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Major depressive disorder is characterized by the deficiencies of monoamine neurotransmitters, neurotrophic factors and persistent neuroinflammation. Microglial activation has been associated with neuroinflammation-related mental diseases, accompanied by NLR family pyrin domain containing 3 (NLRP3) inflammasome. Here, we investigated the effect of NLRP3 inhibition by its small molecular inhibitor MCC950 on inflammatory activity and depressive-like mice induced by chronic unpredictable mild stress (CUMS), followed by the behavioral tests including sucrose preference test and forced swimming test. NLRP3/caspase-1/IL-1β signaling and microglial morphology in the prefrontal cortex were measured. The results showed that CUMS caused a decrease in sucrose preference and an increase in immobility time, which were reversed by NLRP3 inhibitor MCC950. In addition, NLRP3 inhibition decreased the number of microglia and changed the activated state of microglia to a resting state by morphology 3D reconstruction. Moreover, NLRP3 inhibition inactivated NLRP3/caspase-1/IL-1β signaling in the prefrontal cortex. The results from immunofluorescence demonstrated that NLRP3 and IL-1β expression was decreased in microglia in response to MCC950 treatment. Accordingly, proinflammatory cytokines were also decreased by NLRP3 inhibition. In conclusion, this study demonstrates that microglial NLRP3 inhibition prevents stress-induced neuroinflammation in the prefrontal cortex and suggests that microglial NLRP3 could be one of the potential therapeutic targets for depression treatment.

Depression is a serious mental illness, mainly characterized as large mood swings and sleep, diet, and cognitive function disorders. NLPR3, one of the inflammasomes that can be activated by a variety of stimuli to promote the maturation and secretion of pro-inflammatory cytokines, has been considered to be involved in the pathophysiology of depression. In this study, the putative role of CY-09, a selective and direct inhibitor of NLRP3, was evaluated in the lipopolysaccharide (LPS)-induced mice. The results of the study indicated that CY-09 significantly decreased the levels of NLRP3 in the hippocampus of LPS-induced mice. In addition, CY-09 increased the sucrose preference and shortened the immobility time in LPS-induced mice, suggesting the antidepressant-like effects of inhibiting NLRP3 inflammasome. Biochemical analysis showed that LPS significantly activated the NLRP3/ASC/cytokine signaling pathway and caused microglial activation, while CY-09 prevented the changes. Moreover, CY-09 increased the brain-derived neurotrophic factor (BDNF) only in microglia but not in the whole hippocampus. Meanwhile, CY-09 did not promote neurogenesis in the hippocampus of LPS mice. In conclusion, the results of the study showed that the antidepressant-like effects of NLRP3 inhibitor CY-09 were mediated by alleviating neuroinflammation in microglia and independent of the neurotrophic function in the hippocampus.

To predict the ignition time and mass loss rate of rigid polyurethane foam (RPU) under various radiative conditions, numerical models with a multi-step thermal degradation process have been developed based on thermogravimetric and combustion experiments. Kinetic parameters are computed via Particle Swarm Optimization with a five-step mechanism. Combustion properties of RPU under various external radiative conditions have been analyzed. From both surface absorption and in-depth absorption, one-dimensional ignition models have been established and solved via COMSOL Multiphysics. According to the ignition criterion, ignition temperature, the numerical ignition model has been established and validated by experimental results. The critical mass flux and its relationship with the external heat flux have been discussed. Moreover, the mass loss rate has been predicted by numerical models. The proposed models in this work potentially have the guiding significance for charring property polymer combustion.

Nutritional Risk Screening index is a standard tool to assess nutritional risk, but epidemiological data are scarce on controlling nutritional status (CONUT) as a prognostic marker in acute haemorrhagic stroke (AHS). We aimed to explore whether the CONUT may predict a 3-month functional outcome in AHS. In total, 349 Chinese patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. The cohort patients were divided into high-CONUT (≥ 2) and low-CONUT (< 2) groups, and primary outcomes were a poor functional prognosis defined as the modified Rankin Scale (mRS) score of ≥ 3 at post-discharge for 3 months. Odds ratios (OR) with 95 % confidence intervals (CI) for the poor functional prognosis at post-discharge were estimated by using a logistic analysis with additional adjustments for unbalanced variables between the high-CONUT and low-CONUT groups. A total of 328 patients (60·38 ± 12·83 years; 66·77 % male) completed the mRS assessment at post-discharge for 3 months, with 172 patients at malnutrition risk at admission and 104 patients with a poor prognosis. The levels of total cholesterol and total lymphocyte counts were significantly lower in high-CONUT patients than low-CONUT patients (P = 0·012 and < 0·001, respectively). At 3-month post discharge, there was a greater risk for the poor outcome in the high-CONUT compared with the low-CONUT patients at admission (OR: 2·32, 95 % CI: 1·28, 4·17). High-CONUT scores independently predict a 3-month poor prognosis in AHS, which helps to identify those who need additional nutritional managements.

Aripiprazole (ARI), a second-generation atypical antipsychotic drug approved for schizophrenia treatment, shows good efficacy against depression. However, the poorly aqueous solubility of ARI leads to low bioavailability and increased dose-related side effects, seriously limiting its application in pharmaceutics. Herein, we demonstrated the fabrication of ARI and poly (methyl vinyl ether

Summary Background and aims Malnutrition is prevalent among individuals with acute ischaemic stroke (AIS) and may worsen clinical outcomes. There is no consensus on the best tool for nutritional screening in this population. The present study compared four screening tools and one diagnostic tool in terms of their prognostic significance in predicting short-term and long-term outcomes in AIS patients. Methods We included patients admitted to five major hospitals in Wenzhou and diagnosed with a primary diagnosis of AIS from October 1 to December 31, 2018. The Controlling Nutritional Status (CONUT) score, the Geriatric Nutritional Risk Index (GNRI), the Malnutrition Universal Screening Tool (MUST), the Nutritional Risk Screening Tool 2002 (NRS-2002) and the European Society for Clinical Nutrition and Metabolism diagnostic criteria for malnutrition (ESPEN-DCM) were assessed at admission. The clinical outcomes were evaluated by the modified Rankin Scale (mRS) and mortality at 3 months and 12 months after discharge. Results Five hundred and ninety-three patients were included in our prospective study. The mean age was 67.3 ± 12.0 years. Based on the mRS score, 125 patients exhibited poor functional recovery (an mRS ≥3) at 3 months after discharge. Seventeen patients died during the 3-month follow-up period, and the other 25 did not survive 12 months. Multivariate binary logistic regression revealed that inadequate nutritional status at admission, as determined by the CONUT, GNRI, MUST, NRS-2002 and ESPEN-DCM, were independently associated with poor outcomes in AIS patients 3 months after discharge. Both MUST ≥2 and NRS-2002 ≥ 3 showed significant associations with poor outcomes at 12-month post-discharge. Further analysis with the receiver operator characteristic (ROC) curve showed similar results, where all the tools predicted the poor outcomes at 3 months while only the NRS-2002 and MUST scores were significantly associated with the mRS at 12 months post-discharge. Moreover, the area under the curve (AUC) of MUST and NRS-2002 were significantly larger than those for the other tools. The optimal cut-off values of the MUST and NRS-2002 to predict poor outcomes were scores of ≥2 and ≥ 3 points, respectively. Conclusions Our data supported a deleterious effect of inadequate nutrition, as evidenced by the nutrition screening tools or ESPEN-DCM, on clinical outcomes during and beyond the acute phase of AIS. We recommended the use of the MUST and NRS-2002 in guiding nutritional support in AIS patients, as they have higher predictive power and can predict both short-term and long-term outcomes.

Diosgenin is a well-known steroid saponin possessing neuroprotective activities. However, it is unknown whether diosgenin could alleviate depression-like symptoms.The antidepressant-like effect of diosgenin was investigated in mice induced by chronic restraint stress. The effects of diosgenin on behaviors, inflammation, neuroendocrine, neurotrophic function, and gut microbiota were evaluated.The results showed that diosgenin alleviated the depressive-like behaviors in mice. In addition, diosgenin was found to reduce serum concentrations of proinflammatory cytokines and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Besides, diosgenin could activate hippocampal brain-derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway and improve the expression of postsynaptic protein PSD95. Meanwhile, the neurogenesis which was inhibited by chronic restraint stress, was totally reversed by diosgenin. Moreover, diosgenin increased the abundance of phylum Firmicutes and the genus Lactobacillus in stressed mice. The results further showed that diosgenin caused a strong correlation between gut microbiota composition and inflammation, the HPA axis activity, or hippocampus neurotrophic function.Only male mice were used for evaluation in the present study, which limits the understanding of effects of diosgenin on the both sexes. In addition, the results only indicate microbiota at the phylum or genus mediate the regulation of neuroinflammation, neuroendocrine, and neurotrophic function, but does not elucidate how microbiota modulate the systems via their primary or secondary metabolites.The present study shows that diosgenin exerts the antidepressant activity, which is associated with the enhancement of neurotrophic function and the inhibition of inflammatory and neuroendocrine activities via the regulation of gut microbiota.

Experiments and theoretical analysis were conducted to investigate the upward flame spread over a homogenous PMMA plate and an array of discrete thermally thin PMMA elements. In the experiment, a digital video camera was used to record the flame spread process. An electronic balance and thermocouples were adopted to monitor the mass loss and pyrolysis front position, respectively, as a function of time. In the theoretical analysis, the mass loss rate of PMMA was correlated to the heat transfer during flame spread. The experimental results show that the flame spread rate peaks in the case of discrete PMMA elements with a fuel coverage around 80% rather than 100% (the homogenous case) because the gap with an appropriate spacing between neighboring elements accelerates the flame spread. However, the flame cannot spread over an array of discrete fuels at a coverage of 50% or smaller where the gap is too large to allow effective heat transfer required for flame spread. A smaller coverage of PMMA results in a larger mass loss rate per area since the gaps between elements can entrain more air to promote the burning. A logarithmic relation, that can well describe the mass loss rate as a function of PMMA coverage, was proposed based on the theoretical analysis and the fitting of experimental measurements.

Lung cancer is the leading cause of cancer death worldwide and accounts for more than one-third of all newly diagnosed cancer cases in China. Therefore, it is of great clinical significance to explore new driver gene mutations in non-small-cell lung cancer (NSCLC). Using an initial bioinformatic analysis, we identified somatic gene mutations in 13 patients with NSCLC and confirmed these mutations by targeted sequencing in an extended validation group of 88 patients. Recurrent mutations were detected in UNC5D (7.9%), PREX1 (5.0%), HECW1 (4.0%), DACH1 (2.0%), and GPC5 (2.0%). A functional study was also performed in UNC5D mutants. Mutations in UNC5D promoted tumorigenesis by abolishing the tumor suppressor function of the encoded protein. Additionally, in ten patients with lung squamous cell carcinoma, we identified mutations in KEAP1/NFE2L2 that influenced the expression of target genes in vivo and in vitro. Overall, the results of our study expanded the known spectrum of driver mutations involved in the pathogenesis of NSCLC.

Malnutrition is confirmed to be associated with poor outcomes in stroke patients. The present study aimed to confirm that being at risk of malnutrition assessed by Nutritional Risk Screening Tool 2002 (NRS-2002) and the Controlling Nutritional Status (CONUT) score predicts poor outcomes at 3 months in acute ischemic stroke (AIS) patients. In total, 682 patients with AIS were recruited within 7 days of stroke onset consecutively and 110 were dropped out. They were screened for risk of malnutrition using NRS-2002 and the CONUT score. The primary outcome is the follow-up modified Rankin Scale (mRS) score. Poor outcomes were defined as an (mRS) score ≥ 3 at 3 months post discharge. There was a significant difference in the mRS score at 3 months between patients at risk of malnutrition compared to those not at risk assessed by NRS-2002(P

Hypoxia promotes drug resistance and induces the expression of hypoxia inducible factor (HIF)‑1α in liver cancer cells. However, to date, no selective HIF‑1α inhibitor has been clinically approved. The aim of this study is to investigate a drug‑targetable molecule that can regulate HIF‑1α under hypoxia. The present study demonstrated that hyperactivation of dual‑specificity tyrosine‑phosphorylation‑regulated kinase 1A (DYRK1A)/HIF‑1α signaling was associated with an increased risk of liver cancer. In addition, DYRK1A knockdown using small interfering RNA transfection or treatment with harmine, a natural alkaloid, significantly reduced the protein expression levels of HIF‑1α in liver cancer cells under hypoxic conditions

Thyroid fine-needle aspiration samples from 278 patients with 310 thyroid nodules were collected. Sanger sequencing and ddPCR were conducted to detect theTheddPCR has higher sensitivity than Sanger sequencing and we propose ddPCR as a supplement to Sanger sequencing in molecular testing of

Lagotis brachystachya Maxim is a characteristic herb commonly used in Tibetan medicine. Tibetan medicine records it as an important medicine for the clinical treatment of “Yellow Water Disease,” the symptoms of which are similar to that of arthritis. Our previous study showed that the flavonoid fraction extracted from L. brachystachya could attenuate hyperuricemia. However, the effects of the active flavonoids on gouty arthritis remain elusive, and the underlying mechanism is not understood. In the present study, the effects of the active flavonoids were evaluated in rats or Raw264.7 cells with gouty arthritis induced by monosodium urate (MSU) crystal, followed by the detection of TLR4, MyD88, pNF-κB, and NLR family pyrin domain-containing 3 (NLRP3) expression. The swelling of the ankle joint induced by MSU crystal began to be relieved 6 h post the administration with the active flavonoids. In addition, the active flavonoids not only alleviated MSU crystal-induced inflammation in synovial tissues by histopathological examination but also reduced tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the joint tissue fluid of MSU crystal-induced rats. Furthermore, Western blot analysis indicated that the active flavonoids reduced the production of these cytokines by inhibiting the TLR4/MyD88/NF-κB pathway and decreasing NLRP3 expression in synovial tissues of rats. More importantly, the inhibition of TLR4/MyD88/NF-κB pathway and NLRP3 expression was also confirmed in MSU-induced Raw264.7 cells. In conclusion, these results indicated that the active flavonoids from L. brachystachya could effectively attenuate gouty arthritis induced by MSU crystal through the TLR4/MyD88/NF-κB pathway and NLRP3 expression in vivo and in vitro, suggesting several potential candidates for the treatment of gouty arthritis.

Background Molecular testing for oncogenic mutations in fine‐needle aspiration has showed high predictive value in identifying malignant lesions from thyroid nodules with indeterminate cytology. Methods To figure out an efficient and economical gene panel for most medical institutions in China, we designed a five‐gene panel including BRAF/NRAS/KRAS/HRAS/TERT genes and conducted a retrospective study to evaluate the role of this five‐gene diagnostic panel in differential diagnosis of thyroid nodules. Results A total of 665 patients with 695 thyroid nodules were investigated in the current study. The fine‐needle aspiration biopsy and surgically separated thyroid tissue specimens were harvested to test BRAF, TERT, NRAS, KRAS, and HRAS mutations. We identified 261 mutations in 665 patients, including 177 V600E mutations in BRAF. Three hundred and sixty‐nine patients who underwent thyroid surgery after completion of the initial clinical and cytological evaluation were enrolled in the final analysis. The diagnostic sensitivity, specificity, and accuracy of the combination of FNAB cytology and five‐gene detection were 74.7%, 93.8%, and 84.8%, respectively. BRAF V600E and five‐gene panel could recognize 46.4% and 53.6% of papillary thyroid carcinoma in the patients with cytologically indeterminate nodules. Conclusion The five‐gene panel can effectively improve the sensitivity, negative predictive value, and accuracy of fine‐needle aspiration biopsy cytology, especially in the patients with cytologically indeterminate nodules., Our study focuses on the feasibility and utility of a five‐gene panel containing BRAF/RAS/TERT mutation detection in the improvement of fine‐needle aspiration biopsy (FNAB) cytology in differential diagnosis of thyroid nodules in China. Our results demonstrated that BRAF/five‐gene mutations detected in FNAB samples can effectively improve the sensitivity, negative predictive value (NPV), and accuracy of FNAB cytology, while kept the specificity and positive predictive value (PPV).

Vinpocetine is widely used to treat cerebrovascular diseases. However, the effect of vinpocetine to treat hepatocellular carcinoma (HCC) has not been investigated. In this study, we revealed that vinpocetine was associated with antiproliferative activity in HCC cells, but induced cytoprotective autophagy, which restricted its antitumor activity. Autophagy inhibitors improved the antiproliferative activity of vinpocetine in HCC cells. Sorafenib is effective to treat advanced HCC, but the effect of autophagy induced by sorafenib is indistinct. We demonstrated vinpocetine plus sorafenib suppressed the cytoprotective autophagy activated by vinpocetine in HCC cells and significantly induced apoptosis and suppressed cell proliferation in HCC cells. In addition, vinpocetine plus sorafenib activates glycogen synthase kinase 3β (GSK-3β) and subsequently inhibits cytoprotective autophagy induced by vinpocetine in HCC cells. Meanwhile, overexpression of GSK-3β was efficient to increase the apoptosis induced by vinpocetine plus sorafenib in HCC cells. Our study revealed that vinpocetine plus sorafenib could suppress the cytoprotective autophagy induced by vinpocetine and subsequently show synergistically anti-HCC activity via activating GSK-3β and the combination of vinpocetine and sorafenib might reverse sorafenib resistance via the PI3K/protein kinase B/GSK-3β signaling axis. Thus, vinpocetine may be a potential candidate for sorafenib sensitization and HCC treatment, and our results may help to elucidate more effective therapeutic options for HCC patients with sorafenib resistance.

Congenital hypothyroidism (CH) is a highly prevalent but treatable neonatal endocrine disorder. Thyroid dyshormonogenesis is the main cause of congenital hypothyroidism in Chinese CH patients, and DUOX2 is the most frequent mutated gene involved in H2O2 production. In humans, the primary sources for H2O2 production are DUOX1 and DUOX2, while in zebrafish there is only a single orthologue for DUOX1 and DUOX2. In this study, duox mutant zebrafish were generated through knockdown duox by morpholino or knockout duox by CRISPR Cas9. The associated phenotypes were investigated and rescued by thyroxine (T4) treatment. Mutant zebrafish displayed hypothyroid phenotypes including growth retardation, goiter and, infertility. Homozygous mutants in adults also displayed extrathyroidal abnormal phenotypes, including lacking barbels, pigmentation defects, erythema in the opercular region, ragged fins, and delayed scales. All these abnormal phenotypes can be rescued by 10 nM T4 treatment. Strikingly, the fertility of zebrafish was dependent on thyroid hormone; T4 treatment should be continued and cannot be stopped over 2 weeks in hypothyroid zebrafish in order to achieve fertility. Thyroid hormones played a role in the developing and maturing of reproductive cells. Our work indicated that duox mutant zebrafish may provide a model for human congenital hypothyroidism.

Controlling Nutritional Status (CONUT) Score is useful for the nutritional screening. We aimed to explore whether the CONUT score may predict a 3-month functional outcome in hemorrhagic stroke (AHS). Totally, 349 patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. Poor functional outcomes were defined as the modified Rankin Scale (mRS) score of ≥ 3 at 3 months. A total of 328 patients (mean age, 60.4 ± 12.83 years; 66.8% male) were included, 172 (52.40%) patients at malnutrition risk and 104 (31.7%) patients with a poor prognosis. High-CONUT patients had lower total lymphocyte counts and total cholesterol levels than low-CONUT patients (p < 0.001 and p = 0.012). At 3-month post discharge, patients with malnutrition risk had higher hospitalization costs (p = 0.021), lower Barthel Index (p = 0.001), and more infectious complications (p = 0.002) than those without, and there was a greater risk for poor functional outcomes in the high-CONUT compared with the low-CONUT patients at admission (adjusted odds ratio: 2.32, 95% confidence interval: 1.28-4.17). High-CONUT scores predict a 3-month poor prognosis in AHS, which may help identify the AHS patients who need additional nutritional managements.

Gynostemma pentaphyllum is a herbal medicine widely used in Asian countries, and its saponin extracts have been shown to possess potent anti-inflammatory effects. Gypenoside XVII, an active ingredient isolated from Gynostemma pentaphyllum, has been found to alleviate the inflammation induced by LPS in the BV2 microglia, according to our preliminary study. This study aims to evaluate whether Gypenoside XVII could attenuate depression-like symptoms in vivo and tries to demonstrate the involvement of the complement regulation in its antidepressant-like effect. The results showed that Gypenoside XVII significantly attenuated depression-like behaviors in the forced swimming test, tail suspension test and sucrose preference test. It also alleviated the acute stress-induced hyperactivity of serum corticosterone levels. Additionally, Gypenoside XVII significantly inhibited the activation of microglia and the expression of C3 in mice exposed to chronic unpredictable mild stress (CUMS). Meanwhile, the activation of C3aR/STAT3 signaling and the expression of proinflammatory cytokines was reversed by Gypenoside XVII. Moreover, CUMS induced excessive synaptic pruning by activating microglia, while Gypenoside XVII restored it in the prefrontal cortex. Our data demonstrated that Gypenoside XVII, the active ingredient of Gynostemma pentaphyllum, produced the antidepressant-like effects in mice, which was mediated by the inhibition of complement C3/C3aR/STAT3/cytokine signaling in the prefrontal cortex.

Background The monocyte/high-density lipoprotein ratio (MHR) has emerged as a promising alternative biomarker in the fields of cardiovascular disease and atrial fibrillation (AF). This retrospective study was aimed to explore the predictive value of the MHR for the late recurrence of AF after radiofrequency ablation. Methods From April 2015 to October 2018, patients with paroxysmal AF who had undergone radiofrequency catheter ablation at Subei People’s Hospital of Jiangsu Province were enrolled in our study. All the participants were observed until November 2019 after the procedure. During the postoperative follow up, the patients were categorized into the recurrence group and maintenance of sinus rhythm group based on who had experienced AF recurrence. Results One hundred twenty-five patients were diagnosed with paroxysmal AF, with an average age of 61.2 ± 9.3 years. Forty-seven patients had developed late recurrence during a mean follow up of 25.1 ± 12.0 months. The AF recurrence event rates were significantly increased in the highest MHR tertile compared with those in the lowest MHR tertile (22.0% vs. 57.1%; P OR = 1.34; 95% CI = 1.12 ~ 1.60; P = 0.001) and left atrial diameter (LAD) (OR = 1.21, 95% CI = 1.08 ~ 1.35; P = 0.001) were independent risk factors predicting the recurrence of AF after radiofrequency ablation. Furthermore, receiver operating characteristic (ROC) curve analysis revealed that the area under the curve (AUC) of the MHR was 0.712 (95% CI = 0.618 ~ 0.806; P = 0.000) and that of LAD was 0.739 (95% CI = 0.653 ~ 0.814; P = 0.000). Z-test found no significant difference between the MHR and LAD regarding the AUC (Z = 0.451; P = 0.652). Conclusion An elevated preablation MHR was associated with an increased risk of the postoperative recurrence of AF. Additionally, the MHR independently predicted the late recurrence of paroxysmal AF after radiofrequency ablation, with the same predictive value as LAD.

Interleukin-17 (IL-17), also called IL-17A, is an important regulator of cardiac diseases, but its role in calcium-related cardiac dysfunction remains to be explored. Thus, we investigated the influence of IL-17 on calcium handling process and its contribution to the development of heart failure. Mice were subjected to transaortic constriction (TAC) to induce heart failure. In these mice, the levels of IL-17 in the plasma and cardiac tissue were significantly increased compared with the sham group. In 77 heart failure patients, the plasma level of IL-17 was significantly higher than 49 non-failing subjects, and was negatively correlated with cardiac ejection fraction and fractional shortening. In IL-17 knockout mice, the shortening of isolated ventricular myocytes was increased compared with that in wild-type mice, which was accompanied by significantly increased amplitude of calcium transient and the upregulation of SERCA2a and Cav1.2. In cultured neonatal cardiac myocytes, treatment of with IL-17 (0.1, 1 ng/mL) concentration-dependently suppressed the amplitude of calcium transient and reduced the expression of SERCA2a and Cav1.2. Furthermore, IL-17 treatment increased the expression of the NF-κB subunits p50 and p65, whereas knockdown of p50 reversed the inhibitory effects of IL-17 on SERCA2a and Cav1.2 expression. In mice with TAC-induced mouse heart, IL-17 knockout restored the expression of SERCA2a and Cav1.2, increased the amplitude of calcium transient and cell shortening, and in turn improved cardiac function. In addition, IL-17 knockout attenuated cardiac hypertrophy with inhibition of calcium-related signaling pathway. In conclusion, upregulation of IL-17 impairs cardiac function through NF-κB-mediated disturbance of calcium handling and cardiac remodeling. Inhibition of IL-17 represents a potential therapeutic strategy for the treatment of heart failure. Take home Figure. IL-17 promotes the development of heart failure. Upregulation of IL-17 activates NF-κB, which in turn suppresses the expression of CACNA1C encoding the pore-forming subunit of voltage gated Ltype calcium channel Cav1.2 and ATP2A2 encoding SERCA2a. Decreased expression of Cav1.2 and SERCA2a reduced cardiac contractility due to impaired calcium handling and promoted cardiac hypertrophic growth through the activation of calcium related signaling pathway, which eventually led to heart failure. PLN, phospholamban; SERCA2a, sarcoplasmic reticulum Ca2+-ATPase2a; RYR2, ryanodine receptor 2; CAMKII, calcium/calmodulin-dependent kinase II

Via applying the mixed-ligand approach, a new Cu(II)-bearing coordination polymer (CP) with the chemical formula of [Cu(1,4-chdc)(L)(H2O)]n (1, (1,4-H2chdc = 1,4-cyclohexanedicarboxylic acid, L = 2-(4-fluorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) has been successfully prepared under hydrothermal condition. The single-crystal X-ray diffraction study shows that CP 1 shows a 1D chain-like structure which is further extended into a 2D supramolecular network via the H-bond interactions. Furthermore, a sonochemical treatment method was applied to produce the nanosized 1 with the size distribution around 200 nm. To detect the cell proliferation of MGC-803 (human gastric cancer cell lines) after treated with nano 1, the Cell Counting Kit-8 (CCK-8) assay was performed in this experiment. Besides, the MGC-803 cell apoptosis was determined by Annexin V-FITC/PI (FITC = fluorescein isothiocyanate, PI = propidium iodide) apoptosis detection kit in flow cytometer and western blot after treated with nano 1. A new Cu(II)-bearing coordination polymer has been prepared under hydrothermal conditions. A sonochemical treatment method was applied to produce the nanosized 1 with the size distribution around 200 nm. The anti-cancer activity of nano 1 has been evaluated via the Cell Counting Kit-8 (CCK-8) assay and Annexin V-FITC/PI.

Primary central nervous system lymphoma, a rare primary intracranial tumor, is highly malignant and usually associated with poor prognosis. Recent years, owing to the remarkable progress in intervention techniques, survival time reported has been significantly prolonged. Strategies targeting alleviation and remission are primarily depended on the early diagnosis. However, due to the heterogeneity of the clinical symptoms and imaging features, the disease is frequently misdiagnosed especially in the early phase, rendering a delay of optimal treatment. Herein, we reported the case of a 61-year-old man who was initially misdiagnosed as demyelinating encephalopathy. MRI images showed multifocal lesions across the cerebral cortex and deep white matter, which are not strengthened on contrast enhancements. In respect of clinical symptoms, no significant progress was observed over about 11 months. Finally, the diagnosis was revealed by brain biopsy. After reviewing all the images of the patient, we found that the corpus callosum was involved early in the course of the disease. Therefore, for multifocal intracranial lesions involving the corpus callosum, we should always be vigilant about the possibility of primary central nervous system lymphoma. Histopathological examination of brain biopsy is helpful for early definitive diagnosis.

Objective Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited. Design and methods One hundred ten patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees. Results Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands. Conclusions Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.

// Man-Man Zhang 1, * , Feng Sun 1, * , Bing Cui 2, * , Le-Le Zhang 1 , Ya Fang 1 , Yan Li 1 , Rui-Jia Zhang 1 , Xiao-Ping Ye 1 , Yu-Ru Ma 1 , Bing Han 1 and Huai-Dong Song 1 1 The Core Laboratory in Medicine Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China 2 Department of Transfusion, The Hospital Affiliated to Jiangsu University, Zhenjiang 212001, China * These authors should be regarded as joint first authors Correspondence to: Huai-Dong Song, email: huaidong_s1966@163.com Bing Han, email: foxhb1423@126.com Keywords: UNC5D; papillary thyroid carcinoma; tumor-suppressive function; lymph node metastasis; BRAF mutation Received: March 31, 2017 Accepted: June 28, 2017 Published: October 10, 2017 ABSTRACT Background : Studies have shown an association of the UNC5D gene with kidney and bladder cancer and neuroblastoma. We investigated whether UNC5D acts as a tumor suppressor in papillary thyroid carcinoma (PTC). Methods : Primary PTC tumors and matched normal thyroid tissues were obtained from 112 patients to detect UNC5D mRNA by real-time PCR. Genomic DNA sequencing was performed to detect BRAF mutation in PTC tumors. The association between UNC5D expression and clinicopathological data from PTC patients was reviewed retrospectively. PTC-derived cancer cell lines TPC-1 and K1 with stable transfection of UNC5D were used to investigate the functions of UNC5D . Flow cytometry, CCK-8, Transwell assay and scratch tests were used to examine cell cycle distribution, proliferation and migration. Results : The expression of UNC5D was significantly decreased in PTC compared with adjacent normal thyroid tissues. Lower UNC5D expression was significantly associated with aggressive tumor behaviors, such as lymph node metastasis and BRAF mutation. Overexpression of UNC5D significantly suppressed malignant cell behaviors, including cell proliferation and migration, as well as tumor growth in vivo . Conclusions : These findings suggest a potential tumor suppressor role of UNC5D in PTC progression; and provide insight into potential clinical relevance for the prognosis of PTC.

Graves’ disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early-onset patients have a shorter exposure time to environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early-onset GD, eleven single nucleotide polymorphisms (SNPs) and their related SNPs (R2 > 0.6), SNPs located within a ± 1-Mb region of the FOXP3 gene, and twenty validated GD-risk SNPs were selected and screened for genotyping in 3,735 GD and 4,893 control patients to investigate whether early-onset GD is a subtype of GD with distinct susceptibility genes. Ultimately, we did not confirm the reported genetic markers of early-onset GD in our Chinese Han population but found that a GD-risk SNP located in the human leukocyte antigen class I region—rs4947296—was more strongly correlated with early-onset GD than non-early onset GD. In addition, heterogeneity analysis of GD patients suggests that it may be more reasonable to define early-onset GD as an onset age ≤ 20 years.

This study investigates the prospective of utilizing kitchen wastewater and food wastes, biofuels industry byproducts as alternative water and carbon sources. Kitchen wastewater did not impede cellular growth rate of the evolved Phaeodactylum strain E70, which indicates its potential as an alternative to freshwater resources. Among the organic wastes assessed, food waste hydrolysate significantly increased cell growth. Supplement of crude glycerol in cultivation medium enhances the total fatty acid content. Mixed food waste hydrolysate and crude glycerol remarkably increased both the cell density and total fatty acid content. Also, the supplement of butylated hydroxytoluene alleviated the oxidative stress induced by impurities in organic wastes and concomitantly increased microalgal total fatty acids and polyunsaturated fatty acids content. The experimental results reported in this study show that a waste-based biorefinery could lead to utilization of organic waste resources for the efficient production of value-added products.

Scope Degraded porphyran is a bioactive polysaccharide extracted from Porphyra species. According to the previous studies, it produced anti-inflammatory activity, but little is known about its effects on depression. Methods and results As inflammation is one of the critical factors involved in the development of depression, this study aimed to elucidate the potential antidepressant-like effects of degraded porphyran. The results showed that acute porphyran treatment decreased the immobility time in despair tests. In addition, subchronic porphyran administration reversed depressive-like behaviors in lipopolysaccharide (LPS)-treated mice. Meanwhile, porphyran inhibited NF-κB/NLRP3 signaling, proinflammatory cytokine release and microglial activation in the hippocampus. Moreover, chronic porphyran treatment activated hippocampal brain-derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway in chronic unpredictable mild stress (CUMS) in mice. As a result, neurogenesis and spinogenesis were maintained. Conclusions The findings of the present study indicate that degraded porphyran intake provides a potential strategy for depression treatment, which was mediated by the inhibition of neuroinflammation and the enhancement of neurogenesis and spinogenesis in the central nervous systems. This article is protected by copyright. All rights reserved.

Dunaliella salina is a promising microbial host for the sustainable production of bioenergy and valuable compounds. D. salina can be mixotrophically cultivated using a pure organic carbon source. However, pure organic carbon sources remarkably enhance the cost of cultivation and constrain the development of upscale microalgal cultivation. This study examined the feasibility of using low-value food waste supplemented with fulvic acid in D. salina mixotrophic cultivation for lipid and carotenoid accumulation. The glucose-rich hydrolysate was first obtained via enzymatic hydrolysis from selected food waste. This hydrolysate was an appropriate source of organic carbon for microalgal mixotrophy based on a two-stage cultivation strategy for investigating the biomass and accumulation of valuable products. In addition, fulvic acid, which contains oxygen-rich and carbon-poor functional groups, was used in the second stage to maximise the production of biomass (3.1 ± 0.2 g/L), lipids (0.75 ± 0.03 g/L) and carotenoids (0.52 ± 0.03 g/L). The biodiesel quality of the lipid derived from D. salina biomass based on food waste hydrolysate met the previously approved standards. These data illustrate a sustainable and efficient algal-based food waste biorefinery strategy for the co-production of bioenergy and bioactive compounds, and offer key insights to address the issues of global food waste and algal-based resource utilisation.

Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high-risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12-paired normal-tumor tissues were subjected to whole-genome/whole-exome sequencing. From these, 367 non-silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non-mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.

Bioconversion of food waste into value-added products is a promising way to tackle the global food waste management problem. In this study, a novel valorisation strategy for bioenergy and lutein production via microalgal fermentation was investigated. Significant amount of glucose was recovered from enzymatic hydrolysis of food waste. The resultant hydrolysate was then utilised as culture medium in mixotrophic cultivation of Chlorella sp. to obtain high levels of lipid and lutein, whose accumulation patterns were consistent with molecular analyses. The resultant algal lipid derived from microalgal biomass using food hydrolysate was at high quality in terms of biodiesel properties. Further, in semi-continuous fermentation, the average algal biomass was 6.1 g L-1 with 2.5 g L-1 lipid and 38.5 mg L-1 lutein using hydrolysate with an initial glucose concentration of 10 g L-1. Meanwhile, the resultant algal biomass was 6.9 g L-1 with 1.8 g L-1 lipid and 63.0 mg L-1 lutein using hydrolysate with an initial glucose concentration of 20 g L-1, which suggests food waste hydrolysate could trigger algal products preferences. The experimental results of this study suggested the potential of microalgae as a platform for bioconversion of food waste into high-value products, especially sustainable bioenergy.