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Studying the role of psychological resilience in self-perceived stress and mental disorders among family members of medical workers can help us understand its importance in mental health care and guide us to develop psychological intervention strategies for family members of medical workers.A total of 671 family members of medical workers were enrolled. Self-perceived stress, resilience, depression symptoms, anxiety symptoms, and post-traumatic stress disorder (PTSD) symptoms were measured in our research.The prevalence of anxiety, depression, and PTSD symptoms among relatives of medical workers were 49.0 %, 12.2 %, and 20.3 % respectively during the COVID-19 epidemic. According to the Multivariate regression model, compared with family members of doctor, family members of nurse and medical technologists were more likely to report anxiety symptoms. Female members of medical staff were more likely to have PTSD symptoms than male counterparts; and family members of medical technologist appeared to less likely have PTSD symptoms than family members of either doctor or nurse. The mediation analysis confirmed that mental resilience mediated the relationship between self-perceived stress and anxiety symptoms.Single cross-sectional study design without the follow-up comparative analysis, only self-reported measurements were adopted, and inadequate pre-set demographic variables.To the best of our knowledge, our study firstly demonstrated the risk of psychological distress present in the family members of medical providers during the COVID-19 epidemic. Meanwhile, our findings highlighted the importance of mental resilience in family members of frontline medical workers as it mediated the relationship between self-perceived stress and anxiety symptoms.

It is an intriguing approach to target the ecto-5'-nucleotidase CD73 to confer synergetic beneficial survival in cancer patients, along with clinically established immunotherapy targets. In this study, a fully human, subnanomolar affinity CD73 antibody IBI325 was developed using the yeast display platform. Compared with Oleclumab, IBI325 was equivalent in hCD73 affinity and more potent in cell-bound and soluble CD73 enzymatic inhibition, and no hook effects were observed. Correspondingly, adenosine monophosphate-mediated immune suppression was reversed by IBI325, and significant T cell proliferation and release of cytokines were observed. Also, IBI325 enhanced the T cell recall response by inducing interferon-γ secretion. The antitumor efficacy of IBI325 was investigated in a hPBMC-reconstituted NOG mouse model, and a hCD73 knock-in mouse model. Consequently, IBI325 induced a significant tumor regression by inducing intratumoral immune cell expansion, and a combo therapy of IBI325 and aPD-1 was superior in efficacy than aCD73 or aPD-1 monotherapy. Additionally, the binding epitopes of CD73 to IBI325 were distinct from previously reported aCD73 therapeutics. IBI325 displayed acceptable pharmacokinetics and sufficient tolerable safety profiles to support clinical development. In conclusion, the pharmacology, pharmacokinetics, and toxicity profiles of IBI325 with complete CD73 inhibition were characterized, and encouraging preclinical outcomes were reported.

A variety of methods based on air quality models, including tracer methods, the brute-force method (BFM), decoupled direct method (DDM), high-order decoupled direct method (HDDM), response surface models (RSMs) and so on forth, have been widely used to study the transport of air pollutants. These methods have good applicability for the transport of air pollutants with simple formation mechanisms. However, differences in research conclusions on secondary pollutants with obvious nonlinear characteristics have been reported. For example, the tracer method is suitable for the study of simplified scenarios, while HDDM and RSMs are more suitable for the study for nonlinear pollutants. Multiple observation techniques, including conventional air pollutant observation, lidar observation, air sounding balloons, vehicle-mounted and ship-borne technology, aerial surveys, and remote sensing observations, have been utilized to investigate air pollutant transport characteristics with time resolution as high as 1 sec. In addition, based on a multi-regional input-output model combined with emission inventories, the transfer of air pollutant emissions can be evaluated and applied to study the air pollutant transport characteristics. Observational technologies have advantages in temporal resolution and accuracy, while modeling technologies are more flexible in spatial resolution and research plan setting. In order to accurately quantify the transport characteristics of pollutants, it is necessary to develop a research method for interactive verification of observation and simulation. Quantitative evaluation of the transport of air pollutants from different angles can provide a scientific basis for regional joint prevention and control.

The purpose of this study was to assess the effects of butylphthalide on cognitive deficiencies following sleep deprivation (SD).The influence of butylphthalide on cognitive function changes in SD-induced mice was evaluated. Nissl staining and HE staining were used to analyze the morphology changes of the hippocampal formation. The changes in cognitive function of SD-induced mice were detected by the Morris water maze. Inflammatory factors, apoptosis, and signal pathway-related proteins in the mice hippocampus were detected.SD increased escape latency and path length for mice to reach the hidden platform, decreased the time and range of activity in the target area, and reduced the number and time for traversing the target area. Butylphthalide significantly improved the cognitive decline of SD-induced spatial exploration and learning/memory ability. Butylphthalide also decreased the degeneration of hippocampal neurone, neuronal apoptosis, and inflammatory factors in hippocampus tissue. In addition, butylphthalide activated the nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase 1 (HO-1) pathway.Butylphthalide alleviated SD-induced cognitive decline, neuronal apoptosis, and inflammation by activating Nrf2/HO-1 pathway. We suggested that butylphthalide may be a prospective candidate for the alleviation of cognitive deficit induced by SD.

Sepsis remains one of the leading causes of death globally, in spite of advanced developments in intensive care and better understandings of pathophysiology related to sepsis. There is no special treatment or drug available for sepsis, currently. Under normal circumstances, neutrophil is a major player in acute infection control. However, during sepsis, the migration abilities and antimicrobial functions of neutrophils are impaired, resulting in a dysregulated immune response. Recent studies have indeed demonstrated that blocking or reversing neutrophil migration and impaired antibacterial function can improve the outcomes in septic animal models. This article systemically synthesized information regarding related factors and signaling involved in the functions of neutrophils in sepsis. This review also discussed the possibility that neutrophils be used as a marker for specific diagnosis and/or prediction of the outcomes of sepsis.

Background Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. Methods We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. Results Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. Conclusions CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.

This study compared the diagnostic accuracy of percutaneous fistula contrast-enhanced ultrasound (CEUS) combined with 360° 3-D transrectal ultrasound (TRUS) imaging (CEUS + 360°-TRUS) with that of conventional transrectal ultrasound in the diagnosis of complex anal fistulas. A total of 156 patients clinically diagnosed with complex anal fistula from January 2020 to December 2021 were studied and randomly divided into an experimental group (n = 82) and a control group (n = 74). Patients in the experimental group were examined by percutaneous fistula CEUS combined with CEUS + 360°-TRUS, while patients in the control group were examined using TRUS. The detection of fistulas (main tract, branch and internal orifice) and the accuracy of Parks classification were compared between the two groups. Recurrences were followed up at 1, 3 and 6 mo after the surgery. A total of 156 patients were included, aged 23-68 y (average: 37.7 ± 18.2 y). In both groups, the course of disease waslt;1 mo in 128 cases, 1-2 mo in 22 cases andgt;3 mo in 6 cases. A total of 474 fistulas were confirmed by surgery in the aforementioned patients, including 224 main fistulas, 250 branch pipes and 254 internal orifices. The CEUS + 360°-TRUS group had 96.87%, 90.41% and 90.14% diagnostic accuracy for the main tract, branch and internal orifice, which was statistically significant (plt; 0.001) compared with the 85.00%, 70.00% and 72.46% for the TRUS group, respectively. The overall accuracy of Parks classification of anal fistula in the CEUS + 360°-TRUS group was significantly higher than that in the TRUS group (90.24% vs. 78.38%, plt; 0.001). After 6 mo of follow-up, the recurrence rate in the CEUS + 360°-TRUS group was 4.87%, and the recurrence rate in the TRUS group was 18.91%. Percutaneous fistula CEUS combined with transrectal 360° 3-D imaging has significantly higher accuracy than conventional TRUS in the diagnosis of complex anal fistula, especially for anal fistula branches, internal openings and Parks classification and is beneficial in reducing post-operative occurrence of complex anal fistulas.

Uncontrollable hemorrhage and subsequent wound infection are severe threats to life, especially for the deep noncompressible massive bleeding. However, traditional hemostatic materials are ineffective for extreme bleeding and subsequent wound infection. Here, we prepared an injectable shape memory hydroxyethyl cellulose/soy protein isolate based composite sponge (EHSS) for rapid noncompressible hemorrhage and prevention of wound infection. The nano silver (AgNPs)-loaded shape memory sponge (EHP@Ag) was fabricated by mussel-inspired polydopamine coating EHSS sponge, then reducing and immobilizing AgNPs in situ. The EHP@Ag sponges showed rapid blood-triggered shape recovery speed, which is beneficial for administering noncompressible hemorrhage. The results of the hemostatic experiment in vivo demonstrated that EHP@Ag sponge exhibited a desirable hemostasis effect (hemostasis time: 22.75 ± 3.86 s, blood loss: 285.25 ± 24.93 mg) compared to the commercial gelatin sponge (hemostasis time: 49.25 ± 3.30 s, blood loss: 755.50 ± 24.45 mg). Meanwhile, the EHP@Ag sponge has an efficient antibacterial property. Furthermore, the antibacterial experiment in vivo showed that the EHP@Ag sponges could kill bacteria effectively and reduce the bacteria-induced inflammatory response. In summary, the shape memory sponges can quickly control bleeding and avoid bacterial infection, which shows great potential for clinical application as a multifunctional hemostatic agent.

Appropriate dosage of vancomycin is critical for safety and efficacy in treating infectious diseases. Various population pharmacokinetic (PPK) models have been established. To lay a foundation for the clinical application, it is important to perform external validation of the published model. The aim of this study was to find the most suitable vancomycin PPK model for treatment of infection in China amongst all studied models developed for adults.A systematic literature search of published population vancomycin pharmacokinetic analyses was performed using the PubMed database. The identified models were evaluated in ten independent cohorts from China. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis. The median prediction error (MPE), the distribution of prediction error (PE), and normalized prediction distribution errors (NPDE) were calculated and described. Predictive performance was evaluated by bias and accuracy.A total of 449 vancomycin concentrations from 397 infected participants were used for external validation. The MPE of the three models from the Chinese population was less than 10%. Half of the models had an acceptable MPE. For patients with different site infections and different renal functions, each model differed in its predictive ability to some extent. The NPDE results showed that all models had an obvious bias.None of the models had good performance in both prediction- and simulation-based diagnostics. Carrying out sufficient external validation of the PPK model before clinical application is of utmost importance. In clinical practice, the model's population closest to the application population should be used.

The pathogenesis of Hirschsprung's disease (HSCR) remains unclear but might involve genes participating in neural crest development. Gene methylation controls the expression of many genes and is involved in the development and migration of neural crest cells, but the involvement of demethylation in HSCR is unknown. This study aimed to investigate the expression of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) (a demethylation protein) in patients with HSCR.This is a retrospective study of surgical specimens from paediatric patients with and without HSCR (e.g., intussusception and incarcerated hernia) obtained from 07/2015 to 08/2017. TET1 expression was determined by qRT-PCR, western blotting, and immunohistochemistry. The levels of 5-hydroxymethylcytosine were determined by the dot blot assay.The specimens of 35 patients with HSCR and 25 controls were collected. The median TET1 mRNA expression values were 1.028 [HSCR-stenotic (S)], 0.908 [HSCR-dilated (D)], and 0.467 (control) (HSCR-S vs. control: P = 0.002; HSCR-D vs. control: P = 0.008; HSCR-S vs. HSCR-D: P = 0.44). TET1 protein levels followed a similar pattern. The intensity of immunostaining identified higher expression of TET1 in HSCR colon tissues compared with control tissues. The 5-hmC levels in HSCR stenotic segment samples were significantly higher than those in controls.The expression of TET1 is higher in paediatric patients with HSCR than in controls. DNA demethylation initiated by TET1 may be related to HSCR, which demonstrates that TET1 may play a role in the development of HSCR.

Epithelial-to-mesenchymal transition (EMT) activation is important in cancer progression and metastasis. Evidence indicates that nc886 is a representative Pol III gene that processes microRNA products via Dicer and further downregulates its target gene transforming growth factor- β1 (TGF-β1), which is the most prominent inducer of EMT in prostate cancer (PC). Consistent with the previous literature, we found that nc886 downregulation was strongly associated with metastatic behavior and showed worse outcomes in PC patients. However, little is known about the association between nc886 and the EMT signaling pathway. We developed a PC cell model with stable overexpression of nc886 and found that nc886 changed cellular morphology and drove MET. The underlying mechanism may be related to its promotion of SNAIL protein degradation via ubiquitination, but not to its neighboring genes, TGFβ–induced protein (TGFBI) and SMAD5, which are Pol II-transcribed. TGF-β1 also override nc886 promotion of MET via transient suppression the transcription of nc886, promotion of TGFBI or increase in SMAD5 phosphorylation. Both nc886 inhibition and TGFBI activation occur regardless of their methylation status. The literature suggests that MYC inhibition by TGF-β1 is attributed to nc886 downregulation. We incidentally identified MYC-associated zinc finger protein (MAZ) as a suppressive transcription factor of TGFBI, which is controlled by TGF-β1. We elucidate a new mechanism of TGF-β1 differential control of Pol II and the transcription of its neighboring Pol III gene and identify a new EMT unit consisting of nc886 and its neighboring genes.

Chronic kidney disease (CKD) is recognized as a serious global health problem due to its high prevalence and all-cause mortality. The aim of this research was to identify critical biomarkers and construct an integrated model for the early prediction of CKD. By using existing RNA-seq data and clinical information from CKD patients from the Gene Expression Omnibus (GEO) database, we applied a computational technique that combined the random forest (RF) and artificial neural network (ANN) approaches to identify gene biomarkers and construct an early diagnostic model. We generated ROC curves to compare the model with other markers and evaluated the associations of selected genes with various clinical properties of CKD. Moreover, we highlighted two biomarkers involved in energy metabolism pathways: pyruvate dehydrogenase kinase 4 (PDK4) and zinc finger protein 36 (ZFP36). The downregulation of the identified key genes was subsequently confirmed in both unilateral ureteral obstruction (UUO) and ischemia reperfusion injury (IRI) mouse models, accompanied by decreased energy metabolism. In vitro experiments and single-cell sequencing analysis proved that these key genes were related to the energy metabolism of proximal tubule cells and were involved in the development of CKD. Overall, we constructed a composite prediction model and discovered key genes that might be used as biomarkers and therapeutic targets for CKD.

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.