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We aimed to investigate the species composition of a small mammal community and the prevalence of Echinococcus spp. in a typical endemic area of the Tibetan Plateau. One pika and five rodent species were identified based on the morphological characteristics of 1278 small mammal specimens collected during 2014–2019. Detection of Echinococcus DNA in tissue samples from small mammal specimens revealed that Ochotona curzoniae (pika, total prevalence: 6.02%, 26/432), Neodon fuscus (5.91%, 38/643), N. leucurus (2.50%, 3/120), and Alexandromys limnophilus (21.74%, 10/46) were infected by both E. multilocularis and E. shiquicus; Cricetulus longicaudatus (16.67%, 1/6) was infected by E. shiquicus; and no infection was detected in N. irene (0/15). Neodon fuscus and O. curzoniae were the two most abundant small mammal species. There was no significant difference in the prevalence of pika and the overall rodent species assemblage (6.26%, 53/846); however, the larger rodent populations suggested that more attention should be paid to their role in the transmission of echinococcosis in the wildlife reservoir, which has long been underestimated. Moreover, although DNA barcoding provides a more efficient method than traditional morphological methods for identifying large numbers of small mammal samples, commonly used barcodes failed to distinguish the three Neodon species in this study. The close genetic relationships between these species suggest the need to develop more powerful molecular taxonomic tools.

BackgroundNumerous observational studies have investigated the risk of prostate cancer (PCa) in patients diagnosed with Parkinson’s Disease (PD). However, the existence of a definitive association remains uncertain.MethodsSystematic searches were performed on PubMed, Web of Science, Scopus, and Google Scholar for studies published up to October 1, 2023. For Mendelian randomized (MR) causal inference, we employed pooled data from the IPDGC and PRACTICAL Consortium. The inverse variance weighted (IVW) method served as the principal technique for estimating odds ratios (ORs) and 95% confidence intervals (CIs) for the associations under investigation.ResultsCumulative analysis of nine studies revealed no significant association between patients diagnosed with PD and the subsequent incidence of PCa ([relative ratio] RR = 0.89, 95%CI = 0.73 to 1.08, P = 0.237). However, subgroup analyses indicated a reduced occurrence of PCa in Caucasian patients with PD (RR = 0.81, 95%CI = 0.69 to 0.95, P = 0.011). MR analyses failed to establish a significant link between increased genetic susceptibility to PD and the risk of PCa (IVW OR = 1.025, 95%CI = 0.997 to 1.054, P = 0.082). Sensitivity analyses further corroborated the robustness of these results.ConclusionBoth observational meta-analysis and MR analysis based on genetic variation do not support an association between PD patients and the subsequent risk of PCa. Further research is warranted to unravel the potential underlying mechanisms linking these two diseases.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023473527.

Abstract Background Pulmonary fibrosis is a major category of end-stage changes in lung diseases, characterized by lung epithelial cell damage, proliferation of fibroblasts, and accumulation of extracellular matrix. Peroxiredoxin 1 (PRDX1), a member of the peroxiredoxin protein family, participates in the regulation of the levels of reactive oxygen species in cells and various other physiological activities, as well as the occurrence and development of diseases by functioning as a chaperonin. Methods Experimental methods including MTT assay, morphological observation of fibrosis, wound healing assay, fluorescence microscopy, flow cytometry, ELISA, western blot, transcriptome sequencing, and histopathological analysis were used in this study. Results PRDX1 knockdown increased ROS levels in lung epithelial cells and promoted epithelial-mesenchymal transition (EMT) through the PI3K/Akt and JNK/Smad signalling pathways. PRDX1 knockout significantly increased TGF-β secretion, ROS production, and cell migration in primary lung fibroblasts. PRDX1 deficiency also increased cell proliferation, cell cycle circulation, and fibrosis progression through the PI3K/Akt and JNK/Smad signalling pathways. BLM treatment induced more severe pulmonary fibrosis in PRDX1-knockout mice, mainly through the PI3K/Akt and JNK/Smad signalling pathways. Conclusions Our findings strongly suggest that PRDX1 is a key molecule in BLM-induced lung fibrosis progression and acts through modulating EMT and lung fibroblast proliferation; therefore, it may be a therapeutic target for the treatment of BLM-induced lung fibrosis.

Abstract Background N7-methylguanosine (m7G) is closely associated with tumor prognosis and immune response in many cancer types. The correlation between m7G and bladder cancer (BC) needs further study. We aimed to orchestrate molecular subtypes and identify key genes for BC from the perspective of m7G. Methods RNA-seq and clinical data of BC patients were extracted from TCGA and GSE13507 datasets. The patients were subtyped by “ConsensusClusterPlus” and “limma.” The clusters were validated by the Kaplan‒Meier curves, univariable and multivariate Cox regression models, the concordance index, and calibration curves. The immunotherapy response was evaluated by immune checkpoints, immune infiltration, TIDE score, and IMvigor210 cohort. Genomics of Drug Sensitivity in Cancer was utilized to predict the chemotherapy response between the clusters. Results The m7G-related cluster was ultimately established by EIF4G1, NUDT11, NUDT10, and CCNB1. The independent prognostic value of the m7G-related cluster was validated by the TCGA and GSE13507 datasets. The cluster was involved in immune-associated pathways, such as neutrophil degranulation, antigen processing cross-presentation, and signaling by interleukins pathways. Meanwhile, cluster 2 was positively correlated with many immune checkpoints, such as CD274, CTLA4, HAVCR2, LAG3, PDCD1, and PDCD1LG2. The cluster 2 was significantly correlated with a higher TIDE score than the cluster 1. Furthermore, in the IMvigor210 cohort, patients in the cluster 1 had a higher response rate than those in the cluster 2. Patients in the cluster 2 were sensitive to many chemotherapies. Conclusions We successfully determined molecular subtypes and identified key genes for BC from the perspective of m7G, thereby providing a roadmap for the evolution of immunotherapy and precision medicine.

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cell survival in cancers such as prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since the widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC versus adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors — but not catalytic inhibitors — reduced NEPC cell survival. RNA-Seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1’s catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1’s noncatalytic function may be a promising treatment strategy for NEPC.

BackgroundLess than 1% of children develop femoral neck fractures (FNF), making them uncommon. However, they may have dangerous side effects, like avascular necrosis. Even though several risk factors for postoperative avascular necrosis have been identified, there is still debate regarding them. In this investigation, a meta-analysis was performed to examine the potential causes of postoperative avascular necrosis in children with FNF.MethodsWe conducted a thorough literature search to find risk factors for avascular necrosis (AVN) after internal fixation of pediatric FNF. Until December 2022, we searched several databases, including PubMed, Embase, Cochrane Library, Web of Science, CNKI, Orthosearch, and Sinomed. Software Zotero 6.0 and Stata 17.0 were used to organise and synthesise the data. Finally, a sensitivity and publication bias test was carried out.ResultsOur study includes a total of 15 case-control studies involving 814 patients. The risk of postoperative AVN increased with age at fracture encounter (95% CI: 0.64–1.88, P = 0.0003), initial fracture displacement (95% CI: 1.87–9.54, P = 0.0005), and poor fracture reduction (95% CI:1.95–22.34, P = 0.0024) were risk factors for postoperative AVN. There was no significant relationship between gender and postoperative AVN (95% CI: 0.52–1.31, P = 0.41). Conversely, Postoperative AVN and reduction methods have no connection with each other (95% CI: 0.77–2.66, P = 0.25), procedure time (95% CI: 0.43–2.99, P = 0.16), or injury mechanism (95% CI: 0.32–2.26, P = 0.75). The incidence of post-operative AVN varies between Delbet fracture types (95% CI: 0.15–0.31, P

Skin aging is a complex process involving intricate genetic and environmental factors. In this study, we performed a comprehensive analysis of the transcriptional regulatory landscape of skin aging in canines. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify aging-related gene modules. We subsequently validated the expression changes of these module genes in single-cell RNA sequencing (scRNA-seq) data of human aging skin. Notably, basal cell (BC), spinous cell (SC), mitotic cell (MC), and fibroblast (FB) were identified as the cell types with the most significant gene expression changes during aging. By integrating GENIE3 and RcisTarget, we constructed gene regulation networks (GRNs) for aging-related modules and identified core transcription factors (TFs) by intersecting significantly enriched TFs within the GRNs with hub TFs from WGCNA analysis, revealing key regulators of skin aging. Furthermore, we demonstrated the conserved role of CTCF and RAD21 in skin aging using an H2O2-stimulated cell aging model in HaCaT cells. Our findings provide new insights into the transcriptional regulatory landscape of skin aging and unveil potential targets for future intervention strategies against age-related skin disorders in both canines and humans.

Abstract Background Patients with unilateral cleft lip and palate were associated with different nasomaxillary complex from the normal population. Although the biomechanical effects of conventional rapid palatal expansion (Hyrax expansion) and bone-borne rapid palatal expansion (micro-implant-assisted expansion) in non-cleft patients have been identified by multiple studies, little is known in patients with unilateral cleft lip and palate. The purpose of this study was to investigate and compare the biomechanical effects of the conventional and bone-borne palatal expanders in a late adolescence with unilateral cleft lip and palate. Methods A cone beam CT scan of a late adolescence with unilateral cleft lip and palate was selected to construct the three-dimensional finite element models of teeth and craniofacial structures. The models of conventional and born-borne palatal expanders were established to simulate the clinical maxillary expansion. The geometric nonlinear theory was applied to evaluate the Von Mises stress distribution and displacements in craniofacial structures and teeth. Results Bone-borne palatal expander achieved more transverse movement than conventional palatal expander in the whole mount of craniofacial regions, and the maximum amount of expansion was occurred anteriorly along the alveolar ridge on cleft-side. The expanding force from born-borne palatal expander resulted in more advancement in nasomaxillary complex than it in conventional palatal expander, especially in the anterior area of the minor segment of maxilla. Stresses from the both expanders distributed in similar patterns, but larger magnitudes and ranges were generated using the bone-borne expander around the maxillary buttresses and pterygoid plates of sphenoid bone. The maximum expanding stresses from born-borne palatal expander were concentrated on palatal slope supporting minscrews, whereas those from conventional palatal expander were concentrated on the anchoring molars. In addition, the buccal tipping effect of teeth generated using the bone-borne expander was less than it using the conventional palatal expander. Conclusion Bone-borne expander generated enhanced skeletal expansion at the levels of alveolar and palate in transversal direction, where the miniscrews contributed increased expanding forces to maxillary buttresses and decreased forces to buccal alveolar. Bone-borne expanders presented a superiority in correcting the asymmetric maxilla without surgical assistant in late adolescence with unilateral cleft lip and palate.

Abstract Background C1q/TNF-related protein 9 (CTRP9) and adiponectin (APN) have beneficial metabolic regulatory and vasoprotective effects. This study explored alteration of CTRP9 and APN multimers during onset of ischemic stroke and development, to provide novel clinical and experimental basis for recognition and prevention of ischemic stroke. Methods There were 269 patients with ischemic stroke and 182 control subjects included in this study. Serum levels of CTRP9 and APN multimers in different disease stages were measured. Results Serum CTRP9, total APN (tAPN), and high-molecular weight (HMW) APN decreased gradually in stage I (acute stage, within 72 h of onset) of ischemic stroke and increased during stage III (11th day to one month) and stage IV (1 month after), compared to control. In the non-hyperlipidemia group, serum CTRP9, tAPN, and HMW were decreased in ischemic stroke patients compared to control (P

The gray leaf spot caused by Cercospora zeina has become a serious disease in maize in China. The isolates of C. zeina from Yunnan, Sichuan, Guizhou, Hubei, Chongqing, Gansu, and Shaanxi were collected. From those, 127 samples were used for genetic diversity analysis based on inter-simple sequence repeat (ISSR) and 108 samples were used for multi-gene sequence analysis based on five gene fragments. The results indicated that populations of C. zeina were differentiated with a relatively high genetic level and were classified into two major groups and seven subgroups. The intra-population genetic differentiation of C. zeina is the leading cause of population variation in China, and inter-population genetic similarity is closely related to the colonization time and spread direction. The multi-gene sequence analysis of C. zeina isolates demonstrated that there were nine haplotypes. Genetic diversity and multi-gene sequence revealed that Yunnan population of C. zeina, the earliest colonizing in China, had the highest genetic and haplotype diversity and had experienced an expansion event. With the influence of the southwest monsoon in the Indian Ocean, C. zeina from Yunnan gradually moved to Sichuan, Guizhou, Shaanxi, Gansu, and Chongqing. Meanwhile, C. zeina was transferred directly from the Yunnan into the Hubei Province via seed and then came into Shaanxi, Henan, and Chongqing along with the wind from Hubei.

As an excellent fluorescent nanomaterial, carbon quantum dots (CQDs) have the properties of small molecular weight, small particle size, high fluorescence stability, no optical flicker, wide excitation spectrum, continuous, long adjustable emission wavelength, good biocompatibility and low toxicity. At present, it has been widely used in biological detection, in vivo and in vitro imaging, drug delivery and diagnostic drugs. This review presents a broad overview of recent progress in synthesis, optical properties, and biomedical applications of CQDs. The synthesis methods of CQDs are first introduced, followed by an extensive discussion of its purification, surface functionalization methods and stability. Furthermore, the optical properties of CQDs are presented, with an emphasis on photoluminescence mechanism and the relationship between synthesis conditions and optical properties. This review's much focus is given to the biomedical applications of CQDs, including detection, imaging (in vivo and in vitro imaging) and drug delivery (targeted therapy, photodynamic and photothermal therapy, and immunological and gene therapy). Finally, we cover the key issues and future prospects/advances that CQDs still have to deal with in the biomedical sector as well as possible solutions.

Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to substitute NAFLD in 2020. This new term highlights the systematic metabolic disturbances that accompany fatty liver. We evaluated the correlations between MAFLD and subclinical carotid atherosclerosis (SCA) based on a nationwide health examination population in China.MethodsWe performed a nationwide cross-sectional population and a Beijing retrospective cohort from 2009 to 2017. SCA was defined as elevated carotid intima-media thickness. The multivariable logistic and Cox models were used to analyze the association between MAFLD and SCA.Results153,482 participants were included in the cross-sectional study. MAFLD was significantly associated with SCA in fully adjusted models, with an odds ratio of 1.66; 95% confidence interval (CI): 1.62-1.70. This association was consistent in the cohort, with a hazard ratio (HR) of 1.31. The association between baseline MAFLD and incident SCA increased with hepatic steatosis severity. Subgroup analysis showed an interaction between age and MAFLD, with a higher risk in younger groups (HR:1.67, 95% CI: 1.17-2.40).ConclusionIn this large cross-section and cohort study, MAFLD was significantly associated with the presence and development of SCA. Further, the risk was higher among MAFLD individuals with high hepatic steatosis index and young adults.

Abstract Introduction Adiponectin is a potent vascular protective molecule. Recent findings have suggested adiponectin resistance during early diabetes. However, the molecular mechanisms responsible remain unidentified. Here, we took an unbiased approach to identify whether hyperlipidemic plasma molecules exist that bind and inhibit adiponectin function, contributing to adiponectin resistance and diabetic vascular injury. Methods Adult rats were randomly assigned to receive either a normal or a high‐fat diet for 8 weeks. Plasma was co‐immunoprecipitated with anti‐APN antibody and analyzed by mass spectrometry. The APN binding molecules and their effect upon APN biological activity were determined. Results As expected, the high‐fat‐diet increased plasma triglyceride, total cholesterol, and low‐density lipoprotein. Importantly, the circulating APN level was significantly increased at this time point. Mass spectrometry identified 18 proteins with increased APN binding in hyperlipidemic plasma, among which four proteins critical in lipid metabolism, including apolipoprotein A1 (APOA1), APOA4, APOC1, and paraoxonase 1, were further investigated. Incubating recombinant APN with APOA1 markedly (P

In Alzheimer’s disease and ischemic stroke, intranasal insulin can act as a neuroprotective agent. However, whether intranasal insulin has a neuroprotective effect in intracerebral hemorrhage and its potential mechanisms remain poorly understood. In this study, a mouse model of autologous blood-induced intracerebral hemorrhage was treated with 0.5, 1, or 2 IU insulin via intranasal delivery, twice per day, until 24 or 72 hours after surgery. Compared with saline treatment, 1 IU intranasal insulin treatment significantly reduced hematoma volume and brain edema after cerebral hemorrhage, decreased blood-brain barrier permeability and neuronal degeneration damage, reduced neurobehavioral deficits, and improved the survival rate of mice. Expression levels of p-AKT and p-GSK3β were significantly increased in the perihematoma tissues after intranasal insulin therapy. Our findings suggest that intranasal insulin therapy can protect the neurological function of mice after intracerebral hemorrhage through the AKT/GSK3β signaling pathway. The study was approved by the Ethics Committee of the North Sichuan Medical College of China (approval No. NSMC(A)2019(01)) on January 7, 2019.

Purpose: Many studies identified that the preoperative neutrophil-to-lymphocyte ratio (PNLR) was associated with patient prognosis in non-muscle-invasive bladder cancer (NMIBC). We hypothesized that PNLR could be prognostic in patients with histological variants of NMIBC (VH-NMIBC). Materials and Methods: This retrospective study included patients with VH-NMIBC admitted at our center between January 2009 and May 2019. The best cut-off value of NLR was measured by the receiver operating characteristic curve and Youden index. The Kaplan-Meier method and Cox proportional hazard regression models were employed to evaluate the association between PNLR and disease prognosis, including recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Results: A total of 243 patients with VH-NMIBC were enrolled in our study. According to the Kaplan-Meier method results, patients with PNLR ≥2.2 were associated with poor RFS (p

The dried and ripe fruits of Alpinia oxyphylla and ripe fruits of Alpinia oxyphylla Miquel (AO) have the effects of tonifying kidney-essence and nourishing intelligence and thus have been widely used in treating dementia. Alzheimer’s disease (AD) is a typical form of neurodegenerative dementia with kidney-essence deficiency in Traditional Chinese Medicine (TCM). So far, there is a lack of systematic studies on the biological basis of tonifying kidney-essence and nourishing intelligence and the corresponding phytochemicals. In this study, we investigated the targets of AO in tonifying kidney-essence and nourishing intelligence based on the key pathophysiological processes of neurodegenerative dementia. According to ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry data and Lipinski’s rule of five, 49 bioactive phytochemicals from AO were identified, and 26 of them were found to target 168 key molecules in the treatment of neurodegenerative dementia. Nine phytochemicals of AO were shown to target acetylcholinesterase (ACHE), and 19 phytochemicals were shown to target butyrylcholinesterase (BCHE). A database of neurodegenerative dementia with kidney-essence deficiency involving 731 genes was constructed. Furthermore, yakuchinone B, 5-hydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl) heptan-3-one (5-HYD), oxyhylladiketone, oxyphyllacinol, butyl-β-D-fructopyranoside, dibutyl phthalate, chrysin, yakuchinone A, rhamnetin, and rhamnocitrin were identified as the key phytochemicals from AO that regulate the pathogenesis of neurodegenerative dementia in a multitargeted manner. The approach of studying the pharmacological mechanism underlying the effects of medicinal plants and the biological basis of TCM syndrome may be helpful in studying the translation of TCM.

Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.

ObjectiveTo compare the safety and efficacy of enucleation and hepatectomy for the treatment of hepatic hemangioma (HH).MethodsA systematic literature search was conducted to identify studies evaluating enucleation versus hepatectomy for HH starting from the time of database creation to February 2022. Extraction of the data used in this study was done from the literature. The differences between the two surgical approaches were evaluated by comparing and analyzing the relevant data by means of meta-analysis.ResultsA total of 1,384 patients (726 underwent enucleation, and 658 with hepatectomy) were included in our meta-analysis from 12 studies. Enucleations were associated with favorable outcomes in terms of operation time [mean difference (MD): −39.76, 95% confidence interval (CI): −46.23, −33.30], blood loss (MD: −300.42, 95% CI: −385.64, −215.19), length of hospital stay (MD: −2.33, 95% CI: −3.22, −1.44), and postoperative complications (OR: 0.57, 95% CI: 0.44–0.74). There were no differences between the groups in terms of patients needing transfusion (OR: 0.85, 95% CI: 0.50, 1.42), inflow occlusion time (MD: 1.72, 95% CI: −0.27, 3.71), and 30-day postoperative mortality (OR: 0.23, 95% CI: 0.02–2.17).ConclusionCompared with hepatectomy, enucleation is found to be effective at reducing postoperative complications, blood loss, and operation time and shortening the length of hospital stay. Enucleation is similar to hepatectomy in terms of inflow occlusion time, 30-day postoperative mortality, and patients needing transfusing to hepatectomy.

The prognostic value of the lymphocyte-to-monocyte ratio during induction (ILMR) remains unclear in non-muscle-invasive bladder cancer (NMIBC) patients receiving Bacillus Calmette-Guérin (BCG). We aimed to determine and compare the prognostic value of the ILMR, preoperative lymphocyte-to-monocyte ratio (PLMR) and their dynamic changes (PILMR). This study collected the data from NMIBC patients receiving BCG treatment in our institution. The prognostic value of the PLMR, ILMR and PILMR was analyzed by the Kaplan−Meier method and Cox proportional hazard regression models. The concordance index and receiver operating characteristic curve analysis were employed to compare the prognostic value of these three factors. Our study enrolled 197 patients. These patients included 170 male patients, and the mean age was 64.17 years. During the follow-up time, 85 patients experienced recurrence, and 55 patients experienced progression. According to the results of COX multivariable analysis, PLMR (P=0.011) and ILMR (P

Immune checkpoint inhibitor-related pneumonitis (CIP) is a rare but well-recognized immune-related adverse event (irAE), causes 35% of irAE related deaths. However, the mechanism of CIP remains unclear and no evidence-based treatment except for glucocorticoids is available. Herein, we report the case of a patient with metastatic bladder cancer who received tislelizumab and was diagnosed with CIP. The patient underwent transbronchial cryobiopsy. The patient was treated with glucocorticoid, but CIP recurred when the glucocorticoid tapering. The paraffine-embedded lung tissue was sectioned, stained with 31 heavy-metal tagged antibodies, and analyzed using imaging mass cytometry (IMC) technology. We identified multiple immune cell subsets in the lung tissue and observed the infiltration of memory T cells and the CD4+ DC subset. The data indicated the great potential of IMC technology in the identification and characterization of irAEs. Further investigation is warranted to identify the mechanism of action of CIP.

In this study, 40CrMnSiB steel cylindrical shells were tempered at 350, 500 and 600 °C to study the effect of tempering temperature on the dynamic process of expansion and fracture of the metal shell. A mid-explosion recovery experiment for the metal cylinder under internal explosive loading was designed, and the wreckage of the casings at the intermediate phase was obtained. The effects of different tempering temperatures on the macroscopic and microscopic fracture characteristics of 40CrMnSiB steel were studied. The influence of tempering temperatures on the fracture characteristic parameters of the recovered wreckage were measured and analyzed, including the circumferential divide size, the thickness and the number of the circumferential divisions. The results show that as the tempering temperature was increased from 350 to 600 °C, at first, the degree of fragmentation and the fracture characteristic parameters of the recovered wreckage changed significantly and then became essentially consistent. Scanning electron microscopy analysis revealed flow-like structure characteristics caused by adiabatic shear on different fracture surfaces. At the detonation initiation end of the casing, fracturing was formed by tearing along the crack, which existed a distance from the initiation end and propagated along the axis direction. In contrast, the fracturing near the middle position consists of a plurality of radial shear fracture units. The amount of alloy carbide that was precipitated during the tempering process increased continuously with tempering temperature, leading to an increasing number of spherical carbide particles scattered around the fracture surface.

ABSTRACT Objective: To determine the discrepancy of crown-root morphology of anterior teeth, using cone-beam computed tomography (CBCT), and to provide a guidance for proper torque expression. Methods: A total of eligible 200 CBCT were imported into Invivo v. 5.4 software, to obtain the middle labio-lingual sections of anterior teeth. AutoCAD 2007 software was applied to measure the crown-root angulation (Collum angle) and the angle formed by a tangent to the center of the labial surface and the long axis of the crown (labial surface angle). SPSS 18.0 was used for statistical comparisons of the two measurements, at the level of p< 0.05, and the Pearson correlation analysis was applied to investigate the association between the two measurements. Results: The value of Collum angle in maxillary central incisor was close to 0°. Significantly negative Collum angle in lateral incisors and maxillary canine, and positive value in mandibular canine were detected (p < 0.001). The labial surface angle in canine was significantly greater than the intra-arch incisors (p< 0.001), and no significant difference was detected between the central and lateral incisors (p > 0.05). Notably, there was also a significant positive correlation between the two measurements. Conclusions: The crown-root angulations were greatly different among anterior teeth. Accompanying the obvious crown-root angulations, the canines both in maxillary and mandibular arches presented considerable labial surface curvatures. Hence, equivalent deviation during bracket bonding might cause greater torque expression error and increase the risk of alveolar fenestration and dehiscence.

The particles stimulated nucleation (PSN) triggered by coarsened T1 phase (Al2CuLi) in Al–Cu–Li alloys is investigated to analyze the formation of recrystallization texture that is unusual from typical PSN. The specimens were uniaxially compressed to a series of compression amount and the recrystallization process is characterized by electron backscattered diffraction (EBSD), scanning electron microscope (SEM) and transmission electron microscope (TEM). Results showed that the recrystallization occurred by progressive rotation of the matrix units that separated by the three-dimensional arranged T1 precipitates. The rotation of the units towards was observed in the initial grains of various orientations all through the recrystallization process. The massively formed fine grains contribute to a strong fiber texture. The fraction of recrystallization is 67% and the grains are averagely 2.5 μm in the specimen received a stain of 1.61. The PSN initiated by coarsened T1 phase fosters the feasibility to obtain textured and refined structure in Al–Cu–Li alloys which will facilitate the performance improvement of the fabricated components.

Abstract A phytochemical investigation of the EtOH extract of the flowers of Lagerstroemia indica L. led to the isolation and characterization of a new pyrrole alkaloid, named lagerindicine (1), along with four known compounds (2–5). Their structures were elucidated by the detailed spectroscopic analysis and comparison with literature data, whereas the structure, in particularly, the absolute configuration (AC) of 1, was firmly determined by total synthesis. All the isolates were evaluated for their cytotoxic effects against human colon cancer cell (HCT-116), and compound 3 exhibited weak cytotoxicity with IC50 value of 28.4 μM. Graphic Abstract

Argonaute 2 (AGO2) binds RAS and is required for cellular transformation. Here, the authors establish a KRAS-driven mouse model of pancreatic cancer with conditional loss of AGO2 and show that the early phase of neoplastic lesion initiation is dependent on EGFR/RAS but not AGO2, while AGO2 is required for pancreatic ductal adenocarcinoma progression and metastasis.

Phase-frequency characteristics of approximate sinusoidal geomagnetic signals can be used for projectile roll positioning and other high-precision trajectory correction applications. The sinusoidal geomagnetic signal deforms in the exposed and magnetically contaminated environment. In order to preciously recognize the roll information and effectively separate the noise component from the original geomagnetic sequence, based on the error source analysis, we propose a moving horizon based wavelet de-noising method for the dual-observed geomagnetic signal filtering where the captured rough roll frequency value provides reasonable wavelet decomposition and reconstruction level selection basis for sampled sequence; a moving horizon window guarantees real-time performance and non-cumulative calculation amount. The complete geomagnetic data in full ballistic range and three intercepted paragraphs are used for performance assessment. The positioning performance of the moving horizon wavelet de-noising method is compared with the band-pass filter. The results show that both noise reduction techniques improve the positioning accuracy while the wavelet de-noising method is always better than the band-pass filter. These results suggest that the proposed moving horizon based wavelet de-noising method of the dual-observed geomagnetic signal is more applicable for various launch conditions with better positioning performance.

Abstract Background Tamoxifen (TAM) is a cell type-specific anti-estrogen and is applied to improve the survival of patients with estrogen receptor positive (ER +) breast cancer. However, long-term TAM use can induce serious drug resistance, leading to breast cancer recurrence and death in patients. Further, it is almost useless among patients with estrogen receptor negative (ER −) breast cancer. Shikonin (SK) is a natural product broadly explored in cancer therapy. Some studies have demonstrated the combined treatment of SK and clinical anticancer drugs including TAM on various tumors. However, the combined effect of SK and 4-hydroxytamoxifen (4-OHT) on ER- breast cancer is not known. The current study aimed to assess the combination effects of SK and 4-OHT on human breast cancer cells, MCF-7 (ER +) and MDA-MB-435S (ER −), in vitro and in vivo and to investigate the underlying mechanisms. Methods CCK-8 assays and flow cytometry were conducted to determine the cell viability and apoptotic profiles of human breast cancer cell lines (MCF-7 and MDA-MB-435S) treated with SK, 4-OHT, and the combination. ROS and JC-1 assays were used to determine ROS level and mitochondrial membrane potential. Western blot analysis was performed to investigate proteins that are associated with apoptosis. Haematoxylin & Eosin (HE) staining was used to detect the tumor and kidney morphology of mice. TUNEL and immunohistochemical staining were performed to detect Ki67 expression level and cell apoptotic profile in tumor tissues. Results SK and 4-OHT synergistically inhibited MCF-7 and MDA-MB-435S cell proliferation and promoted apoptosis by reducing mitochondrial membrane potential and increasing the intracellular ROS level. The combination of SK and 4-OHT activated the mitochondrial-dependent apoptosis and the death receptor pathways, significantly regulating the PI3K/AKT/Caspase 9 signaling pathway. Compared with SK and 4-OHT alone, the combination of SK and 4-OHT could better inhibit tumor growth in mice. Conclusion The combination of SK and 4-OHT shows highly efficient anticancer effects on breast cancer therapy. SK may be a promising candidate as an adjuvant to 4-OHT for breast cancer treatments, especially for ER- breast cancer.

This study aimed at elucidating some characteristics of the shock wave overpressure generated by a non-traditional layered charge comprising an inner high-energy explosive and an outer polymer matrix composite. Two models for predicting the peak overpressure (Δpm) of the charge were established, namely, a model based on the initial parameters of the blast wave, and a model considering the weakening of the explosion energy through the introduction of polymer matrix cladding. The overpressure of a typical layered charge was experimentally measured for model validation. It was found that the difference between the Δpm predicted by the two models and the experimental data is less than 15.12% and 14.17%, respectively. The model that was established based on the conservation of energy law, is in best agreement with the experimental data under different cladding/charge mass ratios (αm). The model that was based on the initial parameters of the blast wave obtained a low predicted value when αm was 0.4–0.8, which is attributed to the non-uniformity of the gas-solid mixture during the explosive dispersion stage.

BackgroundThere have been reports of increasing azole resistance in Candida tropicalis, especially in the Asia-Pacific region. Here we report on the epidemiology and antifungal susceptibility of C. tropicalis causing invasive candidiasis in China, from a 9-year surveillance study.MethodsFrom August 2009 to July 2018, C. tropicalis isolates (n = 3702) were collected from 87 hospitals across China. Species identification was carried out by mass spectrometry or rDNA sequencing. Antifungal susceptibility was determined by Clinical and Laboratory Standards Institute disk diffusion (CHIF-NET10–14, n = 1510) or Sensititre YeastOne (CHIF-NET15–18, n = 2192) methods.ResultsOverall, 22.2% (823/3702) of the isolates were resistant to fluconazole, with 90.4% (744/823) being cross-resistant to voriconazole. In addition, 16.9 (370/2192) and 71.7% (1572/2192) of the isolates were of non-wild-type phenotype to itraconazole and posaconazole, respectively. Over the 9 years of surveillance, the fluconazole resistance rate continued to increase, rising from 5.7 (7/122) to 31.8% (236/741), while that for voriconazole was almost the same, rising from 5.7 (7/122) to 29.1% (216/741), with no significant statistical differences across the geographic regions. However, significant difference in fluconazole resistance rate was noted between isolates cultured from blood (27.2%, 489/1799) and those from non-blood (17.6%, 334/1903) specimens (P-value < 0.05), and amongst isolates collected from medical wards (28.1%, 312/1110) versus intensive care units (19.6%, 214/1092) and surgical wards (17.9%, 194/1086) (Bonferroni adjusted P-value < 0.05). Although echinocandin resistance remained low (0.8%, 18/2192) during the surveillance period, it was observed in most administrative regions, and one-third (6/18) of these isolates were simultaneously resistant to fluconazole.ConclusionThe continual decrease in the rate of azole susceptibility among C. tropicalis strains has become a nationwide challenge in China, and the emergence of multi-drug resistance could pose further threats. These phenomena call for effective efforts in future interventions.

BackgroundThe use of medicinal plant ingredients is one of the goals of developing potential drugs for treating depression. Compelling evidence suggests that anti-inflammatory medicines may block the occurrence of depression. We studied the effect of a natural compound, emodin, on the development of psychosocial stress-induced depression and the underlying mechanisms.MethodsChronic unpredicted mild stress (CUMS) for 7 weeks was performed to replicate psychosocial stress in rats. The sucrose preference test, force swimming test, and open field test were used to evaluate their behaviors. The differentially expressed proteins in the hippocampus were analyzed using proteomics. Nissl staining and Golgi staining were used to detect the loss of neurons and synapses, immunohistochemical staining was used to detect the activation of microglia, and the enzyme-linked immunosorbent assay was used to detect the levels of pro-inflammatory cytokines. Western blotting, immunofluorescence, and quantitative polymerase chain reaction were also performed.ResultsHippocampal inflammation with up-regulated 5-lipoxygenase (5-LO) was observed in the depressed rats after CUMS exposure. The upregulation of 5-LO was caused by decreased miR-139-5p. To observe the effect of emodin, we screened out depression-susceptible (DeS) rats during CUMS and treated them with emodin (80 mg/kg/day). Two weeks later, emodin prevented the depression behaviors in DeS rats along with a series of pathological changes in their hippocampi, such as loss of neurons and spines, microglial activation, increased interleukin-1β and tumor necrosis factor-α, and the activation of 5-LO. Furthermore, we demonstrated that emodin inhibited its excess inflammatory response, possibly by targeting miR-139-5p/5-LO and modulating glycogen synthase kinase 3β and nuclear factor erythroid 2-related factor 2.ConclusionThese results provide important evidence that emodin may be a candidate agent for the treatment of depression and established a key role of miR-139-5p/5-LO in the inflammation of depression.

Objective To analyze the clinical features of autonomic nerve dysfunction and sympathetic skin response (SSR) in patients with gout. Methods A total of 25 patients with gout diagnosed from March 2017 to January 2018 were enrolled, including 10 patients with tophus and 8 patients with autonomic nerve dysfunction(symptomatic). EMG was used to detect SSR. Results The main symptoms of autonomic nervous dysfunction in the gout group were abnormal sweat glands. Compared with the normal control group, the lower extremity latency period of patients in the gout group was prolonged (Z=⁃2.136, P =0.033) and the amplitude was reduced (Z =⁃2.959, P =0.003). Lower extremity amplitude of the symptomatic group was lower than that of the normal control group (Z =⁃3.426, P = 0.001) and the asymptomatic group (Z = ⁃3.308, P=0.001). The lower extremity amplitude of patients in tophout group was lower than that in the control group(Z =⁃3.176, P=0.001) and the non⁃tophout group(Z =⁃2.301, P= 0.021), while the lower extremity latency period of patients without tophout was prolonged(Z=⁃2.518, P= 0.120)and the amplitude was reduced(Z=⁃2.327, P=0.020),which were statistically significant different from the control group. Conclusions Abnormal autonomic nerve function exists in gout patients, mainly in lower limb injury, especially in patients with tophus or symptoms of autonomic nerve dysfunction. SSR can objectively evaluate the autonomic nerve function state.

Abstract Background To determine the discrepancy of crown-root morphology of central incisors among different types of skeletal malocclusion using cone-beam computed tomography (CBCT) and to provide guidance for proper torque expression of anterior teeth and prevention of alveolar fenestration and dehiscence. Methods In this retrospective study, a total of 108 CBCT images were obtained (ranging from 18.0 to 30.0 years, mean age 25.8 years). Patients were grouped according to routine sagittal and vertical skeletal malocclusion classification criteria. The patients in sagittal groups were all average vertical patterns, with Class I comprised 24 patients—14 females and 10 males; Class II comprised 20 patients—13 females and 7 males; and Class III comprised 22 subjects—13 females and 9 males. The patients in vertical groups were all skeletal Class I malocclusions, with low angle comprised 21 patients—12 females and 9 males; average angle comprised 24 patients; and high angle comprised 21 patients—11 females and 10 males. All the CBCT data were imported into Invivo 5.4 software to obtain a middle labio-lingual section of right central incisors. Auto CAD 2007 software was applied to measure the crown-root angulation (Collum angle), and the angle formed by a tangent to the central of the labial surface of the crown and the long axis of the crown (labial surface angle). One-way analysis of variance (ANOVA) and Scheffe’s test were used for statistical comparisons at the P

Existing literature has shown that the control force at the nose could cause dynamic instability for controlled projectiles. To lower the adverse impact on the dual-spin projectile with fixed canards under the premise of meeting guidance system requirements, the influence of control moment provided by a motor on the flight stability is analyzed in this paper. Firstly, the effect of the rolling movement on stability is analyzed based on the stability criterion derived using the Hurwitz stability theory. Secondly, the evaluation parameters combining the features of different control periods that could assess the variation of stability features after the motor torque are obtained. These effective formulas are used to indicate that, to reduce the flight instability risks, the stabilized rolling speed of roll speed keeping period should be as small as possible; the variation trend of motor torque during the rolling speed controlling period and the roll angle of the forward body during roll angle switching period are recommended corresponding to the projectile and trajectory characteristics. Moreover, detailed numerical simulations of 155 mm dual-spin projectile are satisfactory agreement with the theoretical results. Keywords: Dual-spin projectile, Fixed canards, Control strategy, Flight stability

This paper presents a study on plastic deformation behavior of Cu–50Ta alloy at temperatures of 286–473 K and strain-rate of 0.01–6200 s ^−1 . The effects of temperature, strain-rate, and strain on the yield strength, flow stress, and strain-rate sensitivity coefficient were determined. A phenomenological model was established to predict variation of the strain-rate sensitivity coefficient for Cu–50Ta alloy under dynamic compression. A Johnson–Cook constitutive model was established to predict the equivalent stress–equivalent plastic strain relationship under extreme deformation (high temperature and strain-rate). The results showed that the plastic deformation behavior of Cu–50Ta alloy was affected by temperature, strain-rate, and strain. The material exhibited obvious strain-rate strengthening and thermal softening. As the strain-rate increased, the yield strength logarithmically increased. At a temperature of 286 K, the strain-rate increased from 0.01 s ^−1 to 6200 s ^−1 , and the yield strength increased from 543.75 MPa to 881.13 MPa. In addition, the yield strength linearly decreased as the deformation temperature increased. Under conditions of dynamic deformation, the variation of strain-rate sensitivity coefficient could be expressed as a function of strain-rate and strain. The phenomenological model accurately described the variation of the strain-rate sensitivity coefficient of Cu–50Ta under dynamic deformation conditions. The Johnson–Cook constitutive parameters, calibrated by experimental data, described the plastic deformation behavior of the alloy under high-velocity impact.

Background The development of pathological cardiac hypertrophy involves the coordination of a series of transcription activators and repressors, while their interplay to trigger pathological gene reprogramming remains unclear. NULP1 (nuclear localized protein 1) is a member of the basic helix‐loop‐helix family of transcription factors and its biological functions in pathological cardiac hypertrophy are barely understood. Methods and Results Immunoblot and immunostaining analyses showed that NULP1 expression was consistently reduced in the failing hearts of patients and hypertrophic mouse hearts and rat cardiomyocytes. Nulp1 knockout exacerbates aortic banding‐induced cardiac hypertrophy pathology, which was significantly blunted by transgenic overexpression of Nulp1. Signal pathway screening revealed the nuclear factor of activated T cells (NFAT) pathway to be dramatically suppressed by NULP1. Coimmunoprecipitation showed that NULP1 directly interacted with the topologically associating domain of NFAT3 via its C‐terminal region, which was sufficient to suppress NFAT3 transcriptional activity. Inactivation of the NFAT pathway by VIVIT peptides in vivo rescued the aggravated pathogenesis of cardiac hypertrophy resulting from Nulp1 deficiency. Conclusions NULP1 is an endogenous suppressor of NFAT3 signaling under hypertrophic stress and thus negatively regulates the pathogenesis of cardiac hypertrophy. Targeting overactivated NFAT by NULP1 may be a novel therapeutic strategy for the treatment of pathological cardiac hypertrophy and heart failure.

The shock response of aluminum powder/rubber matrix composites containing 40, 50, and 60 vol% Al was investigated using the plate impact test and explosive loading technique. The shock stress in the range of 0.61–13.97 GPa was measured and the free surface velocity of the specimen was monitored using the displacement interferometer system for any reflector. The composites' shock Hugoniots were obtained in terms of shock velocity, particle velocity, and shock stress, and a theoretical model for predicting the Hugoniots of the composites was proposed. The results revealed that a steady shock front was generated and propagated in the composites. The shock stress was attenuated with the propagation distance and the attenuation effect became more obvious as the stress increased. The shock velocity had a linear relationship with the particle velocity and the relationships for the composites with 40 and 50 vol% Al were very similar. By comparing the Hugoniots of the three materials and rubber, it was found that the shock behavior of the composites was similar to that of the matrix rubber. Additionally, the rubbery type shock response changed as the aluminum content increased. The shock behavior of the composites was adequately described by the proposed theoretical model.

Background: The growth rate of centenarians was unusually rapid in recent decades, ushering in an era of longevity. This study aims to explore the difference between centenarians and non-centenarians using quantitative research, and to scientifically guide residents to develop the correct lifestyle and health care ways.Methods: From October 2013 to August 2017. A cross-sectional survey was conducted on 271 centenarians and 570 non-centenarians by using a questionnaire to assess longevity and health issues which was developed for the needs of the study, who came from 29 counties and districts in 11 cities of Zhejiang province, China. Two hundred and fifty-five valid questionnaires were returned, with an effective response rate of 94.1%. Meanwhile, data of 526 non-centenarians from Zhejiang province was collected as a control group, with an effective response rate of 92.3%.Results: The prevalence rates of tumor, stomach and duodenal ulcer, diabetes, bronchial asthma, and chronic obstructive pulmonary disease, tuberculosis among centenarians were all lower than those among non-centenarians. The oral health of centenarians is better than that of non-centenarians. The consumption of coarse cereals, pasta, other staple foods and fruits among centenarians was higher than that of non-centenarians. The percentage of centenarians who smoke or engage in recreational activities every day was lower than that of non-centenarians.Conclusions: We should give full play to the role of preventive medicine and health management to safeguard the health of residents. Pay attention to oral health, and develop the good habit of loving teeth. The diet should be rich and varied, and increase the intake of grains and fruits. Give up smoking, limit alcohol, spirit-preserving with calming, follow the law of scientific regimen.

Abstract Background Shikonin is a naphthoquinone secondary metabolite with important medicinal value and is found in Lithospermum erythrorhizon. Considering the limited knowledge on the membrane transport mechanism of shikonin, this study investigated such molecular mechanism. Results We successfully isolated an ATP-binding cassette protein gene, LeMDR, from L. erythrorhizon. LeMDR is predominantly expressed in L. erythrorhizon roots, where shikonin accumulated. Functional analysis of LeMDR by using the yeast cell expression system revealed that LeMDR is possibly involved in the shikonin efflux transport. The accumulation of shikonin is lower in yeast cells transformed with LeMDR-overexpressing vector than that with empty vector. The transgenic hairy roots of L. erythrorhizon overexpressing LeMDR (MDRO) significantly enhanced shikonin production, whereas the RNA interference of LeMDR (MDRi) displayed a reverse trend. Moreover, the mRNA expression level of LeMDR was up-regulated by treatment with shikonin and shikonin-positive regulators, methyl jasmonate and indole-3-acetic acid. There might be a relationship of mutual regulation between the expression level of LeMDR and shikonin biosynthesis. Conclusions Our findings demonstrated the important role of LeMDR in transmembrane transport and biosynthesis of shikonin.

To study the dynamic plastic properties of high-purity molybdenum materials at high temperature and high strain rate, we designed tests to compare the mechanical behaviour of two high-purity molybdenum materials with different purities and two with different processing deformation conditions under dynamic impact compression in the temperature range of 297–1273 K. We analysed the molybdenum materials’ sensitivities to the strain-hardening effect, strain rate-strengthening effect, and temperature-softening effect as well as the comprehensive response to the combined effect of the strain rate and temperature, the adiabatic impact process, and the microstructure at high temperature and high strain rate. Furthermore, based on a modified Johnson–Cook constitutive model, we quantitatively analysed the flow stresses in these materials. The calculation results strongly agree with the test results. Our findings indicate that the high-purity molybdenum materials show consistent sensitivity to the combined effect of strain rate and temperature regarding the dynamic plastic properties. The materials with higher purity are less sensitive to the combined effect of the strain rate and temperature, and those with less processing deformation experience more pronounced strain-hardening effects. Under high strain rate at room temperature, these materials are highly susceptible to impact embrittlement and decreases in dynamic plastic properties due to intergranular fracture in the internal microstructure. However, increasing the impact environment temperature can significantly improve their plastic properties. The higher the temperature, the better the plastic properties and the higher the impact toughness.

Abstract Signal transducer and activator of transcription 3 (STAT3) is hyper-activated in diversiform human tumors and has been validated as an attractive therapeutic target. Current research showed that a natural product, shikonin, along with its synthetic analogues, is able to inhibit the activity of STAT3 potently. The potential space of shikonin in developing novel anti-cancer agents encouraged us to carry out the investigation of the probable binding mode with STAT3. From this foundation, we have designed new types of STAT3 SH2 inhibitors. Combined simulations were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Among the entities, PMM-172 exhibited the best anti-proliferative activity against MDA-MB-231 cells with IC50 value 1.98 ± 0.49 μM. Besides, it was identified to decrease luciferase activity, induce cell apoptosis and reduce mitochondrial transmembrane potential in MDA-MB-231 cells. Also, PMM-172 inhibited constitutive/inducible STAT3 activation without affecting STAT1 and STAT5 in MDA-MB-231 cells, and had no effect in non-tumorigenic MCF-10A cells. Moreover, PMM-172 suppressed STAT3 nuclear localization and STAT3 downstream target genes expression. Overall, these results indicate that the antitumor activity of PMM-172 is at least partially due to inhibition of STAT3 in breast cancer cells.

Abstract Salmonella have developed a sophisticated machinery to evade immune clearance and promote survival in the infected cells. Previous studies were mostly focused on either bacteria itself or host cells, the interaction mechanism of host-pathogen awaits further exploration. In the present study, we show that Salmonella can exploit mammalian cell non-classical microRNA processing machinery to further process bacterial small non-coding RNAs into microRNA-like fragments. Sal-1, one such fragment with the highest copy number in the infected cells, is derived from Salmonella 5′-leader of the ribosomal RNA transcript and has a ‘stem’ structure-containing precursor. Processing of Sal-1 precursors to mature Sal-1 is dependent on host cell Argonaute 2 (AGO2) but not Dicer. Functionally, depleting cellular Sal-1 strongly renders the Salmonella bacteria less resistant to the host defenses both in vitro and in vivo. In conclusion, we demonstrate a novel strategy for Salmonella evading the host immune clearance, in which Salmonella produce microRNA-like functional RNA fragments to establish a microenvironment facilitating bacterial survival.

A novel liquid settling method was investigated and applied to fabricate TC4 spherical particle reinforced AZ91 alloy matrix composites. This method was called liquid state settling technique in which TC4 particles would settle down under the force of gravity. High volume fraction (50%) particle reinforced AZ91 composites could be easily obtained via this novel method. This is difficult to achieve for other traditional liquid fabrication methods. In addition, there was a good dispersion of TC4 particles in the AZ91 matrix and no clusters were found, which indicate that this method was feasible. Interfacial reaction occurred and the reaction product was confirmed to be Al2Ti. Three kinds of pre-dispersion technologies were used before the settling process and different interfacial microstructures were found. Theoretical calculation and experimental results both indicated that the interfacial product which was embedded in the matrix strengthened the composites and improved the tensile strength.

Alzheimer’s disease (AD) is a growing concern in modern society, and effective drugs for its treatment are lacking. Uncaria rhynchophylla (UR) and its main alkaloids have been studied to treat neurodegenerative diseases such as AD. This study aimed to uncover the key components and mechanism of the anti-AD effect of UR alkaloids through a network pharmacology approach. The analysis identified 10 alkaloids from UR based on HPLC that corresponded to 90 anti-AD targets. A potential alkaloid target-AD target network indicated that corynoxine, corynantheine, isorhynchophylline, dihydrocorynatheine, and isocorynoxeine are likely to become key components for AD treatment. KEGG pathway enrichment analysis revealed the Alzheimers disease (hsa05010) was the pathway most significantly enriched in alkaloids against AD. Further analysis revealed that 28 out of 90 targets were significantly correlated with Aβ and tau pathology. These targets were validated using a Gene Expression Omnibus (GEO) dataset. Molecular docking studies were carried out to verify the binding of corynoxine and corynantheine to core targets related to Aβ and tau pathology. In addition, the cholinergic synapse (hsa04725) and dopaminergic synapse (hsa04728) pathways were significantly enriched. Our findings indicate that UR alkaloids directly exert an AD treatment effect by acting on multiple pathological processes in AD.

A target localization algorithm, which uses the measurement information from onboard GPS and onboard laser detector to acquire the target position, is proposed to obtain the accurate position of ground target in real time in the trajectory correction process of semi-active laser terminal correction projectile. A target localization model is established according to projectile position, attitude and line-of-sight angle. The effects of measurement errors of projectile position, attitude and line-of-sight angle on localization accuracy at different quadrant elevation angles are analyzed through Monte-Carlo simulation. The simulation results show that the measurement error of line-of-sight angle has the largest influence on the localization accuracy. The localization accuracy decreases with the increase in quadrant elevation angle. However, the maximum localization accuracy is less than 7 m. The proposed algorithm meets the accuracy and real-time requirements of target localization.

A roll-decoupled course correction fuze with canards can improve the hit accuracy of conventional unguided ammunitions. The fuze increases accuracy by reducing the effect of angular and translational motion produced by the cyclical yawing forces applied on the projectile. In order to investigate the influence of yawing forces on angular motion, a theoretical solution of the total yaw angle function with the cyclical yawing forces is deduced utilizing the 7 degrees of freedom (7-DOF) model designed for this calculation. Furthermore, a detailed simulation is carried out to determine the influence rules of yawing force on angular motion. The calculated results illustrate that, when the rotational speed of the forward part is close to the initial turning rate, the total yaw angle increases and the flight range decreases sharply. Moreover, a yawing force at an appropriate frequency is able to correct the gun azimuth and elevation perturbation to some extent.

The properties and applications of Ag nanowires (AgNWs) are closely related to their morphology and composition. Therefore, controlling the growth process of AgNWs is of great significance for technological applications and fundamental research. Here, silver nanowires (AgNWs) were synthesized via a typical polyol method with the synergistic effect of Cl−, Br−, and Fe3+ mediated agents. The synergistic impact of these mediated agents was investigated intensively, revealing that trace Fe3+ ions provided selective etching and hindered the strong etching effect from Cl− and Br− ions. Controlling this synergy allowed the obtainment of highly uniform AgNWs with sub-30 nm diameter and an aspect ratio of over 3000. Transparent conductive films (TCFs) based on these AgNWs without any post-treatment showed a very low sheet resistance of 4.7 Ω sq−1, a low haze of 1.08% at a high optical transmittance of 95.2% (at 550 nm), and a high figure of merit (FOM) of 1210. TCFs exhibited a robust electrical performance with almost unchanged resistance after 2500 bending cycles. These excellent high-performance characteristics demonstrate the enormous potential of our AgNWs in the field of flexible and transparent materials.

Shengjiang Xiexin decoction (SXD), a classic traditional Chinese medical formula chronicled in Shang Han Lun, is used in modern clinical practice to decrease gastrointestinal toxicity induced by the chemotherapeutic drug irinotecan (CPT-11). In this study, the effect of SXD on the pharmacokinetics of CPT-11 and its active metabolites (SN-38 and SN-38G), and the underlying mechanisms were further examined. An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of CPT-11, SN-38, and SN-38G in the plasma, bile, liver, intestine, and intestinal contents of control and SXD-pre-treated rats after intravenous administration of CPT-11. SXD pretreatment increased the area under the curve (AUC) and the initial plasma concentration (C0) of CPT-11 but decreased the plasma clearance (CL). The AUC and the maximum plasma concentration (Cmax) of SN-38 decreased, whereas the Cmax of SN-38G increased. Compared with that of the control group, the biliary excretion of CPT-11, SN-38, and SN-38G was inhibited. The CPT-11, SN-38, and SN-38G concentrations in the liver, intestine, and intestinal contents were different between the two groups. Furthermore, the hepatic expression of multidrug resistance-associated protein-2 (Mrp-2), P-glycoprotein (P-gp), and carboxylesterase 2 (CES2) was significantly down-regulated by SXD, while the hepatic and jejunal uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) expression was elevated. The hydrolysis of CPT-11 to SN-38 by CES and the glucuronidation of SN-38 to SN-38G by UGT were affected by liver and jejunum S9 fractions from rats pre-treated with SXD. Therefore, this study demonstrated for the first time that SXD could alter the pharmacokinetics of CPT-11 and its metabolites to alleviate CPT-11-induced diarrhea. And the underlying mechanism of drug interaction between CPT-11 and SXD involves decreasing hepatic Mrp-2 and P-gp expression and altering the activities of CES and UGT.