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Second near-infrared window fluorescence imaging (NIR-II FI) has attracted tremendous attention in bioimaging. Until now, most probes for NIR-II FI are nanomaterials that are metabolized via hepatobiliary metabolism. Such a metabolic pathway may take several months, causing long-term toxicity. Herein, we design and synthesize a renal-clearable PEGylated semiconducting oligomer (PSO) for the NIR-II FI of tumor. PSO is composed of a semiconducting oligomer (SO) backbone as an NIR-II fluorescence reporter and four poly(ethylene glycol) (PEG) side chains as water-soluble enhancers. PSO can emit an NIR-II fluorescence signal with the maximum emission at 1000 nm under the excitation of 808 nm light. PSO shows good biocompatibility and can be partially cleared out of body via renal clearance. PSO can be utilized for the NIR-II FI of tumor as it can effectively accumulate into tumor.

Background: As one of the most utilized commercial composite boar lines, Duroc pigs have been introduced to China and undergone strongly human-induced selection over the past decades. However, the efficiencies and limitations of previous breeding of Chinese Duroc pigs are largely understudied. The objective of this study was to uncover directional polygenic selection in the Duroc pig genome, and investigate points overlooked in the past breeding process., Results: Here, we utilized the Generation Proxy Selection Mapping (GPSM) on a dataset of 1067 Duroc pigs with 8,766,074 imputed SNPs. GPSM detected a total of 5649 putative SNPs actively under selection in the Chinese Duroc pig population, and the potential functions of the selection regions were mainly related to production, meat and carcass traits. Meanwhile, we observed that the allele frequency of variants related to teat number (NT) relevant traits was also changed, which might be influenced by genes that had pleiotropic effects. First, we identified the direction of selection on NT traits by [Formula: see text], and further pinpointed large-effect genomic regions associated with NT relevant traits by selection signature and GWAS. Combining results of NT relevant traits-specific selection signatures and GWAS, we found three common genome regions, which were overlapped with QTLs related to production, meat and carcass traits besides "teat number" QTLs. This implied that there were some pleiotropic variants underlying NT and economic traits. We further found that rs346331089 has pleiotropic effects on NT and economic traits, e.g., litter size at weaning (LSW), litter weight at weaning (LWW), days to 100 kg (D100), backfat thickness at 100 kg (B100), and loin muscle area at 100 kg (L100) traits., Conclusions: The selected loci that we identified across methods displayed the past breeding process of Chinese Duroc pigs, and our findings could be used to inform future breeding decision., (© 2022. The Author(s).)

Hypoxic-ischemic (HI) induced perinatal white matter injury (PWMI) is a major cause of neurologic disabilities characterized by selective oligodendroglial death and myelin disruption. Galectin-3 (Gal-3) modulates postnatal subventricular zone gliogenesis and attenuates ischemic injury. However, the association between Gal-3 and myelin formation still remains unclear. In this study, we first perform Gal-3 knockdown (KD) to identify the importance of Gal-3 on myelin formation. Our results show impeded myelin formation, manifested by Olig2/CC1 (+) mature oligodendrocytes number, expression of oligodendroglial maturation-associated markers (MBP and CNPase), and myelin thickness and integrity. Then we perform recombinant Gal-3 (rGal-3) administration by intracerebroventricular injection. Notably, although rGal-3 administration shows no beneficial effect on oligodendrogenesis and myelin formation under normal condition, our results show that rGal-3 administration attenuates cognitive deficits and drives remyelination after PWMI, which are coupled to signs of enhanced myelin resiliency and cognition. Also, our results indicates that the significant increases in substrates for remyelination of rGal-3 administration are accompanied by enhanced Iba-1 (microglia marker)/ Mrc1 (M2 marker) (+) microglia and decreased Iba-1/ iNOS (M1 marker) (+) microglia. Altogether, our data in this research confirm the association between Gal-3 and myelin formation, underscore its position for the capacity for remyelination and restoration of function, and unveils the efficacy of rGal-3 administration with anti-inflammatory phenotype microglia (M2 microglia) activation. Thus, the findings suggest that Gal-3 plays a significant role in myelin formation and remyelination restoration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Diao, Qiu, Gao, Wang, Chen, Xiao, Li and Chen.)

Objectives: Cognitive impairment may affect one-third of stroke survivors. Cardiovascular risk factors and stroke severity were known to be associated with cognitive function after stroke. However, it is unclear whether cardiovascular risk factors directly affect cognition after stroke, indirectly affect cognition by changing stroke severity, or both. Moreover, the effect of a combination of hypertension and diabetes mellitus was conflicting. We aimed to investigate the multiple direct and indirect associations and inspire potential intervention strategies., Materials and Methods: From February 2020 to January 2021, 350 individuals received cognitive tests within 7 days after incident stroke. Cognitive tests were performed using the Chinese version of the Mini-Mental State Examination (MMSE). A moderated mediation model was constructed to test the indirect associations between cardiovascular and demographic risk factors and cognition mediated through stroke severity, the direct associations between risk factors and cognition, and the moderating effects of hypertension and diabetes., Results: Age (estimate, -0.112), atrial fibrillation (estimate, -4.092), and stroke severity (estimate, -1.994) were directly associated with lower cognitive function after stroke. Vascular disease (estimate, 1.951) and male sex (estimate, 2.502) were directly associated with better cognition after stroke. Higher education level was associated with better cognition directly (estimate, 1.341) and indirectly (estimate, 0.227) through stroke severity. The combination of hypertension decreased the magnitude of the negative association between atrial fibrillation and cognition (estimate, from -4.092 to -3.580)., Conclusion: This is the first Chinese study exploring the moderated and mediating associations between cardiovascular risk factors, stroke severity, and cognitive function after stroke. Age, female sex, and atrial fibrillation were directly associated with lower cognition after stroke. The combination of hypertension might have a positive effect on cognition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hua, Zhou, Chen, Tang, Diao and Fang.)

This article studies the finite-time tracking control problem for the single-link flexible-joint robot system with actuator failures and proposes an adaptive fuzzy fault-tolerant control strategy. More precisely, the issue of "explosion of complexity" is successfully solved by incorporating the command filtering technology and the backstepping method. The unknown nonlinearities are identified with the help of the fuzzy logic system. An event-triggered mechanism with the relative threshold strategy is exploited to save communication resources. Furthermore, the proposed control design can guarantee that the tracking error converges to a small neighborhood of origin within a finite time by taking full advantage of the finite-time stability theory. Finally, the simulation example is presented to further verify the validity of the proposed control method.

Introduction: Drug-related problems (DRPs) refer to events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes. DRPs might be severe for children with chronic diseases managed at primary health care institutions, but the relevant research is scarce. Objective: In this cross-sectional study, we aimed to explore the prevalence, types, causes, and influencing factors of DRPs in children with chronic diseases in a Chinese primary health care institution. Methods: We recruited children with chronic diseases who visited the pediatric outpatient department in a primary health care institution from July 1 to 12 October 2021. Clinical pharmacists identified DRPs through medication therapy reviews, classified the types and causes of DRPs, and distinguished the manifested DRPs that affected the outcome and potential DRPs that were going to affect the outcome. Results: A total of 188 children with chronic diseases was included, and 584 DRPs were identified in 89.89% of participants. The most common type of DRPs was "treatment effectiveness" (a manifested problem or potential problem with the effect of the pharmacotherapy; 83.56%), of which 67.29% were potential DRPs. The second common type was "treatment safety" (patient suffers or could suffer from an adverse drug event; 14.21%), of which 89.16% were potential DRPs. The most common cause of DRPs was related to the process of use (42.24%), such as "patient uses/takes less drug than prescribed or does not take the drug at all," "patient stores drug inappropriately," and "patient administers/uses the drug in a wrong way." The second common cause was related to the process of dispensing (29.83%), such as "necessary information not provided or incorrect advice provided" and "prescribed drug is not available." The third common cause was related to the process of prescribing (26.21%), such as "drug dose is too low" and "no or incomplete drug treatment despite an existing indication." The number of combined medications was an influencing factor for the frequency of DRPs ( p < 0.05). Conclusion : This cross-sectional study showed that the current situation regarding DRPs among children with chronic diseases managed in the primary health care institution was serious. The types of DRPs were mainly related to treatment effectiveness, and improper usage of medications was one of the main causes of DRPs. The number of combined drugs was the influencing factor for the frequency of DRPs. In the future, pharmacists should consider formulating pharmaceutical intervention strategies for this specific group according to the characteristics of DRPs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ni, Yang, Zeng, Li, Diao, Li, Wu, Liu, Jia, Cheng and Zhang.)

Plants of the Elaeagnaceae family are widely used to treat various health disorders owing to their natural phytochemicals. Seabuckthorn (Hippophae rhamnoides L.) is an economically and ecologically important species within the family with richness of biologically and pharmacologically active substances. Here, we present a chromosome-level genome assembly of seabuckthorn (http://hipp.shengxin.ren/), the first genome sequence of Elaeagnaceae, which has a total length of 849.04 Mb with scaffold N50 of 69.52 Mb and 30 864 annotated genes. Two sequential tetraploidizations with one occurring ~36-41 million years ago (Mya) and the last ~24-27 Mya were inferred, resulting in expansion of genes related to ascorbate and aldarate metabolism, lipid biosynthesis, and fatty acid elongation. Comparative genomic analysis reconstructed the evolutionary trajectories of the seabuckthorn genome with the predicted ancestral genome of 14 proto-chromosomes. Comparative transcriptomic and metabonomic analyses identified some key genes contributing to high content of polyunsaturated fatty acids and ascorbic acid (AsA). Additionally, we generated and analysed 55 whole-genome sequences of diverse accessions, and identified 9.80 million genetic variants in the seabuckthorn germplasms. Intriguingly, genes in selective sweep regions identified through population genomic analysis appeared to contribute to the richness of AsA and fatty acid in seabuckthorn fruits, among which GalLDH, GMPase and ACC, TER were the potentially major-effect causative genes controlling AsA and fatty acid content of the fruit, respectively. Our research offers novel insights into the molecular basis underlying phytochemical innovation of seabuckthorn, and provides valuable resources for exploring the evolution of the Elaeagnaceae family and molecular breeding., (© 2022 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Two new quinones, 4-(5-hydroxy-1,4-dioxo-1,4-dihydronaphtha-len-3-ylamino)-butyric acid methyl ester (compound 1 ) and 1,3-dimethoxycarbonyl-8-hydroxy-9,10-anthraquinone ( 2 ), and six known compounds ( 3-8 ) were isolated from the roots of Juglans mandshurica Maxim., a member of the Juglandaceae family. The chemical structures of the compounds were elucidated by nuclear magnetic resonance spectroscopy and compared with data from the literature. The isolated compounds were evaluated for their ability to inhibit the production of nitric oxide, tumour necrosis factor-α, and interleukin-6 by the mouse macrophage RAW 264.7 cell line after lipopolysaccharide stimulation in vitro . We found that compounds 1-4 exhibited potent anti-inflammatory effects, as indicated by suppression of lipopolysaccharide-stimulated nitric oxide and cytokine production with 50% inhibitory concentrations between 20.09 μM and 27.63 μM. These results identify two novel quinones from J. mandshurica with potential utility as anti-inflammatory compounds.

As a new epigenetic mark, DNA N6-adenine (6mA) methylation plays an important role in various biological processes and has been reported in many prokaryotic organisms in recent years. However, the distribution patterns and functions of DNA 6mA modification have been poorly studied in non-model crops. In this study, we observed that the methylation ratio of 6mA was about 0.016% in the sea buckthorn (Hippophae rhamnoides L.) genome using mass spectrometry. We first constructed a comprehensive 6mA landscape in sea buckthorn genome using nanopore sequencing at single-base resolution. Distribution analysis suggested that 6mA methylated sites were widely distributed in the sea buckthorn chromosomes, which were similar to those in Arabidopsis and rice. Furthermore, reduced 6mA DNA methylation is associated with different expression of genes related to the fruit-ripening process in sea buckthorn. Our results revealed that 6mA DNA modification could be considered an important epigenomic mark and contributes to the fruit ripening process in plants., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Silvicultural practices greatly improve the economic value of wood products from forests. Stem dimensions, wood density, and stem form are closely linked to end-product performance. This research aimed to examine the effects of stand density and stem height on variables that reflect ring growth and wood properties of Sassafras tzumu stands during the self-thinning phase. Between the ages of 10 and 40 years, the number of stems per hectare has declined from 1,068 to 964 due to density-dependent mortality. As the relative stand density decreased, there were significant reductions in the average tree ring width (5.07-3.51 mm) and increases in latewood proportions (49.88-53.49%) and the density of the annual growth ring (165.60-708.58 kg/m 3 ). Therefore, ring density, earlywood density, and latewood density increased with decreasing relative stand density after self-thinning occurred. Ring width, earlywood width, and latewood width significantly increased from the base to the apex of the stem. Stand density and stem height had additive effects on S. tzumu wood properties during the self-thinning phase. A shift in the growth allocation along the longitudinal stem in response to self-thinning resulted in decreasing radial growth, increasing wood density, and improved stem form. In summary, we found a significant influence of stand density on tree ring growth, wood quality, and stem form of S. tzumu trees during the self-thinning phase., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Diao, Sun, Forrester, Soares, Protásio and Jiang.)

Background: C-reactive protein (CRP) is an important biomarker of inflammation and plays a pivotal role in predicting the clinical prognosis of cardiovascular and cerebrovascular diseases. However, the mechanism of inflammation influencing the outcome of patients with ischemic stroke are unknown., Aims: We aim to investigate the association between hsCRP and mRS in 194 eligible patients by therapy-stratified analyses., Methods: The modification effects of antiplatelet therapy on the association between mRS and different exposure variables were analyzed. The retained variables were analyzed in the receiver operating characteristic (ROC) curve to discriminate patients with poor outcome., Results: hsCRP was positively correlated with mRS in therapy-stratified analyses. There was a statistical modification effect of antiplatelet therapy on the association of hsCRP and mRS (P for interaction = 0.0101). The discriminative effect of poor outcome was further verified by ROC curve analyses (AUC with from 0.758 to 0.872, AUC without from 0.709 to 0.713)., Conclusions: hsCRP is correlated with the clinical outcome of patients treated with IVrt-PA, and may be a better predictor of post-thrombolytic functional outcome in patients with previous antiplatelet therapy than in non-used patients., (© 2022. The Author(s).)

In this paper, the effects of different ignition positions and equivalence ratios on the explosion characteristics of syngas in a half-open Hele-Shaw duct were investigated. The ignition points are set at distances of 0 and 500 mm from the closed end. Moreover, the research range of equivalence ratio is 0.8-1.2. The experimental results indicate that different ignition positions and equivalence ratios influence the flame front structure and the dynamic characteristics of flame propagation. When the ignition position is at the closed end, the flame front undergoes several typical propagation stages before eventually reaching the open end of the duct. The time required by the flame to reach the open end decreases as the equivalence ratio increases. Meanwhile, when the ignition is in the middle of the duct, the flame simultaneously spreads to the open and closed ends. The time required to reach both sides decreases with the increase in the equivalence ratio. The flame front structure and pressure are primarily affected by the ignition position and the equivalence ratio. At the same ignition position, flame propagation velocity and maximum overpressure increase with the equivalence ratio. The pressure oscillation becomes more intense when the ignition position is close to the open end. At IP 500 , when the equivalence ratio is 0.8, multiple finger-shaped flame fronts emerge, accompanied by high-frequency flame oscillations. This study can provide guidance for the study of the flame propagation characteristics of syngas in millimeter-scale burners., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Interleukin-18 (IL-18), a pro-inflammatory cytokine, is thought to be associated with inflammation in many neurological diseases such as ischemic stroke and poststroke depression, but the role of IL-18 in inflammatory injury after intracerebral hemorrhage (ICH) remains unclear. In this study, we established the ICH model in male mice and found that IL-18 expression including protein and mRNA levels was significantly increased in brain tissues after ICH. Meanwhile, exogenous IL-18 exacerbated cerebral hematoma and neurological deficits following ICH. In the IL-18 knockout group, the size of hematoma and neurological functions after ICH was decreased compared with the wild-type group, suggesting the critical role of IL-18 on the modulation of brain injury after ICH. Importantly, exogenous IL-18 increased microglial activation in brain tissues after ICH. Furthermore, IL-18 knockout resulted in the reduction of activated microglia after ICH. These results indicated that IL-18 may regulate the inflammatory response after ICH through the activation of microglia. Thus, IL-18 is expected to be a promising therapeutic target for secondary brain injury after ICH., (© 2022 Wiley Periodicals LLC.)

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. The incidences of HCC and HCC-related deaths have increased over the last several decades. However, the treatment options for advanced HCC are very limited. Long noncoding RNAs (lncRNAs) wrapped in exosomes can change the expression of their target genes in recipient cells, thereby regulating the behavior of recipient cells. Increasing evidence has demonstrated that there is a correlation between the activation of exosomal lncRNAs and the development of HCC. In this review article, we highlighted the functions of exosomal lncRNAs in the development of HCC, showing that exosomal lncRNAs play a vital role in the growth and progression of HCC and are targets for HCC., (Copyright © 2022. Published by Elsevier Inc.)

Research on crop sexuality is important for establishing systems for germplasm innovation and cultivating improved varieties. In this study, androecious persimmon trees were treated with various concentrations of ethrel (100, 500, and 1,000 mg/L) and zeatin (1, 5, and 10 mg/L) to investigate the morphological, physiological, and molecular characteristics of persimmon. Ethrel at 1,000 mg/L and zeatin at 10 mg/L both significantly reduced the stamen length and pollen grain diameter in androecious trees. Ethrel treatment also led to reduced stamen development with degenerated cellular contents; zeatin treatment promoted the development of arrested pistils via maintaining relatively normal mitochondrial morphology. Both treatments altered carbohydrate, amino acid, and endogenous phytohormone contents, as well as genes associated with hormone production and floral organ development. Thereafter, we explored the combined effects of four chemicals, including ethrel and zeatin, as well as zebularine and 5-azacytidine, both of which are DNA methylation inhibitors, on androecious persimmon flower development. Morphological comparisons showed that stamen length, pollen viability, and pollen grain diameter were significantly inhibited after combined treatment. Large numbers of genes involving in carbohydrate metabolic, mitogen-activated protein kinase (MAPK) signaling, and ribosome pathways, and metabolites including uridine monophosphate (UMP) and cyclamic acid were identified in response to the treatment, indicating complex regulatory mechanisms. An association analysis of transcriptomic and metabolomic data indicated that ribosomal genes have distinct effects on UMP and cyclamic acid metabolites, explaining how male floral buds of androecious persimmon trees respond to these exogenous chemicals. These findings extend the knowledge concerning sexual differentiation in persimmon; they also provide a theoretical basis for molecular breeding, high-yield cultivation, and quality improvement in persimmon., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Li, Suo, Han, Diao, Mai, Wang, Yuan, Ye, Pu, Zhang, Sun, Li and Fu.)

Memristors based on two-dimensional (2D) materials can exhibit great scalability and ultralow power consumption, yet the structural and thickness inhomogeneity of ultrathin electrolytes lowers the production yield and reliability of devices. Here, we report that the self-limiting amorphous SiO x (∼2.7 nm) provides a perfect atomically thin electrolyte with high uniformity, featuring a record high production yield. With the guidance of physical modeling, we reveal that the atomic thickness of SiO x enables anomalous resistive switching with a transition to an analog quasi-reset mode, where the filament stability can be further enhanced using Ag-Au nanocomposite electrodes. Such a picojoule memristor shows record low switching variabilities (C2C and D2D variation down to 1.1 and 2.6%, respectively), good retention at a few microsiemens, and high conductance-updating linearity, constituting key metrics for analog neural networks. In addition, the stable high-resistance state is found to be an excellent source for true random numbers of Gaussian distribution. This work opens up opportunities in mass production of Si-compatible memristors for ultradense neuromorphic and security hardware.

Sea buckthorn is a typical drought-resistant tree species. However, there is a general lack of understanding of the pattern of DNA methylation linked with sea buckthorn responses to drought, and its relationship with drought tolerance mechanisms. In this study, we performed whole-transcriptome RNA sequencing and methylome sequencing in response to drought stress to explore differentially expressed mRNAs, miRNAs, lncRNAs and circRNAs in sea buckthorn leaves. Based on predicted DE pairs, we constructed a competitive endogenous RNA network, which revealed potential transcriptional regulatory roles in response to drought stress. The results of methylome sequencing revealed that the DNA methylation level was increased in sea buckthorn leaves under drought stress. We identified 13,405 differentially methylated regions between CK and TR. We found one DMR-associated DEG (Vacuolar-sorting receptor 6) involved in the ABA accumulation pathway. In addition, two DNA methyltransferases (HrMET1 and HrDRM1) were closely associated with drought-induced hypermethylation in sea buckthorn. Together, we firstly conducted a comprehensive transcriptomic and epigenetic analysis of sea buckthorn under drought stress, providing a resource for further study of the potential functions of genes, miRNAs, lncRNAs, circRNAs and DNA methyltransferases., Competing Interests: Declaration of Competing Interest No potential conflict of interest was reported by the authors., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: To systematically evaluate the safety and effectiveness of different dosages of recombinant human interferon α 1b (IFN α 1b) inhaled for bronchiolitis in children., Methods: 7 databases, including PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, Wanfang Database, and VIP, were searched. The search time was from their inception dates to March 28, 2022. A randomized controlled trial (RCT) of 2  μ g/kg IFN α 1b (low dosage group) monotherapy or in combination with other drugs vs. 4  μ g/kg IFN α 1b (high dosage group) monotherapy or in combination with the other drugs was included. The risk of bias 2.0 evaluated the RCT's quality, and the grading of recommendations assessment, development and evaluation (GRADE) tool was used for evaluating the overall quality of the evidence. Then, a meta-analysis was performed by RevMan 5.4., Results: A total of 13 RCTs with 1719 children were included. The meta-analysis results showed that the high dosage group was significantly shorter than the low dosage group of the duration of hospital stays (MD = -0.40, 95%CI (-0.73, -0.07), P  = 0.02) (low quality), three depressions sign disappearing time (MD = -0.60, 95%CI (-1.05, -0.14), P  = 0.010) (low quality), and wheeze disappearing time (MD = -0.62, 95%CI (-1.17, -0.06),  = 0.03) (low quality). There was no significant difference between the two groups in coughing disappearing time, pulmonary rales disappearing time, wheezing sound disappearing time, or adverse event rates., Conclusions: Compared with low dosage IFN α 1b, high dosage IFN α 1b reduces the duration of hospital stays, the disappearance time of the three depression signs, and the disappearance time of wheeze in the treatment of bronchiolitis in children. Limited by the low quality of the evidence, the conclusions still need to be supported by high-quality studies., Competing Interests: The author reports no conflicts of interest in this work., (Copyright © 2022 Jiefeng Luo et al.)

Introduction: The association between miRNA-499 rs3746444 and a variety of autoimmune diseases has been reported. However, these results were contradictory and just focused on one or two autoimmune diseases. The present study aims to examine the possible association between rs3746444 polymorphism and the risk of autoimmune diseases., Methods: The studies that evaluated the association between miRNA-499 gene polymorphism and autoimmune diseases were retrieved. Five different genetic models were used to evaluate the association. The random-effects model was used to pool the effect sizes. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the associations. Stratification analyses were performed by ethnicity and type of autoimmune diseases. False-positive report probability (FPRP) was performed for determining noteworthy associations., Results: Seventeen articles (twenty studies) involving 4,376 cases and 4,991 controls were identified and included in our meta-analysis. The pooled ORs of all eligible case-control studies indicated a significant association between miRNA-499 gene polymorphism and autoimmune diseases: (T vs. C: OR = 0.877; 95% CI: 0.774, 0.993; P = 0.039). Stratified analysis indicated a significant association across both Caucasian (TT vs. TC+CC: OR = 0.779; 95% CI: 0.622, 0.976; P = 0.030) and Asian (T vs. C: OR = 0.895; 95% CI: 0.808, 0.992; P = 0.035) populations. There was also a significant association in Behcet's disease, rheumatoid arthritis, systemic lupus erythematosus, and ulcerative colitis populations., Conclusions: Our meta-analysis suggested that the miRNA-499 rs3746444 polymorphism was associated with an elevated risk of autoimmune diseases in the overall analysis as well as Caucasian and Asian populations., Competing Interests: The authors have declared that no competing interests exist.

Pine resin is one of the best known and most exploited non-wood products. Resin is a complex mixture of terpenes produced by specialized cells that are dedicated to tree defense. Chemical defenses are plastic properties, and concentrations of chemical defenses can be adjusted based on environmental factors, such as resource availability. The slope orientation (south/sunny or north/shady) and the altitude of the plantation site have significant effects on the soil nutrient and the plant performance, whereas little is known about how the slope affects the pine resin yield and its components. In total, 1180 slash pines in 18 plots at different slope positions were established to determine the effects on the α- and β-pinene content and resin production of the slash pine. The near-infrared spectroscopy (NIR) technique was developed to rapidly and economically predict the turpentine content for each sample. The results showed that the best partial least squares regression (PLS) models for α- and β-pinene content prediction were established via the combined treatment of multiplicative scatter correction-significant multivariate correlation (MSC-sMC). The prediction models based on sMC spectra for α- and β-pinene content have an R 2 of 0.82 and 0.85 and an RMSE of 0.96 and 0.82, respectively, and they were successfully implemented in turpentine prediction in this research. The results also showed that a barren slope position (especially mid-slope) could improve the α-pinene and β-pinene content and resin productivity of slash pine, and the β-pinene content in the resin had more variances in this research.

Background: Research on pharmacoeconomics (PE) promotes the rational allocation of medical resources, which has received attention in the last decade. We conducted a scientometric analysis of PE to determine the current status and frontiers, and promote cooperation and development., Methods: The Web of Science Core Collection-Science Citation Index Expanded was adopted to retrieve publications associated with PE from 2012-2021. After screening publications, CiteSpace 3.8.R3 was used to conduct a scientometric analysis. We analyzed terms, including publications and citations, countries/regions, institutions, journals, authors, keywords, and references., Results: In total, 4,715 documents published from 2012-2021 were included in this study, of which 3,829 were articles and 886 were reviews. The documents were cited 54,596 times, at an average of 11.58 times per document. 121 countries/regions and 410 institutions were involved. The top 3 countries/regions by the number of publications were the United States of America (n=1,790), England (n=601), and China (n=403), while the institution with the most publications was Pfizer. Pharmacoeconomics was the main journal of PE, with 310 publications in all, and the top 3 cited journals were New England Journal of Medicine (citation times =1,620), Value in Health (citation times =1,306), and Lancet (citation times =1,255). Bin Wu was the most productive author (n=16), while World Health Organization was the most influential author (citation times =387). 524 keywords altogether were found, and the top 3 keywords by frequency were therapy (frequency =318), impact (frequency =305), and cost-effectiveness (frequency =296). The keyword "modifying antirheumatic drug" associated with rheumatoid arthritis (RA) has continued bursting from 2016-2021. Guide to the methods of technology appraisal 2013 by the National Institute for Health and Care Excellence, was the most frequently cited publication on PE (citation times =65). Cluster 0 labeled as "cost-effectiveness analysis" (CEA) was the largest and latest cluster, and its citing articles focused on the CEA of first-line treatment for non-small cell lung cancer (NSCLC)., Conclusions: The economic analysis of disease-modifying antirheumatic drugs related to RA was a popular topic in the last 6 years, and CEA of NSCLC first-line treatment was at the frontier of PE., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1050/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Visual inspection of hepatocellular carcinoma cancer regions by experienced pathologists in whole-slide images (WSIs) is a challenging, labor-intensive, and time-consuming task because of the large scale and high resolution of WSIs. Therefore, a weakly supervised framework based on a multiscale attention convolutional neural network (MSAN-CNN) was introduced into this process. Herein, patch-based images with image-level normal/tumor annotation (rather than images with pixel-level annotation) were fed into a classification neural network. To further improve the performances of cancer region detection, multiscale attention was introduced into the classification neural network. A total of 100 cases were obtained from The Cancer Genome Atlas and divided into 70 training and 30 testing data sets that were fed into the MSAN-CNN framework. The experimental results showed that this framework significantly outperforms the single-scale detection method according to the area under the curve and accuracy, sensitivity, and specificity metrics. When compared with the diagnoses made by three pathologists, MSAN-CNN performed better than a junior- and an intermediate-level pathologist, and slightly worse than a senior pathologist. Furthermore, MSAN-CNN provided a very fast detection time compared with the pathologists. Therefore, a weakly supervised framework based on MSAN-CNN has great potential to assist pathologists in the fast and accurate detection of cancer regions of hepatocellular carcinoma on WSIs., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Azithromycin (AZI) is increasingly used for childhood asthma despite limited and inconsistent data. We aimed to evaluate the efficacy and safety of AZI in childhood asthma., Methods: We searched seven databases to include randomized controlled trials (RCTs) of AZI in the treatment of childhood asthma. Four reviewers independently screened the records. Risk of Bias 2 was used to assess the quality of RCTs. Risk ratios with 95% confidence interval (CI) from dichotomous outcomes, and mean difference (MD) with 95% CI from continuous outcomes were pooled., Results: We included 19 eligible reports from 17 studies. The prevalence of exacerbations in AZI + budesonide (BUD) + β 2 agonist (BA) group was lower than BUD + BA group (four [13%] vs. 19 [63%], p < 0.05) in 6- 14 years old children with chronic persistent asthma. AZI plus antiasthma drugs (AADs) could improve the posttreatment childhood asthma control test score (MD = 2.97; 95% CI, 2.39-3.54) compared to AADs alone in children with chronic persistent asthma. AZI plus AADs could improve posttreatment forced expiratory volume in 1 s of predicted value/forced vital capacity % (MD = 10.24%; 95% CI, 6.44%-14.03%) and posttreatment peak expiratory flow % of predicted value (MD = 7.00%; 95% CI, 2.53%-11.47%) compared to AADs alone in children with chronic persistent asthma. The most common adverse reactions of AZI combined with other drugs were gastrointestinal reactions., Conclusions: AZI may be beneficial in improving some clinical symptoms and lung functions in older asthma children (over 6 years old) with persistent asthma. But it still requires further research., (© 2021 Wiley Periodicals LLC.)

Slash pine (Pinus elliottii Engelm.) is an important timber and resin species in the United States, China, Brazil and other countries. Understanding the genetic basis of these traits will accelerate its breeding progress. We carried out a genome-wide association study (GWAS), transcriptome-wide association study (TWAS) and weighted gene co-expression network analysis (WGCNA) for growth, wood quality, and oleoresin traits using 240 unrelated individuals from a Chinese slash pine breeding population. We developed high quality 53,229 single nucleotide polymorphisms (SNPs). Our analysis reveals three main results: (1) the Chinese breeding population can be divided into three genetic groups with a mean inbreeding coefficient of 0.137; (2) 32 SNPs significantly were associated with growth and oleoresin traits, accounting for the phenotypic variance ranging from 12.3% to 21.8% and from 10.6% to 16.7%, respectively; and (3) six genes encoding PeTLP, PeAP2/ERF, PePUP9, PeSLP, PeHSP, and PeOCT1 proteins were identified and validated by quantitative real time polymerase chain reaction for their association with growth and oleoresin traits. These results could be useful for tree breeding and functional studies in advanced slash pine breeding program., Competing Interests: The authors have declared that no competing interests exist.

Background: Carboxylic acid reductases (CARs) represent useful tools for the production of aldehydes from ubiquitous organic carboxylic acids. However, the low catalytic efficiency of these enzymes hampers their application., Methods: Herein, a CAR originating from Mycobacterium smegmatis was redesigned through rational hinge engineering to enhance the catalytic efficiency., Results: Based on the unique domain architecture of CARs and their superfamily, a mutagenesis library of the hinge region was designed. The best mutant R505I/N506K showed a 6.57-fold improved catalytic efficiency. Molecular dynamics simulations showed the increased catalytic efficiency was due to the strong binding of the acyl-AMP complex with it. Meanwhile, the ε-nitrogen atom of Lys610 frequently interacted with the ribose-ring oxygen atom of the complex, the distance (d1) between them represents a great indicator for that. The d1 value was used as a nimble indicator to evaluate unexplored mutants of that region for enhanced activity by in silico mutational experiments. Overall, eight mutants were identified to show higher enhanced activity compared with wild-type enzyme and R505F/N506G showed the highest catalytic efficiency., Conclusion: Altogether, the two-step strategy used here provided useful references for the engineering of CARs and other similar multiple-domain enzymes., (© 2021 Wiley-VCH GmbH.)

Background: The overall survival rate of osteosarcoma (OS) patients has not been improved for 30 years, and the diagnosis and treatment of OS is still a critical issue. To improve OS treatment and prognosis, novel kinds of theranostic modalities are required. Molecular optical imaging and phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), are promising strategies for cancer theranostics that exhibit high imaging sensitivity as well as favorable therapeutic efficacy with minimal side effect. In this study, semiconducting polymer nanoparticles (SPN-PT) for OS-targeted PTT/PDT are designed and prepared, using a semiconducting polymer (PCPDTBT), providing fluorescent emission in the second near-infrared window (NIR-II, 1000 - 1700 nm) and photoacoustic (PA) signal in the first near-infrared window (NIR-I, 650 - 900 nm), served as the photosensitizer, and a polyethylene glycolylated (PEGylated) peptide PT, providing targeting ability to OS., Results: The results showed that SPN-PT nanoparticles significantly accelerated OS-specific cellular uptake and enhanced therapeutic efficiency of PTT and PDT effects in OS cell lines and xenograft mouse models. SPN-PT carried out significant anti-tumor activities against OS both in vitro and in vivo., Conclusions: Peptide-based semiconducting polymer nanoparticles permit efficient NIR-II fluorescence/NIR-I PA dual-modal imaging and targeted PTT/PDT for OS., (© 2022. The Author(s).)

A series of biopsies and reports showed autoimmune diseases might be involved in the process of local inflammation related to spontaneous cervicocranial arterial dissection (SCCAD) occurrence. This retrospective case-control study examined the association between SCCADs and autoimmune diseases in patients and control subjects from 2014 to 2020. SCCAD patients and age/sex-matched control subjects were recruited, and clinical data were collected. SCCAD was confirmed by digital subtraction angiography or high-resolution magnetic resonance imaging. The study included 215 SCCAD patients and 430 control subjects. Totally, 135 (62.8%) of the 215 cases were found SCCAD in the anterior circulation, 26 (12.0%) patients involved multiple vessels. Autoimmune disease occurred in 27 (12.6%) cases with SCCAD and 4 (0.9%) control subjects (p<0.001). A conditional multivariable logistic regression model was used to calculate the odds ratio for SCCAD among patients with a history of autoimmune disease, adjusting for hypertension, diabetes, hyperlipidemia, and smoking. After adjustment, autoimmune diseases were associated with SCCAD (p<0.001). After sub-analysis by a similar modeling strategy, significant associations were still observed in different subgroups, such as female group and male group as well as intramural hematoma (IMH) group and Non-IHM group. The association of SCCAD with autoimmune disease suggested that autoimmune mechanisms may be involved in some etiologies of SCCAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Song, Yang, Yang, Diao, Huang, Wang, Xu and Yang.)

Central poststroke pain (CPSP) is a neuropathic pain syndrome that usually occurs after cerebrovascular accidents. Currently, the pathogenesis of CPSP is not fully understood. Purinergic P2X4 receptor (P2X4R) is implicated in neuropathic pain including CPSP. Herein, we demonstrated that the levels of microRNA-133b-3p (miR-133b-3p), which targets P2X4R transcripts, were significantly downregulated in the ventral posterolateral nucleus of the thalamus (VPL), cerebrospinal fluid (CSF), and plasma of CPSP rats. The expression levels of miR-133b-3p negatively correlated with the severity of allodynia. Genetic knockdown of P2X4R in the VPL protected CPSP rats against allodynia. Similarly, genetic overexpression of miR-133b-3p in the VPL reversed the allodynia established in CPSP rats via downregulation of P2X4R expression. Treatment using gabapentin in CPSP rats significantly restored the decreased miR-133b-3p expression in the VPL, CSF, and plasma and blocked allodynia in CPSP rats. The administration of an miR-133b-3p inhibitor into the VPL abolished the antiallodynic activity of gabapentin. This mechanism was associated with P2X4R expression and involved the endogenous opioid system. Human patients with CPSP showed decreased plasma levels of miR-133b-3p compared with those of control participants. Logistic regression analysis of our patient cohort showed that determining plasma levels of miR-133b-3p may be useful for CPSP diagnosis and treatment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: This study was performed to identify the association between the total magnetic resonance imaging burden of small vessel disease and the occurrence of post-stroke dysphagia in patients with a single recent small subcortical infarct (RSSI)., Methods: We retrospectively identified all patients with a magnetic resonance imaging-confirmed single RSSI. The water-swallowing test and volume-viscosity swallow test were performed within the first 24 h following admission to assess swallowing. Demographic and clinical data were extracted from our stroke database. Based on brain magnetic resonance imaging, we independently rated the presence of cerebral microbleeds, lacunes, white matter hyperintensities and enlarged perivascular spaces. The presence of each small vessel disease feature was summed to determine the total small vessel disease burden, ranging from 0 to 4., Results: In total, 308 patients with a single RSSI were enrolled. Overall, 54 (17.5%) were diagnosed with post-stroke dysphagia. The risk factors related to post-stroke dysphagia included the following: older age, higher National Institute of Health Stroke Scale scores, higher C-reactive protein level and higher fibrinogen level. Based on multiple logistic regression, National Institute of Health Stroke Scale scores and total small vessel disease burden were independent risk factors of post-stroke dysphagia in patients with a single RSSI, after adjusting for age, gender, history of hypertension, C-reactive protein level and fibrinogen level., Conclusions: Dysphagia in patients with a single RSSI was associated with a more severe total small vessel disease burden as reflected by MRI. Total MRI of cerebral small vessel disease burden may predict dysphagia in these patients. Furthermore, more severe total small vessel disease burden was associated with systemic inflammation., (© 2021. The Author(s).)

Choroid thickness measured from optical coherence tomography (OCT) images has emerged as a vital metric in the management of retinal diseases such as high myopia. In this paper, we propose a novel group-wise context selection network (referred to as GCS-Net) to segment the choroid of either normal or high myopia eyes. To deal with the diverse choroid thickness and the variable shape of the pathological retina, GCS-Net adopts the group-wise channel dilation (GCD) module and the group-wise spatial dilation module, which can automatically select group-wise multi-scale information under the guidance of channel attention or spatial attention, and enhance the consistency between the receptive field and the target area. Furthermore, a boundary optimization network with a new edge loss is incorporated to improve the resulting choroid boundary by deep supervision. Experimental results evaluated on a dataset composed of 1650 clinically obtained OCT B-scans show that the proposed GCS-Net can achieve a Dice similarity coefficient of 95.97 ± 0.54%, which outperforms some state-of-the-art segmentation networks., (© 2021 Institute of Physics and Engineering in Medicine.)

Previous studies demonstrated that diabetic stroke patients had a poor prognosis and excess complement system activation in the peripheral blood. In this study, the association of serum complement levels with the prognosis of diabetic stroke was examined. Patients with acute ischemic stroke were recruited and were divided into two groups according to their history of diabetes. Baseline data on the admission, including C3 and C4 were collected. Neurologic function at discharge was the primary outcome and was quantified by the National Institutes of Health Stroke Scale (NIHSS). A total of 426 patients with acute ischemic stroke (116 diabetic strokes and 310 non-diabetic strokes) were recruited in this study. There were significant differences between the two groups in hypertension, coronary disease, triglyceride, high-density lipoprotein cholesterol, fasting blood sugar, C4, and mortality rates. Furthermore, the values of complement protein levels were divided into tertiles. In the diabetic stroke group, serum C4 level at the acute phase in the upper third was independently associated with NIHSS score at discharge and concurrent infection. These associations were not significant in non-diabetic stroke. High serum C4 level at admission, as a unique significant predictor, was associated with unfavorable clinical outcomes in the diabetic stroke, independently of traditional risk factors., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Vitex negundo var. heterophylla (Franch.) Rehder is a common small shrub in northern China. In order to study the fine nectar characteristics and water and soil conservation characteristics of V. negundo , the analysis of chloroplast genome would provide theoretical basis for economic development and germplasm utilization of V. negundo . The chloroplast genome sequence (accession number MW366787) of V. negundo was accepted by high-throughput sequencing technology using a plant from Jiulongshan, Mentougou District, Beijing, China. The total length of the chloroplast genome is 154,438 bp, and the A, T, C and G content of the whole genome is 30.48, 31.26, 19.42, and 18.84%, respectively. The phylogenetic analysis of 16 Verbenaceae plants (including V. negundo ) with Arabidopsis thaliana as the outgroup was carried out by the maximum likelihood method; and the result shows that V. negundo is relatively closed to Vitex rotundifolia ., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

In plants, recent studies have revealed that N6-methyladenosine (m 6 A) methylation of mRNA has potential regulatory functions of this mRNA modification in many biological processes. m 6 A methyltransferase, m 6 A demethylase and m 6 A-binding proteins can cause differential phenotypes, indicating that m 6 A may have critical roles in the plant. In this study, we depicted the m 6 A map of sea buckthorn ( Hippophae rhamnoides Linn.) transcriptome. Similar to A. thaliana , m 6 A sites of sea buckthorn transcriptome is significantly enriched around the stop codon and within 3'-untranslated regions (3'UTR). Gene ontology analysis shows that the m 6 A modification genes are associated with metabolic biosynthesis. In addition, we identified 13,287 different m 6 A peaks (DMPs) between leaf under drought (TR) and control (CK) treatment. It reveals that m 6 A has a high level of conservation and has a positive correlation with mRNA abundance in plants. GO and KEGG enrichment results showed that DMP modification DEGs in TR were particularly associated with ABA biosynthesis. Interestingly, our results showed three m 6 A demethylase ( HrALKBH10B, HrALKBH10C and HrALKBH10D ) genes were significantly increased following drought stress, which indicated that it may contributed the decreased m 6 A levels. This exhaustive m 6 A map provides a basis and resource for the further functional study of mRNA m 6 A modification in abiotic stress.

Background and purpose: Early recognition and management of post-stroke dysphagia (PSD) based on MRI may reduce the incidence of complications. Combining clinical symptoms with applications of MRI, we aimed to identify the risk factors of PSD, develop a prediction scale with high accuracy and map key dysphagia brain areas. Methods: A total of 275 acute ischemic stroke patients were enrolled in this study, and 113 (41.1%) patients were diagnosed with PSD. All patients underwent the water-swallowing test (WST) and volume-viscosity swallow test (V-VST) within first 24 h following admission to assess swallowing. Vascular factors were evaluated and MRI brain scans were obtained within 3 days after symptom onset for each participant admitted to the hospital. T -test, chi-squared test and Fisher's exact test were used to investigate the associations of various patient characteristics with dysphagia, and multivariable logistic regression models were used to construct a prediction scale. Scale accuracy was assessed using receiver operating characteristic (ROC) analysis. We extracted white matter hyperintensities for each patient as potential brain lesions. Voxel-based lesion-symptom mapping (VLSM) was used to identify key brain areas for dysphagia. Results: Risk factors related with PSD were older age, history of atrial fibrillation, higher fasting blood glucose, NIH stroke scale, TOAST classification, progressive stroke, middle cerebral artery lesion and anterior cerebral artery lesion. Three variables with most significant associations, including NIH stroke scale, TOAST classification and progressive stroke, combined with age and gender, were used to construct a dysphagia prediction scale with high accuracy (AUC = 0.86). VLSM identified left inferior parietal gyrus as a key brain region for PSD. Conclusion: Risk factors of PSD were identified and a predictive model of dysphagia was constructed intelligently and automatically. The left inferior parietal gyrus was identified as a key brain area for dysphagia, which provides a new symptom-based treatment target for early rehabilitation in the future., Competing Interests: CL was employed by company Shanghai Zhiyu Software Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Tang, Wang, Ding, Zhu, Zhou, Diao, Kong, Cai, Li, Yao and Fang.)

Background: Cognitive decline (CD) occurs frequently in elderly patients with cerebral small vessel disease (CSVD). In China, elderly patients are more likely to enter healthcare in community hospitals where no magnetic resonance imaging (MRI) is available. This study aimed to explore the screening value of Sylvian fissure ratio (SFR) on CD and compare its gender difference from community-transferred patients. Methods: We performed a single-center, observational study (collected between April 1, 2016, and March 1, 2019) to evaluate the association between Montreal Cognitive Assessment (MoCA) and SFR in 203 eligible community-transferred patients. Baseline characteristics of patients were collected during hospitalization. Multiple linear regression analyses were used to estimate the effect of variables on MoCA, and interactions between select variables were analyzed in different models. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative effect of SFR to severe CD. Results: We identified that a meaningful SFR cutoff of 0.05 had important screening value (likelihood ratio test, p = 0.067) on CD. The ratio had a lower screen value in males when compared to females (adjusted β, -5.54; 95% CI, -8.78 to -2.30 vs. adjusted β, -1.01; 95% CI, -2.84 to 0.82). The gender difference was further verified by ROC curve analysis, in which this discriminative effect was more potent in females (from 0.878 to 0.948) compared to males (from 0.838 to 0.837). Conclusion: An SFR of 0.05 may be more useful to distinguish CD in female patients with CSVD than male patients in whom the syndrome is suspected clinically., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Qin, Ai, Jordan, Guo, Li, Diao, Zhao, Liu, Xue, Wang and Fang.)

Hyaluronan is one of the major components of the neural extracellular matrix (ECM) and provides structural support in physiological conditions. Altered hyaluronan regulation is implicated in the pathogenesis of white matter injury (WMI), such as perinatal WMI, multiple sclerosis (MS), traumatic brain injury (TBI). Early research reported diverse central nervous system (CNS) insults led to accumulated high-molecular-weight (HMW) hyaluronan in hypomyelinating/demyelinating lesions. Furthermore, recent findings have shown an elevated production of hyaluronan fragments in WMI, possibly resulting from HMW hyaluronan degradation. Subsequent in vitro studies identified bioactive hyaluronan fragments with a specific molecular weight (around 2x10 5 Da) regulating oligodendrocyte precursor cells (OPCs) maturation and myelination/remyelination in WMI. However, it is unclear about the effective hyaluronidases in generating bioactive hyaluronan fragments. Several hyaluronidases are proposed recently. Although PH20 is shown to block OPCs maturation by generating bioactive hyaluronan fragments in vitro, it seems unlikely to play a primary role in WMI with negligible expression levels in vivo. The role of other hyaluronidases on OPCs maturation and myelination/remyelination is still unknown. Other than hyaluronidases, CD44 and Toll-like receptors 2 (TLR2) are also implicated in HMW hyaluronan degradation in WMI. Moreover, recent studies elucidated bioactive hyaluronan fragments interact with TLR4, initiating signaling cascades to mediate myelin basic protein (MBP) transcription. Identifying key factors in hyaluronan actions may provide novel therapeutic targets to promote OPCs maturation and myelination/remyelination in WMI., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by the Notch3 gene mutation, has its unique clinical and imaging characteristics. Here we present a Chinese family with a novel mutation on exon 10 of Notch3 gene., Methods: Clinical and MRI data of the three patients in the family during the 7-year follow-up were collected. The CADASIL Scale Score was calculated to evaluate the disease risk of the three patients at their first admission or clinic visit. Five family members underwent genetic test., Results: Genetic test confirmed the diagnosis of CADASIL in this family. A novel mutation of p.C533S on exon 10 of Notch3 gene was detected. The CADASIL score of the proband and her sister was both 17 and that of her brother was 14., Conclusions: Our report not only expands the mutation spectrum of Notch3 gene in CADASIL, but also shows the distinct heterogeneity of CADASIL patients in the same family with the same mutation., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background & Aims: The development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD., Methods: This multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination., Results: A total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0-48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m 2 (IQR 23.8-28.1 kg/m 2 ). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained., Conclusions: The inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD., Lay Summary: The development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease., Competing Interests: Conflicts of interest The authors have declared no conflict of interest related to the study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Somatic variation has been demonstrated in tissue culture regenerated plants of many species. In the genus Populus , phenotypic variation caused by changes in 5-methylcytosine within the plant genome have been reported. To date, the phenotypic and epigenetic stability of plants regenerated from sequential regeneration has not been tested in trees. In this study, we detected DNA methylation of CCGG sites in regenerated plants of five generations in Populus nigra using methylation-sensitive amplified polymorphisms, and evaluated their growth performance and physiological traits. About 10.86-26.80% of CCGG sites in the regenerated plant genome were demethylated and 5.50-8.45% were methylated, resulting in significantly lower DNA methylation levels among all regenerated plants than among donor plants. We detected a significant difference in methylation levels between first regeneration regenerated plants (G1) and those of the other four generations (G2-G5); there were no significant differences among the four later generations. Therefore, the dramatic decrease in DNA methylation levels occurred only in the first and second poplar regenerations; levels then stabilized later in the regeneration process, indicating that two regeneration events were sufficient to change the methylation statuses of almost all CCGG sites sensitive to regeneration. Differences in growth and physiological traits were observed between regenerated plants and donor plants, but were significant only among plants of certain generations. Significant correlations were detected between methylation level and transpiration rate, net photosynthetic rate, peroxidase activity, and instant water utilization efficiency, indicating the involvement of epigenetic regulation in this unpredictable phenotypic variation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Wang, Diao, Zhong, Wu, Wang, Su and Zhang.)

With the availability of high-density single-nucleotide polymorphism (SNP) data and the development of genotype imputation methods, high-density panel-based genomic prediction (GP) has become possible in livestock breeding. It is generally considered that the genomic estimated breeding value (GEBV) accuracy increases with the marker density, while studies have shown that the GEBV accuracy does not increase or even decrease when high-density panels were used. Therefore, in addition to the SNP number, other measurements of 'marker density' seem to have impacts on the GEBV accuracy, and exploring the relationship between the GEBV accuracy and the measurements of 'marker density' based on high-density SNP or whole-genome sequence data is important for the field of GP. In this study, we constructed different SNP panels with certain SNP numbers (e.g., 1 k) by using the physical distance (PhyD), genetic distance (GenD) and random distance (RanD) between SNPs respectively based on the high-density SNP data of a Germany Holstein dairy cattle population. Therefore, there are three different panels at a certain SNP number level. These panels were used to construct GP models to predict fat percentage, milk yield and somatic cell score. Meanwhile, the mean (d¯) and variance (σd2) of the physical distance between SNPs and the mean (r2¯) and variance (σr22) of the genetic distance between SNPs in each panel were used as marker density-related measurements and their influence on the GEBV accuracy was investigated. At the same SNP number level, the d¯ of all panels is basically the same, but the σd2, r2¯ and σr22 are different. Therefore, we only investigated the effects of σd2, r2¯ and σr22 on the GEBV accuracy. The results showed that at a certain SNP number level, the GEBV accuracy was negatively correlated with σd2, but not with r2¯ and σr22. Compared with GenD and RanD, the σd2 of panels constructed by PhyD is smaller. The low and moderate-density panels (< 50 k) constructed by RanD or GenD have large σd2, which is not conducive to genomic prediction. The GEBV accuracy of the low and moderate-density panels constructed by PhyD is 3.8~34.8% higher than that of the low and moderate-density panels constructed by RanD and GenD. Panels with 20-30 k SNPs constructed by PhyD can achieve the same or slightly higher GEBV accuracy than that of high-density SNP panels for all three traits. In summary, the smaller the variation degree of physical distance between adjacent SNPs, the higher the GEBV accuracy. The low and moderate-density panels construct by physical distance are beneficial to genomic prediction, while pruning high-density SNP data based on genetic distance is detrimental to genomic prediction. The results provide suggestions for the development of SNP panels and the research of genome prediction based on whole-genome sequence data.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by β - amyloid (Aβ), neurofibrillary tangles, and neuronal cell death. Aggressive Aβ accumulation accelerates senile plaque formation and perturbs endoplasmic reticulum (ER) function. Aβ accumulation-induced changes stimulate the unfolded protein response (UPR), which can trigger neuronal apoptosis. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), whose activation is stress-dependent, increases the phosphorylation of eukaryotic translation initiation factor-2α (eIF2α). eIF2α promotes the synthesis of β-site APP cleavage enzyme 1 (BACE1), which in turn facilitates Aβ generation and subsequent neuronal apoptosis. In this study, we investigated whether berberine could improve cognitive deficits in the triple-transgenic mouse model of Alzheimer's disease (3 × Tg AD) mice. Our results revealed that berberine treatment may inhibit PERK/eIF2α signaling-mediated BACE1 translation, thus reducing Aβ production and resultant neuronal apoptosis. Further, berberine may have neuroprotective effects, via attenuation of ER stress and oxidative stress. In sum, our study demonstrates the therapeutic potential of berberine for treating AD.

Purpose : Adipose-derived stem cells (ADSCs) are ideal for cell-based therapies to support bone regeneration. It is vital to understand the critical genes and molecular mechanisms involved in the functional regulation of ADSCs for enhancing bone regeneration. In the present study, we investigated the Gremlin 1 (GREM1) effect on ADSCs osteogenic differentiation and senescence. Materials and methods : The in vitro ADSCs osteogenic differentiation potential was evaluated by determining alkaline phosphatase (ALP) activity, mineralization ability, and the expression of osteogenic markers. Cell senescence is determined by SA-β-gal staining, telomerase assay, and the expression of aging markers. Results : GREM1 overexpression in ADSCs reduced ALP activity and mineralization, inhibited the expression of osteogenic related genes OCN, OPN, DSPP, DMP1 , and BSP , and key transcription factors, RUNX2 and OSX . GREM1 knockdown in ADSCs enhanced ALP activity and mineralization, promoted the expression of OCN, OPN, DSPP, DMP1, BSP, RUNX2 , and OSX . GREM1 overexpression in ADSCs reduced the percent SA-β-Gal positive cells, P16 and P53 expressions, and increased telomerase activity. GREM1 knockdown in ADSCs increased the percentage of SA-β-Gal positive cells, P16 and P53 expressions, and reduced telomerase activity. Furthermore, GREM1 reduced the mRNA expression levels of BMP2, BMP6, and BMP7. Conclusions : In summary, our findings suggested that GREM1 inhibited ADSCs senescence and osteogenic differentiation and antagonized BMP transcription.

Objective: To study the effect of bone morphogenetic protein (BMP) antagonist Gremlin 1 (GREM1) on the function of stem cells from apical papilla (SCAPs) and explore its mechanism., Methods: After isolation and culturing of stem cells from apical papilla in vitro , immunofluorescent staining was done to examine the subcellular localization of GREM1 in SCAPs. Transfection with lentiviral GREM 1 shRNA was done to knock-down the GREM 1. The SCAPs were subjected to osteogenic induction in both the GREM 1 knockdown group and the control group, and the knockdown effect of GREM 1 was examined using real time-PCR and Western blot. Two groups of cells were collected and the alkaline phosphatase (ALP) activity was measured 7 d after osteogenic induction. Alizarin red staining was done 3 weeks after osteogenic/odontogenic induction and real time-PCR was done after 0, 1, 2, 3 weeks of osteogenic induction to examine the expression of osteogenic/odontogenic marker genes, including osteocalcin ( OCN ), osteopontin ( OPN ), bone sialoprotein ( BSP ), dentin matrix protein 1 ( DMP 1), dentin sialophosphoprotein ( DSPP ) and and the critical transcription factor osterix ( OSX ), Runt-related transcription factor 2 ( RUNX 2), and distal-less homebox 2 ( DLX 2). Two groups of cells were collected, and CCK-8 and CFSE assay were used to evaluate changes in cell proliferation. In addition, real time-PCR was used to examine the expression of senescence-related genes p 53 and wide-type activated factor 1 ( Waf 1), a regulatory factor of the cell cycle, stemness associated gene krupple-like factor 4 ( KLF 4), and SRY related HMG box-2 ( SOX 2), and the expression of bone morphogenetic protein ( BMP ) 2, 4, 5, 6, 7, 9 after GREM 1 knockdown., Results: Immunofluorescence staining showed that the expression of GREM1 in the nucleus was higher than that in the cytoplasm. Real time-PCR and Western blot affirmed that GREM 1 was knocked down steadily. The ALP activity of the GREM 1 knockdown group was higher than that of the control group ( P <0.05), and the alizarin red staining was lighter than that of the control group. The expression of OCN and DMP 1 increased in the first, second and third week, OPN was increased in the second week, BSP increased in the third week, DSPP increased in the first week, and the difference was statistically significant ( P <0.05). The key osteogenic transcription factors RUNX 2, OSX , and DLX 2 all increased at different stages, and the difference was statistically significant ( P <0.05). CCK-8 and CFSE assay showed that the proliferation ability of the GREM 1 knockdown group decreased ( P <0.05). In the GREM 1 knockdown group, the expression of BMP 2, 6, and 7 increased, the expression of SOX 2 and KLF 4 increased, while the expression of p 53 and Waf 1 decreased ( P <0.05)., Conclusions: The knockdown of GREM 1 enhanced the osteogenic/odontogenic differentiation and stemness of SCAPs and inhibited the proliferation and senescence of SCAPs. Effects of GREM1 on the function of SCAPs maybe achieved through regulating the gene expression of BMP 2, BMP 6, and BMP 7 at the mRNA level., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Background: Women undergoing infertility treatment have poor quality of life. This may cause them to withdraw from or refuse treatment. Women undergoing frozen embryo transfer have a treatment interval. The aim of this study was to investigate the status quo of the fertility quality of life in women undergoing frozen embryo transfer and analyse its predictors., Methods: A cross-sectional survey was conducted from August 2019 to August 2020 among women undergoing frozen embryo transfer in a tertiary hospital reproductive centre in Beijing, China. The survey collected demographic characteristics and treatment data and included the fertility problem inventory, the fertility quality of life scale (FertiQoL) and the state-trait anxiety scale. Multiple linear stepwise regression was used to explore the predictors of fertility quality of life., Results: In total, 1062 women completed the survey. Participants reported that they had high levels of fertility-related stress and anxiety during treatment. They also had lower fertility-related quality of life, and the Treatment FertiQoL scored the lowest. The regression results showed that social concern, trait anxiety, duration of treatment and age were risk factors for diminished fertility quality of life., Conclusion: Chinese women undergoing frozen embryo transfer have relatively poor quality of life. The potential predictors of fertility quality of life include social concern, trait anxiety, duration of treatment and age.

There is strong evidence to suggest that obesity-related proteins play a key role in pathways that are related to breast cancer. In this study, we aimed to establish a robust obesity-related protein score (ORPS) that could be used to assess breast cancer risk. Based on evidence from high-quality systematic reviews and population studies, we selected nine such proteins that are stable in vitro, and measured their circulating concentrations by ELISA in a case-control study conducted in Chengdu, Sichuan, China, with 279 breast cancer cases and 260 healthy controls. Two obesity-related protein scores (ORPS) were calculated using a three-step method, with linear-weighted summation, and the one with a larger area under the curve was chosen for further evaluation. As a result, ORPS (PS 5pre or PS 4post ) was positively correlated with breast cancer risk (premenopausal: OR ≤63 VS >63 3.696, 95% CI 2.025-6.747; postmenopausal: OR ≤38 VS >38 7.100, 95% CI 3.134-16.084), and represented a better risk predictor among obese women compared to non-obese in pre- and postmenopausal women. Among different molecular subtypes, ORPS was positively correlated with Luminal breast cancer, with additionally positive association with triple-negative breast cancer in premenopausal women. The ORPS might be a potential marker of breast cancer risk among Chinese women.

Background: Persimmon (Diospyros kaki Thunb.) has various labile sex types, and studying its sex differentiation can improve breeding efficiency. However, studies on sexual regulation patterns in persimmon have focused mainly on monoecy and dioecy, whereas little research has been published on andromonoecy. In order to reveal the sex differentiation regulation mechanism of andromonoecious persimmon, we performed histological and cytological observations, evaluated OGI and MeGI expression and conducted phytohormones assays and mRNA and small RNA transcriptome analyses of the male and hermaphroditic floral buds of the andromonoecious persimmon 'Longyanyeshi 1'., Results: Stages 2 and 4 were identified as the critical morphological periods for sex differentiation of 'Longyanyeshi 1' by histological and cytological observation. At both stages, OGI was differentially expressed in male and hermaphroditic buds, but MeGI was not. This was different from their expressions in dioecious and monoecious persimmons. Meantime, the results of phytohormones assays showed that high IAA, ABA, GA 3 , and JA levels at stage 2 may have promoted male floral bud differentiation. However, high JA levels at stage 4 and high ZT levels at stages 2 and 4 may have promoted hermaphroditic floral bud differentiation. In these phytohormone biosynthesis and signaling pathways, 52 and 54 differential expression genes (including Aux/IAA, ARFs, DELLA, AHP, A-ARR, B-ARR, CYP735A, CRE1, PP2C, JAZ, MYC2, COI1, CTR1, SIMKK, ACO, and MPK6) were identified, respectively. During the development of male floral buds, five metacaspases genes may have been involved in pistil abortion. In addition, MYB, FAR1, bHLH, WRKY, and MADS transcription factors might play important roles in persimmon floral bud sex differentiation. Noteworthy, miR169v&#95;1, miR169e&#95;3, miR319&#95;1, and miR319 were predicted to contribute to phytohormone biosynthesis and signaling pathways and floral organogenesis and may also regulate floral bud sex differentiation., Conclusion: The present study revealed the differences in morphology and phytohormones content between male and hermaphroditic floral buds of 'Longyanyeshi 1' during the process of sex differentiation, and identified a subset of candidate genes and miRNAs putatively associated with its sex differentiation. These findings can provide a foundation for molecular regulatory mechanism researching on andromonoecious persimmon.