCT MAC but not HSCT RIC deduced to a diagnosis of MDS type refractory cytopenia of children in this patient. His immunodeficiency was secondary to MDS due to somatic acquisition of homozygosity for known pathogenic RAG1 mutation.

Lactobacillus paracasei subsp. paracasei L1 was previously isolated from sweet potato sour liquid. This bacterial species specifically binds onto starch granular surfaces, triggering the enzymatic hydrolysis of raw starch. We investigated the functional and safety properties of strain L1 in vitro to establish its probiotic potential, and analyzed its effect on growth performance and intestinal microflora of chicken in feeding experiments. The optimal growth conditions of strain L1 included low pH and high concentrations of bile salts and NaCl. Its 1-, 2-, and 24-h autoaggregation values were 15.8 ± 1.2%, 20.4 ± 2.3%, and 47.2 ± 0.8%, respectively, with the surface hydrophobicity value at 560 nm of 38.1 ± 2.7%. Further, its adhesion rate to Caco-2 cells was 22.37 ± 1.44%. Strain L1 was resistant to erythromycin and azithromycin, but sensitive to other antibiotics tested. For the feeding experiments, 240 chickens with similar weights were randomly divided into a control (C) group and strain L1 (L) group and fed for 8 weeks. Strain L1 promoted the weight gain of chickens in L group. A significant increase in the population size of the two phyla and 23 genera in the small intestine was observed in the presence of strain L1 (P < 0.05), with 0 phyla and 4 genera showing significant increase in the cecum (P < 0.05). In the small intestine, the abundance of six functional genes at Kyoto Encyclopedia of Genes and Genomes (KEGG) level 2 and 49 genes at KEGG level 3 was significantly increased in group L (P < 0.05), with lesser changes noted in the cecum. An increase in the metabolic pathway functions, including enzyme families and the digestive system, was observed in the intestinal microbiota in the L group compared to the C group. However, the other metabolic pathway functions, including metabolism of fatty acid biosynthesis, as well as metabolism of glycerolipids and propanoate, increased in the cecal microbiota of the L group relative to the C group. These changes are most likely related to the changes in the gut microbiota composition. Collectively, strain L1 supplementation may promote growth performance and improve the intestinal microflora in chicken although further studies are needed to confirm this.

Auxin response factors (ARFs) play fundamental roles in modulating various biological processes including fruit development and abscission via regulating the expression of auxin response genes. Currently, little is known about roles of ARFs in litchi (Litchi chinensis Sonn.), an economically important subtropical fruit tree whose production is suffering from fruit abscission. In this study, a genome-wide analysis of ARFs was conducted for litchi, 39 ARF genes (LcARFs) were identified. Conserved domain analysis showed that all the LcARFs identified have the signature B3 DNA-binding (B3) and ARF (Aux_rep) domains, with only 23 members having the dimerization domain (Aux_IAA). The number of exons in LcARF genes ranges from 2 to 16, suggesting a large variation for the gene structure of LcARFs. Phylogenetic analysis showed that the 39 LcARFs could be divided into three main groups: class I, II, and III. In total, 23 LcARFs were found to be potential targets of small RNAs, with three conserved and one novel miRNA-ARF (miRN43-ARF9) regulatory pathways discovered in litchi. Expression patterns were used to evaluate candidate LcARFs involved in various developmental processes, especially in flower formation and organ abscission. The results revealed that most ARF genes likely acted as repressors in litchi fruit abscission, that is, ARF2D/2E, 7A/7B, 9A/9B, 16A/16B, while a few LcARFs, such as LcARF5A/B, might be positively involved in this process. These findings provide useful information and resources for further studies on the roles of ARF genes in litchi growth and development, especially in the process of fruit abscission.

Seed storability is a main agronomically important trait to assure storage safety of grain and seeds in rice. Although many quantitative trait loci (QTLs) and associated genes for rice seed storability have been identified, the detailed genetic mechanisms of seed storability remain unclear in rice. In this study, a genome-wide association study (GWAS) was performed in 456 diverse rice core collections from the 3K rice genome. We discovered the new nine QTLs designated as qSS1-1, qSS1-2, qSS2-1, qSS3-1, qSS5-1, qSS5-2, qSS7-1, qSS8-1, and qSS11-1. According to the analysis of the new nine QTLs, our results could well explain the reason why seed storability of indica subspecies was superior to japonica subspecies in rice. Among them, qSS1-2 and qSS8-1 were potentially co-localized with a known associated qSS1/OsGH3-2 and OsPIMT1, respectively. Our results also suggest that pyramiding breeding of superior alleles of these associated genes will lead to new varieties with improved seed storability in the future.

The increasing consumption of regenerated cellulose, in particular the viscose fiber, has led to a significant development of dissolving pulps in the last decade. In this review paper, the current status of dissolving pulp with respects to raw materials, manufacturing processes, and some key issues are discussed. Non-wood materials and the process concept of upgrading paper-grade pulp into dissolving pulp are also included. Some recent developments related to the analytical methods of the purity and molecular weight distribution based on the ion chromatography and gel permeation chromatography are discussed. Finally, further processing improvements of purification, such as mechanical, chemical, and enzymatic treatment, and their combinations during the manufacturing process of dissolving pulp, are included.

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.

Objective. Most patients of acute ischemic stroke (AIS) receive treatments in the department of emergency in China. We aimed to examine the status of AIS diagnosis and treatment and the impact of green pathway operation in different regions of China. Methods. In this nationwide survey, information regarding the emergency care of AIS was collected from 451 hospitals in different regions of China, by interviewing 484 physicians from these hospitals. Structured questionnaire was used to explore the status of AIS care and impact of the green pathway. Results. 445 hospitals from 18 provinces, 4 municipalities, and 3 ethnic autonomous regions in China were included in the present study. Overall, the proportion of door-to-needle time (DNT) less than 60 min was 66.08% in the enrolled hospitals (n = 298). Stratified by regions, the results suggested that hospitals located in East regions had shorter DNT time (P=0.036), and more proportion of rtPA (P

Depression has been correlated with metabolic disorders, and the gut microbiota and its metabolites have been reported to be key factors affecting metabolic disorders. Several metabolites generated by the gut microbiota have been reported to exert antidepressant-like effects, including the short chain fatty acid (SCFA) butyrate. However, recent work has suggested that the abundance of butyrate is not significantly changed in neither human nor experimental animals with depression, and butyrate has been reported to decrease upon the administration of prebiotics with antidepressant-like effects. Supplementation of endogenous metabolites that are unchanged in depression may induce additional metabolic disorders and may lead to poorer clinical outcomes. However, the endogenous metabolites that are imbalanced in depression may include several antidepressant candidates that could circumvent these problems. In this study, we used GC-MS spectrometry to study the fecal metabolome of rats under Chronic Unpredictable Mild Stress (CUMS). We carried out static and dynamic metabolomics analyses to identify the differential metabolites between the CUMS rats and control rats. We identified propionic acid, rather than butyric acid, as a differential metabolite of the CUMS rats. Consistent with this, a 1-week intrarectal administration of sodium propionate (NaP, the salt form of propionic acid) induced antidepressant-like effects and partially rebalanced the plasma metabolome. The antidepressant-like effects of NaP were correlated with differential rescue of neurotransmitters in the prefrontal cortex, which may be achieved through the reduction of catabolism of noradrenaline, tryptophan and dopamine, rather than serotonin. These findings support NaP as a potential candidate in fighting depression by administering an endogenous metabolite.

To improve fuel use and energy-conversion efficiency and reduce the emission of pollutants, oxygenation is now deemed an effective chemical treatment of water in supercritical and ultra-supercritical power plants. Supercritical water with dissolved oxygen significantly enhances the oxidation rate of steels in the main steam pipeline and super-heater header. However, at the atomic scale, the mechanism of metal oxidation in supercritical water containing dissolved oxygen is unknown and has not been investigated by simulation. In this work, the oxidation of iron in supercritical water containing dissolved oxygen is studied by ab initio molecular dynamics and first principles calculations. The results indicate that dissolved oxygen in supercritical water dramatically accelerates the oxidation of iron. With the help of oxygen, the decomposition of water occurs on the iron surface, thereby producing more iron oxides and iron hydroxides. Additionally, hydrogen peroxide (H2O2) forms as an intermediate product, instantaneously decomposing to form iron hydroxides, and this is another reason for the enhancement in the oxidation of steel by supercritical water containing dissolved oxygen. Based on the results from ab initio molecular dynamics, we develop herein typical models of water molecules and oxygen molecules reacting directly on the iron surface and then carry out first-principles calculations. The results show that water decomposes on the iron surface only with the assistance of adjacent oxygen molecules and in the absence of surrounding water molecules. This investigation deepens our understanding of the oxidation mechanism of metal in supercritical water containing dissolved oxygen. The ideas and methods implemented in this work can also be used to study other materials exposed to supercritical water involving oxygen.

Summary: Background: The age-specific association between blood pressure and vascular disease has been studied mostly in high-income countries, and before the widespread use of brain imaging for diagnosis of the main stroke types (ischaemic stroke and intracerebral haemorrhage). We aimed to investigate this relationship among adults in China. Methods: 512 891 adults (59% women) aged 30–79 years were recruited into a prospective study from ten areas of China between June 25, 2004, and July 15, 2008. Participants attended assessment centres where they were interviewed about demographic and lifestyle characteristics, and their blood pressure, height, and weight were measured. Incident disease was identified through linkage to local mortality records, chronic disease registries, and claims to the national health insurance system. We used Cox regression analysis to produce adjusted hazard ratios (HRs) relating systolic blood pressure to disease incidence. HRs were corrected for regression dilution to estimate associations with long-term average (usual) systolic blood pressure. Findings: During a median follow-up of 9 years (IQR 8–10), there were 88 105 incident vascular and non-vascular chronic disease events (about 90% of strokes events were diagnosed using brain imaging). At ages 40–79 years (mean age at event 64 years [SD 9]), usual systolic blood pressure was continuously and positively associated with incident major vascular disease throughout the range 120–180 mm Hg: each 10 mm Hg higher usual systolic blood pressure was associated with an approximately 30% higher risk of ischaemic heart disease (HR 1·31 [95% CI 1·28–1·34]) and ischaemic stroke (1·30 [1·29–1·31]), but the association with intracerebral haemorrhage was about twice as steep (1·68 [1·65–1·71]). HRs for vascular disease were twice as steep at ages 40–49 years than at ages 70–79 years. Usual systolic blood pressure was also positively associated with incident chronic kidney disease (1·40 [1·35–1·44]) and diabetes (1·14 [1·12–1·15]). About half of all vascular deaths in China were attributable to elevated blood pressure (ie, systolic blood pressure >120 mm Hg), accounting for approximately 1 million deaths (

Summary: Background: China has high stroke rates despite the population being relatively lean. Uncertainty persists about the relevance of adiposity to risk of stroke types. We aimed to assess the associations of adiposity with incidence of stroke types and effect mediation by blood pressure in Chinese men and women. Methods: The China Kadoorie Biobank enrolled 512 891 adults aged 30–79 years from ten areas (five urban and five rural) during 2004–08. During a median 9 years (IQR 8–10) of follow-up, 32 448 strokes (about 90% confirmed by neuroimaging) were recorded among 489 301 participants without previous cardiovascular disease. Cox regression analysis was used to produce adjusted hazard ratios (HRs) for ischaemic stroke (n=25 210) and intracerebral haemorrhage (n=5380) associated with adiposity. Findings: Mean baseline body-mass index (BMI) was 23·6 kg/m2 (SD 3·2), and 331 723 (67·8%) participants had a BMI of less than 25 kg/m2. Throughout the range examined (mean 17·1 kg/m2 [SD 0·9] to 31·7 kg/m2 [2·0]), each 5 kg/m2 higher BMI was associated with 8·3 mm Hg (SE 0·04) higher systolic blood pressure. BMI was positively associated with ischaemic stroke, with an HR of 1·30 (95% CI 1·28–1·33 per 5 kg/m2 higher BMI), which was generally consistent with that predicted by equivalent differences in systolic blood pressure (1·25 [1·24–1·26]). The HR for intracerebral haemorrhage (1·11 [1·07–1·16] per 5 kg/m2 higher BMI) was less extreme, and much weaker than that predicted by the corresponding difference in systolic blood pressure (1·48 [1·46–1·50]). Other adiposity measures showed similar associations with stroke types. After adjustment for usual systolic blood pressure, the positive associations with ischaemic stroke were attenuated (1·05 [1·03–1·07] per 5 kg/m2 higher BMI); for intracerebral haemorrhage, they were reversed (0·73 [0·70–0·77]). High adiposity (BMI >23 kg/m2) accounted for 14·7% of total stroke (16·5% of ischaemic stroke and 6·7% of intracerebral haemorrhage). Interpretation: In Chinese adults, adiposity was strongly positively associated with ischaemic stroke, chiefly through its effect on blood pressure. For intracerebral haemorrhage, leanness, either per se or through some other factor (or factors), might increase risk, offsetting the protective effects of lower blood pressure. Funding: UK Wellcome Trust, UK Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, Chinese National Natural Science Foundation.

Summary: Background: In developed countries, smoking is associated with increased risk of diabetes. Little is known about the association in China, where cigarette consumption has increased (first in urban, then in rural areas) relatively recently. Moreover, uncertainty remains about the effect of smoking cessation on diabetes in China and elsewhere. We aimed to assess the associations of smoking and smoking cessation with risk of incident diabetes among Chinese adults. Methods: The prospective China Kadoorie Biobank enrolled 512 891 adults (59% women) aged 30–79 years during 2004–08 from ten diverse areas (five urban and five rural) across China. Participants were interviewed at study assessment clinics, underwent physical measurements, and had a non-fasting blood sample taken. Participants were separated into four categories according to smoking history: never-smokers, ever-regular smokers, ex-smokers, and occasional smokers. Incident diabetes cases were identified through linkage with diabetes surveillance systems, the national health insurance system, and death registries. All analyses were done separately in men and women and Cox regression was used to yield adjusted hazards ratios (HRs) for diabetes associated with smoking. Findings: 68% (n=134 975) of men ever smoked regularly compared with 3% (n=7811) of women. During 9 years' follow-up, 13 652 new-onset diabetes cases were recorded among 482 589 participants without previous diabetes. Among urban men, smokers had an adjusted HR of 1·18 (95% CI 1·12–1·25) for diabetes. HRs increased with younger age at first smoking regularly (1·12, 1·20, and 1·27 at ≥25 years, 20–24 years, and

Vascular endothelial cells produce reactive oxygen species (ROS) during the process of energy metabolism in aerobic respiration. A growing body of evidence indicates that excessive ROS is implicated in the pathogenesis of cardiovascular diseases including atherosclerosis. The newly synthesized halophenol, 2,4′,5′-trihydroxyl-5,2′-dibromo diphenylmethanone (TDD), exhibits antioxidative and cytoprotective activities in vitro. In this study, the protective effect of TDD against hydrogen peroxide (H2O2)-induced oxidative injury of EA.hy926 cells was investigated. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyltetrazolium bromide (MTT) assay, while the effect of TDD on the transcription profile of EA.hy926 cells subjected to H2O2-induced oxidative injury was evaluated by microarray analysis. Several signaling pathways, including apoptosis, were significantly associated with TDD. Flow cytometric analysis was used to evaluate anti-apoptotic effect of TDD. Subsequently, RT-PCR and Western blot were used to detect the expressions of the apoptosis-associated protein, Bcl-2 and Bax. Meanwhile the expression of cleaved caspase-3, an executioner of apoptosis, was also detected by Western blot. The results showed that pretreatment of EA.hy926 cells with TDD prevented the decrease of cell viability induced by H2O2, and attenuated H2O2-induced elevation of Bax and cleaved caspase-3 while increased Bcl-2 expressions. In summary, TDD inhibited H2O2-induced oxidative injury of EA.hy926 cells through negative regulation of apoptosis. These findings suggest that TDD is a potential candidate for therapeutic intervention in oxidative stress-associated cardiovascular diseases.

In China, alkaline peroxide mechanical pulping performed with refiner-chemical preconditioning (P-RC APMP) is well known to produce fiber with high bulk, opacity, and light scattering coefficient but weak bonding and strength properties. In this study, the characteristics of different P-RC APMP fiber fractions were investigated, and their effects on bonding strength properties were determined. The results showed that there was only 5.8% R30 fiber fraction and 14.1% P100/R200 fiber fraction, and the specific surface area increased from R30 to P100/R200. The tensile index increased by 51.85% and the bonding index increased by 15.35%, when the fibers were changed from the R30 fraction to the P100/R200 fraction. The short fiber fraction (P100/R200 fraction) had smaller fiber length and coarseness but larger specific surface area and greater surface charge density than the long fiber fraction (R30 fraction). The fiber specific surface area and surface charge density made significant contributions to the bonding capacity, whereas fiber coarseness and length were negatively correlated with the tensile index.

BackgroundBreastfeeding confers substantial benefits to child health and has also been associated with lower risk of maternal cardiovascular diseases (CVDs) in later life. However, the evidence on the effects of CVD is still inconsistent, especially in East Asians, in whom the frequency and duration of breastfeeding significantly differ from those in the West. Methods and ResultsIn 2004–2008, the nationwide China Kadoorie Biobank recruited 0.5 million individuals aged 30 to 79 years from 10 diverse regions across China. During 8 years of follow‐up, 16 671 incident cases of coronary heart disease and 23 983 cases of stroke were recorded among 289 573 women without prior CVD at baseline. Cox regression yielded adjusted hazard ratios (HRs) and 95% CIs for incident CVD by breastfeeding. Overall, ≈99% of women had given birth, among whom 97% reported a history of breastfeeding, with a median duration of 12 months per child. Compared with parous women who had never breastfed, ever breastfeeding was associated with a significantly lower risk of CVD, with adjusted HRs of 0.91 (95% CI, 0.84–0.99) for coronary heart disease and 0.92 (95% CI, 0.85–0.99) for stroke. Women who had breastfed for ≥24 months had an 18% (HR, 0.82; 0.77–0.87) lower risk of coronary heart disease and a 17% (HR, 0.83; 0.79–0.87) lower risk of stroke compared with women who had never breastfed. Among women who ever breastfed, each additional 6 months of breastfeeding per child was associated with an adjusted HR of 0.96 (95% CI, 0.94–0.98) for coronary heart disease and 0.97 (95% CI, 0.96–0.98) for stroke. ConclusionsAmong Chinese women, a history of breastfeeding was associated with an ≈10% lower risk of CVD in later life and the magnitude of the inverse association was stronger among those with a longer duration of breastfeeding.

Modifications to histones, including acetylation and methylation processes, play crucial roles in the regulation of gene expression in plant development as well as in stress responses. However, limited information on the enzymes catalyzing histone acetylation and methylation in non-model plants is currently available. In this study, several histone modifier (HM) types, including six histone acetyltransferases (HATs), 11 histone deacetylases (HDACs), 48 histone methyltransferases (HMTs), and 22 histone demethylases (HDMs), are identified in litchi (Litchi chinensis Sonn. cv. Feizixiao) based on similarities in their sequences to homologs in Arabidopsis (A. thaliana), tomato (Solanum lycopersicum), and rice (Oryza sativa). Phylogenetic analyses reveal that HM enzymes can be grouped into four HAT, two HDAC, two HMT, and two HDM subfamilies, respectively, while further expression profile analyses demonstrate that 17 HMs were significantly altered during fruit abscission in two field treatments. Analyses reveal that these genes exhibit four distinct patterns of expression in response to fruit abscission, while an in vitro assay was used to confirm the HDAC activity of LcHDA2, LcHDA6, and LcSRT2. Our findings are the first in-depth analysis of HMs in the litchi genome, and imply that some are likely to play important roles in fruit abscission in this commercially important plant.

Abscission in plants is an active and highly coordinated physiological process in which organs abscise from the plant body at the abscission zone (AZ) in responding to either developmental or environmental cues. Litchi (Litchi chinensis Sonn.) is an important economic fruit crop widely grown in Southeast Asia particularly in South China. However, the excessive fruit drop during fruit development is a major limiting factor for litchi production. Thus, it is an important agricultural concern to understand the mechanisms underlying the fruit abscission in litchi. Here, we present a review focusing on the molecular events involved in the fruitlet abscission. We also highlight the recent advances on genes specifically associated with fruit abscission and perspectives for future research.

Nicotinamide adenine dinucleotide (NAD), one of the most important coenzymes in the cells, is a substrate of the signaling enzyme CD38, by which NAD is converted to a second messenger, cyclic ADP-ribose, which releases calcium from intracellular calcium stores. Starting with 2′-deoxy-2′-fluoroarabinosyl-β-nicotinamide adenine dinucleotide (ara-F NAD), a series of NAD analogues were synthesized and their activities to inhibit CD38 NAD glycohydrolase (NADase) were evaluated. The adenosine-modified analogues showed potent inhibitory activities, among which 2′-deoxy-2′-fluoroarabinosyl-β-nicotinamide guanine dinucleotide (ara-F NGD) was the most effective one. The structure-activity relationship of NAD analogues was also discussed.

In recent years, the alkaline peroxide mechanical pulping performed with refiner-chemical preconditioning (P-RC APMP) has obtained a wide application in many paper grades in China. This is due to such desirable pulp characteristics as its high bulk, opacity, and light scattering coefficient. However, compared with its bleached chemical pulps, the poplar P-RC APMP has weak bonding strength, which limits its application in value-added products. Usually, the interfiber bonding abilities of different fiber fractions are quite different. In this study, the page bonding strength index (B) and the interfiber bonding abilities (shear bond strength per unit area (b) and relative bonding area (RBA)) of different P-RC APMP fiber fractions were extrapolated by the traditional Page Equation. The results show that the higher B could be obtained when the fiber fraction was shorter or smaller. The same trend was observed for b and RBA. Wet pressing was used to improve the bonding ability, and higher pressure of wet pressing or shorter fiber fraction can lead to obviously higher tensile strength.

In recent years, distributed generation (DG) technology has developed rapidly. Renewable energy, represented by wind energy and solar energy, has been widely studied and utilized. In order to give full play to the advantages of distributed generation and to meet the challenges of DG access to the power grid, the multi-scenario analysis method commonly used in DG optimal allocation method is studied in this paper. In order to solve the problems that may arise from using large-scale scenes in the planning of DG considering uncertainties by using multi-scene analysis method, the cluster analysis method suitable for large-scale scene reduction in scene reduction method is introduced firstly, and then an improved clustering algorithm is proposed. The validity of the scene reduction method is tested, and the feasibility of the reduction method is verified. Finally, the method mentioned in this paper is compared with other commonly used methods through IEEE-33 node system.

The effect of annealing temperature on microstructure and mechanical properties of a cold-rolled Al−10Mg alloy has been investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), electron backscatter diffraction (EBSD) and tensile testing. The results showed that supersaturated Mg precipitated along grain boundaries and deformation bands during annealing treatment and precipitation size and the concentration of solid solution Mg atoms increased with the rising of annealing temperature. When annealed at low temperature, accumulation and annihilation of dislocations were the primary way of recovery; as temperature increased to 300 °C, recrystallized grains were formed around the large size β phase through particle-stimulated nucleation. A high ultimate strength (550 MPa) and a middle ductility (14%) were obtained when the Al−10Mg alloy was annealed at 200 °C for 1 h. The abnormal decrease of elongation when the Al−10Mg alloy was annealed at 250−300 °C was due to the formation of a continuous network distribution of large size β phase particles along grain boundaries.

Due to the capability of utilizing light energy to drive chemical reactions, photocatalysis has been widely accepted as a green technology to help us address the increasingly severe environment and energy issues facing human society. To date, a large amount of research has been devoted to enhancing the properties of photocatalysts. As reported, coupling semiconductors with metals is one of the most effective methods to achieve high-performance photocatalysts. The excellent properties of metal/semiconductor (M/S) nanocomposite photocatalysts originate in two aspects: (i) improved charge separation at the metal-semiconductor interface; and (ii) increased absorption of visible light due to the surface plasmon resonance of metals. So far, many M/S nanocomposite photocatalysts with different structures have been developed for the application in environmental remediation, selective organic transformation, hydrogen evolution, and disinfection. Herein, we will give a review on the M/S nanocomposite photocatalysts, regarding their fundamentals, structures (as well as their typical synthetic approaches), applications and properties. Finally, we will also present our perspective on the future development of M/S nanocomposite photocatalysts.

Understanding host antibody response is crucial for predicting disease severity and for vaccine development. We investigated antibody responses against influenza A(H7N9) virus in 48 serum samples from 21 patients, including paired samples from 15 patients. IgG against subtype H7 and neutralizing antibodies (NAbs) were not detected in acute-phase samples, but ELISA geometric mean titers increased in convalescent-phase samples; NAb titers were 20–80 (geometric mean titer 40). Avidity to IgG against subtype H7 was significantly lower than that against H1 and H3. IgG against H3 was boosted after infection with influenza A(H7N9) virus, and its level in acute-phase samples correlated with that against H7 in convalescent-phase samples. A correlation was also found between hemagglutinin inhibition and NAb titers and between hemagglutinin inhibition and IgG titers against H7. Because of the relatively weak protective antibody response to influenza A(H7N9), multiple vaccinations might be needed to achieve protective immunity. Download MP3 Length: 1:45

CD38 is a multifunctional enzyme/receptor expressed in a variety of mammalian tissues, regulating a wide range of physiological functions. Beginning with the previously reported compound 1, an inhibitor of human CD38 NADase, we synthesized a series of indole-based NH-substituted derivatives with modifications on alkyl chains, changes in substituent groups on aromatic rings, and differences in carbon chain lengths. Compounds 10, 13, 16 and 34 exhibited moderate inhibition of human CD38 NADase. Analysis of the structure-activity relationships showed that the phenylpropionyl moiety was very important for the inhibitory activity. This study provides information for the rational design of CD38 inhibitors.

During August 2006–April 2010, in Beijing, China, 2 rare human enterovirus serotypes, coxsackievirus A21 and enterovirus 68, were detected most frequently in human enterovirus–positive adults with acute respiratory tract infections. Thus, during some years, these 2 viruses cause a substantial proportion of enterovirus-associated adult acute respiratory tract infections.

Background and objective Lung cancer is the leading cause of cancer-related death worldwide. Because the locations of peripheral lung cancer are special, diagnosis of peripheral lung cancer is difficult. The aim of this study was to evaluate diagnostic value of transbronchial lung biopsy (TBLB) in peripheral lung cancer. MethodsTransbronchial lung biopsy (TBLB) were performed in 78 cases of peripheral lung cancer which could not be observed by bronchoscope, 42 cases among whom were diagnosed by pathology and cytologic examination. Thirty-six cases of peripheral lung cancer were not able to be diagnosed by TBLB, 22 cases among them were diagnosed by percutaneous lung biopsy (PNLB), and 14 cases being left were diagnosed by surgical operation, lymphadenopathy biopsy, pleura biopsy and sputum cytologic examination successively. Results The positive rate produced by transbronchial lung biopsy, brush biopsy were 53.8% and 8.9% respectively. The total positive rate was 57.7%. The positive rate produced by TBLB was higher than that of brush biopsy (P

The major therapeutic strategy used to treat exacerbated cystic fibrosis (CF) is antibiotic treatment. As this approach easily generates antibiotic-resistant strains of opportunistic bacteria, optimized antibiotic therapies are required to effectively control chronic and recurrent bacterial infections in CF patients. A promising future for the proper use of antibiotics is the management of lung microbiota. However, the impact of antibiotic treatments on CF microbiota and vice versa is not fully understood. This study analyzed 718 sputum samples from 18 previous studies to identify differences between CF and uninfected lung microbiota and to evaluate the effects of antibiotic treatments on exacerbated CF microbiota. A reference-based OTU (operational taxonomic unit) picking method was used to combine analyses of data generated using different protocols and platforms. Findings show that CF microbiota had greater richness and lower diversity in the community structure than uninfected control (NIC) microbiota. Specifically, CF microbiota showed higher levels of opportunistic bacteria and dramatically lower levels of commensal bacteria. Antibiotic treatment affected exacerbated CF microbiota notably but only transiently during the treatment period. Limited decrease of the dominant opportunistic bacteria and a dramatic decrease of commensal bacteria were observed during the antibiotic treatment for CF exacerbation. Simultaneously, low abundance opportunistic bacteria were thriving after the antibiotic treatment. The inefficiency of the current antibiotic treatment against major opportunistic bacteria and the detrimental effects on commensal bacteria indicate that the current empiric antibiotic treatment on CF exacerbation should be reevaluated and optimized.

Extrahepatic cholangiocarcinoma (EHCC) is a refractory malignancy with poor prognosis due to its early invasion, metastasis and recurrence after operation. Therefore, understanding the mechanisms of invasion and metastasis is the key to the development of new and effective therapeutic strategies for EHCC. In the present study we demonstrated that miR-221 promoted EHCC invasion and metastasis through targeting PTEN and formed a positive feedback loop with β-catenin/c-Jun signaling pathway. We found miR-221 was upregulated in EHCC specimens and CC cell lines. Moreover, miR-221 was found strongly associated with the metastasis and prognosis of EHCC patients. The expression of PTEN was downregulated in EHCC patients and CC cell lines, and was further demonstrated as one of the downstream targets of miR-221. In addition, our data indicated that β-catenin activated miR-221 through c-jun, while miR-221 enhanced β-catenin signaling induced-epithelial-mesenchymal transition (EMT) by targeting PTEN, hence forming a positive feedback loop in EHCC cell lines. In conclusion, our results suggested that miR-221 promotes EMT through targeting PTEN and forms a positive feedback loop with β-catenin/c-Jun signaling pathway in EHCC.