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Matrix-metalloproteinase-13 (MMP13) is important for bone formation and remodeling; however, its role in tooth development remains unknown. To investigate this, MMP13-knockout (Mmp13−/−) mice were used to analyze phenotypic changes in the dentin–pulp complex, mineralization-associated marker-expression, and mechanistic interactions. Immunohistochemistry demonstrated high MMP13-expression in pulp-tissue, ameloblasts, odontoblasts, and dentin in developing WT-molars, which reduced in adults, with human-DPC cultures demonstrating a >2000-fold increase in Mmp13-expression during mineralization. Morphologically, Mmp13−/− molars displayed critical alterations in the dentin-phenotype, affecting dentin-tubule regularity, the odontoblast-palisade and predentin-definition with significantly reduced dentin volume (∼30% incisor; 13% molar), and enamel and dentin mineral-density. Reactionary-tertiary-dentin in response to injury was reduced at Mmp13−/− molar cusp-tips but with significantly more dystrophic pulpal mineralization in MMP13-null samples. Odontoblast differentiation-markers, nestin and DSP, reduced in expression after MMP13-loss in vivo, with reduced calcium deposition in MMP13-null DPC cultures. RNA-sequencing analysis of WT and Mmp13−/− pulp highlighted 5,020 transcripts to have significantly >2.0-fold change, with pathway-analysis indicating downregulation of the Wnt-signaling pathway, supported by reduced in vivo expression of the Wnt-responsive gene Axin2. Mmp13 interaction with Axin2 could be partly responsible for the loss of odontoblastic activity and alteration to the tooth phenotype and volume which is evident in this study. Overall, our novel findings indicate MMP13 as critical for tooth development and mineralization processes, highlighting mechanistic interaction with the Wnt-signaling pathway.

Bufo bufo gargarizans Cantor are precious medicinal animals in traditional Chinese medicine (TCM). Bufadienolides as the major pharmacological components are generated from the venomous glands of B. bufo gargarizans. Bufadienolides are one type of cardiac aglycone with a six-member lactone ring and have properties of antitumor, cardiotonic, tonsillitis, and anti-inflammatory. The biosynthesis of bufadienolides is complex and unclear. This study explored the transcriptome of three different tissues (skin glands, venom glands, and muscles) of B. bufo gargarizans by high-throughput sequencing. According to the gene tissue–specific expression profile, 389 candidate genes were predicted possibly participating in the bufadienolides biosynthesis pathway. Then, BbgCYP11A1 was identified as a cholesterol side chain cleaving the enzyme in engineering yeast producing cholesterol. Furthermore, the catalytic activity of BbgCYP11A1 was studied with various redox partners. Interestingly, a plant NADPH-cytochrome P450 reductase (CPR) from Anemarrhena asphodeloides showed notably higher production than BbgAdx-2A-BbgAdR from B. bufo gargarizans. These results will provide certainly molecular research to reveal the bufadienolides biosynthesis pathway in B. bufo gargarizans.

Abstract Background Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patients with specific pathological or molecular characteristics and cannot guide postoperative adjuvant radiotherapies. Chromosomal instability (CIN), the numerical and structural alterations of chromosomes resulting from ongoing errors of chromosome segregation, is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology and may be applicable to the risk stratification of EC. Results By analyzing CIN25 and CIN70, two reliable gene expression signatures for CIN, we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN. However, the POLE mutant, as a favorable prognostic factor, had elevated CIN signatures, and the CTNNB1 mutant, as an unfavorable prognostic factor, had decreased CIN signatures. Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups. Integrating pathology, CIN signatures and POLE/CTNNB1 mutation stratified stageIendometrioid EC into four groups with improved risk prognostication and treatment recommendations. Conclusions We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC. Our integrated risk model deserves further improvement and validation.

Abstract The goal of the present study was to elucidate the mechanism by which long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) promotes inflammation in Parkinson’s disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce PD development in C57BL/6 mice, and tyrosine hydroxylase (TH) expression was analysed by immunohistochemical analysis. Western blot and qPCR analyses were conducted to assess the expression of protein and mRNA levels, respectively. Lipopolysaccharide/adenosine triphosphate (LPS/ATP) was used to activate microglia in vitro. Chromatin immunoprecipitation (ChIP), RNA pull-down and RNA immunoprecipitation chip (RIP) assays were performed to investigate the interaction among specific molecules. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cell viability and proliferation. Flow cytometry was performed to analyse cell apoptosis after staining. The dichlorofluorescein diacetate (DCFH-DA) assay was used to measure the generation of reactive oxygen species (ROS) in cells. The results showed that MALAT1 was highly expressed in the brains of MPTP-induced PD model mice and in LPS/ATP-induced microglia cells. Knockdown of MALAT1 inhibited elevated nuclear factor (erythroid-derived 2)-like-2 factor (NRF2) expression, thereby inhibiting inflammasome activation and ROS production. MALAT1 was shown to promote neuroinflammation by recruiting enhancer of zeste homologue 2 (EZH2) to the promoter of NRF2, suppressing Nrf2 expression. In summary, MALAT1 epigenetically inhibits NRF2, thereby inducing inflammasome activation and reactive oxygen species (ROS) production in PD mouse and microglial cell models.

Abstract Background The microRNA miR-221-3p has previously been found to be an underlying biomarker of pancreatic cancer. However, the mechanisms of miR-221-3p underlying its role in pancreatic cancer pathogenesis, proliferation capability, invasion ability, drug resistance and apoptosis and the clinicopathological value of miR-221-3p have not been thoroughly studied. Methods Based on microarray and miRNA-sequencing data extracted from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), relevant literature, and real-time quantitative PCR (RT-qPCR), we explored clinicopathological features and the expression of miR-221-3p to determine its clinical effect in pancreatic cancer. Proliferation, migration, invasion, apoptosis and in vitro cytotoxicity tests were selected to examine the roles of mir-221-3p. In addition, several miR-221-3p functional analyses were conducted, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein–protein interaction (PPI) network analyses, to examine gene interactions with miR-221-3p. Results The findings of integrated multi-analysis revealed higher miR-221-3p expression in pancreatic cancer tissues and blood than that in para-carcinoma samples (SMD of miR-221-3p: 1.52; 95% CI 0.96, 2.08). MiR-221-3p is related to survival both in pancreatic cancer and pancreatic ductal adenocarcinoma patients. Cell experiments demonstrated that miR-221-3p promotes pancreatic cancer cell proliferation capability, migration ability, invasion ability, and drug resistance but inhibits apoptosis. Further pancreatic cancer bioinformatics analyses projected 30 genes as the underlying targets of miR-221-3p. The genes were significantly distributed in diverse critical pathways, including microRNAs in cancer, viral carcinogenesis, and the PI3K-Akt signalling pathway. Additionally, PPI indicated four hub genes with threshold values of 5: KIT, CDKN1B, RUNX2, and BCL2L11. Moreover, cell studies showed that miR-221-3p can inhibit these four hub genes expression in pancreatic cancer. Conclusions Our research revealed that pancreatic cancer expresses a high-level of miR-221-3p, indicating a potential miR-221-3p role as a prognosis predictor in pancreatic cancer. Moreover, miR-221-3p promotes proliferation capacity, migration ability, invasion ability, and drug resistance but inhibits apoptosis in pancreatic cancer. The function of miR-221-3p in the development of pancreatic cancer may be mediated by the inhibition of hub genes expression. All these results might provide an opportunity to extend the understanding of pancreatic cancer pathogenesis.

Abstract Background Mucinous adenocarcinoma (MC) is the second most common pathological type of colon carcinoma (CC). Colon cancer liver metastases (CLMs) are common and lethal, and complete resection of the primary tumour and metastases for CLM patients would be beneficial. However, there is still no consensus on the role of surgery for MC with liver metastases (M-CLM). Methods Patients diagnosed with M-CLM or classical adenocarcinoma with CLM (A-CLM) from 2010 to 2013 in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved. The clinicopathological features and overall survival (OS) and cancer-specific survival (CSS) data were compared and analysed. Results The results showed that the M-CLM group had a larger tumour size, more right colon localizations, higher pT and pN stages, more female patients, and more retrieved and positive lymph nodes and accounted for a higher proportion of surgeries than the A-CLM group. The OS and CSS of M-CLM patients who underwent any type of surgery were significantly better than those of patients who did not undergo any surgery, but poorer than those of A-CLM patients who underwent surgery. Meanwhile, the OS and CSS of M-CLM and A-CLM patients who did not undergo any surgery were comparable. Compared with hemicolectomy, partial colectomy led to similar or better OS and CSS for M-CLM, and surgery was an independent protective factor for long-term survival in M-CLM. Conclusions M-CLM had distinct clinicopathological characteristics from A-CLM, and surgery could improve the survival and is an independent favourable prognostic factor for M-CLM. In addition, partial colectomy might be a non-inferiority choice as hemicolectomy for M-CLM according to the results from this study.

Abstract Although guidelines recommend extended surgical resection, radical resection and lymphadenectomy for patients with tumor stage (T)1b gallbladder cancer, these procedures are substantially underutilized. This population‐based, retrospective cohort study aimed to evaluate treatment patterns and outcomes of 401 patients using the US Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013. Results showed that median overall survival (OS) was 69 months for lymphadenectomy patients and 37 months for those without lymphadenectomy. Lymphadenectomy also tended to prolong cancer‐specific survival (CSS), although the differences were not statistically significant. OS and CSS were similar for patients who received simple cholecystectomy and extended surgical resection. Cox proportional hazards regression models revealed survival advantages in patients with stage T1bN0 gallbladder cancer compared to those with stage T1bN1, and patients who received simple cholecystectomy plus lymphadenectomy compared to those who did not receive lymph node dissection. In further analyses, patients undergoing simple cholecystectomy who had five or more lymph nodes excised had better OS and CSS than those without lymph node dissection. In conclusion, survival advantages are shown for patients with T1b gallbladder cancer undergoing surgeries with lymphadenectomy. Future studies with longer follow‐up and control of potential confounders are highly warranted.

Abstract Introduction Lung cancer is the leading causes of cancer-related deaths globally. The most frequent histologic type of lung cancer is non–small-cell lung cancer (NSCLC). NSCLC often undergo epithelial-mesenchymal transition (EMT). The components that control this process are thus promising therapeutic targets. Materials and methods Gli/EMT protein expression levels were examined by western blot in paired NSCLC patient tissues and NSCLC cell lines. Functional analyses were performed to investigate SHH/Gli signaling and EMT in NSCLC cell lines. MTS cell viability, luciferase reporter, and western blot assays were performed to analyze pathway activity, while wound healing and transwell assays were executed to measure cell migration and invasion. Results Higher Gli1 expressions were detected in tumor samples than in paired normal tissues. Differential expression of EMT biomarkers and activation of p-AKT were observed in tumor tissues. N-Shh stimulation of cells significantly increased reporter activity in NSCLC cell lines, while Gli-i treatment of transfected cells showed less relative reporter activity. When subjected to both Gli-i and N-Shh treatment, NSCLC cell lines continued to demonstrate decreased Gli transcriptional activity. Gli inhibition is associated with decreased expression level of p-AKT, N-cadherin and Vimentin. Knockdown of both Gli1 and Gli2 showed decreased EMT, migrative and invasive ability. Cells stimulated by N-Shh demonstrated greater mobility. In addition, AKT-i treated cells also demonstrated inhibited EMT activity. Conclusions This study provides evidence for aberrant upregulation of the Gli signaling pathway and a strong association between expression of Gli versus AKT and EMT markers in NSCLC.

Objectives Carpal tunnel syndrome (CTS) is a common complication in maintenance hemodialysis (MHD) patients and leads to disabilities and increased risk of mortality. Hepatitis C virus (HCV) infection is associated with inflammatory and oxidative stress, and HCV infection can be cured. This study aimed at evaluating the association of HCV infection with CTS. Methods Using a cross-sectional design, anthropometric and laboratory data were collected. Serum β2-microglobulin, HCV antibody and HCV-RNA were measured. CTS was diagnosed according to clinical manifestation, electrophysiological test or ultrasonography. The related factors for CTS were analyzed by multivariate logistic regression. Results This study included 113 participants, of whom 33 (29.2%) patients were positive for HCV antibody and 18 (15.9%) were positive for HCV antibody and HCV-RNA. Thirty-two (28.3%) patients were diagnosed with CTS. There were significant differences in the dialysis vintage, age of onset of MHD, high-sensitivity C-reactive protein, serum β2M, anti-HCV-positive, HCV-RNA-positive, HCV load values and urine volume category between the CTS group and non-CTS group (p

In this study, a wearable prototype system was developed for multiple-gesture rehabilitation using electrical stimulation controlled by a volitional surface electromyography (sEMG) scan of a healthy forearm. The purpose of the prototype system is to reconstruct multiple gestures of a paralysed limb and to simplify the positioning of sEMG detection sites on a healthy forearm. A self-designed eight-channel sEMG detection armband was used to detect the sEMG signal distributions of the muscle groups in healthy forearms. Linear discriminant analysis (LDA) was used to classify the sEMG signal distributions corresponding to different gestures, and then the classification results were mapped to corresponding stimulation channels. The sEMG signal with the maximum root mean square (RMS) was used as the source of stimulus coding for each gesture. Our proposed mean absolute value (MAV)/number of slope sign changes (NSS) dual-coding (MNDC) algorithm was used to encode the sEMG signal into an electrical stimulus with a dynamic pulse width and frequency. The constant-current stimulation armband electrically stimulated multiple muscles in the affected forearm by means of a circuit designed with a time-division multiplexed stimulation channel. An experiment involving 6 able-bodied volunteers showed that when the detection armband was located near the middle of the forearm, the gesture classification accuracy was greater than 90%, and each active sEMG signal was high. Gesture bridge experiments, including grasping, wrist flexion, wrist extension and finger extension, were carried out among six hemiplegic subjects and between one able-bodied volunteer acting as a controller and each of six stroke patients as the controllee. Both sets of results show that the proposed system can reconstruct these four gestures in the controlled subject with a delay of at most 360 ms and with a correlation coefficient of >0.72.

Abstract Flexible photodetectors (FPDs) have been receiving increasing attention in recent years because of their potential applications in electronic eyes, bioinspired sensing, smart textiles, and wearable devices. Moreover, metal halide perovskites (MHPs) with outstanding optical and electrical properties, good mechanical flexibility, low‐cost and low‐temperature solution‐processed fabrication have become promising candidates as light harvesting materials in FPDs. Herein, we comprehensively review the developments of FPDs based on MHPs reported recently. This review firstly provides an introduction with respect to the performance parameters and device configurations of perovskite photodetectors, followed by the specific requirements of FPDs including substrate and electrode materials. Next, chemical compositions, structures and preparation methods of MHPs are presented. Then, the FPDs on the basis of single‐component perovskite and hybrid structure perovskite are discussed, subsequently, self‐powered flexible perovskite photodetectors were presented. In the end, conclusions and challenges are put forward in the field of FPDs based on perovskites.

Radiotherapy (RT), as one of the main methods of clinical tumor treatment, has been applied to the treatment of most solid tumors. However, the effect of RT is compromised by the radiation resistance of tumor hypoxic environment and non-specific damage caused by high-dose radiation. Bismuth chalcogenides (Bi2X3, X = S, Se) based nanodrugs have attracted widespread attention as highly efficient radiosensitizers due to their high photoelectric effect and excellent biocompatibility. More importantly, specially designed nanocomposites can effectively alleviate the radiation resistance of tumor tissues. Here, for the first time, we systematically summarize the latest progresses of Bi2X3 nanodrugs to enhance RT by alleviating the hypoxic tumor microenvironment. These emerging Bi2X3 nanodrugs mainly include three aspects, which are Bi2X3 nanocomposites with high-efficient O2 supply, non-O2-dependent Bi2X3 nanocomposites RT enhancers, and Bi2X3 nanocomposites-based photothermal-enhanced radiosensitizers. These Bi2X3 nanodrugs can effectively overcome the RT resistance of tumor hypoxic microenvironment, and have extremely high therapeutic effects and clinical application prospects. Finally, we put forward the challenges and prospects of Bi2X3 nanomaterials in the field of RT.

In fusion reactors, 14 MeV high-energy neutron irradiation of structural materials will produce large amounts of helium and hydrogen simultaneously with displacement defects. These He and H atoms will interact with displacement defects, leading to He-H synergistic effects and aggravating the irradiation damage. Currently, there exist no available high-flux fusion neutron sources. Additionally, the neutron energy spectrum and the generation of He and H in fission reactors or spallation neutron sources greatly differ from those in fusion reactors. Multi-ion beam irradiation is a promising method to emulate the synergistic effects induced by fusion neutron irradiation. This review summarizes the experimental studies on the He-H synergistic effects, and analyzes the effects of He and H on cavity evolution and swelling under multi-ion beam irradiation. The roles of various experimental factors are also discussed. More systematically controlled experiments are suggested to develop a comprehensive understanding of He-H synergistic effects in structural materials.

Coordinated reaching and grasping movements may be impaired in patients with poststroke hemiplegia. Patients frequently adopt compensatory strategies, which require investigation. This pilot study used kinematic parameters to examine compensatory strategies by assessing the reach-to-grasp-pen movements in patients with stroke and unaffected participants. Twelve patients with stroke with mild impairment (45.16 ± 12.62 years, 2.41 ± 1.97 months), twelve with moderate impairment (50.41 ± 12.92 years, 3.83 ± 3.58 months), and ten healthy individuals (20.6 ± 0.69 years) performed a reach-to-grasp-pen task. Kinematics parameters of upper limb and fingers, such as movement time, number of movement units, index of curvature, spectral arc length, trunk forward transition, trunk lateral transition, elbow extension, shoulder flexion, shoulder abduction, trunk rotation, arm-plane angle, the joint angles of interphalangeal joints of the thumb, index, middle, ring, and little fingers were examined in the study. These parameters were evaluated with two Microsoft Azure Kinect and Leap Motion, which belong to markerless motion capture systems. Patients with stroke showed longer reaching movement time, less smooth movement trajectories, and more trunk rotation (P

The bioassay-guided phytochemical study of an ethnic medicinal plant Aspidopterys obcorda ta Hemsl. var. obcordata results in the isolation of eight new polyoxypregnane derivatives, named aspidatasides A–H (1–8), along with ten known analogs (9–18). The series polyoxypregnane derivatives were screened for their cytoxic activity against HL-60 cells, and compound 2 showed the highest potency with an IC50 8.03 μM. Preliminary structure–activity relationship studies displayed that the sugar chain and double bond could notably impact their biological activity.

Mitochondria, as one of the most critical subcellular organelles of cancer cells, are very vulnerable and often on the verge of oxidative stress. The classic chemodynamic therapy (CDT) directly employs endogenous chemical energy to trigger reactive oxygen species (ROS) burst and destroy tumor cells. However, the effectiveness of CDT is restricted by the limited diffusion distance and short half-life of ROS. From this perspective, the treatment method (mitochondria-targeting chemodynamic therapy nanodrugs, M-CDT nanodrugs) that can generate high levels of ROS at the mitochondrial site is extremely efficient and promising for cancer treatment. Currently, many emerging M-CDT nanodrugs have been demonstrated excellent spatial specificity and anti-cancer efficacy. In this minireview, we review various proof-of-concept researches based on different M-CDT nanodrugs designs to overcome the limits of the efficacy of CDT, mainly divided into four strategies: supplying H2O2, non-H2O2 dependent CDT, eliminating GSH and enhancing by hyperthermia therapy (HT). These well-designed M-CDT nanodrugs greatly increase the efficacy of CDT. Finally, the progress and potential of M-CDT nanodrugs are discussed, as well as their limitations and opportunities.

Insect nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels mainly expressed in the central nervous system of insects. They are the directed targets of many insecticides, including neonicotinoids, which are the most widely used insecticides in the world. However, the development of resistance in pests and the negative impacts on bee pollinators affect the application of insecticides and have created a demand for alternatives. Thus, it is very important to understand the mode of action of these insecticides, which is not fully understood at the molecular level. In this study, we systematically examined the susceptibility of ten Drosophila melanogaster nAChR subunit mutants to eleven insecticides acting on nAChRs. Our results showed that there are several subtypes of nAChRs with distinct subunit compositions that are responsible for the toxicity of different insecticides. At least three of them are the major molecular targets of seven structurally similar neonicotinoids in vivo. Moreover, spinosyns may act exclusively on the α6 homomeric pentamers but not any other nAChRs. Behavioral assays using thermogenetic tools further confirmed the bioassay results and supported the idea that receptor activation rather than inhibition leads to the insecticidal effects of neonicotinoids. The present findings reveal native nAChR subunit interactions with various insecticides and have important implications for the management of resistance and the development of novel insecticides targeting these important ion channels.

In recent times, the excessive accumulation of nitrate has been one of the main reasons for the secondary salinization of greenhouse soils. Light plays a key role in a plant’s growth, development, and response to stress. A low-red to far-red (R:FR) light ratio could enhance plant salinity tolerance, but the mechanism at a molecular level is unclear. Thus, we analyzed the transcriptome responses of tomato seedlings to calcium nitrate stress under either a low R:FR ratio (0.7) or normal light conditions. Under calcium nitrate stress, a low R:FR ratio enhanced both the antioxidant defense system and the rapid physiological accumulation of proline in tomato leaves, which promoted plant adaptability. Using weighted gene co-expression network analysis (WGCNA), three modules including 368 differentially expressed genes (DEGs) were determined to be significantly associated with these plant traits. Functional annotations showed that the responses of these DEGs to a low R:FR ratio under excessive nitrate stress were enriched in the areas of hormone signal transduction, amino acid biosynthesis, sulfide metabolism, and oxidoreductase activity. Furthermore, we identified important novel hub genes encoding certain proteins, including FBNs, SULTRs, and GATA-like transcription factor, which may play a vital role in low R:FR light-induced salt responses. These findings offer a new perspective on the mechanisms and environmental implications behind low R:FR ratio light-modulated tomato saline tolerance.

Coexistence of hydrogen (H) and helium (He) under vacancy (V) supersaturation in the fusion environment alters the dynamic evolution of cavities and ultimately influences the swelling of structural materials. Herein, we investigate H–He interaction around a V as one prototype trapping site for H and He in body-centered cubic (BCC) iron (Fe) utilizing ab initio calculations from the thermal dynamics. First, we demonstrate the significantly stronger He–V interaction than H–V interaction by comparing the dynamic trapping and de-trapping of H with those of He. Furthermore, we confirm the repulsive H–He interaction around the V by examining their hopping around H–He–V complexes. The prior He in the V imposes weak influence on the dynamic trapping of H while enhances H de-trapping. Due to the prior He, more H atoms can be accommodated in the V resulting from larger H–H distances to attenuate repulsive H–H interaction. The dynamic trapping of He by the V is weakly influenced, even though the V is densely coated by the prior H. There exists a critical density of the prior H in the V, below which the prior H enhances He de-trapping. Above this critical density, He de-trapping is inhibited by the prior H. This work provides significant dynamic insights at the atomic scale toward a better understanding of the cavity nucleation and H isotopes/He retention in structural materials in the fusion environment.

We experimentally investigated the detection performance of highly disordered ${{\rm{Nb}}}_{x}{{\rm{Ti}}}_{1-x}{\rm{N}}\,$ based superconducting nanowire single photon detectors (SNSPDs). The dependence on the composition of the transition temperature ${T}_{c}$ for ${{\rm{Nb}}}_{x}{{\rm{Ti}}}_{1-x}{\rm{N}}$ films show a dome-like behavior on the Nb content, with a maximal ${T}_{c}$ at ${x}_{{\rm{Nb}}}\sim 0.65,$ and the ${{\rm{Nb}}}_{0.65}{{\rm{Ti}}}_{0.35}{\rm{N}}$ films also combine relatively large sheet resistance and intermediate residual resistivity ratio. Moreover, 60-nm-wide and 7-nm-thick ${{\rm{Nb}}}_{0.65}{{\rm{Ti}}}_{0.35}{\rm{N}}$ nanowires show a switching current as high as 14.5 μ A, and saturated intrinsic detection efficiency with a plateau of more than 2 μ A at 2.4 K. Finally, the corresponding SNSPDs on an alternative SiO _2 /Ta _2 O _5 dielectric mirror showed a system detection efficiency of approximately 92% for 1550 nm photons, and the timing jitter is around 26 ps. Our results demonstrate that the highly disordered ${{\rm{Nb}}}_{x}{{\rm{Ti}}}_{1-x}{\rm{N}}$ films are promising for fabricating SNSPDs for near- and middle-infrared single photons with high detection efficiency and low timing jitter.

Parker Solar Probe observes unexpectedly prevalent switchbacks, which are rapid magnetic field reversals that last from seconds to hours, in the inner heliosphere, posing new challenges to understanding their nature, origin, and evolution. In this work, we investigate the thermal states, electron pitch-angle distributions, and pressure signatures of both inside and outside the switchbacks, separating a switchback into spike, transition region (TR), and quiet period (QP). Based on our analysis, we find that the proton temperature anisotropies in TRs seem to show an intermediate state between spike and QP plasmas. The proton temperatures are more enhanced in the spike than in the TR and QP, but the alpha temperatures and alpha-to-proton temperature ratios show the opposite trend to the proton temperatures, implying that the preferential heating mechanisms of protons and alphas are competing in different regions of switchbacks. Moreover, our results suggest that the electron-integrated intensities are almost the same across the switchbacks, but the electron pitch-angle distributions are more isotropic inside than outside switchbacks, implying switchbacks are intact structures, but strong scattering of electrons happens inside switchbacks. In addition, the examination of pressures reveals that the total pressures are comparable through an individual switchback, confirming switchbacks are pressure-balanced structures. These characteristics could further our understanding of ion heating, electron scattering, and the structure of switchbacks.

Switchbacks are rapid magnetic field reversals that last from seconds to hours. Current Parker Solar Probe (PSP) observations pose many open questions in regard to the nature of switchbacks. For example, are they stable as they propagate through the inner heliosphere, and how are they formed? In this work, we aim to investigate the structure and origin of switchbacks. In order to study the stability of switchbacks, we suppose the small-scale current sheets therein are generated by magnetic braiding, and they should work to stabilize the switchbacks. With more than 1000 switchbacks identified with PSP observations in seven encounters, we find many more current sheets inside than outside switchbacks, indicating that these microstructures should work to stabilize the S-shape structures of switchbacks. Additionally, we study the helium variations to trace the switchbacks to their origins. We find both helium-rich and helium-poor populations in switchbacks, implying that the switchbacks could originate from both closed and open magnetic field regions in the Sun. Moreover, we observe that the alpha-proton differential speeds also show complex variations as compared to the local Alfvén speed. The joint distributions of both parameters show that low helium abundance together with low differential speed is the dominant state in switchbacks. The presence of small-scale current sheets in switchbacks along with the helium features are in line with the hypothesis that switchbacks could originate from the Sun via interchange reconnection process. However, other formation mechanisms are not excluded.

In general, slow solar wind from the streamer belt forms a high plasma β equatorial plasma sheet around the heliospheric current sheet (HCS) crossing, namely, the heliospheric plasma sheet (HPS). Current Parker Solar Probe (PSP) observations show that the HCS crossings near the Sun could be full or partial current sheet (PCS) crossings, and they share some common features but also have different properties. In this work, using the PSP observations from encounters 4–10, we identify streamer belt solar wind from enhancements in plasma β , and we further use electron pitch angle distributions to separate it into HPS solar wind around the full HCS crossings and PCS solar wind in the vicinity of PCS crossings. Based on our analysis, we find that the PCS solar wind has different characteristics as compared with HPS solar wind: (a) the PCS solar wind could be non-pressure-balanced structures rather than magnetic holes, and the total pressure enhancement mainly results from the less reduced magnetic pressure; (b) some of the PCS solar wind is mirror-unstable; and (c) the PCS solar wind is dominated by very low helium abundance but varied alpha–proton differential speed. We suggest that the PCS solar wind could originate from coronal loops deep inside the streamer belt, and it is pristine solar wind that still actively interacts with ambient solar wind; thus, it is valuable for further investigations of the heating and acceleration of slow solar wind.

Abstract Electrospinning is a unique method to prepare 1‐dimentional nanofiber for large‐scale manufacturing. Here in, we demonstrated chemical sensors based on the semiconducting nanofibers with core‐shell structure by simple single‐nozzle electrospinning with the spontaneous phase separation. The core‐shell structure nanofiber has large active sites which make it highly sensitive to chemical analytes. The thickness of the sensing shell can be tuned by controlling the mass ratio of core and shell components. As a demonstration, the nanofiber‐based sensor exhibits high sensitivity to low‐concentration ammonia (ppb level), as well as stability and reversibility. This unique fast single‐nozzle electrospinning technique used to fabricate semiconducting nanofibers with core‐shell structure provides a facile and designable process for the integration of multifunctional organic semiconducting layer into the organic electronic system.

Immune characteristics were reported correlated to benefit neoadjuvant chemotherapy (NAC) in breast cancer, yet integration of comprehensive genomic alterations and T-cell receptors (TCR) to predict efficacy of NAC needs further investigation. This study simultaneously analyzed TMB (Tumor Mutation Burden), TCRs, and TILs (tumor infiltrating lymphocyte) in breast cancers receiving NAC was conducted in a prospective cohort (n = 22). The next-generation sequencing technology-based analysis of genomic alterations and TCR repertoire in paired breast cancer samples before and after NAC was conducted in a prospective cohort (n = 22). Fluorescent multiplex immunohistochemistry was used to stain CD4, CD8, PD1, TIM3, and cytokeratins simultaneously in those paired samples. TMB in pretreatment tumor tissues and TCR diversity index are higher in non-pCR patients than in pCR patients (10.6 vs. 2.3; p = 0.043) (2.066 vs. 0.467; p = 0.010). TMB and TCR diversity index had linear correlation (y = 5.587x − 0.881; r = 0.522, p = 0.012). Moreover, infiltrating T cells are significantly at higher presence in pCR versus non-pCR patients. Dynamically, the TMB reduced significantly after therapy in non-pCR patients (p = 0.010) but without TCR index change. The CDR3 peptide AWRSAGNYNEQF is the most highly expressed in pre-NAC samples of pCR patients and in post-NAC samples of non-pCR patients. In addition to pCR, high clonality of TCR and high level of CD8+ expression are associated with disease-free survival (DFS). TCR index and TMB have significant interaction and may guide neo-adjuvant treatment in operable breast cancers. Response to NAC in tumors with high TCR clonality may be attributable to high infiltration and expansion of tumor-specific CD8 positive effector cells.

AimThe objective of this research was to determine the static postural control differences measured from a force platform in Type 2 diabetes mellitus (T2DM) and healthy control groups with different levels of body mass index (BMI), and detect the static postural control difference between T2DM and healthy control groups stratified by different BMI category. This research also explored the relationship of BMI and static postural performance.MethodsWe recruited 706 participants with T2DM and 692 healthy controls who were sufficiently matched for age, gender, and BMI in this cross-sectional study. The participants were stratified into three groups by BMI: normal weight, overweight, and obesity. All participants performed two-legged static stance postural control assessment on a firm force platform. The Center of Pressure (CoP) parameters were collected under eyes-open and eyes-closed conditions. Mann–Whitney U test was used to compare the static postural control parameters within each BMI category in both groups. The static postural control parameters among different weight groups were compared by Kruskal–Wallis test, post hoc pair-wise comparison were conducted. Generalized linear model was conducted to examine the association between BMI and static postural control parameters while controlling for confounding factors.ResultsHealthy control group had statistical difference in most CoP parameters compared to T2DM group based on all BMI categories. Normal weight participants presented significant difference compared with overweight and/or obesity for total track length (TTL) and velocity of CoP displacements in Y direction (V-Y) under eyes-open condition, and for most CoP parameters under eyes-closed condition in both groups. There were statistically significant correlations between BMI and most static postural control parameters under only eyes-closed condition according to the result of generalized linear model.ConclusionT2DM patients had impaired static postural control performance compared to healthy controls at all BMI categories. The findings also indicated the association between BMI and static postural control, where higher BMI individuals showed more static postural instability in both T2DM and healthy controls.

This paper presents the results of the density scanning experiment on the 2018 EAST campaign to study the effect of gas fueling on energy confinement of the ELMy H-mode. The experiment is carried out in a USN configuration, with neutral beam and lower hybrid wave heating and gas fueling, with the upper triangularity δup ∼ 0.47. The total stored energy, H98, and βN decrease with normalized density. Compared to the variations in temperature at the pedestal, the core temperature decreases more significantly for both Te and Ti, leading to a large reduction in core pressure and an increase in the pedestal electron collisionality ν*e,ped. The increase in ν*e,ped could reduce the pedestal current and result in a decrease in the value of q in the core region. It was observed that the frequency of type I ELMs increases with density and the edge localized mode size becomes smaller at high density plasma. An m/n = 2/2 tearing mode was observed at the core of the plasma and can coexist with a sawtooth at low density plasma while this tearing mode disappeared at high gas fueling plasma. The reversal radius of the sawtooth (where q = 1) moves toward the magnetic axis as density increases. The degradation in performance with density may be due to two reasons: the more monotonic shear q profile and the weakening of the stabilizing effect of fast ions on ion temperature gradient modes at high density by D2 gas fueling. It seems that there is a strong link between core transport and pedestal parameters which are influenced by gas fueling, resulting in a significant degradation of energy confinement.

The urban groundwater system is complex and affected by the interaction of natural and human factors. Groundwater scarcity can no longer reflect this complex situation, and the concept of groundwater drought can better interpret this situation. The groundwater drought cycle is the time interval in which groundwater droughts occur repeatedly and twice in a row. The study of the groundwater drought cycle can more comprehensively grasp the development characteristics of the groundwater drought, which is of great importance for the development, utilization, and protection of groundwater. This study used monthly observation data from seven groundwater wells in Xuchang, China, in the period 1980–2018. We applied the Kolmogorov–Smirnov test to select the best fitting distribution function and constructed a Standardized Groundwater Index (SGI). We analyzed groundwater drought at different time scales and used Morlet’s continuous complex wavelet transform to analyze the groundwater drought cycles. The following results were obtained: 1) the maximum intensity of groundwater drought in the seven observation wells ranged from 104.40 to 187.10. Well-3# has the most severe groundwater drought; 2) the drought years of well-5# were concentrated in 1984–1987 and 2003–2012 and those in the other wells in 1994–1999 and 2014–2018; and 3) the groundwater drought cycles in the seven observation wells were 97–120 months, and the average period is about 110 months. The cycle length had the following order: well-7# > well-4# > well-5# > well-2# > well-1# > well-3# > well-6. Therefore, Morlet wavelet transform analysis can be used to study the groundwater drought cycles and can be more intuitive in understanding the development of regional groundwater droughts. In addition, through the study of the Xuchang groundwater drought and its cycle, the groundwater drought in Xuchang city has been revealed, which can help local relevant departments to provide technical support and a scientific basis for the development, utilization, and protection of groundwater in the region.

The present study aimed to assess whether women with polycystic ovarian syndrome (PCOS) ≥35 years age undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles experienced a higher cumulative live birth rate (CLBR) over a two-year period compared with age- and body mass index (BMI)-matched patients with tubal factor infertility. Through propensity score matching (PSM) approach, the authors retrospectively analyzed the IVF/ICSI outcomes of 263 PCOS patients (35-46 years of age [mean, 37 years]) and 526 age- and BMI-matched tubal factor controls two years after oocyte retrieval. Multivariate regression analysis was performed to explore factors influencing cumulative live birth. Women with PCOS exhibited better ovarian reserve and response, and higher CLBR in two years compared with age- and BMI-matched controls (CLBR: 55.51% in PCOS vs. 38.02% in control, p

Objective This study aimed to assess the cost-effectiveness of combined scalp acupuncture therapy with speech and language therapy for patients with Broca’s aphasia after stroke.Design A within-trial cost-effectiveness analysis.Settings Community health centres.Subjects A total of 203 participants with Broca’s aphasia after stroke who had been randomly assigned to receive scalp acupuncture with speech and language therapy (intervention) or speech and language therapy alone (control).Intervention Both groups underwent speech and language therapy (30 min per day, 5 days a week, for 4 weeks), while the intervention group simultaneously received scalp acupuncture.Primary outcomes All outcomes were collected at baseline, and after the 4-week intervention and 12-week follow-up. Cost-effectiveness measures included the Chinese Rehabilitation Research Center Standard Aphasia Examination (CRRCAE) and Boston Diagnostic Aphasia Examination (BDAE). Cost–utility was evaluated using quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios were expressed, and sensitivity analysis was conducted.Results The total cost to deliver the intervention was €4001.72, whereas it was €4323.57 for the control group. The incremental cost-effectiveness ratios showed that the intervention was cost-effective (€495.1 per BDAE grade gained; €1.8 per CRRCAE score gained; €4597.1 per QALYs gained) relative to the control over the 12 weeks. The intervention had a 56.4% probability of being cost-effective at the ¥50 696 (€6905.87) Gross Domestic Product (GDP) per capita threshold. Sensitivity analyses confirmed the robustness of the results.Conclusions Compared with speech and language therapy alone, the addition of scalp acupuncture was cost-effective in Chinese communities. As the costs of acupuncture services in China are likely to differ from other countries, these results should be carefully interpreted and remain to be confirmed in other populations.Trial registration number ChiCTR-TRC-13003703.

Background: The aim of this study was to explore the predictive values of quantitative CT indices of the total lung and lung lobe tissue at discharge for the pulmonary diffusion function of coronavirus disease 2019 (COVID-19) patients at 5 months after symptom onset. Methods: A total of 90 patients with moderate and severe COVID-19 underwent CT scans at discharge, and pulmonary function tests (PFTs) were performed 5 months after symptom onset. The differences in quantitative CT and PFT results between Group 1 (patients with abnormal diffusion function) and Group 2 (patients with normal diffusion function) were compared by the chi-square test, Fisher’s exact test or Mann–Whitney U test. Univariate analysis, stepwise linear regression and logistic regression were used to determine the predictors of diffusion function in convalescent patients. Results: A total of 37.80% (34/90) of patients presented diffusion dysfunction at 5 months after symptom onset. The mean lung density (MLD) of the total lung tissue in Group 1 was higher than that in Group 2, and the percentage of the well-aerated lung (WAL) tissue volume (WAL%) of Group 1 was lower than that of Group 2 (all p < 0.05). Multiple stepwise linear regression identified only WAL and WAL% of the left upper lobe (LUL) as parameters that positively correlated with the percent of the predicted value of diffusion capacity of the lungs for carbon monoxide (WAL: p = 0.002; WAL%: p = 0.004), and multiple stepwise logistic regression identified MLD and MLDLUL as independent predictors of diffusion dysfunction (MLD: OR (95%CI): 1.011 (1.001, 1.02), p = 0.035; MLDLUL: OR (95%CI): 1.016 (1.004, 1.027), p = 0.008). Conclusion: At five months after symptom onset, more than one-third of moderate and severe COVID-19 patients presented with diffusion dysfunction. The well-aerated lung and mean lung density quantified by CT at discharge could be predictors of diffusion function in convalesce.

Ganoderma (Ganodermaceae) is a genus of edible and medicinal mushrooms that create a diverse set of bioactive compounds. Ganoderma lingzhi has been famous in China for more than 2000 years for its medicinal properties. However, the genome information of G. lingzhi has not been characterized. Here, we characterized its 49.15-Mb genome, encoding 13,125 predicted genes which were sequenced by the Illumina and PacBio platform. A wide spectrum of carbohydrate-active enzymes, with a total number of 519 CAZymes were identified in G. lingzhi. Then, the genes involved in sexual recognition and ganoderic acid (GA, key bioactive metabolite) biosynthesis were characterized. In addition, we identified and deduced the possible structures of 20 main GA constituents by UPLC-ESI-MS/MS, including a new special ganochlearic acid A. Furthermore, 3996 novel transcripts were discovered, and 9276 genes were predicted to have the possibility of alternative splicing from RNA-Seq data. The alternative splicing genes were enriched for functional categories involved in protein processing, endocytosis, and metabolic activities by KEGG. These genomic, transcriptomic, and GA constituents’ resources would enrich the toolbox for biological, genetic, and secondary metabolic pathways studies in G. lingzhi.

Biosurfactants are a group of surface-active compounds that can be produced by diverse microorganisms. They have been widely used in various industrial fields. Reducing production costs, improving efficiency, and collecting more diverse producing strains have become major challenges in the biosurfactant industry. These challenges could be overcome by screening for more diverse and efficient biosurfactant-producing strains. The conventional methods for the isolation and functional characterization of microorganisms are laborious and biased toward fast-growing or strongly competitive microorganisms. Here, we established a high-throughput approach of single-cell-based cultivation and functional characterization of biosurfactant-producing bacteria (SCCBB). This approach combines single-cell cultivation with the detection of optical distortions. Using this approach, we isolated 431 strains with biosurfactant production potential from petroleum-contaminated soil and oilfield-produced water. The surfactant production capabilities of the strains were subsequently validated using surface tension measurements, TLC, and CMC measurements. To investigate the industrial production potential, we optimized the production conditions of a representative glycolipids-producing strain, Pseudomonas sp. L01, using response surface methodology (RSM). Optimal conditions yielded a crude biosurfactant yield of 8.43 g/L in a flask. Our work provides a high-throughput approach to the isolation and screening of biosurfactant-producing bacteria, as well as other functional bacteria in a wide range of fields.

Filtering methods are usually used to combine the mean sea surface (MSS) and geoid (computable by global geopotential model (GGM)) into a common subspace, to model mean dynamic topography (MDT), which may lead to signal leakage and distortion problems. The use of the rigorous least squares (LS) method and multivariate objective analysis (MOA) alleviates these problems, and the derived MDTs from these two methods show better performance than MDTs derived from filtering methods. However, the advantages and disadvantages of these two methods have not been evaluated, and no direct comparison has yet been conducted between these two approaches regarding the performances in MDT recovery. In this study, we compare the performances of the MOA method with the LS method, providing information with respect to the usability of different methods in MDT modeling over regions with heterogeneous ocean states and hydrological conditions. We combined a recently published mean sea surface called DTU21MSS, and a satellite-only GGM named GO_CONS_GCF_2_DIR_R6, for MDT computation over four typical study areas. The results showed that the MDTs derived from the LS method outperformed the MOA method, especially over coastal regions and ocean current areas. The root mean square (RMS) of the discrepancies between the LS-derived MDT and the ocean reanalysis data was lower than the RMS of the discrepancies computed from the MOA method, by a magnitude of 1–2 cm. The formal error of the MDT estimated by the LS method was more reasonable than that derived from the MOA method. Moreover, the geostrophic velocities calculated by the LS-derived MDT were more consistent with buoy data than those calculated by the MOA-derived solution, by a magnitude of approximately 1 cm/s. The reason can be attributed to the fact that the LS method forms the design matrix segmentally, based on the error characteristics of the GGM, and suppresses high-frequency noise by applying constraints in different frequency bands, which improves the quality of the computed MDT. Our studies highlight the superiority of the LS-derived method versus the MOA method in MDT modeling.

Balanced time perspective refers to the ability to flexibly switch between different temporal foci in an adaptive manner according to the current context. Functional connectivity within the default mode network (DMN) has been suggested to support balanced time perspective. The coupling between the DMN and fronto-parietal network (FPN) may drive many important expressions of internally directed cognition. However, it remains unclear whether balanced time perspective is supported by the interaction between the FPN and DMN. To examine these issues, we recruited 91 participants (52 males with mean age of 19.6, and 39 females with mean age of 20.0) to undergo resting-state brain imaging scan and to complete a questionnaire measuring balanced time perspective. Seed-based voxel-wise functional connectivity analyses implicated midline DMN regions including the anterior medial prefrontal cortex (amPFC) and posterior cingulate cortex (PCC) along with the anterior cingulate cortex (ACC), precuneus, and cerebellum in supporting a balanced time perspective. More importantly, functional connectivity between the right amPFC and right dorsal lateral prefrontal cortex (DLPFC) in the FPN was found to associate with balanced time perspective. Our findings suggest the importance of coordinated brain activity in supporting a balanced time perspective.

Abstract Background Mental disorders are a common finding among patients with unruptured intracranial aneurysms. Case The current case concerns a young man with an anterior communicating artery aneurysm who was misdiagnosed with schizophrenia and bipolar disorder due to his significant psychosis and mood episodes. Having undergone surgery on the unruptured intracranial aneurysm, the patient's psychiatric symptoms disappeared, and he maintained a stable mood during the 3‐year postoperative period. Discussion The case is indicative of the need to consider the possibility of organic brain lesions in patients with first episodes of psychiatric presentations.

ObjectivesProgestin-primed ovarian stimulation (PPOS) is a new ovarian stimulation protocol that can block the luteinizing hormone (LH) surge through progesterone instead of traditional down regulating or gonadotropin-releasing hormone (GnRH) antagonist, and in order to achieve multi-follicle recruitment. This paper aims to investigate the effectiveness of PPOS and its suitability for infertile patients with different ovarian reserve functions.MethodsWe searched published randomized controlled trials (RCTs) about PPOS on Cochrane Library, PubMed, Embase, and Web of Science. The search period spanned from January 1, 2015 to November 16, 2020. The data were extracted, and the meta-analysis was performed on ovarian stimulation as well as embryological and clinical outcomes. The outcomes were pooled by a random effects model, and the risk of heterogeneity was evaluated. Subgroup analysis was performed for different ovarian reserve patients.ResultsThe clinical pregnancy rates and live birth or ongoing pregnancy rates with the PPOS protocol were not different from those with the control group. In the diminished ovarian reserve (DOR) subgroup, the PPOS protocol had a lower rate of premature LH surge [RR = 0.03, 95% CI = 0.01 to 0.13, p < 0.001]. The PPOS protocol had a lower rate of ovarian hyperstimulation syndrome (OHSS) [RR = 0.52, 95% CI = 0.36 to 0.76, p < 0.001, I2 = 0.00%]. The secondary outcomes showed that the number of oocytes retrieved, MII oocytes, and viable embryos was higher than that of the control protocol in DOR patients [(MD = 0.33, 95% CI = 0.30 to 0.36, p < 0.001), (MD = 0.30, 95% CI = 0.27 to 0.33, p < 0.001), (MD = 0.21, 95% CI = 0.18 to 0.24, p < 0.001)] and normal ovarian reserve (NOR) patients [(MD = 1.41, 95% CI = 0.03 to 2.78, p < 0.001), (MD = 1.19, 95% CI = 0.04 to 2.35, p < 0.001), (MD = 1.01, 95% CI = 0.21 to 1.81, p = 0.01)].ConclusionThe findings suggest that PPOS is an effective ovarian stimulation protocol and is beneficial for patients with different ovarian reserve functions, which needs to be validated in more RCTs with larger samples.

Edge localized mode (ELM) mitigation accompanied by density pump-out has been achieved during the application of resonant magnetic perturbation (RMP) with a toroidal mode number of n = 4 on EAST recently. The mean ELM frequency increases by a factor of 2.7 from 86 to 235 Hz with a decreased reduction in ELM loss. The evolution of pedestal electron density measured by a profile reflectometer before and after turning on the RMP current is presented. Both the pedestal density and density gradient show a decrease with application of RMP. The density fluctuation in the pedestal region has been measured by an O-mode fluctuation reflectometer. The broadband density fluctuation with a frequency range of 20–115 kHz is enhanced at the later period of the inter-ELM phase during ELM mitigation. This phenomenon is also observed for magnetic fluctuation measured by magnetic probes mounted in the vacuum vessel. A further study shows that the enhanced broadband fluctuations lead to a decrease in the growth rate of the pedestal density and an increase in divert or particle flux. This result implies that these enhanced broadband fluctuations could lead to an enhancement of outward particle transport. The possible roles of the enhanced fluctuations observed in ELM mitigation are also discussed.

The Varroa destructor mite is a devastating parasite of Apis mellifera honeybees. They can cause colonies to collapse by spreading viruses and feeding on the fat reserves of adults and larvae. Amitraz is used to control mites due to its low toxicity to bees; however, the mechanism of bee resistance to amitraz remains unknown. In this study, we found that amitraz and its major metabolite potently activated all four mite octopamine receptors. Behavioral assays using Drosophila null mutants of octopamine receptors identified one receptor subtype Octβ2R as the sole target of amitraz in vivo. We found that thermogenetic activation of octβ2R-expressing neurons mimics amitraz poisoning symptoms in target pests. We next confirmed that the mite Octβ2R was more sensitive to amitraz and its metabolite than the bee Octβ2R in pharmacological assays and transgenic flies. Furthermore, replacement of three bee-specific residues with the counterparts in the mite receptor increased amitraz sensitivity of the bee Octβ2R, indicating that the relative insensitivity of their receptor is the major mechanism for honeybees to resist amitraz. The present findings have important implications for resistance management and the design of safer insecticides that selectively target pests while maintaining low toxicity to non-target pollinators.

Following publication of the original article [1], the authors reported an error in Fig. 1f.

Abstract Background Oxidized low density lipoprotein receptor 1 (OLR1), a type II membrane protein, has been identified as receptor for oxidized low-density lipoprotein. The current study firstly provided evidence that OLR1 regulated EMT and thus promoted lung metastases in osteosarcoma (OS). Method All relevant experiments were conducted according to the manufacturer’s protocols. In vivo tumor xenograft experiments were carried out in 6- to 16-week-old mice, then maintained in our animal facility under pathogen-free conditions in accordance with the Institutional Guidelines and approval by local authorities. For the use of the clinical materials for research purposes, prior patient’s consent and approval from the Institute Research Ethics Committee were obtained. All statistical analyses were performed using IBM SPSS Statistics 22.0 for Windows. Result Microarrays were adopted to explore the underlying epigenetic mechanisms related to metastasis. 11 genes were identified among total 26,890 differentially expressed genes. After validated in paired primary and metastatic tissues, OLR1 was selected in the current study. The expression levels of OLR1 were tested in 4 widely used cell lines. Cell proliferation, migration and invasion could be enhanced when OLR1 was overexpressed. OLR1 overexpression also triggered G1 to S + G2 phases of cell cycle. Accordingly, cell proliferations, migration and invasion would be reduced when OLR1 was silenced. OLR1-silencing blocked G1 to S + G2 phases of cell cycle. Also, OLR1 silencing effectively suppressed local tumor carcinogenesis and lung metastases in vivo. Moreover, silencing OLR1 repressed the expression of mesenchymal markers (Snail, Twist, and N-cadherin), but induced an epithelial marker (E-cadherin). Conclusion This study indicated a novel molecular mechanism involving the role of OLR1 in lung metastases of osteosarcoma, strengthened the correlation between OLR1 and lung metastases.

Abstract Background To reveal roles of reactive oxygen species (ROS) status in chemotherapy resistance and to develop a ROS scoring system for prognosis prediction in ovarian cancer. Methods We tested the sensitizing effects of ROS elevating drugs to cisplatin (cDDP) in ovarian cancer both in vitro and in vivo. A ROS scoring system was developed using The Cancer Genome Atlas (TCGA) database of ovarian cancer. The associations between ROS scores and overall survival (OS) were analyzed in TCGA, Tothill dataset, and our in-house dataset (TJ dataset). Results ROS-inducing drugs increased cisplatin-induced ovarian cancer cell injury in vitro and in vivo. ROS scoring system was established using 25 ROS-related genes. Patients were divided into low (scores 0–12) and high (scores 13–25) score groups. Improved patient survival was associated with higher scores (TCGA dataset hazard ratio (HR) = 0.43, P

Abstract Background Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo. Results We performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone. Conclusion Collectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

Abstract. Background. Brachydactyly, a developmental disorder, refers to shortening of hands/feet due to small or missing metacarpals/metatarsals and/or phalanges. Isolated brachydactyly type E (BDE), characterized by shortened metacarpals and/or metatarsals, consists in a small proportion of patients with Homeobox D13 (HOXD13) or parathyroid-hormone-like hormone (PTHLH) mutations. BDE is often accompanied by other anomalies that are parts of many congenital syndromes. In this study, we investigated a Chinese family presented with BDE combined with pectus carinatum and short stature. Methods. A four-generation Chinese family was recruited in June 2016. After informed consent was obtained, venous blood was collected, and genomic DNA was extracted by standard procedures. Whole-exome sequencing was performed to screen pathogenic mutation, array comparative genomic hybridization (Array-CGH) analysis was used to analyze copy number variations, and quantitative real-time polymerase chain reaction (PCR), stride over breakpoint PCR (gap-PCR), and Sanger sequencing were performed to confirm the candidate variation. Results. A 3.06-Mb deletion (chr12:25473650–28536747) was identified and segregated with the phenotype in this family. The deletion region encompasses 23 annotated genes, one of which is PTHLH which has been reported to be causative to the BDE. PTHLH is an important regulator of endochondral bone development. The affected individuals showed bilateral, severe, and generalized brachydactyly with short stature, pectus carinatum, and prematurely fusion of epiphyses. The feature of pectus carinatum has not been described in the PTHLH-related BDE patients previously. Conclusions. The haploinsufficiency of PTHLH might be responsible for the disease in this family. This study has expanded the knowledge on the phenotypic presentation of PTHLH variation.

Abstract Background To measure the decentration following SMILE in eyes with high myopic astigmatism and investigate its impact on visual quality. Methods The prospective study was conducted to analyze patients who underwent SMILE for correction of myopia and myopic astigmatism ≥2.5D (high astigmatism group, HA) at the ophthalmology department, Eye and ENT hospital, Shanghai, China.. Patients with myopic astigmatism 0.2 mm) showed no significant association between decentration and visual outcomes of predictability, efficiency, safety, MTF cutoff, OSI, SR and OVs in both groups. Also no significant association was observed between decentration and postoperative astigmatism in either group. A significant relationship between the magnitude of decentration and induced coma and spherical aberration was observed in HA. Conclusions The amount of decentration between HA and LA groups showed no differences. Decentration > 0.20 mm from CSCLR resulted in greater induction of coma and SA after SMILE in eyes with HA.

Abstract Background Pulmonary sarcomatoid carcinoma (SC) consists of both carcinomatous and sarcomatous tumors with high degree of malignancy, rapid progression, and poor prognosis. However, little is known regarding how pulmonary SC develops and progresses. Case presentation A 66-year-old male was initially diagnosed with stage IIIa lung cancer containing both adenocarcinoma (ADC) and SC. Adjuvant chemotherapy was administrated post-surgery, however, recurrence with SC only soon followed. Mutation profiling of the patient’s microdissected ADC and SC components of the primary lesion and recurrent tumor was performed by targeted next-generation sequencing (NGS) of 416 cancer-relevant genes. Our data showed that primary SC/ADC and the recurrent SC shared multiple gene mutations including EGFR, NF1, TP53, CDKN2B, and SMARCA4, while both primary and recurrent SCs had a unique TP53 exon 4 splicing mutation frequently observed in sarcoma. Interestingly, a novel PHF20-NTRK1 fusion was acquired in the recurrent SC, which may be a potential driver for SC recurrence. Conclusions The molecular genetic characteristics of tumor tissues at different stages reveals a linear tumor evolution model in this case, and support that the primary SC derived from the original lung ADC during the evolution of the tumor. We also identified a novel PHF20-NTRK1 fusion, which may contribute to the disease recurrence, and that can be potentially targeted with NTRK1 inhibitors for treatment.

Background Osimertinib (AZD9291), a third‐generation EGFR‐tyrosine kinase inhibitor, can effectively prolong survival in non‐small cell lung cancer (NSCLC) patients with EGFR mutations, particularly T790M mutations; however, acquired resistance to AZD9291 is inevitable, thus exploration of the targets of resistance is urgent. Methods Considering the important role of circular RNAs (circRNAs) in cancers, we established AZD9291‐resistant NSCLC cell lines (H1975/AZDR and HCC827/AZDR) and used microarray analysis to determine the circRNA expression profiles of the cells. The H1975/AZDR and HCC827/AZDR cell lines were induced by gradually increasing the drug concentration. CircRNA microarray expression profiles were obtained from H1975, HCC827, H1975/AZDR, and HCC827/AZDR cells and validated by quantitative reverse transcription PCR. Expression data were analyzed bioinformatically. Results The H1975/AZDR and HCC827/AZDR cell lines were successfully established. The half‐maximal inhibitory concentration and the invasion ability of H1975/AZDR and HCC827/AZDR cells were significantly enhanced. The proliferation rates of H1975/AZDR and HCC827/AZDR were much lower than H1975 and HCC827. Microarray analysis identified 15 504 circRNAs differentially expressed in H1975, HCC827, H1975/AZDR, and HCC827/AZDR cells. Among them, 7966 were upregulated and 7538 were downregulated more than two‐fold. We predicted the possible miRNAs of the top dysregulated circRNAs. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the most modulated circRNAs regulate several cancers and cancer‐related pathways. Conclusion Our results reveal that circRNAs may play a role in NSCLC AZD9291 resistance and might be a promising molecular target candidate for gene therapy.

Background: Non-invasive lung adenocarcinoma could benefit from limited resection, nonetheless, there is a lack of method to determine preoperative tumour invasiveness. We aimed to investigate whether folate receptor-positive circulating tumour cells (FR+-CTCs) in combination with maximum tumour diameter (MTD) determines, before surgery, the invasiveness of small-sized, indeterminate solitary pulmonary nodules (SPNs). Methods: A total of 382 patients with suspicious lung adenocarcinoma on computed tomography who were expected to undergo lung resection were enrolled in this study at three participating institutes and randomly assigned into training and validation cohorts. Before surgery, 3 mL peripheral blood was collected from all participants. FR+-CTCs were analyzed using immunomagnetic leukocyte depletion and quantitated by ligand-targeted PCR method. After surgery, the resected tissues were diagnosed by pathologists according to IASLC/ATS/ERS classification. Findings: FR+-CTC levels in the peripheral blood can differentiate benign from malignant nodules with a sensitivity of 78·6%–82·7% and a specificity of 68·8%–78·4%. Both FR+-CTC and MTD are independent predictive indices of invasive tumours for lung adenocarcinoma ≤2 cm based on multivariate analyses. Further, FR+-CTC count in combination with MTD can differentiate non-invasive cancers from invasive cancers with a sensitivity of 63·6%–81·8% and a specificity of 71·4%–89·7%. Interpretation: Detection of FR+-CTC is a reliable method to differentiate malignancy of indeterminate SPNs. Combining of FR+-CTC count and MTD could possibly enhance preoperative determination of the invasiveness of lung nodules and guide surgeons to select limited lung resection and avoid overtreatment for patients with non-invasive lesions. Fund: None. Keywords: Circulating tumour cells, Folate receptor, Non-small cell lung cancer, Tumour invasiveness, Limited lung resection