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Deoxynivalenol (DON) is one of the most prevalent food-associated mycotoxins, and is known to cause a variety of adverse health effects on human and animals. Upon oral exposure, the intestine is the main target organ of DON. The current study unraveled that DON exposure (2 mg/kg bw/day or 5 mg/kg bw/day) can significantly reshape the gut microbiota in a mouse model. The study characterized the specific gut microbial strains and genes changed after DON exposure and also investigated the recovery of the microbiota upon either 2 weeks daily prebiotic inulin administration or 2 weeks recovery without intervention after termination of DON exposure (spontaneous recovery). The results obtained reveal that DON exposure causes a shift in gut microorganisms, increasing the relative abundance of Akkermansia muciniphila, Bacteroides vulgatus, Hungatella hathewayi, and Lachnospiraceae bacterium 28-4, while the relative abundance of Mucispirillum schaedleri, Pseudoflavonifractor sp. An85, Faecalibacterium prausnitzii, Firmicutes bacterium ASF500, Flavonifractor plautii, Oscillibacter sp. 1-3, and uncultured Flavonifractor sp. decreased. Notably, DON exposure enhanced the prevalence of A. muciniphila, a species considered as a potential prebiotic in previous studies. Most of the gut microbiome altered by DON in the low- and high-dose exposure groups recovered after 2 weeks of spontaneous recovery. Inulin administration appeared to promote the recovery of the gut microbiome and functional genes after low-dose DON exposure, but not after high-dose exposure, at which changes were exacerbated by inulin-supplemented recovery. The results obtained help to better understand the effect of DON on the gut microbiome, and the gut microbiota’s recovery upon termination of DON exposure.

Recent advances in hand gesture recognition have produced more natural and intuitive methods of controlling unmanned aerial vehicles (UAVs). However, in unknown and cluttered environments, UAV motion planning requires the assistance of hand gesture interaction in complex flight tasks, which remains a significant challenge. In this paper, a novel framework based on hand gesture interaction is proposed, to support efficient and robust UAV flight. A cascading structure, which includes Gaussian Native Bayes (GNB) and Random Forest (RF), was designed, to classify hand gestures based on the Six Degrees of Freedom (6DoF) inertial measurement units (IMUs) of the data glove. The hand gestures were mapped onto UAV’s flight commands, which corresponded to the direction of the UAV flight.The experimental results, which tested the 10 evaluated hand gestures, revealed the high accuracy of online hand gesture recognition under asynchronous detection (92%), and relatively low latency for interaction (average recognition time of 7.5 ms; average total time of 3 s).The average time of the UAV’s complex flight task was about 8 s shorter than that of the synchronous hand gesture detection and recognition. The proposed framework was validated as efficient and robust, with extensive benchmark comparisons in various complex real-world environments.

The ITER In-Vessel Coils (IVCs) are crucial components of the Tokamak fusion reactor. They are located within the vacuum vessel (VV) behind the blanket shield modules and are responsible for compensating for fast perturbations of the plasma. There are a total of 176 joints used to connect the IVCs, feeders and feedthrough. The joint structure consists of a central copper conductor, a mineral (MgO) insulation layer, and an outer stainless-steel jacket. Given the inaccessibility of the IVCs once the blanket modules are installed, the highest level of quality is required for the joints. One key item is the welding of the copper conductor which has to be done inside the VV. To address the high thermal conductivity of copper conductor and the challenging constraints working inside the VV, a preheating method by the arc of the welding head has been developed. Macro- and micro-structure examination were performed on the welding cross sections, and tensile tests were carried out to check the strength of the copper joint, which demonstrated that arc preheating does not have a significant impact on the heat-affected zone. After more than 40 welding attempts and several design updates, the copper joint has been successfully developed and can be repeatedly and successfully welded.

With the development of radio telescope technology, the quantity and types of acquired pulsar candidate data have increased dramatically. However, it is difficult to accurately identify pulsar candidates. Therefore, we propose to use multimodal fusion technology, called the multimodal fusion-based pulsar identification model (MFPIM), to build a deep learning model to improve the efficiency and accuracy of pulsar candidate identification. MFPIM treats each diagnostic plot of pulsar candidates as a modality and uses multiple convolutional neural networks to extract effective features from the diagnostic plots. After fusing the features, the commonality of different modalities in high-dimensional space is obtained to ensure that the model can take full advantage of the complementarity between diagnostic plots and thus identify pulsar candidates, achieved better classification performance than other current supervised learning algorithms. In addition, a channel attention mechanism is used in the model to enable it to learn the importance of different channel features so that the model focuses more on the channel information in the input data that is more meaningful for classification, reducing the model size while extracting pulsar diagnostic map features more accurately. We conducted experiments on the Five-hundred-meter Aperture Spherical radio Telescope (FAST) data set, and the results show that MFPIM can effectively identify the pulsars in the FAST data set with an identification accuracy of over 98%. To further verify the robustness of the model, we applied the MFPIM to the High Time Resolution Universe data set using transfer learning, with the test accuracy and F1 score reaching over 99%.

We have performed a spectral-timing analysis of the black hole X-ray binary MAXI J1535-571 during its 2017 outburst, with the aim of exploring the evolution of the inner accretion flow geometry. X-ray reverberation lags are observed in the hard-intermediate state (HIMS) and soft-intermediate state of the outburst. During the HIMS, the characteristic frequency of the reverberation lags ν _0 (the frequency at which the soft lag turns to zero in lag–frequency spectra) increases when the spectrum softens. This reflects a reduction of the spatial distance between the corona and accretion disk, when assuming the measured time lags are associated with the light travel time. We also find a strong correlation between ν _0 and the type-C quasi-periodic oscillation (QPO) centroid frequency ν _QPO , which can be well explained by the Lense–Thirring precession model under a truncated disk geometry. Despite the degeneracy in the spectral modeling, our results suggest that the accretion disk is largely truncated in the low hard state, and moves inward as the spectrum softens. Combine the spectral modeling results with the ν _0 – ν _QPO evolution, we are inclined to believe that this source probably has a truncated disk geometry in the hard state.

To automatically, accurately, and quickly detect local changes in time-series data continuously emitted by X-ray sources, an autoencoder-based unsupervised learning anomaly detection method is proposed. Here, we consider the X-ray burst of GRO J1744-28 as our case study. First, we tested the proposed method using simulation data and a test set based on a phenomenologically motivated light-curve fitting of different burst types. Our method exhibited superior performance, achieving F-scores of 0.969 and 0.936 for the detection of small bursts with low peak count rates such as structured bursts and microbursts, respectively. Then, based on Rossi X-ray Timing Detector observation data for GRO J1744-28 during the outburst period, we identified low-amplitude bursts using the proposed method and analyzed the burst regularity of GRO J1744-28. Our approach does not require complex modeling and has powerful feature extraction and detection capabilities, which can be used to automatically and efficiently detect changes in a data stream.

The first X-ray source catalog of the Insight-HXMT Galactic Plane (∣ b ∣ < 10°) Scanning Survey (GPSS) is presented based on the data accumulated from 2017 June to 2021 August. The 4 yr limit sensitivities at main energy bands can reach 8.2 × 10 ^−12 erg s ^−1 cm ^2 (2−6 keV), 4.21 × 10 ^−11 erg s ^−1 cm ^2 (7−40 keV), and 2.78 × 10 ^−11 erg s ^−1 cm ^2 (25−100 keV). More than 1300 sources have been monitored at a wide band (1−100 keV), of which 223 sources have a signal-to-noise ratio greater than 5. We combined the GPSS data of Insight-HXMT and MAXI and found it feasible to obtain more complete long-term light curves from their scanning results. The flux variabilities at different energy bands of the 223 bright sources are analyzed based on the excess variances. It is found that the fluxes of X-ray binaries are more active than those of supernova remnants and isolated pulsars. Different types of binaries, e.g., low-mass X-ray binaries (LMXBs), high-mass X-ray binaries (HMXBs), neutron star binaries, and black hole binaries, also distinctively show different regularities. In addition, the relations between the hardness ratio (HR) and excess variances, and HR and source types are analyzed. It is obvious that the HRs of HMXBs tend to be harder than those of LMXBs and HMXBs tend to be more active than those of LMXBs.

Along with increasingly serious water pollution, water environmental problems have become major factors that hinder the sustainable development of our economy and society. Reliable evaluation of water quality and accurate prediction of water pollution indicators are the key links in water resource management and water pollution control. In this paper, the water quality data of Lanzhou Xincheng Bridge section in the Yellow River Basin and Sichuan Panzhihua Longdong section in the Yangtze River Basin were used to establish a water quality evaluation model and a prediction model. For the water quality evaluation model, we constructed the research samples by means of equal intervals and uniform distribution of interpolated water quality index data according to Environmental Quality Standards for Surface Water. The training samples were determined by a stratified sampling method, and the water quality evaluation model was established using a T-S fuzzy neural network. The experimental results show that the highest accuracy achieved by the evaluation model in water quality classification was 94.12%. With respect to the water quality prediction model, we propose ARIMA-WNN, which combines the autoregressive integrated moving average model (ARIMA) and a wavelet neural network (WNN) with the bat algorithm (BA) to determine the optimal weight of each individual model. The experimental results show that the highest prediction accuracy of ARIMA-WNN is 68.06% higher than that of the original model.

Previous studies of correlations of microRNA (miR)-499 rs3746444 and miR-196a-2 rs11614913 polymorphisms with glioma risk have yielded inconsistent results. In this study, relationships between these two polymorphisms and glioma risk and survival were evaluated. In total, 605 patients and 1,300 controls were genotyped. rs3746444 increased glioma risk in five genetic models (GA versus AA, odds ratio [OR], 95% confidence interval [CI] = 1.31 [1.05–1.66], p = 0.02; GG versus AA, OR [95% CI] = 10.70 [6.13–18.69], p < 0.0001; GA + GG versus AA, OR [95% CI] = 1.82 [1.47–2.24], p < 0.0001; GG versus AA + GA, OR [95% CI] = 9.99 [5.74–17.40], p < 0.0001; G versus A, OR [95% CI] = 2.18 [1.82–2.60], p < 0.0001). rs11614913 decreased glioma risk in a recessive model (OR [95% CI] = 0.79 [0.64–0.97], p = 0.03). No relationships between either SNP and survival were found. rs3746444 in the miR-499 seed region could affect target recognition. Bioinformatics analyses indicated that miR-499 rs3746444 is involved in various biological processes and pathways, including “cell adhesion molecule binding,” “positive regulation of catabolic process,” “NF-kappa B pathway,” and “PI3K-Akt pathway,” by targeting mRNAs. Our results suggested that miR-499 rs3746444 and miR-196a-2 rs11614913 have crucial roles in glioma susceptibility.

Abstract Background This is a retrospective study that compares mandibular growth changes in skeletal Class II patients treated by rapid maxillary expansion (RME) and following fixed appliance with those patients treated by Twin-Block (TB) and following fixed appliance. Methods Fourteen patients treated by RME and following fixed appliance were included into the RME group. Fifteen patients treated by Twin-Block and following fixed appliance were included into the TB group. Lateral cephalometric radiographs taken before treatment and immediately after fixed appliance treatment were used to evaluate mandibular growth effects. Results The starting forms of the patients in the two groups were examined to be of good comparability. The mandibular length increased significantly in both groups as measured by Co-Gn, Go-Gn and Ar-Gn, but the TB group didn’t show more mandibular growth than the RME group (P > 0.05). Skeletal changes of the mandible in vertical dimension were different in the two groups. The change in FMA was 0.35° in the RME group, while the change was 2.65° in the TB group (P

Abstract Background To compare the survival outcomes between breast-conserving surgery (BCS) and modified radical mastectomy (MRM), and to investigate the role of radiotherapy (RT) in patients with pT1–2N1M0 breast cancer. Methods A total of 4262 women with T1–2N1M0 breast cancer treated at two institutions were retrospectively reviewed. A total of 3858 patients underwent MRM, and 832 (21.6%) of them received postoperative RT (MRM + RT). A total of 404 patients received BCS plus postoperative RT (BCS + RT). All patients received axillary lymph node dissection, while 3.8% of them had upfront sentinel node biopsy. The association of survival outcomes with different surgical modalities (BCS vs. MRM) and the role of RT were evaluated using multivariable proportional hazards regression and confirmed by the propensity score-matching (PSM) method. Results At a median follow-up of 71 months (range of 6–230 months), the 5-year overall survival (OS) rates of the BCS and MRM groups were 96.5 and 92.7%, respectively (P = .001), and the corresponding 5-year disease-free-survival (DFS) and locoregional recurrence (LRR) rates were 92.9 and 84.0%, and 2.0 and 7.0% (P = .001), respectively (P

Abstract Background Complex cryptoglandular perianal fistula (CPAF) is a kind of anal fistula that may cause anal incontinence after surgery. Minimally invasive surgery of anal fistula is constantly emerging. Over the past 20 years, there are several sphincter-sparing surgeries, one of which is autologous adipose-derived stem cell (ADSC) transplantation. However, to date, there is no study regarding the treatment of complex CPAF with ADSC in China. This is the first study in China on the treatment of complex CPAF with ADSC to evaluate its safety and efficacy. Methods Totally, 24 patients with complex CPAF were enrolled in this prospective case-control study from January 2018 to December 2019 in the National Colorectal Disease Center of Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine. Patients were divided into ADSC group and endorectal advancement flap (ERAF) group according to their desire. The healing of fistulas (healing of all treated fistulas at baseline, confirmed by doctor’s clinical assessment and magnetic resonance imaging or transrectal ultrasonography) was evaluated at week 12 after treatment. In addition to their safety evaluation based on adverse events monitored at each follow-up, the patients were also asked to complete some scoring scales at each follow-up including pain score with visual analog score (VAS) and anal incontinence score with Wexner score. Results The closure rates within ADSC group and ERAF group at week 12 were 54.55% (6/11) and 53.85% (7/13), respectively, without significant difference between them. VAS score in ADSC group was significantly lower than that in ERAF group at the 5th day postoperatively [1(0,2) VS 2(2,4), p = 0.011], but no differences were observed at the other time. Wexner score of all patients was not increased with no significant differences between the two groups. Adverse events were observed fewer in ADSC group (27.27%) than that in ERAF group (53.85%), but there was no significant difference between them. Conclusion This study indicated safety and efficiency of ADSC for the treatment of complex CPAF in the short term, which is not inferior to that of ERAF. ADSC may provide a promised and potential treatment for complex CPAF conforming to the future of the treatment, which is reconstruction and regeneration. Trail registration ChiCTR, ChiCTR1800014599. Registered 23 January 2018—retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=24548

Abstract Background There is an increasing application of moderately hypofractionated radiotherapy for prostate cancer. We presented our outcomes and treatment-related toxicities with moderately hypofractionated (67.5 Gy in 25 fractions) radiotherapy for a group of advanced prostate cancer patients from China. Methods From November 2006 to December 2018, 246 consecutive patients with prostate cancer confined to the pelvis were treated with moderately hypofractionated radiotherapy (67.5 Gy in 25 fractions). 97.6% of the patients received a different duration of androgen deprivation therapy. Failure-free survival (FFS), prostate cancer-specific survival (PCSS), overall survival (OS), and cumulative grade ≥ 2 late toxicity were evaluated using the Kaplan–Meier actuarial method. Prognostic factors for FFS, PCSS, and OS were analyzed. Results The median follow-up time was 74 months (range: 6–150 months). For all patients, the 5- and 10-year FFS rates were 80.0% (95% CI: 74.7–85.7%) and 63.5% (95% CI 55.4–72.8%). The failure rates for the intermediate, high-risk, locally advanced, and N1 groups were 6.1%, 13.0%, 18.4%, and 35.7%, respectively (P = 0.003). Overall, 5- and 10-year PCSS rates were 95.7% (95% CI 93.0–98.5%) and 88.2% (95% CI 82.8–93.8%). Prostate cancer-specific mortality rates for the high-risk, locally advanced, and N1 groups were 4.0%, 8.2%, and 23.8%, respectively (P

Introduction: The use of the emergency department (ED) has been increasing, and many visits occur for non-urgent conditions. A similar trend was found among adult visits to the ED for ocular conditions. In this study we analyzed the impact of sociodemographic factors, presentation timing, and the COVID-19 pandemic on pediatric ED (PED) encounters for ophthalmologic conditions. It is important to identify the multifold factors associated with overutilization of the ED for non-urgent conditions. Caring for these patients in an outpatient clinical setting is safe and effective and could decrease ED crowding; it would also prevent delays in the care of other patients with more urgent medical problems and lower healthcare costs. Methods: We retrospectively reviewed electronic health records of PED ocular-related encounters at two children’s hospitals before (January 2014–May 2018) and during the COVID-19 pandemic (March 2020–February 2021). Encounters were categorized based on the International Classification of Diseases codes into “emergent,” “urgent,” and non-urgent” groups. We analyzed associations between sociodemographic factors and degrees of visit urgency. We also compared visit frequencies, degrees of urgency, and diagnoses between pre-pandemic and pandemic data. Results: Pre-pandemic ocular-related PED encounters averaged 1,738 per year. There were highly significant sociodemographic associations with degrees of urgency in PED utilization. During the 12-month pandemic timeframe, encounter frequency contracted to 183. Emergent visits decreased from 21% to 11%, while the proportions of urgent and non-urgent encounters were mostly unchanged. The most common pre-pandemic urgent diagnosis was corneal abrasion (50%), while visual disturbance was most common during the pandemic (92%). During both time periods, eye trauma was the most frequent emergent encounter and conjunctivitis was the most common non-urgent encounter. Conclusion: Sociodemographic factors may be associated with different types of PED utilization for ocular conditions. Unnecessary visits constitute major inefficiency from a healthcare-systems standpoint. The marked decrease in PED utilization and differing proportions of ocular conditions encountered during the pandemic may reflect a decrease in incidence of many of those conditions by social distancing; these changes may also reflect altered parental decisions about seeking care.

Cryptotanshinone (CTS) is a lipophilic constituent of Salvia miltiorrhiza, with a broad-spectrum anticancer activity. We have observed that CTS enhances the efficacy of gefitinib in human lung cancer H1975 cells, yet little is known about its molecular mechanism. To explore how CTS enhances H1975 cell sensitivity to gefitinib, we figured out differential proteins of H1975 cells treated by gefitinib alone or in combination with CTS using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) bioinformatic analyses of the differential proteins were performed. CTS enhanced H1975 cell sensitivity to gefitinib in vitro and in vivo, with 115 and 128 differential proteins identified, respectively. GO enrichment, KEGG analysis, and PPI network comprehensively demonstrated that CTS mainly impacted the redox process and fatty acid metabolism in H1975 cells. Moreover, three differential proteins, namely, catalase (CAT), heme oxygenase 1 (HMOX1), and stearoyl-CoA desaturase (SCD) were validated by RT-qPCR and Western blot. In conclusion, we used a proteomic method to study the mechanism of CTS enhancing gefitinib sensitivity in H1975 cells. Our finding reveals the potential protein targets of CTS in overcoming gefitinib resistance, which may be therapeutical targets in lung cancer.

Background: Gout is a common inflammatory arthritis, and its exact pathogenesis remains unclear. Multiple studies have demonstrated that genetic factors play important roles in the development of gout. This study aims to investigate the genetic basis of gout in a three-generation pedigree of affected individuals.Methods: Whole-exome sequencing (WES), comprehensive variant analyses, and co-segregation testing were performed. The effects of candidate variants on protein localization and cellular expression were analyzed, as were interactions with gout-related genes.Results: After comprehensive bioinformatic analysis, Sanger sequencing validation, and pedigree co-segregation analysis, we identified a rare heterozygous missense variant (c.1891C > T, p.R631C) in CPT2. Although no associated changes in localization were observed, the fluorescence intensity of p.R631C mutants was obviously reduced in comparison to the wild-type protein, suggesting that protein degradation is induced by the mutant. Furthermore, our results also indicate that the c.1891C > T variant influences the ability of CPT2 to bind UCP2.Conclusion: This study identified a rare CPT2 mutation in a large Chinese pedigree with gout. Functional studies were used to define the effect of this mutant. This study provides novel insight into the genetic etiology of gout.

BackgroundColorectal cancer is a common malignant tumor appearing in the gastrointestinal tract. Surgical resection is recognized as the best means to improve patient survival. However, it is controversial whether early oral feeding (EOF) after elective colorectal resection demonstrates safety and efficacy in concerned clinical outcomes.MethodsWe searched PubMed, Embase, Cochrane Library, and CNKI from inception to September 2021. Two authors independently screened the retrieved records and extracted data. EOF was defined as feeding within 24 h after surgery, while traditional oral feeding (TOF) was defined as feeding that started after the gastrointestinal flatus or ileus was resolved. The primary outcome was nasogastric tube insertion, and the secondary outcomes were the length of hospital stay and total complications. Categorical data were combined using odds ratio (OR), and continuous data were combined using mean difference (MD).ResultsWe screened 10 studies from 34 records after full-text reading, with 1,199 patients included in the analysis. Nasogastric tube reinsertion (OR 1.69; 95% CI 1.08 to 2.64, p=0.02) was more frequent in the EOF group, and older ages (>60 years) were associated with higher risk of nasogastric tube reinsertion (OR 2.05; 95% CI 1.05 to 3.99, p = 0.04). Reduced length of hospital stay (MD −1.76; 95% CI −2.32 to −1.21; p < 0.01) and the rate of total complications (OR 0.49; 95% CI 0.37 to 0.65, p < 0.01) were observed in EOF compared with TOF.ConclusionsEOF was safe and effective for patients undergoing elective colorectal surgery, but the higher rate of nasogastric tube reinsertion compared with TOF should not be ignored.

Peach gummosis is one of the most widespread and destructive diseases. It causes growth stunting, yield loss, branch, trunk, and tree death, and is becoming a restrictive factor in healthy and sustainable development of peach production. Although a locus has been identified based on bi-parental quantitative trait locus (QTL) mapping, selection of gummosis-resistant cultivars remains challenging due to the lack of resistant parents and of the complexity of an inducing factor. In this study, an integrated approach of genome-wide association study (GWAS) and comparative transcriptome was used to elucidate the genetic architecture associated with the disease using 195 accessions and 145,456 genome-wide single nucleotide polymorphisms (SNPs). The broad-sense and narrow-sense heritabilities were estimated using 2-year phenotypic data and genotypic data, which gave high values of 70 and 73%, respectively. Evaluation of population structure by neighbor-joining and principal components analysis (PCA) clustered all accessions into three major groups and six subgroups, mainly according to fruit shape, hairy vs. glabrous fruit skin, pedigree, geographic origin, and domestication history. Five SNPs were found to be significantly associated with gummosis disease resistance, of which SNPrs285957, located on chromosome6 across 28 Mb, was detected by both the BLINK and the FarmCPU model. Six candidate genes flanked by or harboring the significant SNPs, previously implicated in biotic stress tolerance, were significantly associated with this resistance. Two highly resistant accessions were identified with low disease severity, which could be potential sources of resistance genes for breeding. Our results provide a fresh insight into the genetic control of peach gummosis disease.

According to the Interface Hypothesis in the field of bilingualism, the interface connecting a linguistic module with a language-external domain (e.g., syntax-discourse) will present prolonged difficulties for adult bilingual learners, as compared with the interface connecting language-internal modules (e.g., syntax-semantics). This study tested whether the Interface Hypothesis is applicable to the acquisition of Mandarin Chinese as a heritage language. An internet-based acceptability judgment task (AJT) was administered to 58 advanced and intermediate adult Chinese heritage speakers to collect data in accuracy and reaction time to investigate the adult heritage speakers’ mastery of referential nominal expressions regulated at the syntax-semantics and syntax-discourse interfaces, respectively, in Mandarin Chinese. The target linguistic phenomena involved three nominal expressions (i.e., the bare N(oun), the [Cl(assifier)-N], and the [Num(eral)-Cl-N]) under four interface-regulated referential readings (i.e., type-denoting, quantity-denoting, indefinite individual-denoting, and definite individual-denoting). In terms of accuracy, the results showed that (i) for the N and the [Num-Cl-N], regardless of the interface type, the advanced group acquired the target phenomena to a nativelike level, who significantly outperformed the intermediate group; (ii) for the [Cl-N], the advanced group exhibited nativelike attainment at the syntax-discourse interface but not at the syntax-semantics interface, and performed significantly better than the intermediate group at both interfaces. Regarding reaction time, no significant differences were reported between the advanced group and the native group for the target structures at either the syntax-semantics or the syntax-discourse interface, while the advanced group performed significantly better than the intermediate group, regardless of the interface type and the structure type. The findings suggest that the nature of the language interface, i.e., whether it pertains to language-external domains (i.e., the external interface) or not (i.e., the internal interface), should not be a reliable factor for predicting the (im)possibility of nativelike attainment of bilingual grammar knowledge, contra the predictions of the Interface Hypothesis. The present study provides new empirical evidence to show that language-external interface properties are not necessarily destined for prolonged difficulties in heritage language acquisition, and that it is possible for adult heritage speakers to make developmental progress in both accuracy and processing efficiency at different types of interfaces.

ObjectiveLung cancer screening has been widely conducted in Western countries. However, population-based lung cancer screening programs in Hebei in China are sparse. Our study aimed to assess the participation rate and detection rate of positive nodules and lung cancer in Hebei province.MethodIn total, 228 891 eligible participants aged 40–74 years were enrolled in the Cancer Screening Program in Hebei from 2013 to 2019. A total of 54 846 participants were evaluated as the lung cancer high-risk population by a risk score system which basically followed the Harvard Risk Index and was adjusted for the characteristics of the Chinese population. Then this high-risk population was recommended for low-dose computed tomography (LDCT) screening. And all participants attended annual passive follow-up, and the active follow-up interval was based on radiologist’s suggestion. All participants were followed-up until December 31, 2020. The overall, group-specific participation rates were calculated, and its associated factors were analyzed by a multivariable logistic regression model. Participation rates and detection of positive nodules and lung cancer were reported.ResultsThe overall participation rate was 52.69%, where 28 899 participants undertook LDCT screening as recommended. The multivariable logistic regression model demonstrated that a high level of education, having disease history, and occupational exposure were found to be associated with the participation in LDCT screening. The median follow-up time was 3.56 person-years. Overall, the positive identification of lung nodules and suspected lung cancer were 12.73% and 1.46% through LDCT screening. After the native and passive follow-up, 257 lung cancer cases were diagnosed by lung cancer screening, and the detection rate of lung cancer was 0.89% in the screening group. And its incidence density was 298.72 per 100,000. Positive lung nodule rate and detection rate were increased with age.ConclusionOur study identified personal and epidemiological factors that could affect the participation rate. Our findings could provide the guideline for precise prevention and control of lung cancer in the future.

BackgroundNovel evidence showed that the Geriatric Nutritional Risk Index (GNRI) may lead to poor prognosis of human cancers. Therefore, we conducted a meta-analysis to explore the impact of GNRI in lung cancer and its prognostic value.MethodsWe searched the databases of PubMed, Web of Science, Embase, Scopus, and Cochrane Library up to July 2021 for relevant research and merged the hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate the association between GNRI and overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) in patients with lung cancer. ResultsEight studies involving 2,399 patients were included in our primary meta-analysis. The results indicated that lower level of GNRI was associated with poorer OS, RFS, and CSS of lung cancer patients (OS: HR = 1.99, 95% CI: 1.68–2.35, p < 0.0001; RFS: HR = 2.34, 95% CI: 1.11–4.95, p = 0.0258; CSS: HR = 2.45, 95% CI: 1.43–4.18, p = 0.0011). The association was robust after subgroup analysis and sensitivity analysis.ConclusionsGNRI may be a prognostic factor of lung cancer, which can lead to poorer survival. However, more prospective studies are necessary to confirm the results.Systematic Review RegistrationInternational Prospective Register of Systematic Reviews (PROSPERO), identifier CRD42021269574.

BackgroundAlthough the predictive value of galectin-3 for heart failure with preserved ejection fraction has been demonstrated, the diagnostic value remains unclear. The present study was performed to address this issue.HypothesisGalectin-3 has diagnostic value for heart failure with preserved ejection fraction.MethodsThis is a diagnostic experiment. We conducted an observational study of 223 patients with combined symptoms of heart failure and diseases that can lead to heart failure with preserved ejection fraction. Patients were grouped into the heart failure group and control group in accordance with the 2016 European Society of Cardiology heart failure guidelines for heart failure with preserved ejection fraction. Baseline information and serum galectin-3 concentration were assessed within 24 h after admission.ResultsSerum galectin-3 concentration was significantly higher in the heart failure group compared with the control group. Binary logistic regression analysis showed that higher galectin-3 concentration was associated with the occurrence of heart failure with preserved ejection fraction. The area under the curve of galectin-3 was 0.763, indicating that galectin-3 has moderate diagnostic value for heart failure with preserved ejection fraction. Galectin-3 >15.974 ng/mL identified heart failure with preserved ejection fraction with 76.0% sensitivity and 71.9% specificity.ConclusionsThere was a correlation between galectin-3 and heart failure with preserved ejection fraction, and galectin-3 was an independent predictor of heart failure with preserved ejection fraction. The diagnostic value of galectin-3 for heart failure with preserved ejection fraction was moderate (AUC: 0.763, 95% CI: 0.696–0.821, P < 0.01, and the sensitivity is 76.0% while the specificity is 71.9% at the threshold 15.974 ng/mL) and was higher than that of interventricular septal thickness or E/A ratio.

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and causes many cancer-related deaths worldwide; in China it is the second most prevalent cause of cancer deaths. Most patients are diagnosed clinically with advanced stage disease. Summary: For more than a decade, sorafenib, a small molecular weight tyrosine kinase-inhibitor (SMW TKI) was the only molecular targeted drug available with a survival benefit for the treatment of advanced HCC. With the development of novel TKIs and immune checkpoint inhibitors (ICIs) for advanced HCC, the management of patients has been greatly improved. However, though angiogenic-based targeted therapy remains the backbone for the systemic treatment of HCC, to date no Chinese guidelines for novel molecular targeted therapies to treat advanced HCC have been established. Our interdisciplinary panel on the treatment of advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists，radiologists，pathologists, orthopedic surgeons, traditional Chinese medicine physicians and interventional radiologists have reviewed the literature in order to develop updated treatment regimens. Key Messages: Panel consensus statements for the appropriate use of new molecular targeted drugs including doses, combination therapies, adverse reaction management as well as efficacy evaluation and predictions for treatment of advanced HCC with evidence levels based on published data are presented, thereby providing an overview of molecular targeted therapies for healthcare professionals.

ABSTRACT: Background: Most patients (≥85%) with minimal-change nephrotic syndrome (MCNS) respond to corticosteroid treatment. However, about 10% to 20% of patients with MCNS have steroid-resistant nephrotic syndrome and 25% to 43% of patients have steroid-dependent nephrotic syndrome or frequent-relapse steroid-sensitive nephrotic syndrome. Patients with refractory MCNS are treated with various second-line therapies. Objectives: This study aimed to evaluate the associations between the use of various second-line therapies and relapse rates in Chinese patients with childhood refractory MCNS. Methods: In this study, patients with childhood nephrotic syndrome renal biopsy proved to be “minimal change” from a single tertiary-care center between January 2002 and July 2018 were identified. A Total of 56 medical charts of patients treated with 1 of these second-line immunosuppressors: cyclophosphamide (CYC), mycophenolate mofetil (MMF), or tacrolimus (TAC) were reviewed. Patients were divided into CYC (n = 24), MMF (n = 20), and TAC (n = 12) groups according to the second-line therapy administered. Baseline characteristics, immune status, immunocomplex deposition in the renal tissue, and treatment outcomes were analyzed. Results: The ratio of patients with steroid-resistant nephrotic syndrome and steroid-dependent nephrotic syndrome in the CYC, MMF, and TAC groups did not differ significantly (P = 0.721). The immunofluorescence assay did not show any significant differences in immunocomplex deposition identified in renal biopsy specimens among the 3 groups. The rate of steroid-free remission in the TAC group (75%) was higher than that in the MMF (55%) and CYC (25%) groups (P = 0.012). At the last follow-up, two-thirds of children in the TAC group had a relapse following discontinuation of therapy. In the TAC group, patients for whom steroids were withdrawn had significantly higher levels of immunoglobulin G at the onset of nephrotic syndrome than those for whom steroids were continued (P = 0.017). In the MMF group, children with relapse had a significantly higher percentage of CD16+CD56+-positive cells than those without relapse (P = 0.042). The relapse rate after treatment discontinuation was significantly different among the 3 groups (P = 0.035). Notably, the relapse rate after treatment discontinuation in the CYC group was lower than those in the other 2 groups (P = 0.035). Conclusions: In this small population of Chinese patients with childhood refractory MCNS, the relapse rate following TAC therapy was higher than that following MMF or CYC therapy. Different proportions of CD16+CD56+-positive cells might be associated with relapse rates in patients with MCNS receiving MMF treatment. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX)

BackgroundCurrent studies have revealed that the platelet to lymphocyte ratio (PLR) may lead to a poor prognosis in lung cancer patients receiving immunotherapy. We conducted a meta-analysis to explore the prognostic value of PLR in lung cancer patients receiving immunotherapy.MethodsWe retrieved potential studies from the PubMed, Web of Science, Embase, and Scopus databases up to June 2021 and merged the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) to evaluate the association between PLR and overall survival (OS) or progression-free survival.ResultsFourteen studies involving 1761 patients were included in our meta-analysis. The results indicated that an elevated level of pretreatment PLR was associated with poorer OS and PFS in lung cancer patients receiving immunotherapy (OS: HR = 1.88, 95% CI: 1.37-2.58; PFS: HR = HR = 1.40, 95% CI: 1.11-1.76). The association remained consistent after subgroup analysis and was robust even after sensitivity analysis.ConclusionsPLR may be a prognostic factor of lung cancer patients receiving immunotherapy, which can lead to worse survival outcomes. However, further studies are necessary for evidence in clinical application.

Background. Heart failure (HF) is defined as the inability of the heart’s systolic and diastolic function to properly discharge blood flow from the veins to the heart. The goal of our research is to look into the possible mechanism that causes HF. Methods. The GSE5406 database was used for screening the differentially expressed genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) network were applied to analyze DEGs. Besides, cell counting Kit-8 (CCK-8) was conducted to observe the knockdown effect of hub genes on cell proliferation. Results. Finally, 377 upregulated and 461 downregulated DEGs came out, enriched in the extracellular matrix organization and gap junction. According to GSEA results, Hoft cd4 positive alpha beta memory t cell bcg vaccine age 18–45 yo id 7 dy top 100 deg ex vivo up, Sobolev t cell pandemrix age 18–64 yo 7 dy dn, and so on were significantly related to gene set GSE5406. 7 hub genes, such as COL1A1, UBB, COL3A1, HSP90AA1, MYC, STAT3 and MAPK1, were selected from PPI networks. CCK-8 indicated silencing of STAT3 promoted the proliferation of H9C2 cells and silencing of UBB inhibited the proliferation of H9C2 cells. Conclusion. Our analysis reveals that COL1A1, UBB, COL3A1, HSP90AA1, MYC, STAT3, and MAPK1 might promote the progression of HF and become the biomarkers for diagnosis and treatment of HF.

The mechanical properties of geogrid-soil interface is very important in design and stability analysis of reinforced soil structure. In order to study the complicated mechanism of geogrid-soil interface, a series of pullout tests of HDPE uniaxial tensile geogrids with the different transverse ribs spacing is used to investigate the interaction characteristics in the laboratory. The test results show that pullout force and displacement curves are characterized as strain softening; compared with the no-reinforced case, the case reinforced with geogrid has larger cohesion and lower friction angles. The ductility of soil is enhanced due to geogrid reinforcement. Based on the basic control equations of the interface and damage theory, trilinear shear stress-displacement damage softening model is proposed to describe the strain-softening characteristics of geogrid-soil interface. Analytical solutions of interface tension, shear stress, and displacement at different stages are derived considering strain softening based on damage, and the development of shear stress and progressive failure mode of the geogrid-soil interface at different pullout stages is revealed. Furthermore, the proposed model is verified by experimental results.

The purpose of this cross-sectional study was to estimate the proportion of Arkansas residents who were infected with the SARS-CoV-2 virus between May and December 2020 and to assess the determinants of infection. To estimate seroprevalence, a state-wide population-based random-digit dial sample of non-institutionalized adults in Arkansas was surveyed. Exposures were age, sex, race/ethnicity, education, occupation, contact with infected persons, comorbidities, height, and weight. The outcome was past COVID-19 infection measured by serum antibody test. We found a prevalence of 15.1% (95% CI: 11.1%, 20.2%) by December 2020. Seropositivity was significantly elevated among participants who were non-Hispanic Black, Hispanic (prevalence ratio [PRs]:1.4 [95% CI: 0.8, 2.4] and 2.3 [95% CI: 1.3, 4.0], respectively), worked in high-demand essential services (PR: 2.5 [95% CI: 1.5, 4.1]), did not have a college degree (PR: 1.6 [95% CI: 1.0, 2.4]), had an infected household or extra-household contact (PRs: 4.7 [95% CI: 2.1, 10.1] and 2.6 [95% CI: 1.2, 5.7], respectively), and were contacted in November or December (PR: 3.6 [95% CI: 1.9, 6.9]). Our results indicate that by December 2020, one out six persons in Arkansas had a past SARS-CoV-2 infection.

Abstract. Background. The effects of oral contrast agents (OCAs) on dosimetry have not been studied in detail. Therefore, this study aimed to examine the influence of OCAs on dose calculation in volumetric-modulated arc therapy plans for rectal cancer. Methods. From 2008 to 2016, computed tomography (CT) images were obtained from 33 rectal cancer patients administered OCA with or without intravenous contrast agent (ICA) and 14 patients who received no contrast agent. CT numbers of organs at risk were recorded and converted to electronic densities. Volumetric-modulated arc therapy plans were designed before and after the original densities were replaced with non-enhanced densities. Doses to the planned target volume (PTV) and organs at risk were compared between the plans. Results. OCA significantly increased the mean and maximum densities of the bowels, while the effects of ICA on these parameters depended on the blood supply of the organs. With OCA, the actual doses for PTV were significantly higher than planned and doses to the bowel increased significantly although moderately. However, the increase in the volume receiving a high-range doses was substantial (the absolute change of intestine volume receiving ≥52 Gy: 1.46 [0.05−3.99, cubic centimeter range: −6.74 to 128.12], the absolute change of colon volume receiving ≥50 Gy: 0.34 [0.01−1.53 cc, range: −0.08 to 3.80 cc]. Dose changes due to ICA were insignificant. Pearson correlation showed that dose changes were significantly correlated with a high intestinal volume within or near the PTV (ρ > 0.5, P 0.3, P

Tumor-associated macrophages (TAMs) generally display an immunosuppressive M2 phenotype and promote tumor progression and metastasis, suggesting their potential value as a target in cancer immunotherapy. Chlorogenic acid (CHA) has been identified as a potent immunomodulator that promotes the polarization of TAMs from an M2 to an M1 phenotype. However, rapid clearance in vivo and low tumor accumulation have compromised the immunotherapeutic efficacy of CHA in clinical trials. In this study, mannosylated liposomes are developed for targeted delivery of CHA to TAMs. The immunoregulatory effects of CHA, along with the overall antitumor efficacy of CHA-encapsulated mannosylated liposomes, are investigated through in vitro and in vivo experiments. The prepared CHA-encapsulated mannosylated liposomes exhibit an ideal particle size, favorable stability, and preferential accumulation in tumors via the mannose receptor-mediated TAMs-targeting effects. Further, CHA-encapsulated mannosylated liposomes inhibit G422 glioma tumor growth by efficiently promoting the polarization of the pro-tumorigenic M2 phenotype to the anti-tumorigenic M1 phenotype. Overall, these findings indicate that CHA-encapsulated mannosylated liposomes have great potential to enhance the immunotherapeutic efficacy of CHA by inducing a shift from the M2 to the M1 phenotype.

Abstract Background To analyze the patterns of locoregional recurrence in breast cancer patients after mastectomy. Methods The retrospective study included 7073 women with breast cancer without post-mastectomy radiotherapy: 4604 (65.1%) had pT1–2 N0 disease (low risk); 2042 (28.9%), pT1–2 N1 (intermediate risk); and 427 (6.0%), pT3–4 and/or pN2–3, or pT1–2 N1 after neoadjuvant chemotherapy (high risk). The distribution of cumulative locoregional recurrence was analyzed. The local recurrence and regional recurrence rates were estimated by the Kaplan-Meier method, and differences were compared with the log-rank test. Multivariate analysis was performed using Cox logistic regression analysis. Results In the median follow-up of 63.0 months, 469 patients had locoregional recurrence: chest wall recurrence in 238 (50.7%) cases, supraclavicular/infraclavicular nodes in 236 (50.3%) cases, axilla in 92 (19.6%), and internal mammary nodes in 50 (10.7%) cases. The 5-year local recurrence and regional recurrence rates were 2.5 and 4.4%, respectively. Subgroup analysis of the three risk groups and five molecular subtypes (luminal A, luminal B-Her2 negative, luminal B-Her2 positive, Her2-enriched, and triple negative) also showed that the chest wall and supraclavicular/infraclavicular nodes were the most common recurrence sites. Age, tumor location, T stage, N stage, and hormone receptor status were independent prognostic factors for both local recurrence and regional recurrence (p

Abstract Background The role of post-mastectomy radiotherapy (PMRT) in the treatment of patients with T1–2N1 breast cancer is controversial. This study’s purpose was to evaluate the risk of recurrence of T1–2N1 breast cancer and the efficacy of PMRT in low-, medium- and high-risk groups of patients. Methods Post-mastectomy patients with T1–2N1 breast cancer were restaged according to the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8th ed.) staging system. Recurrence scores were generated using prognostic factors identified for loco-regional recurrence and distant metastasis in patients without PMRT, and three risk groups were identified. Rates of loco-regional recurrence and distant metastasis were calculated with a competing risk model and compared using Gray’s test. Disease-free survival and overall survival were calculated using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards regression model was used for the multivariate analysis. Results Data from 1986 patients (1521without PMRT; 465 with PMRT) were analyzed. Patients without PMRT were stratified into low-, intermediate- and high-risk groups by age, tumor location, AJCC 8th ed. stage, number of positive nodes and lympho-vascular invasion. The 5-year loco-regional recurrence rate and distant metastasis rates for the three risk groups were significant at 2.5, 5.4 and 16.2% (p

Background Lung cancer is the leading cause of morbidity and mortality worldwide. Small cell lung cancer (SCLC) has been determined to be the most lethal lung malignancy. Few studies have previously analyzed the epidemiological characteristics of SCLC in China. This study analyzed the epidemiological characteristics of SCLC aiming to provide a reference for the prevention of SCLC in Hebei Province. Methods The epidemiological characteristics of SCLC using lung cancer data based on population and hospital cancer registries in Hebei Province between 2008 and 2017 were analyzed. Results The proportion of both population‐ and hospital‐based SCLC cases displayed a significant increasing trend. Moreover, the proportion of males was higher than that for female based on population‐ and hospital‐based cases. The proportion of hospital‐based SCLC cases in counties was higher than that in cities, whereas there were no significant regional differences between cities and counties based on population. The proportion of both population‐ and hospital‐based SCLC cases decreased consistently with increasing age. There was a difference between population‐ and hospital‐based distribution of subcategories of SCLC. Conclusions Significant increases in the proportion of both population‐ and hospital‐based SCLC cases over recent years, particularly in males and in patients aged over 55 years, were observed. Research on the pathogenesis of SCLC in these patients and prevention is urgently required.

Abstract Background Circular RNA (circRNA) is highly expressed in the brain tissue, but its molecular mechanism in cerebral ischemia–reperfusion remains unclear. Here, we explored the role and underlying mechanisms of circRNA antisense non-coding RNA in the INK4 locus (circ_ANRIL) in oxygen–glucose deprivation and reoxygenation (OGD/R)-induced cell injury. Results The expression of circ_ANRIL in OGD/R-induced human brain microvascular endothelial cells (HBMECs) was significantly up-regulated, while that of miR-622 was significantly down-regulated. Overexpression of circ_ANRIL significantly inhibited the proliferation of OGD/R-induced HBMECs and aggravated OGD/R-induced cell apoptosis. Moreover, circ_ANRIL overexpression further increased the secretion of interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in OGD/R-treated HBMECs. The results of bioinformatics analysis and luciferase reporter assay indicated that circ_ANRIL served as an miR-622 sponge to negatively regulate the expression of miR-622 in OGD/R-treated HBMECs. Additionally, circ_ANRIL silencing exerted anti-apoptotic and anti-inflammatory effects by positively regulating the expression of miR-622. Furthermore, inhibition of OGD/R-induced activation of the nuclear factor (NF)-κB pathway by circ_ANRIL silencing was significantly reversed by treatment with miR-622 inhibitor. Conclusions Knockdown of circ_ANRIL improved OGD/R-induced cell damage, apoptosis, and inflammatory responses by inhibiting the NF-κB pathway through sponging miR-622.

FTY720 and IMMH002, prodrugs for sphingosine-1-phosphate receptor 1 (S1P1) agonists, show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats. In this study, FTY720 or IMMH002 analogues (21–24) were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms. Target compounds were synthesized via a convergent route using the key and optically pure building block 9, which was first synthesized via asymmetrically catalyzed amination. The phosphorylation rates of these analogues in rat or human blood were compared. The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound, whereas compound 23 showed improvements in rats, but not in humans. In pharmacokinetics studies of rats, compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002. Thus, our study not only yielded new compounds with therapeutic potential, but also showed species differences between rats and humans in response to the structural modifications, which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.

The concept of in situ 3D bio-printing was previously reported, while its realization has still encountered with several difficulties. The present study aimed to report robotic-assisted in situ 3D bio-printing technology for cartilage regeneration, and explore its potential in clinical application. A six-degree-of-freedom (6-DOF) robot was introduced in this study, and a fast tool center point (TCP) calibration method was developed to improve printing accuracy. The bio-ink consisted of hyaluronic acid methacrylate and acrylate-terminated 4-armed polyethylene glycol was employed as well. The in vitro experiment was performed on a resin model to verify the printing accuracy. The in vivo experiment was conducted on rabbits to evaluate the cartilage treatment capability. According to our results, the accuracy of the robot could be notably improved, and the error of printed surface was less than 30 μm. The osteochondral defect could be repaired during about 60 s, and the regenerated cartilage in hydrogel implantation and in situ 3D bio-printing groups demonstrated the same biomechanical and biochemical performance. We found that the cartilage injury could be treated by using this method. The robotic-assisted in situ 3D bio-printing is highly appropriate for improving surgical procedure, as well as promoting cartilage regeneration. Keywords: In situ 3D bio-printing, Cartilage regeneration, Tissue engineering, Bio-ink crosslinking, Robot

Abstract Nanoparticles (NPs) have been increasingly studied for radiosensitization. The principle of NPs radio-enhancement is to use high-atomic number NPs (e.g. gold, hafnium, bismuth and gadolinium) or deliver radiosensitizing substances, such as cisplatin and selenium. Nowadays, cancer immunotherapy is emerged as a promising treatment and immune checkpoint regulation has a potential property to improve clinical outcomes in cancer immunotherapy. Furthermore, NPs have been served as an ideal platform for immunomodulator system delivery. Owing to enhanced permeability and retention (EPR) effect, modified-NPs increase the targeting and retention of antibodies in target cells. The purpose of this review is to highlight the latest progress of nanotechnology in radiotherapy (RT) and immunotherapy, as well as combining these three strategies in cancer treatment. Overall, nanomedicine as an effective strategy for RT can significantly enhance the outcome of immunotherapy response and might be beneficial for clinical transformation.

Abstract Background We reported that in our previous study that wearing intermittent occlusion therapy glasses (IO-therapy) for 4 hours (h) was non-inferior to patching for 2 h in 3 to 8-year-old children with amblyopia. We hypothesize that an intense regimen of 12-h IO-therapy per day for 4 weeks could be as effective as the standard regimen of 4-h IO-therapy per day for 12 weeks in treating moderate amblyopia in 3 to 8-year-old children. Methods/Design A total of 56 children between 3 and 8 years of age with amblyopia in association with anisometropia and/or strabismus will be enrolled. All participants will be prescribed IO-therapy glasses (Amblyz™), set at 30-s opaque/transparent intervals (i.e., occluded 50% of wear time). They will be randomized to receive the standard regimen for 12 weeks or the intense regimen for 4 weeks. Adherence to using the IO-therapy glasses will be objectively monitored in each participant by means of a microsensor dose monitor. The primary study objective is to compare the effectiveness of an intense regimen to a standard regimen of IO-therapy in 3 to 8-year-old children with moderate amblyopia. The secondary study objectives are to determine whether adherence differs between an intense regimen and a standard regimen of IO-therapy, and to determine the dose-response relationship of IO-therapy. Discussion In addition to testing the effectiveness, this study will test for the first time the association between treatment adherence and the visual outcome of IO-therapy, which will enhance our understanding of the dose-response relationship of IO-therapy. If an intense regimen is shown to be effective, it would alter amblyopia treatment strategies and improve visual outcomes. Trial registration ClinicalTrials.gov: NCT02767856 . Registered on 10 May 2016.

Abstract Background Stable introns and intronic fragments make up the largest population of RNA in the oocyte nucleus of the frog Xenopus tropicalis. These stable intronic sequence RNAs (sisRNAs) persist through the onset of zygotic transcription when synchronous cell division has ended, and the developing embryo consists of approximately 8000 cells. Despite their abundance, the sequence properties and biological function of sisRNAs are just beginning to be understood. Results To characterize this population of non-coding RNA, we identified all of the sisRNAs in the X. tropicalis oocyte nucleus using published high-throughput RNA sequencing data. Our analysis revealed that sisRNAs, have an average length of ~ 360 nt, are widely expressed from genes with multiple introns, and are derived from specific regions of introns that are GC and TG rich, while CpG poor. They are enriched in introns at both ends of transcripts but preferentially at the 3′ end. The consensus binding sites of specific transcription factors such as Stat3 are enriched in sisRNAs, suggesting an association between sisRNAs and transcription factors involved in early development. Evolutionary conservation analysis of sisRNA sequences in seven vertebrate genomes indicates that sisRNAs are as conserved as other parts of introns, but much less conserved than exons. Conclusion In total, our results indicate sisRNAs are selected intron regions with distinct properties and may play a role in gene expression regulation.

The tetravalent dengue vaccine (CYD-TDV; Dengvaxia®) is administered on a three-dose schedule, 6 months apart in those aged ≥9 years in a number of dengue-endemic countries in Asia and Latin America. In this study, CYD63 (NCT02824198), participants aged 9–45 years at first vaccination, and who had received three doses of CYD-TDV in the CYD28 study more than 5 years previously, were randomized 3:1 to receive a booster CYD-TDV dose (Group 1) or placebo (Group 2). Dengue neutralizing antibody geometric mean titres (PRNT50 GMTs) for each of the four dengue serotypes were assessed in sera collected before and 28 days after booster injections. Non-inferiority of the booster immune response versus that induced after the third dose was demonstrated for each serotype if the lower limit of the two-sided 95% confidence interval (CI) was >0.5 for the GMT ratios (GMTRs) between post-booster CYD-TDV dose and post-dose 3 in Group 1. Overall, 118 participants received CYD-TDV booster or placebo and 116 (98.3%) completed the study; two participants were withdrawn because of noncompliance. GMTs in the booster CYD-TDV group increased across all serotypes post-booster injection by 1.74- (serotype 1) to 3.58-fold (serotype 4). No discernible increases were observed in the placebo group. Non-inferiority was demonstrated for serotypes 1, 3, and 4, but not for serotype 2 (GMTR; 0.603 [95% CI, 0.439– 0.829]). No safety issues were observed. These data show that the CYD-TDV booster given 5 or more years later tended to restore GMTs back to levels observed post-dose 3.

Abstract Background The present study aimed to verify whether long noncoding RNA (lncRNA) MALAT1 is involved in brain tissue damage induced by ischemia-reperfusion injury, and to explore the mechanism by which MALAT1 regulates aquaporin 4 (AQP4). Methods In this study, we established glucose deprivation (OGD)/reoxygenation (RX) astrocyte cell model and middle cerebral artery occlusion (MCAO)/reperfusion mouse model in vitro and in vivo. Then cell counting kit-8 assay, flow cytometry analysis, Triphenyltetrazolium chloride (TTC) staining, and western blotting were used to determine cell viability, cell apoptosis, cerebral infarction volume, and the abundance of AQP4, respectively. Results We found that the level of MALAT1 was significantly upregulated in both the MCAO/reperfusion model and OGD/RX model. Knockdown of MALAT1 increased cell viability and reduced cell apoptosis in MA-C cells, while an AQP4 siRNA combined with a siRNA targeting MALAT1 could not enhance this effect. Further experiments showed that MALAT1 positively regulated AQP4 expression via miR-145. The MALAT1 siRNA did not alleviate the exacerbation of damage after miR-145 inhibitor action. However, an miR-145 inhibitor reversed the protection effects of MALAT1, indicating that MALAT1 silencing protects against cerebral ischemia-reperfusion injury through miR-145. TTC staining showed that the infracted area of whole brain was significantly attenuated in treated with sh-MALAT1 group in vivo. Conclusion Taken together, our study confirmed that MALAT1 promotes cerebral ischemia-reperfusion injury by affecting AQP4 expression through competitively binding miR-145, indicating that MALAT1 might be a new therapeutic target for treatment cerebral ischemic stroke.

Psoriasis is characterized by abnormal proliferation of keratinocytes, as well as infiltration of immune cells into the dermis and epidermis, causing itchy, scaly and erythematous plaques of skin. The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently. Here, we showed that IMMH002, a novel orally active S1P1 modulator, desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus. Using different psoriasis animal models, we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PASI score and pathological injure evaluation. Mechanistically, IMMH002 regulated CD3+ T lymphocytes re-distribution by inducing lymphocytes’ homing, thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus. Our results suggest that the novel S1P1 agonist, IMMH002, exert extraordinary capacity to rapidly modulate T lymphocytes distribution, representing a promising drug candidate for psoriasis treatment. Keywords: S1P1, S1P1 agonist, IMMH002, Lymphocyte, Psoriasis

Artificial neural network technique has gained recognition as a powerful technique in microwave modeling and design. This paper proposes a novel deep neural network topology for parametric modeling of microwave components. In the proposed deep neural network, the outputs are S-parameters. The inputs of the proposed model include geometrical variables and the frequency. We divide the hidden layers in the proposed deep neural network topology into two parts. Hidden layers in Part I handle both the geometrical inputs and the frequency inputs while hidden layers in Part II only handle the geometrical inputs. In this way, more training parameters are utilized to specifically learn the relationship between the S-parameters and the geometrical variables, which are more complicated than that between the S-parameters and the frequency. The purpose is to reduce the total number of training parameters in the deep neural network model. New formulations are derived to calculate the derivatives of the error function with respect to training parameters in the deep neural network. Taking advantage of the calculated derivatives, we propose an advanced two-stage training algorithm for the deep neural network. The two-stage training algorithm can determine the number of hidden layers in both parts during the training process and guarantee that the proposed deep neural network model can achieve the required model accuracy. The proposed deep neural network can achieve similar model accuracy with less training parameters compared to the commonly used fully connected neural network. The proposed technique is demonstrated by two microwave parametric modeling examples.

Neuro-transfer function (neuro-TF) approaches have become more and more popular in parametric modeling for electromagnetic (EM) behavior of microwave components. Existing pole-residue-based neuro-TF approach has better capability of dealing with high-order problem than the rational-based neuro-TF approach, but has the discontinuity issue and the associated non-smoothness issue of the poles/residues when the geometrical variations become large while the rational-based neuro-TF approach does not have. This paper addresses this situation and presents a novel hybrid-based neuro-TF technique which systematically combines both pole-residue and rational formats of the transfer functions. Starting with the pole-residue-based transfer functions, we propose a novel technique to automatically identify the poles/residues that are smooth-continuous and the poles/residues that have the discontinuity and non-smoothness issues. The proposed technique converts the poles/residues that have those issues into the coefficients of the rational-based transfer function to solve the discontinuity and non-smoothness issues in the existing pole-residue-based neuro-TF approach. The proposed technique remains the smooth-continuous poles/residues in the pole-residue format of the transfer function to maintain the capability of handling high-order problem. Compared with the existing neuro-TF modeling methods, the proposed technique can obtain better accuracy in challenging applications of large geometrical variations and high order. The proposed technique is illustrated by two examples of parametric modeling of microwave components.

We explored potential biomarkers and molecular mechanisms regarding multiple benefits after bariatric surgery. Differentially expressed genes (DEGs) for subcutaneous adipose tissue (AT) after bariatric surgery were identified by analyzing two expression profiles from the GEO. Subsequently, enrichment analysis, GSEA, PPI network, and gene-microRNAs and gene-TFs networks were interrogated to identify hub genes and associated pathways. Co-expressed DEGs included one that was up-regulated and 22 that were down-regulated genes. The enrichment analyses indicated that down-regulated DEGs were significantly involved in inflammatory responses. GSEA provided comprehensive evidence that most genes enriched in pro-inflammation pathways, while gene-sets after surgery enriched in metabolism. We identified nine hub genes in the PPI network, most of which were validated as highly expressed and hypomethylated in obesity by Attie Lab Diabetes and DiseaseMeth databases, respectively. DGIdb was also applied to predict potential therapeutic agents that might reverse abnormally high hub gene expression. Bariatric surgery induces a significant shift from an obese pro-inflammatory state to an anti-inflammatory state, with improvement in adipocyte metabolic function – representing key mechanisms whereby AT function improves after bariatric surgery. Our study deepens a mechanistic understanding of the benefits of bariatric surgery and provides potential biomarkers or treatment targets for further research.

Abstract Background As one of the main crops in the world, sterility of rice (Oryza sativa L.) significantly affects the production and leads to yield decrease. Our previous research showed that OsPUB73, which encodes U-box domain-containing protein 73, may be associated with male sterility. However, little information is available on this gene that is required for anther development. In the present study, we knocked out OsPUB73 by using the CRISPR/Cas9 system and studied the cytological and transcriptome of the gene-defect associated with pollen development and sterility in the rice variety (Taichung 65). Results The sequence analysis indicated that OsPUB73 was comprised of 3 exons and 2 introns, of which CDS encoded 586 amino acids including a U-box domain. The expression pattern of OsPUB73 showed that it was highly expressed in the anther during meiosis stage. The ospub73 displayed low pollen fertility (19.45%), which was significantly lower than wild type (WT) (85.37%). Cytological observation showed tapetum vacuolated at the meiosis stage and pollen exine was abnormal at the bi-cellular pollen stage of ospub73. RNA-seq analysis detected 2240 down and 571 up-regulated genes in anther of ospub73 compared with WT during meiosis stage. Among of 2240 down-regulated genes, seven known genes were associated with tapetal cell death or pollen exine development, including CYP703A3 (Cytochrome P450 Hydroxylase703A3), CYP704B2 (Cytochrome P450 Hydroxylase704B2), DPW (Defective Pollen Wall), PTC1 (Persistant Tapetal Cell1), UDT1 (Undeveloped Tapetum1), OsAP37 (Aspartic protease37) and OsABCG15 (ATP binding cassette G15), which were validated by quantitative real-time polymerase chain reaction (qRT-PCR). These results suggested OsPUB73 may play an important role in tapetal or pollen exine development and resulted in pollen partial sterility. Conclusion Our results revealed that OsPUB73 plays an important role in rice male reproductive development, which provides valuable information about the molecular mechanisms of the U-box in rice male reproductive development.

BIN1 (amphyphysin-II) is a structural protein involved in T-tubule (TT) formation and phosphatidylinositol-4,5-bisphosphate (PIP2) is responsible for localization of BIN1 to sarcolemma. The goal of this study was to determine if PIP2-mediated targeting of BIN1 to sarcolemma is compromised during the development of heart failure (HF) and is responsible for TT remodeling. Immunohistochemistry showed co-localization of BIN1, Cav1.2, PIP2, and phospholipase-Cβ1 (PLCβ1) in TTs in normal rat and human ventricular myocytes. PIP2 levels were reduced in spontaneously hypertensive rats during HF progression compared to age-matched controls. A PIP Strip assay of two native mouse cardiac-specific isoforms of BIN1 including the longest (cardiac BIN1 #4) and shortest (cardiac BIN1 #1) isoforms as well human skeletal BIN1 showed that all bound PIP2. In addition, overexpression of all three BIN1 isoforms caused tubule formation in HL-1 cells. A triple-lysine motif in a short loop segment between two helices was mutated and replaced by negative charges which abolished tubule formation, suggesting a possible location for PIP2 interaction aside from known consensus binding sites. Pharmacological PIP2 depletion in rat ventricular myocytes caused TT loss and was associated with changes in Ca2+ release typically found in myocytes during HF, including a higher variability in release along the cell length and a slowing in rise time, time to peak, and decay time in treated myocytes. These results demonstrate that depletion of PIP2 can lead to TT disruption and suggest that PIP2 interaction with cardiac BIN1 is required for TT maintenance and function.

Objective: This study aimed to investigate acute hemodynamics of lower extremities during enhanced external counterpulsation with a three-level sequence at the hips, thighs, and calves (EECP-3), two-level sequence at the hips and thighs (EECP-2), and single leg three-level sequence (EECP-1).Methods: Twenty healthy volunteers were recruited in this study to receive a 45-min EECP intervention. Blood flow spectrums in the anterior tibial artery, posterior tibial artery, and dorsalis pedis artery were imaged by Color Doppler ultrasound. Mean flow rate (FR), area, pulsatility index (PI), peak systolic velocity (PSV), end-diastolic velocity (EDV), mean flow velocity (MV), and systolic maximum acceleration (CCAs) were sequentially measured and calculated at baseline during EECP-3, EECP-1, and EECP-2.Results: During EECP-3, PI, PSV, and MV in the anterior tibial artery were significantly higher, while EDV was markedly lower during EECP-1, EECP-2, and baseline (all P < 0.05). Additionally, ACCs were significantly elevated during EECP-3 compared with baseline. Moreover, FR in the anterior tibial artery was significantly increased during EECP-3 compared with baseline (P = 0.048). During EECP-2, PI and MV in the dorsalis pedis artery were significantly higher and lower than those at baseline, (both P < 0.05). In addition, FR was markedly reduced during EECP-2 compared with baseline (P = 0.028). During EECP-1, the area was significantly lower, while EDV was markedly higher in the posterior tibial artery than during EECP-1, EECP-2, and baseline (all P < 0.05). Meanwhile, FR of the posterior tibial artery was significantly reduced compared with baseline (P = 0.014).Conclusion: Enhanced external counterpulsation with three-level sequence (EECP-3), EECP-2, and EECP-1 induced different hemodynamic responses in the anterior tibial artery, dorsalis pedis artery, and posterior tibial artery, respectively. EECP-3 acutely improved the blood flow, blood flow velocity, and ACCs of the anterior tibial artery. In addition, EECP-1 and EECP-2 significantly increased the blood flow velocity and peripheral resistance of the inferior knee artery, whereas they markedly reduced blood flow in the posterior tibial artery.