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Keratin (KRT), a natural fibrous structural protein, can be classified into two categories: "soft" cytosolic KRT that is primarily found in the epithelia tissues (e.g., skin, the inner lining of digestive tract) and "hard" KRT that is mainly found in the protective tissues (e.g., hair, horn). The latter is the predominant form of KRT widely used in biomedical research. The oxidized form of extracted KRT is exclusively denoted as keratose (KOS) while the reduced form of KRT is termed as kerateine (KRTN). KOS can be processed into various forms (e.g., hydrogel, films, fibers, and coatings) for different biomedical applications. KRT/KOS offers numerous advantages over other types of biomaterials, such as bioactivity, biocompatibility, degradability, immune/inflammatory privileges, mechanical resilience, chemical manipulability, and easy accessibility. As a result, KRT/KOS has attracted considerable attention and led to a large number of publications associated with this biomaterial over the past few decades; however, most (if not all) of the published review articles focus on KRT regarding its molecular structure, biochemical/biophysical properties, bioactivity, biocompatibility, drug/cell delivery, and in vivo transplantation, as well as its applications in biotechnical products and medical devices. Current progress that is directly associated with KOS applications in tissue regeneration and drug delivery appears an important topic that merits a commentary. To this end, the present review aims to summarize the current progress of KOS-associated biomedical applications, especially focusing on the in vitro and in vivo effects of KOS hydrogel on cultured cells and tissue regeneration following skin injury, skeletal muscle loss, peripheral nerve injury, and cardiac infarction.

To study the epidemiological correlation and drug resistance of external factors of infection caused by open injury of limbs to pathogens.This experiment is a retrospective study. We took the geographical location and climate of Nanchang, Jiangxi Province, China as the background, analyzed 2017 strains of pathogens from 1589 patients with limb trauma infection in a University Affiliated Hospital from 2012 to 2017. Patients were divided into three groups according to the type of incision: I, In-hospital infection of clean limb incision, II, In-hospital infection with open injury, III, Community infection with open injury of the limb. Groups II and Groups III were divided into six subgroups according to the causes of trauma, including: accidents from non-motor vehicles, machinery, cutting/piercing, pedestrian injuries, struck by/against, pedal cycles, and other injuries. We found eight common pathogens of orthopedic infection, which were mainly divided into Gram-positive bacteria (G+, mainly including Staphylococcus) and Gram-negative bacteria (G-, mainly Enterobacteriaceae). The relationship between main pathogens and damage mechanism, apparent temperature and relative humidity was discussed in this study. SPSS v22.0 was used for statistical analysis of the data. Friedman's two-way ANOVA was used to analyze the difference between the injury mechanism and incidence of pathogenic bacteria. Linear regression was used to determine the trend between the incidence of major pathogens and seasonal temperature and humidity. The level of significance was set as P 0.05.There was no significant difference in the distribution of pathogens between Groups II and Groups III (P0.05). The drug resistance of Groups III was significantly higher than that of Groups II and Groups I. G+ bacteria were resistant to cephalosporin, ceftriaxone and other cephalosporins and erythromycin and other macrolides. They were sensitive to vancomycin and linezolid. G- were resistant to the first- and the second-generation cephalosporins, including cefotetan and cefazolin, and ampicillin and other penicillins, while they were sensitive to third-generation cephalosporins, such as ceftazidime, as well as to levofloxacin and other quinolones, meropenem, and other beta-lactamases. The correlation between the injury mechanism and infection of pathogenic bacteria was not significant. The monthly average apparent temperature and relative humidity were correlated with the infection rate of pathogenic bacteria.In open injury of extremities, apparent temperature and relative humidity is an important risk factor for infection by pathogenic bacteria and the drug resistance of pathogenic bacteria in out-of-hospital infection was lower than that of hospital infection.

HMOs (human milk oligosaccharides) are the third most important nutrient in breast milk. As complex glycans, HMOs play an important role in regulating neonatal intestinal immunity, resisting viral and bacterial infections, displaying anti-inflammatory characteristics, and promoting brain development. Although there have been some previous reports of HMOs, a detailed literature review summarizing the structure-activity relationships and dose-dependent effects of HMOs is lacking. Hence, after introducing the structures and synthetic pathways of HMOs, this review summarizes and categorizes identified structure-function relationships of HMOs. Differential mechanisms of different structural HMOs utilization by microorganisms are summarized. This review also emphasizes the recent advances in the interactions between different health benefits and the variance of dosage effect based on in vitro cell tests, animal experiments, and human intervention studies. The potential relationships between the chemical structure, the dosage selection, and the physiological properties of HMOs as functional foods are vital for further understanding of HMOs and their future applications.

Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite derived from trimethylamine- containing nutrient precursors such as choline, L-carnitine, and betaine, which are rich in many vegetables, fruits, nuts, dairy products, and meats. An increasing number of clinical studies have demonstrated a strong relationship between elevated plasma TMAO levels and adverse cardiovascular events. It is commonly agreed that TMAO acts as an independent risk factor and a prognostic index for patients with cardiovascular disease. Although most animal (mainly rodent) data support the clinical findings, the mechanisms by which TMAO modulates the cardiovascular system are still not well understood. In this context, we provide an overview of the potential mechanisms underlying TMAO-induced cardiovascular diseases at the cellular and molecular levels, with a focus on atherosclerosis. We also address the direct effects of TMAO on cardiomyocytes (a new and under-researched area) and finally propose TMAO as a potential biomarker and/or therapeutic target for diagnosis and treatment of patients with cardiovascular disease.

The detection of microRNA (miRNA) in human serum has great significance for cancer prevention. Herein, a novel self-powered biosensing platform is developed, which effectively integrates an enzymatic biofuel cell (EBFC)-based self-powered biosensor with a matching capacitor for miRNA detection. A catalytic hairpin assembly and hybrid chain reaction are used to improve the analytical performance of EBFC. Furthermore, the matching capacitor is selected as an auxiliary signal amplifying device, and graphdiyne is applied as substrate material for EBFC. The results confirm that the developed method obviously increases the output current of EBFC, and the sensitivity can reach 2.75 μA/pM, which is 786% of pure EBFC. MiRNA can be detected in an expanded linear range of 0.1-100000 fM with a detection limit of 0.034 fM (S/N = 3). It can offer a selective and sensitive platform for nucleotide sequence detection with great potential in clinical diagnostics.

Current medicinal treatments for diseases comprise largely of two categories: small molecular (chemical) (e.g., aspirin) and larger molecular (peptides/proteins, e.g., insulin) drugs. Whilst both types of therapeutics can effectively treat different diseases, ranging from well-understood (in view of pathogenesis and treatment) examples (e.g., flu), to less-understood chronic diseases (e.g., diabetes), classical small molecule drugs often possess significant side-effects (a major cause of drug withdrawal from market) due to their low- or non-specific targeting. By contrast, therapeutic peptides, which comprise short sequences from naturally occurring peptides/proteins, commonly demonstrate high target specificity, well-characterized modes-of-action, and low or non-toxicity in vivo. Unfortunately, due to their small size, linear permutation, and lack of tertiary structure, peptidic drugs are easily subject to rapid degradation or loss in vivo through chemical and physical routines, thus resulting in a short half-life and reduced therapeutic efficacy, a major drawback that can reduce therapeutic efficiency. However, recent studies demonstrate that the short half-life of peptidic drugs can be significantly extended by various means, including use of enantiomeric or non-natural amino acids (AAs) (e.g., L-AAs replacement with D-AAs), chemical conjugation [e.g., with polyethylene glycol], and encapsulation (e.g., in exosomes). In this context, we provide an overview of the major in vivo degradation forms of small therapeutic peptides in the plasma and anti-degradation strategies. We also update on the progress of small peptide therapeutics that are either currently in clinical trials or are being successfully used in clinical therapies for patients with non-infectious diseases, such as diabetes, multiple sclerosis, and cancer. Accepted version

This multicenter prospective, randomized controlled clinical trial compared the clinical performance of supraglottic airway device (SAD) BlockBusterA total of 651 adult patients scheduled for elective surgery in 13 hospitals were randomly allocated into BlockBuster group (n = 351) or Supreme group (n = 300). The primary outcome was oropharyngeal leak pressure (OLP). Duration and ease of insertion, fiberscopic view of positioning, airway manipulations, and complications were also assessed.The OLP was significantly higher in BlockBuster group compared with Supreme group (29.9 ± 4.2 cmHBoth SAD BlockBusterThe trial is registered at www.chictr.org.cn (ChiCTR-ONC-16009105).

To study the effect of orthodontic treatment with extraction on root resorption and alveolar bone morphology of the central incisor in adult patients.Eleven adult patients receiving orthodontic treatment were enrolled, and asked to take cone-beam CT(CBCT) scanning before and after treatment. Root resorption of the upper and lower central incisors after treatment, changes in alveolar bone thickness and height of alveolar bone were measured and compared. Statistical analysis was performed using SPSS 23.0 software package.The length of the tooth and root was reduced to a certain degree. The change in root length of the maxillary incisor was larger than that of the mandibular incisor. The alveolar bone width of the lingual and palatal neck of the central incisor showed some reduction, and alveolar bone width of the palatal neck of the upper central incisor and the middle lingual side of the mandibular central incisor changed to a certain extent. The width of the alveolar bone in the middle labial side of the mandibular central incisor increased, but the alveolar bone on the lingual and palatal side increased after orthodontic treatment, which was more obvious than that of the maxillary central incisor.Orthodontic treatment with tooth extraction is accompanied by a certain degree of root resorption of the central incisor and alveolar bone on the lingual and palatal side. However it is also accompanied by an increase in the amount of alveolar bone on the labial side. More fenestration and dehiscence are observed in the mandible.

Introduction Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swept rapidly throughout the world. So far, no therapeutics have yet proven to be effective. Ribavirin was recommended for the treatment of COVID-19 in China because of its in vitro activity. However, evidence supporting its clinical use with good efficacy is still lacking. Methods A total of 208 confirmed severe COVID-19 patients who were hospitalized in Wuhan Union West Campus between 1 February 2020 and 10 March 2020 were enrolled in the retrospective study. Patients were divided into two groups based on the use of ribavirin. The primary endpoint was the time to clinical improvement. The secondary endpoints included mortality, survival time, time to throat swab SARS-CoV-2 nucleic acid negative conversion, and the length of hospital stay. Results 68 patients were treated with ribavirin while 140 not. There were no significant between-group differences in demographic characteristics, baseline laboratory test results, treatment, and distribution of ordinal scale scores at enrollment, except for coexisting diseases especially cancer (ribavirin group vs no ribavirin group, P = 0.01). Treatment with ribavirin was not associated with a difference in the time to clinical improvement (P = 0.48, HR = 0.88, 95% CI = 0.63–1.25). There were also no significant differences between-group in SARS-CoV-2 nucleic acid negative conversion, mortality, survival time, and the length of hospital stay. Conclusions In hospitalized adult patients with severe COVID-19, no significant benefit was observed with ribavirin treatment.

Current medicinal treatments for diseases comprise largely of two categories: small molecular (chemical) (e.g., aspirin) and larger molecular (peptides/proteins, e.g., insulin) drugs. Whilst both types of therapeutics can effectively treat different diseases, ranging from well-understood (in view of pathogenesis and treatment) examples (e.g., flu), to less-understood chronic diseases (e.g., diabetes), classical small molecule drugs often possess significant side-effects (a major cause of drug withdrawal from market) due to their low- or non-specific targeting. By contrast, therapeutic peptides, which comprise short sequences from naturally occurring peptides/proteins, commonly demonstrate high target specificity, well-characterized modes-of-action, and low or non-toxicity in vivo. Unfortunately, due to their small size, linear permutation, and lack of tertiary structure, peptidic drugs are easily subject to rapid degradation or loss in vivo through chemical and physical routines, thus resulting in a short half-life and reduced therapeutic efficacy, a major drawback that can reduce therapeutic efficiency. However, recent studies demonstrate that the short half-life of peptidic drugs can be significantly extended by various means, including use of enantiomeric or non-natural amino acids (AAs) (e.g., L-AAs replacement with D-AAs), chemical conjugation [e.g., with polyethylene glycol], and encapsulation (e.g., in exosomes). In this context, we provide an overview of the major in vivo degradation forms of small therapeutic peptides in the plasma and anti-degradation strategies. We also update on the progress of small peptide therapeutics that are either currently in clinical trials or are being successfully used in clinical therapies for patients with non-infectious diseases, such as diabetes, multiple sclerosis, and cancer.

Long-term use of a unilateral cochlear implant (CI) may lead to abnormal development of contralateral auditory pathway.To investigate the usefulness of measuring the electrically evoked auditory brainstem response (eABR) with the electrical stimulation at the round window membrane and the effect of unilateral CI use on the contralateral auditory pathway functions.According to duration of unilateral CI use, 45 children with severe or profound sensorineural hearing loss were divided into sCI (≤12 months), lCI (≥24 months) and nCI (no CI use) groups. Intra-operative eABRs evoked by electrical stimulation at the round window membrane were recorded.The latencies of eIII and eV were significantly longer in lCI group than in sCI group and in nCI group, respectively, but not significantly different between sCI group and nCI group. The eABR thresholds and eIII-eV latency intervals were not significantly different among three groups.The eABR evoked by the electrical stimulation at the round window membrane is a reliable and effective way of evaluating functions of the auditory pathway in deaf children. Long-term use of a unilateral CI may promote the degenerative process of the contralateral auditory pathway to the level of the brainstem.

Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) directly interact with intracellular interleukin receptor associated kinase (IRAK) family members to initialize innate immune and inflammatory responses following activation by pathogen-associated or hostderived elements. Although four IRAK family members [IRAK1, 2, 3 (i.e., IRAK-M), and 4] are involved in TLR and IL-1R signaling pathways, IL-1R > IRAK1 signaling appears to be the most studied pathway, with sufficient evidence to support its central role linking the innate immune response to the pathogenesis of various diseases, including cancers, metabolic disorders, and non-infectious immune disorders. However, IRAK1's involvement in cardiovascular diseases was only recently revealed and the detailed mechanism underling the pathogenesis of cardiovascular diseases, such as atherosclerosis, myocardial infarction, and heart failure (all non-infectious disorders), remains largely unknown with very limited publications to date. This review aims to summarize the overall roles of the IRAK family, especially IRAK1, in mediating the development of cardiovascular diseases. NIH [1R15HL140528-01]; College of Veterinary Medicine at Virginia Tech; Edward Via College of Osteopathic Medicine, Interdisciplinary Graduate Education Program of Regenerative Medicine; Internal Research Competition (IRC) [178391] Published version This work was supported by the NIH grant (1R15HL140528-01 for JQH) , One-Health seed grant (PJ6SPVHJ for JQH) by the College of Veterinary Medicine at Virginia Tech and the Edward Via College of Osteopathic Medicine, Interdisciplinary Graduate Education Program of Regenerative Medicine (IGEP-RM for YJZ) , and Internal Research Competition (IRC) Seed Grant (#178391 for JQH) by the College of Veterinary Medicine at Virginia Tech. The funders had no role in the study design, data collection and analysis, decision to publish, and preparation of the manuscript.

Circular RNAs (circRNAs) are a class of single-stranded RNAs with closed loop structures formed by covalent bonds of head and tail. Exploration of circRNAs is continually increasing; however, their functional relevance largely remains to be elucidated. In general, they are stable, abundant, conserved and expressed in tissue-specific manner. These distinct properties and their diverse cellular actions indicate that circRNAs modulate transcription and translation, and may even function as translation templates. Growing evidence reveals that circRNAs contribute to various physiological and pathological processes, including the initiation and progression of cancer. In this review, we present the current knowledge about circRNAs in cancer development, as well as their potential for use as biomarkers and even therapeutic targets. CircRNA's role in immune regulation and antitumour immunotherapy is also discussed. In addition, possible challenges in antitumour therapy are raised, and current progress and future perspectives are provided.

Few studies have investigated the effects of air pollutants on children with acute bronchitis. This study aimed to explore the acute effects of four air pollutants [fine particulate matter (PMThe 49,975 records of hospitalized children with acute bronchitis from medical institutions in nine cities/prefectures, Sichuan Province, China, as well as the simultaneous meteorological data and air pollution data from 183 monitoring sites, were collected from 1 January 2017 to 31 December 2018. A generalized additive model was adopted to analyze the exposure-response and lag effects of hospitalizations of children with acute bronchitis to air pollutants. Stratified analyses were conducted based on sex, age, and season.The single-pollutant model showed that a 10 µg/mThe higher daily average concentrations of four pollutants in Sichuan Province can result in an increased number of children hospitalized for acute bronchitis.

The vestibular aqueduct (VA) width may affect the auditory conduction pathway of large vestibular aqueduct syndrome (LVAS) children.Analyzing the electrically evoked auditory brainstem response (EABR) after cochlear implantation (CI) in severe to profound sensorineural hearing loss (SNHL) children with LVAS.Fifty-four children with SNHL who received CI were selected, including 21 children with LVAS and 33 children without inner ear malformations (IEMs). The VA width was measured in LVAS children. The post-operative EABRs were recorded in all children.For the LVAS group, the VA width was positively correlated with wave III (eIII) latency of EABR at the No. 2 electrode (E2), E5, E8, and E11, the VA width was positively correlated with wave V (eV) latency of EABR at E2, E5, E8, and E11. Only the eV latency of E2 showed a significant difference between the two groups.SNHL children with LVAS and no IEMs have similar conduction of the auditory pathway. In the LVAS group, the conduction of the auditory pathway becomes better with the decrease of VA width. Rational use of post-operative EABRs and the measurement of anatomical parameters can effectively assess the development of part auditory pathways in LVAS children, which may be helpful in predicting post-operative speech and hearing recovery.

Since more than 85% of lung cancer cases are non-small cell lung cancer (NSCLC), finding novel agents with anti-tumor activities is meaningful for NSCLC patients. Mitochondria is essential for cellular energy metabolism in cancer, and regulating mitochondrial bioenergetics is emerging as a practical approach for cancer treatment and prevention. The carbazole scaffold is an active structure showing anti-cancer biological activity, and the structural diversity has been expanded through the improvement and optimization of synthesizing methods. To find novel carbazole derivatives with great anti-tumor potential and explore structures variety, we designed and synthesized a series of 9-(pyrimidin-2-yl)-9H-carbazole derivatives based on the previously reported Cp∗Rh(III)/H

To obtain the normative values of the testis volume of 0－14 years old Chinese boys by ultrasound measurement.We collected the testicular ultrasound data on 1607 Chinese boys with normal testes between January 2016 and June 2019. The boys were aged 0－14 years and divided into 14 age groups, with at least 100 cases in each group. We compared the mean, standard deviation and median of the testis volume among different age groups.The testis grew slowly in volume before 8 years old (0.372－0.678 ml), faster after 9 years old (1.040－4.600 ml), (1.040 ± 0.970) ml at 9－10 years, (1.876 ± 1.631) ml at 10－11 years, (2.831 ± 2.155) ml at 11－12 years, (3.640 ± 2.376) ml at 12－13 years, and (4.600 ± 3.559) ml at 13－14 years, larger in the 0－1 than in the 1－2 years group (［0.403 ± 0.130］ vs ［0.372 ± 0.110］ ml, P = 0.04), negatively correlated in age between the two groups.Ultrasonography is an effective method for the measurement of the testis volume, which can provide the normative values of the testis volume of the 0－14 years old Chinese boys and some evidence for clinical diagnosis and consultation.

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.

To investigate the auditory pathway functions in deaf patients with Mondini malformation using the electrically evoked auditory brainstem response (EABR) during cochlear implantation (CI).A total of 58 patients with severe to profound sensorineural hearing loss (SNHL) were included in this study. Of these patients, 27 cases had Mondini malformation and 31 control cases had no inner ear malformations (IEMs). Intraoperative EABRs evoked by electrical stimulation at the round window niche (RWN) and round window membrane (RWM) were recorded.Patients with Mondini malformation showed significantly lower EABR extraction rates than those with no IEMs did. However, for patients who showed EABRs, no significant difference in EABR thresholds, wave III (eIII) latencies, wave V (eV) latencies or eIII-eV latency intervals was found between two groups.The physiological functions of the peripheral auditory system in patients with Mondini malformation may divide into opposite extremes, as revealed by a robust EABR and the absence of the EABR, respectively. The auditory conduction function should be objectively and individually evaluated for patients with Mondini malformation by the EABR.

Tendinopathy is a complex multifaceted tendinopathy often associated with overuse and with its high prevalence resulting in significant health care costs. At present, the pathogenesis and effective treatment of tendinopathy are still not sufficiently elucidated. The purpose of this research is to intensely explore the genes, functional pathways, and immune infiltration characteristics of the occurrence and development of tendinopathy. The gene expression profile of GSE106292, GSE26051 and GSE167226 are downloaded from GEO (NCBI comprehensive gene expression database) and analyzed by WGCNA software bag using R software, GSE26051, GSE167226 data set is combined to screen the differential gene analysis. We subsequently performed gene enrichment analysis of Gene Ontology (GO) and "Kyoto Encyclopedia of Genes and Genomes" (KEGG), and immune cell infiltration analysis. By constructing the LASSO regression model, Support vector machine (SVM-REF) and Gaussian mixture model (GMMs) algorithms are used to screen, to identify early diagnostic genes. We have obtained a total of 171 DEGs through WGCNA analysis and differentially expressed genes (DEGs) screening. By GO and KEGG enrichment analysis, it is found that these dysregulated genes were related to mTOR, HIF-1, MAPK, NF-κB and VEGF signaling pathways. Immune infiltration analysis showed that M1 macrophages, activated mast cells and activated NK cells had infiltration significance. After analysis of THE LASSO SVM-REF and GMMs algorithms, we found that the gene MACROD1 may be a gene for early diagnosis. We identified the potential of tendon disease early diagnosis way and immune gene regulation MACROD1 key infiltration characteristics based on comprehensive bioinformatics analysis. These hub genes and functional pathways may as early biomarkers of tendon injuries and molecular therapy level target is used to guide drug and basic research.

Nuclear factor (NF)-κB–ty -50mediated neuroinflammation plays a crucial role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). As an important negative feedback regulator of NF-κB, A20 is essential for inflammatory homeostasis. Herein, we tested the hypothesis that A20 attenuates EBI by establishing NF-κB–associated negative feedback after experimental SAH. In vivo and in vitro models of SAH were established. TPCA-1 and lentivirus were used for NF-κB inhibition and A20 silencing/overexpression, respectively. Cellular localization of A20 in the brain was determined via immunofluorescence. Western blotting and enzyme-linked immunosorbent assays were applied to observe the expression of members of the A20/tumor necrosis factor receptor-associated factor 6 (TRAF6)/NF-κB pathway and inflammatory cytokines (IL-6, IL-1β, TNF-α). Evans blue staining, TUNEL staining, Nissl staining, brain water content, and modified Garcia score were performed to evaluate the neuroprotective effect of A20. A20 expression by astrocytes, microglia, and neurons was increased at 24 h after SAH. A20 and inflammatory cytokine levels were decreased while TRAF6 expression was elevated after NF-κB inhibition. TRAF6, NF-κB, and inflammatory cytokine levels were increased after A20 silencing but suppressed with A20 overexpression. Also, Bcl-2, Bax, MMP-9, ZO-1 protein levels; Evans blue, TUNEL, and Nissl staining; brain water content; and modified Garcia score showed that A20 exerted a neuroprotective effect after SAH. A20 expression was regulated by NF-κB. In turn, increased A20 expression inhibited TRAF6 and NF-κB to reduce the subsequent inflammatory response. Our data also suggest that negative feedback regulation mechanism of the A20/TRAF6/NF-κB pathway and the neuroprotective role of A20 to attenuate EBI after SAH.

Metabolic syndrome (MetS) is a set of complex, chronic inflammatory conditions that are characterized by central obesity and associated with an increased risk of cardiovascular diseases. In recent years, microRNAs (miRNAs) have become an important type of endocrine factors, which play crucial roles in maintaining energy balance and metabolic homeostasis. However, its unfavorable properties such as easy degradation in blood and off-target effect are still a barrier for clinical application. Nanosystem based delivery possess strong protection, high bioavailability and control release rate, which is beneficial for success of gene therapy. This review first describes the current progress and advances on miRNAs associated with MetS, then provides a summary of the therapeutic potential and targets of miRNAs in metabolic organs. Next, it discusses recent advances in the functionalized development of classic delivery systems (exosomes, liposomes and polymers), including their structures, properties, functions and applications. Furthermore, this work briefly discusses the intelligent strategies used in emerging novel delivery systems (selenium nanoparticles, DNA origami, microneedles and magnetosomes). Finally, challenges and future directions in this field are discussed provide a comprehensive overview of the future development of targeted miRNAs delivery for MetS treatment. With these contributions, it is expected to address and accelerate the development of effective NA delivery systems for the treatment of MetS.

Fifteen chalcone derivatives 3a-3o were synthesized, and evaluated as multifunctional agents against Alzheimer's disease. In vitro studies revealed that these compounds inhibited self-induced Aβ1-42 aggregation effectively ranged from 45.9-94.5 % at 20 μM, and acted as potential antioxidants. Their structure-activity relationships were summarized. In particular, (2E)-3-[4-(dimethylamino)phenyl]-1-(pyridin-2-yl)prop-2-en-1-one (3g) exhibited an excellent inhibitory activity of 94.5 % at 20 μM, and it could disassemble the self-induced Aβ1-42 aggregation fibrils with ratio of 57.1 % at 20 μM concentration. In addition, compound 3g displayed good chelating ability for Cu2+ , and could effectively inhibit and disaggregate Cu2+ -induced Aβ aggregation. Moreover, compound 3g exerted low cytotoxicity, significantly reversed Aβ1-42 -induced SH-SY5Y cell damage. More importantly, compound 3g remarkably ameliorated scopolamine-induced memory impairment in mice. In summary, all the results revealed compound 3g was a potential multifunctional agent for AD therapy.

Selenium (Se) is an essential element for the maintenance of a healthy physiological state. However, due to environmental and dietary factors and the narrow safety range of Se, diseases caused by Se deficiency or excess have gained considerable traction in recent years. In particular, links have been identified between low Se status, cognitive decline, immune disorders, and increased mortality, whereas excess Se increases metabolic risk. Considerable evidence has suggested microRNAs (miRNAs) regulate interactions between the environment (including the diet) and genes, and play important roles in several diseases, including cancer. MiRNAs target messenger RNAs to induce changes in proteins including selenoprotein expression, ultimately generating disease. While a plethora of data exists on the epigenetic regulation of other dietary factors, nutrient Se epigenetics and especially miRNA regulated mechanisms remain unclear. Thus, this review mainly focuses on Se metabolism, pathogenic mechanisms, and miRNAs as key regulatory factors in Se-related diseases. Finally, we attempt to clarify the regulatory mechanisms underpinning Se, miRNAs, selenoproteins, and Se-related diseases.

Lung cancer is the most commonly diagnosed cancer with a high mortality rate. Cisplatin is one of the most important chemotherapeutic agents for the treatment of lung cancer patients, especially in advanced stages. Recent studies showed that cisplatin may interact with mitochondria which may partly account for its cytotoxicity. In the study, we explored the effect of resistin on cisplatin-induced cytotoxicity in A549 cells and assessed whether mitochondria-dependent apoptosis was involved. Our results found that 25 ng/ml resistin could significantly increase cisplatin-induced apoptosis and G2/M phase arrest, enhance reactive oxygen species generation, exacerbate the collapse of mitochondrial membrane potential, promote the distribution of cytochrome C in the cytoplasm from mitochondria, and activate caspase 3. Therefore, the results suggested that resistin might increase cisplatin-induced cytotoxicity via a mitochondria-mediated pathway in A549 cells. However, the precise mechanism has yet to be explored in the future.

Signal transducer and activator of transcription (STAT) 3 plays a vital role in carcinogenesis and drug response. Platinum-based chemotherapy is the first-line treatment for lung cancer patients, especially those in advanced stages. In the present study, we investigated the association of STAT3 polymorphism rs4796793 with lung cancer susceptibility, platinum-based chemotherapy response, and toxicity. A total of 498 lung cancer patients and 213 healthy controls were enrolled in the study. 467 of them received at least 2-cycle platinum-based chemotherapy. Unconditional logistical regression analysis was used to assess the associations. STAT3 rs4769793 G allele carriers had an increased susceptibility of lung cancer [additive model: adjusted OR (95% CI) 1.376 (1.058–1.789), P = 0.017; recessive model: adjusted OR (95% CI) 1.734 (1.007–2.985), P = 0.047]. Rs4769793 was not significantly associated with platinum-based chemotherapy response in lung cancer patients. STAT3 rs4796793 was associated with an increased risk of severe overall toxicity [additive model: adjusted OR (95% CI) 1.410 (1.076–1.850), P = 0.013; dominant model: adjusted OR (95% CI) 1.638 (1.091–2.459), P = 0.017], especially hematological toxicity [additive model: adjusted OR (95% CI) 1.352 (1.001–1.826), P = 0.049]. STAT3 rs4796793 may be considered as a potential candidate biomarker for the prediction of susceptibility and prognosis in Chinese lung cancer patients. However, well-designed studies with larger sample sizes are required to verify the results.

Purpose: Whether preexisting sarcopenia is an independent risk factor for cancer incidence remains unclear. Therefore, we performed this propensity score (PS)-matched (PSM) population-based cohort study to compare the incidence rate ratios (IRRs) of specific cancers between patients with and without sarcopenia. Patients and Methods: The patients were categorized into two groups according to the presence or absence of sarcopenia, matched at a 4:1 ratio. Results: PS matching yielded a final cohort of 77,608 patients (15,527 in the sarcopenia and 62,081 nonsarcopenia groups) eligible for further analysis. In our multivariate Cox regression analysis, compared with the nonsarcopenia group, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) for cancer risk in the sarcopenia group was 1.277 (1.10 to 1.36; p < 0.001). Furthermore, the adjusted IRRs (95% CIs) for sarcopenia patients were pancreatic cancer 3.77 (1.79 to 4.01), esophageal cancer 3.38 (1.87 to 4.11), lung cancer 2.66 (1.15 to 2.90), gastric cancer 2.25 (1.54 to 3.23), head and neck cancer 2.15 (1.44 to 2.53), colorectal cancer 2.04 (1.77 to 2.30), hepatocellular carcinoma 1.84 (1.30 to 2.36), breast cancer 1.56 (1.12 to 1.95), and ovarian cancer 1.43 (1.10 to 2.29), respectively. Conclusions: Sarcopenia might be a significant cancer risk factor for lung, colorectal, breast, head and neck, pancreas, gastric, esophageal, and ovarian cancer, as well as hepatocellular carcinoma.

Serine/arginine-rich splicing factor 3 (SRSF3) regulates mRNA alternative splicing of more than 90% of protein-coding genes, providing an essential source for biological versatility. This study finds that SRSF3 expression is associated with drug resistance and poor prognosis in pancreatic cancer. We also find that SRSF3 regulates ANRIL splicing and m6A modification of ANRIL in pancreatic cancer cells. More importantly, we demonstrate that m6A methylation on lncRNA ANRIL is essential for the splicing. Moreover, our results show that SRSF3 promotes gemcitabine resistance by regulating ANRIL's splicing and ANRIL-208 (one of the ANRIL spliceosomes) can enhance DNA homologous recombination repair (HR) capacity by forming a complex with Ring1b and EZH2. In conclusion, this study establishes a link between SRSF3, m6A modification, lncRNA splicing, and DNA HR in pancreatic cancer and demonstrates that abnormal alternative splicing and m6A modification are closely related to chemotherapy resistance in pancreatic cancer.

Glutathione peroxidase 1 (GPX1) is a selenium-dependent enzyme that reduces intracellular hydrogen peroxide and lipid peroxides. While past research explored regulations of gene expression and biochemical function of this selenoperoxidase, GPX1 has recently been implicated in the onset and development of chronic diseases. Clinical data have shown associations of human GPX1 gene variants with elevated risks of diabetes. Knockout and overexpression of Gpx1 in mice may induce types 1 and 2 diabetes-like phenotypes, respectively. This review assembles the latest advances in this new field of selenium biology, and attempts to postulate signal and molecular mechanisms mediating the role of GPX1 in glucose and lipid metabolism-related diseases. Potential therapies by harnessing the beneficial effects of this ubiquitous redox-modulating enzyme are briefly discussed.

To investigate the expression of immunoglobulin G (IgG) and its subclasses in patients with multiple myeloma (MM) and lymphoma (LYM) and its correlation with blood cell parameters.129 patients with multiple myeloma and 113 patients with lymphoma diagnosed treated in Sichuan people's Hospital from January to December 2019 were selected and the total IgG and subclass IgG1, IgG2, IgG3 and IgG4, and some parameters of peripheral blood routine in patients were retrospective analyzed. Independent sample t test or nonparametric Mann Whitney U test were used for comparison between the groups. The relationship between IgG subclass and blood cell parameters was analyzed by correlation analysis. For the bivariate normal distribution data, Pearson correlation coefficient was calculated. For bivariate non normal distribution data, the Spearman correlation coefficient was calculated.IgG1 and IgG2 were significantly higher in patients with multiple myeloma than in patients with lymphoma (P=0.001, 0.000, respectively), but IgG3 and IgG4 were significantly lower than in patients with lymphoma (P=0.000, 0.000, respectively), and there was no significant difference for total serum IgG between the two groups (P=0.717). The results showed that the IgG4 content of male patients with multiple myeloma and lymphoma was significantly higher than that of female patients (Z=-3.191, P=0.001); the age, M%, E% of the MM patients were significantly higher than those of the patients with lymphoma (P=0.000, 0.005, 0.019), but WBC, RBC, Hb were significantly lower than those of the patients with lymphoma (P=0.013, 0.000, respectively). The results of Spearman correlation analysis showed that RBC and Hb were decreased with the increasing of IgG and IgG1 in the MM patients(r=0.254, -0.272, -0.248 and -0.289, P=0.004, 0.002, 0.005 and 0.001). With the increasing of IgG4 in the serum of patients with lymphoma, RBC and Hb showed the trendy of decreased (r=-0.240 and, -0.251, respectively, P=0.010, 0.007).The detection of IgG subclass and the correlation between IgG subclass and blood cell parameters are great value in the diagnosis and pathogenesis of multiple myeloma and lymphoma.多发性骨髓瘤和淋巴瘤患者IgG亚类分析及其与血细胞参数的相关性.探讨多发性骨髓瘤（multiple myloma, MM）和淋巴瘤(Lymphoma)患者免疫球蛋白G（immunoglobulin G, IgG）及其亚类的表达水平差异及与血细胞参数的相关性.选择2019年1月-12月在四川省人民院确诊的MM患者129例和淋巴瘤患者113例，分别对总IgG和亚类IgG1、IgG2、IgG3和IgG4及与外周血常规部分参数进行回顾性分析。组间比较采用独立样本t检验或非参数Mann-Whitney U检验，IgG亚类与血细胞参数的关系采用相关分析，对于双变量正态分布资料则计算Pearson相关系数。对于双变量非正态分布资料则计算Spearman相关系数.多发性骨髓瘤患者IgG1和IgG2水平明显高于淋巴瘤患者（P=0.001，P=0.000），IgG3和IgG4水平明显低于淋巴瘤患者（P=0.000，P=0.000），血清总IgG在2组间没有显著差异（P=0.717）；按性别进行分组后的结果显示，男性多发性骨髓瘤和淋巴瘤患者IgG4含量均明显高于女性患者，差异具有统计学意义(Z=-3.191, P=0.001)；多发性骨髓瘤患者的发病年龄、M%、E%明显高于淋巴瘤患者（P=0.000, P=0.005, P=0.019）, 而WBC、RBC、Hb明显低于淋巴瘤患者（P=0.013, P=0.000, P=0.014）。Spearman相关分析显示，随着多发性骨髓瘤患者血清中总IgG与IgG1含量的增高，RBC、Hb有降低趋势（r=-0.254，r=-0.272，r=-0.248和r=-0.289）。随着淋巴瘤患者血清中IgG4含量的增高，患者 RBC、Hb有降低的趋势（r=-0.240,r=-0.251）.IgG亚类检测及与血细胞参数的相关性研究对多发性骨髓瘤和淋巴瘤的诊断及发病机理的探讨等具有重要的临床意义.

Background Acetabular roof lesions (ARLs) in children are uncommon and may involve a variety of diseases. The acetabular roof is the main weight-bearing area of the hip joint, and lesions affecting the acetabular roof lead to fluid accumulation in the hip joint, causing hip pain and claudication. Methods for diagnosing and treating ARLs and the prognosis after treatment are rarely reported. We present our experience in a group of children and teenagers with ARLs to retrospectively explore the clinical and imaging features and histopathological diagnosis and report the treatment methods and follow-up observations. Methods Patients with ARLs admitted to the Children’s Hospital of Chongqing Medical University from April 2011 to September 2018 were selected retrospectively. We collected the basic information of patients (name, sex, age), main symptoms and signs, results of various laboratory tests, treatment methods, and intraoperative observations through the hospital medical record system. We collected X-ray, computed tomography (CT), magnetic resonance imaging (MRI) and pathological examination data through the Picture Archiving and Communications System. Follow-up data were collected through an outpatient medical record system, telephone, and chat software (such as WeChat). We used descriptive methods to analyze the lesion structure and destruction mode based on the imaging findings and histopathological diagnosis. Results There were 14 ARL patients, including 6 with eosinophilic granuloma (EG), 5 with chronic osteomyelitis, 2 with bone cyst, and 1 with tuberculosis. One patient underwent percutaneous needle biopsy, 2 underwent open biopsy, and 11 underwent curettage; among them, 5 patients also underwent bone grafting. These lesions had no characteristic imaging findings, and the diagnosis was mainly based on histopathological examination. Most patients showed complete symptom resolution and good hip function at the 1-year follow-up. Conclusion ARLs are not common in children. The types of lesions are diverse and mostly benign, with EG being most common. Malignant tumors may also occur, such as Ewing’s sarcoma, non-Hodgkin’s lymphoma, metastases and neuroblastoma. CT and MRI can be helpful in diagnosing certain cases, but incisional biopsy is required in most cases.

To explore the clinical efficacy of pancreaticoduodenectomy (PD) combined with vascular resection and reconstruction under robotic surgery system in the treatment of borderline resectable pancreatic cancer.The clinical data of 17 patients with borderline resectable pancreatic cancer who underwent PD combined with vascular resection and reconstruction (see the Video 1 in Supplemental Contents, http://ykxb.scu.edu.cn/article/doi/10.12182/20200760202) under robotic surgery system between August 2011 and September 2018 was analyzed retrospectively.There were 4 cases required conversion because of serious tumor invasion and soft pancreas texture, the other 13 cases were successfully completed. 16 cases (94%) achieved margin-negative resection (R0 resection), 14 cases combined with vein resection, and 3 cases combined with arterial resection. The mean operation time was (401±170) min, the mean blood loss was (647±345) mL, the mean postoperative length of hospital stay was (20±8) d. There was no perioperative death. Postoperative pathology findings and follow-up outcomes were as follows: 1 patient was diagnosed as intraductal papillary mucinous neoplasm (IPMN) and 1 patient was diagnosed as pancreatic neuroendocrine tumors (PNET) (Grade 1), 8 patients with pancreatic ductal adenocarcinoma (PDAC). 1 patient with pancreatic neuroendocrine carcinoma (PNEC) died because of tumor recurrence and metastasis during the follow-up period, the median (Min-Max) survival time was 12 (8-26) months. 5 patients with PDAC and 1 patient with malignant IPMN were currently in the follow-up period.It is safe and feasible to perform RPD with vascular resection and reconstruction. The patient's condition should be fully evaluated before surgery to select the most appropriate treatment.

Purpose Menopause is a crucial physiological transition during a woman’s life, and it occurs with growing risks of health issues like osteoporosis. To identify postmenopausal osteoporosis-related genes, we performed transcriptome-wide expression analyses for human peripheral blood monocytes (PBMs) using Affymetrix 1.0 ST arrays in 40 Caucasian postmenopausal women with discordant bone mineral density (BMD) levels. Methods We performed multiscale embedded gene coexpression network analysis (MEGENA) to study functionally orchestrating clusters of differentially expressed genes in the form of functional networks. Gene sets net correlations analysis (GSNCA) was applied to assess how the coexpression structure of a predefined gene set differs in high and low BMD groups. Bayesian network (BN) analysis was used to identify important regulation patterns between potential risk genes for osteoporosis. A small interfering ribonucleic acid (siRNA)-based gene silencing in vitro experiment was performed to validate the findings from BN analysis. Result MEGENA showed that the “T cell receptor signaling pathway” and the “osteoclast differentiation pathway” were significantly enriched in the identified compact network, which is significantly correlated with BMD variation. GSNCA revealed that the coexpression structure of the “Signaling by TGF-beta receptor complex pathway” is significantly different between the 2 BMD discordant groups; the hub genes in the postmenopausal low and high BMD group are FURIN and SMAD3 respectively. With siRNA in vitro experiments, we confirmed the regulation relationship of TGFBR2–SMAD7 and TGFBR1–SMURF2. Main Conclusion The present study suggests that biological signals involved in monocyte recruitment, monocyte/macrophage lineage development, osteoclast formation, and osteoclast differentiation might function together in PBMs that contribute to the pathogenesis of postmenopausal osteoporosis.

Background The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70–85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL. Methods The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs. Results The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129). Conclusions The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

This study aimed to evaluate the surgical technique and long-term clinical outcomes of all-inside arthroscopic treatment for flexor hallucis longus (FHL) tendon impingement syndrome. We retrospectively evaluated 34 FHL tendon impingement syndrome patients with complete follow-up data who were admitted from June 2015 to August 2018 and underwent the all-inside arthroscopy technique. The subjects consisted of 20 (58.82%) males and 14 (41.18%) females, with a mean age of 32.7 ± 10.2 (range 21-52) years. The cases consisted of 19 (55.88%) right and 15 (44.12%) left feet. The mean disease duration was 18.5 ± 9.1 (range 10-43) months. The visual analogue scale (VAS), American Orthopaedic Foot & Ankle Society (AOFAS), Karlsson Ankle Functional Score (KAFS), and 36-item Short Form Health Survey questionnaire (SF-36) scores for pain were 3.6 ± 1.2, 84.1 ± 9.6, 86.3 ± 10.7, and 94.7 ± 9.3, respectively. All patients were treated with all-inside posterior arthroscopy for the debridement of the FHL tendon sheath combined with partial muscle belly resection. Post-operative follow-up and observation of the patients' pain and ankle movement were evaluated using VAS, AOFAS, KAFS, and SF-36. All incisions were healed in the first stage, and no complications such as nerve, blood vessel, or tendon injuries occurred. The hospital stays were 3 to 5 days, with a mean of 3.7 ± 1.3 days. All patients were followed up for 12 to 36 months, with a mean follow-up time of 25.4 ± 8.5 months. By the last follow-up, the ankle joint and hallux movement were normal and returned to the pre-pain state for these patients. The VAS score decreased to 0.2 ± 0.1, while the AOFAS, KAFS, and SF-36 scores increased to 97.7 ± 8.5, 97.9 ± 8.2, and 118.2 ± 8.4, respectively. Advantages of all-inside posterior arthroscopic partial muscle belly resection for the treatment of FHL tendon impingement syndrome include small surgical trauma, fast functional recovery, and reliable outcomes. This procedure is therefore worthy of clinical attention and promotion.

Regeneration of cardiomyocytes, endothelial cells and vascular smooth muscle cells (three major lineages of cardiac tissues) following myocardial infarction is the critical step to recover the function of the damaged heart. Myeloid ecotropic viral integration site 1 (Meis1) was first discovered in leukemic mice in 1995 and its biological function has been extensively studied in leukemia, hematopoiesis, the embryonic pattering of body axis, eye development and various genetic diseases, such as restless leg syndrome. It was found that Meis1 is highly associated with Hox genes and their cofactors to exert its regulatory effects on multiple intracellular signaling pathways. Recently with the advent of bioinformatics, biochemical methods and advanced genetic engineering tools, new function of Meis1 has been found to be involved in the cell cycle regulation of cardiomyocytes and endothelial cells. For example, inhibition of Meis1 expression increases the proliferative capacity of neonatal mouse cardiomyocytes, whereas overexpression of Meis1 results in the reduction in the length of cardiomyocyte proliferative window. Interestingly, downregulation of one of the circular RNAs, which acts downstream of Meis1 in the cardiomyocytes, promotes angiogenesis and restores the myocardial blood supply, thus reinforcing better regeneration of the damaged heart. It appears that Meis1 may play double roles in modulating proliferation and regeneration of cardiomyocytes and endothelial cells post-myocardial infarction. In this review, we propose to summarize the major findings of Meis1 in modulating fetal development and adult abnormalities, especially focusing on the recent discoveries of Meis1 in controlling the fate of cardiomyocytes and endothelial cells.

Objective Language experience can develop long-term memory traces for speech units in the brain, to ensure efficient processing of speech sounds. However, prelingually deafened children lack sufficient auditory input before cochlear implantation. Whether the experience-dependent long-term memory traces exist in prelingually deafened children with cochlear implants (CIs) remains unclear. Methods We presented CI and normal hearing (NH) children with Mandarin Chinese spoken disyllables in an oddball paradigm and recorded event-related potentials. Each disyllable was defined as a meaningful word or a meaningless pseudoword by the tonal information in the second syllable. Results The amplitude of mismatch negativity (MMN) elicited by words was larger than that elicited by pseudowords in NH children. However, this enhancement of the MMN amplitude was not found in CI children. Behavioral results showed later recognition points for words and lower accuracies for speech comprehension in CI children than in NH children. Furthermore, increased theta power for words compared with pseudowords was only found in NH children. Conclusions Our findings indicate a deficit of long-term memory traces for words in prelingually deafened children with cochlear implants. Significance Early speech input may be crucial to the formation of long-term memory traces for speech units.

A series of indole-based [1,2,4]triazolo [4,3-a]pyridine derivatives was designed and synthesized as novel microtubulin polymerization inhibitors by using a conformational restriction strategy. These compounds exhibited moderate to potent anti-proliferative activities against a panel of cancer cell lines (HeLa, A549, MCF-7 and HCT116). Among them, compound 12d featuring a N-methyl-5-indolyl substituent at the C-6 position of the [1,2,4]triazolo [4,3-a]pyridine core exhibited the highest antiproliferative activity with the IC50 values ranging from 15 to 69 nM, and remarkable inhibitory effect on tubulin polymerization with an IC50 value of 1.64 μM. Mechanistic studies revealed that compound 12d induced cellular apoptosis and cell cycle arrest at the G2/M phase in a dose-dependent fashion. Moreover, compound 12d significantly suppressed wound closure and disturbed microtubule networks.

Compared with children having normal hearing (NH), those with cochlear implants (CIs) perform poorly in spoken language comprehension which involves both low-level acoustic encoding and higher-level cognitive processing. Here, we performed an electroencephalography study to portray this brain dynamics of speech perception in CI children. We presented a Mandarin Chinese monosyllable or four-syllable idiom to CI and NH children, and infrequently varied its lexical tone to form a novel monosyllable or pseudo-idiom in an oddball paradigm. The tone contrast embedded in the monosyllables evoked similar mismatch negativities (MMNs) in CI and NH children at an early stage (~200 ms). However, the amplitude of the MMN evoked by the tone contrast in the idiom context was significantly lower in CI children than in NH children. Furthermore, robust late discriminative negativity (LDN) at a late stage (~500 ms) was found only in NH children, but not in CI children. The MMN and LDN findings indicate deficits of low-level acoustic encoding in a complex context (such as an idiom) and higher-level cognitive processing in CI children, respectively. Both deficient sensory and cognitive processing may contribute to the speech perception difficulties in CI children.

Objectives To investigate the usefulness of measuring the electrically evoked auditory brainstem responses (eABRs) to electrical stimulation at the round window niche (RWN) and round window membrane (RWM) and the effect of deafness duration on functions of the auditory pathway to the level of the brainstem. Methods According to the age at cochlear implantation (CI), 99 children with profound sensorineural hearing loss were divided into four groups: ≤12 months (group A), 13–36 months (group B), 37–60 months (group C) and >60 months (group D). The eABRs were evoked by electrical stimulation at RWN and RWM during the operation of CI. Results The higher eABR extraction rate and lower threshold for RWM stimulation was found than those for RWN stimulation. The eⅢ latencies and eⅢ-eⅤ latency intervals for RWM stimulation were similar among four groups. However, children with earlier CI (group A) showed a significantly shorter eⅤ latency than others. Conclusion The eABR evoked by the electrical stimulation at RWM is more stable and sensitive compared with that at RWN for evaluating functions of the auditory conduction pathway. Development in the upper brainstem pathway may be more vulnerable to long-term deafness as revealed by the eⅤ latency.

Circular RNAs (circRNAs), a group of non-coding RNA characterized by the presence of covalent bonds linking 3' and 5' ends, act as miRNA sponges to participate in the tumorigenesis. Being stable, conserved and cell- or tissue-specific, circRNAs have shown their potentials as molecular markers for cancer. Convenient and noninvasive approaches may be developed based on the roles of circRNAs to diagnose or predict the prognosis of tumors. Although most of the potential mechanisms are not entirely clear, circRNAs have shown a universal and critical role in regulating cellular processes of cancers. This review summarized the classification, formation, characteristics, detection, and biological functions of circRNAs. We proposed the possibility of using circRNAs as biomarkers for cancer diagnosis, treatment and prognosis.

Stem cell-based therapies have demonstrated great potential for the treatment of cardiac diseases, for example, myocardial infarction; however, low cell viability, low retention/engraftment, and uncontrollable in vivo differentiation after transplantation are still major limitations, which lead to low therapeutic efficiency. Biomaterials provide a promising solution to overcome these issues due to their biocompatibility, biodegradability, low/nonimmunogenicity, and low/noncytotoxicity. The present study aimed to investigate the impacts of keratose (KOS) hydrogel biomaterial on cellular viability, proliferation, and differentiation of c-kit+ human cardiac stem cells (hCSCs). Briefly, hCSCs were cultured on both KOS hydrogel-coated dishes and regular tissue culture dishes (Blank control). Cell viability, stemness, proliferation, cellular morphology, and cardiac lineage differentiation were compared between KOS hydrogel and the Blank control at different time points. We found that KOS hydrogel is effective in maintaining hCSCs without any observable toxic effects, although cell size and proliferation rate appeared smaller on the KOS hydrogel compared to the Blank control. To our surprise, KOS hydrogel significantly promoted vascular smooth muscle cell (VSMC) differentiation (∼72%), while on the Blank control dishes, most of the hCSCs (∼78%) became cardiomyocytes. Furthermore, we also observed "endothelial cell tube-like" microstructures formed by differentiated VSMCs only on KOS hydrogel, suggesting a potential capability of the hCSC-derived VSMCs for in vitro angiogenesis. To the best of our knowledge, this is the first report to discover the preferred differentiation of hCSCs toward VSMCs on KOS hydrogel. The underlying mechanism remains unknown. This innovative methodology may offer a new approach to generate a robust number of VSMCs simply by culturing hCSCs on KOS hydrogel, and the resulting VSMCs may be used in animal studies and clinical trials in combination with an injectable KOS hydrogel to treat cardiovascular diseases.

Electrospun microfiber meshes have been shown to support the proliferation and differentiation of many types of stem cells, but the phenotypic fate of c-kit(+) human cardiac stem cells (hCSCs) have not been explored. To this end, we utilized thin (~5µm) elastomeric meshes consisting of aligned 1.7µm diameter poly (ester-urethane urea) microfibers as substrates to examine their effect on hCSC viability, morphology, proliferation, and differentiation relative to cells cultured on tissue culture polystyrene (TCPS). The results showed that cells on microfiber meshes displayed an elongated morphology aligned in the direction of fiber orientation, lower proliferation rates, but increased expressions of genes and proteins majorly associated with cardiomyocyte phenotype. The early (NK2 homeobox 5, Nkx2.5) and late (cardiac troponin I, cTnI) cardiomyocyte genes were significantly increased on meshes (Nkx=2.5 56.2±13.0, cTnl=2.9±0.56,) over TCPS (Nkx2.5=4.2±0.9, cTnl=1.6±0.5, n=9, p0.05 for both groups) after differentiation. In contrast, expressions of smooth muscle markers, Gata6 and myosin heavy chain (SM-MHC), were decreased on meshes. Immunocytochemical analysis with cardiac antibody exhibited the similar pattern of above cardiac differentiation. We conclude that aligned microfiber meshes are suitable for guiding cardiac differentiation of hCSCs and may facilitate stem cell-based therapies for treatment of cardiac diseases.

Intracoronary delivery of c-kit-positive human cardiac stem cells (hCSCs) is a promising approach to repair the infarcted heart, but it is severely limited by the poor survival of donor cells. Cobalt protoporphyrin (CoPP), a well known heme oxygenase 1 inducer, has been used to promote endogenous CO generation and protect against ischemia/reperfusion injury. Therefore, we determined whether preconditioning hCSCs with CoPP promotes CSC survival. c-kit-positive, lineage-negative hCSCs were isolated from human heart biopsies. Lactate dehydrogenase release assays demonstrated that preconditioning CSCs with CoPP markedly enhanced cell survival after oxidative stress induced by H(2)O(2), concomitant with up-regulation of heme oxygenase 1, COX-2, and anti-apoptotic proteins (BCL2, BCL2-A1, and MCL-1) and increased phosphorylation of NRF2. Apoptotic cytometric assays showed that pretreatment of CSCs with CoPP enhanced the cells' resistance to apoptosis induced by oxidative stress. Conversely, knocking down HO-1, COX-2, or NRF2 by shRNA gene silencing abrogated the cytoprotective effects of CoPP. Further, preconditioning CSCs with CoPP led to a global increase in release of cytokines, such as EGF, FGFs, colony-stimulating factors, and chemokine ligand. Conditioned medium from cells pretreated with CoPP conferred naive CSCs remarkable resistance to apoptosis, demonstrating that cytokines released by preconditioned cells play a key role in the anti-apoptotic effects of CoPP. Preconditioning CSCs with CoPP also induced an increase in the phosphorylation of Erk1/2, which are known to modulate multiple pro-survival genes. These results potentially provide a simple and effective strategy to enhance survival of CSCs after transplantation and, therefore, their efficacy in repairing infarcted myocardium.

Establishing an accurate, simple, and rapid serodiagnosis method aiming for specific cancer antigens is critically important for the clinical diagnosis, therapy, and prognostication of cancer. Currently, surface-enhanced Raman scattering (SERS) readout techniques challenge fluorescent-based detection methods in terms of both optical stability and more importantly multiple detection capability, which become more desirable for clinical diagnostics. We thus started using an interference-free mixing SERS emission (m-SERS) readout to simultaneously indicate, for the first time, three specific liver cancer antigens, including α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and ferritin (FER), even in one clinical serum sample. Here, three triple bonds (C≡N and C≡C) coded SERS tags contribute separate SERS emissions located at 2105, 2159, and 2227 cm–1, respectively; must have one-to-one correspondence from AFP, to FER, to CEA, In the process of detection, the mature double antibody sandwich allows the form...

Integrative pharmacology has been used to identify the key active constituents (KACs) of Buchang Naoxintong capsules (BNCs), a traditional Chinese medical preparation; this approach involves the evaluation of the content profiles and drug-like properties of the BNC constituents and development of an ingredient-target network. In this study, we used a sensitive analytical method to simultaneously identify and quantify 16 constituents of BNCs. Metabolism of these constituents by gut microbiota and human oral bioavailability were predicted using an in silico approach, followed by construction of networks to analyze the interactions between BNC constituents, their molecular targets, and proteins known to be the molecular targets for Food and Drug Administration-approved colitis medication. Finally, an animal model of ischemic stroke was used to verify the therapeutic effects of the KACs of BNCs. Amygdalin and paeoniflorin were identified as the KACs because they were the 2 most abundant BNC constituents, having appropriate drug-like properties, and produced therapeutic effects against cerebral ischemia. Amygdalin produced an anti-cerebral ischemia effect, likely by interacting with the glucocorticoid receptor (NR3C1) and serpin peptidase inhibitor, clade C (antithrombin), member 1 (SERPINC1). These results form the basis for conducting studies to identify KACs in traditional medicinal preparations; such studies might improve quality control and allow the in vivo evaluation of synergistic interactions between the complex mixtures of compounds.

Jia-Qiang Zhang, Jian-Qing Zhang, Li-Zhou Fang, Ling Liu, Wei-Ping Fu, Lu-Ming DaiThe Second Department of Respiratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of ChinaBackground: Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung, and HO-1 gene promoter polymorphism has been shown to be associated with the severity and prognosis of COPD patients. N-acetylcysteine (NAC), an antioxidant/mucous modifier, has shown an uncertain benefit in COPD patients. We hypothesized that this polymorphism could be associated with the effectiveness of oral NAC.Methods: A total of 368 patients with COPD were recruited and the polymorphisms of their HO-1 gene promoter were classified into three subclasses according to the number of (GT)n repeats, as previously reported: class S (32 (GT)n repeats). These subjects were then classified as L+ group (with the Lallele: L/L, L/M, L/S) and L- group (without the L allele: M/M, M/S, S/S). All the patients were allocated to standard therapy plus NAC 600 mg bid over a 1-year period and were observed over that year.Results: The L- group saw improvements in forced expiratory volume in 1 second (FEV1) (from 1.44±0.37 to 1.58±0.38, P=0.04) and FEV1% predicted (from 56.6±19.2 to 59.7±17.2, P=0.03). No improvement was found in forced vital capacity of each group and the decline of forced vital capacity in both of the groups was not statistical significant. The number of yearly COPD exacerbations of the L- group was 1.5±0.66 which was lower than the 2.1±0.53 of the L+ group (P

Here, a completely new readout technique, so-called “Click” SERS, has been developed based on Raman scattered light splice derived from nanoparticle (NP) assemblies. The single and narrow (1–2 nm) emission originating from triple bond-containing reporters undergoes dynamic combinatorial output, by means of controllable splice of SERS-active NPs analogous to small molecule units in click chemistry. Entirely different to conventional “sole code related to sole target” readout protocol, the intuitional, predictable and uniquely identifiable “Click” SERS is relies on the number rather than the intensity of combinatorial emissions. By this technique, 10-plex synchronous biomarkers detection under a single scan, and accurate cellular imaging under double exposure have been achieved. “Click” SERS demonstrated multiple single band Raman scattering could be an authentic optical analysis method in biomedicine.

The protein acetylation by histone acetyltransferases (HATs) and histone deacetylases (HDACs) plays a significant role in the development and maturation of the nervous system. HDAC6, belonging to class II HDACs, by regulating the survival, differentiation and maturation of neural cells, plays an important role in the development of the nervous system and participates in multiple pathological processes of cerebral ischemic injury. In addition, HDAC6 participates in the regulation of cognition and emotion of the brain. This article summarized the latest research results in recent years and expounded that HDAC6 inhibitors could produce a positive and effective neuroprotective effect on ischemic stroke by reducing the neuronal damage induced by excitotoxicity and oxidative stress, depressing the release of inflammatory mediators, inhibiting the apoptosis of neurons and promoting the growth of nerve and blood vessel.

In search of effective anticancer agents, fifteen new phosphonate derivatives were designed and synthesized. Their structures were clearly established by elemental analysis, IR, (1)H NMR and (13)C NMR, and their antitumor activities were evaluated by MTT assay. Preliminary results in bioactivity tests indicated that some title compounds exhibited better activity. Among the active compounds, compounds 4e, 4n had better inhibition effect on A-549 cells growth with IC(50) values of 8.7 ± 0.8, 8.2 ± 1.0 μmol·L(-1), the IC(50) values of compound 4c was 9.8 ± 0.9 μmol·L(-1) against SGC-7901 cells and compounds 4l, 4n exhibited more potent activities against EC-109 with IC(50) values of 9.5 ± 0.6, 9.4 ± 0.5 μmol·L(-1).