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Kidney fibrosis is associated with the progression of acute kidney injury to chronic kidney disease. MG53, a cell membrane repair protein, has been shown to protect against injury to kidney epithelial cells and acute kidney injury. Here, we evaluated the role of MG53 in modulation of kidney fibrosis in aging mice and in mice with unilateral ureteral obstruction (UUO) a known model of progressive kidney fibrosis. Mice with ablation of MG53 developed more interstitial fibrosis with age than MG53-intact mice of the same age. Similarly, in the absence of MG53, kidney fibrosis was exaggerated compared to mice with intact MG53 in the obstructed kidney compared to the contralateral unobstructed kidney or the kidneys of sham operated mice. The ureteral obstructed kidneys from MG53 deficient mice also showed significantly more inflammation than ureteral obstructed kidneys from MG53 intact mice. In vitro experiments demonstrated that MG53 could enter the nuclei of proximal tubular epithelial cells and directly interact with the p65 component of transcription factor NF-κB, providing a possible explanation of enhanced inflammation in the absence of MG53. To test this, enhanced MG53 expression through engineered cells or direct recombinant protein delivery was given to mice subject to UUO. This reduced NF-κB activation and inflammation and attenuated kidney fibrosis. Thus, MG53 may have a therapeutic role in treating chronic kidney inflammation and thereby provide protection against fibrosis that leads to the chronic kidney disease phenotype.

LncRNAs are identified as critical regulators in cerebral ischemia/reperfusion injury (CIRI). In this current work, SH-SY5Y cells suffered from oxygen-glucose deprivation/reperfusion (OGD/R) were applied to analyze the biological role of lncRNA NORAD and underlying molecular mechanism in CIRI in vitro. Levels of lncRNA NORAD, miR-30a-5p and YWHAG were measured using RT-qPCR. Bioinformatics analysis predicted the binding sites of lncRNA NORAD to miR-30a-5p and miR-30a-5p to YWHAG. Luciferase reporter assay verified the binding relationships among lncRNA NORAD, miR-30a-5p and YWHAG. Additionally, cell viability was determined using CCK-8 assay, and cell apoptosis was assessed using TUNEL staining and western blot analysis. Moreover, the levels of ROS, MDA, LDH and SOD as well as IL-1β, TNF-α, and IL-6 were assessed via application of the corresponding assay kits. Decreased cell viability and temporarily increased lncRNA NORAD level were observed in SH-SY5Y cells after OGD/R. It was demonstrated that lncRNA NORAD regulated YWHAG expression by sponging miR-30a-5p. Upregulation of lncRNA NORAD contributed to the enhancement of cell viability, the inhibition of cell apoptosis as well as the alleviation of oxidative stress and inflammation in OGD/R-injured SH-SY5Y cells, which were reversed upon elevation of miR-30a-5p. In contrast, downregulation of lncRNA NORAD reduced cell viability, promoted cell apoptosis as well as aggravated oxidative stress and inflammation under OGD/R challenge, and the functions of lncRNA NORAD knockdown in OGD/R injury were abolished by upregulation of YWHAG. Taken together, lncRNA NORAD exerted protective effects against OGD/R-induced neural injury by sponging miR-30a-5p to upregulate YWHAG expression.

Most previous studies in the pathophysiology of major depressive disorder (MDD) focused on fecal samples, which limit the identification of the gut mucosal and luminal microbiome in depression. Here, we address this knowledge gap. Male cynomolgus macaques (Macaca fascicularis) were randomly assigned to a chronic unpredictable mild stress (CUMS) group, or to an unstressed control group. Behavioral tests were completed in both groups. At endpoint, microbe composition of paired mucosal and luminal samples from cecum, ascending, transverse, and descending colons were determined by 16S ribosomal RNA gene sequencing. The levels of 34 metabolites involved in carbohydrate or energy metabolism in luminal samples were measured by targeted metabolomics profiling. CUMS macaques demonstrated significantly more depressive-like behaviors than controls. We found differences in mucosal and luminal microbial composition between the two groups, which were characterized by Firmicutes and Bacteriodetes at the phylum level, as well as Prevotellaceae and Lachnospiraceae at the family level. The majority of discriminative microbes correlated with the depressive-like behavioral phenotype. In addition, we found 27 significantly different microbiome community functions between the two groups in mucosa, and one in lumen, which were mainly involved in carbohydrate and energy metabolism. A total of nine metabolites involved in these pathways were depleted in CUMS animals. Together, CUMS macaques with depressive-like behaviors associated with distinct alterations of covarying microbiota, carbohydrate and energy metabolism in mucosa and lumen. Further studies should focus on the mucosal and luminal microbiome to provide a deeper spatiotemporal perspective of microbial alterations in the pathogenesis of MDD.

Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein-protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a "pocket" or "groove" for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 μM). The direct binding affinity between 13 and PCSK9 was determined with a KD value of 2.50 ± 0.73 μM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted., Graphical abstract Pure drug nano-assemblies (PDNAs), fabricated by self-assembly or co-assembly of pure drug molecules, have attracted considerable attention in cancer treatment, indicating therapeutic advantages including carrier-free property, simple preparation, ultra-high drug loading and co-delivery behavior for combination therapy.Image 1

Trimeric intracellular cation (TRIC) channels have been identified as monovalent cation channels that are located in the ER/SR membrane. Two isoforms discovered in mammals are TRIC-A (TMEM38a) and TRIC-B (TMEM38b). TRIC-B ubiquitously expresses in all tissues, and TRIC-B−/− mice is lethal at the neonatal stage. TRIC-A mainly expresses in excitable cells. TRIC-A−/− mice survive normally but show abnormal SR Ca2+ handling in both skeletal and cardiac muscle cells. Importantly, TRIC-A mutations have been identified in human patients with stress-induced arrhythmia. In the past decade, important discoveries have been made to understand the structure and function of TRIC channels, especially its role in regulating intracellular Ca2+ homeostasis. In this review article, we focus on the potential roles of TRIC-A in regulating cardiac function, particularly its effects on intracellular Ca2+ signaling of cardiomyocytes and discuss the current knowledge gaps.

Introduction Lung injury has several inciting etiologies ranging from trauma (contusion and hemorrhage) to ischemia reperfusion injury. Reflective of the injury, tissue and cellular injury increases proportionally with the injury stress and is an area of potential intervention to mitigate the injury. This study aims to evaluate the therapeutic benefits of recombinant human MG53 (rhMG53) protein in porcine models of acute lung injury (ALI). Materials and Methods We utilized live cell imaging to monitor the movement of MG53 in cultured human bronchial epithelial cells following mechanical injury. The in vivo efficacy of rhMG53 was evaluated in a porcine model of hemorrhagic shock/contusive lung injury. Varying doses of rhMG53 (0, 0.2, or 1 mg/kg) were administered intravenously to pigs after induction of hemorrhagic shock/contusive induced ALI. Ex vivo lung perfusion system enabled assessment of the isolated porcine lung after a warm ischemic induced injury with rhMG53 supplementation in the perfusate (1 mg/mL). Results MG53-mediated cell membrane repair is preserved in human bronchial epithelial cells. rhMG53 mitigates lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury. Ex vivo lung perfusion administration of rhMG53 reduces warm ischemia-induced injury to the isolated porcine lung. Conclusions MG53 is an endogenous protein that circulates in the bloodstream. Therapeutic treatment with exogenous rhMG53 may be part of a strategy to restore (partially or completely) structural morphology and/or functional lung integrity. Systemic administration of rhMG53 constitutes a potential effective therapeutic means to combat ALI.

Background: We aimed to elucidate the mechanism by which hepatitis B virus X (HBx) gene mutations increase the risk of hepatocellular carcinoma (HCC) and identify novel therapeutic targets.Methods: Wild-type and four HBx mutants (M1, A1762T/G1764A; M2, T1674G+T1753C+A1762T/G1764A; M3, C1653T+T1674G+A1762T/G1764A; Ct-HBx, carboxylic acid-terminal truncated HBx) were delivered into the livers of fumarylacetoacetate hydrolase-deficient mice by using the Sleeping Beauty (SB) transposon system, respectively. Seven liver tissues and seven tumor tissues of the SB mouse models were subjected to HBV-capture sequencing. Three liver tissues from WT-HBx mice, three tumor tissues from M3-HBx mice, and three tumor tissues from Ct-HBx mice were subjected to cDNA microarray analysis. HeLa cells stably expressing WT-HBx and the four HBx mutants were also subjected to cDNA microarray assay.Results: The incidence of HCC was higher in the mice injected with M3-HBx or Ct-HBx. M3-HBx had a stronger capacity of upregulating inflammatory cytokines than other HBx variants. HBV-capture sequencing showed that the HBx fragments were mainly integrated into intergenic and intron regions. No significant difference was observed in the number of insertion sites between tumors and liver tissues. Ectopic expression of the HBx mutants, especially M3-HBx and Ct-HBx, significantly increased cell proliferation and the S phase proportion of HepG2 and HeLa cells, compared to WT-HBx. Liver tissues of the SB mice and the transfected cells were subjected to cDNA microarray analysis. Plasminogen activator inhibitor-1 (PAI1) and cell division cycle 20 (CDC20) were identified as novel effectors. M3-HBx and Ct-HBx significantly upregulated the expression of PAI1 and CDC20 in HepG2 and HeLa cells as well as the livers of the SB mice. PAI1 silencing attenuated the effect of M3-HBx and Ct-HBx on the growth of HepG2 cells and greatly decreased the growth of HeLa cells with Ct-HBx. Conclusion: HBx C1653T+T1674G+A1762T/G1764A mutant and Ct-HBx promote carcinogenesis via upregulating PAI1 and CDC20. PAI1, an important player bridging the HBx mutants and HCC, should be a promising candidate as a predictive and prognostic biomarker and therapeutic target in HBV-related HCC.

In this study, we aimed to investigate the relationship between body mass index (BMI), waist circumference (WC) or waist-to-hip ratio (WHR) and oligomenorrhea or irregular menstruation in Chinese women of childbearing age. A total of 1,423 Han women aged 19–39 years who were routinely examined at the Physical Examination Center of Peking University People's Hospital were enrolled by convenience sampling method. All participants were asked to fill up menstrual questionnaires. Binary logistic regression models were used to assess the odds ratio (OR) of different BMI, WC and WHR groups for the prevalence of oligomenorrhea and irregular menstruation. Moreover, we used the ROC curves to compare the predictive effects of BMI, WC and WHR on oligomenorrhea and irregular menstruation. Among the 1,423 participants, 93 women (6.5%) had BMI ≥ 30 kg/m2, 6.5% of the participants had oligomenorrhea, and 22.6% had irregular menstrual menstruation. Overall, those with BMI ≥30 kg/m2 (OR = 2.543; 95%CI 1.332–4.856; p = .005) or WC ≥ 90 cm (OR = 2.023; 95%CI 1.198–3.416; p = .008) were more likely to have long menstrual cycle. The prevalence of irregular menstruation was higher in the BMI ≥30 kg/m2 (OR = 2.509; 95%CI 1.591–3.958; p < .001), WC ≥ 90 cm (OR = 2.299; 95%CI 1.619–3.265; p < .001) and WHR ≥ 0.86 (OR = 1.739; 95%CI 1.293–2.339; p < .001) groups. The ROC curve showed that all three anthropometric indices had predictive effect, while there was no significant difference in predicting oligomenorrhea. WC was a better predictor for irregular menstruation compared with BMI. Obesity, oligomenorrhea and irregular menstruation were common in Chinese women of childbearing age, and obesity was associated with oligomenorrhea and irregular menstruation. Abdominal obesity might have a stronger predictive effect on irregular menstruation.

TRIM family proteins play integral roles in the innate immune response to virus infection. MG53 (TRIM72) is essential for cell membrane repair and is believed to be a muscle-specific TRIM protein. Here we show human macrophages express MG53, and MG53 protein expression is reduced following virus infection. Knockdown of MG53 in macrophages leads to increases in type I interferon (IFN) upon infection. MG53 knockout mice infected with influenza virus show comparable influenza virus titres to wild type mice, but display increased morbidity accompanied by more accumulation of CD45+ cells and elevation of IFNβ in the lung. We find that MG53 knockdown results in activation of NFκB signalling, which is linked to an increase in intracellular calcium oscillation mediated by ryanodine receptor (RyR). MG53 inhibits IFNβ induction in an RyR-dependent manner. This study establishes MG53 as a new target for control of virus-induced morbidity and tissue injury., TRIM proteins are known to play critical roles in the context of viral infection. Here the authors establish MG53 (TRIM72) suppresses IFN and inflammation by modulation of ryanodine receptor related intracellular calcium induction.

MG53 is a member of the TRIM protein family that is predominantly expressed in striated muscles and participates in cell membrane repair. Controversy exists regarding MG53’s role in insulin signaling and manifestation of diabetes. We generated db/db mice with either whole-body ablation or sustained elevation of MG53 in the bloodstream in order to evaluate the physiological function of MG53 in diabetes. To quantify the amount of MG53 protein in circulation, we developed a monoclonal antibody against MG53 with high specificity. Western blot using this antibody revealed lower or no change of serum MG53 levels in db/db mice or patients with diabetes compared with control subjects. Neither whole-body ablation of MG53 nor sustained elevation of MG53 in circulation altered insulin signaling and glucose handling in db/db mice. Instead, mice with ablation of MG53 were more susceptible to streptozotocin-induced dysfunctional handling of glucose compared with the wild-type littermates. Alkaline-induced corneal injury demonstrated delayed healing in db/db mice, which was restored by topical administration of recombinant human (rh)MG53. Daily intravenous administration of rhMG53 in rats at concentrations up to 10 mg/kg did not produce adverse effects on glucose handling. These findings challenge the hypothetical function of MG53 as a causative factor for the development of diabetes. Our data suggest that rhMG53 is a potentially safe and effective biologic to treat diabetic oculopathy in rodents.

Background Photothermal therapy (PTT) has great potential application in the treatment of tumors. However, due to the low penetration of near-infrared light (NIR) and the low concentration of nanomaterials in the tumor site, the application of PTT has been limited. Purpose The objective of this study was to investigate the therapeutic effect of transcatheter intra-arterial infusion of lecithin-modified Bi nanoparticles (Bi-Ln NPs) combined with interventional PTT (IPTT) on hepatocellular carcinoma. Methods Bi-Ln NPs were prepared by emulsifying the hydrophobic Bi nanoparticles and lecithin, and the photothermal conversion and cytotoxicity of Bi-Ln NPs were then measured by infrared imaging and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, respectively. Twenty-four VX2 hepatic carcinoma rabbits were randomly divided into four groups. Rabbits in group A received Bi-Ln NPs by intra-arterial infusion and NIR laser treatment (IA Bi-Ln NPs + Laser), group B received Bi-Ln NPs by intravenous infusion and NIR laser treatment (IV Bi-Ln NPs + Laser), group C received PBS (phosphate buffer saline) via intra-arterial infusion with NIR laser treatment (IA PBS + Laser), group D received PBS via intra-arterial infusion (IA PBS). Transcatheter intra-arterial infusion was conducted by superselective intubation under digital subtraction angiography (DSA) guidance. IPTT was performed by introducing an NIR optical fiber access to the rabbit VX2 hepatic carcinoma under real-time ultrasound guidance. Magnetic resonance imaging (MRI) was performed to evaluate the tumor size. Hematoxylin and eosin (H&E) stain and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were conducted 7 days after treatment to evaluate the necrosis rate and viability of tumor, respectively. Results The Bi-Ln NPs have the advantages of good biological compatibility and high photothermal conversion efficiency. Minimally invasive transcatheter intra-arterial infusion can markedly increase the concentration of Bi-Ln NPs in tumor tissues. IPTT can contribute to the significant improvement in the photothermal efficiency of Bi-Ln NPs. Compared to other groups, the group of IA Bi-Ln NPs + Laser showed a significantly higher tumor inhibition rate (TIR) of 93.38 ± 19.57%, a higher tumor necrosis rate of 83.12 ± 8.02%, and a higher apoptosis rate of (43.26 ± 10.65%) after treatment. Conclusion Transcatheter intra-arterial infusion combined with interventional PTT (IPTT) is safe and effective in eradicating tumor cells and inhibiting tumor growth and may provide a novel and valuable choice for the treatment of hepatocellular carcinoma in the future.

Introduction To improve the accuracy of ultrasound techniques for the assessment of carotid stenosis, we designed a novel carotid artery stenosis ultrasound scale (CASUS), and evaluated its accuracy, reliability, and its value in predicting the occurrence of cardiovascular and cerebrovascular diseases in a prospective study. Methods A total of 750 patients with first-time ischemic stroke and hospitalized within 24 h were enrolled in the study. Using color Doppler ultrasound (CDUS), the degree of stenosis and blood flow (BF) in bilateral internal carotid arteries (ICA) and the V1-V3 segment of vertebral arteries (VA) was assessed. Cubic simulation curves for BF and global blood flow (GBF) over the stenosis score (SS), total stenosis score (TSS), and radiological imaging- total stenosis score (RI-TSS) were fitted and compared. The receiver operating characteristic (ROC) curves using TSS, RI-TSS, or GBF to predict various ischemic stroke endpoints were also analyzed and compared. Results There was a linear relationship between SS and BF both ICA and VA (R2 were 0.734 and 0.783, respectively, both P P P P > 0.05). Conclusions The novel CASUS can better reflect the level of cerebral reperfusion in patients with ischemic stroke and can better predict the occurrence of cardiovascular and cerebrovascular diseases.

Purpose: The aim of this study is to evaluate the influence of arm movements from adduction to abduction on intracavitary electrocardiogram and the position of a catheter tip. Methods: Overall, 192 peripherally inserted central catheter lines were placed under intracavitary electrocardiogram guidance and 188 of them were enrolled in the study. The catheter was first placed at a time point corresponding to the peak P wave with the arm in adduction. The arm was then abducted to 90° without changing catheter insertion length. During the procedure, basal electrocardiogram, intracavitary electrocardiogram, and radiographs with the arm in adduction and abduction were recorded. Amplitude wave changes and catheter movements were measured on electrocardiogram records and radiographs, respectively. Results: In 188 cases, the P wave displayed typical changes, and 97.8% (184/188) catheters were successfully placed correctly. At the peak P wave, the amplitude of the peak P wave was 8.64 times greater than that of the basal P wave, and the P/R ratio was 0.61. When the arm was abducted to 90°, the amplitude of the P wave dropped to 57% of its peak, P/R decreased from 0.61 to 0.34, and the catheter tip moved cephalad 1.00 and 0.77 vertebral body units in male and female patients, respectively. Conclusion: Peripherally inserted central catheter moves toward the heart when the arm position changes from abduction to adduction. Peripherally inserted central catheter tip placement at the peak P wave with patient’s arm in adduction is accurate and can prevent the catheter from advancing too low. R wave can function as a reference for observing P wave changes during peripherally inserted central catheter placement.

Streptococcus agalactiae, also known as group B streptococcus (GBS), can cause pneumonia, meningitis, and bacteremia, making it a pathogen that can increase the risk of death in newborns and immunodeficient individuals. Neutrophils are the first barrier to a host’s innate immune defense against these infections. Fpr2(Formyl peptide receptor 2) is an important chemotactic receptor of neutrophils, though its activation would cause pro- and anti-inflammatory effects. In this study, we found that mice without Fpr2 receptor were highly susceptible to GBS infections. These mice demonstrated decreased chemotaxis to neutrophils, decreased bactericidal ability of neutrophils, and high mortality. RNA-seq and Luminex assay indicated that Fpr2 activates key signal molecules downstream and produces chemokines CXCL1/2 to chemotaxis neutrophils. Like Fpr2-/-, CXCL1/2 or neutrophil depletion impairs host’s ability to defend against GBS infection. Altogether, these data indicate that Fpr2 contributes to a host’s ability to control GBS infection and that a lack of Fpr2 was associated with selective impairment during the production of chemokines CXCL1 and CXCL2 as well as neutrophil recruitment. Here, We clarified that Fpr2, as a chemotactic receptor, could not only directly chemotactic neutrophils, but also regulate the production of chemokines to control infection by chemotactic neutrophils.

The hippocampus is one of the most phylogenetically preserved structures in the mammalian brain. Engaged in a host of diverse cognitive processes, there has been increasing interest in understanding how the hippocampus dynamically supports these functions. One of the lingering questions is how to reconcile the seemingly disparate cytoarchitectonic organization, which favors a dorsal-ventral layering, with the neurofunctional topography, which has strong support for longitudinal axis (anterior-posterior) and medial-lateral orientation. More recently, meta-analytically driven (e.g., big data) approaches have been employed, however, the question remains whether they are sensitive to important task-specific features such as context, cognitive processes recruited, or the type of stimulus being presented. Here, we used hierarchical clustering on functional magnetic resonance imaging (fMRI) data acquired from healthy individuals at 7T using a battery of tasks that engage the hippocampus to determine whether stimulus or task features influence cluster profiles in the left and right hippocampus. Our data suggest that resting state clustering appears to favor the cytoarchitectonic organization, while task-based clustering favors the neurofunctional clustering. Furthermore, encoding tasks were more sensitive to stimulus type than were recognition tasks. Interestingly, a face-name paired associate task had nearly identical clustering profiles for both the encoding and recognition conditions of the task, which were qualitatively morphometrically different than simple encoding of words or faces. Finally, corroborating previous research, the left hippocampus had more stable cluster profiles compared to the right hippocampus. Together, our data suggest that task-based and resting state cluster profiles are different and may account for the disparity or inconsistency in results across studies.

Background: Anxiety disorder is the most prevalent mental disorder in children and adolescents. However, evidence for efficacy and acceptability between individual cognitive behavior therapy (I-CBT) and group cognitive behavior therapy (G-CBT) in anxiety disorders in children and adolescents remains unclear.Methods: Eight electronic databases (PubMed, Embase, Cochrane, Web of Science, CINAHL, PsycINFO, ProQuest, and LILACS) were searched from inception to October 2019. Randomized controlled trials comparing I-CBT with G-CBT for anxiety disorders in children and adolescents were included. The primary outcomes were efficacy (mean change in anxiety symptom scores) at post-treatment and acceptability (all-cause discontinuation). The secondary outcome was remission at post-treatment. Subgroup analyses were also conducted to examine whether the result would be influenced by age, number of treatment sessions, parental involvement, male/female sex, and number of participants.Results: Nine studies were selected in this meta-analysis. The pooled analyses indicated no significant difference between I-CBT and G-CBT for efficacy at post-treatment [standardized mean difference (SMD), −0.14; 95% confidence interval (CI), −0.37 to 0.09], acceptability [odds ratio (OR), 1.30; 95% CI, 0.61–2.77], and remission at post-treatment (OR, 1.15; 95% CI, 0.79–1.66). In the subgroup analysis of age, I-CBT was significantly more effective than G-CBT in adolescents at post-treatment (SMD, −0.77; 95% CI, −1.51 to −0.02), but not in children (SMD, 0.00; 95% CI, −0.02 to 0.20). However, the findings were not materially different from those of the efficacy subgroup analysis of number of treatment sessions, parental involvement, male/female sex, and number of participants.Conclusions: Based on those current evidence, I-CBT was shown to be more beneficial than G-CBT for anxiety disorders in adolescents, but not in children. However, further well-designed clinical studies should be performed to confirm these findings.Systematic Review Registration:http://osf.io/xrjkp, identifier: 10.17605/OSF.IO/XRJKP.

BackgroundAvailable evidence on the comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder (PTSD) in children and adolescents remains uncertain.ObjectiveWe aimed to compare and rank the different types and formats of psychotherapies for PTSD in children and adolescents.MethodsWe searched eight databases and other international registers up to 31 December 2020. The pairwise meta-analyses and frequentist network meta-analyses estimated pooled standardised mean differences (SMDs) and ORs with random-effects model. Efficacy at post-treatment and follow-up, acceptability, depressive and anxiety symptoms were measured.FindingsWe included 56 randomised controlled trials with 5327 patients comparing 14 different types of psychotherapies and 3 control conditions. For efficacy, cognitive processing therapy (CPT), behavioural therapy (BT), individual trauma-focused cognitive–behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing, and group TF-CBT were significantly superior to all control conditions at post-treatment and follow-up (SMDs between −2.42 and −0.25). Moreover, CPT, BT and individual TF-CBT were more effective than supportive therapy (SMDs between −1.92 and −0.49). Results for depressive and anxiety symptoms were similar to the findings for the primary outcome. Most of the results were rated as ‘moderate’ to ‘very low’ in terms of confidence of evidence.ConclusionsCPT, BT and individual TF-CBT appear to be the best choices of psychotherapy for PTSD in young patients. Other types and different ways of delivering psychological treatment can be alternative options. Clinicians should consider the importance of each outcome and the patients’ preferences in real clinical practice.

Respiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological events in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.

Current antidepressants do not confer a clear advantage in children and adolescents with major depressive disorder (MDD). Accumulating evidence highlights the potential antidepressant-like effects of inosine on adult MDD, and gut microbiomes are significantly associated with MDD via the microbiota-gut-brain axis. However, few studies have investigated possible associations between inosine and gut microbiota in adolescents with MDD. The current study investigated the potential antidepressant effects of inosine in adolescent male C57BL/6 mice. After 4 weeks of chronic unpredictable mild stress (CUMS) stimulation, the mice were assessed by body weight, the sucrose preference test (SPT), open field test, and the elevated plus maze (EPM). The microbiota compositions of feces were determined by 16S rRNA gene sequencing. Inosine significantly improved CUMS-induced depressive and anxiety-like behaviors in adolescent mice including SPT and EPM results. Fecal microbial composition differed in the CON+saline, CUMS+saline, and CUMS+inosine groups, which were characterized by 126 discriminative amplicon sequence variants belonging to Bacteroidetes and Firmicute at the phylum level and Muribaculaceae and Lachnospiraceae at the family level. Muribaculaceae was positively associated with depressive and anxiety-like behaviors. KEGG functional analysis suggested that inosine might affect gut microbiota through carbohydrate metabolism and lipid metabolism pathways. The results of the study indicated that inosine improved depressive and anxiety-like behaviors in adolescent mice, in conjunction with the alteration of fecal microbial composition. Our findings may provide a novel perspective on the antidepressant effects of inosine in children and adolescents.

Background The prognosis of pancreatic cancer (PC) is extremely poor, and most patients with metastatic PC still receive palliative care. Here, we report the efficacy and safety of FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, 5-fluorouracil) in the treatment of metastatic PC. Methods We searched PubMed, Web of Science, EBSCO, and Cochrane library databases for articles that described efficacy and safety of FOLFIRINOX in patients with metastatic PC, from January 1996 to July 2020. The primary outcomes targeted included overall survival (OS) and progression-free survival (PFS). Results We found that FOLFIRINOX could directly improve OS rate of patients with metastatic PC (HR 0.76, 95% Cl 0.67–0.86, pppp>0.05). The main adverse events (AEs) targeted hematological toxicity and the gastrointestinal system, and included febrile neutropenia, a reduction in white blood cells and appetite, as well as diarrhea. Conclusion These findings indicated that FOLFIRINOX has potential benefits for the prognosis of patients with metastatic PC. Furthermore, there is no difference between the regimen of FOLFIRINOX and nab-paclitaxel + gemcitabine in this study. The application of FOLFIRINOX should be according to the actual situation of the patients and the experience of the doctors. Graphical abstract

The community-associated Methicillin-resistant Staphylococcus aureus strain (CA-MRSA) is highly virulent and has become a major focus of public health professionals. Phenol-soluble modulins (PSM) are key factors in its increased virulence. δ-Toxin belongs to PSM family and has copious secretion in many S. aureus strains. In addition, δ-toxin exists in the S. aureus culture supernatant as both N-terminus formylated δ-toxin (fδ-toxin) and deformylated δ-toxin (dfδ-toxin) groups. Although δ-toxin has been studied for more than 70 years, its functions remain unclear. We isolated and purified PSMs from the supernatant of S. aureus MW2, and found fibrils and oligomers aggregates by Size Exclusion Chromatography. After analyzing PSM aggregates and using peptide simulations, we found that the difference in the monomer structure of fδ-toxin and dfδ-toxin might ultimately lead to differences in the aggregation ability: fδ-toxin and dfδ-toxin tend to form fibrils and oligomers respectively. Of note, we found that fδ-toxin fibrils enhanced the stability of biofilms, while dfδ-toxin oligomers promoted their dispersal. Additionally, oligomeric dfδ-toxin combined with PSMα to form a complex with enhanced functionality. Due to the different aggregation capabilities and functions of fδ-toxin and dfδ-toxin, we speculate that they may be involved in the regulation of physiological activities of S. aureus. Moreover, the dfδ-toxin oligomer not only provides a new form of complex in the study of PSMα, but also has significance as a reference in oligomer research pertaining to some human amyloid diseases.

Scope The beneficial effects of probiotics in reducing gastrointestinal inflammation and in preventing colorectal cancer have been reported, but the mechanism underlying the immunomodulatory effect of probiotics in inhibiting extra-intestinal tumor progression remains unclear. Methods and results This study shows that probiotic supplementation attenuate lung metastasis of melanoma cells in mice. Feeding mice with VSL#3 probiotics change the composition and proportion of gut microbiota. The changes in gut bacteria composition, such as in the abundance of Lachnospiraceae, Streptococcus, and Lachnoclostridium, are associated with the production of short-chain fatty acids in the gut. The concentrations of propionate and butyrate are upregulated in gut and blood after feeding VSL#3, and the increase in propionate and butyrate levels promotes the expression of chemokine (C-C motif) ligand 20 (CCL20) in lung endothelial cells and the recruitment of T helper 17 (Th17) cells to the lungs via the CCL20/chemokine receptor 6 axis. The recruitment of Th17 cells decreases the number of tumor foci in lungs and attenuates the lung metastasis of melanoma cells in mice. Conclusions The results provide new information on the role and mechanisms of action of probiotics in attenuating extra-intestinal tumor metastasis.

Photodynamic therapy (PDT) is an emerging technology for tumor treatment in which photosensitizer (PS)-mediated light irradiation reduces oxygen, producing high levels of reactive oxygen species (ROS) that can cause vascular injury and effectively kill tumor cells. However, the naturally hypoxic tumor microenvironment is the main obstacle that hinders the photodynamic response in vivo and prevents its extensive application to tumor treatment. Moreover, PDT-mediated oxygen consumption further increases tumor hypoxia, potentially causing a variety of adverse consequences, such as angiogenesis, tumor invasion, and metastasis. To overcome these limitations caused by hypoxia, multiple strategies have been investigated, including the use of oxygen carriers and reactive oxygen supply materials, the regulation of tumor microenvironments, and multimodal therapy including PDT. In this review, we summarize the latest progress in the development of strategies to relieve tumor hypoxia for improved PDT efficacy and better therapeutic effects. In this review, we summarize the latest progress in the development of strategies to relieve tumor hypoxia for improved PDT efficacy, from the design of novel nonreactive oxygen carriers to reactive materials and other strategies, including the regulation of tumor microenvironments and PDT-involved multimodal therapy.

Respiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological findings in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein (rhMG53) in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.

Background To investigate the efficacy and safety of omega-3 fatty acids (O3FA) in treating depressive disorders in children and adolescents. Method We conducted a comprehensive search in electronic databases and hand-searched articles included for relevant studies. We included randomized controlled trials which studied on O3FA for treatment of children and adolescents with depression. The standard mean differences (SMDs) and the odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by a random-effects model. The primary outcomes were end-point depressive symptoms scores (efficacy) and all-cause discontinuation (safety). The secondary outcome of response rate was also assessed. Subgroup analyses were performed by age, severity of depression and dosage. Risk of bias assessment was performed based on the Jadad score and the Cochrane Collaboration’s risk-of-bias method. Results A total of four studies with 153 participants were included. In terms of efficacy, there was no significant difference of end-point depressive symptoms scores between O3FA and placebo (SMD = − 0.12, 95% CI − 0.53 to 0.30, P = 0.58; I2= 30%). In terms of safety, the all-cause discontinuation showed no statistical significance between O3FA and placebo (OR = 1.3, 95% CI 0.58 to 2.93, P = 0.53; I2= 0%). The response rate of O3FA was also not significant better than that of placebo (OR = 1.57, 95% CI 0.26 to 9.39, P = 0.62; I2= 71%). Besides, there were also no significant differences in those subgroup analyses outcomes. The risk of bias of included trials were not high. Conclusions Only considering the limited evidence of O3FA in the acute treatment of major depressive disorder, it did not seem to offer a clear advantage for children and adolescents.

High workloads and heavy academic pressure can have significant implications for the risk for depression and poor quality of life (QoL). This study aimed to investigate QoL and depressive symptoms in medical students undergoing postgraduate neurology specialty training in China. The survey covered demographic characteristics, the 8-itemMedical Outcomes Study Short-Formquestionnaire (SF-8), and the 2-itemPrimary Care Evaluation of Mental Disorders depression screening tool. Logistic regression analysis was used to investigate the determinants of QoL and depressive symptoms. Participants were 1,814 postgraduates from 249 hospitals in 27 Chinese provinces. The mean SF-8 physical and mental component summary scores were 78.17 (standard deviation [SD] 15.20) and 68.33 (SD 17.15), respectively. One-third of respondents had depressive symptoms, and those without depressive symptoms had significantly higher QoL scores. The multivariate regression analysis showed that factors independently associated with depressive symptoms were being in the second year of study, a lower household income, and less sleep time. Although QoL among our sample of Chinese medical students undergoing postgraduate neurology specialty training was favorable relative to other comparable populations, one-third of respondents had depressive symptoms. Accurate measures should be taken to change this situation.

Transparent B and Ga co-doped ZnO (BGZO)/n-ZnO/p-NiO heterojunctions were prepared on flexible polyethylene terephthalate (PET) substrates by RF magnetron sputtering at room temperature. The heterojunction shows high transmittance above 75% in the visible region, high flexibility and a good rectifying behavior. Compared with the heterojunction without BGZO layer, the performance of the device with BGZO layer is significantly improved. The turn-on voltage and the ideality factor of the heterojunction with BGZO layer is 1.2 and 2.3, respectively. The n-BGZO/n-ZnO/p-NiO heterojunction ultraviolet (UV) detectors show high UV sensitivity and fast time response.

Irisin, a muscle-origin protein derived from the extracellular domain of the fibronectin domain-containing 5 protein (FNDC5), has been shown to modulate mitochondria welfare through paracrine action. Here, we test the hypothesis that irisin contributes to cardioprotection after myocardial infarction by preserving mitochondrial function in cardiomyocytes. Animal model studies show that intravenous administration of exogenous irisin produces dose-dependent protection against ischemia/reperfusion (I/R)-induced injury to the heart as reflected by the improvement of left ventricular ejection fraction and the reduction in serum level of cTnI (n = 15, P0.05). I/R-induced apoptosis of cardiomyocytes is reduced after irisin treatment. The irisin-mediated protection has, at least in part, an effect on mitochondrial function because administration of irisin increases irisin staining in the mitochondria of the infarct area. Irisin also reduces I/R-induced oxidative stress as determined by mitochondrial membrane potential evaluation and superoxide FLASH event recording (n = 4, P0.05). The interaction between irisin and superoxide dismutase2 (SOD2) plays a key role in the protective process because irisin treatment increases SOD activity (n = 10, P0.05) and restores the mitochondria localization of SOD2 in cardiomyocytes (n = 5, P0.05). These results demonstrate that irisin plays a protective role against I/R injury to the heart. Targeting the action of irisin in mitochondria presents a novel therapeutic intervention for myocardial infarction.

Background Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC). Methods Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis. Results We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53-/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model. Conclusion Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.

BackgroundThe prognosis of pancreatic cancer (PC) is extremely poor and most patients with metastatic PC still receive palliative care. Here, we report the efficacy and safety of FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, 5-fluorouracil) in the treatment of metastatic PC.MethodsWe searched PubMed, Web of Science, EBSCO, and Cochrane library databases for articles that described efficacy and safety of FOLFIRINOX in patients with metastatic PC, from their inception to July 2020. The primary outcomes targeted included overall survival (OS) and progression-free survival (PFS).ResultsWe found that FOLFIRINOX could directly improve OS rate of patients with metastatic PC (HR: 0.76, 95% Cl: 0.67-0.86, pppp>0.05). The main adverse events (AEs) targeted hematological toxicity and the gastrointestinal system, and included febrile neutropenia, a reduction in white blood cells and appetite, as well as diarrhea.ConclusionThese findings indicated that FOLFIRINOX has potential benefits for the prognosis of patients with metastatic PC. Furthermore, there is no difference between the regimen of FOLFIRINOX and nab-paclitaxel + gemcitabine in this study. The application of FOLFIRINOX should be according to the actual situation of the patients and the experience of the doctors.

Background Depression is a leading cause of disability worldwide. There is increasing evidence showing that depression is associated with the pathophysiology in amygdala; however, the underlying mechanism remains poorly understood. Method We established a rat model of chronic social defeat stress (CSDS) and conducted a series of behavior tests to observe behavioral changes. Then liquid chromatography mass spectrometry (LC–MS)-based metabolomics and isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics were employed to detect metabolomes and proteomes in the amygdala, respectively. Ingenuity pathway analysis (IPA) and other bioinformatic analyses were used to analyze differentially expressed metabolites and proteins. Results The significantly lower sucrose preference index in the sucrose preference test and longer immobile time in the forced swim test were observed in the CSDS rats compared with control rats. In the multi-omics analysis, thirty-seven significantly differentially expressed metabolites and 123 significant proteins were identified. Integrated analysis of differentially expressed metabolites and proteins by IPA revealed molecular changes mainly associated with synaptic plasticity, phospholipase c signaling, and glutamine degradation I. We compared the metabolites in the amygdala with those in the hippocampus and prefrontal cortex from our previous studies and found two common metabolites: arachidonic acid and N-acetyl- l -aspartic acid among these three brain regions. Conclusion Our study revealed the presence of depressive-like behaviors and molecular changes of amygdala in the CSDS rat model, which may provide further insights into the pathogenesis of depression, and help to identify potential targets for antidepressants.

Background & Aims Drug-induced liver injury (DILI) is a leading cause of acute liver failure, and treatment of DILI remains a challenge. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream whose physiological role in protection against DILI has not been examined. Methods Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of MG53 or RIPK3. Live cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. Results Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. Conclusions Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. Lay Summary Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to the medical society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver-cell protection.

Pandemics have become more frequent and more complex during the twenty-first century. Posttraumatic stress disorder (PTSD) following pandemics is a significant public health concern. We sought to provide a reliable estimate of the worldwide prevalence of PTSD after large-scale pandemics as well as associated risk factors, by a systematic review and meta-analysis. We systematically searched the MedLine, Embase, PsycINFO, Web of Science, CNKI, WanFang, medRxiv, and bioRxiv databases to identify studies that were published from the inception up to August 23, 2020, and reported the prevalence of PTSD after pandemics including sudden acute respiratory syndrome (SARS), H1N1, Poliomyelitis, Ebola, Zika, Nipah, Middle Eastern respiratory syndrome coronavirus (MERS-CoV), H5N1, and coronavirus disease 2019 (COVID-19). A total of 88 studies were included in the analysis, with 77 having prevalence information and 70 having risk factors information. The overall pooled prevalence of post-pandemic PTSD across all populations was 22.6% (95% confidence interval (CI): 19.9-25.4%, I2: 99.7%). Healthcare workers had the highest prevalence of PTSD (26.9%; 95% CI: 20.3-33.6%), followed by infected cases (23.8%: 16.6-31.0%), and the general public (19.3%: 15.3-23.2%). However, the heterogeneity of study findings indicates that results should be interpreted cautiously. Risk factors including individual, family, and societal factors, pandemic-related factors, and specific factors in healthcare workers and patients for post-pandemic PTSD were summarized and discussed in this systematic review. Long-term monitoring and early interventions should be implemented to improve post-pandemic mental health and long-term recovery.

Adolescent depression is a common and serious mental disorder with unique characteristics that are distinct from adult depression. The adult non-human primate stress-induced model of depressive-like behavior is an excellent model for the study of mechanisms; however, an adolescent nonhuman primate model is still lacking. Ten male adolescent cynomolgus monkeys were divided into a chronic unpredictable mild stress (CUMS, n = 5) group and a control (CON, n = 5) group by age and weight-matched pairs. The CUMS group was exposed to multiple unpredictable mild stressors for five cycles over 55 days. At baseline, there were no differences between CUMS and CON groups. At endpoint, the CUMS group demonstrated significantly higher depressive-like behavior (huddle posture), and significantly lower locomotion compared with the CON group. Furthermore, depressive-like behavior increased from baseline to endpoint in the CUMS group, but not changed in the CON group. In the attempt for apple test, the CUMS group made significantly fewer attempts for the apple than the CON group. In the human intruder test, the CUMS group showed significantly higher anxiety-like behaviors in the stare phase than the CON group. Hair cortisol level was significantly higher in the CUMS group than the CON group at endpoint, and was also elevated from baseline to endpoint. Metabolic profiling of plasma at endpoint identified alterations in metabolite pathways which overlapped with those of adolescent depression patients. CUMS can induce depressive-like and anxiety-like behaviors, hypercortisolemia, and metabolic perturbations in adolescent cynomolgus monkeys. This is a promising model to study the mechanisms underlying adolescent depression.

Background Porcine reproductive and respiratory syndrome virus (PRRSV) infection can cause severe reproductive failure in sows and respiratory distress in pigs of all ages, leading to major economic losses. To date, there are still no effective strategies to prevent and control PRRSV. Antibody-dependent enhancement (ADE), a phenomenon in which preexisting non-neutralizing antibodies or sub-neutralizing antibodies facilitate virus entry and replication, may be a significant obstacle in the development of effective vaccines for many viruses, including PRRSV. However, the contribution of ADE to PRRSV infection remains controversial, especially in vivo. Whether attenuated PRRSV vaccines prevent or worsen subsequent disease in pigs infected by novel PRRSV strains requires more research. In the present study, in vivo experiments were conducted to evaluate ADE under different immune statuses, which were produced by waiting different lengths of time after vaccination with a commercially available attenuated highly pathogenic PRRSV (HP-PRRSV) vaccine (JXA1-R) before challenging the pigs with a novel heterologous NADC30-like strain. Results Piglets that were vaccinated before being challenged with PRRSV exhibited lower mortality rates, lower body temperatures, higher bodyweight gain, and lower viremia. These results demonstrate that vaccination with JXA1-R alleviated the clinical signs of PRRSV infection in all vaccinated groups. Conclusions The obtained data indicate that the attenuated vaccine test here provided partial protection against the NADC30-like strain HNhx. No signs of enhanced PRRSV infection were observed under the applied experimental conditions. Our results provide some insight into the molecular mechanisms underlying vaccine-induced protection or enhancement in PRRSV.

Objective. To investigate the changes of intestinal flora in elderly patients with Alzheimer’s disease and liver cancer and its correlation with abnormal gastrointestinal motility. Methods. From January 2018 to December 2020, 102 elderly patients with Alzheimer’s disease and liver cancer were selected as the observation group. Eighty-nine healthy patients during the same period were selected as the control group. The two groups of intestinal flora (intestinal microbial diversity) were detected by real-time fluorescent quantitative PCR (RT-qPCR) and high-throughput sequencing. The two groups of serum motilin (MTL) and gastrin (GAS) levels were measured by the Hitachi automatic biochemical analyzer 7600. Pearson correlation analysis software was used to analyze the relationship between changes in the intestinal flora and gastrointestinal motility in elderly patients with Alzheimer’s disease and liver cancer. Results. The contents of Bifidobacteria and Lactobacilli in the observation group were lower than those in the control group, and the contents of Escherichia coli, Helicobacter pylori, and Streptococcus were higher than those in the control group. The Chaol index and Shannon index in the observation group were higher than those in the control group. The gastrointestinal motility levels MTL and GAS of the observation group were higher than those of the control group. The results of Pearson correlation analysis showed that the Chaol index and Shannon index of elderly patients with Alzheimer’s disease and liver cancer were positively correlated with MTL and GAS. Conclusion. Elderly patients with Alzheimer’s disease and liver cancer often have changes in the intestinal flora, which are correlated with abnormal gastrointestinal motility. Strengthening the analysis of changes in patients’ intestinal flora can enhance clinical medication knowledge and improve gastrointestinal motility in patients.

Background Anxiety disorder is the most prevalent mental disorder among children and adolescents, causing significant psychosocial problems and physical health conditions. Cognitive behavioral therapy (CBT) is an effective treatment for anxiety disorder in children and adolescents. And parent-only CBT is an alternative treatment for childhood anxiety disorder, which includes psychologists and parents rather than children in the treatment. As a new type of CBT, parent-only CBT has some advantages. However, it remains unclear whether parent-only CBT interventions are effective for treating children and adolescents with anxiety disorder. Methods In this study, we evaluated the efficacy (the mean change scores of the anxiety rating scale from baseline to post-treatment, standardized mean difference SMD) and acceptability (the proportion of patients in the treatment group who withdrew from treatment early for any reason, risk ratios RRs) of parent-only cognitive behavioral therapy (CBT) for children and adolescents with anxiety disorder. We searched electronic databases, including PubMed, Cochrane Library, Embase, Web of Science, ProQuest, and PsycINFO from inception to June 2019. We included randomized controlled trials (RCTs) comparing parent-only CBT either with waitlist (WL), or CBT with parents in children and adolescents with anxiety disorder. Results Finally, six RCTs with 407 participants were included in the meta-analyses. In terms of efficacy, pooled analyses indicated that parent-only CBT was significantly more effective than WL for reducing anxiety symptoms with SMD of − 0.72 (95% CI − 1.41 to − 0.03, p = 0.04), and more remission rate with RR of 4.33 (37.96% vs. 6.85, 95% CI 1.82 to 10.27, p = 0.0009) at post-treatment. And our analyses showed no evidence that parent-only CBT had significantly greater efficacy than CBT with parents with SMD of 0.21 (95% CI − 0.09 to 0.50, p = 0.17). Acceptability in the parent-only CBT group was not significantly different to the WL group with RR of 0.92 (95% CI 0.52 to 1.62, p = 0.77), and was significantly worse than in the CBT with parents group with RR of 1.93 (95% CI 1.05 to 3.57, p = 0.03). Conclusions Current evidence indicates that parent-only CBT can be an alternative and acceptable intervention for treating children and adolescents with anxiety disorder.

Major depressive disorder is a serious and complex mental illness, and multiple brain regions are involved in its pathogenesis. There is increasing evidence that the amygdala is involved in depression; however, the underlying molecular mechanisms remain unclear. In this study, we applied a combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomic and isobaric tags for relative and absolute quantitation (iTRAQ) proteomic to study changes in the amygdala in a chronic unpredictable mild stress (CUMS) rat model of depression. Differential analysis identified 42 metabolites and 171 proteins that were differentially expressed in the CUMS and control groups. Integrated analyses revealed two major changes in the amygdala of CUMS rats: (1) perturbations in amino acids and carbohydrate metabolism, transport-/catabolism-related proteins activity, and metabolic enzyme activity; (2) abnormal expression of synaptogenesis and oxidative phosphorylation-associated proteins.

Cutaneous lupus erythematosus (CLE) is an autoimmune disease with a broad range of cutaneous manifestations. In skin lesions of CLE, keratinocytes primarily undergo apoptosis. Interferon-κ(IFN-κ) is belonged to type I interferons (type I IFNs) and is selectively produced by keratinocytes. Recently, keratinocytes selectively produced IFN-κ is identified to be a key to trigger type I interferon responses in CLE. Other immune cells such as plasmacytoid dendritic cells (pDCs) are identified to be relevant origin of type I interferons (type I IFNs) which are central to the development of CLE lesions and responsible for mediating Th1 cell activity. Other types of cells such as neutrophils, B cells and Th17 cells also are involved in the development of this disease. The close interaction of those cells composes a comprehensive and complicated network in CLE. In this review, we discussed the aberrant distribution and function of different cells types involved in this disease and will offer a new direction for research and therapy in the near future.