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Background: Pyroptosis of the renal tubular epithelial cells (RTECs) and interstitial inflammation are central pathological characteristics of acute kidney injury (AKI). Pyroptosis acts as a pro-inflammatory form of programmed cell death and is mainly dependent on activation of the NLRP3 inflammasome. Previous studies revealed that acetyl-CoA synthetase 2 (ACSS2) promotes inflammation during metabolic stress suggesting that ACSS2 might regulate pyroptosis and inflammatory responses of RTECs in AKI. Methods and results: The expression of ACSS2 was found to be significantly increased in the renal epithelial cells of mice with lipopolysaccharide (LPS)-induced AKI. Pharmacological and genetic strategies demonstrated that ACSS2 regulated NLRP3-mediated caspase-1 activation and pyroptosis through the stimulation of the KLF5/NF-κB pathway in RTECs. The deletion of ACSS2 attenuated renal tubular pathological injury and inflammatory cell infiltration in an LPS-induced mouse model, and ACSS2-deficient mice displayed impaired NLRP3 activation-mediated pyroptosis and decreased IL-1β production in response to the LPS challenge. In HK-2 cells, ACSS2 deficiency suppressed NLRP3-mediated caspase-1 activation and pyroptosis through the downregulation of the KLF5/NF-κB pathway. The KLF5 inhibitor ML264 suppressed NF-κB activity and NLRP3-mediated caspase-1 activation, thus protecting HK-2 cells from LPS-induced pyroptosis. Conclusion: Our results suggested that ACSS2 regulates activation of the NLRP3 inflammasome and pyroptosis by inducing the KLF5/NF-κB pathway in RTECs. These results identified ACSS2 as a potential therapeutic target in AKI. We found that the expression of ACSS2 was significantly increased in RTECs in septic AKI. ACSS2-deficient mice displayed resistance to renal damage in this model. ACSS2 regulated NLRP3-mediated caspase-1 activation and pyroptosis through the KLF5/NF-κB pathway in RTECs. Pharmacological inhibition of KLF5 suppressed NLRP3 activation and caspase-1 cleavage by downregulating of NF-κB. Our results suggest that ACSS2 is a pro-pathogenic mediator of cell pyroptosis of RTECs and renal inflammation in sepsis-induced AKI. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is an aggressive and fatal disease caused by a subset of cancer stem cells (CSCs). It is estimated that there are approximately 100 000 long noncoding RNAs (lncRNAs) in humans. However, the mechanisms by which lncRNAs affect tumor stemness remain poorly understood. In the present study, it is found that DIO3OS is a conserved lncRNA that is generally downregulated in multiple cancers, including HCC, and its low expression correlates with poor clinical outcomes in HCC. In in vitro cancer cell lines and an in vivo spontaneous HCC mouse model, DIO3OS markedly represses tumor development via its suppressive role in CSCs through downregulation of zinc finger E‐box binding homeobox 1 (ZEB1). Interestingly, DIO3OS represses ZEB1 post‐transcriptionally without affecting its mRNA levels. Subsequent experiments show that DIO3OS interacts with the NONO protein and restricts NONO‐mediated nuclear export of ZEB1 mRNA. Overall, these findings demonstrate that the DIO3OS‐NONO‐ZEB1 axis restricts HCC development and offers a valuable candidate for CSC‐targeted therapeutics for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer (PC) is one of the most lethal malignancies across the world. More than 80% patients are diagnosed at an advanced stage with limited treatment options. PC has the highest frequency of developing cancer cachexia (CC)–sarcopenia (SC) syndrome, but there is no optimal efficient intervention for CC or SC targeting their complicated biological and irreversible processes. As a result, identifying the clinicopathological features and patient characteristics in each advanced PC patient with CC and/or SC is urgently needed to distinguish different wasting phenotypes or body composition and thus support precision medicine and achieve optimal outcomes. We performed a retrospective cohort study of 232 advanced PC patients to determine the differential clinical characteristics of CC and SC and the overlap of CC- or SC-related factors in each patient. The impacts of CC, SC, and their relevant factors on the outcomes of PC patients were also evaluated. Pancreatic cancer (PC) has the highest frequency of developing cancer cachexia (CC)–sarcopenia (SC) syndrome, which negatively influences patients' outcome, quality of life, and tolerance/response to treatments. However, the clinical impacts of CC, SC, and their associated factors on outcomes for advanced PC has yet to be fully investigated. A total of 232 patients were enrolled in this study for the retrospective review of their clinical information and the measurement of skeletal muscle areas at the third lumber vertebra by computed tomography scan to identify CC or SC. The association and concurrent occurrence of clinicopathological features in each patient, prevalence rates, and prognosis with the CC or SC were calculated. CC and SC were observed in 83.6% (n = 194) and 49.1% (n = 114) of PC patients, respectively. Low hemoglobin levels more often occurred in CC patients than in non-CC patients (p = 0.014). Older age (p = 0.000), female gender (p = 0.024), low body mass index (BMI) values (p = 0.004), low hemoglobin levels (p = 0.036), and low albumin levels (p = 0.001) were more often found in SC patients than in non-SC patients. Univariate and multivariate analyses showed that CC was an independent poor prognostic factor of overall survival (OS) and progression-free survival for all patients, the chemotherapy (C/T) subgroup, and the high BMI subgroup. Meanwhile, SC was an independent predictor of poor OS for the subgroups of C/T or high BMI but not for all patients. These findings reveal the clinical differences for CC and SC and provide useful information for predicting the prognosis of advanced PC patients and conducting personalized medicine. [ABSTRACT FROM AUTHOR]

Objective. To get the spatio-temporal distribution of the syphilis epidemic in 31 provinces, municipalities directly under the Central Government and autonomous regions of the mainland of China in 2017. Methods. The data of syphilis incidence in 31 provinces, municipalities and autonomous regions of the mainland of China in 2017 were obtained from the China Public Health Science Data Center, and the time distrbution characteristics of the incidence rates were described. The global Moran's I index and Anselin local Moran's I index were used to analyze the spatial cluster characteristics of the syphilis cases, and then space-time scan analysis based on Poisson distribution was used to explore the spatio-temporal distribution characteristics. Results. In 2017, the number of syphilis cases in the 31 provinces, municipalities, and autonomous regions of the mainland of China was 475 860, and the incidence rate was 34.49/100 000. Latent syphilis accounted for most of the cases, reaching 76.78% (365 353/475 860). August had the highest incidence rate. For the spatial distribution, Xinjiang Uygur Autonomous Region was the provincial-level unit with the highest incidence rate of syphilis, reaching 91.80/100 000. The incidence rates of latent, secondary, tertiary, and congenital syphilis appeared with positive spatial autocorrelation (all P<0.05). The high-high clusters of secondary and tertiary syphilis appeared in Shanghai, Jiangsu, and Zhejiang (all P<0.05), respectively, while the high-high clusters of congenital syphilis appeared in Xinjiang and Tibet (P=0.000). The results of space-time scan analysis showed that the main cluster appeared from April to September in Fujian, Jiangxi, Zhejiang, Shanghai, Jiangsu, Hunan, Anhui, and Guangdong (P=0.000). Compared with the outside area, the relative risk of syphilis in this cluster was 1.59 times. Conclusion. The incidence rate of syphilis in China is relatively high. There are differences in the types and periods of syphilis prevention and control among provinces, municipalities and autonomous regions. From April to September, Fujian, Jiangxi, Zhejiang, Shanghai, Jiangsu, Hunan, Anhui and Guangdong are the key areas for syphilis prevention and control in the mainland of China. [ABSTRACT FROM AUTHOR]

The aim of present study was to evaluate the potential effects of Rhodiola crenulata oral liquid (RCOL) on exhaustive exercise (EE)-induced fatigue in mice. Male Institute of Cancer Research mice from five treatment groups (n=10 per group) were orally administered with sterilized water for the Control and EE groups and/or RCOL at doses of 1.02, 3.03 and 6.06 ml/kg/day, once daily for 2 weeks. Anti-fatigue activity was subsequently evaluated by measuring the levels of creatine kinase (CK), lactic acid (LA), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and total anti-oxidative capability (T-AOC). Histopathology was assessed using hematoxylin and eosin staining. Ultrastructures of mitochondria were observed by transmission electron microscopy. Energy supply capacity was assessed using citrate synthase (CS), succinate dehydrogenase (SDH), Na+-K+-ATPase, and liver and quadriceps glycogen content assays. Expression levels of mRNA and protein associated with mitophagy in the skeletal muscle were measured by reverse transcription-quantitative PCR and western blotting, respectively. RCOL was observed to markedly inhibit fatigue-induced oxidative stress by increasing the activities of SOD, CAT and T-AOC, whilst reducing the accumulation of LA, CK, LDH and MDA. Histological analysis of the quadriceps femoris tissue suggested increased numbers of muscle fibers in the RCOL groups compared with those in the EE group. RCOL administration was found to reverse EE-induced mitochondrial structural damage and alleviated defects inflicted onto the energy supply mechanism by increasing CS, SDH, Na+-K+-ATPase and glycogen levels. Additionally, RCOL reduced the protein expression of PTEN-induced kinase 1 (PINK1), Parkin, microtubule-associated proteins 1A/1B light chain 3, sequestosome 1 and ubiquitin, whilst lowering the gene expression of PINK1 and Parkin. Taken together, results from the present study clarified the anti-fatigue effect of RCOL, where the underlying mechanism may be associated with increased antioxidant activity, enhanced energy production and the inhibition of mitophagy by suppressing the PINK1/Parkin signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes. [ABSTRACT FROM AUTHOR]

Biotransformation has the advantages of low cost and environmental protection and is a preferred method for production of compounds. At present, most 2,5-dihydroxymethylfuran (DHMF) is synthesized by chemical methods. In this study, 12.008 μg/mL DHMF was produced from 9.045 μg/mL 5-hydroxymethylfurfural (5-HMF) with a yield of 1.33 g/g using the crude enzymes from fungus Ganoderma sessile. To elucidate the toxic potential for both compounds, cytotoxicity tests and acute toxicity were evaluated respectively. 5-HMF induced weak cytotoxicity in HCT-8, A549 and SGC-7901 cells and DHMF exerted no cytotoxicity on HCT-8 while induced inhibition proliferation of A549 and SGC-7901 cells. The acute toxicity study showed no mortality happened in any group even at the single dose of 2000 mg/kg body weight. These results suggest it is feasible to convert 5-HMF to DHMF via crude enzymes from fungus G. sessile under mild condition, and that DHMF displays a potential effect of antitumor in vitro with little acute toxicity. [ABSTRACT FROM AUTHOR]

Abstract The cobalt nanoparticles (10 nm) were homogeneously embedded in the porous carbon dodecahedra (about 1 μm in size) through thermal pyrolysis of the ZIF-67 (zeolitic imidazolate framework-67) dodecahedra under an inert atmosphere. The pore sizes of the carbon dodecahedra were found to disperse in three ranges of micropores, small, and large mesopores. Cyclic voltammetry measurements indicated that the porous carbon-cobalt electrode with small particle size (SPC-Co) exhibited better electrocatalytic performance than that with large particle size (LPC-Co), primarily owing to its larger electrocatalytic surface for boosting the redox reaction between iodide and triiodide ions. Dye-sensitized solar cell (DSSC) using the SPC-Co counter electrode (CE) showed a superior photovoltaic conversion efficiency of 10.6%, which was better than those achieved by means of Pt (9.8%) and LPC-Co (9.0%) CEs. The improved photovoltaic behavior of DSSC employing the SPC-Co CE could be attributed to its lower internal resistance than the other CEs. The porous carbon rhombic dodecahedra with embedded cobalt nanoparticles could achieve fast kinetics and high electroactivity in catalyzing the iodide/triiodide redox couple. Graphical abstract Image 1 Highlights • Cobalt nanoparticles are well-distributed in the porous carbon rhombic dodecahedra. • The carbon dodecahedra with different pore sizes provide high electroactivity. • Caron dodecahedron catalyst boosts redox reaction between iodide and triiodide ions. • Dye-sensitized solar cell shows a high photovoltaic conversion efficiency of 10.6%. [ABSTRACT FROM AUTHOR]

Abstract Biliproteins have extended the spectral range of fluorescent proteins into the near-infrared region (NIR, 700–770 nm) of maximal transmission of most tissues and are also favorable for multiplex labeling. Their application, however, presents considerable challenges to increase their stability under physiological conditions and, in particular, to increase their brightness while maintaining the emission in near-infrared regions: their fluorescence yield generally decreases with increasing wavelengths, and their effective brightness depends strongly on the environmental conditions. We report a fluorescent biliprotein triad, termed BDFP1.1:3.1:1.1, that combines a large red-shift (722 nm) with high brightness in mammalian cells and high stability under changing environmental conditions. It is fused from derivatives of the phycobilisome core subunits, ApcE2 and ApcF2. These two subunits are induced by far-red light (FR, 650–700 nm) in FR acclimated cyanobacteria. Two BDFP1.1 domains engineered from ApcF2 covalently bind biliverdin that is accessible in most cells. The soluble BDFP3 domain, engineered from ApcE2, binds phytochromobilin non-covalently, generating BDFP3.1. This phytochromobilin chromophore was added externally; it is readily generated by an improved synthesis in E. coli and subsequent extraction. Excitation energy absorbed in the FR by covalently bound biliverdins in the two BDFP1.1 domains is transferred via fluorescence resonance energy transfer to the non-covalently bound phytochromobilin in the BDFP3.1 domain fluorescing in the NIR around 720 nm. Labeling of a variety of proteins by fusion to the biliprotein triad is demonstrated in prokaryotic and mammalian cells, including human cell lines. Highlights • A near-infrared fluorescent biliprotein triad (BDFP1.1:3.1:1.1, λ Fmax ~ 722 nm) is reported. • The triad is 2.7-fold brighter than the known brightest near-infrared fluorescent biliprotein, iRFP720. • Labeling using the triad is demonstrated in prokaryotic and mammalian cells. • A method for conveniently isolating phytochromobilin for the labeling is established. [ABSTRACT FROM AUTHOR]

Abstract Far-red and near-infrared emitting chromophores extend applications of fluorescent proteins to regions of maximal transmission of most tissues, but present considerable engineering challenges. Far-red adapting cyanobacteria generate a novel set of biliproteins. One of them, ApcF2, from a thermophilic cyanobacterium was subjected to structure-guided, site-directed random and specific mutagenesis, and was screened for bright far-red emission. We report the generation of chromoproteins, termed BDFPs, that are small, bind auto-catalytically the ubiquitous biliverdin as chromophore, express well, and retain their fluorescence in mammalian cells and in the nematode, C. elegans. They are, moreover, photostable and tolerate high temperature, low pH and chemical denaturation. Homo-bichromophoric tandems of these proteins improve labeling, while hetero-bichromophoric systems with large Stokes shifts are suitable for applications like FRET, multi-channel or super-resolution microscopy. The BDFPs compare favorably to other biliproteins and provide a novel, extremely versatile labeling tool-box. Graphical abstract Unlabelled Image Highlights • Three far-red fluorescent phycobiliproteins (λ Fmax ~670 nm), BDFPs, are reported. • Effective brightness of BDFPs is greatly improved by molecular design. • BDFPs of large Stokes shifts between far-red and near-infrared regions are generated. • Far-red BDFPs and near-infrared BDFPs can be applied in dual-color bioimaging. [ABSTRACT FROM AUTHOR]

Objective. To investigate the gut microbiota differences of obese children compared with the control healthy cohort to result in further understanding of the mechanism of obesity development. Methods. We evaluated the 16S rRNA gene, the enterotypes, and quantity of the gut microbiota among obese children and the control cohort and learned the differences of the gut microbiota during the process of weight reduction in obese children. Results. In the present study, we learned that the gut microbiota composition was significantly different between obese children and the healthy cohort. Next we found that functional changes, including the phosphotransferase system, ATP-binding cassette transporters, flagellar assembly, and bacterial chemotaxis were overrepresented, while glycan biosynthesis and metabolism were underrepresented in case samples. Moreover, we learned that the amount of Bifidobacterium and Lactobacillus increased among the obese children during the process of weight reduction. Conclusion. Our results might enrich the research between gut microbiota and obesity and further provide a clinical basis for therapy for obesity. We recommend that Bifidobacterium and Lactobacillus might be used as indicators of healthy conditions among obese children, as well as a kind of prebiotic and probiotic supplement in the diet to be an auxiliary treatment for obesity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Denitrification is significantly inhibited as CLP concentrations increased. • Zero-order kinetic and noncompetitive inhibition model are applicable for NO 3 − reduction. • Short-term exposure to CLP can inhibit microbial metabolism and ETS by inducing ROS. • ETS activity and NAR are the major factors in predicting nitrate reduction rate (DNR). • The nitrite accumulation (NIA) can be mainly predicted by the changes in NADH and NIR. The mass production and extensive application of clopyralid (CLP) have attracted much attention regarding its environmental effect in recent decades. However, studies on the acute responses and the underlying inhibition mechanisms of denitrifiers to CLP exposure are scarce. Herein, the crucial factors in denitrification were quantified through kinetics, metabolic activity analysis, and structural equation modeling (SEM). The acute response mechanisms of denitrifiers under short-term CLP exposure were further proposed according to the quantitative correlation of denitrification performance with C and N metabolism, ETS activity, and oxidative stress. The modified non-competitive inhibition model fitted well to describe the inhibitory characteristics of CLP on the nitrate reduction (R2 = 0.99), which was significantly inhibited with increasing CLP exposure concentrations. Short-term exposure to CLP could inhibit C and N metabolism and electron transport by inducing oxidative stress during denitrification. Quantitative PCR (qPCR) analysis demonstrated that CLP restrained the abundance of nar G and nir S, suggesting that down-regulation of denitrification enzyme expression was highly related to the reduction in nitrogen conversion. Moreover, SEM indicated that ETS activity and NAR were the major factors in predicting NO 3 − reduction rate (DNR) and were mainly influenced by NADH and reactive oxygen species (ROS). Consistently, NADH and NIR were closely correlated with total nitrite accumulation (NIA). Short-term CLP exposure could affect denitrification performance by directly affecting microbial physicochemical properties or indirectly interfering with the abundance of denitrifying functional genes and metabolic activity through oxidative stress. This study provided new insights into acute responses of denitrifiers to short-term CLP exposure. [ABSTRACT FROM AUTHOR]

Classification of traffic signs with partial occlusions is important for traffic sign maintenance and inventory systems. It is also important to help drivers identify possible traffic signs in time. Motivated by human cognitive processes in identifying an occluded sign, a novel structure is designed to explicitly handle occluded samples in this paper. Occlusion maps are analyzed for possible occluded signs, and a new occlusion descriptor is proposed to distinguish occluded signs from negative samples. A series of tests shows that the developed method could effectively handle samples with partial occlusions and thus reduce the missed detections caused by occlusions. The developed method could also be easily used for any other object detection. [ABSTRACT FROM PUBLISHER]

NT157, a small-molecule tyrosine kinase inhibitor, exhibits broad-spectrum anti-tumor activity. However, NT157-mediated inhibition against glioma has not been explored yet. Herein, the anticancer effects and underlying mechanism of NT157 against human giloma growth were evaluated. The results showed that NT157 alone significantly inhibited glioma cells growth in vitro by lunching cell cycle arrest through up-regulating p21 and p27, and down-regulating cell cycle-related factors. NT157 alone also induced significant glioma cells apoptosis, followed by PARP cleavage and caspase-3 activation. Our findings further revealed that NT157 triggered significant DNA damage and dysfunction of PI3K/AKT, MAPKs and EGFR-STAT3 signaling pathways. Addition of several kinases inhibitors effectively abrogated NT157-induced DR5 up-regulation, which further confirmed the significant role of DR5 pathway. Moreover, combined treatment of NT157 and TRAIL showed enhanced apoptosis against U251 and U87 cells. However, Knockdown of DR5 expression significantly attenuated combined treatment-induced PARP cleavage and caspase-3 activation. Importantly, combined administration of NT157 and TRAIL in vivo effectively inhibited glioma xenograft growth of nude mice by inhibiting cell proliferation and angiogenesis, and inducing DNA damage and apoptosis. Taken together, our findings validated the rational design that combined strategy of NT157 and TRAIL to trigger DNA damage and apoptosis by up-regulating DR5 could be a high efficient way to combat human glioma. [Display omitted] • NT157 induced glioma cell cycle arrest and apoptosis. • NT157 enhanced TRAIL's anticancer effect by activating ROS and DR5 expression. [ABSTRACT FROM AUTHOR]

Species of Cystolepiota are known as diminutive lepiotaceous fungi with a worldwide distribution. Previous studies revealed that Cystolepiota is not monophyletic and preliminary DNA sequence data from recent collections suggested that several new species exist. Based on multi-locus DNA sequence data (the nuc rDNA internal transcribed spacer region ITS1-5.8S-ITS2, ITS; the D1–D2 domains of nuc 28S rDNA, LSU; the most variable region of the second-largest subunit of RNA polymerase II, rpb2 and a portion of the translation–elongation factor 1-α. tef1), C. sect. Pulverolepiota forms a distinct clade separating from Cystolepiota. Therefore, the genus Pulverolepiota was resurrected and two combinations, P. oliveirae and P. petasiformis were proposed. With the integration of morphological characteristics, multi-locus phylogeny, and information on geography and habitat, two new species, viz. C. pseudoseminuda and C. pyramidosquamulosa, are described and C. seminuda was revealed to be a species complex containing at least three species, viz. C. seminuda, C. pseudoseminuda, and Melanophyllum eryei. In addition, C. seminuda was re-circumscribed and neo-typified based on recent collections. [ABSTRACT FROM AUTHOR]

Xiaochangliang (XCL), located in the Nihewan Basin of North China, is a key archaeological locality for understanding the behavioural evolution of early humans. XCL dates to ca. 1.36 Ma, making it one of the earliest sites in Northeast Asia. Although XCL represents the first excavation of an Early Pleistocene site in the Nihewan Basin, identified and excavated in the 1970’s, the lithic assemblages have never been published in full detail. Here we describe the lithic assemblages from XCL, providing information on stone tool reduction techniques and the influence of raw materials on artefact manufacture. The XCL hominins used both bipolar and freehand reduction techniques to manufacture small flakes, some of which show retouch. Bipolar reduction methods at XCL were used more frequently than previously recognized. Comparison of XCL with other Early Pleistocene sites in the Nihewan Basin indicates the variable use of bipolar and freehand reduction methods, thereby indicating a flexible approach in the utilization of raw materials. The stone tools from XCL and the Nihewan sites are classifiable as Mode I lithic assemblages, readily distinguished from bifacial industries manufactured by hominins in Eastern Asia by ca. 800 ka. [ABSTRACT FROM AUTHOR]

This paper proposed a small current to ground fault line selection method with time-frequency atom and grey correlation analysis. Firstly, it calculated the base values of fault line and non-fault line based on the number of branch line of small current to ground system. Secondly, it used the matching pursuit method to decompose the transient zero-sequence current of the first 1/4 cycle indexed by Gabor atom, and calculated the damped sinusoidal atoms of every branch line which expressed the characteristic of fault state. Thirdly, it used the theory of grey relational analysis to compute the correlation degree of every damped sinusoidal atom, and got the characteristic value of every branch line. Finally, it calculated the Euclidean distance value between the characteristic values and the base values of fault line and non-fault line, and compared the size of Euclidean distance values to achieve the fault line selection accurately. The method has a lower computational complexity, an accurate fault selection proved by a large number of simulations. It is especially suitable for the multi-branch lines of small current to ground system. [ABSTRACT FROM AUTHOR]

The green biogenic PdAu nanoparticles (bio-PdAu NPs) exhibits remarkable catalytic performance in hydrogenation, which is highly desired. However, the catalytic principles and effectiveness of bio-PdxAuy NPs in response to various catalytic systems (electrocatalysis and suspension-catalysis) are unclear. Herein, a facile synthetic strategy for bio-PdxAuy NPs synthesis with controlled size and the catalytic principles for hydrogen evolution reaction (HER) and azo dye degradation is reported. In the biosynthetic process, the size and composition of the bio-PdxAuy NPs could be precisely controlled by predesigning the precursor mass ratio of Pd/Au, and the Au proportion showed a linear relationship with the size of NPs (R2 = 0.92). The obtained bio-PdxAuy NPs exhibit variable activity in electrocatalysis (HER) and suspension-catalysis (azo dye degradation). For electrocatalysis, the formation of conductive networks that facilitates the extracellular electron transfer is crucial. It was revealed that the bio-Pd2Au8 exhibited superior electrocatalytic performance in HER/toward hydrogen evolution, with a maximum current density of 1.65 mA cm−2, which was 1.54 times higher than that commercial Pd/C (1.07 mA cm−2). The high electrocatalytic activity was attributed to its appropriate size (81.38 ± 6.14 nm) and uniform distribution on the cell surface, which promoted the extracellular electron transfer by constructing a conductive network between catalyst and electrode. However, for suspension-catalysis, the size effect and synergistic effect of bimetallic NPs have a more prominent effect on the degradation of azo dyes. As the increase of Au proportion the particle size decreases, and the catalytic activity of bio-PdxAuy improved significantly. The response principles of bio-PdxAuy proposed in this study provide a reliable reference for the rational design of bio-based bimetallic catalysts with enhanced catalytic performance. [Display omitted] • Series of bio-PdxAuy NPs synthesize by S. oneidensis MR-1. • The mass ratio of Pd(II)/Au(III) is proportional to the particle size. • The conductive network constructed by bio-Pd2Au8 enhances electrocatalytic activity. • The increase of Au content in bio-PdAu improves the degradation activity of azo dyes. [ABSTRACT FROM AUTHOR]

Reliable people counting and human detection is an important problem in visual surveillance. In recent years, the field has seen many advances, but the solutions have restrictions: people must be moving, the background must be simple, and the image resolution must be high. This paper aims to develop an effective method for estimating the number of people and locate each individual in a low resolution image with complicated scenes. The contribution of this paper is threefold. First, postprocessing steps are performed on background subtraction results to estimate the number of people in a complicated scene, which includes people who are moving only slightly. Second, an Expectation Maximization (EM)-based method has been developed to locate individuals in a low resolution scene. In this method, a new cluster model is used to represent each person in the scene. The method does not require a very accurate foreground contour. Third, the number of people is used as a priori for locating individuals based on feature points. Hence, the methods for estimating the number of people and for locating individuals are connected. The developed methods have been validated based on a 4-hour video, with the number of people in the scene ranging from 36 to 222. The best result for estimating the number of people has an average error of 10% over 51 test cases. Based on the estimated number of people, some results of the EM-based method have also been shown. [ABSTRACT FROM PUBLISHER]

Abstract: Methylation of tRNA on the four canonical bases adds structural complexity to the molecule, and improves decoding specificity and efficiency. While many tRNA methylases are known, detailed insight into the catalytic mechanism is only available in a few cases. Of interest among all tRNA methylases is the structural basis for nucleotide selection, by which the specificity is limited to a single site, or broadened to multiple sites. General themes in catalysis include the basis for rate acceleration at highly diverse nucleophilic centers for methyl transfer, using S-adenosylmethionine as a cofactor. Studies of tRNA methylases have also yielded insights into molecular evolution, particularly in the case of enzymes that recognize distinct structures to perform identical reactions at the same target nucleotide. [Copyright &y& Elsevier]

A laminated Pd-Cu alloy/C/Nafion multilayer was prepared to sense O2 atmosphere in a metal-air structure. As a matrix, palladium was doped with various amounts of copper to conduct a preliminary test with optimum response, and four compositions, Pd, Pd8Cu2, Pd6Cu4, and Pd5Cu5, were selected as the candidate electrodes. It was found that the Pd6Cu4/C electrode showed higher sensitivity for all the electrodes. According to the phase identification of X-ray diffraction and X-ray photoelectron spectroscopy tests, the high sensitivity was attributed to the doped Cu, which was merged into the Pd matrix to repel the Pd out of the matrix as a Pd-skin layer on the surface. In the Pd-Cu alloy, the Cu site served as a template reaction site to break the O-O bond and reduce the interaction force of adsorbated oxygen on the Pd site. During the oxygen reduction reaction, not only did the decomposition of O2 molecules occur on the electrode, but the electrode itself proceeded with a phase transformation to high valance of oxide, PdO3. The sensing potential for O2 sensing was determined by polarization curves in which the flat region resulting from a diffusion-control was adopted. Chronoamperometric measurements were employed to construct calibration curves for the selected electrodes. A successive response was measured to test the endurance, which showed appreciable sensitivity decay. We also tested the selectivity by introducing a series of disturbance gases, CO, SO2, and NO2, in which the Pd6Cu4 electrode prevailed over the other electrodes. [ABSTRACT FROM AUTHOR]

Cysteinyl‐tRNA synthetase (CysRS) is highly specific for synthesis of cysteinyl adenylate, yet does not possess the amino acid editing activity characteristic of many other tRNA synthetases. To elucidate how CysRS is able to distinguish cysteine from non‐cognate amino acids, crystal structures of the Escherichia coli enzyme were determined in apo and cysteine‐bound states. The structures reveal that the substrate cysteine thiolate forms a single direct interaction with a zinc ion bound at the base of the active site cleft, in a trigonal bipyramidal geometry together with four highly conserved protein side chains. Cysteine binding induces movement of the zinc ion towards substrate, as well as flipping of the conserved Trp205 indole ring to pack on the thiol side chain. The imidazole groups of five conserved histidines lie adjacent to the zinc ion, forming a unique arrangement suggestive of functional significance. Thus, amino acid discrimination without editing arises most directly from the favorable zinc–thiolate interaction, which is not possible for non‐cognate substrates. Additional selectivity may be generated during the induced‐fit conformational changes that help assemble the active site. [ABSTRACT FROM AUTHOR]

Provides information on a study regarding aminoacylation of transfer RNA (tRNA) of an aminoacyl-tRNA synthetase. Materials and methodology; Results; Discussion on the results.

Biologically synthesized palladium nanoparticles (bio-Pd) have attracted considerable interest as promising green catalysts for environmental remediation. However, the mechanisms by which microorganisms produce bio-Pd remain unclear. In the present study, we investigated the roles of Shewanella oneidensis MR-1 and its NADH dehydrogenases and hydrogenases (HydA and HyaB) in bio-Pd production using formate as the electron donor. The roles of NADH dehydrogenases and hydrogenases were studied by inhibiting NADH dehydrogenases and using hydrogenase mutants (Δ hydA , Δ hyaB , and Δ hydA Δ hyaB), respectively. The results showed ~97% reduction of palladium by S. oneidensis MR-1 after 24 h using 250 μM palladium and 500 μM formate. Electron microscopy images showed the presence of bio-Pd on both the outer and cytoplasmic membranes of S. oneidensis MR-1. However, the inhibition of NADH dehydrogenases in S. oneidensis MR-1 resulted in only ~61% reduction of palladium after 24 h, and bio-Pd were not found on the outer membrane. The mutants lacking one or two hydrogenases removed 91–96% of palladium ions after 24 h and showed more cytoplasmic bio-Pd but less periplasmic bio-Pd. To the best of our knowledge, this is the first study to demonstrate the role of NADH dehydrogenases of S. oneidensis MR-1 in the formation of bio-Pd on the outer membrane. It also demonstrates that the hydrogenases (especially HyaB) of S. oneidensis MR-1 contribute to the formation of bio-Pd in the periplasmic space. This study provides mechanistic insights into the production of biogenic metal nanoparticles towards their possible use in industrial and environmental applications. • S. oneidensis MR-1 deposited bio-Pd on both the outer and cytoplasmic membranes. • The inhibition of NADH dehydrogenases in S. oneidensis MR-1 significantly slowed down the Pd(II) reduction. • The NADH dehydrogenases in S. oneidensis MR-1 participated in the formation of bio-Pd on the outer membrane. • The hydrogenase mutants of S. oneidensis MR-1 produced less periplasmic bio-Pd and more cytoplasmic bio-Pd. • The hydrogenases in S. oneidensis MR-1 promoted the formation of bio-Pd in the periplasmic space. [ABSTRACT FROM AUTHOR]

Corrigendum to "CCT128930 induces G1-phase arrest and apoptosis and synergistically enhances the anticancer efficiency of VS5584 in human osteosarcoma cells" [Biomed. Caspase-3 expression was repeated, and the correct caspase-3 expression appears below. 3B appears below: Graph The correct caspase-3 expression in Fig. [Extracted from the article]

• Microfluidic BBB chips composed of brain microvascular endothelial cells, pericytes, astrocytes and multifarious neurons can simulate the complex and dynamic 3D structure of human brain. • In vitro microfluidic BBB chips reproduce the mesh of the human brain anatomical structure and physiological function. • Brain on a chip has a great potential in exploring the mechanisms of CNS diseases and drug development. • Microfluidized BBB-related target organ chip platform can in vitro comprehensively investigate the dynamic process of brain-related multi-organ diseases. The human blood-brain barrier (BBB) is a complex multi-dimensional reticular barrier system composed of cerebral microvascular endothelial cells, pericytes, astrocytes and a variety of neurons. The conventional in vitro cell culture model fails to truly present the dynamic hemodynamics of BBB and the interaction between neurons. And it is even more impossible to explore brain-related multi-organ diseases, which brings huge obstacles to explore diseases of the central nervous system and the interaction between brain-related multi-organs, and evaluate drug efficacy. Miniaturized microfluidics based BBB chips are being commonly used to co-culture a variety of cells on a small-sized chip to construct a three-dimensional (3D) BBB or BBB-related organ disease models. By combining with other electrophysiological, biochemical sensors or equipment and imaging systems, it can in real time and quickly screen disease-related markers and evaluate drug efficacy. This review systematically summarized the research progress of in vitro BBB and BBB-related organ chips, and analyzed the obstacles of BBB models in depth. Parallelly combined with the current research trends and hot spots, we give the further improvement measures of microfluidic BBB chips. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a highly invasive primary malignant bone tumor. PI3K/mTOR pathway plays a key role in tumor progression, and inhibition of PI3K/mTOR pathway represents a novel strategy in therapy of osteosarcoma. CCT128930 and VS5584 are both inhibitors of PI3K/mTOR, but the anticancer mechanism of CCT128930 or/and VS5584 against human osteosarcoma cells remains unclear. Herein, U2OS and MG63 human osteosarcoma cells were cultured, and the anticancer effects of CCT128930 alone and the combined effect of CCT128930 and VS5584 against human osteosarcoma cells were explored. The results showed that CCT128930 as PI3K/mTOR inhibitor effectively inhibited p-p70 and p-AKT expression and dose-dependently inhibited U2OS cells and MG63 human osteosarcoma cells growth. Further studies found that CCT128930 triggered significant G-1 phase arrest and apoptosis, as convinced by the dysfunction of p27, Cyclin B1, Cyclin D1 and Cdc2, and PARP cleavage and caspase-3 activation. Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways. [ABSTRACT FROM AUTHOR]

Aminoacylation of tRNA generates an aminoacyl-tRNA (aa-tRNA) that is active for protein synthesis on the ribosome. Quantification of aminoacylation of tRNA is critical to understand the mechanism of specificity and the flux of the aa-tRNA into the protein synthesis machinery, which determines the rate of cell growth. Traditional assays for the quantification of tRNA aminoacylation involve radioactivity, either with a radioactive amino acid or with a [3′-32P]-labeled tRNA. We describe here a label-free assay that monitors aminoacylation by biotinylation-streptavidin (SA) conjugation to the α-amine or the α-imine of the aminoacyl group on the aa-tRNA. The conjugated aa-tRNA product is readily separated from the unreacted tRNA by a denaturing polyacrylamide gel, allowing for quantitative measurement of aminoacylation. This label-free assay is applicable to a wide range of amino acids and tRNA sequences and to both classes of aminoacylation. It is more sensitive and robust than the assay with a radioactive amino acid and has the potential to explore a wider range of tRNA than the assay with a [3′-32P]-labeled tRNA. This label-free assay reports kinetic parameters of aminoacylation quantitatively similar to those reported by using a radioactive amino acid, suggesting its broad applicability to research relevant to human health and disease. [ABSTRACT FROM AUTHOR]

Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late‐stage patient prognosis undergoing chemotherapy is challenging. This work shows that the activation of specific oncogenes leads to elevated expression of mRNAs and their corresponding proteins in extracellular vesicles (EVs) circulating in blood. Utilizing an immune lipoplex nanoparticle (ILN) biochip assay, these findings demonstrate that glypican 1 (GPC1) mRNA expression in the exosomes‐rich (Exo) EV subpopulation and GPC1 membrane protein (mProtein) expression in the microvesicles‐rich (MV) EV subpopulation, particularly the tumor associated microvesicles (tMV), served as a viable biomarker for PDAC. A combined analysis effectively discriminated early‐stage PDAC patients from benign pancreatic diseases and healthy donors in sizable clinical from multiple hospitals. Furthermore, among late‐stage PDAC patients undergoing chemotherapy, lower GPC1 tMV‐mProtein and Exo‐mRNA expression before treatment correlated significantly with prolonged overall survival. These findings underscore the potential of vesicular GPC1 expression for early PDAC screenings and chemotherapy prognosis. [ABSTRACT FROM AUTHOR]

The stable phase equilibrium data of Mg2+, NH 4 +//Cl−, SO 4 2−−H 2 O quaternary interaction system and its four ternary subsystems at 363.15 K were determined by isothermal dissolution equilibrium method, and the corresponding stable phase diagrams of the above systems were plotted. According to the phase diagram, there are seven solid phase crystalline regions, which correspond to MgSO 4 ·(NH 4) 2 SO 4 ·6H 2 O, MgSO 4 ·6H 2 O, MgSO 4 ·4H 2 O, MgCl 2 ·6H 2 O, (NH 4) 2 SO 4 , MgCl 2 ·NH 4 Cl·6H 2 O and NH 4 Cl, respectively. MgSO 4 ·(NH 4) 2 SO 4 ·6H 2 O has the largest crystalline region among these crystalline regions, which indicates that the double salt MgSO 4 ·(NH 4) 2 SO 4 ·6H 2 O is the easiest to crystallize out. Based on the extended Pitzer model, the solubility data of the ternary subsystems and the quaternary system were calculated. The results showed that the calculated values were close to the experimental values. According to the comparison between the stable phase diagram of the quaternary system at 298.15 K and 363.15 K, a new process of preparing N–Mg compound fertilizer (MgSO 4 ·(NH 4) 2 SO 4 ·6H 2 O) at 298.15 K and crystallizing NH 4 Cl at 363.15 K by using ammonium sulfate and magnesium chloride as raw materials was designed in this paper and the process route was verified by experiment. [ABSTRACT FROM AUTHOR]

Biosynthesized noble metal nanoparticles (NPs) as promising green catalysts for electrochemical application has invited a lot of attention. However, effective electron transfer between biosynthesized NPs and electrode remains a challenge due to the uncontrollable and poor conductive property of cell substrates. In this study, graphene oxide (GO) was introduced into a bio-Pd synthesis process governed by Shewanella oneidensis MR-1, which was demonstrated to be simultaneously reduced with Pd(II) and transformed to reduced GO (rGO), resulting in the formation of a Pd-cells-rGO composite. Compared to the control without rGO (Pd-cells), the electrochemical conductivity of Pd-cells-rGO composite increased from almost zero to 196 μS cm−1, indicating the rGO facilities the electron transport across the composite. Electrochemical characterizations revealed the electrochemical active surface area (ECSA) of Pd in Pd-cells-rGO was enlarged by increasing the amount of rGO in the composite, clearly indicating that the conductive network created by rGO enable the Pd NPs receive electrons from electrode and become electrochemical active. A considerable enhancement of electrocatalytic activity was further confirmed for Pd-cells-rGO as indicated by 36.7- and 17.2-fold increase (Pd-cells-rGO with Pd/GO ratio of 5/1 vs Pd-cells) of steady state current density toward hydrogen evolution and nitrobenzene reduction at −0.7 V and −0.55 V vs Ag/AgCl, respectively. We also compared the electrocatalytic performance with MWCNTs hybrids Pd-cells-CNTs. It was found that the association of Pd, cells and rGO creates an interactive and synergistic environment to allow higher conductivity and catalytic activity under the same amount of carbon nanomaterial. The strategy developed in this work activates a highly reactive NPs and proposed a designable protocol for enhancing electrocatalytic activity of biocatalysts. • MR-1 self-assembly of Pd-cells-rGO by one-step reduction of Pd(II) and GO • Hybrid rGO improves the stability of Pd NPs to against agglomeration • Pd-cells-rGO can be used as valid electrocatalyst for HER and NB reduction • Synergistic effect of Pd and rGO increases conductivity and quantity of active Pd [ABSTRACT FROM AUTHOR]

In this study, we developed a pro-endothelial-functionalization surface by immobilizing a natural factors-loaded nanoparticle, exosome, onto the poly-dopamine (PDA) coated materials via electrostatic binding. • A novel PDA/Exosome coating was successfully prepared onto the cardiovascular biomaterial. • The PDA/Exosome coating could enhance the endothelial cell growth, CD31 expression and NO release. • The PDA/Exosome coating could regulate SMC into contractile phenotype and macrophage into M2 phenotype. • The PDA/Exosome coating could reduce hyperplasia of the implant. • The PDA/Exosome coating regulated the endothelial cell behavior by entering into cells. Stent intervention as available method in clinic has been widely applied for cardiovascular disease treatment for decades. However, the restenosis caused by late thrombosis and hyperplasia still limits the stents long-term application, and the essential cause is usually recognized as endothelial functionalization insufficiency of the stent material surface. Here, we address this limitation by developing a pro-endothelial-functionalization surface that immobilized a natural factors-loaded nanoparticle, exosome, onto the poly-dopamine (PDA) coated materials via electrostatic binding. This PDA/Exosome surface not only increased the endothelial cells number on the materials, but also improved their endothelial function, including platelet endothelial cell adhesion molecule-1 (CD31) expression, cell migration and nitric oxide release. The pro-inflammation macrophage (M1 phenotype) attachment and synthetic smooth muscle cell proliferation as the interference factors for the endothelialization were not only inhibited by the PDA/Exosome coating, while the cells were also regulated to anti-inflammation macrophage (M2 phenotype) and contractile smooth muscle cell, which may contribute to endothelialization. Thus, it can be summarized this method has potential application on surface modification of cardiovascular biomaterials. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effects to evade immune system recognition. However, the clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, high infiltration of CD8+ T cells could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion. [ABSTRACT FROM AUTHOR]

Background: Postprandial distress syndrome (PDS) has a considerable impact on quality of life. Our previous pilot trial suggested that acupuncture might be a potential treatment option for PDS. We will conduct this large trial to determine the efficacy of acupuncture versus sham acupuncture for PDS.Methods/design: A total of 280 eligible patients who meet the Rome IV criteria for PDS will be randomly allocated to either the acupuncture group or the sham acupuncture group. Each patient will receive 12 sessions over four weeks. The primary outcomes will be the response rate of overall treatment effect (OTE) and the elimination rate of all three cardinal symptoms (postprandial fullness, upper abdominal bloating, and early satiation) at four weeks after randomization. Secondary outcomes will include assessments of the severity of dyspepsia symptoms and disease-specific quality of life at weeks 4, 8, and 16 after randomization. All patients who receive randomization will be included in the intent-to-treat analysis.Discussion: The finding of this trial will provide high-quality evidence on the efficacy of acupuncture for treatment of PDS. Results of this research will be published in peer-reviewed journals.Trial Registration: ISRCTN Registry, ISRCTN12511434 . Registered on 31 March 2017. [ABSTRACT FROM AUTHOR]

Cancer cachexia (CC), characterized by body weight loss and sarcopenia, contributes to over 20% of all cancer-related death. Approximately 80% of pancreatic cancer (PC) patients develop CC during disease progression. Pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, have been correlated with CC; however, its prognostic significance remains unclear. In this study, serum levels of the CC-related cytokines were determined in normal donors and PC patients. IL-8 expression was assessed in PC tissue microarrays. The correlation of levels of each cytokine with disease progression, weight loss, and sarcopenia was calculated. The relationships among the baseline variables, CC, and IL-8 expression with disease progression were examined using univariate and multivariate analyses. Of these mentioned cytokines, only serum IL-8 level was elevated in the locally advanced group (n = 55) compared with the normal (n = 17) and resected groups (n = 55). Serum IL-8 level was positively correlated with CC status, weight loss, sarcopenia, but was negatively correlated with total psoas area (TPA). IL-8 expression in tissue samples was also positively associated with weight loss. Furthermore, serum IL-8 level was an independent predictor of survival. In conclusion, elevated serum IL-8 level significantly correlates with CC and sarcopenia and can be used as a prognostic indicator in PC. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment and portend poor prognosis. However, the molecular mechanisms underlying the tumor promotion of TAMs have not been fully elucidated. Methods: Coculture of gastric cancer cells with U937 cells was performed to investigate the impact of TAMs on cancer cell behavior. MicroRNA (miRNA) microarray and bioinformatics were applied to identify the involved miRNAs and the functional target genes. The regulation of the miRNA on its target gene was studied using anti-miRNA and miRNA mimic. Results: Coculture with CD204+ M2-like TAMs increased proliferation, migration, and epithelial-mesenchymal transition of gastric cancer cells. MiR-210 was the most upregulated miRNA in cancer cells identified by miRNA microarray after coculture. In gastric cancer tissues, miR-210 expression was positively correlated with CD204+ M2-like TAM infiltration. Inactivation of miR-210 by antimir attenuated CD204+ M2-like TAMs-induced cancer cell migration. Using pharmacological inhibitors and neutralizing antibodies, CD204+ M2-like TAMs-secreted TNFα was found to upregulate miR-210 through NF-κB/HIF-1α signaling. Bioinformatics analysis showed netrin-4 (NTN4) as a potential target of miR-210 to suppress gastric cancer cell migration. We also found an inverse expression between miR-210 and NTN4 in cancer cells after coculture or in tumor xenografts. Anti-miR-210 increased NTN4 expression, while miR-210 mimics downregulated NTN4 in cancer cells. Reporter luciferase assays showed that MiR-210 mimics suppressed NTN4 3' untranslated region-driven luciferase activity in cancer cells, but this effect was blocked after mutating miR-210 binding site. Conclusions: CD204+ M2-like TAMs can utilize the TNF-α/NF-κB/HIF-1α/miR-210/NTN4 pathway to facilitate gastric cancer progression. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) poses a significant social and economic burden worldwide. Identifying exposures, risk factors, and biological mechanisms that are causally connected to MDD can help build a scientific basis for disease prevention and development of novel therapeutic approaches. Methods: In this systematic review, we assessed the evidence for causal relationships between putative causal risk factors and MDD from Mendelian randomization (MR) studies, following PRISMA. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. Results: We included methodological details and results from 52 articles. A causal link between lifestyle, metabolic, inflammatory biomarkers, particular pathological states and MDD is supported by MR investigations, although results for each category varied substantially. Conclusions: While this review shows how MR can offer useful information for examining prospective treatment targets and better understanding the pathophysiology of MDD, some methodological flaws in the existing literature limit reliability of results and probably underlie their heterogeneity. We highlight perspectives and recommendations for future works on MR in psychiatry. [ABSTRACT FROM AUTHOR]

Background: RNA binding proteins (RBPs)—regulated gene expression play a vital role in various pathological processes, including the progression of cancer. However, the role of RBP in hepatocellular carcinoma (HCC) remains much unknown. In this study, we aimed to explore the contribution of RBP CCDC137 in HCC development. Methods: We analyzed the altered expression level and clinical significance of CCDC137 in database and HCC specimens. In vitro cell assays and in vivo spontaneous mouse models were used to assess the function of CCDC137. Finally, the molecular mechanisms of how CCDC137 regulates gene expression and promotes HCC was explored. Results: CCDC137 is aberrantly upregulated in HCC and correlates with poor clinical outcomes in HCC patients. CCDC137 markedly promoted HCC proliferation and progression in vitro and in vivo. Mechanistically, CCDC137 binds with FOXM1, JTV1, LASP1 and FLOT2 mRNAs, which was revealed by APOBEC1-mediated profiling, to increase their cytoplasmic localization and thus enhance their protein expressions. Upregulation of FOXM1, JTV1, LASP1 and FLOT2 subsequently synergistically activate AKT signaling and promote HCC. Interestingly, we found that CCDC137 binds with the microprocessor protein DGCR8 and DGCR8 has a novel non-canonical function in mRNA subcellular localization, which mediates the cytoplasmic distribution of mRNAs regulated by CCDC137. Conclusions: Our results identify a critical proliferation-related role of CCDC137 and reveal a novel CCDC137/DGCR8/mRNA localization/AKT axis in HCC progression, which provide a potential target for HCC therapy. [ABSTRACT FROM AUTHOR]

The mechanical properties of a stem cell culture substrate significantly impact cell adhesion, survival, migration, proliferation, and differentiation in vitro. A major challenge in engineering artificial stem cell substrate is to properly identify the relevant physical features of native stem cell niches, which are likely different for each stem cell type. The behavior of tendon stem cells has potentially significant implications for tendon repair. Here, microfiber scaffolds with various modulus of elasticity are fabricated by near-field electrospinning, and their regulating effects on the in vitro behavior of tendon stem cells (TSCs) are discussed in this study. The number of pseudopodia shows a biphasic relationship with the modulus of scaffold. The proliferation, polarization ratio and alignment degree along the fibers of the TSCs increase with the increase of fiber modulus. TSCs cultured on the scaffold with moderate modulus (1429 MPa) show the upregulation of tendon-specific genes (Col-I, Tnmd, SCX and TNCF). These microfiber scaffolds provide great opportunities to modulate TSCs behavior at the micrometer scales. In conclusion, this study provides an instructive mechanical microenvironment for TSCs behaviors and may lead to the development of desirable engineered artificial stem cell substrate for tendon healing. [Display omitted] • The cross PA56 fiber scaffolds with various modulus were fabricated by NEFS. • The proliferation, number and cell polarization ratio of TSCs increased with the modulus. • The number of pseudopodia of TSCs showed a biphasic response to the modulus. • The arrangement of actin cytoskelenton tended to align toward the fiber with the increase of fiber modulus. • Microfiber scaffolds with moderate modulus (1429 MPa) demonstrated the potential to upregulate the tendon-specific genes. [ABSTRACT FROM AUTHOR]

Biliproteins have extended the spectral range of fluorescent proteins into the region of maximal transmission of most tissues and are favorable for multiplexing, but their application presents considerable challenges. Their fluorescence derives from open-chain tetrapyrrole chromophores which often require the introduction of dedicated reductases and lyases. In addition, their fluorescence yield generally decreases with increasing wavelengths and depends strongly on the state of the binding protein. We report fluorescent biliproteins, termed BDFPs, that are derived from the phycobilisome core subunit, ApcF2: this subunit is induced in the thermophilic cyanobacterium, Chroococcidiopsis thermalis, by far-red light and binds phycocyanobilin non-covalently. The BDFPs obtained by molecular evolution of ApcF2 bind the more readily accessible biliverdin covalently while retaining the red-shifted fluorescence in the near-infrared spectral region (~ 710 nm). They are small monomers (~ 15 kDa) and not only show excellent photostability, but are also thermostable up to 80 °C, tolerate acid down to pH 2 and high concentrations of denaturants. The result indicates far-red adapting cyanobacteria as a useful source for designing extremely red-shifted fluorescent markers. In vivo performance of BDFPs as biomarkers in conventional and super-resolution microscopy, alone or fused to target proteins, is exemplified in several mammalian cells, including, human cell lines, in the nematode, Caenorhabditis elegans and, at low pH, in Lactobacillus lactis . [ABSTRACT FROM AUTHOR]

Donggutuo (DGT) is one of the richest archaeological localities in the Nihewan Basin of North China, thereby providing key information about the technological behaviours of early hominins in eastern Asia. Although DGT has been subject of multiple excavations and technological studies over the past several decades, few detailed studies on the lithic assemblages have been published. Here we summarize and describe the DGT lithic assemblages, examining stone tool reduction methods and technological skills. DGT dates to ca. 1.1 Ma, close to the onset of the mid-Pleistocene climate transition (MPT), indicating that occupations at DGT coincided with increased environmental instability. During this time interval, the DGT knappers began to apply innovative flaking methods, using free hand hard hammer percussion (FHHP) to manufacture pre-determined core shapes, small flakes and finely retouched tools, while occasionally using the bipolar technique, in contrast to the earlier and nearby Nihewan site of Xiaochangliang (XCL). Evidence for some degree of planning and predetermination in lithic reduction at DGT parallels technological developments in African Oldowan sites, suggesting that innovations in early industries may be situational, sometimes corresponding with adaptations to changes in environments and local conditions. [ABSTRACT FROM AUTHOR]

Background: Sorafenib (SOR) is the first line treatment for advanced hepatocellular carcinoma (HCC), but resistance develops frequently. Tumor-associated macrophages (TAMs) have been reported to affect the progression of HCC. We therefore aimed to study the role of TAMs in promoting SOR resistance. Methods: Immunofluorescence staining for the M2 marker CD204 and the cancer stem cell (CSC) markers CD44 and CD133 was performed in paired HCC and adjacent noncancerous tissues and HCC tissues stratified by response of SOR treatment. HCC/U937 coculture system and cytokines were used to induce M2 polarization for studying the effects of M2 TAMs on CSC properties and apoptotic death of HCC cells after SOR treatment. Results: Higher expression of CD204, CD44, and CD133 was observed in patients with SOR nonresponse (SNR) than in those with SOR response (SR), suggesting that SNR is positively correlated to levels of CSCs and M2 TAMs. After coculture, M2 TAMs could increase the level of CSCs but decrease SOR-induced apoptosis. Incubation of HCC cells with coculture conditioned medium increased the formation of spheres that were resistant to SOR. Furthermore, CXCL1 and CXCL2 were found to be the potential paracrine factors released by M2 TAMs to upregulate SOR resistance in HCC cells. Treatment with CXCL1 and CXCL2 could increase HCC CSC activity but decrease SOR-induced apoptosis by affecting BCL-2 family gene expression. Using pharmacological inhibitors, CXCR2/ERK signaling was found to be critical to CXCL1- and CXCL2-mediated SOR resistance. Conclusion: This study identified CXCL1, CXCL2, and their downstream CXCR2/ERK signaling as potential therapeutic targets to overcome SOR resistance in HCC. [ABSTRACT FROM AUTHOR]

Single phase multiferroics are rare in nature, because ferroelectric and ferromagnetic orderings require empty d -orbits and filled d -orbits, respectively. Here we demonstrate that ferroelectricity can be induced by ion-pair doping in ferromagnetic oxide such as ferrites with filled d -orbits. Our study shows that a new kind of room temperature multiferroic can be achieved in single phase thin films of CoFe 2 O 4 with Li + -Al 3+ pair substitution of Co 2+ along 〈110〉 direction. A ferroelectric domain mechanism related to ion-pairs in co-doped thin films was revealed. Importantly, a new way for fabricating single phase multiferroic materials is provided in the present study. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is associated with decreased quality of life, high re-admission rate and poor prognosis. In particular, ischemic heart failure (IHF) has a worse prognosis than nonischemic HF. The use of traditional Chinese medicine (TCM) alongside Western medicine to treat HF has developed into an integrative treatment model in China. There have been small clinical trials and experimental studies to demonstrate the efficacy of TCM for treating HF; however, there is still a lack of high-quality trials. Qishen Yiqi dripping pills (QSYQ), a TCM drug, have been commonly used alongside standardized Western medicine to treat IHF. This paper describes the protocol for the clinical assessment of QSYQ in IHF patients.Method: A randomized, double-blind, multicenter, placebo-controlled trial will assess the efficacy and safety of QSYQ in the treatment of IHF. The trial is to enroll 640 IHF patients from 32 hospitals in China. Besides their standardized Western medicine, patients will be randomized to receive treatment of either QSYQ or placebo for 6 months and follow-up monitoring for at least a further 6 months. The primary outcome is increased exercise capacity of patients, which will be measured using the 6-minute walking test (6MWT). The secondary outcomes include composite endpoints: all-cause mortality, frequency of hospitalization or emergency due to cardiovascular events, brain natriuretic peptide levels, left ventricular ejection fraction, and cardiothoracic ratio will be documented, as well as scores on the New York Heart Association classification and Minnesota quality of life index, and information obtained from the four TCM diagnostic methods. Blood lipid tests will also be administered.Discussion: The integrative treatment model of TCM alongside Western medicine has developed into a treatment model in China. The rigorous design of the trial will assure an objective and scientific assessment of the efficacy and safety of QSYQ in the treatment of IHF. [ABSTRACT FROM AUTHOR]

Considering the limited efficacy of current therapies in lung, colorectal, and pancreatic cancers, innovative combination treatments with diverse mechanisms of action are needed to improve patients' outcomes. Chitinase-3 like-1 protein (CHI3L1) emerges as a versatile factor with significant implications in various diseases, particularly cancers, fostering an immunosuppressive tumor microenvironment for cancer progression. Therefore, pre-clinical validation is imperative to fully realize its potential in cancer treatment. We developed phage display-derived fully human monoclonal CHI3L1 neutralizing antibodies (nAbs) and verified the nAbs-antigen binding affinity and specificity in lung, pancreatic and colorectal cancer cell lines. Tumor growth signals, proliferation and migration ability were all reduced by CHI3L1 nAbs in vitro. Orthotopic or subcutaneous tumor mice model and humanized mouse model were established for characterizing the anti-tumor properties of two CHI3L1 nAb leads. Importantly, CHI3L1 nAbs not only inhibited tumor growth but also mitigated fibrosis, angiogenesis, and restored immunostimulatory functions of immune cells in pancreatic, lung, and colorectal tumor mice models. Mechanistically, CHI3L1 nAbs directly suppressed the activation of pancreatic stellate cells and the transformation of macrophages into myofibroblasts, thereby attenuating fibrosis. These findings strongly support the therapeutic potential of CHI3L1 nAbs in overcoming clinical challenges, including the failure of gemcitabine in pancreatic cancer. [Display omitted] • CHI3L1 nAb restricts tumor growth and restores immune functions in various cancers. • CHI3L1 nAb ameliorates tumor fibrosis & angiogenesis in preclinical mouse models. • CHI3L1 nAb inhibits fibroblast activation & macrophage to myofibroblast transition. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to investigate the involvement of the ventral intermediate nucleus of thalamus (Vim) in the tremor- and akinetic-/rigid-related networks in Parkinson's disease ( PD). Methods Tremor-dominant ( TD) and akinetic-/rigid-dominant ( ARD) PD patients were recruited and scanned by resting-state functional MRI. Functional connectivity from the Vim nucleus was analyzed. Results In the TD patients, the Vim nucleus exhibited increased connectivity with the cerebellum/dentate nucleus, primary motor cortex (M1), supplementary motor area ( SMA), premotor cortex, thalamus, globus pallidus, putamen, and parietal cortex compared with the controls, while the connections between the Vim nucleus and M1 and cerebellum/dentate nucleus had positive correlations with the tremor scores. In the ARD patients, the Vim nucleus only showed enhanced connectivity with the globus pallidus and limbic lobe compared with the controls, and no connectivity showed correlation against the akinetic-rigidity scores. TD patients had increased connectivity with the Vim nucleus in the cerebellum, M1, SMA, thalamus, globus pallidus, putamen, and parietal cortex compared with ARD patients. Conclusions This study demonstrates that the Vim nucleus has an important role in the tremor-related network, but not in the akinetic-/rigid-related network. Our finding is helpful to explain the selective effect of Vim deep brain stimulation in PD. [ABSTRACT FROM AUTHOR]

Cantleyoside (CA) is a kind of iridoid glycosides in Pterocephalus hookeri (C. B. Clarke) Höeck. The purpose of this study was to investigate the effects of CA on human rheumatoid arthritis fibroblast synovial cells (HFLS-RA). Cell proliferation of HFLS-RA was assessed by CCK-8. ELISA was used to detect cytokines NO, TNF-α, IL-1β/6, MCP-1, MMP-1/3/9 and metabolism-related ATPase activities and ATP levels. JC-1, DCFH-DA, Fluo-3 AM and Calcein AM probes were used to detect mitochondrial membrane potential (MMP), reactive oxygen species (ROS), Ca2+ and mitochondrial permeability conversion pore (MPTP), respectively. Isolated mitochondria assay was used to detect mitochondrial swelling. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and real-time ATP production were measured using a Seahorse analyzer. Apoptosis was detected by TUNEL and Hoechst staining. Western blot was used to detect the expressions of AMPK/p-AMPK, Sirt 1, IκBα, NF-κB p65/p-NF-κB p65, Bcl-2 and Bax. Cytoplasmic nuclear isolation was also performed to detect the translocation of NF-κB. CA significantly suppressed cell proliferation and the levels of NO, TNF-α, IL-1β/6, MCP-1 and MMP-1/3/9 in HFLS-RA. In addition, CA promoted the apoptosis of HFLS-RA by increasing TUNEL and Hoechst positive cells and the ratio of Bax/Bcl-2. Inhibition of energy metabolism in HFLS-RA by CA reduced OCR, ECAR and real-time ATP generation rate. Importantly, CA promoted p-AMPK and Sirt 1 expression, inhibited IκBα degradation to reduce p-NF-κB and translocation. The results suggest that CA activates the AMPK/Sirt 1/NF-κB pathway by promoting mitochondrial dysfunction, thereby exerting anti-inflammatory and pro-apoptotic effects. [Display omitted] • CA could inhibit inflammatory responses by weakening the expression of inflammatory cytokines, chemokines and MMPs. • CA could induce mitochondrial dysfunction by overloading intracellular ROS and Ca2+ in HFLS-RA. • CA could reduce mitochondrial energy metabolism by restraining OCR, ECAR and real-time ATP production rates in HFLS-RA. • CA could promote apoptosis of HFLS-RA by the activation of AMPK/Sirt 1/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Semaphorins (SEMAs) are axon guidance factors that participate in axonal connections and nerve system development. However, the functional roles of SEMAs in tumorigenesis are still largely uncovered. By using in silico data analysis, we found that SEMA6C was downregulated in pancreatic cancer, and its reduction was correlated with worse survival rates. RNA sequencing revealed that cell cycle-related genes, especially cyclin D1, were significantly altered after blockage of SEMA6C by neutralizing antibodies or ectopic expressions of SEMA6C. Mechanistic investigation demonstrated that SEMA6C acts as a tumor suppressor in pancreatic cancer by inhibiting the AKT/GSK3 signaling axis, resulting in a decrease in cyclin D1 expression and cellular proliferation. The enhancement of cyclin D1 expression and cyclin-dependent kinase activation in SEMA6C-low cancer created a druggable target of CDK4/6 inhibitors. We also elucidated the mechanism underlying SEMA6C downregulation in pancreatic cancer and demonstrated a novel regulatory role of miR-124-3p in suppressing SEMA6C. This study provides new insights of SEMA6C-mediated anti-cancer action and suggests the treatment of SEMA6C-downregulated cancer by CDK4/6 inhibitors. [ABSTRACT FROM AUTHOR]