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IntroductionThe efficacy and safety of 3% diquafosol sodium eye drops in Chinese patients with dry eye in the real-world setting remains unclear.Methods3099 patients with dry eye symptoms were screened according to Asia Dry Eye Society latest recommendation. Among them, 3000 patients were enrolled for a phase IV study. We followed up with multiple clinical characteristics including corneal fluorescein staining, tear break up time, Schirmer’s tests, visual acuity, intraocular pressure, and others. The follow ups were performed at baseline, 2 weeks and 4 weeks after treatment.ResultsBased on the results of corneal fluorescein staining and tear break up time, all age and gender subgroups exhibited obvious alleviation of the symptoms among the patients with dry eye, and the data in elderly group showed the most significant alleviation. All the adverse drug reactions (ADRs, 6.17%) were recorded, among which 6% local ocular ADRs were included. Meanwhile, mild ADRs (91.8%) accounted for the most. Most of the ADRs (89.75%) got a quick and full recovery, with an average time at 15.6 days. 1.37% of patients dropped out of the study due to ADRs.DiscussionThe use of 3% diquafosol sodium eye drop is effective and safe in the treatment of dry eye, with a low incidence of ADRs showing mild symptoms. This trial was registered at Chinese Clinical Trial Registry ID: ChiCTR1900021999 (Registration Date: 19/03/2019).

Metabolic syndrome (MS) is a complex group of metabolic disorders syndrome with hypertension, hyperuricemia and disorders of glucose or lipid metabolism. As an important organ involved in metabolism, the kidney is inevitably attacked by various metabolic disorders, leading to abnormalities in kidney structure and function. Recently, an increasing number of studies have shown that mitochondrial dysfunction is actively involved in the development of metabolic-associated kidney diseases. Mitochondrial dysfunction can be used as a potential therapeutic strategy for the treatment of metabolic-associated kidney diseases. Many natural products have been widely used to improve the treatment of metabolic-associated kidney diseases by inhibiting mitochondrial dysfunction. In this paper, by searching several authoritative databases such as PubMed, Web of Science, Wiley Online Library, and Springer Link. We summarize the Natural Products Protect Against Metabolic-Associated Kidney Diseases by Regulating Mitochondrial Dysfunction. In this review, we sought to provide an overview of the mechanisms by which mitochondrial dysfunction impaired metabolic-associated kidney diseases, with particular attention to the role of mitochondrial dysfunction in diabetic nephropathy, gouty nephropathy, hypertensive kidney disease, and obesity-related nephropathy, and then the protective role of natural products in the kidney through inhibition of mitochondrial disorders, thus providing a systematic understanding of the targets of mitochondrial dysfunction in metabolic-associated kidney diseases, and finally a review of promising therapeutic targets and herbal candidates for metabolic-associated kidney diseases through inhibition of mitochondrial dysfunction.

ObjectiveAltered expression patterns of Na+-K+-2Cl– (NKCC1) and K+-Cl– (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on γ-aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD).Materials and methodsWe sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the non-seizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting.ResultsResults revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non-SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group.ConclusionOur results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs).

PurposeTo investigate the indirect effects of intense pulsed light (IPL) on morphological and pathological changes of the meibomian glands (MGs) in apolipoprotein E knockout (ApoE–/–) mice and explore the underlying mechanisms.MethodsApoE–/– mice were treated with or without IPL three times below the lower eyelids and MGs were not directly exposed to irradiation. The eyelids and ocular surface were observed under a stereoscope. The morphology of MGs was examined by photographing and hematoxylin and eosin staining. Lipid droplets in MGs were examined by Oil Red O staining. The ultrastructure of meibocytes and mitochondria was observed under transmission electron microscopy. The relative gene and protein expression in MGs of upper eyelids was determined by immunostaining, Western blot, and qRT–PCR.ResultsThree IPL treatments decreased the toothpaste-like plugging of orifices and thickening and irregularity of the upper and lower eyelid margins in ApoE–/– mice. The morphology of some MGs improved after IPL treatments, accompanied by increased proliferation of acinar basal cells and decreased ductal keratinization. Furthermore, the accumulation of hyperchromatic lipid droplets in the acini increased, and the lipid droplets distributed in the cells around the acini were round and small. Compared with untreated ApoE–/– mice, oxidative stress and apoptosis were downregulated by IPL treatment, accompanied by the improvements in mitochondrial structure. Further research showed that IPL treatments reduced the levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-17A, IL-6 in MGs and inactivated nuclear factor kappa B (NF-κ B).ConclusionCollectively, the results demonstrate that indirect effects of IPL can improve the structure and function of MGs and mitigate the progression of MGD, which may be related to the indirect effects of photobiomodulation.

This article proposes a new differential-cascading-based dual-stator brushless doubly-fed induction machine with a staggered dual cage rotor. Conventional differential mode of the brushless doubly-fed machine with cage rotor suffers from the low number of rotor bars because of the low equivalent synchronous pole pairs of |p1-p2|, and thus, severe rotor flux leakage, low capacity of magnetic field conversion of the rotor and low efficiency. To overcome the obstacle of the excessive harmonics of the rotor, a design method based on the differential cascading is proposed which enables the cage rotor with a high number of conductor bars even in the case of low pole pairs of |p1-p2|, hence the greatly reduced rotor leakage inductance and enhanced performance of the machine. The rotating magneto-motive force theory is applied to derive the interconnection rule of the staggered dual cage rotor, and meanwhile, the corresponding examples are illustrated. The performance comparisons between the differential cascading and the sum cascading based on the proposed machine are carried out. The results show that the proposed machine based on the differential cascading obtains higher power densities comparing to the sum cascading at the region of sub-natural synchronous speed, while its drawback is the increment of the loss due to the high rotor frequency, gaining lower efficiencies at the region of super-natural synchronous speed.

Background: A high level of lipoprotein(a) can lead to a high risk of cardiovascular events or mortality. However, the association of moderately elevated lipoprotein(a) levels (≥15 mg/dL) with long-term prognosis among patients with coronary artery disease (CAD) is still uncertain. Hence, we aim to systematically analyzed the relevance of baseline plasma lipoprotein(a) levels to long-term mortality in a large cohort of CAD patients.Methods: We obtained data from 43,647 patients who were diagnosed with CAD and had follow-up information from January 2007 to December 2018. The patients were divided into two groups (

Accurate localization of the epileptogenic zone (EZ) is a key factor to obtain good surgical outcome for refractory epilepsy patients. However, no technique, so far, can precisely locate the EZ, and there are barely any reports on the combined application of multiple technologies to improve the localization accuracy of the EZ. In this study, we aimed to explore the use of a multimodal method combining PET-MRI, fluid and white matter suppression (FLAWS)—a novel MRI sequence, and high-frequency oscillation (HFO) automated analysis to delineate EZ. We retrospectively collected 15 patients with refractory epilepsy who underwent surgery and used the above three methods to detect abnormal brain areas of all patients. We compared the PET-MRI, FLAWS, and HFO results with traditional methods to evaluate their diagnostic value. The sensitivities, specificities of locating the EZ, and marking extent removed versus not removed [RatioChann(ev)] of each method were compared with surgical outcome. We also tested the possibility of using different combinations to locate the EZ. The marked areas in every patient established using each method were also compared to determine the correlations among the three methods. The results showed that PET-MRI, FLAWS, and HFOs can provide more information about potential epileptic areas than traditional methods. When detecting the EZs, the sensitivities of PET-MRI, FLAWS, and HFOs were 68.75, 53.85, and 87.50%, and the specificities were 80.00, 33.33, and 100.00%. The RatioChann(ev) of HFO-marked contacts was significantly higher in patients with good outcome than those with poor outcome (p< 0.05). When intracranial electrodes covered all the abnormal areas indicated by neuroimaging with the overlapping EZs being completely removed referred to HFO analysis, patients could reach seizure-free (p < 0.01). The periphery of the lesion marked by neuroimaging may be epileptic, but not every lesion contributes to seizures. Therefore, approaches in multimodality can detect EZ more accurately, and HFO analysis may help in defining real epileptic areas that may be missed in the neuroimaging results. The implantation of intracranial electrodes guided by non-invasive PET-MRI and FLAWS findings as well as HFO analysis would be an optimized multimodal approach for locating EZ.

Chouguiyu, a Chinese traditional fermented fish, is famous for its uniquely strong odor and desirable taste. However, traditional spontaneous fermentation often resulted in contamination and unstable quality of products. In this study, individual or conjunctive inoculation of two indigenous lactic acid bacteria (LAB), Lactococcus lactis M10 and Weissella cibaria M3, was tested for their effect on improving Chouguiyu’s quality. It was shown that inoculation would not affect the system’s pH, while increased the total bacteria count and lactic acid bacteria amounts. Matrix-assisted laser desorption/ionization time-of-flight mass (MALDI-TOF) analysis results revealed that Lactoc. lactis M10 and W. cibaria M3 could quickly occupy a dominant position in the ecosystem, and Lactoc. lactis M10 played an important role in the control of spoilage bacteria. Volatile basic nitrogen (TVB-N), thiobarbituric acid reactive substances (TBARS), and biogenic amines results also showed that Lactoc. lactis M10 had a positive effect on improving the product’s quality. Co-inoculation of Lactoc. lactis M10 and W. cibaria M3 could promote the formation of flavor according to the E-nose and gas chromatography-mass spectrometer (GC-MS) analyses, especially for the aroma-active and key volatile compounds. PCA plots of E-nose and hierarchical clustering analysis of GC-MS profiles revealed that the co-inoculation sample at the fifth day (LW5) was the most similar to the natural fermentation sample at the seventh day (C7). The overall acceptance of LW5 was also the closest to that of C7 in sensory evaluation. In conclusion, mixed starter culture was shown to have a good effect on improving product quality and enhancing flavor with fermentation time shortened by 29%.

Objective: Altered expression patterns of NaC-KC-2Cl􀀀 (NKCC1) and KC- Cl􀀀 (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on g- aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD). Materials and methods: We sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the nonseizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting. Results: Results revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non- SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group. Conclusion: Our results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs). [ABSTRACT FROM AUTHOR]

China consumes 35% of the world’s fertilizer every year; however, most of the nitrogen fertilizers, which are essential for rice cultivation, are not used effectively. In this study, factors affecting the nitrogen leaching loss rate were studied in typical soil and rice varieties in South China. The effects of various irrigation measures on rice growth and nitrogen leaching loss were investigated by conducting experiments with eight groups. These groups included traditional irrigation (TI) and shallow wet irrigation (SWI). The TI is a common irrigation method for farmers in South China, maintaining a water layer of 5-8 cm depth. For SWI, after establishing a shallow water layer usually maintaining at 1-2 cm, paddy is irrigated when the field water level falls to a certain depth, then this process is then repeat as necessary. The nitrogen distribution characteristics were determined using 15N isotope tracing. In addition, the effects of nitrification, denitrification, and microbial composition on soil nitrogen transformation at different depths were studied by microbial functional gene quantification and high-throughput sequencing. The results revealed that in the SWI groups, the total nitrogen leaching loss rate reduced by 0.3-0.8% and the nitrogen use efficiency (NUE) increased by 2.18-4.43% compared with those in the TI groups. After the 15N-labeled nitrogen fertilizer was applied, the main pathways of nitrogen were found to be related to plant absorption and nitrogen residues. Furthermore, paddy soil ammonia-oxidizing archaea were more effective than ammonia-oxidizing bacteria for soil ammonia oxidation by SWI groups. The SWI measures increased the relative abundance of Firmicutes in paddy soil, enhancing the ability of rice to fix nitrogen to produce ammonium nitrogen, thus reducing the dependence of rice on chemical fertilizers. Moreover, SWI enhanced the relative abundance of nirS and nosZ genes within surface soil bacteria, thereby promoting denitrification in the surface soil of paddy fields. SWI also promoted ammonia oxidation and denitrification by increasing the abundance and activity of Proteobacteria, Nitrospirae, and Bacteroidetes. Collectively, SWI effectively reduced the nitrogen leaching loss rate and increase NUE.

Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile arthritis, accompanied by cytokine storm and hemophagocytosis. In addition, COVID-19–related hyperinflammation shares clinical features of MAS. Mechanisms that activate macrophages in MAS remain unclear. Here, we identify the role of miRNA in increased phagocytosis and interleukin-12 (IL-12) production by macrophages in a murine model of MAS. MAS significantly increased F4/80+ macrophages and phagocytosis in the mouse liver. Gene expression profile revealed the induction of Fcγ receptor–mediated phagocytosis (FGRP) and IL-12 production in the liver. Phagocytosis pathways such as High-affinity IgE receptor is known as Fc epsilon RI -signaling and pattern recognition receptors involved in the recognition of bacteria and viruses and phagosome formation were also significantly upregulated. In MAS, miR-136-5p and miR-501-3p targeted and caused increased expression of Fcgr3, Fcgr4, and Fcgr1 genes in FGRP pathway and consequent increase in phagocytosis by macrophages, whereas miR-129-1-3p and miR-150-3p targeted and induced Il-12. Transcriptome analysis of patients with MAS revealed the upregulation of FGRP and FCGR gene expression. A target analysis of gene expression data from a patient with MAS discovered that miR-136-5p targets FCGR2A and FCGR3A/3B, the human orthologs of mouse Fcgr3 and Fcgr4, and miR-501-3p targets FCGR1A, the human ortholog of mouse Fcgr1. Together, we demonstrate the novel role of miRNAs during MAS pathogenesis, thereby suggesting miRNA mimic–based therapy to control the hyperactivation of macrophages in patients with MAS as well as use overexpression of FCGR genes as a marker for MAS classification.

Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, the connection between chronic inflammation and diabetic complications has been revealed. However, the effects of non-steroidal anti-inflammatory drug celecoxib on diabetic sarcopenia remains unclear.Materials and Methods: The streptozotocin (streptozotocin)-induced diabetic sarcopenia model was established. Rotarod test and grip strength test were used to assess skeletal muscle function. Hematoxylin and eosin and immunofluorescence staining were performed to evaluate inflammatory infiltration and the morphology of motor endplates in skeletal muscles. Succinate dehydrogenase (SDH) staining was used to determine the number of succinate dehydrogenase-positive muscle fibers. Dihydroethidium staining was performed to assess the levels of reactive oxygen species (ROS). Western blot was used to measure the levels of proteins involved in inflammation, oxidative stress, endoplasmic reticulum stress, ubiquitination, and autophagic-lysosomal pathway. Transmission electron microscopy was used to evaluate mitophagy.Results: Celecoxib significantly ameliorated skeletal muscle atrophy, improving skeletal muscle function and preserving motor endplates in diabetic mice. Celecoxib also decreased infiltration of inflammatory cell, reduced the levels of IL-6 and TNF-α, and suppressed the activation of NF-κB, Stat3, and NLRP3 inflammasome pathways in diabetic skeletal muscles. Celecoxib decreased reactive oxygen species levels, downregulated the levels of Nox2 and Nox4, upregulated the levels of GPX1 and Nrf2, and further suppressed endoplasmic reticulum stress by inhibiting the activation of the Perk-EIF-2α-ATF4-Chop in diabetic skeletal muscles. Celecoxib also inhibited the levels of Foxo3a, Fbx32 and MuRF1 in the ubiquitin-proteasome system, as well as the levels of BNIP3, Beclin1, ATG7, and LC3Ⅱ in the autophagic-lysosomal system, and celecoxib protected mitochondria and promoted mitochondrial biogenesis by elevating the levels of SIRT1 and PGC1-α, increased the number of SDH-positive fibers in diabetic skeletal muscles.Conclusion: Celecoxib improved diabetic sarcopenia by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and protecting mitochondria, and subsequently suppressing proteolytic systems. Our study provides evidences for the molecular mechanism and treatment of diabetic sarcopenia, and broaden the way for the new use of celecoxib in diabetic sarcopenia.

AimThe objective of this study is to examine the correlation between patient serum cholinesterase (SCHE) concentration and weaning failure in the context of invasive mechanical ventilation (IMV), as well as to identify predictors of ventilator weaning failure. Additionally, this study investigates the potential relationship between SCHE and nutritional risk for developing more effective weaning strategies.MethodA retrospective observational study was conducted. The sample was collected from 227 patients with IMV over 48 h who underwent SBT before weaning. Relevant experimental samples and data collection were analyzed at the time of patient admission and before the initiation of the SBT. The correlation between SCHE and weaning failure was determined by multifactorial logistic regression and propensity matching scores.ResultsWeaning was successful in 127 patients and failed in 100 patients. Depending on the difficulty of weaning, 55 of these patients had difficulty in weaning and 45 had long-term weaning. In the crude cohort, experimental data collected on the day of SBT showed that SCHE concentrations were higher in patients with successful weaning than in those with failed weaning (4,514 u/l vs. 3,190 u/l p

Since May 2022, mutant strains of mpox (formerly monkeypox) virus (MPXV) have been rapidly spreading among individuals who have not traveled to endemic areas in multiple locations, including Europe and the United States. Both intracellular and extracellular forms of mpox virus have multiple outer membrane proteins that can stimulate immune response. Here, we investigated the immunogenicity of MPXV structural proteins such as A29L, M1R, A35R, and B6R as a combination vaccine, and the protective effect against the 2022 mpox mutant strain was also evaluated in BALB/c mice. After mixed 15 μg QS-21 adjuvant, all four virus structural proteins were administered subcutaneously to mice. Antibody titers in mouse sera rose sharply after the initial boost, along with an increased capacity of immune cells to produce IFN-γ alongside an elevated level of cellular immunity mediated by Th1 cells. The vaccine-induced neutralizing antibodies significantly inhibited the replication of MPXV in mice and reduced the pathological damage of organs. This study demonstrates the feasibility of a multiple recombinant vaccine for MPXV variant strains.

BackgroundPerioperative stroke is a potentially devastating complication in surgical patients, which has attracted global attention. This retrospective bibliometric and visual analysis evaluates the status and global trends in perioperative stroke research.MethodsPapers published between 2003 and 2022 were retrieved from the Web of Science core collection. Extracted data were summarized and analyzed using Microsoft Excel and further bibliometric and co-occurrence analyses were conducted using VOSviewer and CiteSpace software.ResultsPublications on perioperative stroke have increased over the years. The USA topped the list of countries with the highest number of publications and citations, while Canada had the highest mean citation frequency. The Journal of Vascular Surgery and Annals of Thoracic Surgery had the highest number of publications and citation frequency for perioperative stroke. Regarding authors, Malas, Mahmoud B. contributed the most publications to the field, and Harvard University had the highest number of publications (409 papers). Based on an overlay visualization map, timeline view, and the strongest strength burst of keywords, “antiplatelet therapy,” “antithrombotic therapy,” “carotid revascularization,” “bleeding complications,” “postoperative cognitive dysfunction,” “intraoperative hypotension,” “thrombectomy,” “cerebral revascularization,” “valve surgery,” “tranexamic acid,” and “frozen elephant trunk” were trending topics in perioperative stroke research.ConclusionPublications regarding perioperative stroke have experienced rapid growth in the past 20 years and are likely to continuously increase. Research on perioperative antiplatelet and antithrombotic, cardiovascular surgery, postoperative cognitive dysfunction, thrombectomy, tranexamic acid, and frozen elephant trunk has attracted increasing attention, and these topics are emerging hotspots of present research and possible candidates for future research.

The objective of this research was to examine gender differences in entrepreneurial venture interests drawing on goal congruity theory, which posits that people adopt gender-stereotypic goal orientations in response to social pressures to conform to traditional gender roles. Aspiring entrepreneurs (N = 351) first wrote about what they believed made an entrepreneur successful. They then completed measures of agentic and communal goal orientations (i.e., male and female stereotypic orientations, respectively) and indicated their interests in starting ventures in stereotypically feminine (e.g., salon), masculine (e.g., auto-repair) and science, technology, engineering, and mathematics (STEM; e.g., software developer) ventures. Analysis of open-ended responses demonstrated that participants ascribed more agentic and, specifically, more dominance attributes to entrepreneurs than communal attributes (e.g., warmth). Bifactor structural equation modeling indicated that, as expected, agentic goal orientations included dimensions of competence, self-direction, and dominance orientations; communal goal orientations were unidimensional. Further, as expected, dominance and communal orientations partially accounted for gender differences in all three career types. We discuss implications for entrepreneurial education and practice from a goal congruity perspective and the use of bifactor modeling to improve the measurement of goal orientations.

Magnesium (Mg) is a promising biodegradable metal for orthopedic applications, and plasma electrolytic oxidation (PEO) has been widely studied as a corrosion protection coating on Mg-based implants. However, the porous structures and easily formed cracks in fluid are disadvantageous for long-term corrosion protection. In this study, a SiO2 layer was deposited on PEO-treated Mg to inhibit the formation of cracks on the PEO layer and prevent the permeation of corrosive fluid. The SiO2 layer did not alter the surface morphology of the PEO layer but considerably enhanced its corrosion resistance. The in vitro culture of MC3T3-E1 cells demonstrated the good cytocompatibility and osteogenic induction ability of SiO2-coated PEO-treated Mg, which could be attributed to Mg and Si ions released from the coating. The coating also favored the angiogenesis behaviors of HUVEC. Furthermore, with the continuous release of Mg and Si ions, the as-prepared implant showed a superior osseointegration ability in a rat bone implantation model. In summary, this newly designed Mg-based implant shows promising potential for orthopedic applications.

BackgroundFew data exist on the immunogenicity and safety of an inactivated enterovirus 71 vaccine (EV71 vaccine) coadministered with trivalent split-virion inactivated influenza vaccine (IIV3) in infants.MethodsThis trial was a phase 4, randomized, controlled trial. Infants aged 6-11 months were eligible, with no history of hand, foot and mouth disease (HFMD) and no history of EV71 vaccine or any influenza vaccine. Eligible infants were randomly assigned to EV71+IIV3 group, EV71 group or IIV3 group. Blood samples were collected on day 0 and 56.ResultsBetween September 2019 and June 2020, 1151 infants met eligibility criteria and 1134 infants were enrolled. 1045 infants were included in the per-protocol population, including 347 in the EV71+IIV3 group, 343 in the EV71 group, and 355 in the IIV3 group. The seroconversion rate (98.56% vs 98.54%; seroconversion rates difference of 0.02% [95% CI: 0.70-0.98]) and GMT (419.05 vs 503.72; GMT ratio of 0.83 [95% CI 0.70 - 0.98]) of EV71 neutralizing antibodies in the EV71+IIV3 group was not inferior to those in the EV71 group. The non-inferiority results for influenza virus antibodies (A/H1N1, A/H3N2 and B) showed that the seroconversion rates and GMTs of the EV71+IIV3 group were non-inferiority to those of the IIV3 group. Systemic and local adverse event rates were similar between groups. None of serious adverse events (SAEs) were related to vaccination.ConclusionsCoadministration of the EV71 vaccine with IIV3 was safe and did not interfere with immunogenicity. These findings support a viable immunization strategy for infants with the EV71 vaccine coadministered with IIV3 in China. This trial is registered with ClinicalTrials.gov, number NCT04091880.

Key pointConsidering that vaccination with the sIPV and DTaP overlap at the ages of 3 and 4 months in China, to reduce the burden of treatment on parents and increase vaccination coverage rates, we designed a postmarket clinical study of co-administration.BackgroundThe Sabin-strain-based inactivated poliovirus vaccine (sIPV) and the diphtheria-tetanus-acellular pertussis vaccine (DTaP) have been licensed in China for many years. To conduct a clinical study on the safety and immunogenicity of the sIPV when administered concomitantly with the DTaP.MethodsThe study population was divided into three groups: group 1 was the sIPV+ DTaP concomitant administration group, group 2 was the sIPV inoculation group, and group 3 was the DTaP inoculation group. Blood samples were collected prevaccination and 30 days postvaccination, and serum antibody levels were detected.ResultsThis study showed that the seropositive and seroconversion rates of type 1, 2 and 3 poliovirus in group 1 were higher than those in group 2, with no statistically significant difference after vaccination (P>0.05). Groups 1 and 3 also showed similar responses for all vaccine antigens except anti-FHA (97.65 (94.09-99.36) vs. 100 (97.89-100)). The geometric mean titers (GMTs) for the DTaP and sIPV among the groups were comparable, and the non-inferiority t test result was P

Peripheral nerve injury is common, and can lead to skeletal muscle atrophy and dysfunction. However, the underlying molecular mechanisms are not fully understood. The transcription factors have been proved to play a key role in denervated muscle atrophy. In order to systematically analyze transcription factors and obtain more comprehensive information of the molecular regulatory mechanisms in denervated muscle atrophy, a new transcriptome survey focused on transcription factors are warranted. In the current study, we used microarray to identify and analyze differentially expressed genes encoding transcription factors in denervated muscle atrophy in a rat model of sciatic nerve dissection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to explore the biological functions of differentially expressed transcription factors and their target genes related to skeletal muscle pathophysiology. We found that the differentially expressed transcription factors were mainly involved in the immune response. Based on correlation analysis and the expression trends of transcription factors, 18 differentially expressed transcription factors were identified. Stat3, Myod1, Runx1, Atf3, Junb, Runx2, Myf6, Stat5a, Tead4, Klf5, Myog, Mef2a, and Hes6 were upregulated. Ppargc1a, Nr4a1, Lhx2, Ppara, and Rxrg were downregulated. Functional network mapping revealed that these transcription factors are mainly involved in inflammation, development, aging, proteolysis, differentiation, regeneration, autophagy, oxidative stress, atrophy, and ubiquitination. These findings may help understand the regulatory mechanisms of denervated muscle atrophy and provide potential targets for future therapeutic interventions for muscle atrophy following peripheral nerve injury.

Safe and effective vaccines against SARS-CoV-2 for children are urgently needed. Here we aimed to assess the safety and immunogenicity of an inactivated COVID-19 vaccine candidate, WIBP-CorV, in participants aged 3-17 years. A randomized, double-blind, placebo-controlled, phase 1/2 clinical trial was conducted in Henan Province, China, in healthy children aged 3-17 years. 240 participants in phase 1 trial and 576 participants in phase 2 trial were randomly assigned to vaccine or control with an age de-escalation in three cohorts (3-5, 6-12 and 13-17 years) and dose-escalation in three groups (2.5, 5.0 and 10.0μg/dose), and received 3 intramuscular injections at day 0, 28, and 56. WIBP-CorV showed a promising safety profile with approximately 17% adverse reactions within 30 days after injection and no grade 3 or worse adverse events. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting. The geometric mean titers of neutralizing antibody ranged from 102.2 to 1065.5 in vaccinated participants at 28 days after the third vaccination, and maintained at a range of 14.3 to 218.2 at day 180 after the third vaccination. WIBP-CorV elicited significantly higher titers of neutralizing antibody in the cohort aged 3-5 years than the other two cohorts. There were no detectable antibody responses in all alum-only groups. Taken together, our data demonstrate that WIBP-CorV is safe and well tolerated at all tested doses in participants aged 3-17 years, and elicited robust humoral responses against SARS-CoV-2 lasted for at least 6 months after the third vaccination. This study is ongoing and is registered with www.chictr.org.cn, ChiCTR2000031809.

At present, there are many kinds of intelligent training equipment in tennis sports, but they all need human control. If a single tennis player uses the robot to return the ball, it will save some human resources. This study aims to improve the recognition rate of tennis sports robots in the return action and the return strategy. The human-oriented motion recognition of the tennis sports robot is taken as the starting point to recognize and analyze the return action of the tennis sports robot. The OpenPose traversal dataset is used to recognize and extract human motion features of tennis sports robots under different classifications. According to the return characteristics of the tennis sports robot, the method of tennis return strategy based on the support vector machine (SVM) is established, and the SVM algorithm in machine learning is optimized. Finally, the return strategy of tennis sports robots under eight return actions is analyzed and studied. The results reveal that the tennis sports robot based on the SVM-Optimization (SVM-O) algorithm has the highest return recognition rate, and the average return recognition rate is 88.61%. The error rates of the backswing, forward swing, and volatilization are high in the return strategy of tennis sports robots. The preparation action, backswing, and volatilization can achieve more objective results in the analysis of the return strategy, which is more than 90%. With the increase of iteration times, the effect of the model simulation experiment based on SVM-O is the best. It suggests that the algorithm proposed has a reliable accuracy of the return strategy of tennis sports robots, which meets the research requirements. Human motion recognition is integrated with the return motion of tennis sports robots. The application of the SVM-O algorithm to the return action recognition of tennis sports robots has good practicability in the return action recognition of tennis sports robot and solves the problem that the optimization algorithm cannot be applied to the real-time requirements. It has important research significance for the application of an optimized SVM algorithm in sports action recognition.

Silk, as a kind of natural fibrin, has been prepared into various biomaterials due to its excellent biocompatibility and mechanicalness. However, there are some controversies on the biocompatibility of silk fibroin (SF), especially when it coexists with sericin. In this study, two kinds of silk from Jiangsu and Zhejiang were degummed with two concentrations of Na2CO3 solution, respectively, to obtain four kinds of silk fibroin. The effects of different degumming treatments on silk fibroin properties were analyzed by means of color reaction, apparent viscosity measurement, and transmission electron microscope and isobaric tags for relative and absolute quantification analyses, and the effects of different silk fibroin membranes on the growth of Schwann cells were evaluated. The results showed that the natural silk from Zhejiang treated with 0.05% Na2CO3 solution had a fuller structure, higher apparent viscosity, and better protein composition. While SF obtained by degumming with 0.5% Na2CO3 solution was more beneficial to cell adhesion and proliferation due to the thorough removal of sericin. This study may provide important theoretical and experimental bases for the selection of biomaterials for fabricating artificial nerve grafts.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder and patients diagnosed with PTSD often express other comorbid health issues, particularly autoimmune and inflammatory disorders. Our previous reports investigating peripheral blood mononuclear cells (PBMCs) from PTSD patients showed that these patients exhibit an increased inflammatory T helper (Th) cell phenotype and widespread downregulation of microRNAs (miRNAs), key molecules involved in post-transcriptional gene regulation. A combination of analyzing prior datasets on gene and miRNA expression of PBMCs from PTSD and Control samples, as well as experiments using primary PBMCs collected from human PTSD and Controls blood, was used to evaluate TP53 expression, DNA methylation, and miRNA modulation on Th17 development. In the current report, we note several downregulated miRNAs were linked to tumor protein 53 (TP53), also known as p53. Expression data from PBMCs revealed that compared to Controls, PTSD patients exhibited decreased TP53 which correlated with an increased inflammatory Th17 phenotype. Decreased expression of TP53 in the PTSD population was shown to be associated with an increase in DNA methylation in the TP53 promotor region. Lastly, the most significantly downregulated TP53-associated miRNA, let-7a, was shown to negatively regulate Th17 T cells. Let-7a modulation in activated CD4+ T cells was shown to influence Th17 development and function, via alterations in IL-6 and IL-17 production, respectively. Collectively, these studies reveal that PTSD patients could be susceptible to inflammation by epigenetic dysregulation of TP53, which alters the miRNA profile to favor a proinflammatory Th17 phenotype.

PurposeTo develop a new interventional oncology technique using indocyanine green (ICG)-based interventional optical imaging (OI) to monitor the synergistic effect of radiofrequency hyperthermia (RFH)-enhanced oncolytic immunotherapy.Materials and MethodsThis study included (1) optimization of ICG dose and detection time-window for intracellular uptake by VX2 tumor cells; (2) in-vitro confirmation of capability of using ICG-based OI to assess efficacy of RFH-enhanced oncolytic therapy (LTX-401) for VX2 cells; and (3) in-vivo validation of the interventional OI-monitored, intratumoral RFH-enhanced oncolytic immunotherapy using rabbit models with orthotopic liver VX2 tumors. Both in-vitro and in-vivo experiments were divided into four study groups (n=6/group) with different treatments: (1) combination therapy of RFH+LTX-401; (2) RFH alone at 42°C for 30 min; (3) oncolytic therapy with LTX-401; and (4) control with saline. For in-vivo validation, orthotopic hepatic VX2 tumors were treated using a new multi-functional perfusion-thermal radiofrequency ablation electrode, which enabled simultaneous delivery of both LTX-401 and RFH within the tumor and at the tumor margins.ResultsIn in-vitro experiments, taking up of ICG by VX2 cells was linearly increased from 0 μg/mL to 100 μg/mL, while ICG-signal intensity (SI) reached the peak at 24 hours. MTS assay and apoptosis analysis demonstrated the lowest cell viability and highest apoptosis in combination therapy, compared to three monotherapies (P

The leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) belonging to G protein-coupled receptors (GPCRs) family, had various regulatory roles at multiple cellular types and numerous targeting sites, and aberrant LGR4 signaling played crucial roles in diseases and carcinogenesis. On the basis of these facts, LGR4 may become an appealing therapeutic target for the treatment of diseases and tumors. However, a comprehensive investigation of its functions and applications was still lacking. Hence, this paper provided an overview of the molecular characteristics and signaling mechanisms of LGR4, its involvement in multiple organ development and participation in the modulation of immunology related diseases, metabolic diseases, and oxidative stress damage along with cancer progression. Given that GPCRs accounted for almost a third of current clinical drug targets, the in-depth understanding of the sophisticated connections of LGR4 and its ligands would not only enrich their regulatory networks, but also shed new light on designing novel molecular targeted drugs and small molecule blockers for revolutionizing the treatment of various diseases and tumors.

Larix olgensis is a tall deciduous tree species that has many applications in the wood fiber industry. Bud mutations are somatic mutations in plants and are considered an ideal material to identify and describe the molecular mechanism of plant mutation. However, the molecular regulatory mechanisms of bud mutations in L. olgensis remain unknown. In this study, dwarfed (or stunted), short-leaved, and multi-branched mutants of L. olgensis were found and utilized to identify crucial genes and regulatory networks controlling the multiple branch structure of L. olgensis. The physiological data showed that the branch number, bud number, fresh and dry weight, tracheid length, tracheid length-width ratio, inner tracheid diameter, and epidermal cell area of mutant plants were higher than that of wild-type plants. Hormone concentration measurements found that auxin, gibberellin, and abscisic acid in the mutant leaves were higher than that in wild-type plants. Moreover, the transcriptome sequencing of all samples using the Illumina Hiseq sequencing platform. Transcriptome analysis identified, respectively, 632, 157, and 199 differentially expressed genes (DEGs) in buds, leaves, and stems between mutant plants and wild type. DEGs were found to be involved in cell division and differentiation, shoot apical meristem activity, plant hormone biosynthesis, and sugar metabolism. Furthermore, bZIP, WRKY, and AP2/ERF family transcription factors play a role in bud formation. This study provides new insights into the molecular mechanisms of L. olgensis bud and branch formation and establishes a fundamental understanding of the breeding of new varieties in L. olgensis.

In China, the majority of patients with hepatocellular carcinoma (HCC) result from long-term infection of hepatitis B. Pathologically, HCC is characterized by rich blood supply, multicentric origins, early vascular invasion and intrahepatic metastasis. Therefore, HCC is not a local disease but a systemic disease at the beginning of its occurrence. For this reason, a comprehensive treatment strategy should be adopted in the management of HCC, including local treatments (such as surgical resection, radiofrequency ablation, microwave ablation, chemical ablation and cryoablation, etc.), organ-level treatments [such as transcatheter arterial infusion of chemotherapy and transcatheter arterial chemoembolization (TACE)], and systemic treatments (such as immunotherapy, antiviral therapy and molecular targeted therapy, etc.). This consensus sets forth the minimally-invasive and multidisciplinary comprehensive guideline of HCC, focusing on the following eight aspects (1) using hepaticarteriography, CT hepatic arteriography (CTHA), CT arterial portography (CTAP), lipiodol CT (Lp-CT), TACE-CT to find the intrahepatic lesion and make precise staging (2) TACE combined with ablation or ablation as the first choice of treatment for early stage or small HCC, while other therapies are considered only when ablation is not applicable (3) infiltrating HCC should be regarded as an independent subtype of HCC (4) minimally-invasive comprehensive treatment could be adopted in treating metastatic lymph nodes (5) multi-level subdivision of M-staging should be used for individualized treatment and predicting prognosis (6) HCC with severe hepatic decompensation is the only candidate criterion for liver transplantation (7) bio-immunotherapy, traditional Chinese medicine therapy, antiviral therapy, and psychosocial and psychopharmacological interventions should be advocated through the whole course of HCC treatment (8) implementation of multicenter randomized controlled trials of minimally-invasive therapy versus surgery for early and intermediate stage HCC is recommended.

To determine whether the neutralization activity of monoclonal antibodies, convalescent sera and vaccine-elicited sera was affected by the top five epidemic SARS-CoV-2 variants in the UK, including D614G+L18F+A222V, D614G+A222V, D614G+S477N, VOC-202012/01(B.1.1.7) and D614G+69-70del+N439K, a pseudovirus-neutralization assay was performed to evaluate the relative neutralization titers against the five SARS-CoV-2 variants and 12 single deconvolution mutants based on the variants. In this study, 18 monoclonal antibodies, 10 sera from convalescent COVID-19 patients, 10 inactivated-virus vaccine-elicited sera, 14 mRNA vaccine-elicited sera, nine RBD-immunized mouse sera, four RBD-immunized horse sera, and four spike-encoding DNA-immunized guinea pig sera were tested and analyzed. The N501Y, N439K, and S477N mutations caused immune escape from nine of 18 mAbs. However, the convalescent sera, inactivated virus vaccine-elicited sera, mRNA vaccine-elicited sera, spike DNA-elicited sera, and recombinant RBD protein-elicited sera could still neutralize these variants (within three-fold changes compared to the reference D614G variant). The neutralizing antibody responses to different types of vaccines were different, whereby the response to inactivated-virus vaccine was similar to the convalescent sera.

PurposeTo validate the feasibility of using peri-tumoral radiofrequency hyperthermia (RFH)-enhanced chemotherapy to obliterate hepatic tumor margins.Method and MaterialsThis study included in vitro experiments with VX2 tumor cells and in vivo validation experiments using rabbit models of liver VX2 tumors. Both in vitro and in vivo experiments received different treatments in four groups (n=6/group): (i) RFH-enhanced chemotherapy consisting of peri-tumoral injection of doxorubicin plus RFH at 42°C; (ii) RFH alone; (iii) doxorubicin alone; and (iv) saline. Therapeutic effect on cells was evaluated using different laboratory examinations. For in vivo experiments, orthotopic hepatic VX2 tumors in 24 rabbits were treated by using a multipolar radiofrequency ablation electrode, enabling simultaneous delivery of both doxorubicin and RFH within the tumor margins. Ultrasound imaging was used to follow tumor growth overtime, correlated with subsequent histopathological analysis.ResultsIn in vitro experiments, MTS assay demonstrated the lowest cell proliferation, and apoptosis analysis showed the highest apoptotic index with RFH-enhanced chemotherapy, compared with the other three groups (p3 cm) hepatic cancers.

Denervation can activate the catabolic pathway in skeletal muscle and lead to progressive skeletal muscle atrophy. At present, there is no effective treatment for muscle atrophy. Histone deacetylase 4 (HDAC4) has recently been found to be closely related to muscle atrophy, but the underlying mechanism of HDAC4 in denervation-induced muscle atrophy have not been described clearly yet. In this study, we found that the expression of HDAC4 increased significantly in denervated skeletal muscle. HDAC4 inhibition can effectively diminish denervation-induced muscle atrophy, reduce the expression of muscle specific E3 ubiquitin ligase (MuRF1 and MAFbx) and autophagy related proteins (Atg7, LC3B, PINK1 and BNIP3), inhibit the transformation of type I fibers to type II fibers, and enhance the expression of SIRT1 and PGC-1 α. Transcriptome sequencing and bioinformatics analysis was performed and suggested that HDAC4 may be involved in denervation-induced muscle atrophy by regulating the response to denervation involved in the regulation of muscle adaptation, cell division, cell cycle, apoptotic process, skeletal muscle atrophy, and cell differentiation. STRING analysis showed that HDAC4 may be involved in the process of muscle atrophy by directly regulating myogenin (MYOG), cell cycle inhibitor p21 (CDKN1A) and salt induced kinase 1 (SIK1). MYOG was significantly increased in denervated skeletal muscle, and MYOG inhibition could significantly alleviate denervation-induced muscle atrophy, accompanied by the decreased MuRF1 and MAFbx. MYOG overexpression could reduce the protective effect of HDAC4 inhibition on denervation-induced muscle atrophy, as evidenced by the decreased muscle mass and cross-sectional area of muscle fibers, and the increased mitophagy. Taken together, HDAC4 inhibition can alleviate denervation-induced muscle atrophy by reducing MYOG expression, and HDAC4 is also directly related to CDKN1A and SIK1 in skeletal muscle, which suggests that HDAC4 inhibitors may be a potential drug for the treatment of neurogenic muscle atrophy. These results not only enrich the molecular regulation mechanism of denervation-induced muscle atrophy, but also provide the experimental basis for HDAC4-MYOG axis as a new target for the prevention and treatment of muscular atrophy.

PurposeTo evaluate the efficacy and safety of percutaneous radiofrequency ablation (RFA) for subcapsular colorectal cancer liver metastases (CLMs).Materials and MethodsWith the approval of the Institutional Review Board, the clinical data of CLM patients who underwent percutaneous RFA for the first time from August 2010 to August 2020 were continuously collected. All CLMs were divided into subcapsular and non-capsular groups. Baseline characteristic data, technical effectiveness, minimal ablative margin, complications, local tumor progression (LTP), and overall survival (OS) between the two groups were analyzed using the t-test or chi-square test. A Cox regression model was used to evaluate the prognostic factors of LTP.ResultsOne hundred and ninety-nine patients (124 males; mean age, 60.2 years) with 402 CLMs (221 subcapsular; mean size, 16.0 mm) were enrolled in the study. Technical effectiveness was achieved in 93.5% (376/402) of CLMs, with a major complication rate of 5.5%. Compared with non-subcapsular tumors, the minimal ablative margin achieved in subcapsular CLM was smaller (χ2 = -8.047, P < 0.001). With a median follow-up time of 23 months (range, 3−96 months), 37.1% of the tumors had LTP. The estimated cumulative OS at 1, 3, and 5 years was 96.1%, 66.0%, and 44.2%, respectively. There were no statistically significant differences between the two groups in terms of technical effectiveness (χ2 = 0.484, P = 0.487), major complications (χ2 = 0.082, P = 0.775), local tumor progression-free survival (LTPFS) (χ2 = 0.881, P = 0.348), and OS (χ2 = 2.874, P = 0.090). Minimal ablative margin, tumor size (≥20 mm), and technical effectiveness were predictors of LTP (all P < 0.05).ConclusionRFA is a safe and effective technique for local tumor control of subcapsular CLMs.

PurposeTo evaluate the treatment effect of radiofrequency-induced hyperthermia (RFH) combined with intra-tumoral chemotherapy for rabbit VX2 liver tumors and explore the underlying mechanism that drives local hyperthermia-enhanced chemotherapy.Materials and MethodsVX2 cell lines and rabbits with liver VX2 tumors were randomly allocated to four treatment groups including: (1) combination therapy of Doxorubicin (DOX) plus hyperthermia/RFH (n=6); (2) DOX only; (3) hyperthermia/RFH only (n=6); and (4) phosphate-buffered saline-treated control (n=6). Cell viability and doxorubicin uptake by VX2 tumor cells were assayed using flow cytometry and fluorescence microscopy 24 h after treatments. Western blot was used to evaluate the expression level of heat shock protein 70 (HSP70) in tumor cells and tissues. For the harvested VX2 tumors, fluorescence microscopy was used to evaluate the distribution and penetration of doxorubicin in tumor tissues and HSP70 expression was analyzed by Western blot and immunohistochemistry.ResultsRFH enhanced the chemotherapeutic effect of doxorubicin in VX2 cells and rabbit liver VX2 tumors resulting in higher apoptosis and lower cell viability. Flowcytometry of VX2 cells showed more apoptotic cells in combination therapy of hyperthermia and DOX, compared with other three groups in-vitro experiments (45.80 ± 1.27% vs 20.66 ± 0.71%, vs 15.16 ± 0.81% and 0.62 ± 0.06%, respectively, p

Insights into the potential candidate hub genes may facilitate the generation of safe and effective immunity against seasonal influenza as well as the development of personalized influenza vaccines for the elderly at high risk of influenza virus infection. This study aimed to identify the potential hub genes related to the immune induction process of the 2018/19 seasonal quadrivalent inactivated influenza vaccines (QIVs) in the elderly ≥60 years by using weighted gene co-expression network analysis (WGCNA). From 63 whole blood samples from16 elderly individuals, a total of 13,345 genes were obtained and divided into eight co-expression modules, with two modules being significantly correlated with vaccine-induced immune responses. After functional enrichment analysis, genes under GO terms of vaccine-associated immunity were used to construct the sub-network for identification and functional validation of hub genes. MCEMP1 and SPARC were confirmed as the hub genes with an obvious effect on QIVs-induced immunity. The MCEMP1 expression was shown to be negatively correlated with the QIVs-associated reactogenicity within 7 days after vaccination, which could be suppressed by the CXCL 8/IL-8 and exacerbated by the Granzyme-B cytotoxic mediator. Meanwhile, the SPARC expression was found to increase the immune responses to the QIVs and contribute to the persistence of protective humoral antibody titers. These two genes can be used to predict QIVs-induced adverse reaction, the intensity of immune responses, and the persistence of humoral antibody against influenza. This work has shed light on further research on the development of personalized QIVs with appropriate immune responses and long-lasting immunity against the forthcoming seasonal influenza.

Although denervated muscle atrophy is common, the underlying molecular mechanism remains unelucidated. We have previously found that oxidative stress and inflammatory response may be early events that trigger denervated muscle atrophy. Isoquercitrin is a biologically active flavonoid with antioxidative and anti-inflammatory properties. The present study investigated the effect of isoquercitrin on denervated soleus muscle atrophy and its possible molecular mechanisms. We found that isoquercitrin was effective in alleviating soleus muscle mass loss following denervation in a dose-dependent manner. Isoquercitrin demonstrated the optimal protective effect at 20 mg/kg/d, which was the dose used in subsequent experiments. To further explore the protective effect of isoquercitrin on denervated soleus muscle atrophy, we analyzed muscle proteolysis via the ubiquitin-proteasome pathway, mitophagy, and muscle fiber type conversion. Isoquercitrin significantly inhibited the denervation-induced overexpression of two muscle-specific ubiquitin ligases—muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), and reduced the degradation of myosin heavy chains (MyHCs) in the target muscle. Following isoquercitrin treatment, mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy-related proteins (ATG7, BNIP3, LC3B, and PINK1); slow-to-fast fiber type conversion in the target muscle was delayed via triggering expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α); and the production of reactive oxygen species (ROS) in the target muscle was reduced, which might be associated with the upregulation of antioxidant factors (SOD1, SOD2, NRF2, NQO1, and HO1) and the downregulation of ROS production-related factors (Nox2, Nox4, and DUOX1). Furthermore, isoquercitrin treatment reduced the levels of inflammatory factors—interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α)—in the target muscle and inactivated the JAK/STAT3 signaling pathway. Overall, isoquercitrin may alleviate soleus muscle atrophy and mitophagy and reverse the slow-to-fast fiber type conversion following denervation via inhibition of oxidative stress and inflammatory response. Our study findings enrich the knowledge regarding the molecular regulatory mechanisms of denervated muscle atrophy and provide a scientific basis for isoquercitrin as a protective drug for the prevention and treatment of denervated muscle atrophy.

In this study, we found miR-362-5p was upregulated in bladder cancer tissues and we predicted that QKI is potential a target of miR-362-5p and MBNL1-AS1 might be able to directly target to miR-362-5p. We attempted to evaluate whether miR-362-5p could play its roles in bladder cancer through regulating QKI (quaking) and whether the expression and function of miR-362-5p could be mediated by lncRNA MBNL1-AS1. We performed the gain- and loss-function experiments to explore the association between miR-362-5p expression and bladder cancer proliferation. In vivo, the nude mice were injected with miR-362-5p knockdown SW780 cells to assess the effects of miR-362-5p on tumor growth. The results showed upregulation of miR-362-5p promoted cell proliferation of bladder cancer cells. MBNL1-AS1 and QKI could directly bind with miR-362-5p, and knockdown of MBNL1-AS1 or QKI could abrogate the regulatory effects of miR-362-5p on bladder cancer cell proliferation. Furthermore, downregulation of miR-362-5p inhibited bladder tumor growth and increased QKI expression. Our data unveiled that miR-362-5p may play an oncogenic role in bladder cancer through QKI and MBNL1-AS1 might function as a sponge to mediate the miR-362-5p expression and function.

Myelin plays a crucial role in axon function recovery following nerve damage, and the interaction between Schwann cells (SCs) and regenerating axons profoundly affects myelin formation. Eph receptor A4 (EphA4), a member of the Eph tyrosine kinase receptor family, regulates cell-cell interactions via its ligand ephrins. However, our current knowledge on how EphA4 regulates the formation of myelin sheaths remains limited. In order to explore the roles of EphA4 in myelination in the peripheral nervous system, we used a combination of (1) a co-culture model of dorsal root ganglion (DRG) explants and SCs, (2) a SC differentiation model induced by db-cAMP, and (3) a regeneration model of crushed sciatic nerves in rats. Our results demonstrated that EphA4 inhibited myelination by inhibiting SC differentiation and facilitating SC proliferation in vitro. The in vivo experiments revealed that EphA4 expression in SCs is upregulated following nerve crush injury and then downregulated during remyelination. Moreover, silencing of EphA4 by siRNA or overexpression of EphA4 by genetic manipulation can accelerate or slow down nerve remyelination in crushed sciatic nerves. Taken together, our results suggest that EphA4 may negatively regulate myelination by abrogating SC differentiation.

Background/Objective: Hematoma expansion (HE) predicts poor outcome and is an appealing treatment target in spontaneous intracerebral hemorrhage (ICH). Clinical evidence has shown an association of HE with peripheral white blood cells (WBC) count, but the individual contributions of leukocyte subtypes between literatures are described inconsistently. Our aim was to determine the relationship between admission absolute and differential leukocyte counts and HE by using different growth definitions.Methods: We analyzed spontaneous ICH patients who underwent baseline cranial computed tomography and blood sampling within 6 h of stroke onset in our institution between September 2013 and August 2018. Hematoma volume was calculated using a semiautomated 3-dimensional reconstruction algorithm. According to commonly used absolute or relative growth definitions (>6 mL, >12.5 mL, or >33%), we defined 5 types of HE. A propensity score-matching analysis was performed to evaluate the influence of complete blood count components on HE across the various growth definitions. The receiver operating characteristic analysis assessed the predictive ability of leukocyte counts for HE.Results: A total of 1,066 patients were included, of whom 11–21% met the 5 HE definitions. After propensity score-matching, except using the definition of >12.5 mL growth or its combination with >33% growth, both WBC and neutrophil count were independently associated with reduced risk of HE (odds ratio [OR] for 103 cells increase; OR, 0.86–0.99; all p < 0.05) after adjusting confounders in multivariate analyses. However, monocyte count was correlated with increased risk of HE under the usage of >12.5 mL expansion definition only (OR, 1.43; p = 0.024). There was no association between lymphocyte count and HE (all p > 0.05). Regardless of the growth definition, admission eosinophil count was directly associated with the risk of HE (OR, 6.92–31.60; all p < 0.05), and was the best predictive subtype with area under the curve 0.64, sensitivity 69.5%, and specificity 58.9% at the optimal cut-off value of 45 cells/μL.Conclusions: Growth definition affects the relationship of HE with leukocyte subtypes counting. Eosinophil count robustly predicts HE, and may be a surrogate when using an inflammatory marker to help select acute ICH patients with high expansion risk for hemostasis treatment in clinical trial and practice.

Skeletal muscle atrophy is associated with pro-inflammatory cytokines. Salidroside is a biologically active ingredient of Rhodiola rosea, which exhibits anti-inflammatory property. However, there is little known about the effect of salidroside on denervation-induced muscle atrophy. Therefore, the present study aimed to determine whether salidroside could protect against denervation-induced muscle atrophy and to clarify potential molecular mechanisms. Denervation caused progressive accumulation of inflammatory factors in skeletal muscle, especially interleukin 6 (IL6) and its receptor, and recombinant murine IL6 (rmIL6) local infusion could induce target muscle atrophy, suggesting that denervation induced inflammation in target muscles and the inflammation may trigger muscle wasting. Salidroside alleviated denervation-induced muscle atrophy and inhibited the production of IL6. Furthermore, the inhibition of phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the decreased levels of suppressor of cytokine signaling (SOCS3), muscle RING finger protein-1 (MuRF1), atrophy F-box (atrogin-1), microtubule-associated protein light chain 3 beta (LC3B) and PTEN-induced putative kinase (PINK1) were observed in denervated muscles that were treated with salidroside. Finally, all of these responses to salidroside were replicated in neutralizing antibody against IL6. Taken together, these results suggest that salidroside alleviates denervation-induced inflammation response, thereby inhibits muscle proteolysis and muscle atrophy. Therefore, it was assumed that salidroside might be a potential therapeutic candidate to prevent muscle wasting.

Skeletal muscle atrophy occurs under various conditions, such as disuse, denervation, fasting, aging, and various diseases. Although the underlying molecular mechanisms are still not fully understood, skeletal muscle atrophy is closely associated with reactive oxygen species (ROS) overproduction. In this study, we aimed to investigate the involvement of ROS in skeletal muscle atrophy from the perspective of gene regulation, and further examine therapeutic effects of antioxidants on skeletal muscle atrophy. Microarray data showed that the gene expression of many positive regulators for ROS production were up-regulated and the gene expression of many negative regulators for ROS production were down-regulated in mouse soleus muscle atrophied by denervation (sciatic nerve injury). The ROS level was significantly increased in denervated mouse soleus muscle or fasted C2C12 myotubes that had suffered from fasting (nutrient deprivation). These two muscle samples were then treated with N-acetyl-L-cysteine (NAC, a clinically used antioxidant) or pyrroloquinoline quinone (PQQ, a naturally occurring antioxidant), respectively. As compared to non-treatment, both NAC and PQQ treatment (1) reversed the increase in the ROS level in two muscle samples; (2) attenuated the reduction in the cross-sectional area (CSA) of denervated mouse muscle or in the diameter of fasted C2C12 myotube; (3) increased the myosin heavy chain (MHC) level and decreased the muscle atrophy F-box (MAFbx) and muscle-specific RING finger-1 (MuRF-1) levels in two muscle samples. Collectively, these results suggested that an increased ROS level was, at least partly, responsible for denervation- or fasting-induced skeletal muscle atrophy, and antioxidants might resist the atrophic effect via ROS-related mechanisms.

Because of the long and unpredictable flowering period in bamboo, the molecular mechanism of bamboo flowering is unclear. Recent study showed that Arabidopsis PIN1-type parvulin 1 (Pin1At) is an important floral activator and regulates floral transition by facilitating the cis/trans isomerization of the phosphorylated Ser/Thr residues preceding proline motifs in suppressor of overexpression of CO 1 (SOC1) and agamous-like 24 (AGL24). Whether bamboo has a Pin1 homolog and whether it works in bamboo flowering are still unknown. In this study, we cloned PvPin1, a homolog of Pin1At, from Phyllostachys violascens (Bambusoideae). Bioinformatics analysis showed that PvPin1 is closely related to Pin1-like proteins in monocots. PvPin1 was widely expressed in all tested bamboo tissues, with the highest expression in young leaf and lowest in floral bud. Moreover, PvPin1 expression was high in leaves before bamboo flowering then declined during flower development. Overexpression of PvPin1 significantly delayed flowering time by downregulating SOC1 and AGL24 expression in Arabidopsis under greenhouse conditions and conferred a significantly late flowering phenotype by upregulating OsMADS56 in rice under field conditions. PvPin1 showed subcellular localization in both the nucleus and cytolemma. The 1500-bp sequence of the PvPin1 promoter was cloned, and cis-acting element prediction showed that ABRE and TGACG-motif elements, which responded to abscisic acid (ABA) and methyl jasmonate (MeJA), respectively, were characteristic of P. violascens in comparison with Arabidopsis. On promoter activity analysis, exogenous ABA and MeJA could significantly inhibit PvPin1 expression. These findings suggested that PvPin1 may be a repressor in flowering, and its delay of flowering time could be regulated by ABA and MeJA in bamboo.