Search

To explore the significance of Fluorine-18 labeled fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in diagnosing connective tissue diseases (CTDs) in fever of unknown origin (FUO) or inflammation of unknown origin (IUO) patients.Clinical and image data of 242 consecutive FUO/IUO patients who underwent PET/CT examination and eventually diagnosed CTDs were retrospectively analyzed, including distribution of diseases, clinical characteristics, and PET/CT imaging findings. The role of FDG PET/CT in differential diagnosis of CTDs was evaluated through clinical questionnaire survey.Patients diagnosed as CTDs accounted for 48.1% of FUO/IUO patients. Among them, adult-onset Still's disease was most frequently diagnosed. Other common diseases included systemic vasculitis, undifferentiated connective tissue disease, rheumatoid arthritis, idiopathic inflammatory myopathy, systemic lupus erythematosus, and polymyalgia rheumatica. On FDG PET/CT examination, 97.9% of the patients had positive findings. Inflammatory lesions were detected in 66.5% and non-specific abnormal uptakes were found in 31.4%. Detected lesions distributed consistently with corresponding susceptible organs and tissues in various diseases. Clinical questionnaire results shown that FDG PET/CT excluded malignant tumors, focal infections, or other typical CTDs in 45.5% of the patients; indicated important diagnostic clues or appropriate biopsy sites in 20.6% of patients; and directly suggested the diagnosis of a CTD in 33.1% of patients.FDG PET/CT could reveal inflammatory lesions in organs and tissues that reflect the clinical characteristics in different CTDs, thus providing an objective evidence for differential diagnosis, classification, and treatment decision of these diseases. Key Points • FDG PET/CT is a useful tool for differential diagnosing connective tissue diseases among patients with fever of unknown origin/inflammatory of unknown origin.

Anti-Mullerian hormone receptor type II (Amhr2) is a key receptor of Amh signaling in regulating gonad development. The amhr2 gene has been identified in numerous species, including a few teleost fishes. However, the roles of Amhr2 in Amh signaling in fish are poorly studied. In this study, an amhr2 homolog from obscure puffer (Takifugu obscurus) was identified, and its molecular characteristics were systematically analyzed. Expression analysis revealed that amhr2 was highly expressed in the gonads of adult pufferfish and significantly upregulated during sex differentiation. Significantly, a sex-linked SNP site was verified in obscure puffer amhr2. Females exhibited a homozygous genotype (C/C), while males possessed a heterozygous genotype (C/G), resulting in an amino acid variation (His/Asp384) in the kinase domain of Amhr2. Then, the functions of the different Amhr2 genotypes were further investigated. The male genotype protein (Amhr2D384) showed an enhanced ability to interact with the type I receptor (Bmpr1a) compared to the female genotype (Amhr2H384). The phosphorylation levels of Smads and activity of the target gene (id3) induced by the male genotype were also much higher than those induced by the female genotype. These results confirmed that the male genotype had an enhanced effect on the Amh signaling pathway compared with the female genotype. This study provides direct experimental evidence for the roles of different Amhr2 genotypes in pufferfish and suggests that amhr2 is responsible for male sex differentiation in obscure puffer.

Dynamic therapy, such as photodynamic therapy (PDT) or chemodynamic therapy (CDT), is one of the most promising therapeutic strategies for tumors. Integrating the advantages of near-infrared-induced PDT and CDT can potentially improve the therapeutic performance. A single primitive nanostructure, CuWO4 nanodots, was developed. It could generate reactive oxygen species under 808 nm light irradiation and release copper ions into the acid tumor microenvironment, thereby boosting Fenton-like reactions. The PDT and CDT would occur when the nanodots were introduced into the tumor tissue and irradiated under 808 nm light. The results of combined PDT and CDT antitumor studies showed the effective inhibition of tumor tissue growth, thereby suggesting that the nanodots are candidate agents for synergistic antitumor applications.

Background Scalp combing, as an ancient method of health care, has been used for thousands of years in traditional Chinese medicine. Although this method is considered to be beneficial for the blood circulation of the head, the underlying mechanisms remain unclear. Methods Both human participants and mice were used in this study. In participants, the scalp was stimulated by combing continuously for 5 min, and the temperature was measured using infrared thermal imaging before and after stimulation. In mice, the temperature was determined before and at 5, 15, and 30 min after a 5-min scalp mechanical stimulation (SMS). Additionally, the vasculature of the mice was labeled with retro-orbital fluorescein isothiocyanate-dextran injection, and the capillaries were observed directly under a confocal microscope. Using in vivo CLARITY imaging and the spectrofluorometric detection of Evans Blue dye extravasation, the blood–brain barrier permeability was assessed. Results SMS increased the temperature of the left ear significantly in human (P = .0247) while can slightly increase the temperature of the right ear and the face without significant difference (P > .05). Moreover, SMS can significantly slow the decrease in the temperature of the external auditory canal at 5 min (P = .0153) and in body temperature at 15 min (P = .0295) after SMS whereas no significant difference in body temperature at 30 min (P > .05) compared with control mice. Furthermore, capillaries of the ear with a diameter of less than 8 μm were significantly dilated (P = .0006) following SMS and the number of dextran dots was higher at 15 min (P > .05) and 30 min (F = 10.98, P = .037) after SMS intervention compared with control mice. Conclusion Our study provides strong evidence to support the notion that scalp combing can improve extra- and intracranial blood circulation under healthy conditions.

Gefitinib (Iressa), is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used in the targeted treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Skin toxicity is the major adverse effect observed in patients treated with EGFR-targeted TKIs such as gefitinib and erlotinib. To date, a corresponding skin animal model has not been established to address the mechanisms of these effects. Therefore, we analyzed the skin rash phenotype and its pathological features in Brown Norway (BN) rats treated with gefitinib 2.5 mg, 5.0 mg, or 10 mg/100 g/day for 4 weeks. We found that treatment with gefitinib led to weight loss, rash, itching, and hair loss in a dose-dependent manner. We also investigated the skin pathology and found that the animal model showed thickening of the epidermis, loss of moisture, and apoptosis of keratinocytes. Immunohistochemistry, flow cytometry, and analysis of monocytes and leukocytes in the blood revealed increased macrophage infiltration was associated with the cutaneous toxicities induced by gefitinib in the BN rats. Finally, we found that gefitinib-induced cutaneous toxicity is significantly associated with three inflammatory cytokines known to be secreted by activated macrophages, TREM-1, CINC-2, and CINC-3.

Objective The long-noncoding RNAs (lncRNAs) have been identified as key players in diverse cellular processes in non-small cell lung cancer (NSCLC). However, the understanding of biological functions and detailed mechanisms of lncRNAs is still limited. Herein, the lncRNA cancer susceptibility candidate 9 (CASC9) on NSCLC progression is investigated. Materials and methods Expressions of CASC9, HuR and cell division cycle 6 (CDC6) in NSCLC tissues were detected with quantitative real-time polymerase chain reaction (qRT-PCR). The cell counting kit-8, transwell assays, and flow cytometry were used to examine cell proliferation, migration, and the cell cycle. Tumor growth in vivo was evaluated by xenograft tumor experiments and immunohistochemistry. RNA-binding protein immunoprecipitation (RIP) was used to identify the interaction between HuR and CDC6, and CASC9 and HuR. Results CASC9, CDC6 and HuR expression were found significantly upregulated in NSCLC tissues, which predicted poorer 5-year overall survival in NSCLC patients. Inhibition of CASC9 significantly reduced the malignancy of NSCLC cells, such as proliferation, migration and cell cycle. In vivo experiments further demonstrated that CASC9 knockdown reduced the tumor growth and the Ki-67 expression. Moreover, CASC9 knockdown inhibited the expression of CDC6 which was detected overexpressed in NSCLC tumor tissues. Then, up-regulation of CDC6 could partly reverse the negative effects of CASC9 on cell proliferation, migration and cell cycle. RIP assay and rescue experiment showed that CASC9 regulated CDC via binding to HuR. Conclusion Our results indicate that CASC9 conferred an aggressive phenotype in NSCLC and might be a pivotal target for this disease.

A systematic investigation into the reactions of Cd(NO3)2·4H2O with o- and p-phenylenediacetic acid within the presence of the semi-rigid 1,4-bis(imidazol-1-ylmethyl)benzene (bimb) co-ligands under...

Hydroxysafflor yellow A (HSYA) is a water-soluble component of the safflower (Carthamus tinctorius), and research has revealed that HSYA exhibits antitumor effects. In the present study, the effects of HSYA on the autophagy of a Hep-G2 liver cancer cell line, as well as the underlying mechanisms, were investigated. Hep-G2 cells were treated with HSYA and the viability of cells was measured using an MTT assay. Western blotting and immunofluorescence assays were performed to determine the expression of light chain 3 II (LC3-II) and p62, as well as the autophagy regulators Beclin 1 and ERK1/2. Transmission electron microscopy was performed to observe the formation of autophagosomes. The combined effects of HSYA and the autophagy inhibitor chloroquine (CQ) were also determined. The results revealed that the viability of Hep-G2 cells decreased with increasing concentrations of HSYA. Furthermore, LC3-II expression increased significantly and the level of p62 decreased significantly in the HYSA group compared with the control group. Additionally, an increase in Beclin 1 expression and a decrease in phosphorylated-ERK1/2 expression was observed in Hep-G2 cells treated with HYSA. Following treatment with CQ and HSYA, a significant increase in the viability of Hep-G2 cells was observed compared with the HSYA group. Collectively, the results indicated that HSYA induced autophagy by promoting the expression of Beclin 1 and inhibiting the phosphorylation of ERK in liver cancer cells. Therefore, HSYA may serve as a potential therapeutic agent for liver cancer.

BackgroundPrevious studies have confirmed an association between C-peptide levels with the risk of cardiometabolic diseases. However, whether circulating C-peptide was related to subclinical myocardial injury (SC-MI) remains unknown.MethodsA total of 3,752 participants without a history of cardiovascular diseases were included in our study from National Health and Nutrition Examination Survey III (NHANES III). Multivariable linear regression was performed to explore the correlation between C-peptide and cardiac injury score (CIIS). Multivariate logistic regression was used to examine the association between C-peptide quartile and SC-MI.ResultsCirculating C-peptide was significantly associated with CIIS (β:0.09, 95% confidence interval [CI]: 0.00–0.17; p = 0.041). Compared with the lowest quartile, the highest quartile of circulating C-peptide increased a 1.48-fold risk of SC-MI (Odds ratio = 1.66, 95% CI: 1.18–1.87; p = 0.001).ConclusionsThe level of C-peptide was independently associated with CIIS and SC-MI, which could serve as a new risk factor of SC-MI.

Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal cross-talk from neighboring electrodes. Local return electrodes within each pixel limit crosstalk, but can over-constrain the electric field, thus precluding efficient stimulation with subretinal pixels smaller than 50 μm. Here we demonstrate high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated computational modeling of the field confinement in such an optically-controlled circuit by ex-vivo and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40 μm pixels matches the pixel pitch, while with 20 μm pixels, it reaches the 28 μm limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to prosthetic vision with acuity as high as 20/80 in atrophic macular degeneration.

Lactic acid bacteria are known to produce extracellular polysaccharides such as α-glucan, levan, and inulin, which are promising for applications in food systems because of their prebiotic properties. In this work, a novel glucansucrase (GS) Gtf-DSM from Lactobacillus ingluviei DSM 14792 was recombinantly expressed and biochemically characterized as a dextransucrase capable of producing a dextran polysaccharide with four types of linkages, including 69% (α1 → 6), 24% (α1 → 3), 6% (α1 → 4), and 1% (α1 → 2). Intriguingly, the dextransucrase Gtf-DSM had a sequence identity of 99.3% with the reuteransucrase GtfO producing a reuteran with 21% (α1 → 6) and 79% (α1 → 4) linkages. Thus, the dextransucrase Gtf-DSM is a unique target for understanding the linkage specificity of GSs and the investigation of site-directed mutagenesis using Gtf-DSM and GtfO as templates is underway.

Peripheral circulating free DNA (cfDNA) is DNA that is detected in plasma or serum fluid with a cell-free status. For cancer patients, cfDNA not only originates from apoptotic cells but also from necrotic tumor cells and disseminated tumor cells that have escaped into the blood during epithelial-mesenchymal transition. Additionally, cfDNA derived from tumors, also known as circulating tumor DNA (ctDNA), carries tumor-associated genetic and epigenetic changes in cancer patients, which makes ctDNA a potential biomarker for the early diagnosis of tumors, monitory and therapeutic evaluations, and prognostic assessments, among others, for various kinds of cancer. Moreover, analyses of cfDNA chromatin modifications can reflect the heterogeneity of tumors and have potential for predicting tumor drug resistance.

Objective This study aimed to determine predictors of microvascular occlusion (MVO) in patients with ST elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (pPCI). Methods This retrospective, observational study consecutively included 113 patients with STEMI undergoing pPCI. Cardiac magnetic resonance imaging was used to determine the presence of MVO in these patients. Biomarkers in serum were routinely tested 1 day after pPCI. Multivariable logistic regression analysis was used to evaluate significant predictors of occurrence of MVO. Results There were 62 patients in the MVO group and 51 patients in the non-MVO group. C-reactive protein (CRP), thrombomodulin, lymphatic vessel endothelial hyaluronan receptor-1, syndecan-1, and troponin T (TnT) levels after the procedure were significantly higher in the MVO group than in the non-MVO group. CRP (hazard ratio [HR]=1.036), TnT (HR=1.316), and syndecan-1 (HR=1.986) levels were independently associated with MVO in patients with acute myocardial infarction after pPCI. Conclusions Levels of CRP, TnT, and syndecan-1 can be used as serum biomarkers for MVO in patients with STEMI receiving pPCI.

BackgroundDilated cardiomyopathy (DCM) is one of the common causes of heart failure. Myocardial injury triggers an inflammatory response and recruits immune cells into the heart. High expression of Krüppel-like factor 2(KLF2) in endothelial cells (ECs) could exert the anti-inflammatory effect. However, the role of extracellular vesicles from KLF2-overexpressed ECs (KLF2-EVs) in DCM remains unclear. Methods and ResultsEVs were separated from the supernatant of KLF2-overexpressed ECs by gradient centrifugation. Mice were administered with a repetitive low-dose doxorubicin (DOX) and then received KLF2- EVs through intravenous injection. Treatment with KLF2- EVs prevented doxorubicin-induced left ventricular dysfunction and reduced recruitment of Ly6high Mo/Mø in myocardium. To identify the mechanisms involved in this beneficial effect we used flow cytometry to detect Ly6high monocytes in bone marrow and spleen tissue. KLF2-EVs increased the retention of Ly6Chigh monocytes in the bone marrow, but not the spleen tissue. KLF2-EVs also significantly downregulated C-C chemokine receptor 2(CCR2) protein expression in cells from the bone marrow. Conclusion EVs derived from KLF2-overexpressed ECs reduced cardiac inflammation and ameliorated left ventricular dysfunction in DCM mice, which is achieved by targeting the CCR2 protein to inhibit Ly6Chigh monocytes mobilizing from bone marrow.

Objective: The study aims to investigate the association of total bilirubin with all-cause and cause-specific mortality in the general population.Methods: A total of 37,234 adults from the United States National Health and Nutrition Examination Survey 1999–2014 were enrolled. Baseline levels of total bilirubin associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by quartile categories with Cox regression models.Results: Higher levels of total bilirubin was positively associated with an increased risk of all-cause mortality [hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.46–1.72; p < 0.001]. Compared with individuals with the lowest quartile of bilirubin, the multivariable adjusted hazard ratio for all-cause mortality was 1.25 (1.14–1.37) for individuals in the highest quartile. Restricted cubic splines indicated that the association was non-linear in cardiovascular mortality and cancer mortality while linear in all-cause mortality.Conclusions: Total bilirubin was associated with all-cause and cause-specific mortality in the general population.

IntroductionThe objective of this study was to explore the role of Curcumin (CUR) in the control of renal cell carcinoma (RCC) as well as the molecular mechanism underlying the effect of CUR.Material and methodsReal-time PCR, Western-blot analysis, immunohistochemistry (IHC) assay, and luciferase assay were utilized to detect the effect of CUR.ResultsMesoscale nanoparticles (particles) could be safely and preferentially accumulated in the kidney in a dose-dependent manner, and the specific localization of particles in the kidney reached its maximum level at a dose of 25 mg/kg. Treatment with CUR alleviated RCC by up-regulating the expression of H19 and miR-675 while down-regulating the expression of HDAC1 and HDAC6 in RCC rats. Furthermore, the underlying mechanism of CUR in the regulation of H19 was explored, and it was revealed that CUR increased H19 expression via increasing the translational efficiency of H19 promoter. Therefore, the treatment with CUR increased the levels of H19 and miR-675 mRNAs while reducing the expression of HDAC1 and HDAC6. According to a computational analysis, HDAC1 and HDAC6 were both direct targets downstream of miR-675, and miR-675 mimics could decrease the luciferase activity of cells transfected by wild-type HDAC1 and HDAC6 3’UTR. In addition, miR-675 but not CTCF reduced the protein levels of HDAC1 and HDAC6. Nevertheless, CTCF increased the luciferase activity of cells transfected by H19 promoter, while miR-675 mimics decreased the effect of CTCF.ConclusionsIn this study, we suggested that CUR could affect the prognosis of RCC by establishing a negative feedback loop of H19/miR-675/HDAC/CTCF.

Effective vaccines are vital to the fight against the COVID-19 global pandemic. As a critical component of a subunit vaccine, the adjuvant is responsible for strengthening the antigen-induced immune responses. Here, we present a new nanovaccine that comprising the Receptor-Binding Domain (RBD) of spike protein and the manganese nanoadjuvant (MnARK), which induces humoral and cellular responses. Notably, even at a 5-fold lower antigen dose and with fewer injections, mice immunized with the MnARK vaccine immunized mice showed stronger neutralizing abilities against the infection of the pseudovirus (~270-fold) and live coronavirus (>8-fold) in vitro than that of Alum-adsorbed RBD vaccine (Alu-RBD). Furthermore, we found that the effective co-delivery of RBD antigen and MnARK to lymph nodes (LNs) elicited an increased cellular internalization and the activation of immune cells, including DC cells, CD4+ and CD8+ T lymphocytes. Our findings highlight the importance of MnARK adjuvant in the design of novel coronavirus vaccines and provide a rationale strategy to design protective vaccines through promoting cellular internalization and the activation of immune-related pathways., Graphical abstract New nanovaccine that comprises RBD of spike protein and the manganese nanoadjuvant (MnARK) induces humoral and cellular responses.

The aim of the present research was to investigate the effects of irisin, a skeletal muscle-derived myokine, on spinal cord injury (SCI) in rats and explore the possible mechanisms. SCI model was constructed in male SD rats. The effects of irisin on SCI rats were assessed via behavior tests including Basso, Beattie, and Bresnahan (BBB) scoring method and inclined plane test, followed by histomorphology tests including HE staining, Nissl staining, and transmission electron microscope examination. Biochemical analyses including PCR, Western blots and ELISA were employed to further evaluate the changes at molecular level of SCI rats. In addition, lipopolysaccharide (LPS)-induced cell damage model was established in PC12 cells to verify the mechanism of irisin’s effect on nerve cells in vitro. Results showed that the BBB score and the angle of incline significantly decreased after SCI surgery, however, chronic irisin treatment improved SCI-induced motor dysfunction. HE and Nissl staining assays showed that SCI surgery induced histological injury of spinal cord, which could be reversed by irisin treatment. Morphological abnormality of nerve cells caused by SCI also could be alleviated by irisin. Further biochemical analyses showed that irisin inhibited SCI-induced overexpression of Interleukin-1β (IL-1β), Interleukin- 6 (IL-6), tumor necrosis factor alpha (TNF-α), inducible nitricoxidesynthase (iNOS) and Cyclooxygenase-2 (COX-2)], as well as nuclear factor kappa-B (NF-κB)p65 in rats, and the positive function of irisin could be reversed by Compound C treatment. In our in vitro study, LPS-induced declines of cell viability and neurite length of PC12 cell were inhibited by irisin treatment, and irisin inhibited LPS-induced overexpression of NF-κBp65, IL-1β, IL-6, TNF-α, iNOS and COX-2. These changes could be reversed by activated protein kinase (AMPK) siRNA pre-treatment. Taken together, irisin could protect the rats from SCI, and its protection is associated with the regulation of adenosine 5'-monophosphate-activated protein kinase (AMPK)- NF-κB signaling pathway.

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease with varying clinical outcomes and it is important to identify new predictors of adverse events and survival in HCM patients. Overweight may independently predict the clinical outcomes of HCM patients. This was a retrospective study. Two hundred six HCM patients were compared classified by the normal group (body mass index

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib, erlotinib, and afatinib, are widely used in clinical practice and remarkably effective in treatment of advanced non-small cell lung cancer. However, there are some adverse effects while taking EGFR-TKIs, among which skin adverse reactions (SAR) are the most common events. At present, the poor outcome of SAR and insufficient research on SAR models need to be addressed. In this study we focused on the SAR models to lay a foundation for mechanism researches. Gefitinib, one of the EGFR-TKIs, was used as SAR inducing agents. We chose C57BL/6 and FVB/N mice as experimental model and they were divided into four groups. The weight and skin moisture of mice were detected every 7 days, itching behavior and abnormal eyelids were tested at 35th day after gavage, and survival rate was also recorded. The weight of unit area hair, length of whiskers and inflammatory cells were evaluated after mice sacrificed. C57BL/6 animals treated with gefitinib showed significant differences in survival rate, weight of unit area hair, skin moisture changes, skin dryness, itching behavior, whisker irregular growth, abnormal eyelids, and inflammatory cells; FVB/N animals treated with gefitinib only showed significant differences in survival rate, whisker irregular growth and abnormal eyelids, compared with the control group, respectively. In this study, we compared the similarities and differences of gefitinib-induced SAR between C57BL/6 and FVB/N mice, which illustrated different patients probably showing different symptoms clinically and provided experimental basis for researching mechanism of EGFR-TKIs induced SAR.

Clarithromycin retained in waste activated sludge (WAS) inevitably enters the anaerobic digestion system. So far, the complex impacts and fate of clarithromycin in continuous operated WAS anaerobic digestion system are still unclear. In this study, two semi-continuous long-term reactors were set up to investigate the effect of clarithromycin on biogas production and antibiotic resistance genes (ARGs) during WAS anaerobic digestion, and a batch test was carried out to explore the potential metabolic mechanism. Experimental results showed that clarithromycin at lower concentrations (i.e., 0.1 and 1.0 mg/L) did not affect biogas production, whereas the decrease in biogas production was observed when the concentration of clarithromycin was further increased to 10 mg/L. Correspondingly, the relative abundance of functional bacteria in WAS anaerobic digestion (i.e., Anaerolineaceae and Microtrichales) was reduced with long-term clarithromycin exposure. The investigation of ARGs suggested that the effect of methylation belonging to the target site modification played a critical role for the anaerobic microorganisms in the expression of antibiotic resistance, and ermF, played dominated ARGs, presented the most remarkable proliferation. In comparison, the role of efflux pump was weakened with a significant decrease of two detected efflux genes. During WAS anaerobic digestion, clarithromycin could be partially degraded into metabolites with lower antimicrobial activity including oleandomycin and 5-O-desosaminyl-6-O-methylerythronolide and other metabolites without antimicrobial activity.

Background It is well known that it is more reliable to investigate the effects of several covariates simultaneously rather than one at time. Similarly, it is more informative to model responses simultaneously, as more often than not, the multiple responses from the same subject are correlated. This is particularly true in the analysis of Mozambique survey data from 2009 and 2018. Method A multiple response predictive model for testing positive for HIV and having sufficient HIV knowledge is modeled to 2009 and 2018 survey data with the use of Bayes estimates. These data are obtained through a hierarchical data structure. The model allows one to address the change in the response to HIV, as it relates to morbidity and to HIV knowledge in Mozambique in the fight against the disease in the last decade. Results A more affluent resident is more likely to test positive, more likely to be more knowledgeable about the disease. Whereas, individuals practicing the Islam faith are less likely to test positive but also less likely to be knowledgeable about the disease. Education, while still a factor, has declined in its impact on testing positive for HIV or being knowledgeable about HIV. Females are more likely to test positive but more likely to be knowledgeable about the disease than men. The rate of impact of affluence on knowledge has increased in the past decade. Marital status (cohabitating or married) showed no impact on the knowledge of the disease. Age had no impact on knowledge suggesting that the message is getting to resident. Conclusions A joint Bayes modeling of correlated binary (testing positive and knowledge about the disease) responses, while accounting for the hierarchy of the data collection, presents an opportunity to extract the extra variation before allocating the variation on the responses as the due of the covariates. The fight against HIV in Mozambique seems to be succeeding. Some knowledge is common among all ages, and Islam religion has a positive effect. While education still shows an influence on the binary responses, it has declined over the last decade.

With the rapid development of new technologies, including artificial intelligence and genome sequencing, radiogenomics has emerged as a state-of-the-art science in the field of individualized medicine. Radiogenomics combines a large volume of quantitative data extracted from medical images with individual genomic phenotypes and constructs a prediction model through deep learning to stratify patients, guide therapeutic strategies, and evaluate clinical outcomes. Recent studies of various types of tumors demonstrate the predictive value of radiogenomics. And some of the issues in the radiogenomic analysis and the solutions from prior works are presented. Although the workflow criteria and international agreed guidelines for statistical methods need to be confirmed, radiogenomics represents a repeatable and cost-effective approach for the detection of continuous changes and is a promising surrogate for invasive interventions. Therefore, radiogenomics could facilitate computer-aided diagnosis, treatment, and prediction of the prognosis in patients with tumors in the routine clinical setting. Here, we summarize the integrated process of radiogenomics and introduce the crucial strategies and statistical algorithms involved in current studies.

Insulin resistance (IR) is an important pathological basis of obesity, diabetes and cardiovascular diseases, and emerging evidence demonstrates aerobic exercise as an efficient therapeutical tool in the management of IR and IR-related metabolic disease. Interleukin-4 (IL-4), an important anti-inflammatory cytokine, was recently proved to be involved in regulation of IR, yet the effect of IL-4 on exercise-induced insulin sensitivity and underlying mechanism was less investigated. In this study, using a mouse model of swimming exercise training (60 min/day, 5 days/week for 8 weeks), we found that long-term swimming exercise promoted insulin sensitivity compared with sedentary groups as indexed by the homeostasis model assessment of insulin resistance (HOMA-IR), glucose and insulin tolerance test. Accompanying with increased insulin sensitivity, swimming exercise increased serum IL-4 levels as well as insulin receptor substrate 1 (IRS-1) and protein kinase B (Akt) phosphorylation. Mechanistically, IL-4 treatment increased insulin-stimulated glucose uptake and Akt phosphorylation in skeletal muscle C2C12 cells, and inhibition of IL-4 signaling via ruxolitinib, a Janus kinase (JAK) inhibitor, attenuated IL-4-induced insulin sensitivity. Taken together, our results demonstrated IL-4 as a novel exercise factor contributing to exercise-induced insulin sensitivity, providing a potential therapeutical target of IR and related metabolic disease.

Objective Our study was designed to investigate whether the indoleamine-2,3-dioxygenase (IDO)-mediated kynurenine/tryptophan (KYN/TRP) pathway participates in the development of emotional deficits from ethanol addiction/withdrawal mice. Methods The expression of proinflammatory factors, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), was tested by enzyme-linked immunosorbent assay (ELISA). The IDO levels in the hippocampus, cerebral cortex, and amygdala were measured by polymerase chain reaction (PCR) and western blot, and the neurotransmitters were tested by high performance liquid chromatography (HPLC). Emotional deficits of mice were evaluated by behavioral tests. Results Expression levels of inflammatory factors (TNF-α, IL-1β, and IL-6) were increased in mice after 4 weeks of alcohol exposure. As for indoleamine 2,3-dioxygenase (IDO) expression, only the subtype IDO1 was found to increase at both mRNA level and protein level in all the tested brain regions of ethanol addiction/withdrawal mice. In behavioral tests, mice exposed to alcohol showed gradually declined memory function accompanied by anxiety-like and depressive-like behaviors. Meanwhile, increased expression of KYN, decreased expression of 5-HT, and abnormal expression of 3-HK and KA were found in the hippocampus, cerebral cortex, and amygdala of ethanol addiction/withdrawal mice. Interestingly, the IDO1 inhibitor, 1-methyl-L-tryptophan (1-MT), reversed all above alterations induced by ethanol in mice. Conclusion Our results suggested that the TRP/KYN pathway, medicated by IDO1, in the hippocampus, cerebral cortex, and amygdala, plays an important role in the development of emotional deficits caused by ethanol addiction and withdrawal.

Background Acute lung injury (ALI) is a life-threatening clinical syndrome without effective treatment. Targeting delivery of glucocorticoid to lung shows potential efficacy for ALI based on their anti-inflammatory and anti-fibrotic properties, breaking through their clinical application limitation due to systemic side effects. This work was aimed to establish lung-targeted dexamethasone (DEX) loaded nanostructured lipid carriers (NLCs) with opposite surface charge and investigate their therapeutic effects on lipopolysaccharide (LPS)-induced ALI mice. Results The diameter of anionic anti-intercellular adhesion molecule 1 (anti-ICAM-1) antibody-conjugated DEX-loaded NLCs (ICAM/DEX/NLCs) and the cationic ones with octadecylamine (ODA) modification (ICAM/DEX/ODA-NLCs) was about 249.9 and 235.9 nm. The zeta potential of ICAM/DEX/NLCs and ICAM/DEX/ODA-NLCs was about − 30.3 and 37.4 mV, respectively. Relative to the non-targeted control and ICAM/DEX/ODA-NLCs, ICAM/DEX/NLCs exhibited higher in vitro cellular uptake in LPS-activated human vascular endothelial cell line EAhy926 after CAM-mediated endocytosis, and stronger in vivo pulmonary distribution in the ALI model mice. In vivo i.v. administration of ICAM/DEX/NLCs significantly attenuated pulmonary inflammatory cells infiltration, and the production of pro-inflammatory cytokine TNF-α and IL-6 in ALI mice. H&E stain also revealed positive histological improvements by ICAM/DEX/NLCs. Conclusions ICAM/DEX/NLCs may represent a potential pulmonary endothelium targeted device, which facilitate translation of DEX into clinical ALI treatment. Electronic supplementary material The online version of this article (10.1186/s12951-018-0431-5) contains supplementary material, which is available to authorized users.

d-Allulose is a low-calorie sweetener and has broad applications in the food, cosmetics, and pharmaceutical industries. Recently, most studies focus on d-allulose production from d-fructose by d-allulose 3-epimerase (DAEase). However, the major blocker of industrial production of d-allulose is the poor thermostability. In this study, site-directed mutagenesis at the interface regions of Dorea sp. DAEase was carried out, and the F154Y/E191D/I193F mutation was obtained. The mutant protein displayed much higher thermostability, with a t1/2 value of 20.47 h (50 °C) and a Tm value of 74.18 °C. Compared with the wild-type DAEase, the t1/2 value at 50 °C increased by 5.4-fold, and the Tm value increased by 17.54 °C. In the d-allulose production from 500 g/L d-fructose, 148.2 g/L d-allulose could be obtained by F154Y/E191D/I193F mutant protein. The results suggest that site-directed mutagenesis at the interface regions is an efficient approach for improving the thermostability of DAEase.

BACKGROUND Anti-tumor properties of hydroxysafflor-yellow A (HSYA) have been recently revealed, as a series of apoptotic factors were confirmed to be regulated by HSYA and associated with peroxisome proliferator-activated receptor Gamma (PPARγ). In this study, we investigated the cell apoptosis mechanism of HSYA via activated PPARγ signal in human gastric carcinoma cells. MATERIAL AND METHODS BGC-823 cells were cultured and divided into 5 independent groups: Tumor, HSYA, HSYA+PPARγ inhibitor (GW9662), and PPARg agonist (RGZ), RGZ+GW9662. Cell proliferative activity was measured by MTT. Apoptosis and cell cycle were detected by flow cytometry. The nuclear translocation of PPARγ was detected by immunofluorescence staining chemistry, and mRNA levels of PPARγ and caspase-3 were measured by real-time qPCR. RESULTS Compared to the RGZ group, the HSYA group (100 µM) showed a similar inhibitory effect on the proliferation process of BGC-823 cells, inducing their apoptosis. As a result, the transition of BGC-823 cells from G0/G1 phase to S phase was blocked. HSYA was also found to promote the nuclear translocation of PPARγ, leading to increased expression of PPARγ and caspase-3. The regulatory effect of HSYA on BGC-823 cells could be further inhibited by PPARγ inhibitor in group GW9662. CONCLUSIONS We report the inhibitory effect of HSYA on the proliferation of BGC-823 cells, which results in activating PPARg-dependent cell cycle blocking and cell apoptosis, suggesting that PPARg is a specific type of HSYA that can induce apoptosis of BGC-823 cells.

Background This study aims to explore the role of indoleamine-2,3-dioxygenase (IDO)/kynurenine (KYN) pathway of tryptophan (TRY) metabolism in behavioral alterations observed in hepatic encephalopathy (HE) rats. Methods Expression levels of proinflammatory cytokines were tested by QT-PCR and ELISA, levels of IDOs were tested by QT-PCR and Western blot, and levels of 5-hydroxytryptamine (5-HT), KYN, TRY, 3-hydroxykynurenine (3-HK), and kynurenic acid (KA) in different brain regions were estimated using HPLC. Effects of the IDO direct inhibitor 1-methyl-l-tryptophan (1-MT) on cognitive, anxiety, and depressive-like behavior were evaluated in bile duct ligation (BDL) rats. Results Increased serum TNF-α, IL-1β, and IL-6 levels were shown in rats 7 days after BDL, and these increases were observed earlier than those in the brain, indicating peripheral immune activation may result in central upregulation of proinflammatory cytokines. Moreover, BDL rats showed a progressive decline in memory formation, as well as anxiety and depressive-like behavior. Further study revealed that IDO expression increased after BDL, accompanied by a decrease of 5-HT and an increase of KYN, as well as abnormal expression of 3-HK and KA. The above results affected by BDL surgery were reversed by IDO inhibitor 1-MT treatment. Conclusion Taken together, these findings indicate that (1) behavioral impairment in BDL rats is correlated with proinflammatory cytokines; (2) TRY pathway of KYN metabolism, activated by inflammation, may play an important role in HE development; and (3) 1-MT may serve as a therapeutic agent for HE. Electronic supplementary material The online version of this article (10.1186/s12974-017-1037-9) contains supplementary material, which is available to authorized users.

The present study aims to investigate the influence of sex/age on depressive-like behaviors in lipopolysaccharide (LPS)-challenged mice model, and explore the underlying mechanisms. Tail suspension test and forced swimming test were used to evaluate the depressive-like behaviors. SIRT1 mRNA expression was assessed by PCR. Levels of 17β-estradiol (E2), SIRT1, NF-κB, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA). In the behavior tests, under the same LPS stimulation, significant depressive-like behavior was observed in young male mice but not in young female mice, however, female mice were more likely to be depressed than male mice in the old age. Moreover, we found age-related depression difference existed only in female mice. In the experiments of mechanism exploration in old female mice, E2 improved LPS-induced depressive-like behavior, and simultaneously elevated SIRT1 levels and downregulated expressions of NF-κB and inflammatory cytokines in the hippocampus and frontal cortex. Interestingly, ERα inhibition, not ERβ inhibition, abolished E2's function. Additionally, SIRT1 antagonist also reversed E2's effects on depressive-like behavior and the expressions of NF-κB and inflammatory cytokines. These results suggested that E2 could protect the old female mice from depression via E2/ERα/SIRT1/NF-κB signaling pathway. In other words, LPS-induced depression was associated with ER-α/SIRT1/NF-κB signaling pathway in old female mice. By comparing the results of mechanism exploration in old male mice and old female mice and the different expression levels of E2, SIRT1, NF-κB and inflammatory cytokines in young female mice and old female mice, we speculate that the age or gender-related depression difference may be associated with the different activation levels of the ERα/SIRT1/NF-κB signaling pathway.

Background: Nasopharyngeal carcinoma (NPC) is a malignant nasopharyngeal disease with a complicated etiology that occurs mostly in southern China. Intestinal flora imbalance is believed to be associated with a variety of organ malignancies. Current studies revealed that the destruction of intestinal flora is associated with NPC, and many studies have shown that intestinal flora can be used as a biomarker for many cancers and to predict cancer. Methods: To compare the differences in intestinal flora compositions and biological functions among 8 patients with familial NPC (NPC_F), 24 patients with sporadic NPC (NPC_S), and 27 healthy controls (NOR), we compared the intestinal flora DNA sequencing and hematological testing results between every two groups using bioinformatic methods. Results: Compared to the NOR group, the intestinal flora structures of the patients in the NPC_F and NPC_S groups showed significant changes. In NPC_F, Clostridium ramosum, Citrobacter spp., Veillonella spp., and Prevotella spp. were significantly increased, and Akkermansia muciniphila and Roseburia spp. were significantly reduced. In NPC_S, C. ramosum, Veillonella parvula, Veillonella dispar, and Klebsiella spp. were significantly increased, and Bifidobacterium adolescentis was significantly reduced. A beta diversity analysis showed significant difference compared NPC_F with NOR based on Bray Curtis (P = 0.012) and Unweighted UniFrac (P = 0.0045) index, respectively. The areas under the ROC curves plotted were all 1. Additionally, the concentrations of 5-hydroxytryptamine (5-HT) in NPC_F and NPC_S were significantly higher than those of NOR. C. ramosum was positively correlated with 5-HT (rcm: 0.85, P < 0.001). A functional analysis of the intestinal flora showed that NPC_F was associated with Neurodegenerative Diseases (P = 0.023) and that NPC_S was associated with Neurodegenerative Diseases (P = 0.045) as well. Conclusion: We found that NPC was associated with structural imbalances in the intestinal flora, with C. ramosum that promoted the elevation of 5-HT and opportunistic pathogens being significantly increased, while probiotics significantly decreased. C. ramosum can be used as a novel biomarker and disease prediction models should be established for NPC. The new biomarkers and disease prediction models may be used for disease risk prediction and the screening of high-risk populations, as well as for the early noninvasive diagnosis of NPC.

Single-cell sequencing (SCS) data provide unprecedented insights into intratumoral heterogeneity. With SCS, we can better characterize clonal genotypes and build phylogenetic relationships of tumor cells/clones. However, high technical errors bring much noise into the genetic data, thus limiting the application of evolutionary tools in the large reservoir. To recover the low-dimensional subspace of tumor subpopulations from error-prone SCS data in the presence of corrupted and/or missing elements, we developed an efficient computational framework, termed RobustClone, to recover the true genotypes of subclones based on the low-rank matrix factorization method of extended robust principal component analysis (RPCA) and reconstruct the subclonal evolutionary tree. RobustClone is a model-free method, fast and scalable to large-scale datasets. We conducted a set of systematic evaluations on simulated datasets and demonstrated that RobustClone outperforms state-of-the-art methods, both in accuracy and efficiency. We further validated RobustClone on 2 single-cell SNV and 2 single-cell CNV datasets and demonstrated that RobustClone could recover genotype matrix and infer the subclonal evolution tree accurately under various scenarios. In particular, RobustClone revealed the spatial progression patterns of subclonal evolution on the large-scale 10X Genomics scCNV breast cancer dataset. RobustClone software is available at https://github.com/ucasdp/RobustClone.

Cyclosporine A (CsA), a widely used immunosuppressant to prevent organ transplant rejection, is associated with an increased cancer risk following transplantation, particularly in the lung. However, the underlying mechanisms remain unclear. In the present study, using human non‑small cell lung cancer A549 cells, it was determined that CsA (0.1 or 1 µM) promoted cell proliferation with glucose alone as the energy source. CsA treatment increased the phosphorylation of protein kinase B (Akt) and consequently the expression of Cyclin D1. Inhibiting Akt signaling with the phosphatidylinositol 3‑kinase inhibitor wortmannin prevented this effect. Mechanistically, CsA treatment increased reactive oxygen species (ROS) generation, and the intracellular ROS scavenger N‑acetyl‑cysteine (NAC) attenuated CsA‑induced cell proliferation as well as the activation of Akt/Cyclin D1 signaling. However, notably, it was demonstrated that CsA treatment decreased cell proliferation and Akt phosphorylation under normal lipid loading. Further investigation indicated that palmitic acid induced excessive generation of ROS, while CsA treatment further stimulated this ROS production. Scavenging intracellular ROS with NAC attenuated the CsA‑mediated inhibition of cell proliferation. Collectively, the results indicated a pleiotropic effect of CsA in the regulation of A549 cell proliferation under different metabolic conditions. This indicated that CsA administration may contribute to increased post‑transplant cancer risk in organ recipients.

In recent years, some viruses have caused a grave crisis to global public health, especially the human coronavirus. A truly effective vaccine is therefore urgently needed. Vaccines should generally have two features: delivering antigens and modulating immunity. Adjuvants have an unshakable position in the battle against the virus. In addition to the perennial use of aluminium adjuvant, nanoparticles have become the developing adjuvant candidates due to their unique properties. Here we introduce several typical nanoparticles and their antivirus vaccine adjuvant applications. Finally, for the combating of the coronavirus, we propose several design points, hoping to provide ideas for the development of personalized vaccines and adjuvants and accelerate the clinical application of adjuvants., Graphical abstract Unlabelled Image

Peptides of the short neuropeptide F (sNPF) family modulate feeding behavior in a wide variety of insect species, including the desert locust, Schistocerca gregaria. Likewise, the nutritional state of the animal can strongly affect sNPF expression. Although several studies have been published describing these nutrient-dependent effects, it remains largely unclear how they are achieved. In this study, we describe a series of in vivo experiments which indicate that it is not the act of feeding in se, but rather the consequent availability of nutrients in the insect's hemolymph that gives rise to the postprandial modulation of sNPF expression. Furthermore, by performing a series of RNAi-mediated knockdown experiments, we were able to show that components of the evolutionarily conserved insulin/insulin-related growth factor (IGF) signaling pathway form a functional link between nutrient levels and sNPF transcript levels.

Hepatocellular carcinoma (HCC) is a serious threat to human health. Chemotherapy drugs such as cisplatin are widely used in cancer treatment, but can cause severe side effects. Hydroxyl safflower yellow A (HSYA) is a water-soluble chalcone glycoside substance extracted from safflowers (Carthamus tinctorius L.) that has been reported to inhibit tumor growth with few side effects. The tumor immune microenvironment is crucial for the proliferation and invasiveness of tumor cells, and it is mediated by forkhead box P3-positive (FOXP3+) regulatory T cells (Tregs) and retinoic acid receptor-related orphan receptor-γ (RORγ)-expressing Th17 cells. FOXP3+ Tregs inhibit immunoreaction and FOXP3 is a key indicator of Tregs. RORγ isoform 2, also known as RORγt, is an important transcription factor in Th17 cells that may promote cancer progression. In the present study, the antitumor effect of HSYA on HCC was investigated, as well as its impact on the tumor immune microenvironment. Following the establishment of a mouse model for HCC, hematoxylin and eosin staining were performed to observe histological changes in liver tumors, and the spleen and thymus were weighed to calculate the spleen and thymus indexes. The proportion of FOXP3+ Tregs in the spleen was determined by flow cytometry, and expression levels of Foxp3 and Rorγt were examined by reverse transcription-quantitative polymerase chain reaction and western blot analysis. The results of the present study showed that cisplatin inhibited tumor growth, caused weight loss and reduced the immunoreactivity of the mice. HSYA inhibited tumor growth without causing significant weight loss. The proportion of FOXP3-expressing Tregs in the spleen and the expression of Foxp3 and Rorγt mRNA decreased following treatment with certain doses of HSYA. In conclusion, HSYA inhibited tumor growth without detrimental effects on the weight of the mice, indicating that HSYA may be suitable as a novel therapy for HCC patients.