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Luoyang is a typical heavy industrial city in China, with a coal-dominated energy structure and serious air pollution. Following the implementation of the clean air actions, the physicochemical characteristics and sources of PM2.5 have changed. A comprehensive study of PM2.5 was conducted from October 16, 2019 to January 23, 2020 to evaluate the effectiveness of previous control measures and further to provide theory basis for more effective policies in the future. Results showed that the aerosol pollution in Luoyang in autumn and winter is still serious with the average concentration of 91.1 μg/m3, although a large reduction (46.9%) since 2014. With the contribution of nitrate increased from 12.5% to 25.1% and sulfate decreased from 16.7% to 11.2%, aerosol pollution has changed from sulfate-dominate to nitrate-dominate. High NO3−/SO42− ratio and the increasing of NO3−/SO42− ratio with the aggravation of pollution indicating vehicle exhaust playing an increasingly important role in PM2.5 pollution in Luoyang, especially in the haze processes. Secondary inorganic ions contributed significantly to the enhancement of PM2.5 during the pollution period. The high value of Cl−/Na+ and EC concentration indicate coal combustion in Luoyang is still serious. The top three contributor sources were secondary inorganic aerosols (33.3%), coal combustion (13.6%), and industrial emissions (13.4%). Close-range transport from the western and northeastern directions were more important factors in air pollution in Luoyang during the sampling period. It is necessary to strengthen the control of coal combustion and reduce vehicle emissions in future policies.

Intraflagellar transport (IFT) is an evolutionarily conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella, including mammalian sperm tails. Depletion of IFT27, a component of the IFT complex, in male germ cells results in infertility associated with disrupted sperm flagella structure and motility. Leucine zipper transcription factor-like 1 (LZTFL1) is an IFT27 associated protein. LZTFL1, also known as BBS17, is a Bardet-Biedl syndrome (BBS) associated protein. Patients carrying biallelic variants of LZTFL1 gene exhibit the common BBS phenotypes. The global Lztfl1 knockout mice showed abnormal growth rate and retinal degeneration, typical of BBS phenotype. However, it is not clear if Lztfl1 has a role in male fertility. The LZTFL1 protein is highly and predominantly expressed in mouse testis. During the first wave of spermatogenesis, the protein is only expressed during spermiogenesis phase from the round spermatid stage and displays a cytoplasmic localization with a vesicular distribution pattern. At the elongated spermatid stage, LZTFL1 is present in the developing flagella and appears also close to the manchette. Fertility of Lztfl1 knockout mice was significantly reduced and associated with low sperm motility and a high level of abnormal sperm (astheno-teratozoospermia). In vitro assessment of fertility revealed reduced fertilization and embryonic development when using sperm from homozygous mutant mice. In addition, we observed a significant decrease of the testicular IFT27 protein level in Lztfl1 mutant mice contrasting with a stable expression levels of other IFT proteins, including IFT20, IFT81, IFT88 and IFT140. Overall, our results support strongly the important role of LZTFL1 in mouse spermatogenesis and male fertility.

Arteriovenous fistula (AVF) is the preferred access for hemodialysis. Percutaneous transluminal angioplasty (PTA) has become a choice for AVF stenosis, and ultrasound has been used in PTA more frequently.This single-center retrospective cohort study analyzed 129 patients who underwent PTA in the First Affiliated Hospital of Chongqing Medical University from January 2016 to December 2016. Angioplasty was performed using a noncompliant high-pressure balloon. The process was visualized by duplex scan. Our inclusion criteria were as follows: (1) stenoses or occlusions were located at the juxta-anastomosis site: the first 5 cm of the vein distal to the anastomosis; (2) stenosis was confirmed with the following conditions: (a) flow rates are 500 mL/min in the brachial artery and 200 mL/min in the fistula during dialysis, and (b) the stenosis diameter is 1.7 mm. We used the Kaplan-Meier curve to show the postintervention primary and secondary patency rates of patients with stenosis and occlusion.Altogether, 129 patients with 76 males were analyzed. Moreover, 104 have AVFs on the left arm, and only one patient had an ulnar-basilic AVF, whereas others had a radial-cephalic AVF. The postintervention primary patency rates are better in occlusion cases (P .05), whereas secondary patency rates have no difference. The postintervention primary patency rates are better in patients without diabetes mellitus (P .05), whereas the secondary patency rates had no difference.For juxta-anastomosis site stenosis or occlusion, PTA can be used to obtain satisfactory results.

Eyes absent 4 (EYA4) participates in an important role in various cancers. Patients with low EYA4 expression have significantly favorable prognosis compared with those with high EYA4 expression. However, the expression and role of EYA4 in lower grade glioma (LGG) has not been fully elucidated.The R2 and UCSC Xena browser based on data from 284 cases in GSE16011 from Gene Expression Omnibus datasets and 530 cases of patients with LGG in The Cancer Genome Atlas database were extracted for bioinformatic analyses. The EYA4 expression in different subtypes of LGG was detected. Kaplan-Meier survival curves were generated to explore the association between EYA4 expression and overall survival (OS) in both datasets.Patients with LGG with lower EYA4 expression had significantly longer 5- and 10-year OS in 2 datasets (P0.001). By matching histological subtypes and gene expression profiles of patients with LGG, oligoastrocytoma and oligodendroglioma groups had lower EYA4 expression and longer OS compared with the astrocytoma group (P0.05). Patients with IDH1 mutations and 1p19q co-deletion had longer 5- and 10-year OS (P0.001), and EYA4 expression was significantly downregulated in these patients (P0.001).This study suggests that EYA4 can be used as a prognostic marker and provide a potential therapeutic target in patients with LGG with IDH1 mutation and 1p19q co-deletion.

BACKGROUND: Many subjects with major depression (MDD) exhibit subthreshold mania symptoms (MDD+). This study investigated, for the first time, using emotional inhibition tasks, whether the neural organization of MDD+ subjects is more similar to bipolar depression (BDD) or to MDD subjects without subthreshold bipolar symptoms (MDD−). METHOD: This study included 118 medication-free young adults (15 – 30 yrs.): 20 BDD, 28 MDD+, 41 MDD− and 29 HC subjects. Participants underwent fMRI during emotional and non-emotional Go/No-go tasks during which they responded for Go stimuli and inhibited response for happy, fear, and non-emotional (gender) faces No-go stimuli. Univariate linear mixed-effects (LME) analysis for group effects and multivariate Gaussian Process Classifier (GPC) analyses were conducted. RESULTS: MDD− group compared to both the BDD and MDD+ groups, exhibited significantly lower activation in parietal, temporal and frontal regions (cluster-wise corrected p

There is no optimal treatment for central vein occlusive disease that remains a major contributor to vascular access impairment. This study aimed to review the outcomes of percutaneous treatment with a mother-child technique in the treatment of symptomatic central venous stenosis (CVS) and central venous occlusion (CVO) in patients on hemodialysis.Data were collected retrospectively and included all consecutive patients with CVS or CVO who were treated with percutaneous angioplasty and stenting. The occlusive lesions were crossed using the mother-child technique with an angiographic catheter-in-guiding catheter system.A total of 36 patients with symptomatic CVS and 45 patients with total CVO were included. The average age and gender composition were similar between the two groups. Patients with CVO had higher prevalence of diabetic nephropathy than CVS (24.4% vs 5.6%; P .05). Lesion success, device success, and procedural success were achieved in 36 (100%), 1 (100%), and 36 (100%) patients in the CVS group and in 43 (95.6%), 11 (100%), and 43 (95.6%) patients in the CVO group, respectively. There were no severe complications or procedure-related deaths in either group. During follow-up (median, 6 months), the primary patency rates were 89.7% (CVS) and 81.0% (CVO) at 6 months and were 54.2% (CVS) and 47.1% (CVO) at 12 months. The assisted primary patency rates were 100% (CVS) and 91.2% (CVO) at 6 and 12 months.With extra backup support of the mother-child technique, percutaneous treatment provides an effective and safe method for recanalization of chronic venous occlusion in patients on hemodialysis.

Background A novel coronavirus disease (COVID-19) in Wuhan has caused an outbreak and become a major public health issue in China and great concern from international community. Myocarditis and myocardial injury were suspected and may even be considered as one of the leading causes for death of COVID-19 patients. Therefore, we focused on the condition of the heart, and sought to provide firsthand evidence for whether myocarditis and myocardial injury were caused by COVID-19. Methods We enrolled patients with confirmed diagnosis of COVID-19 retrospectively and collected heart-related clinical data, mainly including cardiac imaging findings, laboratory results and clinical outcomes. Serial tests of cardiac markers were traced for the analysis of potential myocardial injury/myocarditis. Results 112 COVID-19 patients were enrolled in our study. There was evidence of myocardial injury in COVID-19 patients and 14 (12.5%) patients had presented abnormalities similar to myocarditis. Most of patients had normal levels of troponin at admission, that in 42 (37.5%) patients increased during hospitalization, especially in those that died. Troponin levels were significantly increased in the week preceding the death. 15 (13.4%) patients have presented signs of pulmonary hypertension. Typical signs of myocarditis were absent on echocardiography and electrocardiogram. Conclusions The clinical evidence in our study suggested that myocardial injury is more likely related to systemic consequences rather than direct damage by the 2019 novel coronavirus. The elevation in cardiac markers was probably due to secondary and systemic consequences and can be considered as the warning sign for recent adverse clinical outcomes of the patients.

Background Prognosis of hepatocellular carcinoma (HCC) remains poor despite significant recent improvement in therapy. Recent studies have reported that transglutaminase 3 (TGM3) plays an important role in several human cancer types. However, the role of TGM3 in HCC have not been previously elucidated. Methods We evaluated the role of TGM3 in regulating HCC cell proliferation, migration, and invasion. We also investigated the prognostic significance of TGM3 in an HCC cohort. Finally, we explored the signalling pathways that TGM3 regulates in HCC. Results We identified TGM3 to be overexpressed in HCC compared to normal tissues. Higher expression of TGM3 predicts poor prognosis in HCC patients. TGM3 knockdown led to decreased HCC cell proliferation, invasion, and xenograft tumour growth. TGM3 depletion inhibited AKT, extracellular signal–regulated kinase (ERK), p65, and glycogen synthase kinase 3β (GSK3β)/β-catenin activation, but promoted levels of cleaved caspase 3. Moreover, TGM3 knockdown cells had increased E-cadherin levels and decreased vimentin levels, suggesting that TGM3 contributes to epithelial–mesenchymal transition (EMT) in HCC. Conclusion Our results suggest that TGM3 controls multiple oncogenic pathways in HCC, thereby contributing to increased cell proliferation and EMT, and TGM3 potentially enhances HCC metastasis. TGM3 may serve as a novel therapeutic target in HCC.

Many studies have reported the prognostic value of global strain obtained with speckle tracking echocardiography (STE) in patients with acute myocardial infarction (AMI). However, as a novel method derived from STE, layer-specific strain has seldom been evaluated with respect to prediction of AMI outcomes. We sought to investigate the predictive value of layer-specific strain and whether it has incremental value compared with conventional parameters, such as left ventricular ejection fraction and wall motion score index, and STE parameters. Our study was prospective. Ninety-two patients with first-onset AMI were enrolled and underwent echocardiography before coronary intervention for analysis of global and layer-specific strain. Cox proportional hazard ratio (HR) and receiver operating characteristic curve analyses were performed for the prediction of cardiac events and cardiac death. Fifty-three patients have had cardiac events during follow-up. Endocardial longitudinal strain has received relatively higher HRs for risk predictions of both cardiac events (HR = 1.69) and cardiac death (HR = 3.21) adjusted with clinical data. The areas under the receiver operating characteristic curves of the longitudinal strain at the endocardial layer from layer-specific strain were higher than those of global strain and conventional parameters for cardiac event prediction (p ˂ 0.05, all). Layer-specific strain is valuable for cardiac risk prediction after infarction and has incremental values in addition to conventional and global STE parameters. Myocardial damage at the endocardial layer was closely related to outcomes of AMI patients at long-term follow-ups.

Photodynamic therapy (PDT) is an effective oncotherapy and has been approved for clinical application. Unfortunately, its therapeutic efficacy is usually overshadowed by tumor angiogenesis. Thus, a detailed understanding of the tumor angiogenesis upon PDT is imperative. This study aimed to investigate the potential contribution and mechanism of P-21-activated kinase 1 (PAK1) in PDT-induced tumor angiogenesis. Firstly, we found that PAK1 was upregulated upon PDT and associated with tumor angiogenesis. Then, we elucidated the underlying molecular mechanism. Activation of PAK1 prevents hypoxia-inducible factor 1 alpha (HIF-1α) protein from ubiquitin-mediated degradation. Thereafter, HIF-1α accumulation results in the upregulation of vascular endothelial growth factor (VEGF), thus promoting tumor angiogenesis. More importantly, we determined that PAK1 knockdown effectually repressed tumor angiogenesis, which contributes to enhance the therapeutic effect of PDT. Together, PAK1 is a potential novel pharmaceutical target for inhibiting PDT-induced tumor angiogenesis, and PAK1 suppression in combination with PDT may be a potentially effective strategy for anti-tumor therapy.

Background Shear stress (SS) and renin-angiotensin system (RAS) play important roles in endothelium homeostasis. Previous studies demonstrated that pulsatile shear stress (PSS) reduced the expression and activity of angiotensin-converting enzyme (ACE), however, the effect of SS on angiotensin-converting enzyme 2 (ACE2) expression is unclear. Methods and results We exposed cultured endothelial cells (ECs) to distinct patterns of SS for indicated time points, Western blot and RT-PCR were used to determine the ACE2 expression; En Face staining was used to detect ACE2 expression in vivo; cell proliferation and apoptosis were determined by BrdU staining and TUNEL staining, respectively; the production of NO was detected by a commercial kit; the promoter activity of ACE2 was determined by a Dual-Luciferase Reporter Assay System, inhibitors of ACE2 and signaling pathway were added to the medium 1 h prior for PSS. Our data showed PSS induced a sustained ACE2 expression, but OSS only induced a transient ACE2 expression. The PSS-induced ACE2 expression was higher than that of OSS both in vitro and in vivo. The PSS-induced ACE2 was involved in inhibiting proliferation and inflammation, as well as promoting NO production in ECs. PSS significantly increased ACE2 expression at transcriptional level via activating AMPKα2-KLF2 pathway. Conclusions Our results suggest PSS promotes ACE2 expression via AMPKα2-KLF2 pathway to maintain the normal EC functions.

BACKGROUND: Blue light photodynamic therapy (PDT) is effective for actinic keratosis, but many patients experience stinging pain during illumination. OBJECTIVE: To compare a conventional regimen (1 hour of 5-aminolevulinic acid [ALA] preincubation, followed by blue light) versus a new modified regimen in which blue light is started immediately after ALA application. METHODS: A clinical trial with a bilaterally controlled, intrapatient study design was conducted with 23 patients. Topical 20% ALA was applied to the entire face and/or scalp. On 1 side of the body, blue light was started immediately and continued for either 30, 45, or 60 minutes (simultaneous PDT). On the contralateral side, the blue light began 1 hour after ALA application and lasted 1000 seconds (conventional PDT). Pain was evaluated on a scale from 0 to 10. Actinic keratosis lesion counts were determined by clinical examination and photography. RESULTS: All patients experienced significantly less pain during simultaneous illumination than during the conventional regimen. At 3 months after treatment, lesion clearance was nearly identical on the 2 sides, as determined by statistical testing of noninferiority ± 15% margin. LIMITATIONS: Although bilaterally controlled, the study was relatively small. Additional studies are recommended. CONCLUSION: The modified PDT regimen is essentially painless, yet it provides treatment efficacy similar to a conventional regimen. (J Am Acad Dermatol https://doi.org/10.1016/j.jaad.2019.09.010.)

Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma (HCC) and are associated with increased mortality due to this disease. Inhibiting MDM2 has been demonstrated to be a valid approach for the treatment of HCC. However, most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding, and have limited efficacy against tumors with mutant or deficient p53. In the present study, we developed a novel MDM2 inhibitor (termed SP141) that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer cells. We demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion, independent of p53. Mechanistically, SP141 directly binds the MDM2 protein and promotes MDM2 degradation. The inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to sorafenib. In addition, in orthotopic and patient-derived xenograft models, SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis, without any host toxicity. Furthermore, the inhibition of MDM2 by SP141 is essential for its anti-HCC activities. These results provide support for the further development of SP141 as a lead candidate for the treatment of HCC. Keywords: CRISPR/Cas9, Hepatocellular carcinoma, MDM2, p53-independent, Patient-derived xenograft

Fine particle explosive growth (FPEG) events are frequently observed in heavy haze episodes in Beijing, the characteristics and formation mechanism of which remain not fully understood. In this study, a five year (2013–2017) online observation was conducted in Beijing and the chemical evolution pattern of FPEG events was analyzed to understand its formation mechanism. A total of 132 FPEG events were identified, and steadily decreased from 39 events in 2013 to 19 events in 2017. More than 70% of the FPEG events occurred in winter and autumn, which coincides with adverse weather conditions and enhanced primary emissions. Organic matter (OM) was the dominated components (~30%) in PM2.5, but it only accounted for 10% of total FPEG events as a driven factor, because its contribution usually decreased when the FPEG events developed. In contrast, the secondary inorganic species were the dominated driven factors, and sulfate-driven events accounted >50%. During the period of 2013–2017, the contribution from regional sources decreased significantly mainly due to the reduction of emissions from regional sources, while the contribution from local sources remained largely unchanged, indicating that the local secondary transformation played a leading role in promoting the FPEG events. The low nitrogen oxidation rates (NOR, 0.12 ± 0.07) and the weak increase trend of NOR with elevated RH were observed, indicating the formation of which might be promoted by the homogenous reaction between HNO3 and NH3. In contrast, a significant increase in sulfur oxidation rate (SOR, 0.50 ± 0.19) was observed when RH > 50%, suggesting enhanced heterogeneous oxidation of SO2 in FPEG events. In addition, our analysis suggest the S (IV) heterogeneous oxidation rates in FPEG events depend mainly on the aerosol liquid water content (ALWC) in addition to the aerosol acidity. This study provides observational evidence for understanding the formation mechanism of FPEG events in Beijing.

North China registers frequent air pollution episodes from high PM2.5 concentrations. Shijiazhuang is located at the intensive industrial zone of this region, but there is insufficient data on the chemical composition of PM2.5 and its sources in this city. In this study, the chemical and seasonal characteristics of PM2.5 in Shijiazhuang were investigated based on 12-h integrated PM2.5 measurements made over eight 1-month periods in each season between June 2014 and April 2016 (486 samples). The eight-season average concentration of PM2.5 was 138.8 μg m−3, and the major chemical components were secondary inorganic aerosol (SIA) species of sulfate, nitrate, and ammonium (41.5%), followed by organic matter (25.9%). The mass concentration and most of the chemical components of PM2.5 showed clear seasonal variation, with a winter-high and summer-low pattern. SO42− and NO3− were the dominant components at each pollution level in summer and autumn (18.1%–30.6% and 14.2%–27.0%, respectively). Sufficient gaseous oxidants (O3) concentrations and suitable meteorology conditions were observed in these two seasons. Highest SOR (0.61), SO42−/EC(10.8) and NOR (0.58), NO3−/EC (5.9) were found in summer and autumn, which indicated intense secondary transformation in these two seasons. Organic matter was the dominant species in winter, which increased from 17.1 μg m−3 for clean days (28.7% of PM2.5) to 169.1 μg m−3 (38.4% of PM2.5). The accumulation of primary emissions (coal combustion and biomass burning) was responsible for the increasing OM trend (especially for POC). The highest and leading proportion of mineral dust occurred in spring (20.3%–46.5%) as a result of higher wind speeds (up to 3 m/s). Potential source contribution function (PSCF) analyses implied that the border areas of Hebei, Henan and Shandong Provinces, together with the central area of Shanxi Province, contributed significantly to the PM2.5 pollution in Shijiazhuang, especially in autumn and winter.

Due to inadequate lateral stiffness and insufficient structural redundancy, many single-span reinforced concrete (RC) frames were highly damaged or collapsed in previous earthquakes. This paper presents an experimental study on seismic performance of rehabilitated single-span RC frames. Four frames were strengthened using various retrofitting strategies and one non-retrofitted frame served as the reference specimen. All these frames were fabricated and tested under cyclic loadings. The failure modes, hysteretic behavior, skeleton curve, energy dissipation, strength and stiffness degradation of each frame were evaluated. The validity of different strengthening methods for improving frames’ failure mechanisms and seismic performances was verified. Test results indicated that strength, stiffness, as well as many seismic characteristics of the strengthened frames were improved substantially.

Backgroud The glycogen synthase kinase-3β inhibitor thiadiazolidinone derivative 8 (TDZD-8) has been reported to reduce renal ischemia reperfusion (I/R) injury through inhibiting cell damage. However, it is not known whether TDZD-8 could also play a role in protecting the kidney in rat kidney transplantation with renal cold I/R. The aim of the present study was to explore the possible role of TDZD-8 in protecting renal damage in a cold I/R model of rat kidney transplantation. Methods The rat model of kidney transplantation with renal cold I/R was established. The renal tissue pathomorphologic changes, renal function, oxidative stress, and inflammatory response were evaluated by detection of a series of indices by hematoxylin and eosin staining, commercial kits, enzyme-linked immunosorbent assay, and spectrophotofluorometry, respectively. Results Compared with I/R and Graft groups, renal function was significantly improved in TDZD and TDZD-G groups, which were accompanied by the reduction of renal injury, oxidative stress, and inflammation. Conclusions These results suggest that preconditioning with glycogen synthase kinase-3β inhibitor can attenuate kidney transplantation with renal cold I/R through regulating endogenous antioxidant activity and inflammation.

Background Renal ischemia/reperfusion (I/R) injury (RI/RI) is a common complication of diabetes mellitus (DM) in surgical practice. Oxidative stress plays a crucial role in this process. Recombinant human erythropoietin (rhEPO) is usually used to treat anemia resulting from several diseases. However, the functional involvement of rhEPO in diabetic RI/RI remains unclear. The present study was intended to investigate the antioxidant role of rhEPO on RI/RI in DM rats. Methods The bilateral renal arteries and veins of streptozotocin-induced diabetic rats were subjected to 45 minutes of ischemia followed by 1, 6, and 24 hours of reperfusion with or without rhEPO pretreatment at the beginning of an I/R procedure. The renal tissue pathomorphology, renal function, oxidative stress, and inflammatory response were evaluated by detection of a series of indices by hematoxylin-eosin staining, commercial kits, enzyme-linked immunosorbent assay, and spectrophotofluorometry, respectively. Results Compared to the I/R group, renal function was significantly advanced in the erythropoietin group, whose subjects were also subjected to renal tissue injury, oxidative stress, and inflammation. Conclusion These results suggest that rhEPO preconditioning can attenuate diabetic RI/RI through regulating endogenous antioxidant activity.

Sanggenon O (SO) is a Diels-Alder type adduct extracted fromMorus alba, which has been used for its anti-inflammatory action in the Oriental medicine. However, whether it has regulatory effect on human cancer cell proliferation and what the underlying mechanism remains unknown. Here, we found that SO could significantly inhibit the growth and proliferation of A549 cells and induce its pro-apoptotic action through a caspase-dependent pathway. It could also impair the mitochondria which can be reflected by mitochondrial membrane permeabilization. Besides, SQSTM1 up-regulation and autophagic flux measurement demonstrated that exposure to SO led to autophagosome accumulation, which plays a protective role in SO-treated cells. In addition, knocking down of LC3B increased SO triggered apoptotic cell rates. These results indicated that SO has great potential as a promising candidate combined with autophagy inhibitor for the treatment of NSCLC. In conclusion, our results identified a novel mechanism by which SO exerts potent anticancer activity.

Background Death-associated protein kinase 1 (DAPK1) is a widely distributed serine/threonine kinase that is critical for cell death in multiple neurological disorders, including Alzheimer’s disease and stroke. However, little is known about the role of DAPK1 in the pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder. Methods We used Western blot and immunohistochemistry to evaluate the alteration of DAPK1. Quantitative polymerase chain reaction and fluorescence in situ hybridization were used to analyze the expression of microRNAs in PD mice and patients with PD. Rotarod, open field, and pole tests were used to evaluate the locomotor ability. Immunofluorescence, Western blot, and filter traps were used to evaluate synucleinopathy in PD mice. Results We found that DAPK1 is posttranscriptionally upregulated by a reduction in microRNA-26a (miR-26a) caused by a loss of the transcription factor CCAAT enhancer-binding protein alpha. The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy. Suppressing miR-26a or upregulating DAPK1 results in synucleinopathy, dopaminergic neuron cell death, and motor disabilities in wild-type mice. In contrast, genetic deletion of DAPK1 in dopaminergic neurons by crossing DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment. We further showed that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of α-synuclein at the serine 129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of α-synuclein prevents motor disorders, synucleinopathy, and dopaminergic neuron loss in the MPTP mice. Conclusions miR-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.

Long noncoding RNAs (lncRNAs) are implicated as novel drivers in hepatocellular carcinoma (HCC), but the underlying mechanisms of this relationship with hepatocarcinogenesis are unknown. We report a novel, liver-specific lncRNA LINC01093 that shows significant downregulation in HCC tissues. LINC01093 expression is inversely correlated with cancer embolus and HCC TNM stage and as a prognostic predictor for HCC patients. LINC01093 overexpression significantly suppresses HCC cell proliferation and metastasis in vitro and in vivo. Conversely, its knockdown promotes HCC progression. Mechanistic analyses indicate that LINC01093 directly binds insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), interfering with interaction between IGF2BP1 and glioma-associated oncogene homolog 1 (GLI1) mRNA. The result is degradation of GLI1 mRNA, further affecting expression of GLI1 downstream molecules involved in HCC progression. The liver-enriched lncRNA LINC01093 is a promising prognostic indicator for HCC patients, and the newly identified LINC01093-IGF2BP1-GLI1 axis shows potential for therapeutic targets in HCC.

Pasteurella multocida is the causative agent of a wide range of disease (pasteurellosis) and a zoonotic pathogen in humans. Some pathogenic bacteria are able to exploit host plasminogen for migration across tissue barriers or evade from host innate immunity. However, there is no study on host plasminogen exploitation of P. multocida. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been reported to be a plasminogen receptor in many pathogenic bacteria, but its role in P. multocida exploiting plasminogen has not yet been characterized. The aim of this study was to detect the activity of P. multocida to exploit host plasminogen and evaluate the ability of GAPDH to act as a receptor in the recruitment process. P. multocida could recruit host plasminogen and exhibited plasmin activity when stimulated by urokinase. GAPDH exhibited binding activity to plasminogen. GAPDH Antiserum significantly decrease the plasminogen recruitment activity of P. multocida. In conclusion, P. multocida is able to exploit host plasminogen via GAPDH. To our knowledge, this is the first report on host plasminogen exploitation of P. multocida.

Background Hepatic ischemia/reperfusion-induced pancreatic injury (HI/RPI) is an important pathophysiological phenomenon in clinics. Exenatide is found to have hepatopancreatic protection; however, the half-life of exenatide is extremely short, which limits its clinical application. In the present study, we described an exenatide nanocarrier based on poly(L-lysine)-poly(ethylene glycol)-poly(L-lysine) (PLL-PEG-PLL) and aimed to investigate the protective effects of exenatide/PLL-PEG-PLL on HI/RPI. Methods PLL-PEG-PLL was synthesized and estimated by being applied as a nanocarrier for lengthening delivery of exenatide. Exenatide was loaded into PLL-PEG-PLL by electrostatic interactions at pH 7.4. The loading and release of exenatide from PLL-PEG-PLL were characterized in vitro. The pancreatic protection of exenatide/PLL-PEG-PLL was assessed using the animal model, histopathological examination, blood biochemical indices detection, antioxidant activity, and anti-inflammatory evaluation in vivo. Results Exenatide/PLL-PEG-PLL displayed efficient loading and sustained release. Exenatide/PLL-PEG-PLL complex moderated HI/RPI and enlarged islet functionality compared to free exenatide. Conclusion We propose that the nanocarrier PLL-PEG-PLL may function as a potent exenatide nanocarrier for augmenting anti-HI/RPI pharmacotherapy with unprecedented clinical benefits.

Background Innate lymphoid cells (ILCs) are a newly discovered family of immune cells that have similar cytokine-secreting profiles as T helper cell subsets. Although ILCs are critical for host defense against infections and tissue homeostasis, their roles in tumor development are not well established. Methods We studied the function of ILC3 cells in the liver for the development of hepatocellular carcinoma (HCC) in murine HCC models using flow cytometry, adoptive transfer, and in vitro functional assays. Findings We found that ILC3 lacking the natural cytotoxicity-triggering receptor (NCR−ILC3) promoted the development of HCC in response to interleukin 23 (IL-23). IL-23 serum level is elevated in HCC patients and its high expression is associated with poor clinical outcomes. We found that IL-23 could promote tumor development in murine HCC tumor models. IL-23 promoted the expansion of NCR−ILC3 and its differentiation from group 1 ILCs (ILC1s). Furthermore, NCR−ILC3 initiated IL-17 production upon IL-23 stimulation and directly inhibited CD8+ T cell immunity by promoting lymphocyte apoptosis and limiting their proliferation. Interpretation Together, our findings suggest that NCR−ILC3 initiates the IL-17-rich immunosuppressive tumor microenvironment and promotes the development of HCC, thus may serve as a promising target for future cancer immunotherapy. Fund This work was supported by grants from National Natural Science Foundation of China (81471586, 81571556), the Priority Academic Program Development of Jiangsu Higher Education Institutions, the collaborative Innovation Center of Hematology, start-up grant from National University of Singapore, the Cancer Prevention and Research Institute of Texas CPRIT (RR180017), and the National Cancer Institute's Cancer Center Support (Core) Grant CA016672 (to The University of Texas MD Anderson Cancer Center).

This study, for the first time, compared illness and antidepressant response characteristics of young subjects with major depression (MDD) at low (LRMDD) or high-risk (HRMDD) for developing bipolar disorder with characteristics of young bipolar (BPD) subjects and healthy controls (HC).One hundred and six young (15-30 yr), medication-free subjects MDD subjects (HRMDD, N = 51; LRMDD, N = 55) were compared with 32 BPD (Type I: 14; Type II: 18) as well as 49 HC subjects. Baseline illness characteristics and frequency of comorbid conditions were examined using Analysis of Variance and Cochran-Armitage trend test. Additionally, in MDD subjects, the effect of open-label antidepressant treatment for up to 24 months with periodic assessments was compared between HRMDD and LRMDD groups for treatment response, remission and (hypo)mania switch while controlling for attrition.Significant gradation from LRMDD to HRMDD to BPD groups was found for increasing occurrence of alcohol dependence (p = 0.006), comorbid PTSD (p = 0.006), borderline personality traits (p = 0.001), and occurrence of melancholic features (p 0.005). Antidepressant treatment response was similar between the two groups except that for the 12-month period HRMDD showed a trend for a lower response. Switch to (hypo)mania was infrequent in both groups though the HRMDD showed a higher occurrence of spikes in (hypo)mania symptoms (25% increase in YMRS scores)(p = 0.04).Findings of the study indicate that a substantial proportion of young MDD subjects share BPD illness characteristics. These HRMDD subjects, if treated with antidepressants, need to be monitored for development of BPD.NCT01811147.

MicroRNAs (miRNAs), small noncoding RNA molecules, have emerged as important factors during intervertebral disc degeneration. This study was to determine whether miR-202-3p regulates interleukin-1β (IL-1β)–induced expression of matrix metalloproteinase 1 (MMP-1) in human nucleus pulposus (NP) cells. Human NP cells were stimulated with IL-1β in vitro. MicroRNA arrays were used to determine the expression profile of 1971 human miRNAs and the miRNAs targets were identified using bioinformatics. In IL-1β–stimulated NP cells, 10 microRNAs were down-regulated, 2 microRNAs were up-regulated. There was a significant reduction in hsa-miR-202-3p (miR-202-3p) expression in the severe degenerative disc compared with mild degenerative disc. Down-regulation of miR-202-3p expression by IL-1β was correlated with up-regulation of MMP-1 expression in human NP cells. IL-1β-induced activation of MAP kinase (MAPK) and nuclear factor-κB (NF-κB) decreased miR-202-3p expression and induced MMP-1 expression. MiR-202-3p suppressed IL-1β–induced MMP-1 production. Conversely, treatment with anti-miR-202-3p remarkably increased MMP-1 production. In addition, mutation of the miR-202-3p binding site in the 3’-UTR of MMP-1 mRNA abolished miR-202-3p–mediated repression of reporter activity. Functional analysis showed that miR-202-3p could decrease type II collagen degradation, whereas overexpression of MMP-1 by Lentiviral-shMMP-1 abolished the effect of miR-202-3p on type II collagen degradation. These results suggest that miR-202-3p is an important regulator of MMP-1 in human nucleus pulposus and may contribute to the development of intervertebral disc degeneration.

Aberrant increase in mitochondrial biogenesis is common in human ovarian cancer and has great therapeutic value. In this work, we demonstrate that tigecycline, a FDA-approved broad spectrum antibiotic, selectively targets ovarian cancer cells through inhibition of mitochondrial translation. Tigecycline dose-dependently inhibits proliferation of ovarian cancer cells via arresting them at G2/M phase and induces apoptosis through caspase pathway. At the same concentration, tigecycline either does not or inhibits normal cells in a less extent than ovarian cancer cells. Mechanistically, tigecycline specifically inhibits translation by mitochondrial ribosome but not nuclear or cytosolic ribosome, leading to mitochondrial dysfunction, oxidative stress and damage, AMPK activation and inhibition of mTOR signaling in ovarian cancer cells. We further show that the inhibitory effects on ovarian cancer cell by tigecycline is mediated by its suppression of mitochondrial respiration. Importantly, the combination of tigecycline and cisplatin at sublethal concentration results in much greater efficacy than cisplatin alone in vitro and in vivo. Additionally, the effective dose of tigecycline in ovarian cancer is clinically achievable. Our study suggests that tigecycline is a useful addition to the treatment of ovarian cancer. Our work also highlights the targeted therapeutic potential of mitochondrial respiration in ovarian cancer.

Background Platelet microparticles (PMPs) are closely associated with diabetic macrovascular complications. This study aimed to explore the underlying mechanisms of high glucose-induced PMPs generation. Methods Washed platelets, obtained from the plasma of healthy male Sprague-Dawley rats, were incubated with high glucose. PMPs were isolated using gradient centrifugation and counted by flow cytometry. Expression and activity of ROCK1 and caspase3 were evaluated by real-time PCR, Western blotting, and activity assay kit. Results High glucose enhanced PMPs shedding in the presence of collagen. The mRNA and protein levels of ROCK1, but not ROCK2, were increased in platelets incubated with high glucose. Y-27632, an inhibitor of ROCK, blocked the increased PMPs shedding induced by high glucose. Expression and activity of caspase3 were elevated in platelets under the high glucose conditions. Z-DVED-FMK, a caspase3 inhibitor, inhibited ROCK1 activity and decreased the PMPs generation under high glucose. Conclusion High glucose increased PMPs shedding via caspase3-ROCK1 signal pathway.

An elastic dynamics model for a valve train including combined stiffness of oil film and dry contact between a cam and a tappet, is proposed. Multi-directional elastic deformations of the valve train are solved by discretizing slender components into Rayleigh beam and bar elements. The oil film stiffness is determined by non-Newtonian elastohydrodynamic lubrication in the line contact, whereas the dry contact stiffness is achieved by using finite element contact analysis. A numerical solution for the dynamic model is developed and verified by conducting a dynamic stress experiment. The influences of rotation speed on the oil film stiffness and contact force between the cam and the tappet are discussed, and the combined effects of rotation speed and oil film stiffness on a dynamic transmission error of the valve train are analyzed. Results show that the oil film stiffness decreases when the cam rotation speed increases within a certain range, whereas the sharp increased contact force may enlarge the oil film stiffness when the speed exceeds a critical value. The oil film stiffness variation slight influences the contact force, but such variation significantly affects the dynamic transmission error.

Effective treatment for acute lung injury (ALI) is in high demand. Lung-targeted ternary nanoparticles containing anti-intercellular adhesion molecule-1 (ICAM-1) antibody-conjugated simvastatin-loaded nanostructured lipid carrier (ICAM/NLC), protamine (Pro), and angiopoietin-1 (Ang-1) gene (ICAM-NLC/Pro/Ang) were developed for ALI therapy. The ternary nanoparticles with different weight ratios of ICAM-NLC to Ang-1 gene were prepared via charge interaction. The anti-ICAM-1 antibody-conjugated ternary nanoparticles exhibited higher cellular uptake and transfection efficiency (from 26.7% to 30.9%) in human vascular endothelial cell line EAhy926 than the non-targeted control. The largest size of ICAM-NLC/Pro/Ang (357.1 nm) was employed for further study, which significantly up-regulated in vitro and in vivo Ang-1 protein expression. In vivo i.v. administration of ICAM-NLC/Pro/Ang (357.1 nm) significantly attenuated pulmonary TNF-α and IL-6 levels, inflammatory cell infiltration, and led to positive histological improvements in lipopolysaccharide-induced ALI mice. Collectively, the ICAM-NLC/Pro/Ang that co-delivered simvastatin and Ang-1 gene may represent a potential treatment modality for ALI.

Background: Severe cases of coronavirus disease 2019 (COVID-19) rapidly develoacute respiratory distress leading to respiratory failure, with remarkably high

The emergence of novel plasmid-mediated high-level tigecycline resistance genes tet(X) in the Enterobacteriaceae has increased public health risk for treating severe bacterial infections. Despite growing reports of tet(X)-positive isolates detected in animal sources, the epidemiological association of animal- and environment-derived isolates with human-derived isolates remains unclear. Here, we performed a comprehensive analysis of tet(X4)-positive Escherichia coli isolates collected in a hospital in Guangdong province, China. A total of 48 tet(X4)-positive E. coli isolates were obtained from 1001 fecal samples. The tet(X4)-positive E. coli isolates were genetically diverse but certain strains that belonged to ST48, ST10, and ST877 etc. also have clonally transmitted. Most of the tet(X4) genes from these patient isolates were located on conjugative plasmids that were successfully transferred (64.6%) and generally coexisted with other antibiotic resistance genes including aadA, floR, blaTEM and qnrS. More importantly, we found the IncX1 type plasmid was a common vector for tet(X4) and was prevalent in these patient-derived strains (31.3%). This plasmid type has been detected in animal-derived strains from different species in different regions demonstrating its strong transmission ability and wide host range. Furthermore, phylogenetic analysis revealed that certain strains of patient and animal origin were closely related indicating that the tet(X4)-positive E. coli isolates were likely to have cross-sectorial clonal transmission between humans, animals, and farm environments. Our research greatly expands the limited epidemiological knowledge of tet(X4)-positive strains in clinical settings and provides definitive evidence for the epidemiological link between human-derived tet(X4)-positive isolates and animal-derived isolates.

The detection of cancer cells at the single-cell level enables many novel functionalities such as next-generation cancer prognosis and accurate cellular analysis. While surface-enhanced Raman spectroscopy (SERS) has been widely considered as an effective tool in a low-cost and label-free manner, however, it is challenging to discriminate single cancer cells with an accuracy above 90% mainly due to the poor biocompatibility of the noble-metal-based SERS agents. Here, we report a dual-functional nanoprobe based on dopant-driven plasmonic oxides, demonstrating a maximum accuracy above 90% in distinguishing single THP-1 cell from peripheral blood mononuclear cell (PBMC) and human embryonic kidney (HEK) 293 from human macrophage cell line U937 based on their SERS patterns. Furthermore, this nanoprobe can be triggered by the bio-redox response from individual cells towards stimuli, empowering another complementary colorimetric cell detection, approximately achieving the unity discrimination accuracy at a single-cell level. Our strategy could potentially enable the future accurate and low-cost detection of cancer cells from mixed cell samples.

In temporal lobe epilepsy (TLE), abnormal axon guidance and synapse formation lead to sprouting of mossy fibers in the hippocampus, which is one of the most consistent pathological findings in patients and animal models with TLE. Glypican 4 (Gpc4) belongs to the heparan sulfate proteoglycan family, which play an important role in axon guidance and excitatory synapse formation. However, the role of Gpc4 in the development of mossy fibers sprouting (MFS) and its underlying mechanism remain unknown. Using a pilocarpine-induced mice model of epilepsy, we showed that Gpc4 expression was significantly increased in the stratum granulosum of the dentate gyrus at 1 week after status epilepticus (SE). Using Gpc4 overexpression or Gpc4 shRNA lentivirus to regulate the Gpc4 level in the dentate gyrus, increased or decreased levels of netrin-1, SynI, PSD-95, and Timm score were observed in the dentate gyrus, indicating a crucial role of Gpc4 in modulating the development of functional MFS. The observed effects of Gpc4 on MFS were significantly antagonized when mice were treated with L-leucine or rapamycin, an agonist or antagonist of the mammalian target of rapamycin (mTOR) signal, respectively, demonstrating that mTOR pathway is an essential requirement for Gpc4-regulated MFS. Additionally, the attenuated spontaneous recurrent seizures (SRSs) were observed during chronic stage of the disease by suppressing the Gpc4 expression after SE. Altogether, our findings demonstrate a novel control of neuronal Gpc4 on the development of MFS through the mTOR pathway after pilocarpine-induced SE. Our results also strongly suggest that Gpc4 may serve as a promising target for antiepileptic studies.

Circular RNAs (circRNAs) participate in the progression of many diseases, but knowledge on the role of circRNAs in intervertebral disc degeneration (IDD) is limited. In this study, we discovered the characteristics of a new circRNA (circ_0022382) in human endplate chondrocytes. Currently, real-time quantitative polymerase chain reaction (RT-qPCR) showed that the relative expression level of circ_0022382 was significantly lower under intermittent cyclic tension stimulation than in the control group. circ_0022382, miR-4726-5p and Transforming growth factor 3 (TGF-β3) were evaluated by RT-qPCR, Western Blot and immunofluorescence assay. Additionally, the role and mechanism of circ_0022382 in vivo were also consistent in the rat model. Furthermore, Intermittent cyclic mechanical tension can cause degeneration of endplate chondrocytes. The tension-sensitive circRNA_0022382 was decreased, and we found that circRNA_0022382 promoted morphology of endplate chondrocytes by sponge-binding miR-4726-5p down-regulation of target gene the TGF-β3 expression, thereby alleviating IDD. In a rat model of acupuncture, intervertebral disc injection of circ_0022382 relieved the progression of IDD in vivo. In conclusion, the circ_0022382/miR-4726-5p/TGF-β3 axis plays a key role in the anabolism and catabolism of the endplate chondrocyte extracellular matrix (ECM). It is suggested that circ_0022382 may provide a new approach for the prevention and treatment of IDD.

Residential green space and neighborhood walkability are important foundations of a healthy and sustainable city. Yet, their associations with atherosclerosis, the disease underlying clinical coronary heart disease (CHD), is unknown, especially in susceptible populations. We aim to explore the associations of exposure to residential green space and neighborhood walkability with coronary atherosclerosis. In this study of 2021 adults with suspected CHD, we evaluated the associations of exposure to green space (using Normalized Difference Vegetation Index [NDVI] and enhanced vegetation index [EVI] surrounding each participant’s home) and neighborhood walkability (using walkability index and number of parks near home) with atherosclerosis (using coronary artery calcium score, CAC) using linear regression model adjusted for individual-level characteristics. Mediation analysis was further applied to explore potential mechanisms through the pathways of physical activity, air pollution, and psychological stress. In the primary model, an interquartile increase in annual mean NDVI and EVI within the 1-km area was associated with −15.8% (95%CI: −28.7%, −0.7%), and −18.6% (95%Cl: −31.3%, −3.6%) lower CAC score, respectively. However, an interquartile increase in the walkability index near home was associated with a 7.4% (95% CI: 0.1%, 15.2%) higher CAC score. The combined exposure to a green space area in a 1-km area and the walkability index were inversely associated with atherosclerosis, albeit with a smaller magnitude than a single-exposure model. The findings from a mediation analysis suggested that increased physical exercise and ameliorated particulate matter < 2.5 μm (PM(2.5)) may partially contribute to the relationship between green space and atherosclerosis, and for walkability index, partially explained by increased PM(2.5) exposure. Our study suggested a beneficial association between green space and atherosclerosis, but an adverse association between neighborhood walkability and atherosclerosis. Therefore, urban development that aims to improve neighborhood walkability should jointly account for enhancing green space properties from a public health perspective.

Disruption of carotid vulnerable atherosclerotic plaque is responsible for acute ischemic stroke (AIS) and the early detection and intervention approach are greatly limited. Undertaking a microarray of microRNAs (miRNAs) in the plasma of AIS patients with carotid vulnerable plaques, miR-23a-5p was markedly elevated and was positively correlated with the plaque progression and vulnerability. Correspondingly, we found that miR-23a-5p expression was significantly increased in both plasma and macrophages from atherosclerosis mice. Bioinformatics analysis and in vitro knockdown experiments identified that ATP-binding cassette transporter A1/G1 as a novel target of miR-23a-5p. Luciferase reporter assays showed that miR-23a-5p repressed the 3' untranslated regions (UTR) activity of ABCA1/G1. Moreover, functional analyses demonstrated that transfection of miR-23a-5p inhibitor enhanced cholesterol efflux and decreased foam cell formation through upregulating ABCA1/G1 expression levels. Furthermore, long term in vivo systemically delivered miR-23a-5p antagomir significantly increased ABCA1/G1 expression in the aorta of ApoE-/- mice. Importantly, the miR-23a-5p antagomir therapy significantly reduced atherosclerosis progression and promoted plaque stability. Our observations indicate that miR-23a-5p promotes macrophage-derived foam cell formation and might be a key regulator contributing to atherosclerotic plaque progression and vulnerability.

Brain tissue survival and functional recovery after ischemic stroke greatly depend on cerebral vessel perfusion and functional collateral circulation in the ischemic area. Semaphorin 3E (Sema3E), one of the class 3 secreted semaphorins, has been demonstrated to be a critical regulator in embryonic and postnatal vascular formation via binding to its receptor PlexinD1. However, whether Sema3E/PlexinD1 signaling is involved in poststroke neovascularization remains unknown. To determine the contribution of Sema3E/PlexinD1 signaling to poststroke recovery, aged rats (18 months) were subjected to a transient middle cerebral artery occlusion. We found that depletion of Sema3E/PlexinD1 signaling with lentivirus-mediated PlexinD1-specific-shRNA improves tissue survival and functional outcome. Sema3E/PlexinD1 inhibition not only increases cortical perfusion but also ameliorates blood-brain barrier damage, as determined by positron emission tomography and magnetic resonance imaging. Mechanistically, we demonstrated that Sema3E suppresses endothelial cell proliferation and angiogenic capacity. More importantly, Sema3E/PlexinD1 signaling inhibits recruitment of pericytes by decreasing production of platelet derived growth factor-BB in endothelial cells. Overall, our study revealed that inhibition of Sema3E/PlexinD1 signaling in the ischemic penumbra, which increases both endothelial angiogenic capacity and recruitment of pericytes, contributed to functional neovascularization and blood-brain barrier integrity in the aged rats. Our findings imply that Sema3E/PlexinD1 signaling is a novel therapeutic target for improving brain tissue survival and functional recovery after ischemic stroke.

To investigate whether different quantitative measurements of increased signal intensity (ISI) on T2-weighted magnetic resonance imaging are useful for predicting surgical outcome in patients with cervical spondylotic myelopathy (CSM).We retrospectively reviewed 108 patients with ISI who underwent surgery for CSM. Clinical outcome was evaluated via the Japanese Orthopaedic Association (JOA) score and the recovery rate. Patients were divided into 2 groups based on the JOA recovery rate: good (≥50%) and fair (50%). The quantitative measurements of ISI included the maximum vertical length and the signal change ratio (SCR). C2-C7 sagittal alignment, C2-C7 sagittal vertical axis, C2-C7 range of motion, maximum spinal cord compression, and maximum canal compromise also were assessed.There were no significant differences in cervical sagittal alignment parameters between the groups. Multivariate analysis showed that a longer duration of symptoms, a lower preoperative JOA score, a longer preoperative ISI length, and a greater preoperative SCR were negatively associated with clinical outcomes. Receiver operating characteristic curve analysis showed that the best cutoff values of ISI length and SCR as negative predictors of surgical outcome were 15.50 mm and 1.56, respectively, and the areas under the receiver operating characteristic curve of preoperative ISI length, SCR that discriminate recovery rate of JOA score (≥50%,50%) were 0.8507, 0.8422, respectively, and was 0.8903 for a combination of the 2.Duration of symptoms, preoperative JOA score, preoperative ISI length, and SCR can reflect surgical outcome in patients with CSM; however, cervical sagittal alignment may not affect surgical outcome. Combining ISI length and SCR to depict ISI on T2-weighted magnetic resonance imaging is optimal and accurate. Patients with ISI length15.50 mm and SCR1.56 have fair surgical recovery.

Spodoptera exigua has developed very high resistance to pyrethroid insecticides; however, the mode-of-action target of pyrethroids has not been studied, and the mechanism for target resistance remains elusive in this insect. In this study the resistance level of a field collected population from Huizhou, China was assayed with leaf-dip method and further selected in laboratory. The transcripts of voltage-gated sodium channel gene from S. exigua were cloned and analyzed for the structural characteristics, the relative expression levels of transcripts were measured by quantitative RT-PCR. Finally, detection of the point mutations was performed. The bioassay indicated that Huizhou population had developed 309.5-fold resistance to lambda-cyhalothrin, and the selection in laboratory led to the resistant strain (HZ14-sel) with increased resistance of 423-fold. Nine transcripts of sodium channel with 4517–6149 bp nucleotides were identified from S. exigua, among which only one transcript (SeNav4) encode the functional protein with complete domains, and other eight transcripts were observed to lost some transmembrane segments. The L834F mutation in IIS6 corresponding for the typical kdr mutation “L1014F”, was detected in 50% individuals of HZ14-sel strain. These results suggested that lambda-cyhalothrin resistance is associated with point mutations and expression level changes of sodium channel transcripts in HZ14-sel strain.

Based on the abnormally increased expression of CD44 receptors on renal tubule epithelial cells during ischemia/reperfusion-induced acute kidney injury (AKI), we developed a hyaluronic acid-curcumin (HA-CUR) polymeric prodrug targeting to epithelial cells and then relieving oxidative stress damages. The water solubility of HA-CUR was significantly enhanced and approximately 27-fold higher than that of CUR. Cellular uptake test showed HA-CUR was preferably internalized by H2O2-pretreated tubular epithelial (HK-2) cells compared with free CUR benefiting from the specific binding between HA and CD44 receptors. Biodistribution results further demonstrated the increased accumulation of HA-CUR in kidneys with 13.9-fold higher than that of free CUR. Pharmacodynamic studies indicated HA-CUR effectively ameliorated AKI, and the exact mechanism was that HA-CUR protected renal tubule epithelial cells from oxidative stress damage via inhibiting PtdIns3K-AKT-mTOR signaling pathway. Taken together, this study provides a new therapeutic strategy for the treatment of AKI based on the pathogenesis of the disease.

Chronic stress produces maladaptive pain responses, manifested as alterations in pain processing and exacerbation of chronic pain conditions including irritable bowel syndrome. Female predominance, especially during reproductive years, strongly suggests a role of gonadal hormones. However, gonadal hormone modulation of stress-induced pain hypersensitivity is not well understood. In the present study, we tested the hypothesis that estradiol is pronociceptive and testosterone is antinociceptive in a model of stress-induced visceral hypersensitivity (SIVH) in rats by recording the visceromotor response to colorectal distention after a 3-day forced swim (FS) stress paradigm. FS induced visceral hypersensitivity that persisted at least 2 weeks in female, but only 2 days in male rats. Ovariectomy blocked and orchiectomy facilitated SIVH. Furthermore, estradiol injection in intact male rats increased SIVH and testosterone in intact female rats attenuated SIVH. Western blot analyses indicated estradiol increased excitatory glutamate ionotropic receptor NMDA type subunit 1 expression and decreased inhibitory metabotropic glutamate receptor 2 expression after FS in male thoracolumbar spinal cord. In addition, the presence of estradiol during stress increased spinal brain-derived neurotrophic factor (BDNF) expression independent of sex. In contrast, testosterone blocked the stress-induced increase in BDNF expression in female rats. These data suggest that estradiol facilitates and testosterone attenuates SIVH by modulating spinal excitatory and inhibitory glutamatergic receptor expression. Perspective SIVH is more robust in female rats. Estradiol facilitates whereas testosterone dampens the development of SIVH. This could partially explain the greater prevalence of certain chronic visceral pain conditions in women. An increase in spinal BDNF is concomitant with increased stress-induced pain. Pharmaceutical interventions targeting this molecule could provide promising alleviation of SIVH in women.

Organic carbon (OC) and elemental carbon (EC) in the PM2.5 of urban Beijing were measured hourly with a semi-continuous thermal-optical analyzer from Jan 1, 2013 to Dec 31, 2014. The annual average OC and EC concentrations in Beijing were 17.0 ± 12.4 and 3.4 ± 2.0 μg/m3 for 2013, and 16.8 ± 14.5 and 3.5 ± 2.9 μg/m3 for 2014. It is obvious that the annual average concentrations of OC and EC in 2014 were not less than those in 2013 while the annual average PM2.5 concentration (89.4 μg/m3) in 2014 was slightly reduced as compared to that (96.9 μg/m3) in 2013. Strong seasonality of the OC and EC concentrations were found with high values during the heating seasons and low values during the non-heating seasons. The diurnal cycles of OC and EC characterized by higher values at night and in the morning were caused by primary emissions, secondary transformation and stable meteorological condition. Due to increasing photochemical activity, the OC peaks were observed at approximately noon. No clear weekend effects were observed. Interestingly, in the early mornings on weekends in the autumn and winter, the OC and EC concentrations were close to or higher than those on weekdays. Our data also indicate that high OC and EC concentrations were closely associated with their potential source areas which were determined based on the potential source contribution function analysis. High potential source areas were identified and were mainly located in the south of Beijing and the plain of northern China. A much denser source region was recorded in the winter than in the other seasons, indicating that local and regional transport over regional scales are the most important. These results demonstrate that both regional transport from the southern regions and local accumulation could lead to the enhancements of OC and EC and likely contribute to the severe haze pollution in Beijing.

Summary Conventional water-splitting electrolysis drives the H 2 and O 2 evolution reactions (HER and OER, respectively) simultaneously with large voltage inputs. Herein, two inexpensive iron complexes as proton-independent electron reservoirs (ERs) are described for decoupled water electrolysis. (Ferrocenylmethyl)trimethylammonium chloride and Na 4 [Fe(CN) 6 ], which have proper redox potentials in aqueous media, are able to couple their oxidation with HER. The subsequent reduction of the oxidized ER + is then paired with OER. Both steps require much smaller voltage than that of direct water splitting. Nearly 100% Faradic efficiency and remarkable cycling stability were obtained for both ERs. Such decoupled water splitting could also be driven by photovoltaic cells with small photovoltages under sunlight irradiation. Furthermore, a two-step electrolysis of HER and the oxidation of 5-hydroxymethylfurfural mediated by Na 4 [Fe(CN) 6 ] was demonstrated under alkaline conditions, producing H 2 and 2,5-furandicarboxylic acid. This work presents a decoupled water electrolyzer design with great flexibility and safety advantages.

Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) in china is a critical clinical syndrome with a high short-term mortality. This study aimed to construct and validate a model for neutrophil to lymphocyte ratio (NLR)-based nomogram for 3-month mortality estimation for patients with ACLF.The nomogram was based on a retrospectively study of 96 patients with ACLF. The predictive accuracy and discriminative ability of nomogram were evaluated by a concordance index (C-index), and calibration curve, comparing with model for end-stage liver disease (MELD) score. The results were validated using bootstrap resampling and an external cohort of 88 patients.A total of 184 patients with ACLF were enrolled, with 3-month mortality of 40.76%. The cut-off value for NLR was 5.7 using X-tile program. Patients with NLR5.7 had significantly higher mortality (p0.001). On multivariate analysis of the training cohort, independent factors for survival were age, NLR and total bilirubin, which were all selected into the nomogram. The calibration curve for probability of survival showed optimal agreement between prediction by nomogram and actual observation. The C-index of nomogram was higher than that of MELD score for predicting survival (0.72 vs 0.56). The results were confirmed in validation cohort.The proposed nomogram with NLR resulted in more accurate prognostic prediction for patients with HBV-related ACLF.

BACKGROUND: Prediabetes may be improved or reversed with lifestyle interventions. A worksite wellness program offering financial incentives for participation may be effective in improving the health of employees with prediabetes. We studied the effect of employee health plan financial incentives on health outcomes for employees with prediabetes. METHODS: We conducted a retrospective cohort study using electronic medical record data from January 2008 to December 2012. Our study participants were employees with prediabetes and propensity-matched non-employees with prediabetes and commercial health insurance, all receiving care within one health system. Exposures included fixed annual financial incentives for program participation and later a premium discount divided between program participation and achievement of goals. We used longitudinal linear mixed models to assess yearly changes in glycosylated hemoglobin (HbA1c), weight, and low-density lipoprotein cholesterol in employees versus non-employees. We also compared outcomes of employees by ever- versus never- program participant status. RESULTS: Our study population included 1005 employees and 1005 matched non-employees. The yearly reduction in HbA1c for employees versus matched non-employees did not differ in 2008–2010 but was greater in 2010–2012, when incentives were tied to program participation as well as achievement of goals (−0.10% vs −0.08 %, respectively; P for difference in change [DIC] = .01 from 2010 to 2012). Analyses from both periods showed that employees lost more weight per year than matched non-employees (−1.85 vs −0.21 lb [1 lb=0.45 kg] from 2008 to 2010; P for DIC < .001 and −2.35 vs −0.65 lb from 2010 to 2012; P for DIC < .001). Employees who participated in disease management lost more weight than those who did not (−2.14 vs 0.79 lb yearly before 2010 and −2.82 vs −0.91 after January 1, 2010, P for DIC < .01 and < .001, respectively). CONCLUSION: A worksite wellness program offering health plan financial incentives for participation and outcomes was associated with improvements in weight and HbA1c.

Inhibition of histone deacetylase (HDAC) is a promising therapeutic strategy for various hematologic cancers. Panobinostat has been approved for treating patients with multiple myeloma (MM) by the FDA. Since the mechanism for the resistance of panobinostat to MM remains elusive, we aimed to clarify this mechanism and the synergism of panobinostat with lenalidomide. The mRNA and protein of transcription factor IRF4 were overexpressed in CD138+ mononuclear cells from MM patients compared with in those from healthy donors. Given that direct IRF4 inhibitors are clinically unavailable, we intended to explore the mechanism by which IRF4 expression was regulated in MM. Heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors, and its expression is positively correlated with IRF4 mRNA and protein expression levels. Herein, panobinostat induced acetylation of histone H3K9 and activation of caspase-3 in MM cells, being inversely correlated with the reduction of HO-1/IRF4/MYC protein levels. Adding Z-DEVD-FMK, a caspase-3 inhibitor, abolished the HO-1/IRF4 reduction by panobinostat alone or in combination with lenalidomide, suggesting that caspase-3-mediated HO-1/IRF4/MYC degradation occurred. Given that lenalidomide stabilized cereblon and facilitated IRF4 degradation in MM cells, we combined it with LBH589, an HDAC inhibitor. LBH589 and lenalidomide exerted synergistic effects, and LBH589 reversed the efficacy of lenalidomide on the resistance of CD138+ primary MM cells, in part due to simultaneous suppression of HO-1, IRF4 and MYC. The results provide an eligible therapeutic strategy for targeting MM depending on the IRF4 network and clinical testing of this drug combination in MM patients.

Low fertilization rate is the main reason to limit the development of artificial insemination (AI) technology in ducks. However, the libido of male livestock has been confirmed to be related to semen quality and fertilization rate, and we found that the libido of drakes was different. Thus, the research on the libido of drakes may be the key to further develop and apply AI technology. In this research, we established the first scoring standard for libido evaluation in drakes based on the performance of drakes during training period. Phenotypically, the body weight of high libido group was lighter than that of the other groups, while the weight of testis and epididymis in the high libido group was higher than that in the low libido group. Furthermore, we constructed the first expression profile of hypothalamus, pituitary, testis, and epididymis of drakes with high or low libido. There were 2, 1822, 214, and 892 differentially expressed genes (DEGs) in hypothalamus, pituitary, testis, and epididymis. The expression and sequence of Translocation Associated Membrane Protein 2 (TRAM2) were different in high and low libido drakes, indicating that it may be a candidate gene related to drake's libido. The estrogen, prolactin, and oxytocin signaling pathways were all activated in the pituitary of the low libido group. Meanwhile, the metabolic and oxidative phosphorylation pathways were enriched by DEGs in pituitary, testis and epididymis. Our research reveals that the difference in metabolic may cause changes in body weight of drakes, resulting in altered hormone levels and oxidative phosphorylation of gonad, which negatively affects libido and spermatogenesis in drakes. These results provide novel insights into the avian libido and will help better understand the underlying molecular mechanisms.

MicroRNA-26 (miR-26) has been reported to be connected with tumor progression. MicroRNA-4465 (miR-4465) was one member of miR-26 family, however, the role of miR-4465 in non-small cell lung cancer (NSCLC) was unknown. This study was aimed to explore the function of miR-4465 and investigate whether miR-4465 can be a potential target for treating human NSCLC. QRT-PCR was applied to evaluate the miR-4465 expression levels in NSCLC cells. Then, we demonstrated the role of miR-4465 in NSCLC cells biological characteristics through detecting proliferation, migration and invasion. Luciferase reporter assay and TargetScan were applied to explore the potential target gene of miR-4465. In this study, we found that the miR-4465 expression levels in NSCLC cell lines were significantly reduced when compared to the normal human bronchial epithelial cell lines. And, over expression of miR-4465 could restrain the proliferation, migration and invasion of NSCLC. Moreover, MiR-4465 reduced EZH2 protein expression through the binding sites in 3' -UTR of the EZH2 mRNA, indicating EZH2 may be a direct target gene of miR-4465. Conclusively, miR-4465 suppressed cancer cells proliferation and metastasis by directly targeting the oncogene EZH2 and it may serve as a new potential therapeutic target in NSCLC.

To investigate the association between the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) and the IRF6 rs2235371 (CT) polymorphism in Chinese Han populations.PubMed, Web of Science and EMBASE were searched through May 31, 2016, to select eligible studies. Pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were applied to estimate the risk of NSCL/P associated with the IRF6 rs2235371 polymorphism. Subgroup analyses were conducted according to NSCL/P types (CLO, CPO and CLP) and the geographical location (Northern China and Southern China). Publication bias and sensitivity analyses were performed to assess the reliability of the results.A total of 1275 NSCL/P cases and 1294 controls from seven eligible case-control studies were included. In the overall analysis, a significant association between the IRF6 rs2235371 polymorphism and the risk of NSCL/P was identified under all genetic models, with the exception of the recessive model (T vs. C: OR=0.68, 95%CI=0.60-0.76, P0.00001). A subgroup analysis by NSCL/P types indicated that the variant T allele significantly decreased the risk of CLO and CLP but not CPO. A subgroup analysis of the geographical location further showed significantly decreased susceptibility in Northern China under all genetic models, but in Southern China, only the heterozygote and dominant models showed a significantly decreased risk of NSCL/P. Funnel plot analysis and the Egger linear regression method detected no publication bias.The IRF6 rs2235371 T allele decreased the risk of NSCL/P in Chinese Han populations. However, further studies with large sample sizes should be conducted to confirm this association.