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AbstractBackground Hepatocellular carcinoma lacks ideal diagnostic biomarkers. There is a lack of scientific evaluation of relevant promising biomarkers as well. Therefore this study reanalyzes the related studies of 11 blood biomarkers of HCC, and compares the diagnostic value of these biomarkers for HCC systematically.Methods The relevant literatures on the diagnostic value in HCC of 11 blood indexes in recent 5 years were searched in PubMed, Embase, and Cochrane libraries. Data were extracted and analyzed.Results Finally, 83 literature studies were brought into meta-analysis. The pooled sensitivity and specificity of AFP were 0.61 and 0.87, respectively. The AUC of AFP were 0.78. The AUC and sum of sensitivity and specificity of the combination of AFP and other biomarkers were all significantly higher than that of AFP, including AFP + AFP-L3 + DCP, AFP + DCP, AFP/DCP, AFP + GPC3. Among other biomarkers, the AUC and sum of sensitivity and specificity of biomarkers including DCP, GPC3, GP73, Hsp90alpha, midkine, and OPN were significantly higher than that of AFP. In this study, GP73 had the highest sum of sensitivity and specificity (1.78) and AUC (0.95).Conclusions The pooled sensitivity and specificity of AFP were 0.61 and 0.87, respectively. The AUC of AFP were 0.78. The combination of AFP and other biomarkers improved the diagnostic efficiency. The diagnostic value of biomarkers including DCP, GPC3, GP73, Hsp90alpha, midkine, and OPN was higher than that of AFP. GP73 had the best diagnostic value for HCC with the highest sum of sensitivity and specificity (1.78) and AUC (0.95).KEY MESSAGESThe pooled sensitivity and specificity of AFP were 0.61 and 0.87, respectively. The AUC of AFP were 0.78. The combination of AFP and other biomarkers improved the diagnostic efficiency of HCC.The diagnostic value of biomarkers including DCP, GPC3, GP73, Hsp90alpha, midkine, and OPN was higher than that of AFP.GP73 had the best diagnostic value for HCC.

Objective: To evaluate the intervention effect of resveratrol on rat model of myocardial ischemia-reperfusion injury.Methods: The relevant studies on the intervention of resveratrol on rat models of myocardial ischemia reperfusion injury were searched in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang and China Science and Technology Journal Database from the start of database establishment to January 2023. Data were extracted from studies that met the inclusion criteria. The results included electrocardiogram (ECG) and myocardial injury markers: ST changes, cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), creatine kinase (CK), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH); hemodynamic indicators: heart rate (HR), left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), maximum rate of increase of left ventricular pressure (+dp/dtmax), maximum rate of decrease of left ventricular pressure (−dp/dtmax); oxidative damage indicators: nitric oxide (NO), reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA); inflammatory factors: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6); apoptosis index: B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), cardiomyocyte apoptosis index (AI); heart tissue structure: myocardial infarction size. Finally, a meta-analysis of these results was conducted. The methodological quality of the studies was assessed using the SYRCLE Bias Risk tool.Results: A total of 43 studies were included in the meta-analysis, and the quality of the included studies was assessed. It was found that the evidence quality of these 43 studies was low, and no study was judged to have low risk bias in all risk assessments. The results showed that resveratrol could reduce ST segment, cTn-I, cTn-T, CK, CK-MB, LDH, LVEDP, ROS, MDA, TNF-α, IL-6, AI levels and myocardial infarction size. HR, LVDP, LVSP, +dp/dtmax, NO, Bcl-2, and SOD levels were increased. However, resveratrol had no significant effect on -dp/dtmax and Bax outcome measures.Conclusion: Resveratrol can reduce ST segment in rat model of myocardial ischemia-reperfusion injury, alleviate myocardial injury, improve ventricular systolic and diastolic ability in hemodynamics, reduce inflammatory response and oxidative damage, and reduce myocardial necrosis and apoptosis. Due to the low quality of the methodologies included in the studies, additional research is required.

Background: Malignancies with BRCA1/2 deficiencies are particularly sensitive to PARP inhibitors. Thus, combining PARP inhibitors with agents that impair DNA damage repair to treat BRCA1/2 wild-type PDAC could broaden the clinical use of these promising PARP inhibitors. Here we examined the synergism and mechanism of oncolytic measles virus (rMV-Hu191) with a PARP inhibitor (Olaparib) in vitro and in vivo. Methods: The cell viability assay, cell cycle analysis, colony formation assay, TCID 50 method, western blotting, flow cytometry, DNA comet assay, Mice bearing PDAC xenografts, IF, IHC and TUNEL assay were performed to explore the antitumor efficacy and underlying mechanisms. Results: In this study, we explored the antitumor activities of rMV-Hu191 and Olaparib in two PDAC cell lines harboring wild-type BRCA1/2 genes. Compared to monotherapy, the combination of rMV-Hu191 and Olaparib was able to synergistically cause growth arrest, apoptotic cell death and DNA damage, accompanying with excessive oxidative stress. Mechanistically, the data indicated that the observed synergy depended on the oxidative DNA damage and ROS-dependent apoptosis generating by rMV-Hu191 combined with Olaparib in human PDAC cells. Tumor inhibition and prolonged survival of PDAC mice xenografts in vivo confirmed the synergism of combinational treatment with trivial side-effects. Conclusions: Our findings firstly suggested that combination treatment with rMV-Hu191 and Olaparib had a profound and synergistic therapeutic effect against human PDAC through synthetic lethality. In conclusion, we recommend combining oncolytic rMV-Hu191 with a PARP inhibitor (Olaparib) as a novel therapeutic strategy and provided a potential mechanism for advanced PDAC regardless of BRCA mutation status.

Many two-place physical problems can be explicitly presented as related events model named Alice–Bob systems. In this paper, an integrable Alice–Bob Boussinesq system is introduced via the Boussinesq equation with parameters, which may meet the symmetry transformation of Psˆx (parity with a shift) and Tdˆt (time reversal with a delay). After constructing an Bäcklund transformation, the system has rich symmetry solutions with the aid of auxiliary functions. The structures of obtained soliton solutions, such as the breathers, lumps and their hybrids, are all satisfied the Pˆsx or Tˆdt symmetry. To illustrate the symmetric characteristic, some lower-order solutions and the related dynamic structures are explicitly presented. The residual symmetry and its finite transformation for this system are also verified.

Cardiovascular diseases rank the highest incidence and mortality worldwide. As the most common type of cardiovascular disease, myocardial infarction causes high morbidity and mortality. Recent studies have revealed that extracellular vesicles, including exosomes, show great potential as a promising cell-free therapy for the treatment of myocardial infarction. However, low heart-targeting efficiency and short plasma half-life have hampered the clinical translation of extracellular vesicle therapy. Currently, four major types of strategies aiming at enhancing target efficiency have been developed, including modifying EV surface, suppressing non-target absorption, increasing the uptake efficiency of target cells, and utilizing a hydrogel patch. This presented review summarizes the current research aimed at EV heart targeting and discusses the challenges and opportunities in EV therapy, which will be beneficial for the development of effective heart-targeting strategies.

Objective: This study aimed to evaluate the intervention effect of curcumin in myocardial infarction rodent models.Methods: A systematic retrieval of relevant studies on curcumin intervention in rats or mice myocardial infarction models was conducted, and the data were extracted. The outcome indicators included biochemical blood indicators, such as creatine kinase (CK), creatine kinase isoenzyme (CK-MB), malondialdehyde (MDA), lactate dehydrogenase (LDH) and superoxide dismutase (SOD), as well as cardiac tissue structure indicators, such as left ventricular weight to body weight ratio (LVW/BW), apoptosis index, left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic diameter (LVESD), and myocardial infarction area, and hemodynamic indexes, such as systolic blood pressure (SBP), diastolic blood pressure (DBP), left ventricular end-diastolic pressure (LVEDP), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), maximum rate of left ventricular pressure rise (+dp/dtmax), and maximum rate of left ventricular pressure decline (–dp/dtmax). These results were then analyzed by meta-analysis. Studies were evaluated for methodological quality using the syrcle’s bias risk tool.Results: A total of 24 studies were included in the meta-analysis. The quality assessment of included studies revealed that the evidence was low quality and none of studies was judged as having a low risk of bias across all domains. The results revealed that curcumin could reduce CK-MB, CK, LDH, and MDA levels. They also revealed that it could lower SBP, DBP, LVEDP, LVW/BW, apoptosis index, LVEDD, LVESD, and myocardial infarction area and increase LVEF, LVFS, +dp/dtmax, and–dp/dtmax. However, it had no significant impact on the heart rate and the levels of SOD in the models.Conclusion: Curcumin alleviates myocardial injury and oxidative stress in myocardial infarction rodent models in terms of blood biochemistry indicators, improves the diastolic and systolic capacity of the ventricle in terms of hemodynamic indexes, and reduces the necrosis and apoptosis of cardiomyocytes in terms of tissue structure. The methodological quality of the studies was low and additional research is warranted.

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a newly defined meningoencephalomyelitis. The pathogenesis of GFAP-A is not well understood. The present study measured the expression levels of 200 serological cytokines in GFAP-A patients, NMOSD patients and healthy controls (HCs). The correlations between serum cytokine levels and clinical information in GFAP-A patients were analyzed. A total of 147 serological proteins were differentially expressed in GFAP-A patients compared to HCs, and 33 of these proteins were not observed in NMOSD patients. Serum levels of EG-VEGF negatively correlated with GFAP antibody titers, MIP-3 alpha positively correlated with clinical severity in GFAP-A patients, and LIGHT positively correlated with WBC counts and protein levels in the CSF of GFAP-A patients. These results suggest that GFAP and AQP4 astrocytopathy share some common pathology related to TNF signaling. Serum MIP 3 alpha may be a biomarker to assess clinical severity and a potential target for therapy of autoimmune GFAP astrocytopathy.

Microbes and microbiota dysbiosis are correlated with the development of lung cancer; however, the airway taxa characteristics and bacterial topography in synchronous multiple primary lung cancer (sMPLC) are not fully understood. The present study aimed to investigate the microbiota taxa distribution and characteristics in the airways of patients with sMPLC and clarify specimen acquisition modalities in these patients. Using the precise positioning of electromagnetic navigation bronchoscopy (ENB), we analyzed the characteristics of the respiratory microbiome, which were collected from different sites and using different sampling methods. Microbiome predictor variables were bacterial DNA burden and bacterial community composition based on 16sRNA. Eight non-smoking patients with sMPLC in the same pulmonary lobe were included in this study. Compared with other sampling methods, bacterial burden and diversity were higher in surface areas sampled by bronchoalveolar lavage (BAL). Bacterial topography data revealed that the segment with sMPLC lesions provided evidence of specific colonizing bacteria in segments with lesions. After taxonomic annotation, we identified 4863 phylotypes belonging to 185 genera and 10 different phyla. The four most abundant specific bacterial community members detected in the airway containing sMPLC lesions were Clostridium, Actinobacteria, Fusobacterium, and Rothia, which all peaked at the segments with sMPLC lesions. This study begins to define the bacterial topography of the respiratory tract in patients with sMPLC and provides an approach to specimen acquisition for sMPLC, namely BAL fluid obtained from segments where lesions are located.

Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis. Dimethylarginine dimethylaminohydrolase (DDAH) is a hydrolytic enzyme that is primarily responsible for eliminating asymmetric dimethylarginine, and it plays a role in the pathogenesis of cardiovascular and cerebrovascular diseases. The DDAH2 subtype is expressed in organs rich in induced nitric oxide synthase, including the heart, the placenta, and the cerebral endothelium during cerebral ischemia, in the stress state, or under neurotoxicity. Overexpression of the DDAH2 gene can inhibit asymmetric dimethylarginine-induced peripheral circulating endothelial cell dysfunction. However, it is unknown whether this polymorphism regulates plasma asymmetric dimethylarginine levels in patients with leukoaraiosis. In this double-blind study, we recruited 46 patients with leukoaraiosis and 46 healthy, matched controls. Plasma asymmetric dimethylarginine levels were determined using enzyme-linked immunoassays. Genomic DNA was isolated from whole blood samples, and polymerase chain reaction, SmaI restriction enzyme digestion, restriction fragment length polymorphisms, and agarose electrophoresis were used to detect DDAH2 (-449 G/C) gene polymorphisms. The results revealed that 95.65% of leukoaraiosis patients had recessive genetic models (GG and CG), while 89.13% of healthy control subjects had dominant genetic models (CC and CG). There was a significant difference in the genotype composition ratio between leukoaraiosis patients and healthy controls (P = 0.0002). The frequency of G alleles in the leukoaraiosis patients (71.74%) was significantly higher than in healthy controls, whereas the frequency of C alleles was lower (χ2 = 13.9580, P = 0.0002). Furthermore, asymmetric dimethylarginine concentrations in subjects with the GG genotype were significantly higher than in subjects with the CG and CC genotypes (Kruskal–Wallis H = 24.5955, P < 0.0001). In addition, the GG genotype of DDAH2 (-449 G/C) was more common in patients with leukoaraiosis. These findings suggest that the G allele of DDAH2 (-449 G/C) is a risk factor for leukoaraiosis morbidity and is correlated with high levels of asymmetric dimethylarginine. This study was approved by the Institutional Ethics Committee of the 2nd Affiliated Hospital of Harbin Medical University of China (approval No. KY2016-177) on July 28, 2016.

Purpose: Contrast‐enhanced spectral imaging (CEM) is a new mammography technique, but its diagnostic value in dense breasts is still inconclusive. We did a systematic review and meta‐analysis of studies evaluating the diagnostic performance of CEM for suspicious findings in dense breasts. Materials and Methods: The PubMed, Embase, and Cochrane Library databases were searched systematically until August 6, 2023. Prospective and retrospective studies were included to evaluate the diagnostic performance of CEM for suspicious findings in dense breasts. The QUADAS‐2 tool was used to evaluate the quality and risk of bias of the included studies. STATA V.16.0 and Review Manager V.5.3 were used to meta‐analyze the included studies. Results: A total of 10 studies (827 patients, 958 lesions) were included. These 10 studies reported the diagnostic performance of CEM for the workup of suspicious lesions in patients with dense breasts. The summary sensitivity and summary specificity were 0.95 (95% CI, 0.92–0.97) and 0.81 (95% CI, 0.70–0.89), respectively. Enhanced lesions, circumscribed margins, and malignancy were statistically correlated. The relative malignancy OR value of the enhanced lesions was 28.11 (95% CI, 6.84–115.48). The relative malignancy OR value of circumscribed margins was 0.17 (95% CI, 0.07–0.45). Conclusion: CEM has high diagnostic performance in the workup of suspicious findings in dense breasts, and when lesions are enhanced and have irregular margins, they are often malignant. [ABSTRACT FROM AUTHOR]

Atrial septal defect (ASD) is one of the most prevalent types of congenital heart disease (CHD). The pathogenic role of miRNAs in the development of ASD has not yet been fully elucidated. The aim of this study was to examine the miRNA profile of ASD patients, and to identify the role of miRNAs in the pathogenesis of ASD. We performed a miRNA comparison between the atrial septa of three normal fetuses and three ASD patients by microarray, followed by chromosome clustering and bioinformatic analysis to identify the dysregulated miRNA clusters between these two groups. Furthermore, qRT-PCR in the mouse developing heart was used to exclude differences resulting from the use of unpaired stage patient samples. After normalization, 70 dysregulated miRNAs were detected between the two groups. Advanced chromosome clustering and bioinformatic analysis showed that two upregulated miRNA clusters (miR-29 and miR-143/145) and three downregulated miRNA clusters (miR-17-92, miR-106b-25 and miR-503/424) were associated with ASD. Further qRT-PCR in the mouse developing heart found that the dysregulated expression levels of all the clusters, except the miR-143/145 cluster, were associated with the occurrence of ASD. This study reveals four dysregulated miRNA clusters, which will enable further elucidation of the pathogenic mechanism of ASD.

The human induced pluripotent stem cell (iPSC) line YAHKMUi001-A was derived from the dermal fibroblasts of a patient with Tetralogy of Fallot (TOF), with a mutation in the TBX1 gene (c.928G > A). The skin fibroblasts were obtained from a 4-year-old boy, and were infected with Sendai virus expressing the Yamanaka factors. The YAHKMUi001-A iPSC line expresses pluripotent stem cell markers, displays a normal karyotype, and has the capacity to differentiate into 3 germ layers. This cell line model can be a good tool to study the pathological mechanism of the TBX1 gene mutations associated with TOF.

Keywords: ruthenium catalysis; mandelic acids; alkynes; annulation; isocoumarins EN ruthenium catalysis mandelic acids alkynes annulation isocoumarins 2005 2010 6 10/09/23 20231024 NES 231024 Graph Isocoumarins are an important class of natural lactones, and their skeletal structure is an important part of many active pharmaceutical ingredients. At present, the major methods for synthesizing isocoumarins include (1) the cyclization reaction of I ortho i -halogen-substituted benzoic acids or their esters or amides with 1,3-diketones or internal alkynes; [10][11][12] and (2) the internal cyclization reaction of I ortho i -alkenyl- or alkynyl-substituted benzoic acids or their esters. The reactions of benzaldehydes B 5 b and benzoic acids B 6 b with B 2a b proceeded when the amount of Cu(OAc) SB 2 sb -H SB 2 sb O was increased to 1.5 equivalents and the reaction time was shortened to ten hours. Ruthenium(II)-Catalyzed C-H Annulation of Mandelic Acids with Internal Alkynes to Construct Isocoumarins. [Extracted from the article]

BackgroundSeveral immunosuppressive therapeutic regimens are widely used to treat Graves' ophthalmopathy (GO), including oral glucocorticoids (OGC), intravenous glucocorticoids (IVGC), retrobulbar injections of glucocorticoids (ROGC) and orbital radiotherapy (OR). The priority among these is unknown. This meta-analysis investigated the efficacy and tolerability of the above regimens.MethodsThe PubMed, EMBASE, and Cochrane Library databases and the Chinese Biomedicine Database were searched up to November 18, 2014. Randomized controlled trials (RCTs) comparing monotherapies (OGC, IVGC, ROGC and OR) in patients with moderate-to-severe active GO were selected. The main efficacy measures were the response rate, the standard mean difference (SMD) in the reduction in the clinical activity score (CAS) and the mean difference (MD) in proptosis from baseline to the end of treatment. The main tolerability measure was the risk ratio (RR) for adverse events. The pooled estimates and 95% confidence intervals (95% CIs) were calculated using the RevMan software, version 5.1.ResultsSeven published RCTs involving 328 participants were included in the present meta-analysis, including IVGC versus OGC (3 trials), ROGC versus OGC (3 trials) and OR versus OGC (1 trial). IVGC was more effective than OGC in response rate (RR = 1.48, 95% CI = 1.18-1.87) and had an obvious CAS reduction (SMD = 0.69, 95% CI = 0.13-1.25). IVGC caused fewer adverse events than OGC. ROGC and OGC had no statistically significant difference in response rate (RR = 1.16, 95% CI = 0.94-1.42). OR also did not differ significantly compared with OGC (RR = 0.93, 95% CI = 0.54-1.60). ROGC and OR had fewer adverse events, such as weight gain, compared with OGC.ConclusionsFor patients with GO in the moderate-to-severe active phase, current evidence gave priority to IVGC, which had a statistically significant advantage over OGC and caused fewer adverse events. ROGC and OR did not provide greater efficacy than OGC, although better tolerability and fewer adverse events were shown.

The function of glial cells in axonal regeneration after injury has been the subject of controversy in recent years. Thus, deeper insight into glial cells is urgently needed. Many studies on glial cells have elucidated the mechanisms of a certain gene or cell type in axon regeneration. However, studies that manipulate a single variable may overlook other changes. Here, we performed a series of comprehensive transcriptome analyses of the optic nerve head over a period of 90 days after optic nerve crush (ONC), showing systematic molecular changes in the optic nerve head (ONH). Furthermore, using weighted gene coexpression network analysis (WGCNA), we established gene module programs corresponding to various pathological events at different times post-ONC and found hub genes that may be potential therapeutic targets. In addition, we analyzed the changes in different glial cells based on their subtype markers. We revealed that the transition trend of different glial cells depended on the time course, which provides clues for modulating glial function in further research. [ABSTRACT FROM AUTHOR]

Hypertension represents one of the most common pre-existing conditions and comorbidities in Coronavirus disease 2019 (COVID-19) patients. To explore whether hypertension serves as a risk factor for disease severity, a multi-centre, retrospective study was conducted in COVID-19 patients. A total of 498 consecutively hospitalised patients with lab-confirmed COVID-19 in China were enrolled in this cohort. Using logistic regression, we assessed the association between hypertension and the likelihood of severe illness with adjustment for confounders. We observed that more than 16% of the enrolled patients exhibited pre-existing hypertension on admission. More severe COVID-19 cases occurred in individuals with hypertension than those without hypertension (21% vs. 10%, P = 0.007). Hypertension associated with the increased risk of severe illness, which was not modified by other demographic factors, such as age, sex, hospital geological location and blood pressure levels on admission. More attention and treatment should be offered to patients with underlying hypertension, who usually are older, have more comorbidities and more susceptible to cardiac complications. [ABSTRACT FROM AUTHOR]

Abstract Background Müller cell gliosis not only plays an important physiological role by maintaining retinal neuronal homeostasis but is also associated with multiple pathological events in the retina, including optic nerve crush (ONC) injury. Modulating Müller cell gliosis contributes to the creation of a permissive environment for neuronal survival. However, the underlying mechanism of Müller cell gliosis has remained elusive. Objective To investigate the underlying mechanism of Müller cell gliosis after ONC. Methods Rats with ONC injury were transfected with miRNA-21 (miR-21) agomir (overexpressing miR-21) or antagomir (inhibiting miR-21) via intravitreous injection. Immunofluorescence and western blotting were performed to confirm the effects of miR-21 on Müller cell gliosis. The retinal nerve fiber layer (RNFL) thickness was measured using optical coherence tomography and the positive scotopic threshold response (pSTR) was recorded using electroretinogram. Results In the acute phase (14 days) after ONC, compared with the crushed group, inhibiting miR-21 promoted Müller cell gliosis, exhibiting thicker processes and increased GFAP expression. In the chronic phase (35 days), inhibiting miR-21 ameliorated Müller cell gliosis, which exhibited thicker and denser processes and increased GFAP expression. Retinal ganglion cell (RGC) counts in retinas showed that the number of surviving RGCs increased significantly in the antagomir group. The thickness of the RNFL increased significantly, and pSTR showed significant preservation of the amplitudes in the antagomir group. Conclusions Inhibition of miR-21 promotes RGC survival, RNFL thickness and the recovery of RGC function by modulating Müller cell gliosis after ONC. [ABSTRACT FROM AUTHOR]

Optic nerve injury is a leading cause of irreversible visual impairment worldwide and can even cause blindness. Excessive activation of astrocytes has negative effects on the repair and recovery of retinal ganglion cells following optic nerve injury. However, the molecular and cellular mechanisms underlying astrocyte activation after optic nerve injury remain largely unknown. In the present study, we explored the effects of microRNA-21 (miR-21) on axon regeneration and flash visual evoked potential (F-VEP) and the underlying mechanisms of these effects based on astrocyte activation in the rat model of optic nerve crush (ONC). To the best of our knowledge, this article is the first to report that inhibition of miR-21 enhances axonal regeneration and promotes functional recovery in F-VEP in the rat model of ONC. Furthermore, inhibition of miR-21 attenuates excessive astrocyte activation and glial scar formation, thereby promoting axonal regeneration by regulating the epidermal growth factor receptor (EGFR) pathway. In addition, we observed that the expression of tissue inhibitor of metalloproteinase-3, a target gene of miR-21, was inhibited during this process. Taken together, these findings demonstrate that inhibition of miR-21 regulates the EGFR pathway, ameliorating excessive astrocyte activation and glial scar progression and promoting axonal regeneration and alleviating impairment in F-VEP function in a model of ONC. This study's results suggest that miR-21 may represent a therapeutic target for optic nerve injury. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effect of testosterone on glucolipid metabolism and vascular injury in male rats, and examine the underlying molecular mechanisms. A total of 40 male Sprague-Dawley rats were divided into a control group (n=10), high-fat-diet + castration group (n=10), high-fat-diet + castration + low dose testosterone group (n=10), and high-fat-diet + castration + high dose testosterone group (n=10). Hematoxylin and eosin staining was performed to evaluate the morphology of the thoracic aortic tissues. Immunohistochemical staining was used to detect biomarkers of the phosphoinositide 3-kinase (PI3K) signaling pathway. The mRNA and protein expression levels of PI3K, AKT, insulin receptor substrate-1 (IRS-1), glucose transporter type 4 (GLUT-4), nuclear factor (NF)-κB and tumor necrosis factor (TNF)-α in the aortas were determined using quantitative polymerase chain reaction and Western blot analyses, respectively. Apoptosis in the aortic tissues was detected using a TUNEL assay. Castration induced apoptosis in the animals fed a high-fat-diet, whereas low dose testosterone replacement ameliorated the apoptosis in the aorta. However, the levels of apoptosis was more severe following high-dose testosterone treatment. Low-dose testosterone induced upregulation in the levels of IRS-1, AKT, GLUT-4 protein, NF-κB, TNF-α and PI3K, compared with those in the animals fed a high-fat diet following castration. A high dose of testosterone resulted in a significant decrease in the levels of IRS-1, AKT, GLUT-4, NF-κB, TNF-α and PI3K. Compared with the rats in the high-fat diet + castration group, a low dose of testosterone induced upregulation in the mRNA levels of IRS-1, AKT and GLUT-4, and downregulation of the mRNA levels of NF-κB, TNF-α and PI3K. A high dose of testosterone resulted in a significant decrease in the levels of IRS-1, AKT and GLUT-4, and marked increases in the mRNA levels of NF-κB, TNF-α and PI3K, compared with the low dose group. Castration induced marked disorders of glucolipid metabolism and vascular injuries in the pubescent male rats. Low-dose testosterone treatment was found to ameliorate the vascular damage caused by castration via the PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Aiming at failure of closure segment in a prestressed concrete cable-stayed bridge, a strengthening technology, namely replacing the closure segment, was firstly put forward. But removing the old closure segment was a process of release of internal force and had great risk. So the structural safety possibly induced by removing must be analyzed and confirmed. Based on FEM and summary of engineering experience, the construction stages for removing the old closure segment were simulated, and then some analysis relevant to safety, including thermal effect, dynamic characteristics and global stability of the whole bridge structure, were systematically presented. According to these analysis results, corresponding prevention and control measures were provided to ensure construction safety. Studies showed that, variation range of its structural state between before and after removing is not obvious, and its dynamic characteristics changed little after removing. In addition, structural instability could not be induced by removing, but for the sake of improving construction safety reliability, necessary safety prevention and control measures were indispensable. Analysis on safety of removing the old closure segment constituted the important part of the strengthening technology of replacing the closure segment, and became the theoretical basis of removing partial structural members for existing bridges. [Copyright &y& Elsevier]

Diffuse axonal injury (DAI) is the predominant effect of severe traumatic brain injury and significantly contributes to cognitive deficits. The mechanisms that underlie these cognitive deficits are often associated with complex molecular alterations. α7nAChR, one of the abundant and widespread nicotinic acetylcholine receptors (nAChRs) in the brain, plays important physiological functions in the central nervous system. However, the relationship between temporospatial alterations in the α7nAChR and DAI-related learning and memory dysfunction are not completely understood. Our study detected temporospatial alterations of α7nAChR in vulnerable areas (hippocampus, internal capsule, corpus callosum and brain stem) of DAI rats and evaluated the development and progression of learning and memory dysfunction via the Morris water maze (MWM). We determined that α7nAChR expression in vulnerable areas was mainly reduced at the recovery of DAI in rats. Moreover, the escape latency of the injured group increased significantly and the percentages of the distance travelled and time spent in the target quadrant were significantly decreased after DAI. Furthermore, α7nAChR expression in the vulnerable area was significantly positively correlated with MWM performance after DAI according to regression analysis. In addition, we determined that a selective α7nAChR agonist significantly improved learning and memory dysfunction. Rats in the α7nAChR agonist group showed better learning and memory performance than those in the antagonist group. These results demonstrate that microstructural injury-induced alterations of α7nAChR in the vulnerable area are significantly correlated with learning and memory dysfunctions after DAI and that augmentation of the α7nAChR level by its agonist contributes to the improvement of learning and memory function. [ABSTRACT FROM AUTHOR]

The Rho family of small GTPases was considered as molecular switches in regulating multiple cellular events, including cytoskeleton reorganization. The Rho GTPase-activating proteins (RhoGAPs) are one of the major families of Rho GTPase regulators. RhoGAPs were initially considered negative mediators of Rho signaling pathways via their GAP domain. Recent studies have demonstrated that RhoGAPs also regulate numerous aspects of neuronal development and are related to various neurodegenerative diseases in GAP-dependent and GAP-independent manners. Moreover, RhoGAPs are regulated through various mechanisms, such as phosphorylation. To date, approximately 70 RhoGAPs have been identified; however, only a small portion has been thoroughly investigated. Thus, the characterization of important RhoGAPs in the central nervous system is crucial to understand their spatiotemporal role during different stages of neuronal development. In this review, we summarize the current knowledge of RhoGAPs in the brain with an emphasis on their molecular function, regulation mechanism and disease implications in the central nervous system. [ABSTRACT FROM AUTHOR]

Epigenetic modifications are critical determinants in tumor initiation and progression. This study aims to detect the promoter methylation status and the mRNA expression levels of ATG2B , ATG4D , ATG9A and ATG9B , and then to explore their relationship in invasive ductal carcinomas (IDCs) and matched normal tissues (MNTs) of the breast. Methylation was observed as follows: 61.0% in ATG2B , 46.8% in ATG4D , 56.4% in ATG9A , and 74.0% in ATG9B of IDCs. Meanwhile, their mRNA expression levels of the IDCs was lower than that of the MNTs (P < 0.001, P = 0.019, P < 0.001 and P < 0.001, respectively). Methylated IDCs of ATG2B , ATG9A , ATG9B and unmethylated ATG4D , ATG9B showed significantly lower expression values compared to the MNTs (P = 0.003, P < 0.001, P < 0.001, P = 0.014 and P = 0.002, respectively). The methylations of ATG2B and ATG9B were related to their lower expression levels in IDCs (P = 0.017 and P = 0.023). Moreover, ATG2B methylation was positively associated with the grade (P = 0.024) and TNM stage (P = 0.015); Methylation of ATG4D and ATG9A was positively correlated to lymph node involvement (P = 0.012 and P = 0.018), while methylation of ATG9B appeared susceptible to CK5/6 positive status and deteriorated TNM stages (P = 0.003 and P = 0.012). Moreover, the decreased expression of ATG2B was related to the ER and PR status (P = 0.004 and P = 0.003). The ER, HER-2 and lymph node metastasis status are the determinants to reducing the expression of ATG4D , ATG9A and ATG9B (P = 0.026, P = 0.010 and P = 0.011, respectively). This study highlights the transcriptional inactivation mechanisms of ATG2B , ATG4D , ATG9A and ATG9B promoter methylation status and the possible origin of autophagy signal pathway repression in IDCs. [ABSTRACT FROM AUTHOR]

Background: Myocardial injury is a life-threatening complication of coronavirus disease 2019 (COVID-19). Pre-existing health conditions and early morphological alterations may precipitate cardiac injury and dysfunction after contracting the virus. The current study aimed at assessing potential risk factors for COVID-19 cardiac complications in patients with pre-existing conditions and imaging predictors. Methods and Results: The multi-center, retrospective cohort study consecutively enrolled 400 patients with lab-confirmed COVID-19 in six Chinese hospitals remote to the Wuhan epicenter. Patients were diagnosed with or without the complication of myocardial injury by history and cardiac biomarker Troponin I/T (TnI/T) elevation above the 99th percentile upper reference limit. The majority of COVID-19 patients with myocardial injury exhibited pre-existing health conditions, such as hypertension, diabetes, hypercholesterolemia, and coronary disease. They had increased levels of the inflammatory cytokine interleukin-6 and more in-hospital adverse events (admission to an intensive care unit, invasive mechanical ventilation, or death). Chest CT scan on admission demonstrated that COVID-19 patients with myocardial injury had higher epicardial adipose tissue volume ([EATV] 139.1 (83.8-195.9) vs. 92.6 (76.2-134.4) cm 2 ; P = 0.036). The optimal EATV cut-off value (137.1 cm 2 ) served as a useful factor for assessing myocardial injury, which yielded sensitivity and specificity of 55.0% (95%CI, 32.0-76.2%) and 77.4% (95%CI, 71.6-82.3%) in adverse cardiac events, respectively. Multivariate logistic regression analysis showed that EATV over 137.1 cm 2 was a strong independent predictor for myocardial injury in patients with COVID-19 [OR 3.058, (95%CI, 1.032-9.063); P = 0.044]. Conclusions: Augmented EATV on admission chest CT scan, together with the pre-existing health conditions (hypertension, diabetes, and hyperlipidemia) and inflammatory cytokine production, is associated with increased myocardial injury and mortality in COVID-19 patients. Assessment of pre-existing conditions and chest CT scan EATV on admission may provide a threshold point potentially useful for predicting cardiovascular complications of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wei, Qiao, Chen, Huang, Wang, Yu, Xu, Wu, Wang, Gu, Li, Li, Liu, Yang, Ding, Lu, Yin, Wang, Li, Shi, Qian, Yang and Geng.)

Plant development is regulated by both synergistic and antagonistic interactions of different phytohormones, including a complex crosstalk between ethylene and auxin. For instance, auxin and ethylene synergistically control primary root elongation and root hair formation. However, a lack of chemical agents that specifically modulate ethylene or auxin production has precluded precise delineation of the contribution of each hormone to root development. Here, we performed a chemical genetic screen based on the recovery of root growth in ethylene-related Arabidopsis mutants with constitutive "short root" phenotypes ( eto1-2 and ctr1-1 ). We found that ponalrestat exposure recovers root elongation in these mutants in an ethylene signal-independent manner. Genetic and pharmacological investigations revealed that ponalrestat inhibits the enzymatic activity of the flavin-containing monooxygenase YUCCA, which catalyzes the rate-limiting step of the indole-3-pyruvic acid branch of the auxin biosynthesis pathway. In summary, our findings have identified a YUCCA inhibitor that may be useful as a chemical tool to dissect the distinct steps in auxin biosynthesis and in the regulation of root development., (© 2019 Zhu et al.)

The molecular and cellular mechanisms underlying the anti-proliferative effects of preoptic regulator factor 2 (Porf-2) on neural stem cells (NSCs) remain largely unknown. Here, we found that Porf-2 inhibits the activity of ras-related C3 botulinum toxin substrate 1 (Rac1) protein in hippocampus-derived rat NSCs. Reduced Rac1 activity impaired the nuclear translocation of β-catenin, ultimately causing a repression of NSCs proliferation. Porf-2 knockdown enhanced NSCs proliferation but not in the presence of small molecule inhibitors of Rac1 or Wnt. At the same time, the repression of NSCs proliferation caused by Porf-2 overexpression was counteracted by small molecule activators of Rac1 or Wnt. By using a rat optic nerve crush model, we observed that Porf-2 knockdown enhanced the recovery of visual function. In particular, optic nerve injury in rats led to increased Wnt family member 3a (Wnt3a) protein expression, which we found responsible for enhancing Porf-2 knockdown-induced NSCs proliferation. These findings suggest that Porf-2 exerts its inhibitory effect on NSCs proliferation via Rac1-Wnt/β-catenin pathway. Porf-2 may therefore represent and interesting target for optic nerve injury recovery and therapy.

Background: Traumatic optic nerve injury is a leading cause of irreversible blindness across the world and causes progressive visual impairment attributed to the dysfunction and death of retinal ganglion cells (RGCs). To date, neither pharmacological nor surgical interventions are sufficient to halt or reverse the progress of visual loss. Axon regeneration is critical for functional recovery of vision following optic nerve injury. After optic nerve injury, RGC axons usually fail to regrow and die, leading to the death of the RGCs and subsequently inducing the functional loss of vision. However, the detailed molecular mechanisms underlying axon regeneration after optic nerve injury remain poorly understood., Methods: Research content related to the detailed molecular mechanisms underlying axon regeneration after optic nerve injury have been reviewed., Results: The present review provides an overview of regarding potential strategies for axonal regeneration of RGCs and optic nerve repair, focusing on the role of cytokines and their downstream signaling pathways involved in intrinsic growth program and the inhibitory environment together with axon guidance cues for correct axon guidance. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which contributes to develop improved treatments for optic nerve regeneration. These findings are encouraging and open the possibility that clinically meaningful regeneration may become achievable in the future., Conclusion: Combination of treatments towards overcoming growth-inhibitory molecules and enhancing intrinsic growth capacity combined with correct guidance using axon guidance cues is crucial for developing promising therapies to promote axon regeneration and functional recovery after ON injury., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Reports describing a rapid increase in the cystic volume of anaplastic astrocytoma (AA) in a short time frame are rare. The present study reports the case of a 68-year-old male who was admitted to the No. 9 People's Hospital, Shanghai Jiaotong University School of Medicine (Shanghai, China), with a small cystic brain lesion and positive immunological testing for cysticercosis. Head magnetic resonance imaging (MRI) showed a cystic lesion, 6 mm in diameter, in the left frontal lobe. Neurocysticercosis was suspected and the patient was treated with a clinical trial of albendazole and steroids. A period of 25 days later, the patient's condition had deteriorated, and MRI revealed a cystic lesion in the left frontal lobe; thereafter, the cystic lesion was removed and a diagnosis of AA was established. The tumor was soft, ivory white and gelatinous due to myxoid degeneration. In this case, tumor-related angiogenesis and microvascular extravasation (blood-brain barrier disruption) may have been the main cause of the rapid increase in the cystic volume in such a short time frame. The similarity of the glioma and cysticercus antigens may have been the cause of the positive reactions in the cystic fluid. The present study reports the rare occurrence of a rapid increase of cystic volume and potential diagnostic difficulties.

Neural stem cell (NSC) proliferation and differentiation play a pivotal role in the development of brain, the plasticity of the brain network, and the repair for brain function in CNS diseases. The mechanisms regulating NSC behavior are not well elucidated. Previous studies showed porf-2 functions as a modulator in central nerve system development. We here show that porf-2, a conserved family of RhoGAPs, is highly and specifically expressed in NSCs. We also demonstrate that porf-2 inhibits the proliferation of NSCs in vivo and in vitro, but has no effect on NSC differentiation. We investigated which domain is required for the role of porf-2 on NSC proliferation. By using neurosphere formation and Edu assay we confirmed the GAP domain is necessary for its function. In addition, we surveyed a few classical pathways on NSC proliferation and found that porf-2 inhibits NSC proliferation by suppressing the β-catenin nuclear translocation. Taken together, we show for the first time that porf-2 inhibits NSC proliferation through Wnt/β-catenin pathway by its GAP domain.

In the last decade, the overexpression of hepatoma upregulated protein (HURP) has been reported in hepatocellular carcinoma, adrenocortical tumors and urogenital carcinoma. However, the role of HURP in breast cancer remains unknown. In the present study, a comprehensive analysis was performed to examine the HURP expression level in 43 breast cancer tumor samples and paired adjacent normal tissues. The correlation between the HURP expression level and the clinicopathological characteristics was evaluated. The role of HURP in breast cancer was investigated by quantitative polymerase chain reaction, western blot analysis and cell proliferation assays. HURP expression was found to be significantly increased in the breast cancer samples. The HURP expression level was higher in the tumors with advanced-grade metastasis and was strongly associated with tumor-node-metastasis staging (P=0.003). Transfection and cell proliferation assays suggested that the suppression of HURP expression or the interference in HURP activity in the breast cancer cells inhibited cell proliferation significantly. These data suggest that HURP is associated with the degree of malignancy and the proliferation of breast cancer. HURP could be a tumor biomarker for prognosis and a potential therapeutic drug target for human breast cancer.