Explore the vast range of titles available.

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and has important roles in multiple aspects of cancer aggressiveness. Thus targeting STAT3 promises to be an attractive strategy for treatment of advanced metastatic tumors. Although many STAT3 inhibitors targeting the SH2 domain have been reported, few have moved into clinical trials. Targeting the DNA-binding domain (DBD) of STAT3, however, has been avoided due to its ‘undruggable‘ nature and potentially limited selectivity. In a previous study, we reported an improved in silico approach targeting the DBD of STAT3 that resulted in a small-molecule STAT3 inhibitor (inS3-54). Further studies, however, showed that inS3-54 has off-target effect although it is selective to STAT3 over STAT1. In this study, we describe an extensive structure and activity-guided hit optimization and mechanistic characterization effort, which led to identification of an improved lead compound (inS3-54A18) with increased specificity and pharmacological properties. InS3-54A18 not only binds directly to the DBD and inhibits the DNA-binding activity of STAT3 both in vitro and in situ but also effectively inhibits the constitutive and interleukin-6-stimulated expression of STAT3 downstream target genes. InS3-54A18 is completely soluble in an oral formulation and effectively inhibits lung xenograft tumor growth and metastasis with little adverse effect on animals. Thus inS3-54A18 may serve as a potential candidate for further development as anticancer therapeutics targeting the DBD of human STAT3 and DBD of transcription factors may not be ‘undruggable‘ as previously thought.

A novel dsRNA virus was identified by high-throughput sequencing from tea oil trees in China. Its complete genome of 4714 bp contains two open reading frames (ORFs). ORF1 encodes a putative coat protein (CP) of 702 amino acids (aa), and ORF2 codes for an RNA-dependent RNA polymerase (RdRp) of 855 aa. The virus shares the highest aa sequence identity of 45.21% in RdRp with taro-associated totivirus L (MN_119621), a member of the genus Totivirus in the family Totiviridae. Phylogenetic analysis of the aa sequences of the RdRp places the new virus in a group with other totiviruses, suggesting that this virus, which is provisionally named \"tea-oil camellia-associated totivirus 1\", should be considered a member of the genus Totivirus.

This study aims to investigate the expression status of miRNA-216b in familial hepatocellular carcinoma (HCC) and the correlation between miRNA-216b expression and pathogenesis, as well as the progression of HCC. The expression profile of miRNAs in plasma of peripheral blood between HCC patients with HCC family history and healthy volunteers without HCC family history was determined by microarray. Using real-time quantitative PCR to detect the expression in paired tissues from 150 patients with HCC, miR-216b was selected as its expression value in HCC patients was significantly lower compared with healthy volunteers. Next, miR-216b expression and the clinicopathological features of HCC were evaluated. The effect of miR-216b expression on tumor cells was investigated by regulating miR-216b expression in SMMC-7721 and HepG2 in vitro and in vivo . Finally, we explored mRNA targets of miR-216b. In 150 HCC, 37 (75%) tumors showed reduced miR-216b expression comparing with their adjacent liver tissues. The decreased expression of miR-216b was significantly correlated with tumor volume ( P =0.044), HBV infection ( P =0.026), HBV DNA quantitative ( P =0.001) and vascular invasion ( P =0.032). The 5-year disease-free survival and overall rates after liver resection in low expression and high expression groups of miR-216b are 62% and 54%, 25% and 20%, respectively. MiR-216b overexpression inhibited cell proliferation, migration and invasion, and miR-216b inhibition did the opposite. The expression of hepatitis B virus x protein (HBx) has tight correlation with downregulation of miR-216b. Furthermore, miR-216b downregulated the expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and exerted its tumor-suppressor function through inhibition of protein kinase B and extracellular signal-regulated kinase signaling downstream of IGF2. MiR-216b inhibits cell proliferation, migration and invasion of HCC by regulating IGF2BP2 and it is regulated by HBx.

Despite increasing evidence indicating the essential involvement of selenium (Se) on growth performance, antioxidant capacity, and meat quality of commercial broilers, the effects of different Se sources on local Chinese Subei chickens is unclear. A total of 360 50-day-old male chickens were individually weighed and randomly allocated to four treatment groups. Chickens in each of the four groups were fed diets supplemented with 0.3 mg Se/kg as sodium Se (SS), Se-enriched yeast (SY), selenomethionine (Met-Se), or nano red element Se (Nano-Se) for 40 days. At the end of the experiment, one bird of approximately average weight from each cage was selected and slaughtered, and blood and breast muscles samples were collected. The results showed that there was no significant difference in feed intake, body weight gain, or feed to gain ratio among treatments (P > 0.05). Dietary SY, Met-Se, and Nano-Se supplementation increased the activity of glutathione peroxidase in serum and breast muscles and decreased the concentration of malondialdehyde in serum and carbonyl in breast muscles compared with the SS group (P < 0.05). Moreover, SY, Met-Se, and Nano-Se supplementation increased pH45min, total protein solubility, and myofibrillar protein solubility, as well as decreased the shear force value compared with the SS group (P < 0.05). In addition, birds in the SY and Met-Se groups exhibited lower cooking loss compared with the SS group (P < 0.05). In conclusion, organic Se and Nano-Se supplementation resulted in an improvement of antioxidant capacity and meat quality in local Chinese Subei chickens relative to inorganic Se.

A direct measurement of cosmic-ray electrons and positrons with unprecedentedly high energy resolution reveals a spectral break at about 0.9 teraelectronvolts, confirming the evidence found by previous indirect measurements. A break in the cosmic-ray spectrum The spectrum of cosmic-ray electrons and positrons that arrive at Earth potentially contains information about the sources that accelerated them, and may reveal dark-matter annihilation. The spectrum has previously been measured directly up to around 2 teraelectronvolts (TeV), and indirectly up to around 5 TeV from ground-based Cherenkov arrays, which revealed a possible break in the spectrum. The Dark Matter Particle Explorer (DAMPE) Collaboration reports a direct measurement between 25 gigaelectronvolts and 4.6 TeV, which clearly reveals a spectral break at around 0.9 TeV. High-energy cosmic-ray electrons and positrons (CREs), which lose energy quickly during their propagation, provide a probe of Galactic high-energy processes 1 , 2 , 3 , 4 , 5 , 6 , 7 and may enable the observation of phenomena such as dark-matter particle annihilation or decay 8 , 9 , 10 . The CRE spectrum has been measured directly up to approximately 2 teraelectronvolts in previous balloon- or space-borne experiments 11 , 12 , 13 , 14 , 15 , 16 , and indirectly up to approximately 5 teraelectronvolts using ground-based Cherenkov γ-ray telescope arrays 17 , 18 . Evidence for a spectral break in the teraelectronvolt energy range has been provided by indirect measurements 17 , 18 , although the results were qualified by sizeable systematic uncertainties. Here we report a direct measurement of CREs in the energy range 25 gigaelectronvolts to 4.6 teraelectronvolts by the Dark Matter Particle Explorer (DAMPE) 19 with unprecedentedly high energy resolution and low background. The largest part of the spectrum can be well fitted by a ‘smoothly broken power-law’ model rather than a single power-law model. The direct detection of a spectral break at about 0.9 teraelectronvolts confirms the evidence found by previous indirect measurements 17 , 18 , clarifies the behaviour of the CRE spectrum at energies above 1 teraelectronvolt and sheds light on the physical origin of the sub-teraelectronvolt CREs.

The conjunctive use of surface water and groundwater is practiced worldwide as a measure to address water supply uncertainty. This paper focuses on a scenario in which an aquifer is open to multiple users and examines the impact of such an open-access environment on the stabilization function of conjunctive management. We construct a non-cooperative stochastic dynamic game model where multiple users utilize groundwater intake from a common aquifer as a complement to fluctuating surface water. We also propose a simpler baseline applicable to dynamic environments to compute the benefits of the stabilization function when users are unable to adjust groundwater intake to surface water uncertainties. We then apply the model to the real-world case of the water supply environment of the Cao’e River in China. Simulation results show that open access leads to diminishing stabilization values as higher pumping costs due to declining stocks lead to a weakening of users’ incentive to utilize groundwater flexibly. Furthermore, the stabilization function itself is destabilized as the number of users increases. This is because greater groundwater intake and a decline in stocks amplify variations in pumping costs caused by different patterns of surface-water fluctuation.

Internal tandem duplications (ITDs) in the fms -like tyrosine kinase receptor (FLT3-ITDs) confer a poor prognosis in acute myeloid leukemia (AML). We hypothesized that increased recruitment of the protein tyrosine phosphatase, Shp2, to FLT3-ITDs contributes to FLT3 ligand (FL)-independent hyperproliferation and STAT5 activation. Co-immunoprecipitation demonstrated constitutive association of Shp2 with the FLT3-ITD, N51-FLT3, as well as with STAT5. Knockdown of Shp2 in Baf3/N51-FLT3 cells significantly reduced proliferation while having little effect on WT-FLT3-expressing cells. Consistently, mutation of N51-FLT3 tyrosine 599 to phenylalanine or genetic disruption of Shp2 in N51-FLT3-expressing bone marrow low-density mononuclear cells reduced proliferation and STAT5 activation. In transplants, genetic disruption of Shp2 in vivo yielded increased latency to and reduced severity of FLT3-ITD-induced malignancy. Mechanistically, Shp2 co-localizes with nuclear phospho-STAT5, is present at functional interferon-γ activation sites (GAS) within the BCL2L1 promoter, and positively activates the human BCL2L1 promoter, suggesting that Shp2 works with STAT5 to promote pro-leukemogenic gene expression. Further, using a small molecule Shp2 inhibitor, the proliferation of N51-FLT3-expressing bone marrow progenitors and primary AML samples was reduced in a dose-dependent manner. These findings demonstrate that Shp2 positively contributes to FLT3-ITD-induced leukemia and suggest that Shp2 inhibition may provide a novel therapeutic approach to AML.

Background Acne vulgaris is a prevalent skin condition. We have found that some acromegaly patients have acne. However, no study has examined the relationship between acromegaly and acne. Objective To explore prevalence and correlation of adult acne in patients with acromegaly. Methods For this cross-sectional study, we collected questionnaires, clinical information, and laboratory test results of acromegaly patients from January 2022 to December 2022 at Huashan Hospital. Of the 133 questionnaires returned, 123 had valid responses. Results Of the 123 patients with acromegaly enrolled in this study, 54.5% had adult acne. No statistically significant difference was found in prevalence between male and female patients. 61.2% of adult acne patients reported late-onset acne. Late-onset acne patients first developed acne years before acromegaly diagnosis (mean of 5.6 years for male and 4.5 years for female patients). Some acne patients have received traditional anti-acne treatment. Moreover, 31% of the patients reported no improvement, and only 3.5% of patients claimed complete resolution of acne after treatment. Before acromegaly treatment, the prevalence of adult acne was 51.2%, with mild acne accounting for 73.0%, moderate acne accounting for 23.8%, and severe acne accounting for 3.2%. After acromegaly treatment, the prevalence of adult acne was significantly decreased to 37.4% ( P  = 0.007). An overall decrease in acne severity was noted, with 93.5%, 6.5%, and 0% having mild, moderate, and severe acne, respectively. A total of 83.6% of the patients had self-assessed acne remission, and 33.3% of the patients reported complete acne resolution. However, 9.0% of patients reported that their condition had worsened after acromegaly treatment. After treatment, GH, IGF-1, IGF-1 index, insulin levels, and HOMA-IR decreased significantly in all patients with acromegaly ( P  < 0.05). Acne remission correlated positively with IGF-1 levels, but not with GH levels. The relationship between acromegaly and acne remains to be elucidated. Conclusions Our findings provide preliminary evidence of the high prevalence of adult acne in acromegaly patients, and a high rate of late-onset acne as well. Traditional anti-acne treatments are less effective. Acne could be considerably relieved by treating acromegaly. Acne remission positively correlated with IGF-1 decline as well, which revealed the correlation between acne and IGF-1.

The adaptive iterated particle filter (AIPF) is presented, where the importance density function is updated iteratively by the particle filter itself when necessary. By using a simulated annealing algorithm with an adaptive annealing parameter, the current measurement can be quickly incorporated into the sampling process, resulting in greatly improved sampling efficiency. Simulation results demonstrate the improved performance of the AIPF over the sampling importance resampling filter, unscented Kalman particle filter and auxiliary particle filter.

The nanocomposites are materials, which involve fillers in the nanometer scale, yielding substantial improvements. Polymer‐layered silicate nanocomposites have received much attention during the past decade and have great interest both in the academic field and in industry, since they often give more attractive improvement to material properties than both micro‐ and macrocomposite materials. This extensive review presents recent studies in polymer nanocomposites based on layered silicate. The background, morphology, preparations, and properties of these materials are discussed. The review covers and discusses various modern methods and equipments in the preparation of nanocomposites, deeply focusing on the morphology of nanocomposites and its effects on the overall properties. © 2013 Wiley Periodicals, Inc. Adv Polym Technol 2013, 32, 21368; View this article online at wileyonlinelibrary.com. DOI 10.1002/adv.21368