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Impressive achievements in clinical trials to treat hemophilia establish a milestone in the development of gene therapy. It highlights the significance of AAV-mediated gene delivery to liver. AAV5 is a unique serotype featured by low neutralizing antibody prevalence. Nevertheless, its liver infectivity is relatively weak. Consequently, it is vital to exploit novel AAV5 capsid mutants with robust liver tropism. To this aim, we performed AAV5-NNK library and barcode screening in mice, from which we identified one capsid variant, called AAVzk2. AAVzk2 displayed a similar yield but divergent post-translational modification sites compared with wild-type serotypes. Mice intravenously injected with AAVzk2 demonstrated a stronger liver transduction than AAV5, roughly comparable with AAV8 and AAV9, with undetectable transduction of other tissues or organs such as heart, lung, spleen, kidney, brain, and skeletal muscle, indicating a liver-specific tropism. Further studies showed a superior human hepatocellular transduction of AAVzk2 to AAV5, AAV8 and AAV9, whereas the seroreactivity of AAVzk2 was as low as AAV5. Overall, we provide a novel AAV serotype that facilitates a robust and specific liver gene delivery to a large population, especially those unable to be treated by AAV8 and AAV9.

Abstract Background Convulsive status epilepticus (CSE) is a common neurologic emergency with high morbidity and mortality. This single center study is aimed to assess changes of serum biochemical biomarkers after seizure, and their associations with the development of CSE. Methods From January 2015 to October 2016, a total of 57 CSE patients, and 30 healthy controls without central nervous system diseases were enrolled in Children’s Hospital of Soochow University. CSE patients were further divided into viral encephalitis (VEN, 13 cases), primary generalized epilepsy (PGE, 30 cases), and complex febrile seizures (CFS, 14 cases). The levels of serum biochemical biomarkers were measured using the corresponding commercial ELISA kits. Logistic regression analysis was performed to identify the associations between these biomarkers and diseases. Results At the 1st and 4th day of CSE, neuron-specific enolase (NSE; 1st day: 20.553 ± 5.360, 4th day: 10.094 ± 3.426) and vascular endothelial growth factor (VEGF; 1st day: 153.504 ± 31.246, 4th day: 138.536 ± 25.221) in the CSE group were increased compared to the control (NSE: 6.138 ± 1.941; VEGF: 119.210 ± 31.681). Both the levels of S-100 calcium binding protein B (S-100B; 1st day: 0.738 ± 0.391) and C-reactive protein (CRP; 1st day: 11.128 ± 12.066) were elevated at 1st day of CSE (S-100B: 0.387 ± 0.040; CRP: 3.915 ± 2.064). For glial fibrillary acidic protein (GFAP), it was remarkably upregulated at 4th day of CSE (3.998 ± 1.211). NSE (P = 0.000), S-100B (P = 0.000), CRP (P = 0.011), and VEGF (P = 0.000) at 1st day of CSE, and NSE (P = 0.000), VEGF (P = 0.005), and GFAP (P = 0.000) at 4th day of CSE were significantly associated with the occurrence of CSE. Besides, NSE (P = 0.002), S-100B (P = 0.001), and VEGF (P = 0.002) at 4th day of CSE were significantly associated with VEN. Conclusions The levels of serum NSE, S-100B, CRP, VEGF, and GFAP are associated with CSE.

Autoimmune hepatitis (AIH) is an inflammatory liver disease driven by the hyperactivation of various intrahepatic antigen‐specific T cells due to a breach of immune tolerance. Studies in immunometabolism demonstrate that activated T cells harbor increased levels of reactive oxygen species that cause oxidative DNA damage. In this study, we assessed the potential of DNA damage repair enzyme MutT homolog 1 (MTH1) as a therapeutic target in AIH and karonudib as a novel drug for patients with AIH. We report herein that MTH1 expression was significantly increased in liver samples from patients with AIH compared to patients with chronic hepatitis B and nonalcoholic fatty liver disease and from healthy controls. In addition, the expression of MTH1 was positively correlated with AIH disease severity. We further found abundant T cells that expressed MTH1 in AIH. Next, we found that karonudib significantly altered T‐cell receptor signaling in human T cells and robustly inhibited proliferation of human T cells in vitro. Interestingly, our data reflected a preferential inhibition of DNA damage repair in activated T cells by karonudib. Moreover, MTH1 was required to develop liver inflammation and damage because specific deletion of MTH1 in T cells ameliorated liver injury in the concanavalin A (Con A)‐induced hepatitis model by inhibiting T‐cell activation and proliferation. Lastly, we validated the protective effect of karonudib on the Con A‐induced hepatitis model. Conclusion: MTH1 functions as a critical regulator in the development of AIH, and its inhibition in activated T cells reduces liver inflammation and damage.

Here, Xiao et al. isolate a large panel of antibodies against human metapneumovirus fusion protein from human B cells, and characterize their epitopes, neutralization activities, and antigen binding specificity, providing a useful framework for understanding the immune response against hMPV.

Abstract Over the last decade, oncolytic virus (OV) therapy has shown its promising potential in tumor treatment. The fact that not every patient can benefit from it highlights the importance for defining biomarkers that help predict patients’ responses. As particular self-amplifying biotherapeutics, the anti-tumor effects of OVs are highly dependent on the host factors for viral infection and replication. By using weighted gene co-expression network analysis (WGCNA), we found matrix remodeling associated 8 (MXRA8) is positively correlated with the oncolysis induced by oncolytic virus M1 (OVM). Consistently, MXRA8 promotes the oncolytic efficacy of OVM in vitro and in vivo. Moreover, the interaction of MXRA8 and OVM studied by single-particle cryo-electron microscopy (cryo-EM) showed that MXRA8 directly binds to this virus. Therefore, MXRA8 acts as the entry receptor of OVM. Pan-cancer analysis showed that MXRA8 is abundant in most solid tumors and is highly expressed in tumor tissues compared with adjacent normal ones. Further study in cancer cell lines and patient-derived tumor tissues revealed that the tumor selectivity of OVM is predominantly determined by a combinational effect of the cell membrane receptor MXRA8 and the intracellular factor, zinc-finger antiviral protein (ZAP). Taken together, our study may provide a novel dual-biomarker for precision medicine in OVM therapy.

Abstract Background Different dialysis treatments may affect the composition and structure of the intestinal flora of dialysis-treated chronic kidney disease (CKD) patients. This study aimed to analyze the correlations between the different flora and the nutritional indexes and further explore the potential metabolic pathways in patients with CKD in end-stage renal disease (ESRD). Methods Altogether, 102 patients with ESRD were recruited and categorized into the hemodialysis (HD) group (N = 49) and the peritoneal dialysis (PD) group (N = 53). Their biochemical indexes, anthropometric indicators, and inflammatory markers were determined. The total genomic DNA was extracted for 16S ribosomal DNA sequencing. Furthermore, bioinformatics analysis was employed for functional analysis. Results Anthropometric indicators, including handgrip strength, mid-upper arm circumference, mid-upper arm muscle circumference, and body mass index, in the HD and PD groups showed a positive correlation with butyric acid-producing bacteria (Rosella and Phascolarctobacterium) and a negative correlation with conditional pathogens (Escherichia spp.). Meanwhile, the inflammatory markers, including high-sensitivity C-reactive protein and interleukin-6, were significantly higher in the PD-protein–energy wasting (PEW) group than in the PD-non-protein–energy wasting (NPEW) group; although they showed an increasing trend in the HD-PEW group, no significant difference was noted. Rosella was considerably scarce in the HD-PEW group than in the HD-NPEW group, whereas Escherichia was substantially more abundant in the PD-PEW group than in the PD-NPEW group. Compared with the HD group, the essential amino acid synthesis pathway, amino acid metabolism-related enzyme pathways, and aminoacyl-transfer RNA biosynthesis pathways were weakened in the PD group. Most carbohydrate metabolic pathways were weakened, although the tricarboxylic acid cycle was slightly enhanced. Concurrently, the fatty acid metabolism was enhanced, whereas fatty acid synthesis was weakened; the metabolic pathways of B vitamins were also weakened. These potential metabolic pathways of the various compounds released by intestinal flora showed a significant correlation with blood biochemical indexes, anthropometric indicators, and inflammatory markers. Conclusion In patients with ESRD, different dialysis treatments affected the abundance of butyric acid-producing bacteria (Rosella and Phascolarctobacterium) and conditional pathogens (Escherichia spp.). Butyric acid-producing bacteria showed a positive correlation with PEW and showed a negative correlation with Escherichia. Improving the intestinal diversity and increasing the amount of butyric acid-producing bacteria, such as Blautella, Faecococcus, and Phascolarctobacterium, are potential therapeutic approaches to enhance protein–energy consumption in patients with ESRD.

Abstract Aqueous activities on Mars have gradually declined since the Noachian (>3.7 Ga). Although water can be stored in the subsurface during the latest epochs, geomorphological evidence is still limited. In this study, we used in situ imaging and spectral data acquired by China's Zhurong rover, as well as high‐resolution remote‐sensing data, to investigate the transverse aeolian ridges (TARs) in the Zhurong landing region of Utopia Planitia. A two‐stage evolutionary scenario of the TARs is proposed and polygonal features with hydrated minerals are identified for the first time on the surface of Martian TARs. We discussed the possible formation mechanisms of the polygonal features, and proposed that they could be related to recent aqueous activity and atmosphere‐surface water exchange on Mars, which sheds light on the hydrological cycle of Mars in current cold and dry climate.

Background: Lymphedema is a local form of tissue swelling, which is caused by excessive retention of lymph fluid in interstitial compartment caused by impaired lymphatic drainage damage. Primary lymphedema is caused by developmental lymphatic vascular abnormalities. Most cases are inherited as autosomal dominant, with incomplete penetrance and variable expression. Here we report compound heterozygotes variants in FLT4 of a Chinese family associated with primary lymphedema display autosomal recessive inheritance.Case presentation: Trio-whole-exome sequencing (Trio-WES) was performanced to analyse the underlying genetic cause of a proband with primary lymphedema in a Chinese family. Sanger sequencing was used to validate the variants in proband with primary lymphedema and members of the family with no clinical signs and symptoms. We reported compound heterozygotes for the Fms Related Receptor Tyrosine Kinase 4 (FLT4) gene detected in the proband, who carrying two different point variants. One was a missense variant (NM_182925.5; c.1504G>A, p.Glu502Lys), and the other was a recurrent variant (NM_182925.5; c.3323_3325del, p.Phe1108del). The missense variant c.1504G>A was detected in the proband, unaffected father, and unaffected paternal grandmother but not detected in unaffected paternal grandfather. The recurrent variant c.3323_3325del was detected in the proband, unaffected mother, and unaffected maternal grandfather but not detected in unaffected maternal grandmother. Our results suggests the possibility of an autosomal recessive inherited form of primary lymphedema resulting from variants of FLT4 encoding the vascular endothelial growth factor receptor-3.Conclusion: The results of the present study identifed compound heterozygotes FLT4 variants in a family with primary lymphedema which provides more information for autosomal recessive primary lymphedema caused by FLT4.

Natural orifice transluminal endoscopic surgery (NOTES) associated with less pain, shorter hospital stay, and outstanding cosmetic results has drawn considerable attention from the academic community. For NOTES, pneumoperitoneum is an essential technology to obtain intraperitoneal surgical space, which, however, can have some serious adverse hemodynamic effects. In this paper, we propose a novel intra-abdominal wall-lifting device that can replace the pneumoperitoneum functionally for transvaginal NOTES (vNOTES). The device consists mainly of two layers of elastic strips, namely, the outer strips that are used to lift the abdominal wall for surgical exposure and the inner strip with a camera mounted that can rotate to provide a wide surgical field of view. With the design, gasless vNOTES can be carried out with 82.74% of the operative field provided by pneumoperitoneum, eliminating all complications associated with gas insufflation. The design principle and kinematic analysis of the device are discussed in detail and validated by experiments. Finally, a prototype is fabricated to demonstrate the feasibility of the proposed concept.

BackgroundThe gut microbiome was reported to be associated with dyslipidemia in previous observational studies. However, whether the composition of the gut microbiome has a causal effect on serum lipid levels remains unclear.ObjectiveA two-sample Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationships between gut microbial taxa and serum lipid levels, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and log-transformed triglyceride (TG) levels.Materials and methodsSummary statistics of genome-wide association studies (GWASs) for the gut microbiome and four blood lipid traits were obtained from public datasets. Five recognized MR methods were applied to assess the causal estimates, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates.ResultsThe combined results from the five MR methods and sensitivity analysis showed 59 suggestive causal associations and four significant causal associations. In particular, genus Terrisporobacter was associated with higher LDL-C (PIVW = 3.01 × 10−6) and TC levels (PIVW = 2.11 × 10−4), phylum Actinobacteria was correlated with higher LDL-C level (PIVW = 4.10 × 10−4), and genus Oscillospira was associated with lower TG level (PIVW = 2.19 × 10−6).ConclusionThis research may provide novel insights into the causal relationships of the gut microbiome on serum lipid levels and new therapeutic or prevention strategies for dyslipidemia.

IntroductionProsocial risky behavior (PRB) proposes that individuals take risks for others’ benefits or social welfare, and that this may involve trade-offs between risk and social preferences. However, little is known about the underlying cognitive mechanisms of risk-seeking or aversion during PRB.MethodsThis study adopted the dilemma-priming paradigm to examine the interaction between the risk levels of personal cost and situational urgency on PRB (Experiment 1, N = 88), and it further uncovered the modulation of the risk levels of failure (Experiment 2, N = 65) and peer presence (Experiment 3, N = 80) when helping others.ResultsIn Experiment 1, the participants involved in risky dilemmas made more altruistic choices for strangers in urgent situations compared to those for strangers in non-urgent situations. However, increasing the risk levels of personal cost decreased the frequencies of help offered to strangers in urgent situations. Experiment 2 further established that, similar to the risk of personal cost, increasing the risk levels of failure when helping others also decreased the frequencies of help offered to strangers in urgent situations. Furthermore, in dilemmas involving a low-risk personal cost, Experiment 3 showed that peer presence encouraged the participants to make more altruistic choices when providing help to strangers in non-urgent situations.DiscussionIndividuals demonstrate obvious risk-seeking behavior when helping others and that both non-urgent situations and peer presence weaken the effect of increased risk aversion on PRB in a limited manner.

Colorectal cancer (CRC) is now the third most common malignancy to cause mortality worldwide, and its prognosis is of great importance. Recent CRC prognostic prediction studies mainly focused on biomarkers, radiometric images, and end-to-end deep learning methods, while only a few works paid attention to exploring the relationship between the quantitative morphological features of patients' tissue slides and their prognosis. However, existing few works in this area suffered from the drawback of choosing the cells randomly from the whole slides, which contain the non-tumor region that lakes information about prognosis. In addition, the existing works, which tried to demonstrate their biological interpretability using patients' transcriptome data, failed to show the biological meaning closely related to cancer. In this study, we proposed and evaluated a prognostic model using morphological features of cells in the tumor region. The features were first extracted by the software CellProfiler from the tumor region selected by Eff-Unet deep learning model. Features from different regions were then averaged for each patient as their representative, and the Lasso-Cox model was used to select the prognosis-related features. The prognostic prediction model was at last constructed using the selected prognosis-related features and was evaluated through KM estimate and cross-validation. In terms of biological meaning, Gene Ontology (GO) enrichment analysis of the expressed genes that correlated with the prognostically significant features was performed to show the biological interpretability of our model.With the help of tumor segmentation, our model achieved better statistical significance and better biological interpretability compared to the results without tumor segmentation. Statistically, the Kaplan Meier (KM) estimate of our model showed that the model using features in the tumor region has a higher C-index, a lower p-value, and a better performance on cross-validation than the model without tumor segmentation. In addition, revealing the pathway of the immune escape and the spread of the tumor, the model with tumor segmentation demonstrated a biological meaning much more related to cancer immunobiology than the model without tumor segmentation. Our prognostic prediction model using quantitive morphological features from tumor regions was almost as good as the TNM tumor staging system as they had a close C-index, and our model can be combined with the TNM tumor stage system to make a better prognostic prediction. And to the best of our knowledge, the biological mechanisms in our study were the most relevant to the immune mechanism of cancer compared to the previous studies.

ObjectivesTo evaluate the efficacy of Optical Coherence Tomography (OCT) for detecting cervical lesions in women with minor abnormal cytology results (atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL)).MethodsA prospective study was conducted at gynecologic clinic from Mar 2021 to Sep 2021. The recruited women with cervical cytological findings of ASC-US or LSIL were inspected with OCT before colposcopy-directed cervical biopsy. The diagnostic performance of OCT, alone and in combination with high-risk human papillomavirus (hrHPV) testing were evaluated to detect cervical intraepithelial neoplasia of grade 2 or worse (CIN2+)/CIN3 or worse (CIN3+). The rate of colposcopy referral and the immediate risk of CIN3+ of OCT were calculated.ResultsA total of 349 women with minor abnormal cervical cytology results were enrolled. For detection of CIN2+/CIN3+, the sensitivity and NPV of OCT were lower than those of hrHPV testing (CIN2+: 71.3% vs. 95.4%, 89.0% vs. 91.1%, P < 0.001; CIN3+: 75% vs. 93.8%, 96.5% vs. 95.6%, P < 0.001), but the specificity, accuracy and PPV were higher than those of hrHPV testing (CIN2+: 77.5% vs. 15.6%, 75.9% vs. 35.5%, 51.2% vs. 27.3%, P < 0.001; CIN3+: 69.4% vs. 13.6%, 69.9% vs. 20.9%, 19.8% vs. 9.9%, P < 0.001). OCT combined with hrHPV testing (CIN2+: 80.9%; CIN3+: 72.6%) showed higher specificity than that of OCT alone (P < 0.001). The colposcopy referral rate base on OCT classification was lower than that based on hrHPV testing (34.7% vs. 87.1%, P < 0.001). Patients with hrHPV-positive ASC-US and hrHPV-negative LSIL cytology, the immediate CIN3+ risk in OCT negative cases was less than 4%.ConclusionsOCT alone or combination with hrHPV testing shows good performance for detecting CIN2+/CIN3+ in patients with ASC-US/LSIL cytology. OCT is an effective method for colposcopy triage in women with hrHPV-positive ASC-US and hrHPV-negative LSIL cytology.

Abstract To prevent surgical site infection (SSI), which significantly increases the rate morbidity and mortality, eliminating microorganisms is prominent. Antimicrobial resistance is identified as a global health challenge. This work proposes a new strategy to eliminate microorganisms of deep tissue through electrical stimulation with an ultrasound (US)‐driven implantable, biodegradable, and vibrant triboelectric nanogenerator (IBV‐TENG). After a programmed lifetime, the IBV‐TENG can be eliminated by provoking the on‐demand device dissolution by controlling US intensity with no surgical removal of the device from the body. A voltage of ≈4 V and current of ≈22 µA generated from IBV‐TENG under ultrasound in vitro, confirming inactivating ≈100% of Staphylococcus aureus and ≈99% of Escherichia coli. Furthermore, ex vivo results show that IBV‐TENG implanted under porcine tissue successfully inactivates bacteria. This antibacterial technology is expected to be a countermeasure strategy against SSIs, increasing life expectancy and healthcare quality by preventing microorganisms of deep tissue.

A lot of bioinformatics tools were released to detect structural variants from the sequencing data during the past decade. For a data analyst, a natural question is about the selection of a tool fits for the data. Thus, this study presents an automatic tool recommendation method to facilitate data analysis. The optimal variant calling tool was recommended from a set of state-of-the-art bioinformatics tools by given a sequencing data. This recommendation method was implemented under a meta-learning framework, identifying the relationships between data features and the performance of tools. First, the meta-features were extracted to characterize the sequencing data and meta-targets were identified to pinpoint the optimal caller for the sequencing data. Second, a meta-model was constructed to bridge the meta-features and meta-targets. Finally, the recommendation was made according to the evaluation from the meta-model. A series of experiments were conducted to validate this recommendation method on both the simulated and real sequencing data. The results revealed that different SV callers often fit different sequencing data. The recommendation accuracy averaged more than 80% across all experimental configurations, outperforming the random- and fixed-pick strategy. To further facilitate the research community, we incorporated the recommendation method into an online cloud services for genomic data analysis, which is available at https://c.solargenomics.com/via a simple registration. In addition, the source code and a pre-trained model is available at https://github.com/hello-json/CallerRecommendation for academic usages only.

ObjectiveTo study the contamination level of mineral oil hydrocarbons in complementary foods for infants and young children and assess its potential health impact for consumers aged 0­3 years old in China.MethodsThe contents of mineral oil saturated hydrocarbons （MOSH） and mineral oil aromatic hydrocarbons （MOAH） were determined by on­line high­performance liquid chromatography coupled with gas chromatography and flame ionization detector. Based on the food consumption data of Chinese residents in 2015， the exposure to mineral oil hydrocarbons in complementary foods of Chinese infants and young children aged 0­3 years old was assessed by simple distribution method.ResultsThe overall detection rate of MOSH （C16-C35） in 4 types of complementary foods （canned foods， rice flour， noodles， and biscuits or molar sticks） in total of 138 commercially available complementary food samples was 45.65%， and the mean contamination level in different types of complementary foods was in the range of 0.55-4.40 mg/kg. The MOAH was only detected in 1 sample of noodles and 4 samples of biscuits or molar sticks. The overall detection rate of MOAH was 3.62%. The average daily exposure and high food consumption （P95） daily exposure of MOSH （C16­C35） for complementary foods consumer only population were 6.21 and 19.27 μg/kg·BW， respectively. The margins of exposure of all age groups were higher than 100.ConclusionThe health risk from dietary exposure to MOSH by consuming complementary foods is very low for infants and young children aged 0­3 years old in China. Attention should be paid to the contamination of MOAH in complementary foods for infants and young children.

Abstract QTc interval prolongation is one of the most common antipsychotic-induced side effects which could lead to ventricular tachycardia or Torsade de Pointes, even cardiac arrest. There is very limited understanding on the genetic factors that associated with antipsychotic-induced QTc interval change. We conducted a genome-wide association study (GWAS) of antipsychotic-induced QTc interval change among patients with schizophrenia. A total of 2040 patients with schizophrenia were randomly assigned to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and first-generation antipsychotics; first-generation antipsychotics including haloperidol or perphenazine were also assigned randomly) and received 6-week antipsychotic treatment. We identified two novel loci (rs200050752 in ATAD3B and rs186507741 in SKIL) that were associated with antipsychotic-induced QTc interval change at a genome-wide significance level. The combination of polygenic risk score (PRS), based the GWAS of myocardial infarction from BioBank Japan project, and clinical data (sex, heart rate and QTc interval at baseline) could be applied to predict whether patients with schizophrenia have QTc interval prolongation (10 ms was applied as threshold, P

Abstract Background Genome-wide association studies (GWASs) have identified multiple risk loci for Parkinson’s disease (PD). However, identifying the functional (or potential causal) variants in the reported risk loci and elucidating their roles in PD pathogenesis remain major challenges. To identify the potential causal (or functional) variants in the reported PD risk loci and to elucidate their regulatory mechanisms, we report a functional genomics study of PD. Methods We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) (from neuronal cells and human brain tissues) data and GWAS-identified single-nucleotide polymorphisms (SNPs) in PD risk loci. We then conducted a series of experiments and analyses to validate the regulatory effects of these (i.e., functional) SNPs, including reporter gene assays, allele-specific expression (ASE), transcription factor (TF) knockdown, CRISPR-Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. Results We identified 44 SNPs (from 11 risk loci) affecting the binding of 12 TFs and we validated the regulatory effects of 15 TF binding-disrupting SNPs. In addition, we also identified the potential target genes regulated by these TF binding-disrupting SNPs through eQTL analysis. Finally, we showed that 4 eQTL genes of these TF binding-disrupting SNPs were dysregulated in PD cases compared with controls. Conclusion Our study systematically reveals the gene regulatory mechanisms of PD risk variants (including widespread disruption of CTCF binding), generates the landscape of potential PD causal variants, and pinpoints promising candidate genes for further functional characterization and drug development.

ObjectiveTo carry out the theoretical risk assessment for food colorants in the National food safety standard-standards for uses of food additives (GB 2760—2014) by Budget method and deterministic assessment.MethodsBudget method was applied for calculating the theoretical maximum daily intake of food colorants which had ADI values and maximum use levels. For the additives whose intakes were higher than their ADIs, simple distribution assessment was performed with food consumption data from a Chinese total diet study in 2012.ResultsThere are totally 21 food colorants have both ADI values and maximum use levels in GB 2760—2014. These 21 food colorants were included in the assessment by Budget method . The maximum theoretical daily intake of 15 food colorants exceeded their ADIs. Then, these 15 food colorants were assessed by simple distribution assessment. The result showed that the average intakes were below ADIs but the P95 intakes of 2 food colorants exceeded the ADIs in the whole population. Among consumers, the average intakes were also below ADIs, but the P95 intakes of 8 food colorants exceeded the ADIs.ConclusionThe health risks of most food colorant intakes in the national standard were at low levels. However, a few food colorants showed a requirement for further assessment with the actual concentrations in foods to confirm their health risk level.

Summary Faecal Microbiota Transplantation (FMT) is considered as a promising technology to fight against obesity. Wild boar has leanermuscle and less fat in comparison to the domestic pig, which were thought to be related with microbiota. To investigate the function and mechanism of the wild boar microbiota on obesity, we first analysed the wild boar microbiota composition via 16S rDNA sequencing, which showed that Firmicutes and Proteobacteria were the dominant bacteria. Then, we established a high‐fat diet (HFD)‐induced obesity model, and transfer low and high concentrations of wild boar faecal suspension in mice for 9 weeks. The results showed that FMT prevented HFD‐induced obesity and lipid metabolism disorders, and altered the jejunal microbiota composition especially increasing the abundance of the Lactobacillus and Romboutsia, which were negatively correlated with obesity‐related indicators. Moreover, we found that the anti‐obesity effect of wild boar faecal suspension was associated with jejunal N6‐methyladenosine (m6A) levels. Overall, these results suggest that FMT has a mitigating effect on HFD‐induced obesity, which may be due to the impressive effects of FMT on the microbial composition and structure of the jejunum. These changes further alter intestinal lipid metabolism and m6A levels to achieve resistance to obesity.

Impervious surface area (ISA) mapping at the global scale has entered a new era. Currently, the number of high-resolution global ISA products is gradually increasing; however, a literature review that systematically investigates these ISA products is still lacking, which limits the application of these products. Thus, we provide a comprehensive analysis of the existing high-resolution global ISA products, concentrating on the aspects of the data sources, training samples, features, and methods. Moreover, we evaluate these products at multitemporal and multispatial scales, using a series of independent test samples. The results demonstrate that the multitemporal accuracy of the ISA products presents an increasing trend, due to the increase of the available sensors. Among the continuous time-series products [e.g., the updated new global impervious surface area (GISA 2.0), the global impervious surface area (GISA), global annual urban dynamics, global human settlement layer, and global artificial impervious areas], the accuracy of the GISA 2.0 outperforms the others at global, continental, and regional scales. However, the mapping performance of these products in small towns and arid and rural regions needs to be enhanced. In particular, we focus on the spatio-temporal disagreement of the ISA products. We show that the high disagreement regions are predominantly concentrated in eastern Asia, western Europe, and eastern North America. In addition, the high disagreement regions are characterized by low ISA density, high vegetation coverage, and high albedo bare ground coverage. Additionally, this article concludes with some remarks about the future directions of global ISA mapping.

The micro-channel heat sink (MCHS) is an excellent choice due to its exceptional cooling capabilities, surpassing those of its competitors. In this research paper, a computational fluid dynamics analysis was performed to investigate the laminar flow and heat transfer characteristics of five different configurations of a variable geometry rectangular fin. The study utilized a water-cooled smooth MCHS as the basis. The results indicate that the micro-channel heat sink with a variable geometry rectangular fin has better heat dissipation capacity than a straight-type micro-channel heat sink, but at the same time, it has larger pressure loss. Based on the analysis of various rectangular fin shapes and Reynolds numbers in this study, the micro-channel heat sink with rectangular fins exhibits Nusselt numbers and friction factors that are 1.40–2.02 and 2.64–4.33 times higher, respectively, compared to the smooth heat sink. This significant improvement in performance results in performance evaluation criteria ranging from 1.23–1.95. Further, it is found that at a relatively small Reynolds number, the micro-channel heat sink with a variable geometry rectangular fin has obvious advantages in terms of overall cooling performance. Meanwhile, this advantage will decrease when the Reynolds number is relatively large.

This study aims to investigate the vibration responses on underwater immersed tunnels caused by moving loads, taking into account factors such as the viscoelastic characteristics of riverbed water, foundation soil, and the immersed tunnel itself. An ideal fluid medium is adopted to simulate the water, while a saturated porous medium is used to simulate the riverbed soil layer. The immersed tunnel structure is simplified as an infinitely long viscoelastic Euler beam, and the vibration effects are described by the theory of the standard linear solid model, taking into account structural damping. The coupled dynamic control equations were established by utilizing the displacement and stress conditions at the interface between the ideal fluid medium, the saturated porous medium, and the immersed tunnel structure. The equivalent stiffness of the riverbed water and site foundation was obtained. Furthermore, the numerical solutions of the tunnel displacement, internal forces, and pore pressure in the riverbed site were obtained in the time-space domain using the IFFT (Inverse Fast Fourier Transform) algorithm. The correctness of the model was validated by comparing the results with existing studies. The numerical results show that the riverbed water significantly reduces the Rayleigh wave velocity of the immersed tunnel structure in the riverbed-foundation system. Therefore, it is necessary to control the driving speed during high water levels. As the permeability of the saturated riverbed foundation increases, the vertical displacement, bending moment, and shear force of the beam in the immersed tunnel structure will increase. As the viscosity coefficient of the viscoelastic beam in the immersed tunnel structure increases, the vertical vibration amplitude of the beam will decrease, but further increasing the viscosity coefficient of the beam will have little effect on its vibration amplitude. Therefore, the standard solid model of the viscoelastic beam can effectively describe the creep and relaxation phenomena of materials and can objectively reflect the working conditions of the concrete structure of the immersed tunnel.

The microstructure and properties of non-linear friction stir welded lap joints of the AA6061-T6 aluminum alloy were investigated, with a particular focus on the influence of corner curvature on the formability and mechanical properties of the joints. The research results indicate that for the 6061-T6 aluminum alloy lap joint friction stir welding with a smaller radius (R < 7 mm), there is a more severe accumulation of welding material. When the radius exceeds 7 mm, good macroscopic joint formation can be achieved. Various regions at the joint corners are composed of α-Al and intermetallic precipitations β phases. The microstructure of the heat-affected zone (HAZ) appeared relatively coarse, the weld nugget zone (WNZ) had the finest grain, and partial dissolution of the β phase occurred. The grain size in the middle WNZ at the corner was larger than at the ends, and the grain size on the inner side of the corner was larger than on the outer side. The hardness distribution of the joint exhibited a “W” shape, with the lowest hardness in the inner HAZ. When R ≤ 7, with an increase in R, the shear strength of the friction stir welded joints increased, and then the change became relatively small. The maximum shear strength of the joint was 101.32 ± 6.89 MPa at R = 7, and the fracture mode was primarily a ductile mixed fracture.

In view of the low level of mechanized harvesting of white radish in China and other developing countries and the current situation of “no machine can be used” due to the expensive imported machines, a self-propelled white radish combine harvester was designed based on the material, growth characteristics, and agronomic pattern of white radish. This combines harvester can realize the functions of white radish tassel gathering, deep soil loosening, clamping and conveying, tassel cutting, and collecting. In this research, the overall design of the harvester is described, and the structural and working parameters and kinematic requirements of the tassel gathering device, clamping and conveying device, tassel cutting device, and vibrating deep loosening device are determined by mechanical and kinematic analysis. Innovatively, a range of values for the tassel gathering speed ratio of 1.7–4.2 is proposed for the operation of the tassel gathering device suitable for white radish harvesting. The prototype was bench tested with the loss rate, damaged rate, and impurity rate as performance evaluation indexes. The results show that under the pitch of 240 mm between the taper angle of the tassel-raising device, a speed of 80 rpm for the tassel gathering device gathering claw belt rotation, a speed of 120 rpm for the clamping and conveying pulley rotation, a vibration frequency of 2 Hz and an amplitude of 15 mm for the vibrating deep loosening device, and a forward speed of 0.5 m/s (tassel gathering speed ratio: 1.7). The loss rate was 2.75%, the damage rate was 4.99%, and the impurity rate was 1.64%. During the operation, the innovatively designed white radish leaf gathering device can better fulfill the function of tassel gathering, and the systems worked well together, meeting the requirements of mechanized combined harvesting of white radish, but the adaptability to complex working conditions in the field needs to be further strengthened. This research can provide a reference for the design and optimization of mechanized white radish harvesting equipment.

Organic Rankine cycles (ORCs) have been widely used to convert medium-low-temperature geothermal energy to electricity. Proper cycle layout is generally determined by considering both the thermo-physical properties of the working fluid and the geothermal brine temperature. This work investigates saturated, superheated and supercritical ORCs using R1234yf/R236ea for brine temperatures of 383.15 K, 403.15 K and 423.15 K. The evaporation and condensation pressures were optimized to maximize the net power outputs. The thermodynamic characteristics of the cycles at the optimal conditions were analyzed. The saturated ORCs produced slightly more net power than superheated cycles for the R1234yf mole fraction less than 0.2 due to lower exergy losses in the evaporator and condenser; however, the limited evaporation pressure by the turning point at the higher R1234yf mole fraction led to excessive exergy losses in the evaporator. Two R1234yf mole fractions maximized the net power and exergy efficiency in a superheated cycle, with the maximum net power output occurring at the R1234yf mole fraction of 0.8 for brine temperatures of 383.15 K and 403.15 K. The exergy losses for evaporation were reduced by 6–12.7% due to the use of an IHE, while those for condensation were reduced up to 42% in a superheated cycle for a brine temperature of 423.15 K, resulting in a 1–17.8% increase in the exergy efficiency. A supercritical cycle with an IHE using R1234yf/R236ea (0.85/0.15) generated the maximum net power output for a brine temperature of 423.15 K, 8.2–17.5% higher than a superheated cycle with an IHE.

This study focuses on the synthesis of TiC-TiB2/Fe coatings with varying amounts of aluminum (Al) using tungsten inert gas (TIG) cladding and investigates the impact of Al addition on microstructure refinement and performance enhancement of the coatings. The coatings were prepared on a mild steel substrate using TIG cladding. X-ray diffraction (XRD) analysis revealed the presence of TiC, TiB2, AlxTi, and AlxFe phases in the coatings. Scanning electron microscopy (SEM) images showed that the addition of Al improved the microstructure, reducing defects and enhancing the distribution of reinforcing phases within the coatings. The particle size of the reinforcing phases was significantly refined by the addition of Al. The micro-hardness of the coatings was significantly higher than that of the substrate, with the maximum micro-hardness of the coating reaching 955.5 ± 50.7 HV0.1, approximately six times that of the substrates. However, excessive Al addition led to a reduction in hardness due to a decrease in the quantity of hard phases. The wear tests showed that all the coatings had lower wear loss compared to the substrate material, with the wear loss initially decreasing and then increasing with the increasing Al content. Samples with a 28.57 wt.% Al addition exhibited the best wear resistance, with approximately 16.8% of the wear volume loss compared to mild steel under the same testing conditions, attributed to the optimal combination of reinforcement phase quantity and matrix properties.

Abstract To investigate the optimal blood pressure (BP) levels and relative importance of BP and BP variability in the early phase of acute ischemic stroke (AIS) for hypertensive patients with carotid artery stenosis (CAS). A single‐center cohort study included 750 AIS patients with hypertension and tests were performed for CAS. Participants were categorized to Group 1 (SBP

The Philippine Sea is the largest marginal sea in the Western Pacific Ocean and is divided into two parts by the Kyushu-Palau Ridge (KPR). The western part is the West Philippine Basin, and the eastern part consists of the Shikoku and Parece Vela basins. Based on surveyed data of massive high-resolution multibeam bathymetric data and sub-bottom profiles data collected from the southern section of the KPR from 2018 to 2021, this paper analyzes the topographic and geomorphological features, shallow sedimentary features, and tectonic genesis of the southern section of the KPR, obtaining the following conclusions. The southern section of the KPR has complex and rugged topography, with positive and negative topography alternatingly distributed and a maximum height difference of 4086 m. The slope of seamounts in this section generally exceeds 10° and is up to a maximum of 59°. All these contribute noticeably discontinuous topography. There are primarily nine geomorphological types in the southern section of the KPR, including seamounts, ridges, and intermontane valleys, etc. Among them, seven independent seamount groups are divided by five large troughs, forming an overall geomorphological pattern of seven abyssal seamount groups and five troughs. This reflects the geomorphological features of a deep oceanic ridge. Intramontane basins and intermontane valleys in the southern section of the KPR are covered by evenly thick sediments. In contrast, sediments in ridges and seamounts in this section are thin or even missing, with slumps developing locally. Therefore, the sediments are discontinuous and unevenly developed. The KPR formed under the control of tectonism such as volcanic activities and plate movements. In addition, exogenic forces such as underflow scouring and sedimentation also play a certain role in shaping seafloor landforms in the KPR.©2021 China Geology Editorial Office.

The southern part of the Kyushu-Palau Ridge (KPR) is located at the conjunction of the West Philippine Basin, the Parece Vela Basin, the Palau Basin, and the Caroline Basin. This area has extremely complex structures and is critical for the research on the tectonic evolution of marginal seas in the Western Pacific Ocean. However, only few studies have been completed on the southern part, and the geophysical fields and deep structures in this part are not well understood. Given this, this study finely depicts the characteristics of the gravity and magnetic anomalies and extracts information on deep structures in the southern part of the KPR based on the gravity and magnetic data obtained from the 11th expedition of the deep-sea geological survey of the Western Pacific Ocean conducted by the Guangzhou Marine Geological Survey, China Geological Survey using the R/V Haiyangdizhi 6. Furthermore, with the data collected on the water depth, sediment thickness, and multichannel seismic transects as constraints, a 3D density model and Moho depths of the study area were obtained using 3D density inversion. The results are as follows. (1) The gravity and magnetic anomalies in the study area show distinct zoning and segmentation. In detail, the gravity and magnetic anomalies to the south of 11°N of the KPR transition from high-amplitude continuous linear positive anomalies into low-amplitude intermittent linear positive anomalies. In contrast, the gravity and magnetic anomalies to the north of 11°N of the KPR are discontinuous and show alternating positive and negative anomalies. These anomalies can be divided into four sections, of which the separation points correspond well to the locations of deep faults, thus, revealing different field-source attributes and tectonic genesis of the KPR. (2) The Moho depth in the basins in the study area is 6–12 km. The Moho depth in the southern part of KPR show segmentation. Specifically, the depth is 10–12 km to the north of 11°N, 12–14 km from 9.5°N to 11°N, 14–16 km from 8.5°N to 9.5°N, and 16–25 km in the Palau Islands. (3) The KPR is a remnant intra-oceanic arc with the oceanic-crust basement.which shows noticeably discontinuous from north to south in geological structure and is intersected by NEE-trending lithospheric-scale deep faults. With large and deep faults F3 and F1 (the Mindanao fault) as boundaries overall, the southern part of the KPR can be divided into three zones. In detail, the portion to the south of 8.5°N (F3) is a tectonically active zone, the KPR portion between 8.5°N and 11°N is a tectonically active transition zone, and the portion to the north of 11°N is a tectonically inactive zone. (4) The oceanic crust in the KPR is slightly thicker than that in the basins on both sides of the ridge, and it is inferred that the KPR formed from the thickening of the oceanic crust induced by the upwelling of deep magma in the process of rifting of remnant arcs during the Middle Oligocene. In addition, it is inferred that the thick oceanic crust under the Palau Islands is related to the constant upwelling of deep magma induced by the continuous northwestward subduction of the Caroline Plate toward the Palau Trench since the Late Oligocene. This study provides a scientific basis for systematically understanding the crustal attributes, deep structures, and evolution of the KPR.©2021 China Geology Editorial Office.

Abstract Pulmonary fibrosis is the end stage of a broad range of heterogeneous interstitial lung diseases and more than 200 factors contribute to it. In recent years, the relationship between virus infection and pulmonary fibrosis is getting more and more attention, especially after the outbreak of SARS-CoV-2 in 2019, however, the mechanisms underlying the virus-induced pulmonary fibrosis are not fully understood. Here, we review the relationship between pulmonary fibrosis and several viruses such as Human T-cell leukemia virus (HTLV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV), Epstein–Barr virus (EBV), Murine γ-herpesvirus 68 (MHV-68), Influenza virus, Avian influenza virus, Middle East Respiratory Syndrome (MERS)-CoV, Severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 as well as the mechanisms underlying the virus infection induced pulmonary fibrosis. This may shed new light on the potential targets for anti-fibrotic therapy to treat pulmonary fibrosis induced by viruses including SARS-CoV-2.

Abstract Background To investigate the effect of extubation in the operating room (OR) on mechanical ventilation-related adverse outcomes in patients who undergo liver transplantation. Methods Patients who underwent liver transplantation between January 2016 and December 2019 were included. According to the timing of extubation, patients were divided into OR extubation group and intensive care unit (ICU) extubation group. The propensity score was used to match OR extubation group and ICU extubation group at a 1:2 ratio by demographical and clinical covariates. The primary outcome was a composite of mechanical ventilation-related adverse outcomes, including 30-day all-cause mortality, in-hospital acute kidney injury (stage 2 or 3), and in-hospital moderate to severe pulmonary complications. Secondary outcomes included in-hospital moderate to severe infectious complications, unplanned reintubation rates, ICU and postoperative hospital lengths of stay, and total hospital cost. Results A total of 438 patients were enrolled. After propensity score matching, 94 patients were in OR extubation group and 148 patients were in ICU extubation group. Incidence of the composite mechanical ventilation-related adverse outcomes was significantly lower in OR extubation group than ICU extubation group, even after adjusting for confounding factors (19.1% vs. 31.8%; Odds Ratio, 0.509; 95% Confidence Index [CI], 0.274-0.946; P=0.031). The duration of ICU stay was much shorter in OR extubation group than ICU extubation group (median 4, Interquartile range [IQR] (3 ~ 6) vs. median 6, IQR (4 ~ 8); P

The authors invented a textile magnetoelastic generator, weaving 1D soft fibers with conductive yarns to couple the observed magnetoelastic effect with magnetic induction, which paves a new way for biomechanical-to-electrical energy conversion.

Mathematics is a prerequisite for the development of blockchain technology. The deeply penetrated mathematical ideas support the establishment of the trust mechanism of the whole blockchain system, which makes the blockchain technology autonomous, decentralised, not so easy to tamper, open, anonymous and also possesses other characteristics. Due to these characteristics, the introduction of blockchain will greatly solve a series of problems faced by the quality and acquisition of big data in cities, and release more data vitality. Based on the perspective of chain blocks and big data fusion, this paper puts forward that data are the foundation of modern urban governance. Data management has become the key to modern urban governance. It puts forward that the building of a big data management system based on blockchain will strengthen the construction of the intelligent city and modernisation of urban governance capabilities.

Abstract Oscillating droplet experiments are conducted using the Electromagnetic Levitation (EML) facility under microgravity conditions. The droplet of molten metal is internally stirred concurrently with the pulse excitation initiating shape oscillations, allowing viscosity measurement of the liquid melts based on the damping rate of the oscillating droplet. We experimentally investigate the impact of convection on the droplet’s damping behavior. The effective viscosity arises and increases as the internal convective flow becomes transitional or turbulent, up to 2–8 times higher than the intrinsic molecular viscosity. The enhanced effective viscosity decays when the stirring has stopped, and an overshoot decay pattern is identified at higher Reynolds numbers, which presents a faster decay rate as the constraint of flow domain size becomes influential. By discriminating the impact of convection on the viscosity results, the intrinsic viscosity can be evaluated with improved measurement accuracy.

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has emerged in the last 2 years. The accessory protein ORF7a has been proposed as an immunomodulating factor that can cause dramatic inflammatory responses, but it is unknown how ORF7a interacts with host cells. We show that ORF7a induces cell apoptosis by recruiting the prosurvival factor BclXL to the endoplasmic reticulum (ER) via the exposed C-terminal residues Lys117 and Lys119. Simultaneously, ORF7a activates ER stress via the PERK-elF2α-CHOP pathway and inhibits the expression of endogenous BclXL, resulting in enhanced cell apoptosis. Ubiquitination of ORF7a interrupts the interaction with BclXL in the ER and weakens the activation of ER stress, which to some extent rescues the cells. Our work demonstrates that SARS-CoV-2 ORF7a hires antiapoptosis protein and aggregates on the ER, resulting in ER stress and apoptosis initiation. On the other hand, ORF7a utilizes the ubiquitin system to impede and escape host elimination, providing a promising potential target for developing strategies for minimizing the COVID-19 pandemic. IMPORTANCE Viruses struggle to reproduce after infecting cells, and the host eliminates infected cells through apoptosis to prevent virus spread. Cells adopt a special ubiquitination code to protect against viral infection, while ORF7a manipulates and exploits the ubiquitin system to eliminate host cells' effect on apoptosis and redirect cellular pathways in favor of virus survival. Our results revealed that SARS-CoV-2-encoded accessory protein ORF7a recruits prosurvival factor BclXL to the ER and activates the cellular ER stress response resulting in the initiation of programmed death to remove virus-infected cells. Ubiquitination of ORF7a blocked the recruitment of BclXL and suppressed the ER stress response, which helps to counteract cell apoptosis and rescue cell fate. These findings help us understand the mechanism of SARS-CoV-2 invasion and contribute to a theoretical foundation for the clinical prevention of COVID-19.

Many of the world’s most invasive plants are clonal, and clonal functional traits are suggested to contribute to their invasiveness. Clonal integration is one of the most important clonal functional traits, but it is still unclear whether clonal integration can benefit invasive alien clonal plants more than native ones in heterogeneous environments with reciprocal patchiness of resources and whether invasive plants show a higher capacity of division of labor than native ones in such environments. We grew connected (allowing clonal integration) and disconnected (preventing clonal integration) ramet pairs of an invasive plant Wedelia trilobata and its occurring native congener W. chinensis in the environment consisting of reciprocal patches of light and soil nutrients (i.e., a high-light but low-nutrient patch and a low-light but high-nutrient patch). Clonal integration greatly promoted the growth of the invasive species, but had no significant effect on the native one. Both invasive and native species showed division of labor in terms of morphology, biomass allocation, and/or photosynthetic physiology, but the capacity of labor division did not differ between the invasive and the native species. We conclude that in heterogeneous environments consisting of reciprocal patches of resources, which are common in nature, clonal integration can confer invasive plants a competitive advantage over natives, but this difference is not related to their capacity of labor division. This study highlights the importance of clonal integration for plants in heterogeneous environments and suggests that clonal integration can contribute to the invasion success of alien clonal plants.

ObjectiveEndotoxin-induced uveitis (EIU) is an important tool for human uveitis study. This study was designed to develop a novel EIU model in zebrafish.MethodsAn EIU model in zebrafish was induced by intravitreal lipopolysaccharide (LPS) injection and was assessed dynamically. Optical coherence tomography (OCT) was used to assess infiltrating cells in the vitreous body. The histological changes wereevaluated using HE staining and immune cells were measured by immunofluorescence. The retinal RNA Sequencing (RNA-Seq) was used to explore the transcriptional changes during inflammation. RNA-Seq data were analyzed using time-course sequencing data analysis (TCseq), ClueGO plugin in Cytoscape, and Gene Set Enrichment Analysis (GSEA) software. Flow cytometry and retinal flat mounts were used to dynamically quantify the immune cells.ResultsEIU was successfully induced in zebrafish following intravitreal LPS injection. Inflammation appeared at 4 hours post injection (hpi), reached its peak at 24 hpi, and then resolved at 72 hpi. Immunofluorescence confirmed that massive influx ofneutrophils into the iris and vitreous body, and activation of microglia as evidenced by ameboid-shaped appearance in the retina. Retinal RNA-seq during the EIU course identified four gene clusters with distinct expression characteristics related to Toll-likereceptor signaling pathway, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and extracellular matrix (ECM)-receptor interaction, respectively. Prednisone immersion inhibited the inflammatory response of EIU in zebrafish, whichwas confirmed by decreased neutrophils detected in flow cytometry and retinal flat mounts.ConclusionsWe developed a novel EIU model in zebrafish, which may be particularly useful for gene-editing and high-throughput screening of new drugs for the prevention and treatment of uveitis.

Bio-inspired design translates the knowledge of natural or biological structures or behaviors into novel theories and technologies, providing new directions for research and developments. Although the medical needles for percutaneous intervention technology appear to be mature, biomimetic solutions become popular to further facilitate the performance of the medical needles. In this paper, we review the current state of bio-inspired medical needle designs for percutaneous interventions, including a variety of biomimetic mechanisms and insertion strategies. Existing and experimental designs of biomimetic medical needles are classified into five groups with respect to the applications, while their characteristics are identified and discussed. Such classification and discussion will not only provide technical insights into previous studies but also identify undiscovered directions for future research.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and is a nutritional metabolic disease. Artemisia capillaris (AC) is the above-ground dried part of Artemisia capillaris Thunb. or Artemisia scoparia Waldst. et Kit., a natural medicinal plant with pharmacological effects of heat-clearing and biliary-promoting. In order to evaluate the therapeutic effect of Artemisia capillaris on NAFLD and obesity, experiments were conducted using aqueous extracts of Artemisia capillaris (WAC) to intervene in NAFLD models in vivo and in vitro. In vivo experiments were performed using HFD-fed (high fat diet) C57BL/6 mice to induce NAFLD model, and in vitro experiments were performed using oleic acid to induce HepG2 cells to construct NAFLD cell model. H.E. staining and oil red O staining of liver tissue were used to observe hepatocytes. Blood biochemistry analyzer was used to detect serum lipid levels in mice. The drug targets and mechanism of action of AC to improve NAFLD were investigated by western blotting, qRT-PCR and immunofluorescence. The results showed that C57BL/6 mice fed HFD continuously for 16 weeks met the criteria for NAFLD in terms of lipid index and hepatocyte fat accumulation. WAC was able to reverse the elevation of serum lipid levels induced by high-fat diet in mice. WAC promoted the phosphorylation levels of PI3K/AKT and AMPK in liver and HepG2 cells of NAFLD mice, inhibited SREBP-1c expression, reduced TG and lipogenesis, and decreased lipid accumulation. In summary, WAC extract activates PI3K/AKT pathway, reduces SREBP-1c protein expression by promoting AMPK phosphorylation, and decreases fatty acid synthesis and TG content in hepatocytes. AC can be used as a potential health herb to improve NAFLD and obesity.

Adalimumab and secukinumab are commonly used for moderate to severe psoriasis vulgaris (PV). Although distinct individual responses to and impaired effectiveness of these biological agents occur occasionally, little is known about the underlying reasons. Here, we report a proteomic analysis of psoriatic lesions from patients treated with these drugs using data-independent acquisition mass spectrometry (DIA-MS). Thousands of differentially expressed proteins (DEPs) changed over 12 weeks of treatment. Network analysis showed that DEPs could interact and induce transformation in matrix components, metabolic regulation, and immune response. The results of parallel reaction monitoring (PRM) analysis suggested that S100s, STAT1, KRT2, TYMP, SOD2, HSP90AB1, TFRC, and COL5A1 were the most significantly changed proteins in both groups. There was a positive association between the Psoriasis Area and Severity Index (PASI) score and three proteins (TFRC, IMPDH2, KRT2). Our study findings suggest that inhibition of IL-17A and TNF-α can induce changes in multiple molecules in psoriatic lesions and have an overlapping influence on the immune response and process through direct or indirect effects.

Polymeric nanoparticles (NPs) play an important role in controlled cancer drug delivery. Anticancer drugs can be conjugated or encapsulated by polymeric nanocarriers, which are known as polymeric nanomedicine. Polymeric nanomedicine has shown its potential in providing sustained release of drugs with reduced cytotoxicity and modified tumor retention, but until now, few delivery systems loading drugs have been able to meet clinical demands, so more efforts are needed. This research reviews the current state of the cancer drug-loading system by exhibiting a series of published articles that highlight the novelty and functions from a variety of different architectures including micelles, liposomes, dendrimers, polymersomes, hydrogels, and metal–organic frameworks. These may contribute to the development of useful polymeric NPs to achieve different therapeutic purposes.

Abstract Background Type III Bartter syndrome (BS), often known as classic Bartter syndrome is caused by variants in CLCNKB gene, which encoding the basolateral chloride channel protein ClC‐Kb, and is characterized by renal salt wasting, hypokalemia, metabolic alkalosis, increased renin, and aldosterone levels. Methods A 2‐year‐old boy presented severe malnutrition, severe metabolic alkalosis and severe hypokalemia and was clinically diagnosed with BS. The trio exome sequencing (ES) was performed to discover the genetic cause of this patient, followed by validation using Sanger sequencing and quantitative polymerase chain reaction subsequently. Results The genetic analysis indicated that this patient with a compound heterozygous variants of CLCNKB gene including a novel nonsense variant c.876 T > A and a whole‐gene deletion. The two variants were inherited from his parents, respectively. Subsequently, target sequencing of CLCNKB gene was performed for next pregnancy, and prenatal genetic diagnosis was provided for the family. Conclusions The results of current study identified the compound heterozygous variants in a patient with classic BS. The novel variant expands the spectrum of CLCNKB variants in BS. Our study also indicates that ES is an alternative tool to simultaneously detect single‐nucleotide variants and copy‐number variants.

One of the important purposes of opening protected areas to the public is providing tourists with natural experience products and education so as to stimulate their environmentally responsible behaviours (ERBs) and achieve sustainability. However, there are often contradictions between the recreational use of natural resources and eco-environmental protection, and scholars have not directly determined whether natural experiences always trigger tourist ERBs. To fill this gap, we study the formation of ERBs (including environmentally friendly behaviours, environmental concern-based behaviours and sustainable behaviours) by integrating the mechanisms of tourists’ experiences (including sensory experience, mental involvement and norm arousal) and their effects on ERBs. The results of a sample of 682 tourists at a National Nature Reserve in China affirm that there are spillover effects among tourists’ experiences and that tourists’ experiences influence ERBs. Sensory experience and norm arousal positively affect people’s environmentally friendly behaviours, their behaviours that are based on their concern for the environment and their sustainable behaviours. While mental involvement has a positive impact on environmentally friendly behaviours, a negative impact on sustainable behaviours, and no effect on people’s environmental concern-based behaviours. In addition, mental involvement and norm arousal play an important role in mediating the impacts of sensory experience on ERBs. This study explores the relationship between use and conservation of natural resources via tourists’ experiences and ERBs, and it reveals that tourists’ experience stays in mental involvement, which may not conducive to eco-environmental conservation in the protected areas. It opens the field for future research paths in the exploration of the paradox that emerges out of the natural experience and tourists’ ERBs and provides insights into and points to ecological implications for reserve managers and tourism operators.

Optical clearing technology offers a prospective solution to improve the imaging depth and quality of optical microscopy, but there is still a lack of quantitative standards to accurately evaluate transparency effects so the composition and concentration of most reagents are not optimal. Here, we propose a transparency quantitative analysis method (TQAM) based on the tissue area recognition technique to achieve the high-throughput reagent concentration gradient screening. After optimizations of reagent composition, concentration, operation time and other parameters of the optical clearing, we develop a new ultrafast optical clearing method with quantified analysis (FOCMS) with excellent transparency effect, simple operation, improved imaging depth and quality, minor morphological change and outstanding fluorescence retention. Applied the FOCMS to an application of human brain tissue, significant differences are observed between glioma and normal human brain tissue, while these differences are difficult to be found without the assistance of FOCMS. Therefore, FOCMS shows great application potential in clinical diagnosis and treatment, pathological analysis and so on.

Abstract Mass transfer is an essential factor determining photocatalytic performance, which can be modulated by fluid field via manipulating the kinetic characteristics of photocatalysts and photocatalytic intermediates. Past decades have witnessed the efforts and achievements made in manipulating mass transfer based on photocatalyst structure and composition design, and thus, a critical survey that scrutinizes the recent progress in this topic is urgently necessitated. This review examines the basic principles of how mass transfer behavior impacts photocatalytic activity accompanying with the discussion on theoretical simulation calculation including fluid flow speed and pattern. Meanwhile, newly emerged viable photocatalytic micro/nanomotors with self‐thermophoresis, self‐diffusiophoresis, and bubble‐propulsion mechanisms as well as magnet‐actuated photocatalytic artificial cilia for facilitating mass transfer will be covered. Furthermore, their applications in photocatalytic hydrogen evolution, carbon dioxide reduction, organic pollution degradation, bacteria disinfection and so forth are scrutinized. Finally, a brief summary and future outlook are presented, providing a viable guideline to those working in photocatalysis, mass transfer, and other related fields.

Résumé Contexte Lacryoconservation des spermatozoïdes, méthode efficace pour préserver lafertilité masculine, est très avantageuse pour les hommes atteints de cancer.Malheureusement, comme les médecins et les patients atteints de cancersignorent les possibilités de cryoconservation du sperme, les données surl’évaluation des paramètres spermatiques et le devenir des échantillonscryopréservés parmi les hommes chinois atteints de cancers sont rares. Résultats Lestumeurs masculines ont été classées en six types principaux, tumeurs germinales(26%), néoplasmes hématologiques (28%), cancers de la tête et du cou (19%),tumeurs thoraciques (4%), les tumeurs abdominales (10%), et les autres (13%).Les néoplasmes hématologiques étaient le cancer le plus répandu parmi notrecohorte de patients qui ont opté pour la mise en banque de leur sperme, suivisdes tumeurs à cellules germinales. Les patients atteints de tumeurs germinalesprésentaient les concentrations de spermatozoïdes pré-congélation etpost-décongélation les plus faibles. Nous avons comparé séparément les patientsatteints de tumeurs testiculaires, de lymphome, et de leucémie, et avonsconstaté que ceux atteins de leucémie présentaient les plus bassesconcentrations de spermatozoïdes pré-congélation. Une majorité de patientsatteints de cancer (58 %) ont choisi de conserver en banque leurs échantillonscongelés, tandis que 31 % ont choisi de jeter leurs échantillons congelés. Aufil des ans, seuls 13 patients (4%) sont revenus pour utiliser leurs spermatozoïdespar Assistance Médicale à la Procréation. Parmi les échantillons mis en banque,ceux des patients atteints de tumeurs germinales constituaient la proportion laplus élevée (29,3 %). Par ailleurs, les patients atteins de cancershématologiques constituaient le pourcentage le plus élevé (46.2%) de patientsqui n’avaient eu aucun spermatozoïde congelé. Conclusions Lesdonnées rapportées confirment l’impact délétère des divers cancers sur laqualité du sperme. Les leucémies étaientassociées à la pire qualité du sperme et au plus grand nombre d’échantillons desperme qui ne pouvaient pas être congelés. Nous pensons que la qualité desperme pourrait avoir diminué avant même le traitement antinéoplasique, et quela mise en banque de sperme avant le traitement devrait être fortementrecommandée pour les patients atteints de cancers. Un programme de mise enbanque du sperme avant traitement gonadotoxique nécessite une étroitecoopération entre les centres d’Assistance Médicale à la Procréation et les cliniquesde cancérologie.

Abstract Background Multiple surgical approaches have been proposed to repair the congenital choanal atresia. However, there remains no general consensus about the optimal surgical technique. This study aimed to describe and evaluate outcomes of the endoscopic septonasal flap technique combined with bioabsorbable steroid-eluting stents for repair of congenital choanal atresia in neonates and infants. Methods Clinical data of 37 neonates and infants with congenital choanal atresia who received nasal endoscopic surgery with the flap technique between January 2018 and July 2020 were analyzed retrospectively. All patients underwent the ultra‑low‑dose paranasal sinus computed tomography imaging preoperatively to confirm diagnosis and plan the surgery. In these patients, the mirrored L-shaped flap technique was performed for bilateral atresia and the cross-over L-shaped flap technique was performed for unilateral atresia. A total of 22 patients had silicone stents postoperatively and 15 patients had bioabsorbable steroid-eluting stents postoperatively. Silicone stents were removed at one month postoperatively under secondary general anesthesia, while no anesthesia was needed to remove the bioabsorbable steroid-eluting stents. Postoperative follow-up ranged from 10 months to 3 years. Results The septonasal flap technique was performed in all patients. Compared with the silicone stents group, the average operative duration and the hospital length of stay in the bioabsorbable steroid-eluting stents group were decreased [(97.46 ± 15.37) min vs (83.49 ± 19.16) min t = 13.733, P

Abstract Spinal cord injury (SCI) is a salient traumatic disease that often leads to permanent disability, and motor and sensory impairments. Human umbilical cord mesenchymal stem cells (HucMSCs) have a wide application prospect in the treatment of SCI. This study explored the repair effect of HucMSCs-derived extracellular vesicles (HucMSCs-EVs) on SCI. HucMSCs and HucMSCs-EVs were cultured and identified. The rat model of SCI was established, and SCI rats were treated with HucMSCs-EVs. The motor function of SCI rats and morphology of spinal cord tissues were evaluated. Levels of NeuN, GFAP, and NF200 in spinal cord tissues were detected and cell apoptosis was measured. SCI rats were treated with EVs extracted from miR-29b-3p inhibitor-transfected HucMSCs. The downstream gene and pathway of miR-29b-3p were examined. HucMSCs-EVs-treated rats showed obvious motor function recovery and reduced necrosis, nuclear pyknosis, and cavity. HucMSCs-EVs alleviated spinal cord neuronal injury. miR-29b-3p was poorly expressed in SCI tissues, but highly expressed in EVs and SCI rats treated with EVs. miR-29b-3p targeted PTEN. Inhibition of miR-29b-3p or overexpression of PTEN reversed the repair effect of EVs on SCI. EVs activated the AKT/mTOR pathway via the miR-29b-3p/PTEN. In conclusion, HucMSCs-EVs reduced pathological changes, improved motor function, and promoted nerve function repair in SCI rats via the miR-29b-3p/PTEN/Akt/mTOR axis.

Abstract Background Over 200 schizophrenia risk loci have been identified by genome-wide association studies (GWASs). However, the majority of risk loci were identified in populations of European ancestry (EUR), potentially missing important biological insights. It is important to perform 5 GWASs in non-European populations. Methods To identify novel schizophrenia risk loci, we conducted a GWAS in Han Chinese population (3493 cases and 4709 controls). We then performed a large-scale meta-analysis (a total of 143,438 subjects) through combining our results with previous GWASs conducted in EAS and EUR. In addition, we also carried out comprehensive post-GWAS analysis, including heritability partitioning, enrichment of schizophrenia associations in tissues and cell types, trancscriptome-wide association study (TWAS), expression quantitative trait loci (eQTL) and differential expression analysis. Results We identified two new schizophrenia risk loci, including associations in SHISA9 (rs7192086, P = 4.92 × 10-08) and PES1 (rs57016637, P = 2.33 × 10−11) in Han Chinese population. A fixed-effect meta-analysis (a total of 143,438 subjects) with summary statistics from EAS and EUR identifies 15 novel genome-wide significant risk loci. Heritability partitioning with linkage disequilibrium score regression (LDSC) reveals a significant enrichment of schizophrenia heritability in conserved genomic regions, promoters, and enhancers. Tissue and cell-type enrichment analyses show that schizophrenia associations are significantly enriched in human brain tissues and several types of neurons, including cerebellum neurons, telencephalon inhibitory, and excitatory neurons. Polygenic risk score profiling reveals that GWAS summary statistics from trans-ancestry meta-analysis (EAS + EUR) improves prediction performance in predicting the case/control status of our sample. Finally, transcriptome-wide association study (TWAS) identifies risk genes whose cis-regulated expression change may have a role in schizophrenia. Conclusions Our study identifies 17 novel schizophrenia risk loci and highlights the importance and necessity of conducting genetic study in different populations. These findings not only provide new insights into genetic etiology of schizophrenia, but also facilitate to delineate the pathophysiology of schizophrenia and develop new therapeutic targets.