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We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma‐free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next‐generation sequencing before and after operation. Whole‐exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre‐ and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow‐up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time‐points was associated with significantly shorter recurrence‐free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real‐time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC., Here, we studied the value of circulating tumor DNA (ctDNA), in combination with germline and tissue DNA by whole‐exome sequencing in patients withhepatocellular carcinoma (HCC). Our analysis demonstrated that ctDNA may serve as a real‐time monitoring indicator by accurately reflecting tumor burden, and as a strong independent predictor of recurrence‐free survival in HCC.

With the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, the importance of vaccines in epidemic prevention and public health has become even more obvious than ever. However, the emergence of multiple severe acute respiratory syndrome coronavirus 2 variants worldwide has raised concerns about the effectiveness of current COVID-19 vaccines. Here, we review the characteristics of COVID-19 vaccine candidates in five platforms and the latest clinical trial results of them. In addition, we further discuss future directions for the research and development of the next generation of COVID-19 vaccines. We also summarize the serious adverse events reported recently after the large-scale vaccination with the current COVID-19 vaccines, including the thromboembolism caused by the AstraZeneca and Johnson & Johnson vaccines.

The methyltransferase-like 3 (Mettl3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m6A) modification, which plays an important role in gene post-transcription modulation. Although RNA m6A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m6A level and m6A writer Mettl3 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of m6A in ten-eleven translocation methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.

Background Low-moisture foods (LMFs) are generally considered “lower risk” in terms of food safety, however, the frequent foodborne illnesses involved in the consumption of LMFs has heightened the public concern. The low aw environments also offer considerable protection against microorganisms. Meanwhile, the relatively high contamination risk of mycotoxins in low-moisture foods is a challenge for the food industry. Thermal decontamination techniques usually destroy heat-sensitive nutrients and lower product quality, and they are not adequate for mycotoxins detoxification. Therefore, developing non-thermal decontamination technologies to improve the safety of LMFs is of great interest in both of economics and public health. Scope and approach This review discusses the effects of non-thermal decontamination technologies, including ultraviolet and pulsed light, ionizing irradiation, cold plasma, and ozone, on microbial population and mycotoxin contents on LMFs. Furthermore, the working principles, applications, factors affecting processing efficacy and limitations of these decontamination technologies are summarized. The further research opportunities in commercialization are identified and discussed. Key findings and conclusions Non-thermal decontamination technologies like UV and pulsed light, ionizing irradiation, cold plasma, and ozone have high potential as promising technologies for microbial inactivation and mycotoxin degradation for improving the safety and quality of LMFs. The operating conditions of the treatment, food property, species of microorganisms and mycotoxins are the major determinants affecting the processing efficacy. Further studies are recommended to evaluate the degradant toxicology and its interaction with food components, and particularly scaling-up the technology for commercial applications should be given more attention.

Ultra-high-purity silicon tetrachloride (SiCl4) is demanded as an electronic-grade chemical to meet the stringent requirements of the rapidly developing semiconductor industry. The high requirement for ultra-high-purity SiCl4 has created the need for a high-efficient process for reducing energy consumption as well as satisfying product quality. In this paper, a mass of production technology of ultra-high-purity SiCl4 was successfully developed through chlorination reaction in the ultraviolet (UV)-based photo microreactor coupled with the distillation process. The influences of key operational parameters, including temperature, pressure, UV wavelength and light intensity on the product quality, especially for hydrogen-containing impurities, were quantified by the infrared transmittance of Fourier transform infrared spectroscopy (FT-IR) at 2185 cm−1 and 2160 cm−1 indicating that characteristic vibrational modes of Si H bonds, as well as the operating conditions of distillation were also investigated as key factors for metal impurities removing. The advanced intensification of SiCl4 manufactured by the integration of photo microreactor and distillation achieves the products with superior specifications higher than the standard commercial products.

Summary Background Previous clinical and animal studies suggested that medium-chain triglycerides (MCT) might be an alternative energy substrate for the brain and might benefit patients with Alzheimer's disease (AD), but the clinical evidence is not substantial or totally convincing. Objective To investigate the effects of MCT on cognitive ability in patients with mild to moderate AD and explore the changes in peripheral blood metabolomics. Methods A double-blind, randomized, placebo-controlled crossover study was undertaken in 53 mild to moderate AD patients. Participants were randomized between two sequences (placebo followed by MCT or MCT followed by placebo) and took MCT jelly or placebo jelly (canola oil) by mouth three times daily (total daily fat dose: 17.3 g MCT, or 19.7 g canola oil) for 30 days per phase. The primary outcome was cognition as measured by the Alzheimer's Disease Assessment Scale–Cognitive Subscale, Chinese version (ADAS-Cog-C). The secondary outcome was self-care as measured by the activities of daily living scale (ADL) and changes in plasma metabolites. Results This study showed a significant (p 0.05). The concentrations of TC, HDL-C, β-hydroxybutyrate and acetoacetate were significantly higher in the MCT group than in the placebo group (p Conclusions MCT had positive effects on cognitive ability in mild to moderate AD patients with APOE4−/−. These effects of MCT might be related to the metabolism of LysoPC, oleic acid, linoleic acid and palmitic acid, in addition to the ketogenic effect. Study ID number ChiCTR-IOR-16009737. Registry website WHO ICTRP Search Portal – http://apps.who.int/trialsearch/Default.aspx .

The influences of freezing pretreatment, thermal pretreatments (water blanching and steam blanching) and their combinations on hot-air drying kinetics of Vaccinium bracteatum Thunb (VBT) leaves at 60 °C and key quality attributes were investigated. Generally, all the applied pretreatments accelerated VBT leaf drying process. The sequential freezing (8 h) and water blanching (1 min) pretreatments shortened the drying time by 65.5%. The diffusion modeling results revealed that all the pretreatments intensified water diffusion and external water exchange with hot air during drying. Freezing pretreatments had no preservative effect on phenolics, iridoids, and antioxidant capacity of VBT leaves after dehydration, whereas both thermal pretreatments significantly improved dried VBT leaf quality in these three aspects. On the contrary, thermal pretreatments had destructive effects on activities of polyphenol oxidase and β-glucosidase. Due to the low β-glucosidase activity in dried VBT leaves with thermal pretreatments that participated in the transformation of iridoids to generate dark colorants eventually, the extracts from dried VBT leaves with only thermal pretreatments had weak ability to dye glutinous rice. However, this problem was fixed once extra β-glucosidase was added before rice cooking. Overall, the obtained results can provide guidance for the preservation and drying of VBT leaves that has been poorly studied.

Pollen fertility is an agronomic trait that strongly influences rice yield. Recent studies have revealed that the development of the pollen wall is required for pollen fertility and is regulated by several genes. However, the mechanisms underlying pollen and pollen wall development in rice remain largely unknown. In the present study, a point mutation in a gene on chromosome 1 was identified that resulted in the production of less and shrunken pollen (LSP) and led to defects in pollen wall formation. This gene was named LSP1 and was found to encode a member of the adenosine triphosphate-binding cassette (ABC) transporter G subfamily, OsABCG3. Two other loss-of-function mutants of LSP1/OsABCG3, generated using CRISPR/Cas9 technology, showed the same male sterile phenotype. The LSP1/OsABCG3 gene showed a spatio-temporal expression pattern in the developing anthers, and is an ortholog of the Arabidopsis genes AtABCG1 and AtABCG16, which play an important role in pollen wall development. Mutation of LSP1/OsABCG3 affected the expression of several genes involved in pollen and pollen wall formation. These results suggest that LSP1/OsABCG3 is critical for normal pollen fertility and shed light on the molecular mechanisms underlying rice pollen wall development.

l -Asparaginases have the potential to inhibit the formation of acrylamide, a harmful toxin formed during high temperature processing of food. A novel bacterium which produces l -asparaginase was screened. Type I l -asparaginase gene from Acinetobacter soli was cloned and expressed in Escherichia coli. The recombinant l -asparaginase had an activity of 42.0 IU mL−1 and showed no activity toward l -glutamine and d -asparagine. The recombinant l -asparaginase exhibited maximum catalytic activity at pH 8.0 and 40°C. The enzyme was stable in the pH ranging from 6.0 to 9.0. The activity of the recombinant enzyme was substantially enhanced by Ba2+, dithiothreitol, and β-mercaptoethanol. The Km and Vmax values of the l -asparaginase for the l -asparagine were 3.22 mmol L−1 and 1.55 IU μg−1, respectively. Moreover, the recombinant l -asparaginase had the ability to mitigate acrylamide formation in potato chips. Compared with the untreated group, the content of acrylamide in samples treated with the enzyme was effectively decreased by 55.9%. These results indicate that the novel type I l -asparaginase has the potential for application in the food processing industry.

Intrahepatic cholangiocarcinoma (ICC) remains a highly heterogeneous disease with poor prognosis. Tumor-infiltrating lymphocytes were predictive in various cancers, but their prognostic value in ICC is less clear. A total of 168 ICC patients who had received liver resection were enrolled and assigned to the derivation cohort. Sixteen immune markers in tumor and peritumor regions were examined by immunohistochemistry. A least absolute shrinkage and selection operator model was used to identify prognostic markers and to establish an immune signature for ICC (ISICC ). An ISICC -applied prediction model was built and validated in another independent dataset. Five immune features, including CD3peritumor (P) , CD57P , CD45RAP , CD66bintratumoral (T) and PD-L1P , were identified and integrated into an individualized ISICC for each patient. Seven prognostic predictors, including total bilirubin, tumor numbers, CEA, CA19-9, GGT, HBsAg and ISICC , were integrated into the final model. The C-index of the ISICC -applied prediction model was 0.719 (95% CI, 0.660-0.777) in the derivation cohort and 0.667 (95% CI, 0.581-0.732) in the validation cohort. Compared with the conventional staging systems, the new model presented better homogeneity and a lower Akaike information criteria value in ICC. The ISICC -applied prediction model may provide a better prediction performance for the overall survival of patients with resectable ICC in clinical practice.

Adaptive optics—optical coherence tomography (AO-OCT) is a non-invasive technique for imaging retinal vascular and structural features at cellular-level resolution. Whereas retinal blood vessel density is an important biomarker for ocular diseases, particularly glaucoma, automated blood vessel segmentation tools in AO-OCT have not yet been explored. One reason for this is that AO-OCT allows for variable input axial dimensions, which are not well accommodated by 2D-2D or 3D-3D segmentation tools. We propose a novel bidirectional long short-term memory (LSTM)-based network for 3D-2D segmentation of blood vessels within AO-OCT volumes. This technique incorporates inter-slice connectivity and allows for variable input slice numbers. We compare this proposed model to a standard 2D UNet segmentation network considering only volume projections. Furthermore, we expanded the proposed LSTM-based network with an additional UNet to evaluate how it refines network performance. We trained, validated, and tested these architectures in 177 AO-OCT volumes collected from 18 control and glaucoma subjects. The LSTM-UNet has statistically significant improvement (p &lt, 0.05) in AUC (0.88) and recall (0.80) compared to UNet alone (0.83 and 0.70, respectively). LSTM-based approaches had longer evaluation times than the UNet alone. This study shows that a bidirectional convolutional LSTM module improves standard automated vessel segmentation in AO-OCT volumes, although with higher time cost.

In the present study, a total of 7793 samples from 5 different types of hosts were collected and tested, with a seroprevalence of 2.4% (184/7793). Although the seroprevalence of human and animal brucellosis is relatively low, numbers of human brucellosis cases reported have increased continuously from 2004 to 2018. A total of 118 Brucella strains containing 4 biotypes were obtained, including Brucella melitensis bv.1 (n = 8) and bv.3 (n = 106), Brucella abortus bv.3 (n = 3) and bv.7 (n = 1). Twenty-one shared MLVA-16 genotypes, each composed of 2 to 19 strains obtained from different hosts, suggest the occurrence of a brucellosis outbreak epidemic with multiple source points and laboratory infection events. Moreover, 30 shared MLVA-16 genotypes were observed among 59.6% (68/114) B. melitensis isolates from Zhejiang and strains from other 21 different provinces, especially northern provinces, China. The analysis highlighted the imported nature of the strains from all over the northern provinces with a dominant part from the developed areas of animal husbandry. These data revealed a potential transmission pattern of brucellosis in this region, due to introduced infected sheep leading to a brucellosis outbreak epidemic, and eventually causing multiple laboratory infection events. It is urgent to strengthen the inspection and quarantine of the introduced animals.

Background Mixed evidence challenges preoperative alpha-fetoprotein (AFP) as an independent prognostic factor for patients with hepatocellular carcinoma (HCC) after hepatectomy. Results Daily post-operative decrease of AFP by 9% as compared to the preoperative level (A09) were selected as the Cut-off. The Kaplan-Meier curve showed that A09 was significantly different for OS (P=0.043) and RFS (P=0.03). A decrease in risk by 54% was observed for OS and 32% for RFS in the at-risk population (A09>9%). A better concordance was observed after adding A09 into TNM and BCLC staging systems. Moreover, a consistent concordance was observed in the internal (FDZS5:0.63; FDZS3:0.608) and external (FDZS5:0.85; FDZS3:0.762) validation cohorts, suggesting its prognostic value in HCC population with elevated AFP. Conclusions Decrease in perioperative serum AFP rather than preoperative AFP is an independent prognostic factor for HCC patients after hepatectomy. Cut-off A09 significantly discriminates overall and recurrence-free survival and could be interpret into TNM and BCLC staging systems to improve the stratification power for HCC patients with elevated AFP. Methods Kaplan-Meier curve depicted the differences of overall survival (OS) and recurrence-free survival (RFS). Nomogram and concordance were employed to evaluate the superiority of the current staging system.

Background: Whether microvascular invasion (MVI) adversely influences oncological outcomes for intrahepatic cholangiocarcinoma (ICC) patients remains unclear. The purpose of this study was to determine the impact of MVI on postoperative survival and establish a new predictive model for MVI before surgical intervention in patients with ICC. Methods: In this two-center retrospective study, 556 and 31 consecutive patients who underwent curative liver resection for ICC at ZSH and XJFH were analyzed, respectively. Propensity score matching (PSM) and Cox regression analyses were used to explore the prognostic role of MVI on the OS and DFS. Multivariate logistic regression was used to identify the relative risk factors of MVI, which were incorporated into the nomogram. Results: After PSM, 50 MVI cases matched with 172 non-MVI cases, and no bias was observed between the two groups (propensity score, 0.118 (0.099, 0.203) vs. 0.115 (0.059, 0.174), p=0.251). The multivariate Cox analysis showed that MVI was negatively associated with OS (HR 1.635, 95% CI 1.405-1.993, p=0.04) and DFS (HR 1.596, 95% CI 1.077-2.366, p=0.02). The independent factors associated with MVI were ALT, AFP, tumor maximal diameter, and tumor capsule. The nomogram that incorporated these variables achieved good concordance indexes for predicting MVI. Patients with a cutoff score of 168 were considered to have different risks of the presence of MVI preoperatively. Conclusions: The presence of MVI was an adverse prognostic factor for ICC patients. Using the nomogram model, the risk of an individual patient harboring MVI was determined, which led to a rational therapeutic choice.

Objective There is increasing neuroimaging evidence that type 2 diabetes patients with retinal microvascular complications show abnormal brain functional and structural architecture and are at an increased risk of cognitive decline and dementia. However, changes in the topological properties of the functional brain connectome in diabetic retinopathy (DR) patients remain unknown. The aim of this study was to explore the topological organization of the brain connectome in DR patients using graph theory approaches. Methods Thirty-five DR patients (18 males and 17 females) and 38 healthy controls (HCs) (18 males and 20 females), matched for age, sex, and education, underwent resting-state magnetic resonance imaging scans. Graph theory analysis was performed to investigate the topological properties of brain functional connectome at both global and nodal levels. Results Both DR and HC groups showed high-efficiency small-world network in their brain functional networks. Notably, the DR group showed reduction in the clustering coefficient (P=0.0572) and local efficiency (P=0.0151). Furthermore, the DR group showed reduced nodal centralities in the default-mode network (DMN) and increased nodal centralities in the visual network (VN) (P

Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with poor prognosis. The evaluation of recurrence risk after liver resection is of great importance for ICCs. We aimed to assess the prognostic value of intra- and peritumoral immune infiltrations and to establish a novel histopathology-related immunoscore (HRI) associated with ICC recurrence. A total of 280 ICC patients who received curative resection between February 2005 and July 2011 were enrolled in our study. Patients were randomly assigned to the derivation cohort (n = 176) or the validation cohort (n = 104). Sixteen immune biomarkers in both intra- and peritumoral tissues were examined by immunohistochemistry. The least absolute shrinkage and selection operator (LASSO) Cox model was used to establish the HRI score. Cox regression analysis was used for multivariate analysis. Nine recurrence-related immune features were identified and integrated into the HRI score. The HRI score was used to categorize patients into low-risk and high-risk groups using the X-tile software. Kaplan–Meier analysis presented that the HRI score showed good stratification between low-risk and high-risk groups in both the derivation cohort (P

OBJECTIVE To investigate inhibitory effect of semen litchi drug serum on proliferation of human hepatoma HepG2 cells and its effect on the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9). STUDY DESIGN An experimental study. PLACE AND DURATION OF STUDY College of Pharmacy, Guangxi University of Chinese Medicine, China, from June 2017 to January 2018. METHODOLOGY Semen litchi drug serum with concentrations of 0 mg/kg (control group), 3 g/kg (low dose group), 6 g/kg (medium dose group) and 12 g/kg (high dose group) was used to act on HepG2 cells at the logarithmic phase. Inhibitory effect of semen litchi drug serum on cell growth, expression of VEGF and MMP-9 mRNA and protein was detected. RESULTS Inhibitory effect of semen litchi drug serum on the proliferation of HepG2 cells significantly increased with the increase of drug concentration, which was dose-time dependent. Expression levels of VEGF and MMP-9 mRNA in HepG2 cells after 48 hours of treatment by semen litchi low-dose group, medium-dose group, and high-dose group were lower than those in control group (all p

Purpose: To develop and validate a decision aid to help make individualized estimates of tumor recurrence for patients with resected combined hepatocellular cholangiocarcinoma (CHC). Patients and methods: Risk factors of recurrence were identified in the derivation cohort of 208 patients who underwent liver resection between 1995 and 2014 at Zhongshan Hospital to develop a prediction score. The model was subsequently validated in an external cohort of 101 CHC patients using the C concordance statistic and net reclassification index (NRI). Results: On multivariate analysis, five independent predictors associated with tumor recurrence were identified, including sex, γ-glutamyl transferase, macrovascular invasion, hilar lymphoid metastasis and adjuvant transcatheter arterial chemoembolization. The prediction score was constructed using these 5 variables, with scores ranging from 0 to 5. A patient with a score of 0 had a predicted 1- and 5-year recurrence risk of 11.1% and 22.2%, respectively. In the validation cohort, the NRIs of prediction score vs American Joint Committee on Cancer 7th TNM staging system at 1-year and 5-year were 0.185 (95% CI, 0.090-0.279, P

Plaque characteristics play pivotal roles in ischemic events, but stenosis severity does not accurately reflect carotid plaque volume due to expansive remodeling in some patients with low-grade stenosis (LGS). This study aimed to assess the safety, efficacy, and durability of carotid endarterectomy (CEA) for symptomatic LGS.Study participants comprised 61 consecutive patients who underwent CEA for symptomatic carotid stenosis. Patients were divided into an LGS group (50%, n = 17) and a non-LGS group (≥50%, n = 44). Patient characteristics and short-term (within 30 days of CEA) and long-term outcomes were compared between groups for selective usage of internal shunt and known complications of CEA.Magnetic resonance imaging-detected intraplaque hemorrhage was more significant in LGS than in non-LGS (P = 0.04). For short-term outcomes, no symptomatic infarcts, hyperperfusion syndrome, or acute myocardial infarction was confirmed in either group. Internal shunts were used in 4 LGS (23.5%) and 6 non-LGS (13.6%). Asymptomatic diffusion-weighted imaging-positive lesions were confirmed in 2 LGS patients (11.8%) and 5 non-LGS patients (11.4%), neck hematoma in 1 LGS patient, and transient cranial nerve palsy in 1 LGS patient and 2 non-LGS patients, with no significant differences apparent between groups. For long-term outcomes, 5 non-LGS patients showed restenosis (P = 0.17). Hemorrhagic stroke was not observed in either group. No significant differences were seen for infarct in the ipsilateral carotid territory, any ischemic stroke, AMI, or mortality.CEA represents a safe and feasible therapeutic option for a subset of patients with symptomatic LGS.

BackgroundHepatocellular carcinoma (HCC) is characterized by inflammation and immunopathogenesis. Accumulating evidence has shown that the cystathionine β-synthase/hydrogen sulfide (CBS/H2S) axis is involved in the regulation of inflammation. However, roles of CBS in HCC development and immune evasion have not been systematically investigated, and their underlying mechanisms remain elusive. Here, we investigated the roles of CBS in tumor cells and tumor microenvironment of HCC.Methods236 HCC samples were collected to detect the expression of CBS, cleaved Caspase-3 and paired related homeobox 2 (PRRX2) and the number of immune cells. HCC cell lines were employed to examine the effects of CBS on cellular viability, apoptosis and signaling in vitro. Cbs heterozygous knockout mice, C57BL/6 mice, nude mice and non-obese diabetic severe combined immunodeficiency mice were used to investigate the in vivo functions of CBS.ResultsDownregulation of CBS was observed in HCC, and low expression of CBS predicted poor prognosis in HCC patients. CBS overexpression dramatically promoted cellular apoptosis in vitro and inhibited tumor growth in vivo. Activation of the Cbs/H2S axis also reduced the abundance of tumor-infiltrating Tregs, while Cbs deficiency promoted Tregs-mediated immune evasion and boosted tumor growth in Cbs heterozygous knockout mice. Mechanistically, CBS facilitated the expression cleaved Caspase-3 in tumor cells, and on the other hand, suppressed Foxp3 expression in Tregs via inactivating IL-6/STAT3 pathway. As a transcription factor of IL-6, PRRX2 was reduced by CBS. Additionally, miR-24-3p was proven to be an upstream suppressor of CBS in HCC.ConclusionsOur results indicate the antitumor function of CBS in HCC by inactivation of the PRRX2/IL-6/STAT3 pathway, which may serve as a potential target for HCC clinical immunotherapy.

Background Hereditary hearing loss (HHL) is the most common sensory deficit, which highly afflicts humans. With gene sequencing technology development, more variants will be identified and support genetic diagnoses, which is difficult for human experts to diagnose. This study aims to develop a machine learning-based genetic diagnosis model of HHL-related variants of GJB2, SLC26A4 and MT-RNR1. Methods This case-control study included 1898 subjects, among which 1354 were HHL patients and 544 were carriers. Risk assessment models were established based on variants at 144 sites in three genes related to HHL by building six machine learning (ML) models. We compared the ML models with the genetic risk score (GRS) and expert interpretation (EI) to verify the clinical performance. Findings Among the six ML models, the support vector machine (SVM) showed the best performance. For the prediction of HHL-related gene sites in subjects with variants, the area under the receiver operating characteristic (AUC) of the SVM model was 0.803 (0.680–0.814) in the 10-fold stratified cross-validation and 0.751 (0.635–0.779) in external validation. The predicted results were better than both EI and GRS. Furthermore, 11 sites were identified as the smallest feature set that can be accurately predicted. Interpretation The developed SVM model has great potential to be an efficient and effective tool for HHL prediction when high throughput sequencing data are available. Funding This study was supported by the National Key Research and Development Program (2017YFC1001800).

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, predominating within young adults. Cognitive disorders are common in MS and have are associated with several Magnetic Resonance Imaging (MRI) markers, especially brain atrophy. Many have found the symbol digit modalities test (SDMT) to be the most sensitive individual cognitive measure relevant to MS. However, the relationship between SDMT and regional brain cortex thickness in young adults with relapsing-remitting multiple sclerosis (YA-RRMS) has been little explored. The purpose of this study was to investigate the association between the SDMT and regional cortex thickness in YA-RRMS by FreeSurfer, which is an automatic brain structure segmentation method.Twenty-eight YA-RRMS patients (18-35 years old) were enrolled in the present study. Informed consent and information including gender, age, disease duration, number of relapses, annual relapse rate was collected from all patients. Clinical cognitive evaluations (SDMT and auditory verbal learning test (AVLT)) and daily performance: activities of daily living (ADL) were assessed in the present study. MRI scans were performed at the Institute of Neurosurgery of Tiantan Hospital. Twenty-eight matched healthy controls (HC) MRI data were obtained from Tiantan Hospital database. Data on thirty-four points of bilateral cortical structure thickness using statistically defined brain regions-of-interest from FreeSurfer were obtained from all participants.Patients with RRMS exhibited extensively thinner cerebellar cortex compared with HC. SDMT scores were significantly correlated with AVLT subentries (IM, immediate memory; DRM, delayed recall memory; LTRM, long-term recognition memory) in YA-RRMS patients (P 0.05). SDMT was strongly correlated with regional cortex thickness differences of the right temporal pole (r = 0.68) and bilateral parahippocampal areas (right r = 0.62; left r = 0.60), and moderately correlated with regional cortex thickness differences including the left superior temporal and right insula (r = 0.57 and 0.56, respectively) in YA-RRMS patients.The present study has shown the SDMT is strongly correlated with selected cortex regions including the bilateral parahippocampal area and the right temporal pole which are involved in geometric structures processing.

With the aim for a low-aspect-ratio flying wing configuration, this study explores the influence of wall temperature gradient on the laminar and turbulent boundary layers of aircraft surface and determines the effect on the transition Reynolds number and wall friction drag. A four-equation turbulence model with transition mode is used to numerically simulate the flow around the model. The variation of wall friction coefficient, transition Reynolds number, and turbulent boundary layer flow with wall temperature are emphatically investigated. Results show that when the wall temperature increases from 288 to 500 K, the boundary layer transition Reynolds number for the wing section increased by approximately 28% and the surface friction drags decreases by approximately 10.7%. The hot wall enhances the viscous effects of the laminar temperature boundary layer, reduces the Reynolds shear stress and turbulent kinetic energy, and increases the flow stability. However, the velocity gradient and shear stress in the bottom of the turbulent boundary layer decreases, which leads to reduced friction shear stress on the wall surface. Therefore, for the low-aspect-ratio flying wing model, the hot wall can delay the boundary layer transition and reduce the friction drag coefficient in the turbulent region.

The plant pollen wall protects the male gametophyte from various biotic and abiotic stresses. The formation of a unique pollen wall structure and elaborate exine pattern is a well-organized process, which needs coordination between reproductive cells and the neighboring somatic cells. However, molecular mechanisms underlying this process remain largely unknown. Here, we report a rice male-sterile mutant (l94) that exhibits defective pollen exine patterning and abnormal tapetal cell development. MutMap and knockout analyses demonstrated that the causal gene encodes a type-G non-specific lipid transfer protein (OsLTPL94). Histological and cellular analyses established that OsLTPL94 is strongly expressed in the developing microspores and tapetal cells, and its protein is secreted to the plasma membrane. The l94 mutation impeded the secretory ability of OsLTPL94 protein. Further in vivo and in vitro investigations supported the hypothesis that ETERNAL TAPETUM 1 (EAT1), a basic helix-loop-helix transcription factor (bHLH TF), activated OsLTPL94 expression through direct binding to the E-box motif of the OsLTPL94 promoter, which was supported by the positive correlation between the expression of EAT1 and OsLTPL94 in two independent eat1 mutants. Our findings suggest that the secretory OsLTPL94 plays a key role in the coordinated development of tapetum and microspores with the regulation of EAT1.

Objective. Diabetic retinopathy (DR) is one of the main diabetic microvascular complications in clinical practice, which features a complicated mechanism and insignificant efficacy. Therefore, it is urgent to find effective drugs. Xinjiang Coreopsis tinctoria Nutt is a rare alpine wild plant with unique effects and extremely high medicinal value. Preliminary studies have shown that it can reduce elevated blood sugar, unhealthy lipids, and antioxidants. This study was intended to investigate the protective effect of the effective components of Coreopsis tinctoria Nutt on the retinopathy of db/db diabetic mice and provide experimental basis for exploring the efficacy of Coreopsis tinctoria Nutt and the development of new drugs for the treatment of DR. Method. The db/db diabetic mouse models were used, and the effective components of Coreopsis tinctoria Nutt were obtained from Coreopsis tinctoria Nutt using macroporous resin enrichment method after alcohol extraction. These mice were divided into the normal group, model group, and high-dose Coreopsis tinctoria Nutt groups, the positive drug metformin group, and the metformin and Coreopsis tinctoria Nutt combination group. After these db/db type 2 diabetes mouse models were intervened for 10 weeks, their weight, blood sugar, glycosylated hemoglobin, serum MDA, SOD, and other indicators of each group were tested, and the expression changes of VEGF, ICAM1, PEDF, Bcl-2 in mouse retina were observed by immunohistochemistry method. Result. The effective components of Coreopsis tinctoria Nutt were obtained using macroporous resin enrichment method after alcohol extraction, which were mainly comprised of chlorogenic acid, flavone mariside, mariside, dicaffeoyl quinic acid, and flavone oxanine, with a total content of 532.82 mg/g, and the total flavonoid content of 330 mg/g. The effective components of Coreopsis tinctoria Nutt significantly reduced blood sugar and glycosylated hemoglobin and improved oxidative stress levels in db/db diabetic mice. Meanwhile, they reduced the expression of VEGF and ICAM1 in retinopathy and increased the expression of Bcl-2 and PEDF. The combination of Coreopsis tinctoria Nutt and metformin has the most significant effect. Conclusion. Coreopsis tinctoria Nutt can prevent and treat early diabetic retinopathy by affecting the expression of retinopathy-related factors.

Background. We analyzed the effects of total flavonoids from Dracocephalum moldavica L. (D. moldavica L.) on improving chronic mountain sickness (CMS) in rats using the NMR hydrogen spectrum (1H-NMR) metabonomics technology. Method. We extracted the total flavonoids of D. moldavica L with 60% ethanol reflux. A CMS model was established with 48 Sprague–Dawley (SD) rats, which were then randomly divided into six groups (n = 8): control group (normal saline, 0.4 mL/100 g/d, ig); model group (normal saline, 0.4 mL/100 g/d, ig); nifedipine group (nifedipine tablets, 2.7 mg/kg/d, ig); and high-, middle-, and low-dose groups of total flavonoids from D. moldavica L. (DML.H, DML.M, and DML.L, receiving total flavonoids from D. moldavica L. at 400, 200, and 100 mg/kg/d, ig, respectively). The sera of the rats in all the groups were determined, and NMR hydrogen spectrum metabolomics was analyzed. The serum contents of apolipoproteins A1 (Apo-A1) and E (Apo-E) were determined, and histopathological changes in the brain tissue of each group were observed. Results. Serum tests showed that total flavonoids from D. moldavica L. significantly increased the Apo-A1 and Apo-E levels in rats with CMS ( P < 0.05 ). The results of serum metabonomics showed that total flavonoids from D. moldavica L can alleviate amino acid, energy, and lipid metabolism disorders in rats with CMS. Pathohistological examination of brain tissue showed that these flavonoids improved pathological changes, such as meningeal vasodilation, hyperemia, edema of brain parenchyma, inflammatory cell infiltration, increase in perivascular space, and increase in pyramidal cells. Conclusion. Total flavonoids from D. moldavica L. have potential therapeutic effects on CMS. The possible mechanism is the reduction of oxidative damage through the alleviation of metabolism disorder.