Selective Activation of Cascade Assembly Amplification for DNA Methyltransferase Detection Using a Double-Loop Interlocked DNA Circuit.

Precise and reliable monitoring of DNA adenine methyltransferase (Dam) activity is essential for disease diagnosis and biological analysis. However, existing techniques for detecting Dam activity often rely on specific DNA recognition probes that are susceptible to DNA degradation and exhibit limited target sensitivity and specificity. In this study, we designed and engineered a stable and dynamic DNA nanodevice called the double-loop interlocked DNA circuit (DOOR) that enables the sensitive and selective monitoring of Dam activity in complex biological environments. The DOOR incorporates two interlocked specialized sequences: a palindromic sequence for Dam identification and an initiator sequence for signal amplification. In the presence of Dam, the DOOR is cleaved by double-stranded DNA phosphodiesterase I endonuclease, generating massive double-stranded DNA (dsDNA) units. These units can self-assemble into a long dsDNA scaffold, thereby enhancing the subsequent reaction kinetics. The dsDNA scaffold further triggers a hyperbranched hybrid chain reaction to produce a fluorescent 3D DNA nanonet, enabling more precise monitoring of the Dam activity. The DOOR device exhibits excellent sensitivity, specificity, and stability, rendering it a powerful tool for studying DNA methylation in various biological processes and diseases.

Influence of NH3 flow rate on the photoelectric properties of high Al content p-AlGaN.

High Al content (60%) p-AlGaN with different NH3 flow rates was grown using metal-organic chemical vapor deposition (MOCVD), and changes in its photoelectric properties were studied using the Hall effect tester (Hall) and cathodoluminescence (CL) spectrometer. The results show that the film resistivity increases from 3.8â€…Ω·cm to 46.5â€…Ω·cm with increasing NH3 flow rate. The impurity peak intensity of p-AlGaN grown under high NH3 flow conditions is particularly high, indicating numerous point defects. The results of high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) show a large number of Ga interstitial atoms (Gai) at the interface. As Gai acts as a donor, this may be the main reason for the increase in resistivity. And under high NH3 flow conditions, a lattice distortion and a high density of dislocation occur between p-AlGaN and p-GaN, which can lead to enhanced carrier scattering and decreased mobility. Additional validation via LED growth experiments indicates that the luminescence intensity of samples with low ammonia concentration increased by more than 13000 times.

Identification and Quantification of 5-Methylcytosine and 5-Hydroxymethylcytosine on Random DNA Sequences by a Nanoconfined Electrochemiluminescence Platform.

5-Methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are two of the most abundant epigenetic marks in mammalian genomes, and it has been proven that these dual epigenetic marks give a more accurate prediction of recurrence and survival in cancer than the individual mark. However, due to the similar structure and low expression of 5mC and 5hmC, it is challenging to distinguish and quantify the two methylation modifications. Herein, we employed the ten-eleven translocation family dioxygenases (TET) to convert 5mC to 5hmC via a specific labeling process, which realized the identification of the two marks based on a nanoconfined electrochemiluminescence (ECL) platform combined with the amplification strategy of a recombinase polymerase amplification (RPA)-assisted CRISPR/Cas13a system. Benefiting from the TET-mediated conversion strategy, a highly consistent labeling pathway was developed for identifying dual epigenetic marks on random sequence, which reduced the system error effectively. The ECL platform was established via preparing a carbonized polymer dot embedded SiO2 nanonetwork (CPDs@SiO2), which exhibited higher ECL efficiencies and more stable ECL performance compared to those of the scattered emitters due to the nanoconfinement-enhanced ECL effect. The proposed bioanalysis strategy could be employed for the identification and quantification of 5mC and 5hmC in the range from 100 aM to 100 pM, respectively, which provides a promising tool for early diagnosis of diseases associated with abnormal methylation.

Clinical characteristics and prognostic value of EGFR mutation in stage I lung adenocarcinoma with spread through air spaces after surgical resection.

The clinical data of stage I invasive lung adenocarcinoma patients with spread through air spaces (STAS) who underwent lobectomy from January 1, 2013 to January 1, 2016 at the Department of Thoracic Surgery of Hebei Medical University were analyzed retrospectively, and statistical analysis was carried out to explore their clinical features and prognostic value of EGFR mutation. A total of 280 patients were included in the study cohort, and EGFR mutations were detected in 154 patients. EGFR mutations were more common in non-smokers (p=0.045), females (p<0.001), without vascular tumor thrombus (p=0.037), and histological subtype LPA/APA/PPA (p=0.001). Multivariate analysis of the Cox risk regression model showed that EGFR gene mutation (p=0.807) was not an independent influencing factor of recurrence-free survival (RFS), but EGFR mutation was an independent influencing factor of overall survival (OS) (p=0.012), and OS of patients with EGFR mutation was better. The EGFR mutation also significantly increased the progression-free survival (PFS) of relapsed patients (p<0.001), but the PFS of relapsed EGFR mutation patients who received adjuvant chemotherapy after the operation was worse than that of patients who did not receive adjuvant chemotherapy (p=0.029). EGFR gene mutation is not a risk factor for postoperative recurrence in patients with stage I lung adenocarcinoma with STAS but the 5-year survival rate of patients with EGFR gene mutation is better than that of wild-type. Postoperative adjuvant chemotherapy for patients with EGFR mutation should be carefully considered.

Heterogeneity of humic/fulvic acids derived from composts explains the differences in accelerating soil Cd-hyperaccumulation by Sedum alfredii.

The hyperaccumulating mechanism concerning heavy metal activation or passivation and plant response triggered by fulvic acid (FA) and humic acid (HA) recruitments are investigated herein. We carefully examine the Cd activation effect by various FA and HA, tracing from pig, goat, and duck manure composts to straw compost and commercial materials (i.e., PC, GC, DC, SC, and CM), as well as their roles in plant growth promotion and Cd uptake. Our results indicate that due to the decrease of soil pH and their multiple functional groups, the contents of available Cd (AE-Cd) increased by 4.3-4.8% and 3.6-6.3% when all FA and HA sources were applied for 30 days. A 13.1-19.9% increase in AE-Cd was observed when CFA, DFA, and PFA were applied for five days, and a 9.5% increment was found when PHA was applied for 10 days. In the pot experiment, the Cd accumulation in plants increased by 2.78 and 2.17 folds with PFA and PHA applications, respectively, compared to the blank control group. This result can be attributed to the stimulative effects of the simultaneous Sedum alfredii growth and Cd phytoavailability. Notably, the Cd accumulation increased by 2.26 times with the SFA amendment due to the predominant stimulation effect to the phytoavailable Cd rather than plant growth. However, slight inhibitory effects were observed upon plant growth or Cd uptake, which led to the reduction of the Cd accumulation with DHA, SHA, and CHA employments. Consistently, the corresponding soil Cd removal efficiencies were 43.5% and 34.6% with PFA and PHA, respectively, which hold abundant O- and N-containing groups. Our research aims to gain insights into the ternary interaction in the presence of heavy metal, humic substances, and S. alfredii to simultaneously accelerate Cd activation and hyperaccumulation.

Novel compound heterozygous mutations of DNAH5 identified in a pediatric patient with Kartagener syndrome: case report and literature review.

BACKGROUND: Kartagener syndrome is a subtype of primary ciliary dyskinesia that may exhibit various symptoms including neonatal respiratory distress and frequent infections of the lung, sinus and middle ear because of the impaired function of motile cilia. In addition to typical symptoms of primary ciliary dyskinesia, patients with Kartagener syndrome also show situs inversus. It is an autosomal recessive disorder which is mostly caused by mutations in DNAH5. Kartagener syndrome is often underdiagnosed due to challenges in the diagnosis process. As next-generation sequencing becomes widely used in clinical laboratories, genetic testing provides an accurate approach to the diagnosis of Kartagener syndrome. CASE PRESENTATION: A 7-year-old female patient presented with runny nose of 6 years duration and recurrent cough with phlegm of 2 years duration. Kartagener syndrome was diagnosed through diagnostic tests such as nasal nitric oxide (NO) concentration and transmission electron microscopy, and after performing other exams that corroborated the diagnosis, such as computed tomography, bronchoscopy and hearing test. Whole-exome sequencing was performed for the patient and both parents. The pediatric patient was diagnosed as Kartagener syndrome with the typical symptoms of ciliary dyskinesia including bronchiectasis, sinusitis, conductive hearing loss and situs inversus along with a reduced nasal NO concentration and ciliary abnormalities. The patient carried two novel compound heterozygous mutations in DNAH5, NM_001369:c.12813G > A (p. Trp4271Term) and NM_001369:c.9365delT (p. Leu3122Term). Both mutations lead to premature stop codons and thus are pathogenic. The p. Trp4271Term and p. Leu3122Term mutations were inherited from the father and the mother of the patient individually. A literature review was also conducted to summarize DNAH5 mutations in pediatric patients with Kartagener syndrome across different ethnic groups. CONCLUSIONS: Our study provides a good example of the diagnosis of Kartagener syndrome in pediatric patients using a series of diagnostic tests combined with genetic testing. Two novel loss-of-function mutations in DNAH5 were identified and validated in a pediatric patient with Kartagener syndrome.

Efficacy of Group Reminiscence Therapy on Cognition, Depression, Neuropsychiatric Symptoms, and Activities of Daily Living for Patients With Alzheimer Disease.

The current study aimed to investigate the effects of group reminiscence therapy on cognitive function, depression, neuropsychiatric symptoms, and activities of daily living in patients with mild-to-moderate Alzheimer disease (AD). A single-blind randomized parallel-design controlled trial was conducted between May 1, 2017, and April 30, 2018. Ninety patients with mild-to-moderate AD recruited from Beijing Geriatric Hospital were randomly allocated into intervention (n = 45) and control groups (n = 45). In the intervention group, group-based reminiscence therapy was performed in two 30- to 45-minute sessions weekly for 12 weeks. Control participants received only conventional drug treatments and routine daily care. Alzheimer disease-related symptoms were evaluated using the Alzheimer's Disease Assessment Scale-Cognitive section, the Cornell Scale for Depression in Dementia (CSDD), the Neuropsychiatric Inventory, and the Barthel Index. Four time points were set for data collection: baseline (before treatment), 4 weeks (during treatment), 12 weeks (end of treatment), and 24 weeks (12 weeks posttreatment). χ2 Tests, independent t tests, repeated-measures analysis of variance, and Bonferroni tests were used for data analysis. Significant improvements in depressive and neuropsychiatric symptoms were found in the intervention group compared to the control group (P < .05). Mean CSDD scores in the intervention group were improved at all 3 time points compared to baseline and showed the greatest effect at 12 weeks (t = 2.076, P = .041) and 24 weeks follow-up (t = 3.834, P = .000) compared to controls. Group reminiscence therapy was effective for improving depressive symptoms and was beneficial for treating neuropsychiatric symptoms in patients with AD.

Effects of dietary iron sources on growth performance, iron status, Fe-containing enzyme activity and gene expression related to iron homeostasis in tissues of weaned pigs.

The aim of this study is to evaluate the effects of dietary iron sources on growth performance, iron status and activities of Fe-containing enzymes and gene expression related to iron homeostasis in tissues of weaned pigs. A total of 480 piglets at d 28 (Duroc X Landrace) were allotted to four groups as a factorial arrangement of treatments with 30 pigs/pen (male: female = 1:1) and 4 replicate pens/treatment. The treatments for iron in the diets were: control basal diet (Con); Con + 150 mg Fe/kg as inorganic Fe (iFe); Con + 75 mg Fe/kg as inorganic Fe + 75 mg Fe/kg as organic Fe-peptide complex (iFe+oFe) and Con + 150 mg of Fe/kg as organic Fe-peptide complex (oFe). The feeding trial lasted for 36 days. There were no significant differences in final body weight, ADG, ADFI, and G/F as well as blood hemoglobin and MCHC contents between piglets fed the control and iron-supplemented groups (P > 0.05). The iron supplemented groups exhibited increased iron content in the liver, kidney and spleen as well as the CAT and SDH activities in liver compared to the control group (P < 0.05), while piglets in oFe group experienced greater Fe accumulation and activities of CAT and SDH in the liver than piglets in the iFe group. Compared with the control group, dietary supplementation of iron increased the NCOA4 mRNA expression and decreased the TfR1 mRNA expression in liver of piglets. The TfR1, NCOA4 and Ferritin mRNA expressions of bone marrow in both iFe and iFe+oFe groups were greater than both in the Con and oFe groups. These results suggest that dietary supplementation of iron does not influence the growth performance and hematological parameters in weaned pigs fed a corn-soybean meal basal diet (75.8 mg/kg) from d 28 to d 70, but increased tissue iron status and activities of Fe-containing enzymes at d 70. The addition of organic Fe-peptide complexes presents greater beneficial effects on enhancing tissue Fe accumulation and Fe-containing enzyme activities, which may be involved in different gene expression patterns related to iron intake and transport in tissues of weaned pigs.

Wireframe Orbit-Accelerated Bipedal DNA Walker for Electrochemiluminescence Detection of Methyltransferase Activity.

In spite of the DNA walkers executing the signal accumulation task in the process of moving along the predetermined paths, the enhancement of walking dynamics and walking path controllability are still challenging due to the unprogrammed arrangements of DNA orbits. Taking these dilemmas into account, a bipedal DNA walker was designed skillfully by the virtue of wireframe orbits assembled by DNA cubes in order, which improved the efficiency and the continuity of walking. It could be attributed to the fact that both the contact chance and the dynamic interaction between walking strands and designated orbits were beneficial to minimize the possibility of derailment and improve the accumulation of signal. In addition, the hollow titanium dioxide nanospheres coated with rubrene (Rub@TiO2 NSs) were prepared by the etching of inner silicon dioxide nanoparticles (SiO2 NPs) to regulate the distribution pattern of rubrene (Rub) molecules and expose more electrochemically active sites for high-efficient electrochemiluminescence (ECL). Benefiting by the pore confinement-enhanced ECL, the electron and mass transfer was significantly accelerated because of the hollow structure of Rub@TiO2 NSs. Subsequently, endogenous dissolved oxygen as the coreactant and palladium nanoparticles (Pd NPs) as the coreaction accelerator were employed to constitute a ternary ECL system with explosive signal response. Combining with this ECL platform, the bipedal walker activated by the target can autonomously and directionally move on the DNA wireframe orbits to release the quenching probes continuously. In this way, the biosensor displayed a low detection limit (2.30 × 10-8 U·mL-1) and a wide linear range (1.0 × 10-7 to 1.0 × 10-1 U·mL-1) for the sensitive detection of Dam methyltransferase (Dam MTase) activity. Therefore, a novel strategy for the accurate quantification of epigenetic targets was developed by virtue of improving the walking dynamics of DNA walker and amplifying the ECL of Rub molecules.

An old story with new insights into an ignored issue of metabolites in biochar-amended soil: Effect of biochar on dissipation of carbosulfan as an example.

Carbofuran (CAS) is one of extensively used carbamate pesticides, which is considered as a derivative or a candidate of carbofuran (CAN) for its lower toxicity and persistence. Nevertheless, CAS could be degraded into its toxic metabolites, imposing potential risks on ecological safety. In this paper, biochars, derived from rice straw (RS), chicken manure (CM), corn straw (CS) and tire rubber (TR), were applied in CAS-contaminated soil to explore their effects on the dissipation of CAS and its metabolites. The dissipation rate of CAS was depressed by the amendment of biochar, mainly because biochar inhibited the hydrolysis of CAS by elevating soil pH value. Nevertheless, CS has efficiently enhanced the dissipation of CAN by almost 2-times for its promotion in hydrolysis and biodegradation. CS and CM improved biodegradation by altering the composition and structure of the microbial communities, exhibiting potential for facilitating bioremediation of CAS and CAN. Moreover, steam activated biochar accelerated the dissipation rate by 1.7-2.9 times and 1.3-2.4 times for CAS and CAN, respectively. This study investigated the effects of biochar on CAS and its toxic metabolites as well as possible governing mechanisms, providing rational instruction for biochar application in ambient atmosphere.

Chemotaxonomic variation in volatile component contents and their correlation between climate factors in Chinese prickly ash peels (Zanthoxylum bungeanum Maxim.).

In this study, we analyzed the characteristics of volatile compounds of Chinese prickly ash peels with different climate conditions and their correlation. The data revealed that the contents of limonene and linalool in peels from southwest and northwest regions were higher, and the aroma was stronger, while the contents of ß-myrcene and (E)-ocimene in them from north, east and central China were higher, and the spicy flavor was heavier. Hierarchical cluster analysis demonstrated that the classification had geographical continuity. Through the correlation analysis and path analysis, it was found that the contents of volatile compounds were closely related to the climatic factors. The influence of wind speed and annual average temperature on volatile substances was greater than that of annual average precipitation and annual sunshine duration. This enriched the effect of climatic factors on the accumulation of volatile substances, and promoted the agriculture practices in area having similar climate conditions.

Relationship Between Alzheimer's Disease and Retinal Choroidal Thickness: A Cross-Sectional Study.

BACKGROUND: The choroid is involved directly or indirectly in many pathological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). OBJECTIVE: The objective of this study was to investigate the association between retinal choroidal properties and the pathology of AD by determining choroidal thickness, hippocampus volume, cognitive functions, and plasma BACE1 activity. METHODS: In this cross-sectional study, 37 patients with AD and 34 age-matched controls were included. Retinal choroidal thickness was measured via enhanced depth imaging optical coherence tomography. Hippocampal volume was measured via 3.0T MRI. Cognitive functions were evaluated using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). Plasma BACE1 activity was analyzed using a fluorescence substrate-based plasma assay, and regression model were to analyze the data. RESULTS: Retinal choroidal thickness was significantly thinner in the AD group than in the control group [(114.81±81.30) µm versus (233.79±38.29) µm, p < 0.05]. Multivariable regression analysis indicated that the ADAS-cog scores (ß=-0.772, p = 0.000) and age (ß=-0.176, p = 0.015) were independently associated with choroidal thickness. The logistic regression model revealed that the subfoveal choroidal thickness was a significant predictor for AD (OR = 0.984, 95% CI: 0.972-0.997). CONCLUSION: There was a general tendency of choroid thinning as the cognitive function declined. Although choroidal thickness was not a potential indicator for early stage AD, it was valuable in monitoring AD progression.

[Advanced Nitrogen Removal Characteristics of Low Carbon Source Municipal Wastewater Treatment via Partial-denitrification Coupled with ANAMMOX].

Partial-denitrification coupled with ANAMMOX is a novel biological nitrogen removal technology, which is expected to significantly reduce the external carbon source dosage for advanced nitrogen removal from municipal wastewater. In this study, ANAMMOX sludge was inoculated to investigate advanced nitrogen removal performance and sludge characteristics in a partial-denitrification/ANAMMOX reactor. The results showed that inoculation of ANAMMOX sludge could quickly start the partial-denitrification/ANAMMOX reactor. The effluent total nitrogen concentrations were (4.82±1.84) mg·L-1 with a chemical oxygen demand of 2.19±0.08. Sludge particles larger than 0.20 mm accounted for 86.16% in the reactor. This meant that granular sludge was formed, which was conducive to good retention of ANAMMOX bacteria in the reactor. The external carbon source dosage and the oxygen requirement for nitrification can be reduced by applying partial-denitrification coupled with ANAMMOX to advanced nitrogen removal from the effluent of secondary clarifier in municipal wastewater treatment plants.

TNFAIP3 Interacting Protein 3 Overexpression Suppresses Nonalcoholic Steatohepatitis by Blocking TAK1 Activation.

Nonalcoholic steatohepatitis (NASH) is an unmet clinical challenge due to the rapid increase in its occurrence but the lack of approved drugs to treat it. Further unraveling of the molecular mechanisms underlying NASH may identify potential successful drug targets for this condition. Here, we identified TNFAIP3 interacting protein 3 (TNIP3) as a novel inhibitor of NASH. Hepatocyte-specific TNIP3 transgenic overexpression attenuates NASH in two dietary models in mice. Mechanistically, this inhibitory effect of TNIP3 is independent of its conventional role as an inhibitor of TNFAIP3. Rather, TNIP3 directly interacts with TAK1 and inhibits its ubiquitination and activation by the E3 ligase TRIM8 in hepatocytes in response to metabolic stress. Notably, adenovirus-mediated TNIP3 expression in the liver substantially blocks NASH progression in mice. These results suggest that TNIP3 may be a promising therapeutic target for NASH management.

The dissipation of cyazofamid and its main metabolite in soil response oppositely to biochar application.

Biochars derived from rice straw (RS), corn straw (CS), chicken manure (CM) and tire rubber (TR) were applied to soil to investigate their effects on the dissipation of cyazofamid and its metabolite CCIM (4-chloro-5-p-tolylimidazole-2-carbonitrile), with high acute toxicity compared to cyazofamid. The enhancement of cyazofamid dissipation followed the order of CS > RS > CM, whereas TR depressed the cyazofamid dissipation. Adsorption, hydrolysis and microbial degradation were all involved in cyazofamid dissipation. CM and CS enhanced the contribution of biodegradation to cyazofamid dissipation, which might be related with the shifted microbial community. More importantly, CCIM residual was drastically increased by 8-15 times after biochar application, regardless of biochar type. In total, this study shed light on the issue of build-up of metabolites in biochar-amended soil, especially for metabolites having higher toxicities than parent compounds, providing new insights into potential risk of biochar application for soil remediation.

Comparative efficacy and tolerability of antipsychotics as augmentations in adults with treatment-resistant obsessive-compulsive disorder: A network meta-analysis.

We performed a network meta-analysis to build clear hierarchies of efficacy and tolerability of antipsychotics to augment serotonin reuptake inhibitors (SRIs) for treatment-resistant obsessive-compulsive disorder (OCD) in adults. PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched on September 8, 2018. Randomized controlled trials investigating antipsychotics as augmentation agents were included. Network meta-analyses were performed using frequentist methods. Efficacy was measured by the Yale-Brown Obsessive-Compulsive Scale. Tolerability was measured by side-effect discontinuations. Mean differences (MDs) and odds ratios (ORs) were reported with 95% confidence intervals (CIs). Twenty articles with 790 patients were included. Our analyses showed that there was no significant difference in efficacy between antipsychotic agents. The order of efficacy rankings was inconsistent between primary analysis and sensitivity analyses. We found that there was considerable heterogeneity between studies. Comorbid tics was identified as a significant moderator. All antipsychotics except paliperidone were significantly superior to placebo in the subgroup without comorbid tics, while no antipsychotics was significantly superior to placebo in the comorbid tics subgroup. With respect to tolerability, quetiapine (OR, 3.45; 95% CI, 1.04-11.11) and paliperidone (20.00; 1.01->100) were significantly less tolerable than placebo. Based on this network meta-analysis, antipsychotic agents as augmentations to SRIs might be more effective in treatment-resistant OCD patients without comorbid tics. Definitive determination of which drug is optimal cannot be drawn currently because of the limited numbers of studies and heterogeneity across studies.

Augmentation agents to serotonin reuptake inhibitors for treatment-resistant obsessive-compulsive disorder: A network meta-analysis.

BACKGROUND: Various agents for augmentation of serotonin reuptake inhibitors have been investigated for treatment-resistant obsessive-compulsive disorder (OCD). We aimed to comprehensively compare different augmentation agents for treatment-resistant OCD in adults. METHODS: PubMed, Embase, Web of Science, CENTRAL, the WHO's ICTRP, and ClinicalTrials.gov were searched on February 20, 2018. Pairwise meta-analysis and Bayesian network meta-analysis were performed. The primary outcome was efficacy measured by the Yale-Brown Obsessive Compulsive Scale. The secondary outcomes were tolerability (side-effect discontinuation) and acceptability (all cause discontinuation). Mean differences (MDs) and odds ratios (ORs) were reported with 95% confidence intervals (CIs). RESULTS: Thirty-three articles with 34 trials (1216 patients) were included. Memantine (MD, -8.94; 95% CI, -14.42 to -3.42), risperidone (-4.47, -8.75 to -0.17), topiramate (-6.05, -10.89 to -1.20), lamotrigine (-6.07, -11.61 to -0.50), and aripiprazole (-5.14, -9.95 to -0.28) were significantly superior to placebo. Antipsychotic (-4.09, -6.22 to -1.93) and glutamatergic (-5.22, -7.53 to -2.84) agents were significantly superior to placebo. Considerable heterogeneity was found across studies, and baseline symptom severity was identified as a significant moderator. After baseline severity adjustment, quetiapine (-5.00, -8.59 to -1.29) and olanzapine (-8.28, -15.34 to -1.13) became significantly superior to placebo. CONCLUSIONS: Our study supports the use of antipsychotic or glutamatergic agents as augmentation agents for treatment-resistant OCD. Topiramate, lamotrigine, aripiprazole, olanzapine, risperidone, memantine, and quetiapine are alternative augmentation drugs; however, a definitive conclusion of the best drug remains undetermined because of the considerable heterogeneity and limited numbers of studies and patients for each agent.

Changes of chromium speciation and organic matter during low-temperature pyrolysis of tannery sludge.

The application or disposal of char derived from tannery sludge is directly influenced by the mobility and bioavailability of Cr during pyrolysis process. This study focused on the changes of Cr speciation and organic matter in tannery sludge during low-temperature pyrolysis (100-400 °C) to evaluate the toxicity of char in terms of the leaching possibility of Cr. The results showed that (1) lower char yield and more porous structure were observed after pyrolysis. (2) Higher pyrolysis temperature increased Cr content in the char; however, Cr in this case was converted into the residual fraction which minimized its bioavailability therefore lowers its potential risk to the environment. (3) Organic matters in the acid and alkali leachates were mainly humic acid-like substance, and condensed organic matter might appear at 200 °C and then destruct. (4) Despite the comparatively high content of Cr in the char, the leaching toxicity of char was within the security range according to the national standard of China. The Cr content in the acid and alkali leachates decreased to the range of 16.5-35.3 and 0.2-6.8 mg/L, respectively. It was suggested that the potential toxicity of tannery sludge from Cr could be reduced before utilization or disposal by pyrolysis, especially under 400 °C.

The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis.

Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes. Hepatocyte-specific ablation of Tnfaip3 exacerbated nonalcoholic fatty liver disease- and NASH-related phenotypes in mice, including glucose metabolism disorders, lipid accumulation and enhanced inflammation, in an ASK1-dependent manner. In contrast, transgenic or adeno-associated virus-mediated TNFAIP3 gene delivery in the liver in both mouse and nonhuman primate models of NASH substantially blocked the onset and progression of the disease. These results implicate TNFAIP3 as a functionally important endogenous suppressor of ASK1 hyperactivation in the pathogenesis of NASH and identify it as a potential new molecular target for NASH therapy.

The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. Lack of effective pharmacotherapies for NASH is largely attributable to an incomplete understanding of its pathogenesis. The deubiquitinase cylindromatosis (CYLD) plays key roles in inflammation and cancer. Here we identified CYLD as a suppressor of NASH in mice and in monkeys. CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity. We observed that overexpression of Cyld in hepatocytes concomitantly inhibits lipid accumulation, insulin resistance, inflammation and fibrosis in mice with NASH induced in an experimental setting. Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. Notably, reconstitution of hepatic CYLD expression effectively reverses disease progression in mice with dietary or genetically induced NASH and in high-fat diet-fed monkeys predisposed to metabolic syndrome. Collectively, our findings demonstrate that CYLD mitigates NASH severity and identify the CYLD-TAK1 axis as a promising therapeutic target for management of the disease.