Leveraging Electron Push-Pull Effect for Catalytic Polymerization and Degradation of a Cyclobutane Monomer System.

Ring-opening polymerization (ROP) offers a striking solution to solve problems encountered in step-growth condensation polymerization, including precise control over molecular weight, molecular weight distribution, and topology. This has inspired our interest in ROP of cycloalkanes with an ultimate goal to rethink polyolefins, which clearly poses a number of challenges. Practicality of ROP of cycloalkanes is actually limited by their low polymerizability and elusive mechanisms which arise from significantly varied ring size and non-polar C-C bonds in monomers. In this work, by using Lewis acid/Brønsted base/C(sp3)-H initiator system previously developed in our laboratory, we focus on cyclobutanes and explore the positional and electronic effects of substituents on the ring, namely electron push-pull effect, in promoting controlled polymerization to afford densely functionalized poly(cyclobutanes), as well as catalytic degradation of obtained polymers for upcycling. More importantly, experiments and DFT calculations unveil considerable population of Lewis-acid-induced thermostabilized 1,4-zwitterions, which distinguish cyclobutanes from cyclopropanes and others. All these findings would shed light on catalytic synthesis and degradation of saturated all-carbon main-chain polymers, as well as small molecule transformations of cyclobutanes.

Sphenopalatine ganglion stimulation: a comprehensive evaluation across diseases in randomized controlled trials.

Background: Current literature extensively covers the use of sphenopalatine ganglion stimulation (SPGs) in treating a broad spectrum of medical conditions, such as allergic rhinitis, cluster headaches, and strokes. Nevertheless, a discernible gap in the systematic organization and analysis of these studies is evident. This paper aims to bridge this gap by conducting a comprehensive review and analysis of existing literature on SPGs across various medical conditions. Methods: This study meticulously constructed a comprehensive database through systematic computerized searches conducted on PubMed, Embase, CNKI, Wanfang, VIP, and CBM up to May 2022. The inclusion criteria encompassed randomized controlled trials (RCTs) published in either Chinese or English, focusing on the therapeutic applications of SPGs for various medical conditions. Both qualitative and quantitative outcome indicators were considered eligible for inclusion. Results: This comprehensive study reviewed 36 publications, comprising 10 high-quality, 23 medium-quality, and three low-quality articles. The study investigated various diseases, including allergic rhinitis (AR), ischemic strokes (IS), cluster headache (CH), primary trigeminal neuralgia (PTN), pediatric chronic secretory otitis (PCSO), refractory facial paralysis (RFP), chronic tension-type headache (CTTH), as well as the analysis of low-frequency sphenopalatine ganglion stimulation (LF-SPGs) in chronic cluster headache (CCH) and the impact of SPGs on Normal nasal cavity function (NNCF). SPGs demonstrate efficacy in the treatment of AR. Regarding the improvement of rhinoconjunctivitis quality of life questionnaire (RQLQ) scores, SPGs are considered the optimal intervention according to the SUCRA ranking. Concerning the improvement in Total Nasal Symptom Score (TNSS), Conventional Acupuncture Combined with Tradiational Chinese Medicine (CA-TCM) holds a significant advantage in the SUCRA ranking and is deemed the best intervention. In terms of increasing Effective Rate (ER), SPGs outperformed both conventional acupuncture (CA) and Western Medicine (WM; P < 0.05). In the context of SPGs treatment for IS, the results indicate a significant improvement in the 3-month outcomes, as evaluated by the modified Rankin Scale (mRS) in the context of Cerebral Cortical Infarction (CCI; P < 0.05). In the treatment of CH with SPGs, the treatment has been shown to have a statistically significant effect on the relief and disappearance of headaches (P < 0.05). The impact of SPGs on NNCF reveals statistically significant improvements (P < 0.05) in nasal airway resistance (NAR), nasal cavity volume (NCV), exhaled nitric oxide (eNO), substance P (SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY). SPGs treatments for PCSO, RFP, and CTTH, when compared to control groups, yielded statistically significant results (P < 0.05). Conclusion: SPGs demonstrate significant effectiveness in the treatment of AR, IS, and CH. Effective management of CCH may require addressing both autonomic dysregulation and deeper neural pathways. However, additional high-quality research is essential to clarify its effects on NNCF, PTN, PCSO, RFP, and CTTH. Systematic Review Registration: PROSPERO, identifier CRD42021252073, https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=312429.

Mechanical properties of municipal solid waste under different stress paths: Effects of plastic content and particle gradation.

Plastics within municipal solid waste (MSW) are non-degradable. As MSW continues to degrade, the relative content of plastics rises, and particle gradation may also change. Moreover, throughout the landfilling process, MSW is subjected to various stress conditions, potentially influencing its mechanical properties. This study explored the effects of varying plastic contents, different particle gradations, and distinct stress paths on the mechanical properties of MSW, and consolidated drained triaxial tests of 42 groups of reconstituted MSW specimens were conducted. The results showed that there was an optimal plastic content of 6-9 % for MSW, where the shear strength of MSW was higher than that of MSW with other plastic contents. When the stress path changed from TC45 to TC72, the optimal plastic content of MSW changed from 6 % to 9 %. As the plastic content increased, both the cohesion and internal friction angle of the MSW initially increased, then subsequently decreased. The impact of plastic content on cohesion was more pronounced than on the internal friction angle, especially at larger strains. Under various stress paths, MSW with distinct particle size distributions demonstrated diverse stress-strain behaviors. Traditional criteria for evaluating well-graded conditions in soils are not suitable for MSW. The effect of gradation on the cohesion of MSW is essentially due to the predominant role of fiber content; the relationship between gradation and the internal friction angle in MSW is complex and correlates closely with the content of both coarse and fine particles, as well as fibers. This study serves as an essential reference for predicting deformations in landfills and analyzing the stability of landfill slopes.

Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

Functional roles of circular RNAs in lung injury.

Lung injury leads to respiratory dysfunction, low quality of life, and even life-threatening conditions. Circular RNAs (circRNAs) are endogenous RNAs produced by selective RNA splicing. Studies have reported their involvement in the progression of lung injury. Understanding the roles of circRNAs in lung injury may aid in elucidating the underlying mechanisms and provide new therapeutic targets. Thus, in this review, we aimed to summarize and discuss the characteristics and biological functions of circRNAs, and their roles in lung injury from existing research, to provide a theoretical basis for the use of circRNAs as a diagnostic and therapeutic target for lung injury.

Both gain- and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia.

KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channel α subunit. Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia (PKD), but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases. Using the whole exome sequencing followed by Sanger sequencing, we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families. The proband of one family (c.496G>A, p.A166T) manifests as episodic ataxia type 1, and the other two (c.877G>A, p.V293I and c.1112C>A, p.T371A) manifest as PKD. The pathogenicity of these variants is confirmed by functional studies, suggesting that p.A166T and p.T371A cause a loss-of-function of the channel, while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected. By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein, we find that these variants tend to cluster around the pore domain, which is similar to epilepsy. Thus, our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype-phenotype correlations of KCNA1 channelopathy.

Automated multimodal imaging of Caenorhabditis elegans behavior in multi-well plates.

Large-scale assays of behavior in model organisms play an important role in genetic screens, drug testing, and the elucidation of gene-behavior relationships. We have developed an automated, high-throughput imaging and analysis method for assaying behaviors of the nematode C. elegans . We use high-resolution optical imaging to longitudinally record the behaviors of 96 animals at a time in multi-well plates, and computer vision software to quantify the animals' locomotor activity, behavioral states, and egg laying events. To demonstrate the capabilities of our system we used it to examine the role of serotonin in C. elegans behavior. We found that egg-laying events are preceded by a period of reduced locomotion, and that this decline in movement requires serotonin signaling. In addition, we identified novel roles of serotonin receptors SER-1 and SER-7 in regulating the effects of serotonin on egg laying across roaming, dwelling, and quiescent locomotor states. Our system will be useful for performing genetic or chemical screens for modulators of behavior.

Screening and early warning system for chronic obstructive pulmonary disease with obstructive sleep apnoea based on the medical Internet of Things in three levels of healthcare: protocol for a prospective, multicentre, observational cohort study.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea (OSA) are prevalent respiratory diseases in China and impose significant burdens on the healthcare system. Moreover, the co-occurrence of COPD and OSA exacerbates clinical outcomes significantly. However, comprehensive epidemiological investigations in China remain scarce, and the defining characteristics of the population affected by COPD and OSA, alongside their intrinsic relationship, remain ambiguous. METHODS AND ANALYSIS: We present a protocol for a prospective, multicentre, observational cohort study based on a digital health management platform across three different healthcare tiers in five sites among Chinese patients with COPD. The study aims to establish predicative models to identify OSA among patients with COPD and to predict the prognosis of overlap syndrome (OS) and acute exacerbations of COPD through the Internet of Things (IoT). Moreover, it aims to evaluate the feasibility, effectiveness and cost-effectiveness of IoT in managing chronic diseases within clinical settings. Participants will undergo baseline assessment, physical examination and nocturnal oxygen saturation measuring. Specific questionnaires screening for OSA will also be administered. Diagnostic lung function tests and polysomnography will be performed to confirm COPD and OSA, respectively. All patients will undergo scheduled follow-ups for 12 months to record the changes in symptoms, lung functions and quality of life. Primary outcomes include the prevalence and characteristics of OS, while secondary outcomes encompass OS prognosis and the feasibility of the management model in clinical contexts. A total of 682 patients with COPD will be recruited over 12-24 months. ETHICS AND DISSEMINATION: The study has been approved by Peking University Third Hospital, and all study participants will provide written informed consent. Study results will be published in an appropriate journal and presented at national and international conferences, as well as relevant social media and various stakeholder engagement activities. TRIAL REGISTRATION NUMBER: NCT04833725.

Segmentation-free measurement of locomotor frequency in Caenorhabditis elegans using image invariants.

An animal's locomotor rate is an important indicator of its motility. In studies of the nematode C. elegans , assays of the frequency of body bending waves have often been used to discern the effects of mutations, drugs, or aging. Traditional manual methods for measuring locomotor frequency are low in throughput and subject to human error. Most current automated methods depend on image segmentation, which requires high image quality and is prone to errors. Here, we describe an algorithm for automated estimation of C. elegans locomotor frequency using image invariants, i.e., shape-based parameters that are independent of object translation, rotation, and scaling. For each video frame, the method calculates a combination of 8 Hu's moment invariants and a set of Maximally Stable Extremal Regions (MSER) invariants. The algorithm then calculates the locomotor frequency by computing the autocorrelation of the time sequence of the invariant ensemble. Results of our method show excellent agreement with manual or segmentation-based results over a wide range of frequencies. We show that compared to the segmentation method that analyzes a worm's shape, our method is more robust to low image quality. We demonstrate the system's capabilities by testing the effects of serotonin and serotonin pathway mutants on locomotor frequency.

KRT17 From Keratinocytes With High Glucose Stimulation Inhibit Dermal Fibroblasts Migration Through Integrin α11.

Objective: To investigate the effects of overexpressed keratin 17 (KRT17) on the biology of human dermal fibroblasts (HDFs) and to explore the mechanism of KRT17 in diabetic wound healing. Methods: KRT17 expression was tested in diabetic keratinocytes, animal models, and patient skin tissues (Huazhong University of Science and Technology Ethics Committee, [2022] No. 3110). Subsequently, HDFs were stimulated with different concentrations of KRT17 in vitro. Changes in the proliferation and migration of HDFs were observed. Then, identification of KRT17-induced changes in dermal fibroblast of RNA sequencing-based transcriptome analysis was performed. Results: KRT17 expression was upregulated under pathological conditions. In vitro stimulation of HDFs with different concentrations of KRT17 inhibited cell migration. RNA-seq data showed that enriched GO terms were extracellular matrix components and their regulation. KEGG analysis revealed that the highest number of enriched genes was PI3K-Akt, in which integrin alpha-11 (ITGA11) mRNA, a key molecule that regulates cell migration, was significantly downregulated. Decreased ITGA11 expression was observed after stimulation of HDFs with KRT17 in vitro. Conclusion: Increased expression of KRT17 in diabetic pathological surroundings inhibits fibroblast migration by downregulating the expression of ITGA11. Thus, KRT17 may be a molecular target for the treatment of diabetic wounds.

Safety and Efficacy of Endovascular Aortic Repair for Abdominal Aortic Aneurysms with a Hostile Neck Anatomy.

OBJECTIVE: This study aimed to investigate the safety and efficacy of endovascular aortic repair (EVAR) for the treatment of an abdominal aortic aneurysm (AAA) with a hostile neck anatomy (HNA). METHODS: From January 1, 2015 to December 31, 2019, a total of 259 patients diagnosed with an AAA who underwent EVAR were recruited into this study. Based on the morphological characteristics of the proximal neck anatomy, the patients were divided into the HNA group and the friendly neck anatomy (FNA) group. The patients were followed up for up to 4 years. RESULTS: The average follow-up time was 1056.1±535.5 days. Type I endoleak occurred in 4 patients in the HNA group, and 2 patients in the FNA group. Neither death nor intraoperative switch to open repair occurred in either group. The time of the operation was significantly longer in the HNA group (FNA vs. HNA, 99.2±51.1 min vs. 117.5±63.8 min, P=0.011). There were no significant differences in short-term clinical success rate (P=0.228) or midterm clinical success rate (P=0.889) between the two groups. The overall mortality rate was 10.4%, and Kaplan-Meier survival analysis indicated that the two groups had similar cumulative survival rates at the end of the follow-up period (P=0.889). CONCLUSION: EVAR was feasible and safe in patients with an AAA with a proximal HNA. The early and midterm results were promising; however, further studies are needed to verify the long-term effectiveness of EVAR.

Volume overload impedes the maturation of sarcomeres and T-tubules in the right atria: a potential cause of atrial arrhythmia following delayed atrial septal defect closure.

Introduction: Adult patients with atrial septal defects (ASD), the most common form of adult congenital heart disease, often die of arrhythmias, and the immaturity of cardiomyocytes contributes significantly to arrhythmias. ASD typically induces a left-to-right shunt, which then leads to the right atrium (RA) volume overload (VO). Whether or not VO contributes to RA cardiomyocyte immaturity and thereby causes arrhythmias in adult patients with ASD remains unclear. Methods: Here, we developed the first neonatal RA VO mouse model by creating a fistula between the inferior vena cava and abdominal aorta on postnatal day 7. RA VO was confirmed by increases in the mean flow velocity, mean pressure gradient, and velocity time integral across the tricuspid valve, and an increase in the RA diameter and RA area middle section. Results: We found that VO decreased the regularity and length of sarcomeres, and decreased the T-element density, regularity, and index of integrity of T-tubules in RA cardiomyocytes, suggesting that the two most important maturation hallmarks (sarcomere and T-tubules) of RA cardiomyocytes were impaired by VO. Accordingly, the calcium handling capacity of cardiomyocytes from postnatal day 21 (P21) RA was decreased by VO. VO caused a significant elongation of the PR interval. The expression of connexin 43 (Cx43) was decreased in RA VO. Moreover, gene ontology (GO) analysis of the downregulated genes in RA demonstrated that there was an abundance of enriched terms associated with sarcomeres and T-tubules exposed to VO. The results were further verified by qRT-PCR. Conclusions: In conclusion, the first neonatal RA VO mouse model was developed; furthermore, using this neonatal RA VO mouse model, we revealed that VO impeded RA sarcomere and T-tubule maturation, which may be the underlying causes of atrial arrhythmias in adult patients with ASD.

Exogenous IL-25 ameliorates airway neutrophilia via suppressing macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma.

BACKGROUND: Severe asthma is associated with substantial mortality and has unmet therapeutic need. A subset of severe asthma is characterized by neutrophilic airway inflammation. Classically activated (or M1) macrophages which express IL-12 and IL-23 are associated with airway neutrophilia in asthma. Exogenous IL-25 was reported to suppress intestinal inflammation in animal models of inflammatory bowel diseases via suppressing IL-12 and IL-23 production. We hypothesize that IL-25 ameliorates airway neutrophilia via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma. METHODS: In a mouse model of neutrophil-dominant allergic airway inflammation, the effect of mouse recombinant IL-25 on airway inflammation were assessed by H&E staining and bronchoalveolar lavage (BAL) cell counting. The percentage of M1 macrophages in lung tissue and BAL cells were analyzed by flow cytometry. Quantitative PCR and immunostaining were performed to measure the expression of Il12, Il23, and inflammatory cytokines. Mechanistic experiments were performed in primary culture of macrophages from mouse lungs. The expression of IL-12, IL-23 and IL-25 in sputum was analyzed in a cohort of severe asthma and subjects with eosinophilic or non-eosinophilic asthma. RESULTS: Intranasal administration of IL-25 markedly decreased the number of neutrophils in BAL cells in a murine model of neutrophil-dominant allergic airway inflammation. Moreover, exogenous IL-25 decreased the number of M1 macrophages, and reduced the expression of IL-12, IL-23 in the lungs of the mouse model. Exogenous IL-25 also inhibited the expression of inflammatory cytokines IL-1ß, IFN-γ, TNF-α and IL-17 A. In vitro, IL-25 suppressed IL-12 and IL-23 expression in lipopolysaccharide (LPS)-stimulated primary culture of mouse pulmonary macrophages. Mechanistically, IL-25 inhibited LPS-induced c-Rel translocation to nucleus via STAT3-dependent signaling. In a cohort of severe asthma, IL-25 protein levels in sputum were significantly lower than control subjects. The transcript levels of IL-12 and IL-23 were increased whereas IL-25 transcripts were decreased in sputum cells from subjects with non-eosinophilic asthma compared to eosinophilic asthma. CONCLUSIONS: IL-25 expression is downregulated in subjects with severe or non-eosinophilic asthma. Exogenous IL-25 ameliorates airway neutrophilia, at least in part, via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23.

Electrospun compliant heparinized elastic vascular graft for improving the patency after implantation.

The low patency rate after artificial blood vessel replacement is mainly due to the ineffective use of anticoagulant factors and the mismatch of mechanical compliance after transplantation. Electrospun nanofibers with biomimetic extracellular matrix three-dimensional structure and tunable mechanical strength are excellent carriers for heparin. In this work, we have designed and synthesized a series of biodegradable poly(ester-ether-urethane)ureas (BEPU), following compound with optimized constant concentration of heparin by homogeneous emulsion blending, then spun into the hybrid BEPU/heparin nanofibers tubular graft for replacing rats' abdominal aorta in situ for comprehensive performance evaluation. The results in vitro demonstrated that the electrospun L-PEUUH (LDI-based PEUU with heparin) vascular graft was of regular microstructure, optimum surface wettability, matched mechanical properties, reliable cytocompatibility, and strongest endothelialization in situ. Replacement of resected abdominal artery with the L-PEUUH vascular graft in rat showed that the graft was capable of homogeneous hybrid heparin and significantly promoted the stabilization of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), as well as stabilizing the blood microenvironment. This research demonstrates the L-PEUUH vascular graft with substantial patency, indicating their potential for injured vascular healing.

Nanofibers with homogeneous heparin distribution and protracted release profile for vascular tissue engineering.

In clinic, controlling acute coagulation after small-diameter vessel grafts transplantation is considered a primary problem. The combination of heparin with high anticoagulant efficiency and polyurethane fiber with good compliance is a good choice for vascular materials. However, blending water-soluble heparin with fat-soluble poly (ester-ether-urethane) urea elastomer (PEEUU) uniformly and preparing nanofibers tubular grafts with uniform morphology is a huge challenge. In this research, we have compounded PEEUU with optimized constant concentration of heparin by homogeneous emulsion blending, then spun into the hybrid PEEUU/heparin nanofibers tubular graft (H-PHNF) for replacing rats' abdominal aorta in situ for comprehensive performance evaluation. The in vitro results demonstrated that H-PHNF was of uniform microstructure, moderate wettability, matched mechanical properties, reliable cytocompatibility, and strongest ability to promote endothelial growth. Replacement of resected abdominal artery with the H-PHNF in rat showed that the graft was capable of homogeneous hybrid heparin and significantly promoted the stabilization of vascular smooth muscle cells (VSMCs) as well as stabilizing the blood microenvironment. This research demonstrates the H-PHNF with substantial patency, indicating their potential for vascular tissue engineering.

Anoikis resistance of small airway epithelium is involved in the progression of chronic obstructive pulmonary disease.

Background: Anoikis resistance is recognized as a crucial step in the metastasis of cancer cells. Most epithelial tumors are distinguished by the ability of epithelial cells to abscond anoikis when detached from the extracellular matrix. However, no study has investigated the involvement of anoikis in the small airway epithelium (SAE) of chronic obstructive pulmonary disease (COPD). Methods: Anoikis-related genes (ANRGs) exhibiting differential expression in COPD were identified using microarray datasets obtained from the Gene Expression Omnibus (GEO) database. Unsupervised clustering was performed to classify COPD patients into anoikis-related subtypes. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were used to annotate the functions between different subtypes. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were leveraged to identify key molecules. The relative proportion of infiltrating immune cells in the SAE was quantified using the CIBERSORT and ssGSEA computational algorithms, and the correlation between key molecules and immune cell abundance was analyzed. The expression of key molecules in BEAS-2B cells exposed to cigarette smoke extract (CSE) was validated using qRT-PCR. Results: A total of 25 ANRGs exhibited differential expression in the SAE of COPD patients, based on which two subtypes of COPD patients with distinct anoikis patterns were identified. COPD patients with anoikis resistance had more advanced GOLD stages and cigarette consumption. Functional annotations revealed a different immune status between COPD patients with pro-anoikis and anoikis resistance. Tenomodulin (TNMD) and long intergenic non-protein coding RNA 656 (LINC00656) were subsequently identified as key molecules involved in this process, and a close correlation between TNMD and the infiltrating immune cells was observed, such as activated CD4+ memory T cells, M1 macrophages, and activated NK cells. Further enrichment analyses clarified the relationship between TNMD and the inflammatory and apoptotic signaling pathway as the potential mechanism for regulating anoikis. In vitro experiments showed a dramatic upregulation of TNMD and LINC00656 in BEAS-2B cells when exposed to 3% CSE for 48 hours. Conclusion: TNMD contributes to the progression of COPD by inducing anoikis resistance in SAE, which is intimately associated with the immune microenvironment.

Identifying the potential transcriptional regulatory network in Hirschsprung disease by integrated analysis of microarray datasets.

Objective: Hirschsprung disease (HSCR) is one of the common neurocristopathies in children, which is associated with at least 20 genes and involves a complex regulatory mechanism. Transcriptional regulatory network (TRN) has been commonly reported in regulating gene expression and enteric nervous system development but remains to be investigated in HSCR. This study aimed to identify the potential TRN implicated in the pathogenesis and diagnosis of HSCR. Methods: Based on three microarray datasets from the Gene Expression Omnibus database, the multiMiR package was used to investigate the microRNA (miRNA)-target interactions, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Then, we collected transcription factors (TFs) from the TransmiR database to construct the TF-miRNA-mRNA regulatory network and used cytoHubba to identify the key modules. Finally, the receiver operating characteristic (ROC) curve was determined and the integrated diagnostic models were established based on machine learning by the support vector machine method. Results: We identified 58 hub differentially expressed microRNAs (DEMis) and 16 differentially expressed mRNAs (DEMs). The robust target genes of DEMis and DEMs mainly enriched in several GO/KEGG terms, including neurogenesis, cell-substrate adhesion, PI3K-Akt, Ras/mitogen-activated protein kinase and Rho/ROCK signaling. Moreover, 2 TFs (TP53 and TWIST1), 4 miRNAs (has-miR-107, has-miR-10b-5p, has-miR-659-3p, and has-miR-371a-5p), and 4 mRNAs (PIM3, CHUK, F2RL1, and CA1) were identified to construct the TF-miRNA-mRNA regulatory network. ROC analysis revealed a strong diagnostic value of the key TRN regulons (all area under the curve values were more than 0.8). Conclusion: This study suggests a potential role of the TF-miRNA-mRNA network that can help enrich the connotation of HSCR pathogenesis and diagnosis and provide new horizons for treatment.

Observation of structural switch in nascent SAM-VI riboswitch during transcription at single-nucleotide and single-molecule resolution.

Growing RNAs fold differently as they are transcribed, which modulates their finally adopted structures. Riboswitches regulate gene expression by structural change, which are sensitive to co-transcriptionally structural biology. Here we develop a strategy to track the structural change of RNAs during transcription at single-nucleotide and single-molecule resolution and use it to monitor individual transcripts of the SAM-VI riboswitch (riboSAM) as transcription proceeds, observing co-existence of five states in riboSAM. We report a bifurcated helix in one newly identified state from NMR and single-molecule FRET (smFRET) results, and its presence directs the translation inhibition in our cellular translation experiments. A model is proposed to illustrate the distinct switch patterns and gene-regulatory outcome of riboSAM when SAM is present or absent. Our strategy enables the precise mapping of RNAs' conformational landscape during transcription, and may combine with detection methods other than smFRET for structural studies of RNAs in general.

Poly(ferulic acid)-hybrid nanofibers for reducing thrombosis and restraining intimal hyperplasia in vascular tissue engineering.

Small-diameter blood vascular transplantation failure is mainly caused by the vascular materials' unreliable hemocompatibility and histocompatibility and the unmatched mechanical properties, which will cause unstable blood flow. How to solve the problems of coagulation and intimal hyperplasia caused by the above factors is formidable in vascular replacement. In this work, we have synthesized poly(ferulic acid) (PFA) and prepared poly(ester-urethane)urea (PEUU)/silk fibroin (SF)/poly(ferulic acid) (PFA) hybrid nanofibers vascular graft (PSPG) by random electrospinning and post-double network bond crosslinking for process optimization. The results in vitro demonstrated that the graft is of significant anti-oxidation, matched mechanical properties, reliable cytocompatibility, and blood compatibility. Replacing resected rat abdominal aorta and rabbit carotid artery models with PSPG vascular grafts indicated that the grafts are capable of homogeneous hybrid PFA significantly promoted the stabilization of endothelial cells and the ingrowth of smooth muscle cells, meanwhile stabilizing the immune microenvironment. This research demonstrates the PSPG vascular graft with substantial patency, indicating their potential for injured vascular healing.

Identification and functional characterization of novel variants of MAPT and GRN in Chinese patients with frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most common cause of dementia after Alzheimer's disease, characterized by distinct changes in behavior, personality, and language. Our study performed whole exome sequencing and repeat-primed PCR analysis in 29 unrelated FTD patients. Consequently, 2 known pathogenic variants (MAPT: p.P301L; TBK1: p.I450Kfs), and 4 novel variants (MAPT: p.R406Q, p.D430H, p.A330D; GRN: c.350-2A>G) were identified. The functional analysis results showed that phosphorylated tau levels were higher in cells expressing p.R406Q and p.D430H tau than those expressing wild-type tau, especially at the Thr205, Thr231, and Ser396 phosphorylation epitopes. Besides, the p.R406Q and p.D430H variants of MAPT impaired the ability of tau to bind to the microtubules and increased tau self-aggregation. Furthermore, we found that the c.350-2A>G variant caused exon 5 skipping. Our results showed that p.R406Q, p.D430H, and c.350-2A>G variants were classified as pathogenic. Finally, we summarized the clinical characterization of patients carrying pathogenic variants of MAPT in the East Asia populations. Our results broaden the genetic spectrum of FTD with MAPT and GRN variants.