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With the growing recognition of the importance of children’s play in both public and academic communities, research on this topic has steadily increased. However, Jerome J. Bruner’s comprehensive interpretation of children’s play remains underexplored within the field of education. By delving into J. Bruner’s original works and his academic contributions, this article seeks to highlight J. Bruner’s core perspectives and educational practices concerning children’s play. This article first traces J. Bruner’s academic trajectory, from his studies on primate play to his explorations of children’s play, elucidating how J. Bruner drew insights from animal play research and successfully applied them to the study of children’s play. Specifically, J. Bruner illustrated how play functions as a low-risk learning mechanism, enabling children to explore skills and adapt to social rules in a safe environment. Subsequently, the article discusses J. Bruner’s theory of children’s play, emphasizing that play is not only a key medium for children’s cognitive and linguistic development, but also an essential avenue for them to engage with and understand the real world. Play serves a pivotal role in simulating daily life, fostering narrative skills and learning social norms. Furthermore, this article focuses on J. Bruner’s educational stance on practices in children’s play, including the integration of games with subject content, the principle of moderate participation by adults and peers, and approaches to stimulating creativity and problem-solving abilities through games. Finally, based on J. Bruner’s theory and the contribution of children’s play, this study recommends that the play behavior of target children should be further observed. The duration of children’s play rounds and the complexity of the play can be investigated in depth. In this way, the educational value of children’s play can be fully leveraged.

Knowledge of amoxicillin (AMX) pharmacokinetics (PK) and tissue residues in fish, which is necessary for prudent drug use, remains limited. The study aimed to explore the PK characteristics of AMX in Nile tilapia (Oreochromis niloticus) reared at 25 and 30 °C as well as to determine optimal dosages and drug withdrawal time (WDT). In the PK investigation, the fish received a single dose of 40 mg/kg AMX via oral gavage, and the optimal dosage was determined by the pharmacokinetic-pharmacodynamic approach. In the tissue residue study, the fish were orally gavaged with 40 mg/kg/day AMX once daily for 5 days and the WDT was established by the linear regression analysis. The results revealed the temperature-dependent drug elimination; the clearance relative to bioavailability (CL/F) and elimination half-life at 30 °C (0.180 L/kg/h and 6.06 h, respectively) were about twice those at 25 °C (0.090 L/kg/h and 10.49 h, respectively). The optimal dosages at the minimum inhibitory concentration (MIC) of 2 μg/mL were 10.97 (25 °C) and 41.03 (30 °C) mg/kg/day, respectively. Finally, following the multiple oral administration, the muscle/skin residue of AMX on day 1 after the last dosing at 25 and 30 °C were 548 and 264 ng/g, respectively. The average tissue residues were depleted below the maximum residue limits (MRL) of 50 μg/kg on day 5 (25 °C) and 3 (30 °C), respectively, and the WDT were 6 and 4 days when rearing at 25 and 30 °C, respectively. This knowledge serves as a practical guideline for responsible use of AMX in treating bacterial diseases in Nile tilapia aquaculture.

Abstract The outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 highlight the need for countermeasures to prevent future coronavirus pandemics. Given the unpredictable nature of spillover events, preparing antibodies with broad coronavirus-neutralizing activity is an ideal proactive strategy. Here, we investigated whether SARS-CoV-2 infection and vaccination could provide cross-neutralizing antibodies (nAbs) against zoonotic sarbecoviruses. We evaluated the cross-neutralizing profiles of plasma and monoclonal antibodies constructed from B cells from coronavirus disease 2019 (COVID-19) convalescents and vaccine recipients; against sarbecoviruses originating from bats, civets, and pangolins; and against SARS-CoV-1 and SARS-CoV-2. We found that the majority of individuals with natural infection and vaccination elicited broad nAb responses to most tested sarbecoviruses, particularly to clade 1b viruses, but exhibited very low cross-neutralization to SARS-CoV-1 in both natural infection and vaccination, and vaccination boosters significantly augmented the magnitude and breadth of nAbs to sarbecoviruses. Of the nAbs, several exhibited neutralization activity against multiple sarbecoviruses by targeting the spike receptor-binding domain (RBD) and competing with angiotensin-converting enzyme 2 (ACE2) binding. SCM12-61 demonstrated exceptional potency, with half-maximal inhibitory concentration (IC50) values of 0.001–0.091 μg/mL against tested sarbecoviruses; while VSM9-12 exhibited remarkable cross-neutralizing breadth against sarbecoviruses and SARS-CoV-2 Omicron subvariants, highlighting the potential of these two nAbs in combating sarbecoviruses and SARS-CoV-2 Omicron subvariants. Collectively, our findings suggest that vaccination with an ancestral SARS-CoV-2 vaccine, in combination with broad nAbs against sarbecoviruses, may provide a countermeasure for preventing further sarbecovirus outbreaks in humans.

Abstract The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation process plays a crucial role in bone formation and homeostasis and is regulated by two intricate processes: cell signal transduction and transcriptional gene expression. Various essential cell signaling pathways, including Wnt, BMP, TGF-β, Hedgehog, PTH, FGF, Ephrin, Notch, Hippo, and Piezo1/2, play a critical role in facilitating osteoblast differentiation, bone formation, and bone homeostasis. Key transcriptional factors in this differentiation process include Runx2, Cbfβ, Runx1, Osterix, ATF4, SATB2, and TAZ/YAP. Furthermore, a diverse array of epigenetic factors also plays critical roles in osteoblast differentiation, bone formation, and homeostasis at the transcriptional level. This review provides an overview of the latest developments and current comprehension concerning the pathways of cell signaling, regulation of hormones, and transcriptional regulation of genes involved in the commitment and differentiation of osteoblast lineage, as well as in bone formation and maintenance of homeostasis. The paper also reviews epigenetic regulation of osteoblast differentiation via mechanisms, such as histone and DNA modifications. Additionally, we summarize the latest developments in osteoblast biology spurred by recent advancements in various modern technologies and bioinformatics. By synthesizing these insights into a comprehensive understanding of osteoblast differentiation, this review provides further clarification of the mechanisms underlying osteoblast lineage commitment, differentiation, and bone formation, and highlights potential new therapeutic applications for the treatment of bone diseases.

Abstract Wnts are secreted, lipid-modified proteins that bind to different receptors on the cell surface to activate canonical or non-canonical Wnt signaling pathways, which control various biological processes throughout embryonic development and adult life. Aberrant Wnt signaling pathway underlies a wide range of human disease pathogeneses. In this review, we provide an update of Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and diseases. The Wnt proteins, receptors, activators, inhibitors, and the crosstalk of Wnt signaling pathways with other signaling pathways are summarized and discussed. We mainly review Wnt signaling functions in bone formation, homeostasis, and related diseases, and summarize mouse models carrying genetic modifications of Wnt signaling components. Moreover, the therapeutic strategies for treating bone diseases by targeting Wnt signaling, including the extracellular molecules, cytosol components, and nuclear components of Wnt signaling are reviewed. In summary, this paper reviews our current understanding of the mechanisms by which Wnt signaling regulates bone formation, homeostasis, and the efforts targeting Wnt signaling for treating bone diseases. Finally, the paper evaluates the important questions in Wnt signaling to be further explored based on the progress of new biological analytical technologies.

Summary: Cancer cachexia mouse models are needed to recapitulate the clinical features of patients with cachexia. Here, we present a protocol for the establishment and evaluation of cancer cachexia mouse models. We delineate the steps in preparing tumor cells for inoculation and surgical procedures. After the establishment of these mouse models, we describe essential techniques to assess cancer cachexia, including grip strength evaluation, tissue collection, and the calculation of cross-sectional areas of muscle tissue.For complete details on the use and execution of this protocol, please refer to Liu et al.,1 Yang et al.,2 Shi et al.,3 and Zhou et al.4 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Objective: Glucocorticoid-induced osteoporosis (GIOP) represents a major complication arising from the long-term use of glucocorticoids, which are widely prescribed for various inflammatory and autoimmune conditions. Despite its prevalence, the current therapeutic options for GIOP are limited in terms of efficacy, safety profiles, and patient compliance. The Modified Danggui Buxue Decoction (DGBXD), a traditional Chinese herbal formulation, has shown promise in preliminary studies for its potential osteoprotective effects. The present study aimed to explore the mechanistic underpinnings of DGBXD's action on GIOP using network pharmacology and molecular docking approaches, bridging traditional medicine with modern pharmacological insights. Method: Network pharmacology is applied to screen drug-active compounds and potential core target proteins for disease treatment and to explore the drugs’ therapeutic mechanisms. Result: Altogether, 78 DGBXD active compounds and 223 DGBXD-related, 146 component-disease common, and 2168 GIOP-associated target genes were obtained. The PPI network had 43 nodes and 462 edges, and a total of 10 core target genes, including TP53, JUN and MAPK3, were identified. The results of the GO enrichment analysis implied that DGBXD might participate in biological activities, including responses to oxidative stress and nutrient levels. The outcomes of the KEGG pathway enrichment analysis showed that DGBXD may treat GIOP through TNF, IL-17, and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathways. Based on to the molecular docking results, biologically active compounds (beta-carotene, formononetin, luteolin, and isorhamnetin) exhibited good binding to AKT1 and ESR1. Conclusion: DGBXD may aid in GIOP treatment by modulating multiple therapeutic targets and signaling pathways.

Abstract Tumorous bone defects present significant challenges for surgical bio‐reconstruction due to the dual pathological conditions of residual tumor presence and extensive bone loss following excision surgery. To address this challenge, a “thermal switch” smart bone scaffold based on the silicene nanosheet‐modified decalcified bone matrix (SNS@DBM) is developed by leveraging the natural affinity between collagen and silicene, which is elucidated by molecular dynamics simulations. Benefitting from its exceptional photothermal ability, biodegradability, and bioactivity, the SNS@DBM “thermal switch” provides an integrated postoperative sequential thermotherapy for tumorous bone loss by exerting three levels of photothermal stimulation (i.e., strong, moderate, and nonstimulation). During the different phases of postoperative bioconstruction, the SNS@DBM scaffold realizes simultaneous residual tumor ablation, tumor recurrence prevention, and bone tissue regeneration. These biological effects are verified in the tumor‐bearing nude mice of patient‐derived tissue xenografts and critical cranium defect rats. Mechanism research prompts moderate heat stimulus generated by and coordinating with SNSs can upregulate osteogenic genes, promote macrophages M2 polarization, and intensify angiogenesis of H‐type vessels. This study introduces a versatile approach to the management of tumorous bone defects.

Abstract Background To predict the microvascular invasion (MVI) in patients with cHCC-ICC. Methods A retrospective analysis was conducted on 119 patients who underwent CT enhancement scanning (from September 2006 to August 2022). They were divided into MVI-positive and MVI-negative groups. Results The proportion of patients with CEA elevation was higher in the MVI-positive group than in the MVI-negative group, with a statistically significant difference (P = 0.02). The MVI-positive group had a higher rate of peritumoral enhancement in the arterial phase (P = 0.01) whereas the MVI-negative group had more oval and lobulated masses (P = 0.04). According to the multivariate analysis, the increase in CEA (OR = 10.15, 95% CI: 1.11, 92.48, p = 0.04), hepatic capsular withdrawal (OR = 4.55, 95% CI: 1.44, 14.34, p = 0.01) and peritumoral enhancement (OR = 6.34, 95% CI: 2.18, 18.40, p

Abstract Background Aortoesophageal fistula (AEF) is a rare but typically life-threatening condition. Although several treatment strategies exist, including conservative treatment with intraluminal stent graft and open thoracic aortic replacement, the overall outcome remains poor, ranging from 16 to 39%. Furthermore, esophageal reconstruction methods vary between hospitals. Herein, we report a case of aortoesophageal fistula treated using one-stage total reconstruction. Case presentation This case involved a 58-year-old woman who developed acute type A aortic dissection and underwent successful total arch replacement at the other hospital. However, she developed AEF 1 year later and underwent urgent thoracic endovascular aortic repair, which eventually failed. We performed thoracic aortic replacement, total esophagectomy, gastric tube reconstruction, and omental flap in a one-stage operation. The patient was extubated the next day and transferred to the general ward on postoperative day 3. Computed tomography revealed favorable results. Conclusions For postoperative AEF, dedicated debridement with reconstruction is more effective than conservative treatment. In an experienced center, post-procedure-related AEF can be easily treated using one-stage reconstruction.

Objective: The aim of this study was to investigate the correlation between hormone receptor levels and telomere length (TL) in infertile women with and without polycystic ovary syndrome (PCOS). Materials and methods: This prospective cohort study recruited a total of 431 cumulus oocyte complex (COC) from 88 infertile women between July 2012 and June 2014. The participants were divided into three groups: young age (

Background: Despite increasing concerns about the association between remdesivir and bradycardia in severe coronavirus disease 2019 (COVID-19) patients receiving remdesivir, information on its clinical course and precipitating factors is limited. Our aim was to investigate possible triggers of bradycardia after remdesivir administration. Methods: We retrieved the medical records of hospitalized severe and critical COVID-19 patients who received remdesivir from May 1, 2021 to June 30, 2021. Bradycardia was defined as two episodes of a heart rate (HR)

Abstract Long-term humoral immunity to SARS-CoV-2 is essential for preventing reinfection. The production of neutralizing antibody (nAb) and B cell differentiation are tightly regulated by T follicular help (TFH) cells. However, the longevity and functional role of TFH cell subsets in COVID-19 convalescents and vaccine recipients remain poorly defined. Here, we show that SARS-CoV-2 infection and inactivated vaccine elicited both spike-specific CXCR3+ TFH cell and CXCR3− TFH cell responses, which showed distinct response patterns. Spike-specific CXCR3+ TFH cells exhibit a dominant and more durable response than CXCR3− TFH cells that positively correlated with antibody responses. A third booster dose preferentially expands the spike-specific CXCR3+ TFH cell subset induced by two doses of inactivated vaccine, contributing to antibody maturation and potency. Functionally, spike-specific CXCR3+ TFH cells have a greater ability to induce spike-specific antibody secreting cells (ASCs) differentiation compared to spike-specific CXCR3− TFH cells. In conclusion, the persistent and functional role of spike-specific CXCR3+ TFH cells following SARS-CoV-2 infection and vaccination may play an important role in antibody maintenance and recall response, thereby conferring long-term protection. The findings from this study will inform the development of SARS-CoV-2 vaccines aiming to induce long-term protective immune memory.

Nutrient release from sediment is considered a significant source for overlying water. Given that nutrient release mechanisms in sediment are complex and difficult to simulate, traditional approaches commonly use assigned parameter values to simulate these processes. In this study, a nitrogen flux model was developed and coupled with the water quality model of an urban lake. After parameter sensitivity analyses and model calibration and validation, this model was used to simulate nitrogen exchange at the sediment–water interface in eight scenarios. The results showed that sediment acted as a buffer in the sediment–water system. It could store or release nitrogen at any time, regulate the distribution of nitrogen between sediment and the water column, and provide algae with nitrogen. The most effective way to reduce nitrogen levels in urban lakes within a short time is to reduce external nitrogen loadings. However, sediment release might continue to contribute to the water column until a new balance is achieved. Therefore, effective measures for reducing sediment nitrogen should be developed as supplementary measures. Furthermore, model parameter sensitivity should be individually examined for different research subjects.

As the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed that CBFB (subunit of a heterodimeric Cbfβ/Runx1, Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the chondrocyte-specific deletion of Cbfb in tamoxifen-induced Cbfbf/f;Col2a1-CreERT mice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed that Cbfβ deficiency in articular cartilage resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/Yap signaling and Tgfβ signaling. Immunostaining and western blot validated these RNA-seq analysis results. ACLT surgery-induced OA decreased Cbfβ and Yap expression and increased active β-catenin expression in articular cartilage, while local AAV-mediated Cbfb overexpression promoted Yap expression and diminished active β-catenin expression in OA lesions. Remarkably, AAV-mediated Cbfb overexpression in knee joints of mice with OA showed the significant protective effect of Cbfβ on articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression of Cbfβ may be the cause of OA. Moreover, Local admission of Cbfb may rescue and protect OA through decreasing Wnt/β-catenin signaling, and increasing Hippo/Yap signaling and Tgfβ/Smad2/3 signaling in OA articular cartilage, indicating that local Cbfb overexpression could be an effective strategy for treatment of OA.

SARS-CoV-2 is the third known coronavirus (CoV) that has crossed the animal-human barrier in the last two decades. However, little structural information exists related to the close genetic species within the SARS-related coronaviruses. Here, we present three novel SARS-related CoV spike protein structures solved by single particle cryo-electron microscopy analysis derived from bat (bat SL-CoV WIV1) and civet (cCoV-SZ3, cCoV-007) hosts. We report complex glycan trees that decorate the glycoproteins and density for water molecules which facilitated modeling of the water molecule coordination networks within structurally important regions. We note structural conservation of the fatty acid binding pocket and presence of a linoleic acid molecule which are associated with stabilization of the receptor binding domains in the "down" conformation. Additionally, the N-terminal biliverdin binding pocket is occupied by a density in all the structures. Finally, we analyzed structural differences in a loop of the receptor binding motif between coronaviruses known to infect humans and the animal coronaviruses described in this study, which regulate binding to the human angiotensin converting enzyme 2 receptor. This study offers a structural framework to evaluate the close relatives of SARS-CoV-2, the ability to inform pandemic prevention, and aid in the development of pan-neutralizing treatments.

Abstract The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood. We found that Atp6i deficient mice (Atp6i −/− ) arrested tooth root formation, indicated by truncated Hertwig’s epithelial root sheath (HERS) progression. Furthermore, Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation. Atp6i −/− mice had largely decreased expression of odontoblast differentiation marker gene expression profiles (Col1a1, Nfic, Dspp, and Osx) in the alveolar bone. Atp6i −/− mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers. Additionally, there was a significant reduction in Smad2/3 activation, inhibiting transforming growth factor-β (TGF-β) signaling in Atp6i −/− odontoblasts. Through treating pulp precursor cells with Atp6i −/− or wild-type OC bone resorption-conditioned medium, we found the latter medium to promote odontoblast differentiation, as shown by increased odontoblast differentiation marker genes expression (Nfic, Dspp, Osx, and Runx2). This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization, whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i −/− OC conditioned medium. Importantly, ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i −/− mice tooth germs were transplanted under mouse kidney capsules. Collectively, our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation. As such, this study uncovers TGF-β1 /Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.

Objectives: Limited data on clinical and microbiological efficacy, patient mortality, and other associated factors are available for ceftazidime/avibactam (CAZ/AVI)-based regimens for carbapenem-resistant Gram-negative bacteria (CR-GNB). This study aimed to assess these issues retrospectively using multicenter data. Methods: This multicenter study included CR-GNB infected patients treated with CAZ/AVI-based regimens for more than three days. Patient characteristics, bacterial culture reports, drug-sensitivity test results, and antibiotic use, including CAZ/AVI use, were extracted from the patient's clinical records. The clinical and microbiological efficacy of the combined drug regimen and patient mortality were evaluated according to corresponding definitions. Univariate and multivariate logistic regressions were performed to explore the efficacy and mortality-related factors. Results: A total of 183 patients with CR-GNB infection were considered for the analysis according to the inclusion and exclusion criteria. After the treatment of CAZ/AVI-based regimens, the clinical efficacy was 75.4 %. The 7-day microbial efficacy and clearance rate after treatment were 43.7 % and 66.0 %, respectively. Moreover, 30-day all-cause and in-hospital mortality were 11.5 % and 14.2 %, respectively. Harboring renal dysfunction (creatinine clearance rate (CCR) of

IntroductionSince December 2019, the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has presented considerable public health challenges. Multiple vaccines have been used to induce neutralizing antibodies (nAbs) and memory B-cell responses against the viral spike (S) glycoprotein, and many essential epitopes have been defined. Previous reports have identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-reactive naïve B cells and preexisting memory B cells in unexposed individuals. However, the role of these spike-reactive B cells in vaccine-induced immunity remains unknown.MethodsTo elucidate the characteristics of preexisting SARS-CoV-2 S-reactive B cells as well as their maturation after antigen encounter, we assessed the relationship of spike-reactive B cells before and after vaccination in unexposed human individuals. We further characterized the sequence identity, targeting domain, broad-spectrum binding activity and neutralizing activity of these SARS-CoV-2 S-reactive B cells by isolating monoclonal antibodies (mAbs) from these B cells.ResultsThe frequencies of both spike-reactive naïve B cells and preexisting memory B cells before vaccination correlated with the frequencies of spike-reactive memory B cells after vaccination. Isolated mAbs from spike-reactive naïve B cells before vaccination had fewer somatic hypermutations (SHMs) than mAbs isolated from spike-reactive memory B cells before and after vaccination, but bound SARS-CoV-2 spike in vitro. Intriguingly, these germline-like mAbs possessed broad binding profiles for SARS-CoV-2 and its variants, although with low or no neutralizing capacity. According to tracking of the evolution of IGHV4-4/IGKV3-20 lineage antibodies from a single donor, the lineage underwent SHMs and developed increased binding activity after vaccination.DiscussionOur findings suggest that spike-reactive naïve B cells can be expanded and matured by vaccination and cocontribute to vaccine-elicited antibody responses with preexisting memory B cells. Selectively and precisely targeting spike-reactive B cells by rational antigen design may provide a novel strategy for next-generation SARS-CoV-2 vaccine development.

This paper proposed a high-sensitivity phase imaging eddy current magneto-optical (PI-ECMO) system for carbon fiber reinforced polymer (CFRP) defect detection. In contrast to other eddy current-based detection systems, the proposed system employs a fixed position excitation coil while enabling the detection point to move within the detection region. This configuration effectively mitigates the interference caused by the lift-off effect, which is commonly observed in systems with moving excitation coils. Correspondingly, the relationship between the defect characteristics (orientation and position) and the surface vertical magnetic field distribution (amplitude and phase) is studied in detail by theoretical analysis and numerical simulations. Experiments conducted on woven CFRP plates demonstrate that the designed PI-ECMO system is capable of effectively detecting both surface and internal cracks, as well as impact defects. The excitation current is significantly reduced compared with traditional eddy current magneto-optical (ECMO) systems.

Abstract Background Obesity is increasing globally, which affects multiple human functions, including reproductive health. Many women with overweight and obesity of child-bearing years are treated with assisted reproductive technology (ART). However, the clinical impact of body mass index (BMI) on pregnancy outcomes after ART remains to be determined. Therefore, this population-based retrospective cohort study aimed to assess whether and how higher BMI affects singleton pregnancy outcomes. Methods This study used the large nationally representative database of the US National Inpatient Sample (NIS), extracting data of women with singleton pregnancies who had received ART from 2005 to 2018. Diagnostic codes of the International Classification of Diseases, Ninth and Tenth edition (ICD-9 and ICD-10) were used to identify females admitted to US hospitals with delivery-related discharge diagnoses or procedures and secondary diagnostic codes for ART, including in vitro fertilization. The included women were further categorized into three groups based on BMI values

Highlights Recent progress in noble metal-decorated (NM-D) semiconducting metal oxides (SMOs) gas sensors are summarized. Gas sensing mechanisms related to noble metal decoration are carefully discussed. Crucial challenges facing the development of NM-D SMOs gas sensors are analyzed.

Objective: The pharmacokinetics performance and clinical pregnancy rate of two vaginal progesterone gel, Progeson™ and Crinone™, were compared in this study. Materials and methods: In the pharmacokinetics performance, Progeson showed similar long-term dissolution rate as Crinone. In the clinical study, 141 subjects undergone in vitro fertilization (IVF) treatments were included to compare serum progesterone level and clinical pregnancy rates. Results: Among the subjects, 78 subjects received fresh embryo transfer and 63 subjects received frozen embryo transfer via natural cycle endometrial preparation protocol. In each group, subjects were given either Crinone™ or Progeson™ for luteal phase support without combination with other progesterone products. The study showed that Crinone™ group led to higher estrogen level at mid-luteal phase in the fresh embryo transfer group, and Progeson™ group led to higher progesterone level at mid-luteal phase and pregnancy test day in the frozen-thawed embryo transfer group. Conclusion: Subjects received Crinone™ or Progeson™ had similar rate of pregnancy, live birth, and stillbirth in both fresh embryo transfer and frozen-thawed embryo transfer group. Thus, Progeson™ might be a suitable substitute for Crinone™ in assisted reproductive therapy.

Abstract Arsenic compounds have been applied treating acute promyelocytic 1eukemia and solid tumors with brief mechanism investigations. In fact, we have demonstrated that sodium arsenite plus dimethylarsenic acid could activate apoptosis in MA‐10 mouse Leydig tumor cells by inducing caspase pathways. However, detail underlying mechanisms how caspase cascade is regulated remains elusive. Therefore, the apoptotic mechanism of sodium arsenite plus dimethylarsenic acid were examined in MA‐10 cells in this study. Our results reveal that Fas/FasL protein expressions were stimulated by sodium arsenite plus dimethylarsenic acid in MA‐10 cells. In addition, reactive oxygen species (ROS) generation, cytochrome C release, Bid truncation, and Bax translocation were induced in MA‐10 cells by arsenic compounds. Moreover, activation of p38, JNK and ERK1/2, MAPK pathways was stimulated while Akt phosphorylated levels and Akt expression were decreased by sodium arsenite plus dimethylarsenic in MA‐10 cells. In conclusion, sodium arsenite and dimethylarsenic acid did activate MAPK pathway plus ROS generation, but suppress Akt pathway, to modulate caspase pathway and then induce MA‐10 cell apoptosis.

Type 2 diabetes mellitus (T2DM) has become a major health problem, threatening the quality of life of nearly 500 million patients worldwide. As a typical multifactorial metabolic disease, T2DM involves the changes and interactions of various metabolic pathways such as carbohydrates, amino acid, and lipids. It has been suggested that metabolites are not only the endpoints of upstream biochemical processes, but also play a critical role as regulators of disease progression. For example, excess free fatty acids can lead to reduced glucose utilization in skeletal muscle and induce insulin resistance; metabolism disorder of branched-chain amino acids contributes to the accumulation of toxic metabolic intermediates, and promotes the dysfunction of β-cell mitochondria, stress signal transduction, and apoptosis. In this paper, we discuss the role of metabolites in the pathogenesis of T2DM and their potential as biomarkers. Finally, we list the effects of anti-hyperglycemic drugs on serum/plasma metabolic profiles.

Abstract Runt-related transcription factor 1 (Runx1) plays a key role in cartilage formation, but its function in articular cartilage formation is unclear. We generated non-inducible and inducible Runx1-deficient mice (Runx1 f/f Col2α1-Cre and Runx1 f/f Col2α1-CreER mice) and found that chondrocyte-specific Runx1-deficient mice developed a spontaneous osteoarthritis (OA)-like phenotype and showed exacerbated articular cartilage destruction under OA, characterized by articular cartilage degradation and cartilage ossification, with decreased Col2α1 expression and increased Mmp13 and Adamts5 expression. RNA-sequencing analysis of hip articular cartilage from the Runx1 f/f Col2α1-Cre mice compared to that from wild-type mice and subsequent validation analyses demonstrated that Runx1 is a central regulator in multiple signaling pathways, converging signals of the Hippo/Yap, TGFβ/Smad, and Wnt/β-catenin pathways into a complex network to regulate the expression of downstream genes, thereby controlling a series of osteoarthritic pathological processes. RNA-sequencing analysis of mutant knee joints showed that Runx1’s role in signaling pathways in articular cartilage is different from that in whole knee joints, indicating that Runx1 regulation is tissue-specific. Histopathologic analysis confirmed that Runx1 deficiency decreased the levels of YAP and p-Smad2/3 and increased the levels of active β-catenin. Overexpression of Runx1 dramatically increased YAP expression in chondrocytes. Adeno-associated virus-mediated Runx1 overexpression in the knee joints of osteoarthritic mice showed the protective effect of Runx1 on articular cartilage damaged in OA. Our results notably showed that Runx1 is a central regulator of articular cartilage homeostasis by orchestrating the YAP, TGFβ, and Wnt signaling pathways in the formation of articular cartilage and OA, and targeting Runx1 and its downstream genes may facilitate the design of novel therapeutic approaches for OA.

ABSTRACT Dengue virus (DENV) is the most widespread arbovirus, causing symptoms ranging from dengue fever to severe dengue, including hemorrhagic fever and shock syndrome. Four serotypes of DENV (DENV-1 to -4) can infect humans; however, no anti-DENV drug is available. To facilitate the study of antivirals and viral pathogenesis, here we developed an infectious clone and a subgenomic replicon of DENV-3 strains for anti-DENV drug discovery by screening a synthetic compound library. The viral cDNA was amplified from a serum sample from a DENV-3-infected individual during the 2019 epidemic; however, fragments containing the prM-E-partial NS1 region could not be cloned until a DENV-3 consensus sequence with 19 synonymous substitutions was introduced to reduce putative Escherichia coli promoter activity. Transfection of the resulting cDNA clone, plasmid DV3syn, released an infectious virus titer of 2.2 × 102 focus-forming units (FFU)/mL. Through serial passages, four adaptive mutations (4M) were identified, and addition of 4M generated recombinant DV3syn_4M, which produced viral titers ranging from 1.5 × 104 to 6.7 × 104 FFU/mL and remained genetically stable in transformant bacteria. Additionally, we constructed a DENV-3 subgenomic replicon and screened an arylnaphthalene lignan library, from which C169-P1 was identified as exhibiting inhibitory effects on viral replicon. A time-of-drug addition assay revealed that C169-P1 also impeded the internalization process of cell entry. Furthermore, we demonstrated that C169-P1 inhibited the infectivity of DV3syn_4M, as well as DENV-1, DENV-2, and DENV-4, in a dose-dependent manner. This study provides an infectious clone and a replicon for the study of DENV-3 and a candidate compound for future development against DENV-1 to -4 infections. IMPORTANCE Dengue virus (DENV) is the most prevalent mosquito-transmitted virus, and there is no an anti-dengue drug. Reverse genetic systems representative of different serotype viruses are invaluable tools for the study of viral pathogenesis and antiviral drugs. Here, we developed an efficient infectious clone of a clinical DENV-3 genotype III isolate. We successfully overcame the instability of flavivirus genome-length cDNA in transformant bacteria, an unsolved issue for construction of cDNA clones of flaviviruses, and adapted this clone to efficiently produce infectious viruses following plasmid transfection of cell culture. Moreover, we constructed a DENV-3 subgenomic replicon and screened a compound library. An arylnaphthalene lignan, C169-P1, was identified as an inhibitor of virus replication and cell entry. Finally, we demonstrated that C169-P1 exhibited a broad-spectrum antiviral effect against the infections with DENV-1 to -4. The reverse genetic systems and the compound candidate described here facilitate the study of DENV and related RNA viruses.

Objectives: Augmented renal clearance (ARC) is a state of enhanced renal function commonly observed in 30%–65% of critically ill patients despite normal serum creatinine levels. Using unadjusted standard dosing regimens of renally eliminated drugs in ARC patients often leads to subtherapeutic concentrations, poor clinical outcomes, and the emergence of multidrug-resistant bacteria. We summarized pharmaceutical, pharmacokinetic, and pharmacodynamic research on the definition, underlying mechanisms, and risk factors of ARC to guide individualized dosing of antibiotics and various strategies for optimizing outcomes.Methods: We searched for articles between 2010 and 2022 in the MEDLINE database about ARC patients and antibiotics and further provided individualized antibiotic dosage regimens for patients with ARC.Results: 25 antibiotic dosage regimens for patients with ARC and various strategies for optimization of outcomes, such as extended infusion time, continuous infusion, increased dosage, and combination regimens, were summarized according to previous research.Conclusion: ARC patients, especially critically ill patients, need to make individualized adjustments to antibiotics, including dose, frequency, and method of administration. Further comprehensive research is required to determine ARC staging, expand the range of recommended antibiotics, and establish individualized dosing guidelines for ARC patients.

Abstract Background Hepatitis C virus (HCV) infection increased the risk of hepatocellular carcinoma. Identification of host factors required for HCV infection will help to unveil the HCV pathogenesis. Adaptive mutations that enable the replication of HCV infectious clones could provide hints that the mutation-carrying viral protein may specifically interact with some cellular factors essential for the HCV life cycle. Previously, we identified D559G mutation in HCV NS5B (RNA dependent RNA polymerase) important for replication of different genotype clones. Here, we searched for the factors that potentially interacted with NS5B and investigated its roles in HCV infection. Methods Wild-type-NS5B and D559G-NS5B of HCV genotype 2a clone, J6cc, were ectopically expressed in hepatoma Huh7.5 cells, and NS5B-binding proteins were pulled down and identified by mass spectrometry. The necessity and mode of action of the selected cellular protein for HCV infection were explored by experiments including gene knockout or knockdown, complementation, co-immunoprecipitation (Co-IP), colocalization, virus infection and replication, and enzymatic activity, etc. Results Mass spectrometry identified a number of cellular proteins, of which protein phosphatase 2 regulatory subunit B’delta (PPP2R5D, the PP2A regulatory B subunit) was one of D559G-NS5B-pulled down proteins and selected for further investigation. Co-IP confirmed that PPP2R5D specifically interacted with HCV NS5B but not HCV Core and NS3 proteins, and D559G slightly enhanced the interaction. NS5B also colocalized with PPP2R5D in the endoplasmic reticulum. Knockdown and knockout of PPP2R5D decreased and abrogated HCV infection in Huh7.5 cells, respectively, while transient and stable expression of PPP2R5D in PPP2R5D-knockout cells restored HCV infection to a level close to that in wild-type Huh7.5 cells. Replicon assay revealed that PPP2R5D promoted HCV replication, but the phosphatase activity and catalytic subunit of PP2A were not affected by NS5B. Conclusions PPP2R5D interactes with HCV NS5B and is required for HCV infection in cultured hepatoma cells through facilitating HCV replication.

Abstract Objectives We aimed at investigating whether serum exosomal miR‐16‐5p could be utilized as an immunotherapy biomarker in lung adenocarcinoma (LUAD) patients administered by programmed cell death ligand‐1 (PD‐L1) inhibitors, and to evaluate its functions in LUAD progression. Methods Sixty LUAD sufferers and 20 healthy controls (HCs) were covered in this work. We applied both IHC and WB to examine PD‐L1 level in clinical tissue samples and utilized WB to quantify PD‐L1 expression in LUAD cells and LUAD xenograft tissues, respectively. Transmission electron microscopy (TEM), WB, and nanoparticle tracking analysis (NTA) were executed to confirm the exosomes isolated from serum specimens and cell culture media. To quantify of exosomal miR‐16‐5p level from serum and culture medium of cultured cell, qRT‐PCR experiment was utilized. The connection between tissue PD‐L1 level and serum exosomal miR‐16‐5p expression in PD‐L1‐positive sufferers administered by PD‐L1 inhibitors was verified using Spearman correlation coefficient analysis. In addition, the overall survival (OS) and progression‐free survival (PFS) rates among PD‐L1 inhibitor managed sufferers were acquired through a follow‐up visit. Finally, we used a group of assays, including 5‐bromo‐2′‐dexoyuridine (BrdU) and colony formation test, wound healing experiment, flow cytometry, and nude mice xenograft experiment, to explore the functions of circulating exosomal miR‐16‐5p on LUAD cell proliferation, apoptosis, and migration, as well as tumor development, respectively. Results PD‐L1 expression was positively related to T stage (tumor size stage), and PD‐L1 inhibitor treatment reduced the PD‐L1 expression and mitigated T stage in PD‐L1‐positive LUAD sufferers. For PD‐L1‐positive LUAD sufferers, elevated PD‐L1 expression or reduced serum exosomal miR‐16‐5p level were linked to longer PFS and OS upon PD‐L1 inhibitor treatment. The number of exosomes in patient's serum was more than that in the serum of healthy individuals, and PD‐L1 inhibitor treatment decreased the number of serum‐derived exosomes in PD‐L1‐positive LUAD sufferers. Exosome‐derived miR‐16‐5p was downregulated in patient's serum and cell culture medium, and this was negatively linked to tumor stage and PD‐L1 expression. Meanwhile, PD‐L1 inhibitor treatment could increase the serum exosomal miR‐16‐5p expression, and the expression change of serum exosomal miR‐16‐5p was diametrically related to PD‐L1 after the treatment. Moreover, the overexpression of PD‐L1 accelerated tumor growth and decreased the exosomal miR‐16‐5p content in cell culture media, while exosomal miR‐16‐5p overexpression in cell culture media inhibited tumor development by decreasing the PD‐L1 expression. Exosomal miR‐16‐5p overexpression in cell culture media also depressed LUAD cell proliferation and migration, and stimulated cell apoptosis, especially in the cells which cultured in the mediums with PD‐L1 inhibitor in vitro. Conclusions Serum exosomal miR‐16‐5p may be a latent tumor inhibitor and a new biomarker for PD‐L1 inhibitor‐dependent immunotherapy in LUAD by regulating the PD‐L1 expression.

Enterovirus A71 (EV-A71) infection typically causes mild illnesses, such as hand-foot-and-mouth disease (HFMD), but occasionally leads to severe or fatal neurological complications in infants and young children. Currently, there is no specific antiviral treatment available for EV-A71 infection. Thus, the development of an effective anti-EV-A71 drug is required urgently. Cordycepin, a major bioactive compound found in Cordyceps fungus, has been reported to possess antiviral activity. However, its specific activity against EV-A71 is unknown. In this study, the potency and role of cordycepin treatment on EV-A71 infection were investigated. Results demonstrated that cordycepin treatment significantly reduced the viral load and viral ribonucleic acid (RNA) level in EV-A71-infected Vero cells. In addition, EV-A71-mediated cytotoxicity was significantly inhibited in the presence of cordycepin in a dose-dependent manner. The protective effect can also be extended to Caco-2 intestinal cells, as evidenced by the higher median tissue culture infectious dose (TCID50) values in the cordycepin-treated groups. Furthermore, cordycepin inhibited EV-A71 replication by acting on the adenosine pathway at the post-infection stage. Taken together, our findings reveal that cordycepin could be a potential antiviral candidate for the treatment of EV-A71 infection.

Abstract Background Altered adipose tissue (AT) metabolism in cancer‐associated weight loss via inflammation, lipolysis, and white adipose tissue (WAT) browning is primarily implicated from rodent models; their contribution to AT wasting in cancer patients is unclear. Methods Energy expenditure (EE), plasma, and abdominal subcutaneous WAT were obtained from men (aged 65 ± 8 years) with cancer, with (CWL, n = 27) or without (CWS, n = 47) weight loss, and weight‐stable non‐cancer patients (CON, n = 26). Clinical images were assessed for adipose and muscle area while plasma and WAT were assessed for inflammatory, lipolytic, and browning markers. Results CWL displayed smaller subcutaneous AT (SAT; P = 0.05) and visceral AT (VAT; P = 0.034) than CWS, and displayed higher circulating interleukin (IL)‐6 (P = 0.01) and WAT transcript levels of IL‐6 (P = 0.029), IL‐1β (P = 0.042), adipose triglyceride lipase (P = 0.026), and browning markers (Dio2, P = 0.03; PGC‐1a, P = 0.016) than CWS and CON. There was no difference across groups in absolute REE (P = 0.061), %predicted REE (P = 0.18), circulating free fatty acids (FFA, P = 0.13) or parathyroid hormone‐related peptide (PTHrP; P = 0.88), or WAT protein expression of inflammation (IL‐6, P = 0.51; IL‐1β, P = 0.29; monocyte chemoattractant protein‐1, P = 0.23) or WAT protein or gene expression of browning (uncoupling protein‐1, UCP‐1; P = 0.13, UCP‐1, P = 0.14). In patients with cancer, FFA was moderately correlated with WAT hormone‐sensitive lipase transcript (r = 0.38, P = 0.018, n = 39); circulating cytokines were not correlated with expression of WAT inflammatory markers and circulating PTHrP was not correlated with expression of WAT browning markers. In multivariate regression using cancer patients only, body mass index (BMI) directly predicted SAT (N = 25, R2 = 0.72, P

Summary: Whether hypervariable region 1 (HVR1)-targeting antibodies elicited during natural hepatitis C virus (HCV) infection contribute to virus clearance and what is the mechanism underlying remain unclear. Here, we demonstrated that treatment of HCV-infected hepatoma Huh7.5 cells with the IgGs purified from 2 of 28 (7.1%) chronic hepatitis C (CHC) patients efficiently controlled the infection, for which genotype 1b HVR1 (1bHVR1)-binding antibody was critical. Moreover, we found that 1bHVR1 peptide was superior to 2aHVR1 in rabbit immunization to elicit antibodies neutralizing genotypes 1a, 2a, 3a, and 4a. The neutralization effect of 1bHVR1 IgG could be augmented by HH-1, an antibody constructed from CHC memory B cells but without binding to HVR1 peptide. Mechanistic studies showed that 1bHVR1 antisera and IgGs disrupted the interaction of E2-SR-B1 receptor. This study highlights the neutralizing activity of HVR1 antibody elicited by CHC patients and generated by HVR1-immunization against the established infections of multiple HCV genotypes.

Abstract Background Cancer cachexia, characterized by muscle and fat tissue wasting, is a major determinant of cancer‐related mortality without established treatment. Recent animal data revealed that cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 as surface proteins on extracellular vesicles (EVs). Here, we test a therapeutic strategy for ameliorating cancer cachexia by inhibiting the release of Hsp70 and Hsp90 using proton pump inhibitor omeprazole. Methods Omeprazole effect on Hsp70/90 release through EVs by Lewis lung carcinoma (LLC) cells in vitro, serum levels of Hsp70/90 and Hsp70/90‐carrying EVs in LLC tumour‐bearing mice, and LLC‐induced muscle protein degradation pathways in C2C12 myotubes and mice were determined. Omeprazole effect on endolysosomal pH and Rab27b expression in LLC cells were analysed. Results Omeprazole treatment of LLC cells inhibited Hsp70/90 and Hsp70/90‐carrying EV release in a dose‐dependent manner (1 to 10 μM) and attenuated the catabolic activity of LLC cell‐conditioned medium on C2C12 myotubes. Systemic omeprazole administration to LLC tumour‐bearing mice (5 mg/kg/day subcutaneously) for 2 weeks blocked elevation of serum Hsp70, Hsp90, and Hsp70/90‐carrying EVs, abrogated skeletal muscle catabolism, and prevented loss of muscle function as well as muscle and epididymal fat mass without altering tumour growth. Consequently, median survival increased by 23.3%. Mechanistically, omeprazole increased cancer cell endolysosomal pH level dose‐dependently (0.1 to 1 μM) by inhibiting vacuolar H+‐ATPase. Further, omeprazole suppressed the highly elevated expression of Rab27b, a key regulator of EV release, in LLC cells. Conclusions Omeprazole ameliorates cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90.

To observe the effect of magnesium ion on vascular function in rats after long-term exhaustive exercise. Forty male SD rats were divided into two groups, the control group (CON group, n = 20) and the exhaustive exercise group (EEE group, n = 20). Exhausted rats performed 1W adaptive swimming exercise (6 times/W, 15min/time), and then followed by 3W formal exhaustive exercise intervention. Hematoxylin and eosin (HE) staining was used to detect the morphological changes of rat thoracic aorta. The contents of interleukin-1 β (IL-1β) and tumor necrosis factor–α (TNF-α) in serum of rats were determined by enzyme-linked immunosorbent assay (ELISA), and the contents of malondialdehyde (MDA), reactive oxygen species (ROS), nitric oxide (NO) and endothelin 1 (ET-1) in serum of rats were determined by biochemical kit. Vascular ring test detects vascular function. Compared with the CON group, the smooth muscle layer of the EEE group became thicker, the cell arrangement was disordered, and the integrity of endothelial cells was destroyed; the serum Mg2+ in EEE group was decreased; the serum levels of IL-1β, TNF-α, MDA and ROS in EEE group were significantly higher than those in the CON group (P are all less than 0.05); the serum NO content in EEE group was significantly decreased, and the ratio of NO/ET-1 was significantly decreased. In the exhaustion group, the vasoconstriction response to KCl was increased, and the relaxation response to Ach was weakened, while 4.8mM Mg2+ could significantly improve this phenomenon (P are all less than 0.01). The damage of vascular morphology and function in rats after exhaustion exercise may be related to the significant increase of serum IL-1β, TNF-α, ROS, MDA and ET-1/NO ratio in rats after exhaustion exercise, while Mg2+ can significantly improve the vasomotor function of rats after exhaustion exercise.

IntroductionThe Middle East respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are two highly contagious coronaviruses causing MERS and COVID-19, respectively, without an effective antiviral drug and a long-lasting vaccine. Approaches for diagnosis, therapeutics, prevention, etc., particularly for SARS-CoV-2 that is continually spreading and evolving, are urgently needed. Our previous study discovered that >60% of sera from convalescent COVID-19 individuals, but

Abstract Background Breast cancer remains one of the most dreadful female malignancies globally, in which cancer stem cells (CSCs) play crucial functions. Circular RNAs have drawn great attention in cancer research area and propofol is a widely applied intravenous anesthetic agent. Methods: In the current study, we explored the function of circular RNA nucleolar and coiled-body phosphoprotein 1 (circNOLC1) in CSCs of breast cancer and the inhibitory impact of propofol on circNOLC1. Results The expression of circNOLC1 was induced in breast cancer tissues compared with the non-tumor tissues. The silencing of circNOLC1 was able to repress the viability of breast cancer cells. Meanwhile, the numbers of colony formation were suppressed by circNOLC1 knockdown in breast cancer cells. The inhibition of circNOLC1 reduced the invasion and migration ability of breast cancer cells. The mRNA and protein levels of E-cadherin were enhanced but Vimentin levels were reduced by the silencing of circNOLC1. The repression of circNOLC1 decreased the side population (SP) ratio in breast cancer cells. Meanwhile, the sphere formation ability of breast cancer cells was attenuated by the silencing of circNOLC1. The levels of ATP-binding cassette (ABC) superfamily G member 2 (ABCG2), c-Myc, B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1), and SRY-box transcription factor 2 (Sox2) were repressed by the depletion of circNOLC1 in the cells. Regarding to the mechanism, circNOLC1 functioned as a competing endogenous RNAs (ceRNAs) for microRNA-365a-3p (miR-365a-3p) and the inhibition of miR-365a-3p rescued circNOLC1 depletion-repressed proliferation and cancer stem cell activity of breast cancer. MiR-365a-3p targeted signal transducer and activator of transcription 3 (STAT3) in breast cancer cells and circNOLC1 enhanced STAT3 expression by sponging miR-365a-3p. The overexpression of STAT3 could reverse miR-365a-3p or circNOLC1 depletion-inhibited proliferation and cancer stem cell properties of breast cancer. Interestingly, the expression of circNOLC1 and STAT3 was repressed by the treatment of propofol. The enrichment of STAT3 on circNOLC1 promoter was inhibited by propofol. The expression of circNOLC1 was suppressed by the silencing of STAT3 in the cells. The inhibition of circNOLC1 expression by propofol was rescued under the co-treatment of STAT3 overexpression. The overexpression of circNOLC1 rescued propofol-attenuated proliferation and cancer stem cell functions in vitro and in vivo. Conclusions Thus, we concluded that circNOLC1 contributes to CSCs properties and progression of breast cancer by targeting miR-365a-3p /STAT3 axis and propofol inhibited circNOLC1 by repressing STAT3 in a feedback mechanism.

AIM: To explore the effects of femtosecond laser-assisted in situ keratomileusis(FS-LASIK), topography guided LASIK(TG-LASIK)and small incision lenticule extraction(SMILE)on postoperative visual quality and higher-order aberrations(HOA)in patients with refractive errors.METHODS: A total of 296 patients(586 eyes)with simple myopia or myopic astigmatism who were admitted to refractive center of the hospital between December 2019 and February 2020 were enrolled. Under the premise of determining surgical indications, the patients chose to undergo FS-LASIK, TG-LASIK and SMILE voluntarily. Among them, there were 95 cases(189 eyes)in FS-LASIK group, 104 cases(205 eyes)in TG-LASIK group and 97 cases(192 eyes)in SMILE group. The data such as visual acuity, diopter, corneal topography, HOA and contrast sensitivity were collected before and at 6, 12mo after surgery.RESULTS:The uncorrected visual acuity, best corrected visual acuity, spherical equivalent and spherical equivalent refraction at 6mo after surgery were better than those before surgery(P0.05). At 6, 12mo after surgery, regularity index of corneal surface and surface asymmetry index in TG-LASIK group were significantly lower than those in SMILE group and FS-LASIK group(P0.05). At 6, 12mo after surgery, total HOA, clover aberration and coma at 6mo spherical aberration in FS-LASIK group were significantly higher than those in TG-LASIK group and SMILE group(P

This study was conducted to determine the optimal doses and minimum effective concentrations (MECs) of tricaine methanesulfonate (MS-222) in marketable-size Asian seabass reared at two temperatures (22 and 28 °C). Serum biochemical parameters, pharmacokinetics, and tissue distributions of MS-222 following immersion at the determined optimal doses were also evaluated in order to delineate possible mechanisms dictating the temperature difference. The definition of optimal dose is set as the dose when fish attain stage III anesthesia within 5 min, sustain this stage for 3 min, and re-attain equilibrium within 5 min. The MEC is the fish serum MS-222 concentration when stage III anesthesia is reached. The results showed that water temperature exerted no or minimal impact on the designated parameters. The optimal doses at 22 and 28 °C were 140 and 150 µg/mL, while the MECs were 70.48 and 78.27 µg/mL, respectively. Fish exposed to the optimal doses of MS-222 had significantly elevated blood concentrations of lactate, glucose, calcium, magnesium, and sodium, while the blood pH was significantly decreased. The fish eliminated MS-222 faster at 28 °C than at 22 °C, with serum half-lives of 18.43 and 37.01 h, respectively. Tissue-specific distribution patterns were evident. Irrespective of water temperature, MS-222 peaked at 5 min for the brain and gill but peaked slightly later at 10–20 min for the liver and kidney. Most tissues exhibit a gradual decline of drug concentration except for the gill, which was maintained at a steady level. Muscle is the least perfused tissue with the lowest drug concentration throughout the 90 min period. This study provided physiological and pharmacokinetic evidence contributing to a better understanding of the actions of MS-222 in Asian seabass at different temperatures.

Objective Based on the morphological characteristics of glenoid and greater tuberosity (GT) fractures and the relationship between them, we explored the injury mechanism of acute anterior shoulder dislocation associated with glenoid and GT fractures. Methods From December 2013 to December 2019, we retrospectively reviewed the clinical data of patients who were diagnosed with acute anterior shoulder dislocation associated with glenoid and GT fractures in our hospital. According to the fracture site, a glenoid fracture group and a greater tuberosity fracture (GT) group were established, and the morphological characteristics of both glenoid and GT fractures were measured and statistically analyzed. Results A total of 41 patients (43 shoulders) met the inclusion criteria (39 unilateral shoulders and 2 bilateral shoulders). The mean age was 50.21 years (range, 22–71 years). A total of 27 shoulder injuries (62.8%) were split GT fractures and 33 shoulder injuries (76.7%) were combined with rotator cuff tears. The mean size of glenoid fragments was 30.16% and the mean displacement was 8.85 mm. The mean size of GT fragments was 28.43 mm. The mean superoinferior and anteroposterior displacements of the GT fragment were 6.77 mm and 4.96 mm, respectively. There was a negative correlation between the size of glenoid and GT fracture fragments (r = −0.64, P < 0.05). The glenoid fragments in the Ideberg type Ia glenoid fracture group were smaller than those in the Ideberg type II glenoid fracture group (28.41% and 40.95%, respectively), while the size of GT fragments in the type Ia group were larger than those in the type II group (29.77 mm and 20.21 mm, respectively) (P < 0.05). The GT fragments in the split GT fracture group were larger than those in the avulsion or depression GT fracture group (33.69 mm, 19.07 mm and 21.12 mm, respectively), while the size of glenoid fragments in the split GT fracture group were smaller than those in the avulsion or depression GT fracture group (23.57%, 41.37%, and 43.42%, respectively) (P

Objective To report the clinical and radiological outcomes of arthroscopically assisted surgery for combination of glenoid and greater tuberosity fractures after traumatic shoulder dislocation. Methods From December 2013 to December 2018, patients with concomitant fracture of the greater tuberosity and glenoid who underwent arthroscopically assisted surgery were retrospectively reviewed. Fifteen patients were included. Preoperative computed tomography (CT) scans with 3D reconstruction were performed to evaluate the fracture configuration and associated fractures. All patients underwent arthroscopically assisted surgery under general anesthesia with brachial plexus anesthesia in the lateral position. Under the arthroscopic approach, a comprehensive inspection of the joints was firstly conducted to examine the injury of bones and other tissues. With arthroscopy support, closed reduction and internal fixation of both fractures were performed with suture anchors, with or without additional cannulated screws. At the same time, other injuries were also repaired under the arthroscope. Patients were followed up (6 weeks，8 weeks，3 months，6 months，1 year after surgery) regularly for at least 1 year. At the follow‐up, clinical outcomes (Constant score, ASES score, range of motion, and VAS score) and radiological outcomes were analyzed. Results Of the 15 patients, there are seven cases of men, eight cases of women; aged 22–66 years, with an average age of 48 years; left shoulder for five cases, 10 cases of the right shoulder. The injury mechanisms were: a simple fall (n = 9), an epileptic seizure (n = 1), a high fall injury (n = 2), and a traffic accident (n = 3). Of the 15 cases of glenoid fracture, 11 cases were type Ia and four cases were type II according to the Ideberg Classification System. The mean size of the glenoid fracture fragment was 28.4% (range, 8.7%–47.2%). According to the Mutch classification system, the fractures of the greater tuberosity were divided into: five cases of avulsion, one case of compression, and nine cases of split. Average time of follow‐up was 38.2 months (range, 12–70 months), and one case was lost to follow‐up. With fractures healing well, almost all patients had a good joint function. At the final follow‐up, mean anterior flexion was 157°; mean external rotation was 40°; mean internal rotation was T11 level; the mean Constant–Murley score was 94.6 points (range, 70–100 points); the mean ASES score was 94.6 points (range, 79–100 points); and the mean VAS score was 0.4 points (range, 0–2 points). No recurrent instability or re‐dislocation occurred. No patient had revision surgery. Conclusion Arthroscopic management of glenoid and greater tuberosity bipolar fractures was useful and effective with minimal injury, and it achieved satisfactory clinical and radiological outcomes at a mean follow‐up time of more than 3 years.

Abstract Background Diabetic retinopathy (DR) is a specific neurovascular complication of diabetes mellitus (DM). Clinically, family history is a widely recognized risk factor for DR, assisting diagnosis and risk strata. However, among a great amount of DR patients without hereditary history like hypertension and diabetes, direct and simple risk factors to assist clinical decisions are still required. Herein, we intend to investigate the associated risk factors for these DR patients based on systemic inflammatory response indexes, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Methods We consecutively enrolled 1030 patients with a definite diagnosis of type 2 diabetes mellitus (T2DM) from the endocrinology department of the Second hospital of People in Yun Nan. Based on funduscopy and family history checking, we excluded patients with a family history of hypertension and diabetes and finally enrolled 264 patients with DR and 206 patients with non-diabetic retinopathy (NDR). Through correlation analysis, univariate and multivariate regression, we further explore the association between NLR, PLR, and DR. On top of that, we investigate the effect of NLR and PLR on risk reclassification of DR. Results Compared with NDR patients, NLR and PLR levels are significantly higher among DR patients (NLR: 2.36 ± 1.16 in DR group versus 1.97 ± 1.06 in NDR group, p

BackgroundOsteoid osteoma is a common benign bone tumor, and clinically there is severe local pain that typically worsens at night. The conventional CT-guided radiofrequency ablation (RFA) was widely used in the treatment of osteoid osteoma (OO), which could result in some radiation-related and imprecise complications due to the overdose of radiation exposure. This study aimed to compare the surgical effect of robot-assisted RFA with O-arm navigation and conventional CT-guided RFA in the treatment of OO.MethodsSixty-two patients who underwent robot-assisted RFA with O-arm navigation (Robot-RFA, n = 24) or CT-guided RFA (CT-RFA, n = 38) were included in this retrospective cohort study. The mean follow-up time was 23.3 months. The intra-operative data, primary technical success rate, visual analog scale (VAS), and post-operative complications were analyzed.ResultsPrimary technical success was obtained in 23 patients who had robot-assisted RFA, and 35 patients who had conventional CT-guided RFA. One patient in Robot-RFA group and three patients in CT-RFA group with pain recurrence received repeat-RFA and had a secondary success. Mean operation time and dose of radiation exposure were lower in Robot-RFA group than that in CT-RFA group. The Robot-RFA group took fewer K-wire adjustment times for each patient than the CT-RFA group. There was a statistically significant difference in the mean operation time, dose of radiation exposure, and K-wire adjustment times between the groups (p < 0.05). No complications associated with the procedure were reported in the two groups during the follow-up period.ConclusionRobot-assisted RFA with O-arm navigation is a safer and more precise strategy in the treatment of osteoid osteoma with less operation time and radiation exposure compared with the conventional CT-guided radiofrequency ablation.

In the early 1960s, heat shock proteins (HSPs) were first identified as vital intracellular proteinaceous components that help in stress physiology and reprogram the cellular responses to enable the organism’s survival. By the early 1990s, HSPs were detected in extracellular spaces and found to activate gamma-delta T-lymphocytes. Subsequent investigations identified their association with varied disease conditions, including autoimmune disorders, diabetes, cancer, hepatic, pancreatic, and renal disorders, and cachexia. In cardiology, extracellular HSPs play a definite, but still unclear, role in atherosclerosis, acute coronary syndromes, and heart failure. The possibility of HSP-targeted novel molecular therapeutics has generated much interest and hope in recent years. In this review, we discuss the role of Extracellular Heat Shock Proteins (Ec-HSPs) in various disease states, with a particular focus on cardiovascular diseases.

Background/Objective. Impaired glucose tolerance (IGT) is an intermediate metabolic state between normal and diabetes and shows insulin resistant (IR) which to be linked with mitochondria dysfunction. This study is aimed at investigating whether aerobic exercise increases Mfn2 to promote mitochondrial function and improve glucose tolerance and insulin sensitivity in mice with high-fat diet. Methods. Male C57BL/6J mice were randomly divided into six different experimental groups (8 animals/group): (1) normal group (NOR), (2) normal control group (NC), (3) normal + exercise group (NE), (4) IGT group (IGT), (5) IGT control group (IC), and (6) IGT+ exercise group (IE).The exercise group received aerobic exercise for 8 weeks. After the intervention, a blood glucose meter was used to detect the level of glucose tolerance in the mouse’s abdominal cavity; a biochemical kit was used to detect serum lipid metabolism indicators, malondialdehyde, and superoxide dismutase levels; the ELISA method was used to detect serum insulin and mouse gastrocnemius homogenate LDH, PDH, SDH, and CCO levels. Western blot method was used to detect the protein expression levels of NOX4, PGC-1α, and Mfn2 in the gastrocnemius muscle of mice. Results. (1) Mice with high-fat diet for 30 weeks showed impaired glucose tolerance, insulin resistance, and lipid metabolism disorders. The level of LDH, PDH, SDH, and CCO in the gastrocnemius homogenate of mice was reduced. The expressions of NOX4 protein were significantly upregulated, while the expressions of PGC-1α and Mfn2 proteins were significantly downregulated. (2) 8-week aerobic exercise improved the disorders of glucose and lipid metabolism in IGT mice and increased homogenized LDH, PDH, SDH, and CCO levels, and the expressions of NOX4, PGC-1α, and Mfn2 proteins in the gastrocnemius muscle of mice were reversed. It is speculated that aerobic exercise can accelerate energy metabolism. Conclusion. (1) C57BL/6 mice were fed high fat for 30 weeks and successfully constructed a mouse model of reduced diabetes; the mice with reduced diabetes have impaired glucose tolerance, insulin resistance, and lipid metabolism disorders; (2) 8 weeks of aerobic exercise improve glucose tolerance, reduce glucose tolerance in mice, reduce insulin resistance, improve lipid metabolism disorders, and reduce oxidative stress; (3) 8-week aerobic exercise reduces skeletal muscle NOX4 expression and increases glucose tolerance; reduces the expression of LDH, PDH, SDH, and CCO in mouse skeletal muscle; increases the expression level of mitochondrial fusion protein 2 and PGC-1α; improves glucose tolerance; reduces energy metabolism of mouse skeletal muscle; reduces oxidative stress; and reduces insulin resistance. It is speculated that aerobic exercise can accelerate energy metabolism. This process may involve two aspects: firstly, increase the expression level of oxidative metabolism enzymes and promote the tricarboxylic acid cycle; secondly, increase the expression of Mfn2 and accelerate mitochondria fission or fusion to regulate energy metabolism, thereby reducing oxidative stress and insulin resistance.