Search

Abstract In this study, we investigated the status and influencing factors of coronavirus disease 2019 (COVID-19) vaccination in patients with chronic obstructive pulmonary disease (COPD). A questionnaire on COVID-19 vaccination in patients with COPD was developed. The clinical characteristics, COVID-19 vaccination status, other relevant vaccinations, and vaccination status of the patients with COPD were collected anonymously. Logistic regression analysis was used to analyze the factors influencing COVID-19 vaccination in patients with COPD. There were 1898 returned questionnaires, of which 1874 were valid. The proportion of patients who completed the COVID-19 vaccination program was 78.60%. Factors influencing the COVID-19 vaccination rate were: the age of individuals who were 75–85 years old and > 85 years old, acute exacerbation 3–4 times in the previous year, comorbid cardiovascular and endocrine system diseases, failure to take regular medication for COPD, application of non-invasive ventilation machines, believing that their current health condition has deteriorated, believing that the current COVID-19 vaccine is not safe, medical staff not specifying whether they would recommend vaccination against COVID-19, medical staff not recommending the COVID-19 vaccine, and fear of adverse reactions and aggravation of COPD. Patients with COPD had a high COVID-19 vaccination rate in China, whereas patients with pneumonia, influenza, and herpes zoster had a low vaccination rate. Improving the patients’ understanding of the safety and effectiveness of the vaccine and promoting effective communication between medical staff and patients would help increase the vaccination rate of patients with COPD.

Objective: An alternative to conventional posterior lumbar interbody fusion (PLIF) is a PLIF with transpedicular oblique screw fixation system. An assessment of new fixation system's viability and efficacy is conducted through a comparison of its biomechanical properties with those of conventional PLIF. Method: A comprehensive finite element model (FEM) of the lumbar regions L1-L5 was developed and the surgical segment L3-L4 was chosen to comprise the surgical models of both traditional PLIF and new PLIF. In new PLIF model, an analysis was conducted on segmental range of motion (RoM), cage stress, inferior endplates stress, vertebral stress, and internal fixation stress. Three-dimensional printers are utilized to fabricate and assemble the fusion cage and vertebrae, and compression test machines are employed to execute physiological load and extreme load experiments on new PLIF, so as to verify the accuracy of the FEM analysis and the mode of fatigue exhibited by new PLIF. Results: In new PLIF, the maximum stress on the inferior endplates under physiological loads was reduced in comparison to conventional PLIF. While the maximum stress on the cage, vertebral body, and screw increased, it remained within an acceptable range. The experimental data indicates that new fixation system can endure a vertical load exceeding 2800 N and an ultimate bending moment of 77 Nm. Conclusion: The new PLIF exhibits a comparable RoM to its predecessor, simultaneously mitigating inferior endplate stress and accommodating physiological loads, which reduce the amount of surgical incision and fusion fixation instruments. Consequently, it emerges as a sanguine surgical approach to fuse the degenerative lumbar spine.

Summary: Background: Adolescent idiopathic scoliosis (AIS) is the most common spinal disorder in children, characterized by insidious onset and rapid progression, which can lead to severe consequences if not detected in a timely manner. Currently, the diagnosis of AIS primarily relies on X-ray imaging. However, due to limitations in healthcare access and concerns over radiation exposure, this diagnostic method cannot be widely adopted. Therefore, we have developed and validated a screening system using deep learning technology, capable of generating virtual X-ray images (VXI) from two-dimensional Red Green Blue (2D-RGB) images captured by a smartphone or camera to assist spine surgeons in the rapid, accurate, and non-invasive assessment of AIS. Methods: We included 2397 patients with AIS and 48 potential patients with AIS who visited four medical institutions in mainland China from June 11th 2014 to November 28th 2023. Participants data included standing full-spine X-ray images captured by radiology technicians and 2D-RGB images taken by spine surgeons using a camera. We developed a deep learning model based on conditional generative adversarial networks (cGAN) called Swin-pix2pix to generate VXI on retrospective training (n = 1842) and validation (n = 100) dataset, then validated the performance of VXI in quantifying the curve type and severity of AIS on retrospective internal (n = 100), external (n = 135), and prospective test datasets (n = 268). The prospective test dataset included 268 participants treated in Nanjing, China, from April 19th, 2023, to November 28th, 2023, comprising 220 patients with AIS and 48 potential patients with AIS. Their data underwent strict quality control to ensure optimal data quality and consistency. Findings: Our Swin-pix2pix model generated realistic VXI, with the mean absolute error (MAE) for predicting the main and secondary Cobb angles of AIS significantly lower than other baseline cGAN models, at 3.2° and 3.1° on prospective test dataset. The diagnostic accuracy for scoliosis severity grading exceeded that of two spine surgery experts, with accuracy of 0.93 (95% CI [0.91, 0.95]) in main curve and 0.89 (95% CI [0.87, 0.91]) in secondary curve. For main curve position and curve classification, the predictive accuracy of the Swin-pix2pix model also surpassed that of the baseline cGAN models, with accuracy of 0.93 (95% CI [0.90, 0.95]) for thoracic curve and 0.97 (95% CI [0.96, 0.98]), achieving satisfactory results on three external datasets as well. Interpretation: Our developed Swin-pix2pix model holds promise for using a single photo taken with a smartphone or camera to rapidly assess AIS curve type and severity without radiation, enabling large-scale screening. However, limited data quality and quantity, a homogeneous participant population, and rotational errors during imaging may affect the applicability and accuracy of the system, requiring further improvement in the future. Funding: National Key R&D Program of China, Natural Science Foundation of Jiangsu Province, China Postdoctoral Science Foundation, Nanjing Medical Science and Technology Development Foundation, Jiangsu Provincial Key Research and Development Program, and Jiangsu Provincial Medical Innovation Centre of Orthopedic Surgery.

Abstract Preterm labor, a condition associated with various risk factors such as a history of prior preterm birth (PTB) and multiple pregnancies, has recently seen an increasing focus on its potential link with dyslipidemia. This study aims to investigate the relationship between dyslipidemia in expectant mothers and the risks of PTB. We studied 6963 mothers who gave birth at the International Peace Maternal and Child Health Hospital of Shanghai Jiaotong University School of Medicine in 2020, among which, 437 women had PTB. We extracted clinical and lipid data from electronic records, using multivariable logistic regression and restricted cubic spline models to explore the link between lipid concentrations (by quartiles) in pregnancy stages and PTB risk. The PTB rate was 6.3%. Early pregnancy in the PTB group showed elevated ApoA, ApoB, CHOL, LDL, and TG levels compared to controls (all P

Estrogen receptor-positive (ER+) breast cancer seriously endangers the women's physical and mental health worldwide and ER targeting therapy is vital. Here, we found that a citrus polymethoxyflavones (PMFs)-rich hydrolysate (C–H) and its major components (nobiletin and 3-methoxynobiletin) potently degrade ERα protein via the ubiquitin-proteasome pathway, thereby impairing the proliferation of ER+ breast cancer cells. Moreover, our study exhibited that C–H combined with tamoxifen (TAM) inhibited the cell proliferation of ER+ breast cancer in vitro. It was further confirmed that C–H decreased tumor growth of ER+ breast cancer in tumor-bearing 129 mice in vivo and improved the efficacy of tamoxifen. Our study revealed that the citrus PMFs have potential applications as pharmaceutical and healthcare products in breast cancer treatment by targeting ERα protein degradation.

Objective: Inhaled corticosteroids (ICS) are widely used in chronic obstructive pulmonary disease (COPD) patients as a treatment option. However, ICS may also increase the risk of pneumonia and alter the composition of airway microbiota. In clinical application, the overuse of ICS exists pervasively and may potentially lead to adverse effects. Whether the long-term use of ICS confers enough benefit to COPD patients to justify its use so far remains unknown. Therefore, this study employed a single-center retrospective cohort study to compare alterations in airway function and the sputum microbial community structure between COPD patients who had undergone either long-term or short-term treatment with ICS.Methods: Sixty stable COPD patients who had used ICS were recruited and classified into the long-term use group (more than 3 months) and short-term use group (less than 3 months). The demographic features and clinical information of the subjects were investigated and their sputum samples were collected and subjected to metagenomic next-generation sequencing (mNGS).Results: The study found that compared with short-term ICS use, long-term ICS use did not further improve the clinical airway function, decrease the number of acute exacerbations, or decrease hospital readmission. In terms of sputum microbiota, the long-term use of ICS significantly altered the beta diversity of the microbial community structure (p < 0.05) and the top three phyla differed between the two groups. At the genus level, long-term ICS induced higher relative abundances of Abiotrophia, Schaalia, Granulicatella, Mogibacterium, Sphingobium, and Paraeggerthella compared to short-term ICS use. Additionally, alpha diversity was positively associated with clinical airway indicators (pre-bronchodilatory FEV1 and pre-bronchodilatory FVC) in the long-term ICS group. The relative abundances of Rothia, Granulicatella, Schaalia, and Mogibacterium genera had positive correlations with the eosinophil % (of all white blood cells). Conclusion: This study reveals the effect of long-term and short-term ICS use on sputum microbiota among COPD patients and provides a reference for the appropriate application of clinical ICS treatment in COPD patients.

When encountering heavy oil reservoirs during drilling, due to the change in pressure difference inside the well, heavy oil will invade the drilling fluid, and drilling fluid will spill into the reservoir along the formation fractures, affecting the drilling process. A supramolecular polymer gel-based temporary plugging agent was prepared using acrylamide (AM), butyl acrylate (BA), and styrene (ST) as reacting monomers, N, N-methylenebisacrylamide (MBA) as a crosslinking agent, ammonium persulfate (APS) as an initiator, and poly(vinyl alcohol) (PVA) as a non-covalent component. A supermolecular polymer gel with a temperature tolerance of 120 °C and acid solubility of 90% was developed. The experimental results demonstrated that a mechanically robust, thermally stable supramolecular polymer gel was successfully synthesized through the copolymerization of AM, BA, and ST, as well as the in situ formation hydrogen bonding between poly (AM-co-BA-co-ST) and PVA, leading to a three-dimensional entangled structure. The gel-forming solution possessed excellent gelling performance even in the presence of a high content of salt and heavy oil, demonstrating superior resistance to salt and heavy oil under harsh reservoir conditions. High-temperature and high-pressure plugging displacement experiments proved that the supramolecular polymer gel exhibited high pressure-bearing capacity, and the blocking strength reached 5.96 MPa in a wedge-shaped fracture with a length of 30 cm. Furthermore, the dissolution rate of the supramolecular polymer gel was as high as 96.2% at 120 °C for 48 h under a 15% HCl solution condition.

Scoliosis, characterized by spine deformity, is most common in adolescent idiopathic scoliosis (AIS). Manual Cobb angle measurement limitations underscore the need for automated tools. This study employed a vertebral landmark extraction method and Feedforward Neural Network (FNN) to predict scoliosis progression in 79 AIS patients. The novel intervertebral angles matrix format showcased results. The mean absolute error for the intervertebral angle progression was 1.5 degrees, while the Pearson correlation of the predicted Cobb angles was 0.86. The accuracy in classifying Cobb angles (45°) was 0.85, with 0.65 sensitivity and 0.91 specificity. The FNN demonstrated superior accuracy, sensitivity, and specificity, aiding in tailored treatments for potential scoliosis progression. Addressing FNNs’ over-fitting issue through strategies like “dropout” or regularization could further enhance their performance. This study presents a promising step towards automated scoliosis diagnosis and prognosis.

Musculoskeletal soft tissue injuries are very common and usually occur during both sporting and everyday activities. The intervention of adjuvant therapies to promote tissue regeneration is of great importance to improving people’s quality of life and extending their productive lives. Though many studies have focused on the positive results and effectiveness of the LIPUS on soft tissue, the molecular mechanisms standing behind LIPUS effects are much less explored and reported, especially the intracellular signaling pathways. We incorporated all research on LIPUS in soft tissue diseases since 2005 and summarized studies that uncovered the intracellular molecular mechanism. This review will also provide the latest evidence-based research progress in this field and suggest research directions for future experiments.

Objective: Exercise can produce a large number of cytokines that may benefit cancer patients, including Interleukin 15 (IL-15). IL-15 is a cytokine that has multiple functions in regulating the adaptive and innate immune systems and tumorigenesis of lung and breast cancers. However, the roles of IL-15 in other types of cancer remain unknown. In this article, we try to systematically analyze if IL-15 is a potential molecular biomarker for predicting patient prognosis in pan-cancer and its connection with anti-cancer effects of exercise.Methods: The expression of IL-15 was detected by The Cancer Genome Atlas (TCGA) database, Human protein Atlas (HPA), and Genotype Tissue-Expression (GTEX) database. Analysis of IL-15 genomic alterations and protein expression in human organic tissues was analyzed by the cBioPortal database and HPA. The correlations between IL-15 expression and survival outcomes, clinical features, immune-associated cell infiltration, and ferroptosis/cuproptosis were analyzed using the TCGA, ESTIMATE algorithm, and TIMER databases. Gene Set Enrichment Analysis (GSEA) was performed to evaluate the biological functions of IL-15 in pan-cancer.Results: The differential analysis suggested that the level of IL-15 mRNA expression was significantly downregulated in 12 tumor types compared with normal tissues, which is similar to the protein expression in most cancer types. The high expression of IL-15 could predict the positive survival outcome of patients with LUAD (lung adenocarcinoma), COAD (colon adenocarcinoma), COADREAD (colon and rectum adenocarcinoma), ESCA (esophageal carcinoma), SKCM (skin cutaneous melanoma), UCS (uterine carcinosarcoma), and READ (rectum adenocarcinoma). Moreover, amplification was found to be the most frequent mutation type of IL-15 genomic. Furthermore, the expression of IL-15 was correlated to the infiltration levels of various immune-associated cells in pan-cancer assessed by the ESTIMATE algorithm and TIMER database. In addition, IL-15 is positively correlated with ferroptosis/cuproptosis-related genes (ACSL4 and LIPT1) in pan-cancer. Levels of IL-15 were reported to be elevated in humans for 10–120 min following an acute exercise. Therefore, we hypothesized that the better prognosis of pan-cancer patients with regular exercise may be achieved by regulating level of IL-15.Conclusion: Our results demonstrated that IL-15 is a potential molecular biomarker for predicting patient prognosis, immunoreaction, and ferroptosis/cuproptosis in pan-cancer and partly explained the anti-cancer effects of exercise.

BackgroundPrevious studies have probed the brain static activity pattern in bipolar disorder across different states. However, human intrinsic brain activity is time-varying and dynamic. There is a lack of knowledge about the brain dynamical pattern in bipolar disorder across different mood states.MethodsThis study used the dynamical degree centrality (dDC) to investigate the resting-state whole-brain dynamical pattern voxel-wise in a total of 62 bipolar disorder [28 bipolar depression (BD), 13 bipolar mania (BM), 21 bipolar euthymia (BE)], and 30 healthy controls (HCs). One-way analysis of variance (ANOVA) was applied to explore the omnibus differences of the dDC pattern across all groups, and Pearson’s correlation analysis was used to evaluate the relationship between the dDC variability in detected regions with clinical symptom severity.ResultsOne-way ANOVA analysis showed the omnibus differences in the left inferior parietal lobule/middle occipital gyrus (IPL/MOG) and right precuneus/posterior cingulate cortex (PCUN/PCC) across all groups. The post hoc analysis revealed that BD showed decreased dDC in the IPL/MOG compared with all other groups, and both BD and BM exhibited decreased dDC in the PCUN/PCC compared with BE and HCs. Furthermore, correlation analysis showed that the dDC variability of the IPL/MOG and PCUN/PCC negatively correlated with the depression symptom levels in all patients with bipolar disorder.ConclusionThis study demonstrated the distinct and shared brain dynamical pattern of the depressive, manic, and euthymia states. Our findings provide new insights into the pathophysiology of bipolar disorder across different mood states from the dynamical brain network pattern perspective.

The Silurian strata in the Shunbei No. 5 fault zone have the characteristics of long open holes, easy leakage and complex leakage. In the early stages, plugging technologies and methods such as bridging plugging, cement, chemical consolidation and high-water-loss plugging have poor effects and low plugging efficiency. Plugging slurry directly prepared with drilling fluid has low filtration characteristics, and the main reason is that the plugging material cannot filter quickly after the fluid enters the fracture. Based on the basic principle of fast filtration, the main plugging fluid M-Fluid, the micro-elastic high-strength main plugging agent M-Block and the filling agent Filling-Seal have been developed. In combination with the water-loss and wall-building properties of the circulating drilling fluid after plugging, a fast plugging technology for fractured volcanic rock formation has been established. The laboratory evaluation experiment showed that the filtration rate increased rapidly with the increase of temperature, and the filtration rate was about 0.31~0.79 mL/s, while the filtration rate of the drilling fluid was 0.0067 mL/s under the same conditions. The pressure-bearing capacity of various plugging evaluation methods, such as the simulated fracture of a large-grain sand bed, artificial fracture of small core and full-size core and multi-form fracture of double core, all exceed 5 MPa, and the system has a good plugging effect for complex fractures.

Diabetic nephropathy (DN) is a complication of diabetes mellitus (DM) that frequently results in renal disease, and is characterized by a variety of symptoms, including albuminuria. It has been shown that apoptosis of glomerular mesangial cells (MCs) can aggravate albuminuria and contribute to the development of diabetic glomerulosclerosis. Hence, determination of the mechanisms leading to MC apoptosis may help us gain insights into the pathogenesis of DN. As our understanding of the role of high glucose (HG) in MC apoptosis remains elusive, we explored the interplay between X‐box binding protein 1 (XBP1) and MC apoptosis in this study. XBP1 was observed to be downregulated both in vivo and in vitro. Treatment of XBP1‐overexpressing cells with HG resulted in a decrease of reactive oxygen species (ROS) and a suppression of cell apoptosis, concomitant with decreases in cleaved caspase‐3 and Bax. Subsequent analyses demonstrated that XBP1 overexpression inhibited the expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and enhanced the activation of AKT in MCs exposed to HG. In addition, XBP1‐induced injuries in MC were reversed by overexpression of PTEN, and XBP1 inhibited apoptosis, which was mediated by the activated PTEN/AKT signaling pathway. Thus, our data indicate that XBP1 can activate the PTEN/AKT signaling pathway, thereby alleviating oxidative stress caused by HG or MC apoptosis. These findings suggest that XBP1 may have potential in the development of treatment methods for DN.

Thallium bromide (TlBr) is a compound semiconductor with a band gap of 2.68 eV making it ideal for room temperature radiation detection. The high atomic numbers, 81 and 35, and the high density of 7.56 g/cm3 give it excellent gamma-ray stopping power. TlBr is a cubic material that melts congruently at a relatively low temperature (~480°C). These properties make it relatively easy to grow good quality crystals with high yield. As a result of improvements in the purification of TlBr mobility-lifetime product of electrons, μτe, is now on the order of 10−2 cm2/V, which is similar to that of CZT. High μτe enables the fabrication of thicker detectors with good charge collection and energy resolution. The properties of TlBr make it ideal for use in room temperature gamma radiation operation [1]. Single carrier devices such as small pixel arrays [2] and Frisch collar devices [3] which were developed for CZT can also been applied to TlBr. For example, better than 1% FWHM at 662 keV has been obtained for single pixel events with small (e.g., 3 × 3 pixels, 1-mm pitch, 5-mm thick) arrays.

Mercury pollution in the atmospheric environment is a matter of international concern. Mercury in coal-fired flue gas is the first human mercury emission source and has become the focus of national mercury pollution control. The catalytic performance of zerovalent mercury (Hg0) in coal-fired flue gas was studied by using manganese-cerium-aluminum oxide as catalyst. The effects of metal loading ratio, reaction temperature, calcination temperature, and O2 and SO2 concentration on the efficiency of Hg0 catalytic removal were investigated, and the Mn-Ce/γ-Al2O3 catalysts before and after the reaction were characterized by BET, SEM, XRD, and XPS to analyze the physicochemical properties of the samples. The results show that the mercury removal efficiency of the composite catalyst with Mn, Ce, and Al as the active component is higher than that of the single metal catalyst. The catalytic activity of Mn0.1Ce0.02Al is the best, the optimum reaction temperature is 150°C, the optimum calcination temperature is 400°C, and the O2 concentration in the conventional flue gas condition satisfies the effective oxidation of Hg0; SO2 in the flue gas can seriously inhibit the oxidation of Hg0.

Background: This study compared adaptive resilience among patients with schizophrenia, bipolar disorder, and healthy controls, and examined the relationship of resilience to cognitive function.Methods: A sample of 81 patients diagnosed with schizophrenia, 34 with bipolar disorder, and 52 healthy controls completed the Connor-Davidson Resilience Scale (CD-RISC) and cognitive tests of verbal comprehension, executive functioning, and working memory. Paired comparison of diagnostic groups on CD-RISC and cognitive tests was conducted. Linear regression was used to identify the independent association of clinical diagnoses and neurocognition with resilience deficits.Results: Both patient groups showed significantly lower CD-RISC scores and poorer cognitive function than healthy controls and the schizophrenia group scored lower than bipolar group on these measures as well. CD-RISC scores were positively correlated with all three cognitive measures in the entire sample but not within the diagnostic subgroups. Multiple regression analysis showed differences in CD-RISC between diagnostic groups were not mediated by differences in these three measures of neurocognition.Discussion: Schizophrenia and bipolar disorder are associated with impairments in both resilience and cognitive function but the impairment in resilience appears to be independent of deficits in cognitive function measured here and may reflect unmeasured dimensions of cognitive function, other impairments or environmental factors.

Abstract Background Owing to the harmfulness and seriousness of Schistosomiasis japonica in China, the control and prevention of S. japonica transmission are imperative. As the unique intermediate host of this disease, Oncomelania hupensis plays an important role in the transmission. It has been reported that the snail population in Qiangliang Lake district, Dongting Lake Region has been naturally declining and is slowly becoming extinct. Considering the changes of environmental factors that may cause this phenomenon, we try to explore the relationship between circumstance elements and snails, and then search for the possible optimum scopes of environmental factors for snails. Methods Moisture content of soil, pH, temperature of soil and elevation were collected by corresponding apparatus in the study sites. The LISA statistic and GWR model were used to analyze the association between factors and mean snail density, and the values in high-high clustered areas and low-low clustered areas were extracted to find out the possible optimum ranges of these elements for snails. Results A total of 8,589 snail specimens were collected from 397 sampling sites in the study field. Besides the mean snail density, three environmental factors including water content, pH and temperature had high spatial autocorrelation. The spatial clustering suggested that the possible optimum scopes of moisture content, pH, temperature of the soil and elevation were 58.70 to 68.93%, 6.80 to 7.80, 22.73 to 24.23°C and 23.50 to 25.97 m, respectively. Moreover, the GWR model showed that the possible optimum ranges of these four factors were 36.58 to 61.08%, 6.541 to 6.89, 24.30 to 25.70°C and 23.50 to 29.44 m, respectively. Conclusion The results indicated the association between snails and environmental factors was not linear but U-shaped. Considering the results of two analysis methods, the possible optimum scopes of moisture content, pH, temperature of the soil and elevation were 58.70% to 68.93%, 6.6 to 7.0, 22.73°C to 24.23°C, and 23.5 m to 26.0 m, respectively. The findings in this research will help in making an effective strategy to control snails and provide a method to analyze other factors.

Calcium carbonate biomimetic crystallization remains a topic of interest with respect to biomineralization areas in recent research. It is not easy to conduct high-throughput experiments with only a few macromolecule reagents using conventional experimental methods. However, the emergence of microdroplet array technology provides the possibility to solve these issues efficiently. In this article, surface-tension-confined droplet arrays were used to fabricate calcium carbonate. It was found that calcium carbonate crystallization can be conducted in surface-tension-confined droplets. Defects were found on the surface of some crystals, which were caused by liquid flow inside the droplet and the rapid drop in droplet height during the evaporation. The diameter and number of crystals were related to the droplet diameter. Polyacrylic acid (PAA), added as a modified organic molecule control, changed the CaCO3 morphology from calcite to vaterite. The material products of the above experiments were compared with bulk-synthesized calcium carbonate by scanning electron microscopy (SEM), Raman spectroscopy and other characterization methods. Our work proves the possibility of performing biomimetic crystallization and biomineralization experiments on surface-tension-confined microdroplet arrays.

Pulmonary fibrosis is a progressive and irreversible fibrotic lung disorder with high mortality and few treatment options. Recently, induced pluripotent stem (iPS) cells have been considered as an ideal resource for stem cell-based therapy. Although an earlier study demonstrated the therapeutic effect of iPS cells on pulmonary fibrosis, the exact mechanisms remain obscure. The present study investigated the effects of iPS cells on inflammatory responses, transforming growth factor (TGF)-β1 signaling pathway, and epithelial to mesenchymal transition (EMT) during bleomycin (BLM)-induced lung fibrosis. A single intratracheal instillation of BLM (5 mg/kg) was performed to induce pulmonary fibrosis in C57BL/6 mice. Then, iPS cells (c-Myc-free) were administrated intravenously at 24 h following BLM instillation. Three weeks after BLM administration, pulmonary fibrosis was evaluated. As expected, treatment with iPS cells significantly limited the pathological changes, edema, and collagen deposition in lung tissues of BLM-induced mice. Mechanically, treatment with iPS cells obviously repressed the expression ratios of matrix metalloproteinase-2 (MMP-2) to its tissue inhibitor -2 (TIMP-2) and MMP-9/TIMP-1 in BLM-induced pulmonary tissues. In addition, iPS cell administration remarkably suppressed BLM-induced up-regulation of pulmonary inflammatory mediators, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and prostaglandin E2. We further demonstrated that transplantation of iPS cells markedly inhibited BLM-mediated activation of TGF-β1/Mothers against decapentaplegic homolog 2/3 (Smad2/3) and EMT in lung tissues through up-regulating epithelial marker E-cadherin and down-regulating mesenchymal markers including fibronectin, vimentin and α-smooth muscle actin. Moreover, in vitro, iPS cell-conditioned medium (iPSC-CM) profoundly inhibited TGF-β1-induced EMT signaling pathway in mouse alveolar epithelial typeⅡcells (AECⅡ). Collectively, our results suggest that transplantation of iPS cells could suppress inflammatory responses, TGF-β1/Smad2/3 pathway and EMT during the progression of BLM-induced pulmonary fibrosis, providing new useful clues regarding the mechanisms of iPS cells in the treatment for this disease.

Dengue virus (DENV) is a re-emerging arthropod borne flavivirus that infects more than 300 million people worldwide, leading to 50,000 deaths annually. Because dendritic cells (DC) in the skin and blood are the first target cells for DENV, we sought to investigate the early molecular events involved in the host response to the virus in primary human monocyte-derived dendritic cells (Mo-DC). Using a genome-wide transcriptome analysis of DENV2-infected human Mo-DC, three major responses were identified within hours of infection - the activation of IRF3/7/STAT1 and NF-κB-driven antiviral and inflammatory networks, as well as the stimulation of an oxidative stress response that included the stimulation of an Nrf2-dependent antioxidant gene transcriptional program. DENV2 infection resulted in the intracellular accumulation of reactive oxygen species (ROS) that was dependent on NADPH-oxidase (NOX). A decrease in ROS levels through chemical or genetic inhibition of the NOX-complex dampened the innate immune responses to DENV infection and facilitated DENV replication; ROS were also essential in driving mitochondrial apoptosis in infected Mo-DC. In addition to stimulating innate immune responses to DENV, increased ROS led to the activation of bystander Mo-DC which up-regulated maturation/activation markers and were less susceptible to viral replication. We have identified a critical role for the transcription factor Nrf2 in limiting both antiviral and cell death responses to the virus by feedback modulation of oxidative stress. Silencing of Nrf2 by RNA interference increased DENV-associated immune and apoptotic responses. Taken together, these data demonstrate that the level of oxidative stress is critical to the control of both antiviral and apoptotic programs in DENV-infected human Mo-DC and highlight the importance of redox homeostasis in the outcome of DENV infection.

BACKGROUND: Generalized anxiety disorder (GAD) is a common anxiety disorder that usually begins in adolescence. Childhood maltreatment is highly prevalent and increases the possibility for developing a variety of mental disorders including anxiety disorders. An earlier age at onset of GAD is significantly related to maltreatment in childhood. Exploring the underpinnings of the relationship between childhood maltreatment and adolescent onset GAD would be helpful in identifying the potential risk markers of this condition. METHODS: Twenty-six adolescents with GAD and 25 healthy controls participated in this study. A childhood trauma questionnaire (CTQ) was introduced to assess childhood maltreatment. All subjects underwent high-resolution structural magnetic resonance scans. Voxel-based morphometry (VBM) was used to investigate gray matter alterations. RESULTS: Significantly larger gray matter volumes of the right putamen were observed in GAD patients compared to healthy controls. In addition, a significant diagnosis-by-maltreatment interaction effect for the left thalamic gray matter volume was revealed, as shown by larger volumes of the left thalamic gray matter in GAD patients with childhood maltreatment compared with GAD patients without childhood maltreatment as well as with healthy controls with/without childhood maltreatment. A significant positive association between childhood maltreatment and left thalamic gray matter volume was only seen in GAD patients. CONCLUSIONS: These findings revealed an increased volume in the subcortical regions in adolescent GAD, and the alterations in the left thalamus might be involved in the association between childhood maltreatment and the occurrence of GAD.

OBJECTIVE: The schizophrenic patients with high suicide risk are characterized by depression, better cognitive function, and prominent positive symptoms. However, the neurobiological basis of suicide attempts in schizophrenia is not clear. The suicide in schizophrenia is implicated in the defects in emotional process and decision-making, which are associated with prefrontal-cingulate circuit. In order to explore the possible neurobiological basis of suicide in schizophrenia, we investigated the correlation of prefrontal-cingulate circuit with suicide risk in schizophrenia via dynamic casual modelling. METHOD: Participants were 33 first-episode schizophrenic patients comprising of a high suicide risk group (N = 14) and a low suicide risk group (N = 19). A comparison group of healthy controls (N = 15) were matched for age, gender and education. N-back tasking functional magnetic resonance imaging data was collected. RESULTS: Compared with healthy controls group, the two patients groups showed decreased task-related suppression during 2-back task state versus baseline state in the left posterior cingulate and medial prefrontal cortex; the hyper-connectivity from the left posterior cingulate cortex to the left medial prefrontal cortex existed in both schizophrenic patients groups, but hypo-connectivity in the opposite direction only existed in the schizophrenic patients group with high suicide risk. CONCLUSIONS: The hyper-connectivity from the left posterior cingulate cortex to the left medial prefrontal cortex may suggest that the abnormal effective connectivity was associated with risk for schizophrenia. The hypo-connectivity in the opposite direction may represent a possible correlate of increased vulnerability to suicide attempt.

Chronic viral infections lead to persistent CD8 T cell activation and functional exhaustion. Expression of programmed cell death-1 (PD-1) has been associated to CD8 T cell dysfunction in HIV infection. Herein we report that another negative regulator of T cell activation, CD160, was also upregulated on HIV-specific CD8 T lymphocytes mostly during the chronic phase of infection. CD8 T cells that expressed CD160 or PD-1 were still functional whereas co-expression of CD160 and PD-1 on CD8 T cells defined a novel subset with all the characteristics of functionally exhausted T cells. Blocking the interaction of CD160 with HVEM, its natural ligand, increased HIV-specific CD8 T cell proliferation and cytokine production. Transcriptional profiling showed that CD160(-)PD-1(+)CD8 T cells encompassed a subset of CD8(+) T cells with activated transcriptional programs, while CD160(+)PD-1(+) T cells encompassed primarily CD8(+) T cells with an exhausted phenotype. The transcriptional profile of CD160(+)PD-1(+) T cells showed the downregulation of the NFκB transcriptional node and the upregulation of several inhibitors of T cell survival and function. Overall, we show that CD160 and PD-1 expressing subsets allow differentiating between activated and exhausted CD8 T cells further reinforcing the notion that restoration of function will require multipronged approaches that target several negative regulators.

BackgroundTwo major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS).ObjectivesThis study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A.MethodsClinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure.ResultsThe SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%.ConclusionsThese findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.