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Simple Summary Conventional serum markers such as carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and tissue polypeptide antigen (TPA) have a low sensitivity in predicting the prognosis of locoregional esophageal squamous cell carcinoma cell (ESCC). In our clinical study, we found high serum elafin to be an independent outcome predictor for stage I-IIIA ESCC, considering T, N, overall stage, and treatment. In vitro experiments showed that adding recombinant elafin drove ESCC cell proliferation, migration and invasion, while shRNA attenuated elafin levels, abrogating those effects. Our results suggested serum elafin might be a noninvasive biomarker to predict the outcome of locoregional ESCC and could potentially be used as a therapeutic target. Abstract Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor known to have locally advanced and metastatic features which cause a dismal prognosis. We sought to determine whether elafin, a non-invasive and secretory small-molecule marker, could be used to predict prognosis in locoregional ESCC patients in human and in vitro studies. In our human study, 119 subjects were identified as having incident and pathologically-proved ESCC with stage I-IIIA tumors from southern Taiwan between 2000 and 2016. We measured their serum elafin levels at baseline and followed them until the date of cancer death or until January 2020, the end of this study. Those with high serum elafin levels were found to have a 1.99-fold risk (95% confidence interval: 1.17–3.38) shorter survival than those who did not. In our in vitro experiments, elevated elafin levels were found to drive ESCC cell proliferation, migration and invasion, while attenuation of elafin level by shRNA abrogated those effects. We concluded that elafin promotes ESCC motility and invasion and leads to a worse clinical prognosis in ESCC patients without distant metastasis.

Transition-metal dichalcogenides (TMDCs) present great potential in the area of noble metals recovery and separation. Herein, a one-pot solvothermal method was carried out to fabricate CuS nanoparticles (CuS NPs). The morphology structure and physical properties of the CuS NPs were characterized by scanning electron microscope (SEM), transmission electron microscopy (TEM), high-resolution TEM (HRTEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), N2 adsorption-desorption, and thermogravimetric analysis. Successful attempts to apply CuS NPs to the noble metal capture were firstly made. CuS NPs demonstrated highly selective binding and extremely efficient capture of Au3+, Pd2+ and Pt4+. The selectivity and capture capacity order were Au3+ > Pd2+ > Pt4+ > other metal ions. The enormous capacities for Au3+ (2.92 mmol g−1, 574.7 mg g−1), Pd2+ (1.13 mmol g−1, 222.2 mg g−1), and Pt4+ (0.72 mmol g−1, 142.9 mg g−1), and high distribution coefficients (Kd) of Au3+ (3.12 × 106 mL g−1), Pd2+ (2.24 × 106 mL g−1), and Pt4+ (6.220 × 103 mL g−1) placed the CuS NPs at the top known for such capture. Sorption isotherm of Au3+, Pd2+ and Pt4+ accorded with the Langmuir model suggesting homogeneous adsorption sites. The sorption kinetics for Au3+, Pd2+ and Pt4+ followed a pseudo-second-order model and the capture process was endothermic driven. The adsorption may occur by the reduction reaction of Au3+ and Pd2+ with CuS NPs as a captor in the hydrochloric systems, while it may occur by electrostatic interaction and electron-mediated coordination interaction for Pt4+. After the capture of noble metals, the crystallites of the CuS NPs retained the original shape, suggesting good stability and reversibility. This work proposes a new strategy to capture and recover noble metals and further expands the applications of TMDCs in pollution control.

Background: The leaves and roots of Panax ginseng are rich in ginsenosides. However, the chemical compositions of the leaves and roots of P. ginseng differ, resulting in different medicinal functions. In recent years, the aerial parts of members of the Panax genus have received great attention from natural product chemists as producers of bioactive ginsenosides. The aim of this study was the isolation and structural elucidation of novel, minor ginsenosides in the leaves of P. ginseng and evaluation of their antiinflammatory activity in vitro. Methods: Various chromatographic techniques were applied to obtain pure individual compounds, and their structures were determined by nuclear magnetic resonance and high-resolution mass spectrometry, as well as chemical methods. The antiinflammatory effect of the new compounds was evaluated on lipopolysaccharide-stimulated RAW 264.7 cells. Results and conclusions: Two novel, minor triterpenoid saponins, ginsenoside LS1 (1) and 5,6-didehydroginsenoside Rg3 (2), were isolated from the leaves of P. ginseng. The isolated compounds 1 and 2 were assayed for their inhibitory effect on nitric oxide production in LPS-stimulated RAW 264.7 cells, and Compound 2 showed a significant inhibitory effect with IC50 of 37.38 μM compared with that of NG-monomethyl-L-arginine (IC50 = 90.76 μM). Moreover, Compound 2 significantly decreased secretion of cytokines such as prostaglandin E2 and tumor necrosis factor-α. In addition, Compound 2 significantly suppressed protein expression of inducible nitric oxide synthase and cyclooxygenase-2. These results suggested that Compound 2 could be used as a valuable candidate for medicinal use or functional food, and the mechanism is warranted for further exploration. Keywords: Antiinflammatory activity, Panax ginseng, Triterpenoid saponins

Two new flavonoid glycosides, named oroxin C (1) and oroxin D (scutellarein 4'-methyl ether 7-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside, 2), together with eight known flavonoids (3–10), were isolated from the seeds of Oroxylum indicum. Their structures were elucidated unambiguously by spectroscopic techniques and chemical methods. Anti-inflammatory and cytotoxic activities of all the isolated compounds were evaluated. Chrysin (3) and chrysin-6-C-β-D-glucopyranosyl-8-C-α-L-arabinopyranoside (10) showed moderate inhibitory effects aganist the LPS-induced NO production in murine RAW264.7 macrophages with IC50 values of 18.63 ± 0.91 and 28.69 ± 0.43 μM, respectively. Chrysin (3) exhibited weak cytotoxic activity aganist A549, HepG2 and SW480 human cancer cell lines with IC50 values of 40.88 ± 3.85, 50.55 ± 2.59 and 91.60 ± 4.27 μM, respectively.

In this study, the fluorine-doped tin oxide (FTO) film on a glass substrate was etched by using a femtosecond pulsed laser with a wavelength of 1030 nm, a repetition rate of 1 MHz and a pulse duration of 262 fs. The effect of laser fluence and scanning speed on the quality of the groove etched on the FTO film surface was systematically studied, trying to improve the groove quality. The results indicated that in order to obtain high quality grooves for use on touch screens, a balance needed to be achieved between laser fluence and scanning speed. Excessive laser fluence caused cracks at the bottom of the groove with shoulder protrusions formed at the edge of the groove, and the scanning speed had a considerable influence on the groove width at the same time. After discussing and comparing the results of five groups of experiments, the best groove quality was determined at the scanning speed of 3000 mm/s and the laser fluence of 1.1 J/cm2. In this case, the edge of the groove was sharp without obvious cracks and shoulder-like protrusions, and the groove width was 7.92 μm, which made it possible to process small etched areas for touch screen. Furthermore, the optimal parameters were confirmed to be available for processing a pattern on the touch screen sensor layer with a line spacing of 5 μm.

Alternating current electrical dynamometer is a common device to measure the torque of engines, such as the gasoline engine. In order to solve the problems such as high cost, high energy consumption and complicated measurement system which exists in the direct measurement on the torque of alternating current electrical dynamometer, copper loss and iron loss are taken as two key factors and a soft-sensing model on the torque of alternating current electrical dynamometer is established using the fuzzy least square support vector machine (FLS-SVM). Then, the FLS-SVM parameters such as penalty factor and kernel parameter are optimized by adaptive genetic algorithm, torque soft-sensing is investigated in the alternating current electrical dynamometer, as well as the energy feedback efficiency and energy consumption during the measurement phase of a gasoline engine loading continual test is obtained. The results show that the minimum soft-sensing error of torque is about 0.0018, and it fluctuates within a range from −0.3 to 0.3 N-m. FLS-SVM soft-sensing method can increase by 1.6% power generation feedback compared with direct measurement, and it can save 500 kJ fuel consumption in the gasoline engine loading continual test. Therefore, the estimation accuracy of the soft measurement model on the torque of alternating current electrical dynamometer including copper loss and iron loss is high and this indirect measurement method can be feasible to reduce production cost of the alternating current electrical dynamometer and energy consumption during the torque measurement phase of a gasoline engine, replacing the direct method of torque measurement.

Timing resilient design has shown significant promise in mitigating the excess margins associated with rare worst-case data and increased process, voltage, and temperature variations. However, resilient circuits need error detecting sequential logic (EDL) to detect timing errors which incur area and power overhead. This paper proposes two alternatives to reduce the overhead in two-phase latch-based resilient circuits. The first is a new resiliency-aware graph-based approach to solve the retiming problem. The second uses a virtual resynthesis library to enable commercial synthesis tools to recognize the EDL overhead and optimize total area during retiming. We compare both approaches to a commercially standard retiming approach, which ignores the resiliency overheads, on a wide variety of benchmarks. Our experimental results show that our methods are computationally efficient and reduce the total circuit area by an average of up to 10%–15% when compared to traditional retiming.

Two novel cucurbitane glycosides, named as 11-oxomogroside III A1 and 7β-methoxy-mogroside V, along with sixteen known ones were isolated from the fruits of Siraitia grosvenori SWINGLE. The structures of the new compounds were characterized by chemical and extensive spectral methods.

A metal-formate framework with novel topology of (49·66)2(412·63), [DMA]2[FeIIIFe2II(HCOO)9] (DMA = (CH3)2NH2+), has been synthesized via solvothermal method, which exhibits long-range weak ferromagnetic ordering below 33 K. The Mossbauer spectra demonstrated the composite of the complex is a mixture valence of FeIII and FeII.

Selective laser ablation (SLA) of silver (Ag) films, which were deposited on glass substrates by radio frequency (RF) magnetron sputtering, was performed by using a 532 nm nanosecond (ns) pulsed laser. Two kinds of simple and mask-free SLA strategies featured by two new scanning paths (i.e. frame-typed serial scanning, FTSS, and frame-line combined scanning, FLCS) were proposed to improve the edge quality and optical transmittances of the SLA patterns. The effects of laser scanning speed (v), hatch distance (HD) and scanning path on edge quality of the laser-ablated grooves and SLA patterns were systematically studied. The results indicated that compared with the conventional line-typed cyclic scanning (LTCS) path, which resulted in unsmooth edge with semicircle-shaped boundaries and some Ag residues, the proposed scanning paths of FTSS and FLCS produced clean and smooth edges without obvious heat-affected zone and Ag residues under the condition of using a v value of 15 mm/s and an HD value of 90 μm. As a result, the as-obtained SLA patterns exhibited relatively high optical transmittances. The simple methods of adopting the FTSS or FLCS path for improving the edge quality during SLA and thus the optical transmittance of SLA patterns may have great potential application in various fields.

Multivariate longitudinal data arisen in medical studies often exhibit complex features such as censored responses, intermittent missing values, and atypical or outlying observations. The multivariate- t linear mixed model (MtLMM) has been recognized as a powerful tool for robust modeling of multivariate longitudinal data in the presence of potential outliers or fat-tailed noises. This paper presents a generalization of MtLMM, called the MtLMM-CM, to properly adjust for censorship due to detection limits of the assay and missingness embodied within multiple outcome variables recorded at irregular occasions. An expectation conditional maximization either (ECME) algorithm is developed to compute parameter estimates using the maximum likelihood (ML) approach. The asymptotic standard errors of the ML estimators of fixed effects are obtained by inverting the empirical information matrix according to Louis' method. The techniques for the estimation of random effects and imputation of missing responses are also investigated. The proposed methodology is illustrated on two real-world examples from HIV-AIDS studies and a simulation study under a variety of scenarios.

Graphical abstract, Highlights • Six new natural compounds were isolated from Millettia pachyloba Drake. • The cytotoxic activities of these new compounds were evaluated. • Ten (3–5, 9, 12, 17–19, 24, and 25) of 28 isolated compounds showed cytotoxicity. • The ten cytotoxic compounds induced autophagy in cancer cells. • Compound 9 induced apoptosis and autophagy, suggesting it could be a potential anticancer drug candidate., In this study, systematic separation and subsequent pharmacological activity studies were carried out to identify cytotoxic natural products from the dried stems of Millettia pachyloba Drake. Five previously undescribed isoflavones, pachyvones A–E; one previously undescribed xanthone, pachythone A; and twenty-two known compounds were obtained. The structures of these compounds were assigned on the basis of 1D/2D NMR data and high-resolution electrospray ionization mass spectroscopy analysis. Preliminary activity screening with HeLa and MCF-7 cells showed that ten compounds (3–5, 9, 12, 17–19, 24, and 25) had potential cytotoxicity. Further in-depth activity studies with five cancer cell lines (HeLa, HepG2, MCF-7, Hct116, and MDA-MB-231) and one normal cell line (HUVEC) revealed that these ten compounds showed specific cytotoxicity in cancer cells, with IC50 values ranging from 5 to 40 μM, while they had no effect on normal cell lines. To investigate whether the cytotoxicity of these ten compounds was associated with autophagy, their autophagic effects were evaluated in GFP-LC3-HeLa cells. The results demonstrated that compound 9 (durmillone) significantly induced autophagy in a concentration-dependent manner and had the best activity as an autophagy inducer among all of the compounds. Therefore, compound 9 was selected for further study. The PI/Annexin V double staining assay and Western blotting results revealed that compound 9 also induced obvious apoptosis in HeLa and MCF-7 cells, which suggests that it mediates cytotoxic activity through activation of both apoptosis and autophagy. Taken together, this study identified ten natural cytotoxic products from the dried stems of Millettia pachyloba Drake, of which compound 9 induced apoptosis and autophagy and could be an anticancer drug candidate.

Summary Hongkong kumquat (Fortunella hindsii) is a wild citrus species characterized by dwarf plant height and early flowering. Here, we identified the monoembryonic F. hindsii (designated as ‘Mini‐Citrus’) for the first time and constructed its selfing lines. This germplasm constitutes an ideal model for the genetic and functional genomics studies of citrus, which have been severely hindered by the long juvenility and inherent apomixes of citrus. F. hindsii showed a very short juvenile period (~8 months) and stable monoembryonic phenotype under cultivation. We report the first de novo assembled 373.6 Mb genome sequences (Contig‐N50 2.2 Mb and Scaffold‐N50 5.2 Mb) for F. hindsii. In total, 32 257 protein‐coding genes were annotated, 96.9% of which had homologues in other eight Citrinae species. The phylogenomic analysis revealed a close relationship of F. hindsii with cultivated citrus varieties, especially with mandarin. Furthermore, the CRISPR/Cas9 system was demonstrated to be an efficient strategy to generate target mutagenesis on F. hindsii. The modifications of target genes in the CRISPR‐modified F. hindsii were predominantly 1‐bp insertions or small deletions. This genetic transformation system based on F. hindsii could shorten the whole process from explant to T1 mutant to about 15 months. Overall, due to its short juvenility, monoembryony, close genetic background to cultivated citrus and applicability of CRISPR, F. hindsii shows unprecedented potentials to be used as a model species for citrus research.

The morphology and phylogeny of two little-known species, Loxodes kahli Dragesco & Njine, 1971 and L. rostrumMuller, 1786, isolated from freshwater muddy sediments in China, were investigated based on live features, infraciliature, and small subunit ribosomal DNA (SSU rDNA) sequence data. Loxodes kahli is distinguished from its congeners mainly by the number and arrangement of macronuclei (6–17 in one row) and the number of right somatic ciliary rows (11–26). The Chinese populations of L. kahli also exhibit differences with other populations in terms of the body size and the number of right ciliary rows. The characteristics of L. rostrum are consistent with those of previous studies except for the number of right ciliary rows (9–10). The studied species were redefined based on the new information and previous descriptions. This study also gave a brief morphological summary of the species in the genus Loxodes by an identification key. SSU rDNA sequence-based phylogenetic analyses revealed that both species are grouped with their congeners, supporting the monophyly of the genus Loxodes.

A selective, simple and environment-friendly type fluorescence sensing platform between upconversion nanoparticles (UCNPs) and melanin-like polymer utilizing the photoinduced electron-transfer (PET) mechanism was developed. The effective fluorescence quenching of UCNPs by melanin-like polymers could detect tyramine and tyrosinase (TYR) activity through the bio-catalysed oxidation of tyramine to the melanin-like polymer products. At optimal conditions, the range of linearity in detection was 0.167–33.3 μΜ for tyramine, and the limit of detection of tyramine was 0.026 μΜ. The linear range of TYR was 0.0033–1 U·mL−1, and the limit of detection of TYR was 0.003 U·mL−1. Furthermore, the strategy could be applied to real sample analysis with satisfactory results.

Objectives The aim of this study was to investigate whether the direct damage of the articular fibrous layers without condylar fracture, combined with discectomy, was enough to induce temporomandibular joint (TMJ) ankylosis. Study Design Bilateral TMJ surgery was performed in 8 growing sheep. The lateral 2/3 of disc removal (DR) was performed on the control side, whereas the lateral 2/3 of disc and articular fibrous layers removal (DFLR) were performed on the experimental side. Four and 4 animals were sacrificed respectively at 1 and 3 months postoperatively. Results Fibrous ankylosis was achieved on the DFLR side of the 2 of 4 sheep, and fibro-osseous ankylosis in the other 2 sheep at 1 month after surgery. Fibro-osseous ankylosis developed on the DFLR side of 4 sheep at 3 months postoperatively. On the DR side of animals, pathological characteristics of TMJ osteoarthritis could be found, however no evidence of ankylosis was observed. The scores of TMJ ankylosis for the DR side were significantly lower than that of the DFLR side at different time points ( P Conclusion This study demonstrated that removal of articular fibrous layers combined with discectomy can lead to traumatic TMJ ankylosis.

For studying how crystal field perturbation influence magnetic relaxation behaviors of Ln-SMMs, four complexes of [Ln(H2L)(NO3)(H2O)(EtOH)](NO3)2·H2O (Ln = Dy (1), Tb (2)) and [Ln(L)(NO3)(MeOH)2] (Ln = Dy (3), Tb (4)) were synthesized by utilizing planar pentadentated Schiff-base ligand H2L [2,6-diylbis(ethan-1-yl-1-ylidene)di(isonicotinohydrazide)] under different alkaline conditions. They all have similar mononuclear structures with LnIII ion in nine-coordinated muffin geometry. Crystal field was slightly perturbed by deprotonating H2L ligand and using different solvent molecules in DyIII complex 3, which result in field-induced two-step relaxation processes with almost 3-fold increase in Ueff of 57.52 K (SR) and 28.49 K (FR) than 20.63 K for complex 1 showing one-step relaxation process. This work gives another example of improving SMM behavior simply by subtle crystal field perturbation.

Background: Positive surgical margins are independent risk factor for biochemical recurrence, local recurrence, and distant metastasis after radical prostatectomy. However, limited predictive tools are available. This study aimed to develop and validate a preoperative nomogram for predicting positive surgical margins after laparoscopic radical prostatectomy (LRP). Methods: From January 2010 to March 2016, a total of 418 patients who underwent LRP without receiving neoadjuvant therapy at Peking University Third Hospital were retrospectively involved in this study. Clinical and pathological results of each patient were collected for further analysis. Univariable and multivariable logistic regression (backward stepwise method) were used for the nomogram development. The concordance index (CI), calibration curve analysis and decision curve analysis were used to evaluate the performance of our model. Results: Of 418 patients involved in this study, 142 patients (34.0%) had a positive surgical margin on final pathology. Based on the backward selection, four variables were included in the final multivariable regression model, including the percentage of positive cores in preoperative biopsy, clinical stage, free prostate specific antigen (fPSA)/total PSA (tPSA), and age. A nomogram was developed using these four variables. The concordance index (C-index) of the nomogram was 0.722 in the development cohort and 0.700 in the bootstrap validations. The bias-corrected calibration plot showed a limited departure from the ideal line with a mean absolute error of 2.0%. In decision curve analyses, the nomogram showed net benefits in the range from 0.2 to 0.7. Conclusion: A nomogram to predict positive surgical margins after LRP was developed and validated, which could help urologists plan surgical procedures. Key words: Prostate cancer; Positive surgical margins; Laparoscopic radical prostatectomy; Nomogram

The Taiwan Strait (TS) directly connects two of the richest fishing grounds in the world - the East China Sea (ECS) and the South China Sea (SCS). Carbon and nutrient supplies are essential for primary production and the Yangtze River is an important source for the ECS. However the ECS is severely P-limited. The TS transports an order of magnitude more carbon and a factor of two more phosphate (P) to the ECS than the Yangtze River does. To evaluate the temporal variability of these supplies, the total alkalinity (TA), dissolved inorganic carbon (DIC), nitrate plus nitrite (N), P, and silicate (Si) fluxes through the TS were estimated using empirical equations for these parameters and the current velocity, which was estimated using the Hybrid Coordinate Ocean Model (HYCOM). These empirical equations were derived from in situ salinity and temperature and measured chemical concentrations that were collected during 57 cruises (1995–2014) with a total of 2096 bottle samples. The 24-month moving averages of water, carbon, and nutrient fluxes significantly increase with time, so does the satellite chlorophyll a concentration. More importantly, the increased supply of the badly needed P from the TS is more than that from the Yangtze River.

Fear extinction is generally considered a form of new learning that inhibits previously acquired fear memories. Here, by tracking immediate early gene expression in vivo, we found that contextual fear extinction training evoked distinct neural ensembles in mouse retrosplenial cortex (RSC). The optogenetic reactivation of these extinction-activated neurons in the RSC was sufficient to suppress a fear response, while the reactivation of conditioning-activated neurons in the same area promoted a fear response. The generation of such an extinction-memory-related neural ensemble was associated with adult neurogenesis, as abolishing newborn neurons in the adult hippocampus via X-ray irradiation eliminated both the extinction-activated neurons in the RSC and the optogenetic-reactivation-induced suppression of contextual fear memory. Therefore, switching from fear to no fear in response to the same context is modulated by the RSC through an extinction-activated neural ensemble, the generation of which might require adult neurogenesis in the hippocampus.

We used atomic force microscopy to characterize the surface topography of p-GaN exposed to N2 and NH3 plasma under quasi-atmospheric pressure using a microwave-excited plasma source with a microstrip line structure. The exposure time was varied from 2 to 20 min at a substrate temperature of 700 °C. Under both N2 and NH3 plasma exposure for 2 min, the ridge-shaped features on the surface of as-grown p-GaN dulled immediately and the surface roughness decreased remarkably, whereas the atomic step structure of the surface was maintained. The step crossing and bunching of the surface disappeared with increasing exposure time to both types of plasma. However, increasing the NH3 plasma exposure time to 20 min led to the formation of pits and appearance of particles along the step edges, resulting in drastic roughening of the surface. Thus, GaN surfaces can be smoothed without the destruction of their step structures via moderate plasma exposure under quasi-atmospheric pressure, and these plasma sources could prospectively be used in metal-organic chemical vapor deposition systems for nitride semiconductor growth.

Background Triple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC. Methods Data from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model. Findings TCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter. Interpretation These findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.

Background: Triple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC. Methods: Data from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model. Findings: TCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter. Interpretation: These findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.

Using different N-oxide ligands to tune the Ln–Ln magnetic interactions and their magnetic relaxation behaviors, herein, three one-dimensional chain complexes, [Ln(hfac)3(4,4′BipyNO)]∞ (Ln = Dy(1), Tb(2) and Ho(3); 4,4′BipyNO = 4,4′-bipyridine-N,N′-dioxide), and three dinuclear complexes, [Ln(hfac)3(PzNO)]2 (Ln = Dy(4), Tb(5) and Ho(6); PzNO = pyrazine-N-oxide), were synthesized and characterized. The central LnIII ions of the six complexes are in an analogous LnO8 coordination environment. Magnetic investigations indicated that the chain complex 1 with negligible Dy–Dy magnetic interactions through the 4,4′BipyNO ligand and low DyIII symmetry (D2d) showed a poor slow relaxation behavior with the average energy barrier of 11.79 K under a 600 Oe dc field. However, for the complex 4, the relatively stronger Dy–Dy antiferromagnetic interactions (J = −2.36 cm−1) through the μ-O PzNO ligand combined with an improved DyIII symmetry (near D4d) significantly enhance the Ueff to 226.73 K, which records the highest Ueff for any beta-diketone constructed SMMs and also the third-highest one among all DyIII-only dimers under zero dc field to date. This study also provides another example of conspicuously improving the energy barrier of Ln-SMMs by the synergistic effect of strengthened Dy–Dy magnetic interactions and improved DyIII symmetry.

Broomcorn millet (Panicum miliaceum L.) has strong tolerance to abiotic stresses, and is probably one of the oldest crops, with its earliest cultivation that dated back to ca. ~10,000 years. We report here its genome assembly through a combination of PacBio sequencing, BioNano, and Hi-C (in vivo) mapping. The 18 super scaffolds cover ~95.6% of the estimated genome (~887.8 Mb). There are 63,671 protein-coding genes annotated in this tetraploid genome. About ~86.2% of the syntenic genes in foxtail millet have two homologous copies in broomcorn millet, indicating rare gene loss after tetraploidization in broomcorn millet. Phylogenetic analysis reveals that broomcorn millet and foxtail millet diverged around ~13.1 Million years ago (Mya), while the lineage specific tetraploidization of broomcorn millet may be happened within ~5.91 million years. The genome is not only beneficial for the genome assisted breeding of broomcorn millet, but also an important resource for other Panicum species., Broomcorn millet is one of the oldest crops cultivated by human that has strong abiotic stress tolerance. To facilitate genome assisted breeding of this and related species, the authors report its genome assembly and conduct comparative genome structure and evolution analyses with foxtail millet.

A novel nickel(ii) complex, [Ni(2,2'-bpy)3](H2SBTC)(H2O)5 (1) (2,2'-bpy = 2,2'-bipyridyl), was synthesized based on [Ni(2,2'-bpy)3]2+ discrete units and a partially deprotonated sulfonate-carboxylate ligand of H4SBTC (5-sulfonyl-1,2,4-benzentricarboxylic acid). The adjacent [Ni(2,2'-bpy)3]2+ cationic units were connected to H2SBTC2- anions by hydrogen bonds to form a one-dimensional (1-D) chain. The 1-D chains were further linked using hydrogen bonds from free water molecules and H2SBTC2- anions to generate a two-dimensional (2-D) plane structure. The proton conductivity of 1 reaches 1.3 × 10-4 S cm-1 at 318 K, 98% RH. Furthermore, hybrid membranes composed of polyvinyl alcohol (PVA) and 1 as fillers were prepared with different mass percentages. The proton conductivity of 1@PVA-5 was found to be 1.6 × 10-3 S cm-1 at 313 K and 98% RH. The large number of alcoholic hydroxyl groups in PVA promote the resulting conductivity.

The norepinephrine neurons in locus coeruleus (LC-NE neurons) are essential for sleep arousal, pain sensation, and cocaine addiction. According to previous studies, cocaine increases NE overflow (the profile of extracellular NE level in response to stimulation) by blocking the NE reuptake. NE overflow is determined by NE release via exocytosis and reuptake through NE transporter (NET). However, whether cocaine directly affects vesicular NE release has not been directly tested. By recording quantal NE release from LC-NE neurons, we report that cocaine directly increases the frequency of quantal NE release through regulation of NET and downstream protein kinase C (PKC) signaling, and this facilitation of NE release modulates the activity of LC-NE neurons and cocaine-induced stimulant behavior. Thus, these findings expand the repertoire of mechanisms underlying the effects of cocaine on NE (pro-release and anti-reuptake), demonstrate NET as a release enhancer in LC-NE neurons, and provide potential sites for treatment of cocaine addiction.

Purpose: The glycoprotein Trop-2 is frequently overexpressed in human malignancies and linked to worse outcome. A Trop2-targeting antibody-drug conjugate, sacituzumab govitecan, has been approved by the FDA for patients with unresectable locally advanced or metastatic triple-negative breast cancer. Trop-2 enhances Akt phosphorylation in numerous cancer cell lines, while the opposite findings are also reported suggesting the cell context-dependent effect of Trop-2. Blockade of PI3K/Akt pathway mediates anti-tumor mechanism of anti-HER2 agents. In this study, we aim to investigate the role of Trop-2 in HER2-positive breast cancer. Experimental design: The archival samples comprising different breast cancer subtypes were analyzed using immunohistochemical staining. The public databases, including, Metabric, KM plotter, ROC plotter, were used to verify the prognostic role and clinical significance of Trop-2 in HER2-positive breast cancer. In vitro tumor models, the transwell migration, invasion and sphere assays, were applied for evaluation of cancer progression. The apoptotic cells were determined by flow cytometry using Annexin V/propidium iodide double staining. Results: We analyzed a cohort of 986 breast cancer patients and found that HER2-positive breast cancer harbored higher Trop-2 protein expression than other breast cancer subtypes. Higher levels of Trop-2 and phospho-Akt in HER2-positive breast cancer tissues compared with normal tissues. Trop-2 expression was correlated with tumor stage and phospho-Akt level. HER2-positive breast cancer patients with high level of Trop-2 protein were linked to worse recurrence-free survival. Consistently, data from the public databases exhibited patients with higher level of Trop-2 transcript had shorter recurrence-free survival and overall survival of HER2-positive breast cancer. Overexpression of Trop-2 increased cell migration, invasion and sphere number in SK-BR-3 and BT-474 cells. In contrast, knockdown of Trop-2 suppressed cell motility and sphere formation. Trop-2-expressing cells had better cell viability compared to control cells in the presence of lapatinib or neratinib treatment. Lapatinib- and neratinib-induced cell apoptosis was rescued by Trop-2 overexpression. Notably, patients responded to anti-HER2 therapy had lower Trop-2 transcript expression than non-responders. Conclusion: These results suggested that the oncogenic role of Trop-2 in HER2-positive breast cancer and Trop-2 expression might confer resistance to anti-HER2 therapy. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Pei-Yi Chu, Chun-Teng Huang, Wan-Lun Wang, Chi-Cheng Huang, Po-Han Lin, Ling-Ming Tseng. Significance of Trop-2 in HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5127.

Endoscopic submucosal dissection (ESD) has become the standard treatment for superficial esophageal squamous cell neoplasia (SESCN); however, local recurrence still occurs occasionally even in patients who meet the current curative criteria. Esophageal ducts of the submucosal gland may serve as a pathway for the spread of SESCN to a deeper layer. However, the clinical impact of ductal involvement (DI) in patients undergoing ESD has yet to be investigated.We consecutively enrolled patients with SESCN who were treated with ESD. The resected specimens were meticulously reviewed in multiple section slices for the presence and resected margins of DI, and their correlations with clinical factors were evaluated.A total of 210 lesions were analyzed, of which 78 (37.1%) presented with DI. The presence of submucosal invasion, lymphovascular invasion (LVI), and DI were indicators of worse prognosis (P .05). Deep extended DIs were misdiagnosed as deep submucosal invasive cancer in 4 cases (2%). Of the 185 patients who met the criteria for curative ESD (ie, R0 resection and no deep submucosal invasion or LVI), 11 (5.9%) developed local recurrence/metastasis during a mean follow-up of 55.2 months (range, 6 to 140) months. Compared with patients with without DI, patients with DI had worse recurrence-free survival (P = .008, log-rank test) and a higher local risk of recurrence (12.7% vs 2.5%) after curative ESD (hazard ratio, 4.20; P = .038).A precise histological assessment of DI in SESCN is crucial after ESD, given that DI is common and associated with worse outcome. Whether total removal of esophageal glands/ducts can improve outcome requires future study.

A new triterpene diglycoside, tibesaikosaponin V (TKV), was isolated from the methanol extract of the roots of Bupleurum chinense DC. by normal and reversed phase column chromatography. The chemical structure of this new compound was elucidated based on extensive spectroscopic analysis, including 1D and 2D NMR, HR-ESI-MS, and chemical degradation method. Our results indicated that TKV inhibited lipid accumulation and triacylglycerol content occurred without cytotoxicity to 3T3-L1 adipocytes. Furthermore, TKV significantly suppressed the mRNA expression of nuclear transcription factors such as, peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). These results suggest that TKV shows the ability to inhibit 3T3-L1 preadipocyte differentiation of and may have therapeutic potential for obesity and its associated metabolic disorders.

Finite mixtures of multivariate skew distributions have become increasingly popular in recent years due to their flexibility and robustness in modeling heterogeneity, asymmetry and leptokurticness of the data. This paper introduces a novel finite mixture of multivariate scale-shape mixtures of skew-normal distributions to enhance strength and flexibility when modeling heterogeneous multivariate data that contain more extreme non-normal features. A computational tractable ECM algorithm which consists of analytically simple E- and CM-steps is developed to carry out maximum likelihood estimation of parameters. The asymptotic covariance matrix of parameter estimates is derived from the observed information matrix using the outer product of expected complete-data scores. We demonstrate the utility of the proposed approach through simulated and real data examples.

Laparoscopic sleeve gastrectomy (LSG) has been proved to be the most effective treatment strategy for the treatment of type 2 diabetes mellitus (T2DM) with a body mass index ≥ 30 kg/m2 achieving high remission rates. However, there are few clinical studies on the treatment of T2DM patients with a body mass index less than 30 kg/m2 by LSG. This study aims to study the effect of LSG on type 2 diabetes mellitus(T2DM) in patients with a body mass index (BMI) less than 30 kg/m2. The clinical data of 25 patients with type 2 diabetes mellitus (T2DM) and body mass index 23.23–29.97 kg/m2 who were treated by LSG at the Department of Bariatric and Metabolic Surgery in China-Japan Union Hospital of Jilin University from May 2016 to May 2017 were retrospectively analyzed. The changes of fasting plasma glucose, glycosylated hemoglobin, insulin resistance index, body weight, body mass index, waist circumference, blood pressure, heart rate, blood lipids, and uric acid were analyzed at 3 months, 6 months, and 12 months after operation, respectively. All the clinical data were analyzed by SPSS 22.0. They were tested with a single-sample K-S test to determine whether they were normal distribution data. The normal distribution data were analyzed by a matched t test, and the Mann-Whitney test was used to examine skewed data. All patients (9 males, 16 females) with a median age of 57(24~65) years were treated successfully by laparoscopic sleeve gastrectomy. The median duration of type 2 diabetes mellitus was 10(0~20)years. The preoperative fasting plasma glucose, glycosylated hemoglobin, body weight, body mass index, and waist circumference were 10.32 ± 2.66 mmol/L,8.20 ± 1.47%,76.54 ± 10.02 kg,27.92 ± 1.72 kg/m2, and 99.88 ± 5.38 cm, respectively. The meaning fasting plasma glucose was 7.26 ± 1.36 mmol/L, 6.90 ± 1.07 mmol/L, and 6.62 ± 0.97 mmol/L, respectively, at 3, 6, and 12 months after operation. The mean HbAlc in the same observation intervals was 6.88 ± 1.23%,6.54 ± 1.02%, and 6.51 ± 0.89%, respectively. The body weight was 62.18 ± 8.38 kg,59.07 ± 8.58 kg, and 58.62 ± 8.53 kg, respectively. The corresponding body mass index was 22.56 ± 1.56 kg/m2, 21.35 ± 1.58 kg/m2, and 21.24 ± 1.86 kg/m2, respectively. The waist circumference was 82.84 ± 5.10 cm,78.60 ± 5.21 cm, and 76.92 ± 5.21 cm, respectively. The complete remission rates of type 2 diabetes mellitus were 40%, 60%, and 68%, respectively, at 3, 6, and 12 months after operation. The complete remission rates for insulin resistance index were 52.4%, 80%, and 80%, postoperatively, at 3, 6, and 12 months, respectively. The complete remission rates of hypertension were 22.2%, 50%, and 75%,respectively, at 3,6, and 12 months after operation. The complete remission rates of hypertriglyceridemia were 66.7%, 66.7%, and 100%,and the complete remission rates of hypercholesterolemia were 41.7%, 60%, and 100%;the abnormal elevations of plasma cholesterol in two patients with normal cholesterol before operation were significantly higher, postoperatively, at 3 monthsand 6 months, respectively. The complete remission rates of hyperuricemia were 37.5%, 33.3%, and 100% in the same observation period, respectively. The abnormal elevations of uric acid in two patients with normal uricemia before operation were significantly higher at postoperative 3 months. LSG has a significant effect on patients with type 2 diabetes mellitus whose BMI less than 30 kg/m2 in a short time, but its long-term effectiveness needs to be further followed up.

Two new lanthanide complexes of nitronyl nitroxide radical have been synthesized and characterized on the structure, magnetism and fluorescence: [Ln(hfac)3(NITPh-(OCH3)2)2](Ln = (Tb(1),Dy(2)), (NITPh-(OCH3)2 = 2-(3′,4′-dimethoxy-phenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide); hfac = hexafluoroacetylacetonate). Two complexes crystallize in monoclinic space group C2/c, which have similar mononuclear structures. The central metal ion is eight coordinated by six oxygen atoms from three hfac molecules and two oxygen atoms from two nitronyl nitroxide radicals. The varying temperature magnetic susceptibility indicates that there are weak antiferromagnetic interaction between metal ions and nitronyl nitroxide radicals in complexes 1 (zJ′ = −0.145 cm−1) and 2 (zJ′ = −0.140 cm−1). Ac magnetic susceptibility studies exhibit no single-molecule magnet behavior in complexes 1 and 2. In addition, the fluorescence properties of 1 show that it is an excellent fluorescent probe of recognizing Cr2O72− anion. Because of the linear relationship at low concentration and detection limit reached 1 × 10−7 M, it can be used as a luminescence-based sensor for quantitative analysis.

A simple transparent cover-assisted laser annealing strategy, which used a coverglass or a PET sheet as the transparent cover, was proposed to improve photoelectric properties of fluorine-doped tin oxide (FTO) thin films. Pure laser annealing was also performed for comparison. Transparent cover-assisted laser annealing was found to be more effective for producing densely distributed particles, decreasing surface roughness and increasing grain size, thus enhancing transmittance and conductivity of the film. More importantly, compared with coverglass-assisted laser annealing, PET-assisted laser annealing enabled the film surface to be covered with more uniform and denser particles and exhibit a remarkable increase in grain size. Therefore the film had the highest total transmittance of 84.32%, the highest specular transmittance of 75.88%, a slightly decreased haze of 10.01% and the lowest sheet resistance of 7.36 Ω/sq. The simple PET-assisted laser annealing method may be a promising substitution for the conventional laser annealing treatment.

Recent research has confirmed the feasibility of backdoor attacks in deep reinforcement learning (RL) systems. However, the existing attacks require the ability to arbitrarily modify an agent's observation, constraining the application scope to simple RL systems such as Atari games. In this paper, we migrate backdoor attacks to more complex RL systems involving multiple agents and explore the possibility of triggering the backdoor without directly manipulating the agent's observation. As a proof of concept, we demonstrate that an adversary agent can trigger the backdoor of the victim agent with its own action in two-player competitive RL systems. We prototype and evaluate BackdooRL in four competitive environments. The results show that when the backdoor is activated, the winning rate of the victim drops by 17% to 37% compared to when not activated. The videos are hosted at https://github.com/wanglun1996/multi_agent_rl_backdoor_videos.

Soil-shrinkage curve (SSC) is an intrinsic constitutive relationship characterizing soil deformation due to variation of water content under drying. The determination of SSC has been chall...

A Zr-based metal-organic polyhedron (MOP) was self-assembled in a porous MOF host, DUT-68, successfully to synthesize MOP-1@DUT-68. The MOP guest (MOP-1) has a diameter of about 20 A, larger than that of the square windows (pore sizes of ∼14 A) of DUT-68 but smaller than that of the rhombicuboctahedral cage (27.7 A), which means that the migration and leaching of MOP-1 could be effectively prohibited if MOP-1 is encapsulated in the MOF's cavities. The proton conductivity of MOP-1@DUT-68 is 1.14×10-3 S cm-1 (at 80 °C under 98 % relative humidity), which is three orders of magnitude higher than that of DUT-68. Compared with MOP-1⊂DUT-68, which was synthesized by impregnation, MOP-1@DUT-68 is more prone to form faster proton-conduction pathways and thus provides higher proton conductivity.

Herein, TKP-2-1, a water-soluble polysaccharide with a weight-average molecular weight of 1693 kDa, was isolated from the seed kernels of Tamarindus indica L. UV, FT-IR, GC–MS and 1D, 2D-NMR data analysis revealed that TKP-2-1 is chiefly composed of a (1 → 4)-β-D-glucan backbone with side chains of α-D-xylopyranosyl, α-D-xylopyranosyl-(1 → 4)-β-D-galactopyranosyl and β-D-galactopyranosyl-(1 → 2)-α-D-xylopyranosyl sugar moieties linked to the C-6 positions of the glucose residues. Furthermore, TKP-2-1 exhibited a potent immunostimulatory activity through enhancing phagocytosis and NO production, as well as the expression of iNOS, IL-1β, IL-6, and TNF-α in RAW264.7 macrophages. Mechanistically, TKP-2-1 caused the degradation of IκBα and nuclear translocation of NF-κB p65, and phosphorylation of ERK, JNK and p38 MAPK in RAW264.7 cells. Specific inhibitors of NF-κB, ERK, JNK, and p38 MAPK obviously abolished TKP-2-1-induced NO production in RAW264.7 cells, respectively. Thus, TKP-2-1 from the seed kernels of T. indica might potentially be used as a natural immunomodulator in functional foods.