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Imperata cylindrica Beauv.var. major (Nees) C.E.Hubb., commonly known as BaiMaoGen (BMG), a medicinal and edible traditional Chinese medicinal (TCM) herb commonly used in health supplements, has been observed to offer protective effects against gastrointestinal disorders. However, the specific bioactive compounds and their molecular mechanisms have not been fully elucidated. This study employed ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and systematic network pharmacology to analyze and identify the key active components and their interactions with biological targets. Thirty-six main active compounds, including 3,4-dihydroxybenzoic acid and p-hydroxybenzoic acid, were identified and analyzed for their interaction with key protein targets using molecular docking and dynamic simulations. This combined approach highlighted the therapeutic pathways involved, particularly the PI3K/AKT signaling pathways, providing new insights into the molecular basis of BMG's gastroprotective effects. Our findings suggested that BMG's complex multi-target action can potentially be harnessed to develop effective treatments for gastrointestinal toxicity., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Every-other-day fasting (EODF) is a form of caloric restriction that alternates between periods of normal eating and fasting, aimed at preventing and treating diseases. This approach has gained widespread usage in basic research on neurological conditions, including spinal cord injury, and has demonstrated significant neuroprotective effects. Additionally, EODF is noted for its safety and feasibility, suggesting broad potential for application. This study aims to evaluate the therapeutic effects of EODF on spinal cord injury and to investigate and enhance its underlying mechanisms. Initially, the SCI rat model was utilized to evaluate the effects of EODF on pathological injury and motor function. Subsequently, considering the enhancement of metabolism through EODF, bile acid metabolism in SCI rats was analyzed using liquid chromatography-mass spectrometry (LC-MS), and the expression of the bile acid receptor TGR5 was further assessed. Ultimately, it was confirmed that EODF influences the activation of microglia and NLRP3 inflammasomes associated with the TGR5 signaling, along with the expression of downstream pyroptosis pathway related proteins and inflammatory cytokines, as evidenced by the activation of the NLRP3/Caspase-1/GSDMD pyroptosis pathway in SCI rats. The results demonstrated that EODF significantly enhanced the recovery of motor function and reduced pathological damage in SCI rats while controlling weight gain. Notably, EODF promoted the secretion of bile acid metabolites, activated TGR5, and inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway and inflammation in these rats. In summary, EODF could mitigate secondary injury after SCI and foster functional recovery by improving metabolism, activating the TGR5 signaling and inhibiting the NLRP3 pyroptosis pathway., 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. Author Contributions., (Copyright © 2024 Song, Pang, Chen, Wang, Hu, Feng, Wang, Liu and Zhang.)

In our research, we utilized six small-fruited pepper germplasms as materials, selected cotyledons with the petiole and hypocotyls as explants, and conducted in vitro regeneration studies. Our outcomes specify that the most suitable explant is cotyledon with the petiole, and the suitable genotype is HNUCA341. The optimal medium for inducing and elongating adventitious buds for this genotype is Murashige and Skoog medium (MS) + 9.12 μM Zeatin (ZT) + 0.57 μM 3-Indoleacetic acid (IAA), with a bud induction rate of 44.4%. The best rooting induction medium is MS + 1.14 μM IAA, with a rooting rate of 86.7%. Research on the addition of exogenous hormones has revealed that the induction speed of buds in small-fruited pepper (HNUCA341) in the combination of ZT and IAA hormones (abbreviated as ZI) is quicker, and the induction effect is better. The histological observations indicate that ZI treatment accelerates the initiation of explant division and differentiation, causing a shorter duration of vascular-bundle tissue production. The plant hormone signaling pathway was significantly enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, including ARR9 (LOC107843874, LOC107843885), ARR4 (LOC107848380, LOC107862455), AHK4 (LOC107870540), AHP1 (LOC107839518), LAX2 (LOC107846008), SAUR36 (LOC107852624), IAA8 (LOC107841020), IAA16 (LOC107839415), PYL4 (LOC107843441), and PYL6 (LOC107871127); these significantly enriched genes may be associated with in vitro regeneration. In addition, the carbon metabolism pathway and plant mitogen-activated protein kinase (MAPK) signaling pathway are also significantly enriched in KEGG. The results of the Gene Ontology (GO) analysis revealed that differentially expressed genes related to carbon metabolism and fixation, photosynthesis and MAPK signaling pathways were upregulated under ZI treatment. It was found that they might be associated with enhanced regeneration in vitro. Furthermore, we also screened out differentially expressed transcription factors, primarily from the MYB, bHLH, AP2/ERF, and NAC families. Overall, our work accumulated important data for the in-depth analysis of the molecular mechanism of in vitro regeneration of pepper, and provides valuable germplasm for establishing an efficient stable pepper genetic-transformation system based on tissue culture.

Evidence has demonstrated that exoskeleton robots can improve intestinal function in patients with spinal cord injury (SCI). However, the underlying mechanisms remain unelucidated. This study investigated the effects of exoskeleton-assisted walking (EAW) on intestinal function and intestinal flora structure in T2-L1 motor complete paraplegia patients. The results showed that five participants in the EAW group and three in the conventional group reported improvements in at least one bowel management index, including an increased frequency of bowel evacuations, less time spent on bowel management per day, and less external assistance (manual digital stimulation, medication, and enema usage). After 8 weeks of training, the amount of glycerol used in the EAW group decreased significantly ( p < 0.05). The EAW group showed an increasing trend in the neurogenic bowel dysfunction (NBD) score after 8 weeks of training, while the conventional group showed a worsening trend. Patients who received the EAW intervention exhibited a decreased abundance of Bacteroidetes and Verrucomicrobia , while Firmicutes , Proteobacteria , and Actinobacteria were upregulated. In addition, there were decreases in the abundances of Bacteroides , Prevotella , Parabacteroides , Akkermansia , Blautia , Ruminococcus 2 , and Megamonas . In contrast, Ruminococcus 1 , Ruminococcaceae UCG002 , Faecalibacterium , Dialister , Ralstonia , Escherichia-Shigella , and Bifidobacterium showed upregulation among the top 15 genera. The abundance of Ralstonia was significantly higher in the EAW group than in the conventional group, and Dialister increased significantly in EAW individuals at 8 weeks. This study suggests that EAW can improve intestinal function of SCI patients in a limited way, and may be associated with changes in the abundance of intestinal flora, especially an increase in beneficial bacteria. In the future, we need to further understand the changes in microbial groups caused by EAW training and all related impact mechanisms, especially intestinal flora metabolites. Clinical trial registration : https://www.chictr.org.cn/., 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 © 2024 Hu, Feng, Lu, Pang, Zhang, Liu, Gou, Bai, Wang, Chang, Yin, Wang, Xiao, Wang, Cheng, Chang and Wang.)

Introduction: The ancient ivories unearthed from the Sanxingdui Ruins site are valuable cultural relics, however, the microbial biodeterioration on ivories during temporary cold storage poses a great threat to their later long-term preservation., Methods: Here, the combination of high-throughput sequencing and biochemical assays was applied for the in-depth investigation of the key deteriorative microorganisms colonizing on the ivories and the tracing of their origin, as well as the assessment of the ethanol disinfection impact on the microbial communities on ivories., Results: It was observed that the surfaces of ivories were scattered by the fungal patches of white, dark grey, and hedge green colors during cold storage. The high-throughput sequencing results showed that the genera Mortierella (38.51%), Ilyonectria (14.43%), Penicillium (1.15%), and Aspergillus (1.09%) were the dominant fungi, while Pseudomonas (22.63%), Sphingopyxis (3.06%), and Perlucidibaca (2.92%) were the dominant bacteria on ivories. The isolated Aspergillus A-2 resulted in the highest amount of calcium releasing from the degradation of hydroxyapatite (HAP), the main component of ivory, by the organic acids produced, including oxalic acid and citric acid. The fast expectation-maximization for microbial source tracking (FEAST) analysis revealed that the majority of the fungi (57.45%) and bacteria (71.84%) colonizing on the ivories were derived from the soils surrounding ivories in the sacrifice pits, indicating soils as the primary source for the spoilage microbes growing on ivories. The dominant strains could degrade cellulose, the key components of wet cotton towels commonly applied on ivories for moisture maintenance, aiding the spoilage microbes colonizing on ivories. Notably, the ivory disinfection with 75% ethanol during the cleansing significantly decreased the relative abundance of the dominant genera of Ilyonectria , Aspergillus , and Pseudomonas , with Mortierella becoming the dominant one on ivories., Discussion: Together, the fungi, particularly Aspergillus and Penicillium , played a significant role in the microbial biodeterioration of unearthed ancient ivories by producing the organic acids. These results may improve the control of the microbial biodeterioration and develop more efficient strategies for the long-time conservation of unearthed ancient ivories and other cultural relics., 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 © 2024 Lao, Zhou, Wu, Wang, Wu, Lv, Liu, Xie, Dinnyés, Yuan, Tan and Sun.)

The development of probiotics capable of quickly colonizing the intestines of animals is important in promoting the healthy growth of livestock. The aim of this study was to screen lactic acid bacteria (LAB) from the intestinal microbiota of chickens with potential applications, and to evaluate their probiotic properties and antagonistic abilities against Salmonella pullorum , Staphylococcus aureus , and Escherichia coli . The results showed that a total of 79 strains with the characteristics of LAB were isolated from the chicken cecum microbiota, of which 7 strains exhibited strong inhibitory activity against S . pullorum , S. aureus , and E. coli . Performing 16s rDNA sequencing revealed that these seven strains were Lactiplantibacillus pentosus ( n = 1), Lactiplantibacillus plantarum ( n = 3), Lactiplantibacillus paraplantarum ( n = 1), Lactiplantibacillus argentoratensis ( n = 1), and Lactiplantibacillus fabifermentans ( n = 1). Among them, L. pentosus R26 and L. plantarum R32 exhibited superior antibacterial activity. These two strains demonstrated high lactic acid production ability, with survival rates of 86.29% and 87.99% after 3 h of treatment at pH 1.5, 86.66% and 85.52% after 3 h of treatment with 0.5% bile salts, 90.03% and 88.16% after 2 h of treatment with simulated gastric fluid, and 98.92% and 98.22% after 2 h of treatment with simulated intestinal fluid, respectively. Co-cultivation with L. pentosus R26 for 24 h resulted in 50% of the pathogens being antagonized, while almost complete inhibition was observed following 72 h of co-cultivation. In conclusion, L. pentosus R26 and L. plantarum R32 exhibited high antibacterial activity and acid production capability, while also demonstrating satisfactory tolerance to low pH values and high concentrations of bile salts and digestive fluid. The probiotic characteristics and stress resistance of L. pentosus R26 were slightly superior to those of L. plantarum R32, indicating its potential for development as a probiotic.

Objective: This study aimed to assess the impact of a hydroethanolic extract of walnut green husks (WGH) on rumen fermentation and the diversity of bacteria, methanogenic archaea, and fungi in sheep fed a high-concentrate diet., Methods: Five healthy small-tailed Han ewes with permanent rumen fistula were selected and housed in individual pens. This study adopted a self-controlled and crossover design with a control period and an experimental period. During the control period, the animals were fed a basal diet (with a ratio of concentrate to roughage of 65:35), while during the treatment period, the animals were fed the basal diet supplemented with 0.5% hydroethanolic extract of WGH. Fermentation parameters, digestive enzyme activities, and microbial diversity in rumen fluid were analyzed., Results: Supplementation of hydroethanolic extract of WGH had no significant effect on feed intake, concentrations of total volatile fatty acids, isovalerate, ammonia nitrogen, and microbial protein (p>0.05). However, the ruminal pH, concentrations of acetate, butyrate and isobutyrate, the ratio of acetate to propionate, protozoa count, and the activities of filter paper cellulase and cellobiase were significantly increased (p<0.05), while concentrations of propionate and valerate were significantly decreased (p<0.05). Moreover, 16S rRNA gene sequencing revealed that the relative abundance of rumen bacteria Christensenellaceae R7 group, Saccharofermentans, and Ruminococcaceae NK4A214 group were significantly increased, while Ruminococcus gauvreauii group, Prevotella 7 were significantly decreased (p<0.05). The relative abundance of the fungus Pseudomonas significantly increased, while Basidiomycota, Fusarium, and Alternaria significantly decreased (p<0.05). However, there was no significant change in the community structure of methanogenic archaea., Conclusion: Supplementation of hydroethanolic extract of WGH to a high-concentrate diet improved the ruminal fermentation, altered the structure of ruminal bacterial and fungal communities, and exhibited beneficial effects in alleviating subacute rumen acidosis of sheep.

Key Message: Exogenous SL positively regulates pepper DS by altering the root morphology, photosynthetic character, antioxidant enzyme activity, stomatal behavior, and SL-related gene expression. Drought stress (DS) has always been a problem for the growth and development of crops, causing significant negative impacts on crop productivity. Strigolactone (SL) is a newly discovered class of plant hormones that are involved in plants' growth and development and environmental stresses. However, the role of SL in response to DS in pepper remains unknown. DS considerably hindered photosynthetic pigments content, damaged root architecture system, and altered antioxidant machinery. In contrast, SL application significantly restored pigment concentration modified root architecture system, and increased relative chlorophyll content (SPAD). Additionally, SL treatment reduced oxidative damage by reducing hydrogen peroxide (H 2 O 2 ) (24-57%) and malondialdehyde (MDA) (79-89%) accumulation in pepper seedlings. SL-pretreated pepper seedlings showed significant improvement in antioxidant enzyme activity, proline accumulation, and soluble sugar content. Furthermore, SL-related genes (CcSMAX2, CcSMXL6, and CcSMXL3) were down-regulated under DS. These findings suggest that the foliar application of SL can alleviate the adverse effects of drought tolerance by up-regulating chlorophyll content and activating antioxidant defense mechanisms., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is extensively validated in Otof-deficient mice. However, the clinical safety and efficacy of AAV-OTOF is not reported. Here, AAV-OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non-human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV-OTOF is delivered into one cochlea of a 5-year-old deaf patient and into the bilateral cochleae of an 8-year-old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure-tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5-year-old patient can be restored to the normal range at 1 month after AAV-OTOF injection, while the 8-year-old patient can hear the conversational sounds. Most importantly, the 5-year-old patient can hear and recognize speech only through the AAV-OTOF-injected ear. This study is the first to demonstrate the safety and efficacy of AAV-OTOF in patients, expands and optimizes current OTOF-related gene therapy and provides valuable information for further application of gene therapies for deafness., (© 2024 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Alzheimer's disease (AD) is a prevalent neurodegenerative disease that has become one of the main factors affecting human health. It has serious impacts on individuals, families, and society. With the development of population aging, the incidence of AD will further increase worldwide. Emerging evidence suggests that many physiological metabolic processes, such as lipid metabolism, are implicated in the pathogenesis of AD. Bile acids, as the main undertakers of lipid metabolism, play an important role in the occurrence and development of Alzheimer's disease. Tauroursodeoxycholic acid, an endogenous bile acid, has been proven to possess therapeutic effects in different neurodegenerative diseases, including Alzheimer's disease. This review tries to find the relationship between bile acid metabolism and AD, as well as explore the therapeutic potential of bile acid taurocursodeoxycholic acid for this disease. The potential mechanisms of taurocursodeoxycholic acid may include reducing the deposition of Amyloid-β protein, regulating apoptotic pathways, preventing tau hyperphosphorylation and aggregation, protecting neuronal synapses, exhibiting anti-inflammatory properties, and improving metabolic disorders. The objective of this study is to shed light on the use of tauroursodeoxycholic acid preparations in the prevention and treatment of AD, with the aim of identifying effective treatment targets and clarifying various treatment mechanisms involved in this disease., 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 © 2024 Song, Liu, Wang, Hu, Li, Zhu, Pang and Zhang.)

In this study, 14 structurally novel gefitinib-1,2,3-triazole derivatives were synthesized using a click chemistry approach and characterized by 1 H NMR, 13 C NMR and high-resolution mass spectrometry (HRMS). Preliminary cell counting kit-8 results showed that most of the compounds exhibit excellent antitumor activity against epidermal growth factor receptor wild-type lung cancer cells NCI-H1299, A549 and NCI-H1437. Among them, 4b and 4c showed the most prominent inhibitory effects. The half maximal inhibitory concentration (IC 50 ) values of 4b were 4.42 ± 0.24 μM (NCI-H1299), 3.94 ± 0.01 μM (A549) and 1.56 ± 0.06 μM (NCI-1437). The IC 50 values of 4c were 4.60 ± 0.18 µM (NCI-H1299), 4.00 ± 0.08 μM (A549) and 3.51 ± 0.05 μM (NCI-H1437). Furthermore, our results showed that 4b and 4c could effectively inhibit proliferation, colony formation and cell migration in a concentration-dependent manner, as well as induce apoptosis in H1299 cells. In addition, 4b and 4c exerted its anti-tumor effects by inducing cell apoptosis, upregulating the expression of cleaved-caspase 3 and cleaved-PARP and downregulating the protein levels of Bcl-2. Based on these results, it is suggested that 4b and 4c be developed as potential new drugs for lung cancer treatment.

Objective: Emerging evidence suggests the biological implications of N6-methyladenosine (m6A) in carcinogenesis. Herein, we systematically analyzed the role of m6A modification in renal cell carcinoma (RCC) progression., Methods: Based on 23 m6A regulators, unsupervised clustering analyses were conducted to determine m6A modification subtypes across 893 RCC specimens in the Cancer Genome Atlas (TCGA) cohort. By performing principal component analysis (PCA) analysis, m6A scoring system was developed for evaluating m6A modification patterns of individual RCC patients. The activity of signaling pathways was assessed by gene-set variation analysis (GSVA) algorithm. The single-sample gene set enrichment analysis (ssGSEA) algorithm was applied for quantifying the infiltration levels of immune cells and the activity of cancer immunity cycle. Drug responses were estimated by genomics of drug sensitivity in cancer (GDSC), the Cancer Therapeutics Response Portal (CTRP) and Preservice Research Institute for Science and Mathematics (PRISM) database., Results: Five m6A modification subtypes were characterized by different survival outcomes, oxidative stress, cancer stemness, infiltrations of immune cells, activity of cancer immunity cycle, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression and microsatellite instability (MSI) levels. According to m6A score, RCC patients were categorized into high and low m6A score groups. Patients with high m6A score displayed a prominent survival advantage, and the prognostic value of m6A score was confirmed in two anti-PD-1/PD-L1 immunotherapy cohorts. m6A score was significantly linked to oxidative stress-related genes, and high m6A score indicated the higher sensitivity to axitinib, pazopanib and sorafenib and the lower sensitivity to sunitinib., Conclusion: This study analyzed the extensive regulatory mechanisms of m6A modification on oxidative stress, the tumor microenvironment, and immunity. Quantifying m6A scores may enhance immunotherapeutic effects and assist in developing more effective agents., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Published by IMR Press.)

OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof-related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell-specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual-AAV-OTOF-hybrid strategy to transfer full-length OTOF is generated, which can stably restore hearing in adult OTOF p.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild-type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: In recent years, lower limb walking exoskeletons have been widely used in the study of spinal cord injury (SCI)., Objective: To explore the effect of a lower limb walking exoskeleton on quality of life and functional independence in patients with motor complete SCI., Methods: This was a multi-center, single blind, randomized controlled trial. A total of 16 SCI patients were randomly assigned to either the exoskeleton-assisted walking (EAW) group (n= 8) or the conventional group (n= 8). Both groups received conventional rehabilitation training, including aerobic exercise and strength training. The EAW group additionally conducted the exoskeleton-assisted walking training using an AIDER powered robotic exoskeleton for 40-50 minutes, 5 times/week for 8 weeks. World Health Organization quality of life-BREF (WHOQOL-BREF) and the Spinal Cord Independence Measure III (SCIM-III) were used for assessment before and after training., Results: There was an increasing tendency of scores in the psychological health, physical health, and social relationships domain of WHOQOL-BREF in the EAW group after the intervention compared with the pre-intervention period, but there was no significant difference (P> 0.05). SCIM-III scores increased in both groups compared to pre-training, with only the conventional group showing a significant difference after 8 weeks of training (P< 0.05)., Conclusion: A lower limb walking exoskeleton may have potential benefits for quality of life and activities of daily living in patients with motor complete SCI.

Walnut green husks (WGHs), by-products of walnut production, are believed to possess antimicrobial properties, making them a potential alternative to antibiotics. In this study, the antibacterial activities of three extracts, derived from WGH, against Staphylococcus aureus , Bacillus subtilis , and Escherichia coli were investigated, and the antibacterial mechanisms of an anhydrous ethanol extract of WGH (WGHa) were examined. The results showed that WGHa exhibited inhibitory effects on all tested bacteria. The ultrahigh-performance liquid chromatography-tandem mass spectrometry analysis revealed that the major active compounds present in WGHa were terpenoids, phenols, and flavonoids. Treatment with WGHa resulted in the leakage of intracellular ions and alkaline phosphatase; a reduction in intracellular ATP content, ATPase activity, and nucleic acid content; as well as cellular metabolic viability. The transmission electron microscopy images showed varying degrees of cell deformation and membrane damage following WGHa treatment. The transcriptome sequencing and differentially expressed gene enrichment analyses revealed an up-regulation in pathways associated with RNA degradation, translation, protein export, and oxidative phosphorylation. Conversely, pathways involved in cell movement and localization, as well as cell wall organization and carbohydrate transport, were found to be down-regulated. These findings suggest that WGHa alters cell membrane permeability and causes damage to the cell wall. Additionally, WGHa interferes with cellular energy metabolism, compromises RNA integrity, and induces DNA replication stress, consequently inhibiting the normal growth and proliferation of bacteria. These findings unveiled the antimicrobial mechanisms of WGHa, highlighting its potential application as an antibiotic alternative.

Endovascular embolization using microcoils can be an effective technique to treat artery aneurysms. However, microcoils with fixed designs are difficult to adapt to all aneurysm types. In this paper, a photocurable ultratough shape memory organogel with a curing time of only 2 s and megapascal-level mechanical properties is proposed. Then, it is used to manufacture the personalized 4D microcoil with a wire diameter of only 0.3 mm. The improved mechanical modulus (511.63 MPa) can reduce the possibility of microcoils' fracture during embolization. Besides, the fast body-temperature-triggering shape memory ability makes the 4D microcoil applicable in vivo. These 4D microcoils are finally delivered into the rabbit, and successfully blocked the blood flow inside different aneurysms, with neoendothelial cells and collagen fibers growing on the microcoil surface snugly, indicating full aneurysm recovery. This 4D organogel microcoil can potentially be used in personalized clinical translation on human beings., (© 2023 Wiley-VCH GmbH.)

Objective: To explore the gender differences of the association between sensory impairment (SI) and the risk of cognitive decline and possible cognitive impairment, no dementia (CIND)., Method: Data were drawn from three waves of the nationally representative survey of China Longitudinal Healthy Longevity Survey (CLHLS) between 2011/12-2018 surveys, involving 6138 participants aged 65 or older who had no CIND at the baseline. Multivariate linear or logistic regression models were employed to examine the effect of SI on cognitive decline and CIND risk by gender stratification, respectively., Results: Hearing impairment and visual impairment were associated with lower MMSE scores, and the strength of the association was stronger in men than in women. Hearing impairment was related to an elevated risk of CIND both in men and women (Men: OR=2.46; 95% CI=1.81, 3.35; Women: OR=1.43; 95% CI=1.09, 1.88). However, the effect of visual impairment on CIND was statistically significant only in men (OR=1.43; 95% CI=1.09, 1.88). The risk of cognitive decline and CIND were significantly higher with single and dual SI than those without SI, except for women with single visual impairment., Conclusion: SI is independently associated with cognitive decline and CIND risk, and the association differed by gender. Further researches should clarify the mechanism between SI and cognitive function among older adults, especially for gender differences., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A novel ratiometric electrochemical aptasensor was proposed for carcinoembryonic antigen (CEA) detection based on exonuclease III (Exo III)-assisted recycling and rolling circle amplification (RCA) strategies. A thiolated ferrocene-labeled hairpin probe 2 (Fc-HP2) was fixed on the gold nanoparticles (AuNPs)-modified gold electrode (AuE) surface through Au-S bonds. The presence of CEA led to the release of trigger, which hybridized with the 3'-protruding of hairpin probe 1 (HP1) and triggered the Exo III cleavage reaction, accompanied by the releasing of trigger and generation of new DNA fragment which was used for the successive hybridization with Fc-HP2. After the Exo III cleavage process, the remaining Fc-HP2 fragments hybridized as primers with the RCA template to initiate the RCA process, and long single-stranded polynucleotides were produced for methylene blue (MB) binding. Such changes resulted in the signal of Fc (I Fc ) decreased and that of MB (I MB ) increased, achieving a linear relationship between I MB /I Fc and logarithm of CEA concentrations ranging from 1.0 pg mL -1 to 100.0 ng mL -1 with a detection limit of 0.59 pg mL -1 . Additionally, the developed aptasensor had been successfully applied to detect CEA in human serum samples. Therefore, the proposed strategy might provide a new platform for clinical detections of CEA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Lung adenocarcinoma (LUAD) is an aggressive malignancy with a poor prognosis. In this study, we explored the critical role and mechanism of circ&#95;0010235 in the pathogenesis of LUAD. The expression levels of circ&#95;0010235, microRNA (miR)-1249-3p, and homeobox A13 (HOXA13) were gauged by quantitative real-time PCR (qRT-PCR) and Western blot. Cell proliferation, cycle progression, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-Deoxyuridine (Edu), flow cytometry, and transwell assays, respectively. The direct relationship between miR-1249-3p and circ&#95;0010235 or HOXA13 was validated by dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays. Xenograft experiments were used to examine the role of circ&#95;0010235 in vivo. Circ&#95;0010235 was significantly overexpressed in human LUAD. Silencing of circ&#95;0010235 hindered LUAD cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, as well as diminished tumor growth in vivo. Mechanistically, circ&#95;0010235 targeted and inhibited miR-1249-3p. Moreover, circ&#95;0010235 depletion repressed cell malignant behaviors by upregulating miR-1249-3p. HOXA13 was identified as a direct and functional target of miR-1249-3p. Furthermore, circ&#95;0010235 regulated HOXA13 expression by competing for shared miR-1249-3p. Our findings demonstrate that the circ&#95;0010235/miR-1249-3p/HOXA13 axis is implicated in the pathogenesis of LUAD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study is to investigate the changes of lymphocyte subsets and the gut microbiota in Chinese Han patients with spinal cord injury (SCI). We enrolled 23 patients with SCI and 21 healthy controls. Blood and fecal samples were collected. The proportion of lymphocyte subsets was detected by flow cytometry. 16S rDNA sequencing of the V4 region was used to analyze the gut microbiota. The changes of the gut microbiota were analyzed by bioinformatics. Correlation analysis between gut microbiota and lymphocyte subsets was performed. CD4 + cells, CD4 + /CD8 + ratio and CD4 + CD8 + cells in peripheral blood of SCI patients were significantly lower than those of the control group ( P < 0.05). There was no significant difference in B cells and CIK cells between the SCI group and the control group. The gut microbiota community diversity index of SCI patients was significantly higher than that of healthy controls. In SCI patients, the relative abundance of Lachnospiraceae (related to lymphocyte subset regulation), Ruminococcaceae (closely related to central nervous system diseases), and Escherichia-Shigella (closely related to intestinal infections) increased significantly, while the butyrate producing bacteria (Fusobacterium) that were beneficial to the gut were dramatically decreased. Correlation analysis showed that the five bacterial genera of SCI patients, including Lachnospiraceae UCG-008, Lachnoclostridium 12, Tyzzerella 3, Eubacterium eligens group, and Rumencocciucg-002, were correlated with T lymphocyte subsets and NK cells. In the SCI group, the flora Prevotella 9, Lachnospiraceae NC2004 group, Veillonella, and Sutterella were positively correlated with B cells. However, Fusobacterium and Akkermansia were negatively correlated with B cells. Moreover, Roseburia and Ruminococcaceae UCG-003 were positively correlated with CIK cells. Our results suggest that the gut microbiota of patients with SCI is associated with lymphocyte subsets. Therefore, it is possible to improve immune dysregulation in SCI patients by modulating gut microbiota, which may serve as a new therapeutic method for SCI., 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 Pang, Wang, Xiong, Liu, Ma, Gou, He, Cheng, Wang, Zheng, Sun, Bai, Bai and Zhang.)

During mammalian brain development, how different astrocytes are specified from progenitor cells is not well understood. In particular, whether astrocyte progenitor cells (APCs) start as a relatively homogenous population or whether there is early heterogeneity remains unclear. Here, we have dissected subpopulations of embryonic mouse forebrain progenitors using single-cell transcriptome analyses. Our sequencing data revealed two molecularly distinct APC subgroups at the start of gliogenesis from both dorsal and ventral forebrains. The two APC subgroups were marked, respectively, by specific expression of Sparc and Sparcl1, which are known to function in mature astrocytes with opposing activities for regulating synapse formation. Expression analyses showed that SPARC and SPARCL1 mark APC subgroups that display distinct temporal and spatial patterns, correlating with major waves of astrogliogenesis during development. Our results uncover an early molecular divergence of APCs in the mammalian brain and provide a useful transcriptome resource for the study of glial cell specification., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Objectives: Spinal cord injury (SCI) is a disastrous central nervous system (CNS) disorder, which was intimately associated with oxidative stress. Studies have confirmed that Iridoids Effective Fraction of Valeriana jatamansi Jones (IEFV) can scavenge reactive oxygen species. This study aimed to confirm the efficacy of IEFV in ameliorating SCI., Methods: For establish the SCI model, the Sprague-Dawley rats underwent a T10 laminectomy with transient violent oppression by aneurysm clip. Then, the rats received IEFV intragastrically for 8 consecutive weeks to evaluate the protective effect of IEFV on motor function, oxidative stress, inflammation and neurotrophic factors in SCI rats., Results: Basso, Beattie and Bresnahan scores, hematoxylin and eosin (H&E) staining and transmission electron microscopy experiments found IEFV protected motor function and alleviated neuron damage. Meanwhile, IEFV treatment decreased the release of malondialdehyde, interleukin-6 (IL-6), cyclooxygenase-2 and tumor necrosis factor-α. Moreover, IEFV treatment elevated the expression levels of brain-derived neurotrophic factor and nerve growth factor of SCI rats. Finally, administration of IEFV significantly inhibited the expression of p-p65 and toll-like receptor 4 (TLR4)., Conclusions: This study suggests that IEFV could attenuate the oxidative stress and inflammatory response of the spinal cord after SCI, which was associated with inhibition of the TLR4/nuclear factor-kappaB signaling pathway., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

This study investigated the effects of bioactive peptides derived from solid-state fermentation of cottonseed meal on the growth performance, apparent dietary digestibility, serum biochemical parameters, protein metabolism, antioxidant activity, and immunity in yellow-feathered broilers. A total of two hundred forty 21-days-old male broilers were randomly divided into four groups with six replicates per group. The control group received a basal diet and three experimental groups were fed diets with 1%, 2%, and 3% cottonseed meal bioactive peptides (CSBP) replacing equivalent protein of cottonseed meal in basic diet. Dietary supplementation of 2% and 3% CSBP increased the average daily weight gain, crude protein digestibility, total serum protein, and immunoglobulin (Ig) G contents in serum (P < 0.05). The 3% CSBP increased albumin, total antioxidant capacity, spleen weight/bodyweight, interleukin-6, and IgM, while reducing the feed to gain ratio, total cholesterol, urea nitrogen, total superoxide dismutase, glutathione peroxidase, and malondialdehyde contents in serum (P < 0.05). The 2% CSBP diet increased PepT1 expression in duodenum, jejunum, and ileum (P < 0.05). The 1%, 2%, and 3% CSBP diets increased S6kinase-polypeptide-1 and inositol-3-hydroxylase expression in chest and leg muscles (P < 0.05). The CSBP addition in diets can improve growth performance, nutrient digestibility, protein metabolism, antioxidant, and immune capabilities of yellow-feathered broilers., (© 2022 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.)

Abstract: Every-other-day fasting is effective for a variety of major human diseases, but the safety of these interventions is uncertain for patients with spinal cord injury. A randomized controlled study was conducted to investigate the safety of every-other-day fasting in patients with spinal cord injury. Participants who met the diagnostic inclusion and exclusion criteria were randomly divided into the control and every-other-day fasting groups. In the every-other-day fasting group, fasting lasted from 09:00 p.m. on day 1 to 06:00 p.m. on the following day (day 2). Dinner on day 2 was restricted to approximately 30% of the average daily calorie intake. The changes in plasma glucose were recorded daily for 2 days and every other day from the third day after every-other-day fasting intervention. The changes in albumin, prealbumin, plasma potassium, serum sodium, blood calcium, body weight, and body mass index were monitored at the baseline and at the end of the every-other-day fasting intervention. The results showed that compared with the control group, the mean blood glucose levels were significantly decreased from the second week after every-other-day fasting intervention. The body weight of patients in the every-other-day fasting group was notably reduced compared with that at baseline, whereas in body mass index, no obvious differences were observed before and after treatment with every-other-day fasting. In general, every-other-day fasting could be considered as a safe approach for individuals with spinal cord injury., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Proton radiation (PR) and microgravity (μ G ) are two key factors that impact living things in space. This study aimed to explore the combined effects of PR and simulated μ G (Sμ G ) on bone function. Mouse embryo osteoblast precursor cells (MC3T3-E1) were irradiated with proton beams and immediately treated with Sμ G for 2 days using a three-dimensional clinostat. All samples were subjected to cell viability, alkaline phosphatase (ALP) activity and transcriptome assays. The results showed that cell viability decreased with increasing doses of PR. The peak ALP activity after PR or Sμ G alone was lower than that obtained with the non-treatment control. No difference in cell viability or ALP activity was found between 1 Gy PR combined with Sμ G (PR-Sμ G ) and PR alone. However, 4 Gy PR-Sμ G resulted in decreased cell viability and ALP activity compared with those obtained with PR alone. Furthermore, Gene Ontology analysis revealed the same trend. These results revealed that PR-Sμ G may lead to reductions in the proliferation and differentiation capacities of cells in a dose-dependent manner. Our data provide new insights into bone-related hazards caused by multiple factors, such as PR and μ G , in the space environment., 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 Ma, Kong, Gong, Wang, Liu and Sui.)

Long noncoding RNAs (lncRNAs) are involved in the progression of various cancers, including hepatocellular carcinoma (HCC). However, the biological functions of lncRNA small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) and the underlying mechanisms remain unclear. In this study, we revealed that SUMO1P3 expression was enhanced in HCC tissues and cell lines, positively associating with tumor size and number, poor differentiation, lymphatic and distant metastasis, TNM stage, and poor prognosis in HCC patients. In vitro assays showed that SUMO1P3 depletion reduced HCC cell viability and proliferation by hindering cyclin D1 expression and Akt phosphorylation. SUMO1P3 knockdown induced HCC cell apoptosis, as indicated by increased Bax and cleaved caspase-3 expression and the decreased Bcl-2 level. SUMO1P3 silencing suppressed HCC cell migration and invasion by increasing epithelial marker E-cadherin expression and decreasing mesenchymal marker vimentin expression, as well as reducing matrix metalloproteinase (MMP)-2 and MMP-9 levels. Consistently, SUMO1P3 depletion in HCC cells retarded tumor growth and lung metastasis in vivo . Overall, these results supported the applicability of SUMO1P3 as a useful predictor of HCC prognosis and a potential therapeutic target for HCC patients.

Objective: To explore the effects of off-pump coronary artery bypass grafting (OPC) on clinical efficacy, cardiac function and the occurrence of major adverse cardiovascular events (MACE) in patients with coronary heart disease., Methods: According to different surgical methods, 93 patients with coronary heart disease who were hospitalized and treated in our hospital were collapsed into the off-pump coronary artery bypass grafting group (OPC group) and the extracorporeal circulation coronary artery bypass grafting group (PC group). The perioperative indexes, cardiac function indexes, postoperative recovery, quality of life, the incidence of MACE and adverse reactions and the survival rate of patients in PC group and OPC group were analyzed and compared., Results: Compared with the PC group, the operation time and blood transfusion volume of OPC group were both largely decreased (P<0.05), but the number of bypass grafts was similar (P>0.05). The cardiac function index of OPC group was much higher than that of PC group (P<0.05). The postoperative recovery after operation of OPC group was better than that of PC group (P<0.05). The scores of quality of life scale in OPC group were markedly higher than those in PC group (P<0.05). The incidence of MACE in OPC group was obviously lower than that in PC group (P<0.05). Patients in in the OPC group had slightly lower incidence of adverse reactions, and slightly higher survival rate than the PC group, but there was no statistical difference (P>0.05)., Conclusion: Compared with PC, OPC has a significantly better therapeutic effect on patients with coronary heart disease, which can significantly improve the perioperative indices and cardiac function, and enhance the quality of life of patients., Competing Interests: None., (AJTR Copyright © 2021.)

Background: Patients with breast cancer often experience severe psychological distress, especially anxiety and depression, leading to poorer quality of life, shortened survival time and increased mortality.The objective of the review will be to summarise data on the prevalence and risk factors of anxiety and depression in patients with breast cancer., Methods and Analysis: Two reviewers will be applied in seven databases, including Web of Science, PubMed, EMBASE, Wan Fang Data Knowledge Service Platform, Chinese Biomedical Literature Database, Chinese Scientific Journal Database (VIP database), China National Knowledge Infrastructure and for studies on the prevalence and risk factors of depression in patients with breast cancer, which should be published from inception to Feb 2020 in English, Chinese, French and Spanish. The selection of studies, data extraction and risk of bias assessment will be done independently by two reviewers. Data synthesis will be carried out using RevMan V.5.3 software. The heterogeneity will be determined by the I² test. Publication bias will be evaluated by generating a funnel plot and performing the Begg and Egger test. The quality of the systematic review will be assessed using the Grading of Recommendations Assessment, Development and Evaluation Tool criteria., Ethics and Dissemination: No ethical approval is required. This protocol will not involve individual patient information and endangering participant rights. The results will be reported in a peer-reviewed journal or disseminated in relevant conferences., Osf Registration Number: DOI 10.17605/OSF.IO/D6A4P., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The occurrence of aortic dissection is related to the proliferation and metastasis of vascular smooth muscle cells. In our present study, we found that the expression of miR-140-5p was inhibited in the wall of abdominal aorta of aortic dissection patients. However, the mechanism of miR-140-5p in the development of aortic dissection is unclear., Material and Methods: We detected the expression of miR-140-5p and NCK Associated Protein 1 (NCKAP1) in blood vessel of aortic dissection patients and normal people by PCR. Next, we established the miR-140-5p overexpression and miR-140-5p inhibition vascular smooth muscle cells (CRL-1999 cells). The BrdU assays, wound healing assays and transwell assays were performed to detect the proliferation and invasion ability of these cells. Finally, luciferase reporter assay was performed to detect the relationship between miR-140-5p and NCKAP1., Results: The expression of miR-140-5p was suppressed in blood vessel of aortic dissection patients, and the levels of NCKAP1 in those tissues were upregulated. Overexpression of miR-140-5p inhibited the proliferation, migration and invasion of vascular smooth muscle cells. miR-140-5p targeted and suppressed the expression of NCKAP1., Conclusions: miR-140-5p repressed the proliferation, migration and invasion of vascular smooth muscle cells by targeting and inhibiting the expression of NCKAP1. Furthermore, the results of our study suggest new strategies and targets for the clinical treatment of arterial dissection.

Objectives: Spinal cord injury (SCI) is a disabling central nervous system disorder. This study aimed to explore the effects of repetitive trans-spinal magnetic stimulation (rTSMS) of different spinal cord segments on movement function and growth-associated protein-43 (GAP43) and 5-hydroxytryptamine (5-HT) expression in rats after acute SCI and to preliminarily discuss the optimal rTSMS treatment site to provide a theoretical foundation and experimental evidence for clinical application of rTSMS in SCI., Methods: A rat T10 laminectomy SCI model produced by transient application of an aneurysm clip was used in the study. The rats were divided into group A (sham surgery), group B (acute SCI without stimulation), group C (T6 segment stimulation), group D (T10 segment stimulation), and group E (L2 segment stimulation)., Results: In vivo magnetic stimulation protected motor function, alleviated myelin sheath damage, decreased NgR and Nogo-A expression levels, increased GAP43 and 5-HT expression levels, and inhibited terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and apoptosis-related protein expression in rats at 8 weeks after the surgery., Conclusions: This study suggests that rTSMS can promote GAP43 and 5-HT expression and axonal regeneration in the spinal cord, which is beneficial to motor function recovery after acute SCI.

Background: Vascular dementia (VD) is a kind of acquired intelligence impairment syndrome caused by a series of cerebrovascular factors leading to brain tissue damage. Scalp acupuncture is widely used to treating VD. However, there is no a systematic review has been used to assess the efficacy and safety of scalp acupuncture therapy for VD. Therefore, the purpose of this paper is to systematically evaluate the effects of scalp acupuncture on VD., Methods: We will search the following databases from their inception to July 2020: PubMed, Chinese National Knowledge Infrastructure (CNKI), Wan Fang Database, Embase, Medline, Chinese Biomedical Literature Database (CBM), EBSCO, Web of Science, Technology Periodical Database (VIP), the Chongqing VIP Chinese Science and Cochrane Library. At the same time, we will retrieve other resources including conference articles, and gray literature. The randomized controlled trials (RCTs) in English or Chinese associated with scalp acupuncture for VD will be included. Our study data collection and analysis will be conducted independently by 2 reviewers, and Rev Man V.5.3.5 statistical software will be used to performing meta-analysis., Results: This review research will provide a high-quality synthesis to evaluate the efficacy and safety of scalp acupuncture for patients with VD., Conclusion: This study will provide available evidence to judge whether scalp acupuncture is an effective and safe intervention for patients with VD. It also will provide reliable evidence for its widespread application., Ethics and Dissemination: This systematic review will provide convincing evidence for both patients and clinicians. It does not require ethical approval and the results will be published in a peer-reviewed journal., Osf Registration Number: DOI 10.17605/OSF.IO/7CYZR.

Background: Nowadays, acupoint catgut embedding is being used widely in the treatment of migraine. So far, there is no a systematic review has been conducted. Therefore, the purpose of this paper is to systematically evaluate the efficacy and safety of acupoint catgut embedding on migraine., Methods: We will search the following databases from their inception to May 2020: PubMed, Embase, Medline, EBSCO, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wan Fang Database, the Chongqing VIP Chinese Science and Technology Periodical Database, Cochrane Library. In addition, we will manually retrieve other resources including conference articles, and gray literature. The randomized controlled trials in English or Chinese associated with acupoint catgut embedding for migraines will be included. The data collection and analysis will be conducted independently by 2 reviewers. Meta-analysis will be performed using Rev Man V.5.3.5 statistical software., Results: This study will provide a high-quality synthesis to evaluate the efficacy and safety of acupoint catgut embedding for patients with migraine., Conclusion: This systematic review will provide evidence to judge whether acupoint catgut embedding is an effective and safe intervention for patients with migraines. It will provide reliable evidence for its extensive application., Osf Registration Number: DOI 10.17605/OSF.IO/RP9NW.

Balanced proliferation and differentiation of neural progenitor cells (NPCs) are critical for brain development, but how the process is regulated and what components of the cell division machinery is involved are not well understood. Here we report that SEPT7, a cell division regulator originally identified in Saccharomyces cerevisiae, interacts with KIF20A in the intercellular bridge of dividing NPCs and plays an essential role in maintaining the proliferative state of NPCs during cortical development. Knockdown of SEPT7 in NPCs results in displacement of KIF20A from the midbody and early neuronal differentiation. NPC-specific inducible knockout of Sept7 causes early cell cycle exit, precocious neuronal differentiation, and ventriculomegaly in the cortex, but surprisingly does not lead to noticeable cytokinesis defect. Our data uncover an interaction of SEPT7 and KIF20A during NPC divisions and demonstrate a crucial role of SEPT7 in cell fate determination. In addition, this study presents a functional approach for identifying additional cell fate regulators of the mammalian brain., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

To reduce the environmental pollution from cement production and the damage to natural resources from aggregate mining in the concrete industry, a relatively new concrete, termed geopolymer recycled lump concrete (GRLC), which uses geopolymer as the binding material to replace traditional cement and uses large demolished concrete lumps (DCLs) to partly replace concrete, is prepared in this study. Cubic and cylindrical GRLC specimens containing fresh geopolymer concrete and DCLs were tested under axial compression with various parameters, including the compressive strength levels of both fresh geopolymer concrete and DCLs, and the replacement ratio of DCLs. The compressive behavior of the GRLC specimens was compared with traditional cement recycled lump concrete (CRLC) specimens, with test results showing that GRLC specimens possess higher compressive strength than CRLC specimens under the same experimental conditions, which is due to the strengthening effect that fresh geopolymer concrete has on the DCLs. From the scanning electron microscope pattern of the GRLC specimen, it is found that the geopolymer bonds well with the old mortar attached to DCLs. As the replacement ratio increases from 0% to 33%, the elastic modulus of GRLC increases by 5%-11% but Poisson's ratio remains almost constant (in the 0.16-0.17 range). Based on the measured strength and the predicted results, which coincide with one another well, a modified method for predicting the compressive strength of GRLC cubic and cylindrical specimens is proposed., Competing Interests: The authors declare no conflict of interest.

Dietary protein from fermented cottonseed meal (FCSM), widely used in poultry diets in China, had regulating effects on lipid metabolism. To understand the effects of FCSM on lipid metabolism in broilers, we analyzed the biochemical indexes, enzyme activity, hormone level and metabolites in serum responses to FCSM intake. One hundred and eighty 21-d-old Chinese yellow feathered broilers (536.07±4.43 g) were randomly divided into 3 groups with 6 replicates and 3 diets with 6 % supplementation of unfermented CSM (control group), FCSM by C. Tropicalis (Ct CSM) or C. tropicalis plus S. Cerevisae (Ct-Sc CSM). Result showed that: (1) FCSM intake decreased significantly the content of triglyceride (TAG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (P<0.05) in serum; (2) FCSM intake could significantly increase enzyme activity of acetyl CoA carboxylase (ACC), lipoprotein lipase (LPL), fatty acid synthase (FAS) and hormone sensitive lipase (HSL) (P<0.05); (3) Ct-Sc CSM intake increased significantly the levels of adiponectin (ADP) (P<0.05); (4) FCSM intake caused significant metabolic changes involving glycolysis, TCA cycle, synthesis of fatty acid and glycogen, and metabolism of glycerolipid, vitamins B group and amino acids. Our results strongly suggested that FCSM intake could significantly affect lipid metabolism via multiple pathways. These findings provided new essential information about the effect of FCSM on broilers and demonstrated the great potential of nutrimetabolomics, through which the research complex nutrients are included in animal diet., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The characteristics of DNA methylation changes that occur during neurogenesis in vivo remain unknown. We used whole-genome bisulfite sequencing to quantitate DNA cytosine modifications in differentiating neurons and their progenitors isolated from mouse brain at the peak of embryonic neurogenesis. Localized DNA hypomethylation was much more common than hypermethylation and often occurred at putative enhancers within genes that were upregulated in neurons and encoded proteins crucial for neuronal differentiation. The hypomethylated regions strongly overlapped with mapped binding sites of the key neuronal transcription factor NEUROD2. The 5-methylcytosine oxidase ten-eleven translocation 2 (TET2) interacted with NEUROD2, and its reaction product 5-hydroxymethylcytosine accumulated at the demethylated regions. NEUROD2-targeted differentially methylated regions retained higher methylation levels in Neurod2 knockout mice, and inducible expression of NEUROD2 caused TET2-associated demethylation at its in vivo binding sites. The data suggest that the reorganization of DNA methylation in developing neurons involves NEUROD2 and TET2-mediated DNA demethylation., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Alternative pre-mRNA splicing (AS) produces multiple isoforms of mRNAs and proteins from a single gene. It is most prevalent in the mammalian brain and is thought to contribute to the formation and/or maintenance of functional complexity of the brain. Increasing evidence has documented the significant changes of AS between different regions or different developmental stages of the brain, however, the dynamics of AS and the possible function of it during neural progenitor cell (NPC) differentiation is less well known. Here, using purified NPCs and their progeny neurons isolated from the embryonic mouse cerebral cortex, we characterized the global differences of AS events between the 2 cell types by deep sequencing. The sequencing results revealed cell type-specific AS in NPCs and neurons that are important for distinct functions pertinent to the corresponding cell type. Our data may serve as a resource useful for further understanding how AS contributes to molecular regulations in NPCs and neurons during cortical development.

Balanced symmetric and asymmetric divisions of neural progenitor cells (NPCs) are crucial for brain development, but the underlying mechanisms are not fully understood. Here we report that mitotic kinesin KIF20A/MKLP2 interacts with RGS3 and plays a crucial role in controlling the division modes of NPCs during cortical neurogenesis. Knockdown of KIF20A in NPCs causes dislocation of RGS3 from the intercellular bridge (ICB), impairs the function of Ephrin-B-RGS cell fate signaling complex, and leads to a transition from proliferative to differentiative divisions. Germline and inducible knockout of KIF20A causes a loss of progenitor cells and neurons and results in thinner cortex and ventriculomegaly. Interestingly, loss of function of KIF20A induces early cell cycle exit and precocious neuronal differentiation without causing substantial cytokinesis defect or apoptosis. Our results identify a RGS-KIF20A axis in the regulation of cell division and suggest a potential link of the ICB to regulation of cell fate determination.

In this study, the immunomodulatory activity of oligopeptide (CP) derived from solid-state fermented cottonseed meal were investigated in immunosuppressed BALB/c mice models by treatment with cyclophosphamide (CY). Results indicated that oligopeptide increased the thymus and spleen indices of CY-treated mice. The count of plague forming cells (PFC) and the content of half serum hemolysis (HC 50 ) in immunosuppressive mice were restored to the normal level in CP-10 and CP-20 groups while the cytokines interleukin (IL)-2, IL-6, and tumor necrosis factor alpha (TNF-α) were increased significantly in CP-20 group. Similar increasing the immunoglobulin of IgG and IgM content in the serum of CP-10 group were also observed. These findings indicated that oligopeptide derived from solid-state fermented cottonseed meal had a strong immune-enhancing activity as well as a protective effect against immunosuppression induced by cyclophosphamide in mice., Competing Interests: Compliance with ethical standardsThe authors declare that they have no conflict of interest.

Background: Research interests toward single cell analysis have greatly increased in basic, translational and clinical research areas recently, as advances in whole-transcriptome amplification technique allow scientists to get accurate sequencing result at single cell level. An important step in the single-cell transcriptome analysis is to identify distinct cell groups that have different gene expression patterns. Currently there are limited bioinformatics approaches available for single-cell RNA-seq analysis. Many studies rely on principal component analysis (PCA) with arbitrary parameters to identify the genes that will be used to cluster the single cells., Results: We have developed a novel algorithm, called SAIC (Single cell Analysis via Iterative Clustering), that identifies the optimal set of signature genes to separate single cells into distinct groups. Our method utilizes an iterative clustering approach to perform an exhaustive search for the best parameters within the search space, which is defined by a number of initial centers and P values. The end point is identification of a signature gene set that gives the best separation of the cell clusters. Using a simulated data set, we showed that SAIC can successfully identify the pre-defined signature gene sets that can correctly separated the cells into predefined clusters. We applied SAIC to two published single cell RNA-seq datasets. For both datasets, SAIC was able to identify a subset of signature genes that can cluster the single cells into groups that are consistent with the published results. The signature genes identified by SAIC resulted in better clusters of cells based on DB index score, and many genes also showed tissue specific expression., Conclusions: In summary, we have developed an efficient algorithm to identify the optimal subset of genes that separate single cells into distinct clusters based on their expression patterns. We have shown that it performs better than PCA method using published single cell RNA-seq datasets.

During cellular differentiation, genes important for differentiation are expected to be silent in stem/progenitor cells yet can be readily activated. RNA polymerase II (Pol II) pausing and bivalent chromatin marks are two paradigms suited for establishing such a poised state of gene expression; however, their specific contributions in development are not well understood. Here we characterized Pol II pausing and H3K4me3/H3K27me3 marks in neural progenitor cells (NPCs) and their daughter neurons purified from the developing mouse cortex. We show that genes paused in NPCs or neurons are characteristic of respective cellular functions important for each cell type, although pausing and pause release were not correlated with gene activation. Bivalent chromatin marks poised the marked genes in NPCs for activation in neurons. Interestingly, we observed a positive correlation between H3K27me3 and paused Pol II. This study thus reveals cell type-specific Pol II pausing and gene activation-associated bivalency during mammalian neuronal differentiation., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Colorectal cancer patients with diabetes had the high risks of total mortality. High expression of MSX2 is related to development of diabetes. There are few reports about the clinical implications and function of MSX2 in colorectal cancer (CRC). The purpose of this study is to investigate the relationship between the expression of MSX2 and clinical relevance and discover the possible mechanism of MSX2 in the development of CRC. Compared with adjacent tissues, the expression of MSX2 was higher in tumor tissues in both mRNA and protein levels ( P < 0.01). Kaplan-Meier survival analysis showed that high mRNA expression of MSX2 was associated with short survival time ( P = 0.013). Chi-squared test analysis indicated that MSX2 expression was related to tumor size ( P = 0.04), tumor locus ( P = 0.025), clinical stage ( P < 0.001), tumor invasion ( P = 0.003), lymphatic metastasis ( P = 0.01), and distant metastasis ( P = 0.033). In vitro experiments demonstrated that knockdown of MSX2 expression attenuated cell proliferation and invasion, promoted cell cycle arrest and apoptosis, and inactivated Akt phosphorylation. In conclusion, MSX2 played a crucial role in the progression of CRC and may be a potential novel prognostic factor and therapeutic target for CRC therapy. Our work may provide certain enlightenment for investigating the mechanism of MSX2 in the process of diabetes., Competing Interests: The authors declare that there are no competing interests.

In the cerebral cortex, projection neurons and interneurons work coordinately to establish neural networks for normal cortical functions. While the specific mechanisms that control productions of projection neurons and interneurons are beginning to be revealed, a global characterization of the molecular differences between these two neuron types is crucial for a more comprehensive understanding of their developmental specifications and functions. In this study, using lineage tracing power of combining Tbr2(Eomes)-GFP and Dcx-mRFP reporter mice, we prospectively separated intermediate progenitor cell (IPC)-derived neurons (IPNs) from non-IPC-derived neurons (non-IPNs) of the embryonic cerebral cortex. Molecular characterizations revealed that IPNs and non-IPNs were enriched with projection neurons and interneurons, respectively. Expression profiling documented cell-specific genes including differentially expressed transcriptional regulators that might be involved in cellular specifications, for instance, our data found that SOX1 and SOX2, which were known for important functions in neural stem/progenitor cells, continued to be expressed by interneurons but not by projection neurons. Transcriptome analyses of cortical neurons isolated at different stages of neurogenesis revealed distinct temporal patterns of expression of genes involved in early-born or late-born neuron specification. These data present a resource useful for further investigation of the molecular regulations and functions of projection neurons and interneurons., (© 2015 Wiley Periodicals, Inc.)

Granulocyte colony-stimulating factor (G-CSF) is an essential regulator of neutrophil trafficking and is highly expressed in multiple tumors. Myeloid derived suppressor cells (MDSCs) promote neoplastic progression through multiple mechanisms by immune suppression. Despite the findings of G-CSF function in colon cancer progression, the precise mechanism of G-CSF on MDSCs regulation and its blockade effects on tumor growth remains a worthy area of investigation. In this study we observed an overexpression of G-CSF in a mouse colitis-associated cancer (CAC) model, which was consistent with the accumulation of MDSCs in mouse colon tissues. Further in vitro studies demonstrated that G-CSF could promote MDSCs survival and activation through signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, compared with isotype control, anti-G-CSF mAb treatment demonstrated reduced MDSC accumulation, which led to a marked decrease in neoplasm size and number in mice. Our results indicated that G-CSF is a critical regulating molecule in the migration, proliferation and function maintenance of MDSCs, which could be a potential therapeutic target for colitis-associated cancer.

We report that the mammalian 5-methylcytosine (5mC) oxidase Tet3 exists as three major isoforms and characterized the full-length isoform containing an N-terminal CXXC domain (Tet3FL). This CXXC domain binds to unmethylated CpGs, but, unexpectedly, its highest affinity is toward 5-carboxylcytosine (5caC). We determined the crystal structure of the CXXC domain-5caC-DNA complex, revealing the structural basis of the binding specificity of this domain as a reader of CcaCG sequences. Mapping of Tet3FL in neuronal cells shows that Tet3FL is localized precisely at the transcription start sites (TSSs) of genes involved in lysosome function, mRNA processing, and key genes of the base excision repair pathway. Therefore, Tet3FL may function as a regulator of 5caC removal by base excision repair. Active removal of accumulating 5mC from the TSSs of genes coding for lysosomal proteins by Tet3FL in postmitotic neurons of the brain may be important for preventing neurodegenerative diseases., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

RAFT polymerization was utilized to prepare an amphiphilic block copolymer containing both hydrophilic and hydrophobic segments. The self-assembly behavior of the block copolymer into nano-scale particulate structures was studied in both water and polar organic solvents. Uniform micelle assemblies were stabilized by reaction within the hydrophobic core, which contained pendant azide groups, through copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry with a dialkyne crosslinker. The reaction preceded efficiently with negligible residual azide functionality and resulted in core-shell nanogel structures that were analyzed by a variety of techniques including light scattering, electron microscopy and the ability to take up hydrophobic molecules. Both thermo- and pH-responsive character of the nanogels and the linear polymers from which they were made were studied through cloud point testing at different pH levels. It was found that these nanogel dispersions in water exhibited the highest cloud point temperatures indicating a highly stable nanogel structure. The solvent-dispersed nanogels were used as building blocks to form extended polymer networks through the inter- as well as intra-particle reaction between hydroxyl groups within the hydrophilic domain of the nanogel shell by crosslinking with a diisocyanate. It was found that as little as 10 wt% nanogel dispersions in solvent reached the percolation threshold to yield highly porous macroscopic networks; while 50 wt% concentrations achieved densely packed and interdigitated nanogels to afford relatively homogeneous structures.

Objective: This study examines how nanogel structure correlates with photopolymerization and key polymer properties upon addition of nanogels with latent reactivity into a monomer dispersant to produce polymer/polymer composites., Methods: Two nanogels that retained RAFT functionality based on the synthetic approach were prepared to have different branching densities. These reactive nanogels were dispersed in triethylene glycol dimethacrylate at 0-40 wt%. Reaction kinetics, volumetric shrinkage and shrinkage stress associated with the photopolymerization of nanogel-modified formulations were measured in real time with mechanical properties of the polymers also evaluated. The basic structure of RAFT-derived nanogel particles was examined by the preparation of a separate nanogel constructed with degradable disulfide crosslinking groups. The model nanogel molecular weight and polydispersity were compared before and after degradation., Results: Despite the controlled radical synthetic approach, the nanogels, which are composed of multiple interconnected, short primary chains, presented relatively high polydispersity. Through addition of the reactive nanogels to a monomer that both infiltrates and disperses the nanogels, the photopolymerization rate was moderately reduced with the increase of nanogel loading levels. Volumetric shrinkage decreased proportionally with nanogel concentration; however, a greater than proportional reduction of polymerization-induced stress was observed. Mechanical properties, such as flexural strength, storage modulus were maintained at the same levels as the control resin for nanogel systems up to 40 wt%., Significance: This study demonstrated that beyond the use of RAFT functionality to produce discrete nano-polymeric structures, the residual chain end groups are important to maintain reactivity and mechanical properties of nanogel-modified resin materials., (Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.)

Photo-reactive nanogels with an integrated photoinitiator-based functionality were synthesized via a Reversible Addition-Fragmentation Chain Transfer (RAFT) process. Without additional free initiators, this nanogel is capable of radical generation and initiating polymerization of a secondary monomer (i.e. dimethacrylate) that infiltrates and disperses the nanogel particles. Due to the presence of RAFT functionality and the fact that all initiating sites are initially located within the nanogel structure, gelation can be delayed by sequencing the polymerization from the nanogel to the bulk matrix. During polymerization of a nanogel-filled resin system, a progressive delay of gelation conversion from about 2 % for conventional chain growth polymerization to 18 % for the same monomer containing 20 wt% nanogel additive was achieved. A significant delay of stress development was also observed with much lower final stress achieved with the nanogel-modified systems due to the change of network formation mechanics. Compared with the nanogel-free dimethacrylate control, which contained uniformly distributed free initiator, the flexural modulus and mechanical strength results were maintained for the photopolymers with nanogel contents greater than 10 wt%. There appears to be a critical interparticle spacing of the photo-reactive nanogel that provides effective photopolymerization while providing delayed gelation and substantial stress reduction.

This paper reports a series of photopolymerizable polysiloxane-modified nanogels for regulating surface microstructure and gradient property of polymers, which were synthesized by solution polymerization under different feed ratios of a methacrylate-modified polysiloxane, urethane dimethacrylate (UDMA) and isobornyl methacrylate (IBMA) in the presence of a thiol chain transfer agent. The nanogel structure and composition were characterized by proton nuclear magnetic resonance ( 1 H-NMR), Fourier transform-infrared spectroscopy (FT-IR), transmission electron microscope (TEM), gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). The dispersion of these nanogels in triethylene glycol dimethacrylate (TEGDMA) can reduce the onset and magnitude of shrinkage stress during polymerization without compromise to mechanical properties of the resulting polymers. Most importantly, as demonstrated by elemental analysis and X-ray photoelectron spectroscopy (XPS), the nanogels exhibit good self-floating ability in the monomer/polymer matrix and the increase of polysiloxane content in the nanogel can enhance the self-floating capability due to the lower surface tension and energy associated with the polysiloxane component. As a result, the polysiloxane-modified nanogels can spontaneously form a concentration gradient that can be locked in upon photopolymerization leading to a well-controlled heterogeneous polymer that presents a gradient change in thermal stability. With the increase of polysiloxane content, the thermal stability of the polymer was improved significantly. Furthermore, the enrichment of the nanogel on the surface resulting from the good self-floating ability can reduce the dispersion surface energy of gradient polymer film and generate a more hydrophobic surface with altered surface microstructure. These photopolymerizable polysiloxane-modified nanogels are demonstrated to have potential broad application in the preparation of gradient polymer with controlled surface properties.

Reactive nanogels with diverse chemical and physical compositions were synthesized using solution free radical polymerization. Conventional monomer resins show a reduction in polymerization shrinkage and stress as well as improved bond strength when nanogels are used as a filler. Nanogels dispersed in inert solvent at appropriate concentrations form macroscopic networks with chemical compositions that are not directly available from the starting monomers.