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Accumulating data suggest cerebrospinal fluid (CSF) neurogranin (Ng) as a potential biomarker for cognitive decline and neurodegeneration in Alzheimer disease (AD). To investigate whether the CSF Ng can be used for diagnosis, prognosis, and monitoring of AD, we examined 111 cognitively normal (CN) controls, 193 mild cognitive impairment (MCI) patients and 95 AD patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Correlations were tested between baseline CSF Ng levels and baseline core AD biomarkers and longitudinal glucose metabolism, brain atrophy and cognitive decline. We detected that CSF Ng levels increased with disease severity, and correlated with phosphorylated tau and total tau levels within each diagnostic group. High baseline CSF Ng levels correlated with longitudinal reductions in cortical glucose metabolism within each diagnostic group and hippocampal volume within MCI group during follow-up. In addition, high baseline CSF Ng levels correlated with cognitive decline as reflected by decreased cognitive scale scores. The CSF Ng levels predicted future cognitive impairment (adjusted hazard ratio:3.66, 95%CI: 1.74-7.70, P = 0.001) in CN controls. These data demonstrate that CSF Ng offers diagnostic utility for AD and predicts future cognitive impairment in CN individuals and, therefore, may be a useful addition to the current AD biomarkers.

Physical exercise promotes motor skill learning in normal individuals and those with neurological disorders but its mechanism of action is unclear. We find that one week of voluntary wheel running enhances the acquisition of motor skills in normal adult mice. One week of running also induces switching from ACh to GABA expression in neurons in the caudal pedunculopontine nucleus (cPPN). Consistent with regulation of motor skills, we show that the switching neurons make projections to the substantia nigra (SN), ventral tegmental area (VTA) and ventrolateral-ventromedial nuclei of the thalamus (VL-VM). Use of viral vectors to override transmitter switching blocks the beneficial effect of running on motor skill learning. We suggest that neurotransmitter switching provides the basis by which sustained running benefits motor skill learning, presenting a target for clinical treatment of movement disorders.

We demonstrate the rapid photodarkening (PD) phenomenon in Tm-doped fiber (TDF) core pumped by a laser at 1080 nm and the bleaching effect of deuterium (${{\rm D}_2}$D 2 ) on PD TDF. By ${{\rm D}_2}$D 2 loading for seven days, the PD-induced excess loss (PIEL) in the visible (VIS) and near-infrared (NIR) region have been largely eliminated, and no degradation was observed within 30 days. PD resistance of the ${{\rm D}_2}$D 2 pretreated TDF has been investigated as well. The formation of color centers based on defects and precursors in the silica matrix and the mechanism of ${{\rm D}_2}$D 2 bleaching are discussed.

In various kinds of carcinomas, the special AT-rich sequence-binding protein 2 (SATB2) with its atypical expression promotes the metastasis and progression of the tumor, though in the oral squamous cell carcinoma (OSCC) its inherent mechanism and the status of SATB2 remain unclear. The role played by the SATB2 expression in the OSCC cell lines and tissue samples in the target of miR-34a downstream is the intended endeavor of this study. In te OSCCs the miR-34a expression was determined by quantitative real-time polymerase chain reaction (q-PCR), while the SATB2 expression in the cell lines and tissue samples in OSCC was analyzed with the q-PCR and the western blot. Studies in both in vitro and in vivo of the effects of miR-34a on the initiation of OSCC were conducted. As a direct target of the miR-34a the SATB2 was verified with the luciferase reporter assay. In cases where the miR-34a levels were low, the SATB2 in OSCCs seemed to be overexpressed. Besides, both in the in vitro and in vivo a suppression of migration, invasion, and cell growth was caused by miR-34a by down regulating the SATB2 expression. The SATB2 being a direct target of miR-34a was confirmed by the cotransfection of miR-34a mimics specifically the decrease in the expression of luciferase of SATB2-3'UTR-wt reporter. As a whole, our study confirmed the inhibition of miR-34a in the invasion, proliferation, and migration of the OSCCs, playing a potential tumor suppressor role with SATB2 as its downstream target., (© 2019 Wiley Periodicals, Inc.)

Objective: To analyze the clinical pathological characteristics and incidence of thyroid cancer. Methods: The clinical and pathological data of 21 980 thyroid cancer patients who underwent surgery in the Department of Thyroid Surgery of the First Affiliated Hospital of Zhengzhou University from January 2012 to December 2018, including the gender, age, pathological type, tumor size, tumor number, central and lateral lymph node metastasis, was retrospectively analyzed. Results: There were 16 895 females and 5 085 males (gender ratio: 3.3 to 1), aged 4 to 95 (47.6±11.8) years old. Except for 2012, the average onset age of females was higher than that of males, and both genders showed a trend of early onset over time (females: Z= -2.703, P= 0.007; males: Z= -3.004, P= 0.003). The proportion of female aged 25 to 39 and male aged 20 to 39 was increasing, but the proportion of both genders aged over 60 was decreasing (all P< 0.05). With the increase of tumor length and diameter, the positive rate of central lymph nodes metastasis ( Z= -2.205, P= 0.027) and lateral lymph node metastasis ( Z= -2.205, P= 0.027) gradually increased. Conclusions: The onset age of thyroid cancer exhibited a much younger trend, with an increasing proportion of women aged 25-39 and men aged 20-39. Therefore, it should be suggested to strengthen the screening of people in the corresponding age range. The newly diagnosed thyroid cancer was mainly thyroid micropapillary carcinoma, with a high proportion of lymph node metastasis and multiple foci, and thus the optimal treatment methods need to be carefully considered.

Background: Loss of function of triggering receptor expressed on myeloid cell 2 (TREM2), a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). Whether TREM2 levels are pathologically altered during the preclinical phase, and whether cerebrospinal fluid (CSF) soluble TREM2 protein (sTREM2) has a relationship with major pathological processes including Aβ and tau deposition are still unclear., Methods: According to the NIA-AA criteria, 659 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups, stage 0 (normal Aβ 1-42 , T-tau and P-tau), stage 1 (low Aβ 1-42 , normal T-tau and P-tau), stage 2 (low Aβ 1-42 and high T-tau or P-tau), and suspected non-AD pathology (SNAP) (normal Aβ 1-42 and high T-tau or P-tau), to examine changes of CSF sTREM2 in the preclinical AD. Biomarker cut-off was based on the assumption that one-third of adults with normal cognition have AD pathology., Results: The level of CSF sTREM2 in the stage 1 decreased compared with the stage 0 (P < 0.001), and then increased in the stage 2 (P = 0.008). SNAP individuals also had significantly increased CSF sTREM2 (P < 0.001). Results of multiple linear regressions also showed positive correlations of CSF sTREM2 with Aβ 1-42 (β = 0.192, P < 0.001), T-tau (β = 0.215, P < 0.001) and P-tau (β = 0.123, P < 0.001)., Conclusion: CSF sTREM2 levels are dynamic in preclinical AD. Aβ pathology is associated with a decrease in CSF sTREM2 in the absence of tau deposition and neurodegeneration. However, tau pathology and neurodegeneration are associated with an increase in CSF sTREM2.

Circular RNAs (circRNAs) have been shown to regulate the development and progression of various cancers. However, the expression and function of circRNAs in papillary thyroid cancer (PTC) remain largely unknown. This study is aimed to investigate the potential roles of circEIF3I in PTC and elucidate the functional mechanism. We found that the expression of circEIF3I was significantly upregulated in PTC tissues compared to adjacent normal tissues. CircEIF3I expression was positively associated with tumor size, TNM stage and metastasis. CircEIF3I knockdown remarkably suppressed the proliferation, migration and invasion of PTC cells. Mechanistically, circEIF3I promoted KIF2A expression through competitively interacting with miR-149. In conclusion, circEIF3I upregulation in PTC tissues facilitates KIF2A expression by inhibiting miR-149, leading to malignant progression of PTC. This study suggested circEIF3I/miR-149/KIF2A axis might be a potential therapeutic target., Competing Interests: None., (AJCR Copyright © 2020.)

Despite the high profile of aconine in WuTou injection, there has been no preparative technology or structural studies of its salt as the pharmaceutical product. The lack of any halide salt forms is surprising as aconine contains a tertiary nitrogen atom. In this work, aconine was prepared from the degradation of aconitine in Aconiti kusnezoffii radix (CaoWu). A green chemistry technique was applied to enrich the lipophilic-poor aconine. Reaction of aconine with hydrochloride acid resulted in protonation of the nitrogen atom and gave a novel salt form (C 25 H 42 NO 9 + ·Cl - ·H 2 O; aconine hydrochloride monohydrate, AHM), whose cation in the crystal structure was elucidated based on extensive spectroscopic and X-ray crystallographic analyses. The AHM crystal had a Z' = 3 structure with three independent cation-anion pairs, with profound conformational differences among the aconine cations. The central framework of each aconine cation was compared with that of previously reported aconitine, proving that protonation of the nitrogen atom induced the structure rearrangement. In the crystal of AHM, aconine cations, chloride anions and water molecules interacted through inter-species O-H...Cl and O-H...O hydrogen bonds; this complex hydrogen-bonding network stabilizes the supramolecular structure. The seriously disordered solvent molecules were treated using the PLATON SQUEEZE procedure [Spek (2015). Acta Cryst. C71, 9-18] and their atoms were therefore omitted from the refinement. Bioactivity studies indicated that AHM promoted in vitro proliferative activities of RAW264.7 cells. Molecular docking suggested AHM could target cardiotoxic protein through the hydrogen-bonding interactions. The structural confirmation of AHM offers a rational approach for improving the pharmaceutical technology of WuTou injection.

Elevated serum uric acid (SUA) has been reported to be associated with an increased risk of cardiovascular diseases, but the role of SUA in intracranial atherosclerosis remains unclear. To investigate the association between SUA and intracranial atherosclerotic stenosis (ICAS), we evaluated 1522 subjects (305 with ICAS, 1217 without ICAS) with magnetic resonance angiography (MRA). Subjects were classified into ten groups according to the deciles of the SUA level. The rate of ICAS reached a minimum in the seventh decile (6.0-6.3 mg/dL; reference group). After adjusting for confounding factors, multivariate logistic regression analysis demonstrated that both low SUA level (≤ 3.8 mg/dL; OR, 2.34; 95% CI, 1.29-4.39; p = 0.006) and high SUA level (≥ 7.8 mg/dL; OR, 2.10; 95% CI, 1.15-3.92; p = 0.017) conferred greater risk for ICAS. In multivariable analysis with a quadratic model which used SUA as a continuous variable, a U-shaped association between SUA and the rate of ICAS was confirmed (α > 0; p < 0.001). The estimated SUA level associated with the lowest rate of ICAS was 6.2 mg/dL. In conclusion, our findings suggest a U-shaped association between ICAS and SUA.

Background: Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease nowadays. Changes in diet and lifestyle have led to a dramatic increase in the prevalence of NAFLD around the world. This meta-analysis is to investigate the efficacy of physical activity intervention on liver-specific endpoints in the population with NAFLD, including hepatic enzyme, serum lipid, glucose metabolism and intra-hepatic lipid., Methods: PubMed and China National Knowledge Infrastructure (CNKI) databases were searched for randomized clinical trials of physical activity intervention on NAFLD patients through April 20th, 2019. Effect sizes were reported as standardized mean difference (SMD) and 95% confidence intervals (CI). Quality of included studies was assessed according to the Cochrane risk of bias tool. Meta-analyses were conducted using random-effect or fixed-effect models depending on the significance of heterogeneity. Subgroup analyses according to types and duration of physical activity were conducted to investigate clinical variability., Results: Nine studies with a cumulative total of 951 participants met selection criteria. Physical activity was found associated with small reductions in hepatic enzyme parameters: ALT (SMD -0.17, 95% CI:-0.30 to - 0.05), AST (SMD -0.25, 95% CI: - 0.38, - 0.13) and GGT (SMD -0.22, 95% CI: - 0.36, - 0.08). Significant small improvements were also found in serum lipid parameters including TC (SMD = - 0.22, 95% CI: - 0.34, - 0.09), TG (SMD = - 0.18, 95% CI: - 0.31 to - 0.06) and LDL-C (SMD = - 0.26, 95% CI: - 0.39 to - 0.13). Significant improvement was also found in intra-hepatic lipid content (SMD = - 0.21, 95% CI: - 0.36 to - 0.06) There was no difference between physical intervention group and control group in HDL and three glucose metabolism parameters. Subgroup analysis suggested both aerobic exercise alone and resistance exercise alone can improve most liver function and longer period of exercise generally had better improvement effect., Conclusions: Our findings suggest that physical activity alone can only slightly improve hepatic enzyme levels, most serum lipid levels and intra-hepatic lipid content in non-diabetic patients with NAFLD.

Objective: Glioma is a malignant brain cancer capable of spreading to the microenvironment. Long non-coding RNA (lncRNA) X inactive specific transcript (XIST) was recognized as a significant regulator in many cancers. However, the molecular mechanism of XIST in glioma cell radio-sensitivity requires further exploration., Patients and Methods: The expression of XIST, microRNA (miR)-329-3p and cyclic AMP response element-binding protein 1 (CREB1) was evaluated by quantitative Real-time polymerase chain reaction (qRT-PCR). Cell viability and apoptosis were examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry, respectively. Transwell assay was performed to detect cell invasion. Protein expression of gamma-H2AX (γ-H2AX) and CREB1 was determined by Western blot. The correlation between miR-329-3p and XIST or CREB1 was determined by dual-luciferase reporter assay. Animal models were established by subcutaneously injecting U251 cells transfected with sh-XIST and sh-NC., Results: XIST and CREB1 were overexpressed whereas miR-329-3p was low-expressed in glioma tumors and cells compared with the normal counterparts. XIST knockdown inhibited cell proliferation, invasion and induced cell apoptosis by enhancing cell sensitivity to X-ray radiation in glioma. Then, we discovered that miR-329-3p directly interacted with XIST or CREB1 in glioma. In addition, miR-329-3p inhibitor abolished XIST silencing-induced regulatory effects on cell proliferation, apoptosis, invasion, and radio-sensitivity. Meanwhile, miR-329-3p inhibitor counteracted CREB1 silencing-induced inhibition on cell progression and facilitation on radio-sensitivity in glioma. Moreover, we found that XIST could increase CREB1 expression by sponging miR-329-3p. Animal experiments revealed that XIST silencing restrained tumor growth in vivo., Conclusions: XIST accelerates cell proliferation, invasion and inhibits cell apoptosis by repressing radio-sensitivity of glioma via enhancing CREB1 expression through sponging miR-329-3p, representing prospective methods for glioma treatment.

Grape seed procyanidins (GSPs), widely known for their beneficial health properties, fail to bring about the expected improvement in piglets' growth performance. The effects of dietary supplementation with GSPs on nutrient utilisation may be a critical influencing factor. Hence, the purpose of this study was to investigate the effects of dietary supplementation with GSPs on nutrient utilisation and gut function in weaned piglets. One hundred and twenty crossbred piglets were allocated randomly to four treatment groups, with three replicate pens per treatment and 10 piglets per pen. Each group was given one of the four dietary treatments: the basal diet (control group) or the basal diet with the addition of 50-, 100- or 150-mg/kg GSPs. The trial lasted 28 days. Faeces were collected from d 12 to 14 and from d 26 to 28 for measuring the coefficient of total tract apparent digestibility (CTTAD) of the nutrients. Blood samples were collected on d 14 and 28 for detecting the blood biochemical parameters. Two piglets per pen were slaughtered to collect the pancreas and intestinal digesta for evaluating the digestive enzyme activity and the coefficient of ileal apparent digestibility (CIAD) of the nutrients. On d 14 and 28, supplementation with 150-mg/kg GSPs significantly decreased the CTTAD of DM and CP in piglets. On d 14, GSPs supplementation at a concentration of 150 mg/kg led to a remarkable decrease in the CIAD of CP and gross energy (GE). On d 28, GSPs supplementation at a dose of 150 mg/kg generated a marked decline in the CIAD of DM, GE, CP and ether extract. Grape seed procyanidins supplementation at concentrations of 100 or 150 mg/kg inhibited the activities of lipase and amylase. In contrast, the jejunum mucosa maltase and sucrase activities increased due to the inclusion of GSPs at a concentration of 100 mg/kg in the piglet diet. Compared with the levels of the control group, the serum glucose and total protein levels were enhanced significantly by supplementation with GSPs at 100 mg/kg and reduced dramatically at 150 mg/kg. The serum diamine oxidase activity and endotoxin levels were decreased by GSPs supplementation in piglet diets. In conclusion, higher concentrations of GSPs in weaned piglet diets attenuated nutrient digestion and inhibited digestive enzyme activity; however, suitable concentrations of GSPs could promote brush-border enzyme activity, enhance serum glucose and total protein concentrations and decrease epithelial permeability.

Postoperative malnutrition is a major issue among gastrointestinal cancer patients. Because n-3 polyunsaturated fatty acids (n-3 PUFAs) have immunological benefits, n-3 PUFAs are widely used in oral nutritional supplements (ONS). However, n-3 PUFAs in ONS reduced patients' compliance with ONS and affected the role of ONS in maintaining the postoperative nutritional status of patients. The aim of this study was to systematically explore the benefits of enteral nutrition rich in n-3 PUFAs in maintaining the nutritional status of patients after gastrointestinal surgery. Databases including PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP databases were searched through March 16, 2019. The references of related reviews and studies were assessed up to March 16, 2019. The effect sizes from individual studies were calculated as the standardized mean difference (SMD), mean difference (MD), and risk ratio (RR) with 95% confidence intervals (95% CIs). A total of 11 studies (n = 977) were included. In this systematic review and meta-analysis, we observed that enteral supplementation of n-3 PUFAs had no significant effect on weight (MD, 1.09; 95% CI, -0.90, 3.08), body mass index (MD, 0.55; 95% CI, -1.45, 2.54), albumin (SMD, 0.39; 95% CI, -0.10, 0.87), wound infections (RR, 0.87, 95% CI, 0.57, 1.33), or pneumonia (RR, 0.98; 95% CI, 0.60, 1.59) in gastrointestinal cancer patients. Thus, compared with enteral nutritional without n-3 PUFAs, enteral nutritional rich in n-3 PUFAs has no significant effects on nutritional status, incidence of pneumonia, or wound infections among gastrointestinal cancer patients during postoperative convalescence.

Ecological stoichiometry provides a new method for understanding the characteristics, driving forces and mechanisms of C, N and P coupled cycles. However, there are few reports on the variation in ecological stoichiometry of plants during their growth. In this study, we fitted the total elemental mass of different module based on the size of Nitraria tangutorum, and derived the ecological stoichiometry models of different module and whole ramet by measuring the biomass and nutrient concentrations of the current-year stems in 2017, 2-year-old stems, more than 2-year-old stems, leaves, roots and layerings of N. tangutorum ramet. Our results showed that the derivation model could well reflect the changes in ecological stoichiometry during plant growth. The old stems and the layering had higher N:P and C:P, while leaves,current-year stems, and roots had lower N:P and C:P. The whole plant nutrient elements cumulative rate was P:N:C during the growth process. These results were consistent with the growth rate hypothesis and allometric theory, and provide evidence for nutrient reabsorption. This model could be used as an effective way to analyze the dynamic characteristics of elements in plant growth.

Purpose: To investigate the effect of miR-138 targeting PLD2 gene on proliferation and migration of oral cancer cells., Methods: After oral cancer cells were transfected with miR-138, the expression level of microRNA-138 was detected by RT-PCR assay, the proliferation ability was detected by MTT assay, and cell cycle distribution was detected by flow cytometry. Transwell migration assay was used to detect cell migration ability, Western blotting assay was used to detect the expression levels of MMP-9, PLD2 and cyclin D1 in gastric cancer cells. Luciferase assay was used to report the targeting relationship between microRNA-138 and PLD2 gene. SPSS 21.0 software package was used to analyze the data., Results: After miR-138 was transfected into oral cancer cells, the relative expression level of miR-138 was 4.28±0.16, which was significantly higher than that of blank control and miR-NC group (P<0.05). Luciferase reporter gene assay showed that the relative activity of PLD2 wild plasmid luciferase was significantly lower in oral cancer cells transfected with microRNA-138 than in other groups (P<0.05); The expression level of PLD2 gene in miR-138 group was significantly lower than that in blank control group and miR-NC group (P<0.05). After oral cancer cells were transfected with miR-138, the proliferation ability of oral cancer cells in miR-373 group was significantly lower than that in control group and miR-NC group (P<0.05). Flow cytometry showed that the ratio of G0/G1 phase was (64.39±6.49)% in the group of miR-138, which was significantly higher than that in the blank control group and the group of miR-NC(P<0.05); The ratio of S phase in the group of miR-138 was(13.28±3.16)%, which was significantly lower than that in the blank control group and the group of miR-NC (P<0.05); There was no significant difference in the ratio of G2/M phase among the groups (P>0.05). Transwell experiment showed that the number of migrating cells transfected with miR-138 in oral cancer cells was 138.46±24.37, which was significantly lower than that in blank control group and miR-NC group(P<0.05). Western blotting experiments showed that the relative levels of MMP-9, vimentin and cyclin D1 in the miR-138 group were 0.14±0.04, 0.17±0.02 and 0.15±0.03, respectively, which were significantly lower than those in the blank control group and the miR-NC group(P<0.05)., Conclusions: miR-138 can target PLD2 gene expression and inhibit the proliferation and migration of oral cancer cells.

Background: In strawberry cultivation, continuous cropping (CC) obstacles seriously threaten production. A patented soil amendment (SA) can effectively relieve the CC obstacles to strawberry cultivation, but knowledge of the recovery mechanisms underlying this phenomenon is limited., Results: In this study, transcriptomic profiling of strawberry roots in soil with and without the SA was conducted using RNA-Seq technology to reveal gene expression changes in response to SA treatment. In total, 188 differentially expressed genes (DEGs), including 144 upregulated and 44 downregulated DEGs, were identified. SA treatment resulted in genotype-dependent responses, and the response pattern, including an overall increase in the expression of nutrient transport genes and a decrease in the expression of defense response genes, may be a possible mechanism underlying recovery strategies in strawberry roots after the application of the SA to CC soil. We also found that 9 Hsp genes involved in plant defense pathways were all downregulated in the SA-treated roots., Conclusions: This research indicated that strawberry plants reallocated defense resources to development when SA treatment alleviated the stress caused by a CC soil environment. The present study provides an opportunity to reveal the fundamental mechanisms of the tradeoff between growth and defense in strawberry.

Objective: To examine protein changes in the hippocampus of APP/PS1 transgenic mice after blueberry extracts (BB) intervention. Methods: Eight APP/PS1 transgenic mice were randomly assigned to Alzheimer's disease (AD)+BB group ( n =4) and AD+control group ( n =4). After a 16-week treatment, 2-DE and MALDI-TOF-MS were used to compare the proteomic profiles of the hippocampus in the two groups and Western blot was used to confirm the important differentially expressed proteins. Results: Twelve proteins were differentially expressed between the two groups. Nine of them were identified. Cytochrome b-c1 complex subunit 6, beta-actin, dynamin 1, and heat shock cognate 71 were up-regulated in AD+BB group, while a-enolase, stress-induced-phosphoprotein 1, malate dehydrogenase (MDH), MDH 1, and T-complex protein 1 subunit beta were down-regulated, respectively. Importantly, some of the identified proteins (e.g. dynamin 1) are known to be involved in cognitive impairment. Western blot analysis of hippocampus dynamin 1 expression confirmed the proteomic findings. Conclusions: The consumption of BB modulates the expression of proteins that are linked to the improvements of cognitive dysfunction in hippocampus of APP/PS1 transgenic mice.

Background: Hypometabolism detected by fluorodeoxyglucose F18 positron emission tomography ([18F] FDG PET) is an early neuropathologic changes in Alzheimer's disease (AD) and provides important pathologic staging information., Objective: This study aimed to discover genetic interactions that regulate longitudinal glucose metabolic decline in AD-related brain regions., Methods: A total of 586 non-Hispanic white individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts that met all quality control criteria were included in this study. Genome-wide association study of glucose metabolic decline in regions of interest (ROIs) was performed with linear regression under the additive genetic model., Results: We identified two novel variants that had a strong association with longitudinal metabolic decline in different ROI. Rs4819351-A in gene 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) demonstrated reduced metabolic decline in right temporal gyrus (p = 3.97×10-8, β= -0.016), while rs13387360-T in gene LOC101928196 demonstrated reduced metabolic decline in left angular gyrus (p = 1.69×10-8, β= -0.027)., Conclusion: Our results suggest two genome-wide significant SNPs (rs4819351, rs13387360) in AGPAT3 and LOC101928196 as protective loci that modulate glucose metabolic decline. These two genes should be further investigated as potential therapeutic target for neurodegeneration diseases.

Objective: The aim of this study was to clarify the role of TCF19 in influencing the malignant progression of colorectal cancer (CRC) by negatively regulating WWC1., Patients and Methods: Relative expression levels of TCF19 and WWC1 in CRC tissues and cells were detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The prognosis of CRC patients was assessed by the Kaplan-Meier method. Meanwhile, the correlation between TCF19 and pathological indexes of CRC patients was evaluated. Regulatory effects of TCF19/WWC1 on viability, colony formation ability, and migration in HT29 and HCT-8 cells were evaluated. Finally, rescue experiments were conducted to elucidate a negative feedback loop of TCF19/WWC1 in influencing the progression of CRC., Results: TCF19 was significantly up-regulated in CRC, while WWC1 was down-regulated. High-level TCF19 or low-level WWC1 indicated worse survival of CRC patients. Besides, TCF19 expression level was positively correlated with the occurrence of distant metastasis in CRC. Silence of TCF19 significantly attenuated proliferative and migratory capacities of HT29 cells. However, overexpression of TCF19 yielded the opposite trends in HCT-8 cells. WWC1 expression was negatively regulated by TCF19 in CRC tissues. In addition, knockdown of WWC1 abolished the regulatory effect of TCF19 on CRC cells., Conclusions: TCF19 is closely correlated with the occurrence of distant metastasis and poor prognosis of CRC. Furthermore, it aggravates the malignant progression of CRC via negatively regulating WWC1.

Background: As cognitive function declines with age, identifying factors affecting the trajectory of cognitive decline is an indispensable step toward developing intervention strategies to improve the quality of the elderly life., Objective: We performed a genome-wide association study (GWAS) focusing on memory function to explore single nucleotide polymorphisms (SNPs) associated with the rate of memory decline., Methods: Seven hundred and nine eligible non-Hispanic Caucasians from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included for analysis after quality control. GWAS was performed with linear regression. We subsequently tested whether the associations remained significant in subgroup analysis and also examined the impact of SNPs on the longitudinal changes in other neuropsychological measures and amyloid pathology., Results: We identified rs13374761-A in SLAMF1 gene associated with less memory decline (MAF = 0.071, β= 0.0103, p = 4.14×10-8). Subgroup analysis showed stability of results across groups with different diagnosis at baseline. Rs13374761-A also had protective effects on global cognition (p = 0.024), episodic memory (p = 0.024), and semantic memory (p = 0.042), and exerts protection against a decrease in CSF Aβ42 concentration (p = 0.0463) and an increase in Aβ loading in cerebral cortex (p = 0.00666) among minor allele carriers., Conclusion: A novel variant in gene SLAMF1 affects the rate of memory decline in the aged population. Given the protective effect of this variant, SLAMF1 should be further investigated as a potential preventive and therapeutic target for monitoring cognition trajectories.

Cadmium (Cd), as one of the most toxic heavy metals, has become a widespread environmental contaminant and threats the food quality and safety. The protective effect of selenium (Se) on Cd-induced tissue lesion and cytotoxicity in chicken has been extensively reported. The objective of this study was to investigate the antagonistic effect of Se on Cd-induced damage of chicken pectoral muscles via analyzing the trace elements and amino acids profiles. Firstly, 19 trace elements contents were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that under Cd exposure, the contents of Cd, lead (Pb), mercury (Hg), aluminum (Al), and lithium (Li) were significantly elevated, and the contents of Se, iron (Fe), and chromium (Cr) were significantly reduced. However, supplementing Se significantly reversed the effects induced by Cd. Secondly, the amino acids contents were detected by L-8900 automatic amino acid analyzer. The results showed that supplementing Se increased significantly Cd-induced decrease of valine (Val), leucine (Leu), arginine (Arg), and proline (Pro). Thirdly, the results of principal component analysis (PCA) showed that cobalt (Co), manganese (Mn), silicium (Si), and Pro may play special roles in response to the process of Se antagonizes Cd-induced damage of pectoral muscles in chickens. In summary, these results indicated that different trace elements and amino acids possessed and exhibited distinct responses to suffer from Se and/or Cd in chicken pectoral muscles. Notably, Se alleviated Cd-induced adverse effects by regulating trace elements and amino acids profiles in chicken pectoral muscles.

The present study aims to provide anatomical evidence for clinical application of the medial sural artery perforator (MSAP) flap. The current study investigated the vascular anatomy of the flap, evaluated the postoperative appearance and function of the donor and recipient sites, and investigate the clinical value in reconstruction of oral cavity. Six lower limbs of Chinese adult cadavers were microsurgically dissected. The locations and courses of the medial sural artery perforators were identified and recorded, which provided an anatomical basis for clinical application. Then, 16 clinical cases employing this flap were evaluated, ranging from 3×4cm to 6×8cm, and were employed for defects in the oral cavity region. Sixteen clinical cases with intraoral soft tissue defects, which included four clinical cases with inner cheek defects, were successfully followed up for 10-47 months (24 months on average). The donor site function, contour of recipient site and oral function recovery were evaluated as acceptable or better in cases with intraoral soft tissue defect, which were further verifying the value of clinical application of MSAP in repairing oral cavity defects. Moreover, two typical clinical cases were described in detail. To conclude, the MSAP flap is a favorable choice for small- to medium-size defects based on minor donor site morbidity, satisfactory oral function recovery, perforator stability and adaptation of the pedicle for anastomosis in the oral cavity region., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Background: The role of cerebral microbleeds (CMBs) in cognitive impairment remains controversial., Objective: To investigate the possible links between the presence, progression, number, and location of CMBs and cognition., Methods: We assessed 792 subjects from the Alzheimer's Disease Neuroimaging Initiative who underwent both brain 3 Tesla MRI scans and cognitive testing. The association between CMBs and cognitive change was explored using linear mixed-effects models (LME)., Results: Presence and number of CMBs were associated with memory (β= -0.03, p = 0.015; β= -0.01, p = 0.003), executive function (β= -0.04, p = 0.010; β= -0.01, p = 0.014), and global cognitive function (β= -0.06, p = 0.025; β= -0.03, p < 0.001). Progression of CMBs showed significant negative associations with executive function (β= -0.05, p = 0.025) and global cognitive function (β= -0.12, p = 0.015). The relations with cognitive performance (memory, executive function and global cognitive function) were mainly driven by lobar CMBs (β= -0.03, p = 0.041; β= -0.04, p = 0.010; β= -0.07, p = 0.029, respectively), especially those located in temporal lobe (β= -0.08, p = 0.027; β= -0.13, p = 0.001; β= -0.26, p < 0.001, respectively). Furthermore, white matter hyperintensities may mediate the association between CMBs and cognition., Conclusion: The presence, progression, number, and location of CMBs, especially those located in temporal lobe, are associated with cognitive decline. These findings suggest CMBs play a role in cognitive impairment.

Cerebral microbleeds are the presence of a group of pathological processes affecting the small arteries, arterioles, capillaries, and venules of the brain. Previous studies showed that cerebral microbleeds were associated with higher risk of dementia and stroke. We conducted a genome-wide association study of cerebral microbleeds to identify novel loci associated with the presence and progression of cerebral microbleeds. This study included 454 individuals composed by 176 subjects with cerebral microbleeds and 278 subjects without cerebral microbleeds in a non-Hispanic/Latino white population. Association of genetic variants with the presence and progression of cerebral microbleeds was assessed by logistic regression model. Potential genetic risk variants Apolipoprotein E (ApoE) polymorphisms were independently genotyped and checked the association with the presence and progression of cerebral microbleeds. No single-nucleotide polymorphisms (SNPs) associated with the presence or progression of cerebral microbleeds were identified at genome-wide significant level (P < 1 × 10 -8 ). A total of 19 SNPs were associated with the presence of microbleeds at suggestive level (P < 1 × 10 -5 ). One SNP was associated with lower progression risk for cerebral microbleeds with suggestive evidence (P < 1 × 10 -5 ). ApoE ε4ε4 was independently associated with the presence and progression of cerebral microbleeds (odds ratio = 2.54, 95% confidence interval 1.08-6.00 and odds ratio = 5.1, 95% confidence interval 1.36-19.16). We highlighted 19 novel SNPs associated with the presence of cerebral microbleeds and one novel SNP associated with the progression of cerebral microbleeds for the first time. ApoE ε4ε4 was confirmed independently associated with the presence and progression of cerebral microbleeds.

Background: Several studies have shown risky behaviors and risk tolerance are associated with Alzheimer's disease. However, the underlying causality remains unclear. Risky behavior and risk tolerance may induce the onset of Alzheimer's disease, and/or vulnerability to Alzheimer's disease may result in more risky behaviors., Objective: To examine bidirectional relationships between risky behavior, risk tolerance, and Alzheimer's disease using Mendelian randomization method for assessing potential causal inference., Methods: This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with risky behaviors and risk tolerance (n = 370, 771- 939, 908), and Alzheimer's disease (n = 71, 880 - 37, 613) as genetic instruments from large meta-analyses of genome-wide association studies., Results: Our results support a strong protective casual effect of risk-taking tendency on AD (odds ratio [OR] = 0.79; 95% CI, 0.67- 0.94, p = 0.007). There was weak statistically significant relationship between number of sexual partners and AD (OR = 0.50, 95% CI, 0.27- 0.93, p = 0.04), and between family history of AD and automobile speeding propensity (OR = 1.018, 95% CI, 1.005 to 1.031; p = 0.007). Contrary to expectations, there was no statistically significant causal effect of AD on risk-taking tendency (β=  0.015, 95% CI, - 0.005 to 0.04; p = 0.14)., Conclusion: Under Mendelian randomization assumptions, our results suggest a protective relationship between risk-taking tendency and the risk of AD. This finding may provide valuable insights into Alzheimer's disease pathogenesis and the development of preventive strategies.

Background: The National Institute on Aging and Alzheimer's Association proposed an ATN classification system which divided Alzheimer's disease biomarkers into three binary classes: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N)., Objective: To estimate the prevalence of each profile and to describe the demographic characteristics of each group in Chinese cognitively intact older adults., Methods: In this cross-sectional study, 561 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were classified into eight groups using cerebrospinal fluid amyloid-β 42/40 as A, phosphorylated tau as T, and total tau as N. Multinomial models were used to determine the estimated prevalence of the eight groups., Results: The number and proportion of 561 participants in each ATN profile were 254 A-T-N- (45.3%), 28 A-T+N- (5.0%), 21 A-T-N+ (3.7%), 71 A-T+N+ (12.7%), 78 A + T-N- (13.9%), 14 A + T+N- (2.5%), 21 A + T-N+ (3.7%), and 74 A + T+N+ (13.2%). Individuals in N+ groups tend to be older than N- groups. A+ groups included more female individuals. The prevalence of A-T-N- profile declined with age, while that of A + T+N+ increased continuously., Conclusion: This is the first work to estimate the prevalence of each ATN profile and describe the demographic characteristics of ATN profiles based on a Chinese cohort. The clinical implications of our findings need to be scrutinized further in longitudinal studies of the ATN classification system.

Aim. To compare the effects of once-weekly Dulaglutide with once-daily glargine in poorly oral-antidiabetic controlled patients with type 2 diabetes mellitus (T2DM). Method. A total of 25 patients with T2DM admitted into Department of Endocrinology from December 2012 to August 2013 were randomly assigned into two groups: Dulaglutide group ( n = 16) and glargine group ( n = 9). All patients received either Dulaglutide or glargine treatments for 52 weeks. Continuous glucose monitoring systems (CGMS) were applied to them for two 72 h periods at before and after the treatment each. Patient general clinical data were collected and analyzed. Result. Fast blood glucose ( FBG) of the glargine group declined more significantly than the Dulaglutide group after treatment ( p < 0.05). The mean blood glucose (MBG), standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursion (MAGE) within a day, the largest amplitude of glycemic excursion (LAGE), M -value, absolute means of daily difference (MODD) of glycemic excursion, the percentage of time (≤2.8 mmol/L, ≤3.9 mmol/L, ≥10.0 mmol/L, ≥13.9 mmol/L, 3.9-7.8 mmol/L, and 9-10.0 mmol/L), maximum glycemic value, and minimum glycemic value were similar between the two groups ( p > 0.05). The incidence of hypoglycemia was also similar between the two groups ( p > 0.05). Though serum levels of TNF- α , IL-6, and 8-PGF2 α all decreased, significant reduction was found in TNF- α and 8-PGF2 α . TNF- α was only significantly reduced in the Dulaglutide group, while 8-PGF2 α was seen in both groups. Conclusion. For T2DM patients with poorly controlled oral antidiabetic drugs, once-weekly Dulaglutide not only has the same effect on glucose fluctuation as once-daily glargine but also significantly reduced TNF- α and 8-PGF2 α after a 52 week treatment protocol. This trial is registered with ClinicalTrials.gov NCT01648582., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Jie Wang et al.)

The electro-Fenton (EF) process was applied to treat mother liquor of gas field wastewater (ML-GFW). The Fe-Fe electrodes were used and H 2 O 2 was added to the EF system. Effect of initial pH on chemical oxygen demand (COD) removal efficiency, specific electrical energy consumption (SEEC), specific electrode plate consumption (SEPC) and organic matter removal mechanism was investigated. The results showed that COD removal efficiency reached the maximum (71.9%) at initial pH of 3 after reaction for 3 h. Besides, considering with the SEEC and SEPC, pH of 3 was also the best choice, at which SEEC was 4.7 kW h kg COD -1 , SEPC was 0.82 kgFe kg COD -1 . Organic matter removal was achieved by two ways: oxidation and flocculation, and oxidation played a major role. With the analysis of GC-MS, the possible degradation pathways of the representative contaminants in the ML-GFW were given., Competing Interests: We declare we have no competing interests., (© 2019 The Authors.)

ArgR, a transcriptional regulator belonging to the AraC/XylS family, plays a key role in arginine metabolism regulation. ArgR has also been found to repress the transcription of a lipase gene, but its molecular mechanism is still unknown. In this study, we investigated the molecular mechanism acting on the expression of intracellular lipase gene lipA regulated by ArgR in Pseudomonas protegens Pf-5 through knockout and overexpression of argR, detection of DNA-protein interaction in vivo, determining whole-cell lipase activities of various strains derived from Pf-5, and examining β-galactosidase activities of various lacZ fusions. The results demonstrated that ArgR inhibits lipA expression at the transcriptional level. Further results showed that the inhibition of lipA transcription by ArgR is mediated by binding to the ArgR binding site of lipA promoter to produce steric hindrance, in which the common sequence, TGTCGC is crucial for the ArgR binding. Besides, arginine inhibits lipA expression in both wild-type and argR mutant, and shows a synergistic inhibition on lipA expression when combined with ArgR. To the best of our knowledge, this is the first report on ArgR directly repressing the transcription of a lipase gene., (Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Cd(ii) adsorption onto Fe(ii) modified Layered double hydroxide-graphene oxide (LDH-GO@Fe(ii)) was investigated using batch experiments. With the modification of Fe(ii), LDH-GO maintained its structure, while Fe(ii) species formed non-crystalline iron oxide clusters on the surface of the LDH/GO. A kinetics study indicated that adsorption obeyed a pseudo-second-order rate law. The equilibrium data were fitted well with the Langmuir isotherm model. The maximum adsorption capacity of LDH-GO@Fe(ii) 10 was 28.98 mg g -1 , higher those that of pure LDH-GO and LDH-GO@Fe(ii) 50 . The increased sorption capacities could be explained by the increased specific surface area. Modification with Fe(ii) would lead to the generation of amorphous Fe oxides and Fe could occupy the binding sites for Cd(ii), thus excess Fe in the structure will restrain the adsorption of Cd(ii). The XRD and XPS patterns revealed the formation of Cd(OH) 2 after adsorption. Batch experiments indicated that precipitation and surface complexation were the main pathways for Cd(ii) removal., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: To summarize the clinical and pathological characteristics of IgG4-related ophthalmic disease (IgG4-ROD) involving the lacrimal gland. Methods: A retrospective case series study. Forty cases (56 eyes) of lacrimal gland lesions were collected in Tianjin Eye Hospital from January 2003 to January 2018 and confirmed by histopathology as lymphocyte and plasma cell infiltration with fibrosis of lacrimal gland tissue, excluding lymphoma, epithelial tumor, mesenchymal tumor and metastasis tumor. The clinical manifestations, serological and imaging examination of the patients were analyzed. Meanwhile, HE staining and immunohistochemical staining of IgG and IgG4 were performed on the pathological specimens. According to the diagnostic criteria, the cases were divided into the IgG4-ROD group and the non-IgG4-ROD group. The clinical and pathological characteristics of the two groups were statistically analyzed by Pearson chi-square and signed-rank test. Results: In the 40 cases (56 eyes), there were 15 cases (25 eyes) of IgG4-ROD and 25 cases (31 eyes) of non-IgG4-ROD. Statistically significant differences were observed between the two groups in the clinical and pathological characteristics (all P< 0.05). About the distribution of eyes position, there were 10 binocular cases and 5 monocular cases in the IgG4-ROD group, and 6 binocular cases and 19 monocular cases in non-IgG4-ROD group (χ 2 =7.111).There were 21 eyes in the IgG4-ROD group and 5 eyes in the non-IgG4-ROD group about ptosis (χ 2 =25.631), 4 eyes in the IgG4-ROD group and 21 eyes in the non-IgG4-ROD group about ocular protrusion (χ 2 =14.992), 23 eyes in the IgG4-ROD group and 15 eyes in the non-IgG4-ROD group about the clear boundary of the tumor (χ 2 =12.069), 4 eyes in the IgG4-ROD group and 18 eyes in the non-IgG4-ROD group about the involvement of other orbital tissues (χ 2 =10.266) and 7 cases in the IgG4-ROD group and 3 cases in the non-IgG4-ROD group about the association with other systemic diseases (χ 2 =6.009). Compared with the non-IgG4-ROD group, the IgG4-ROD group had a heavier lymphocyte and plasma cell infiltration (+++,++,+; 10, 4, 1 vs . 6, 5, 12 eyes, Z= -3.153), and more lymphoid follicles (+++,++,+; 3, 6, 4 vs. 1, 2, 7 eyes, Z= -3.339), interstitial fibrosis was mostly striate (10 vs. 5 eyes, χ 2 =8.711), and there were a large number of IgG4 + plasma cells [96 (67, 135) vs . 4 (0, 12) cells per high power field, Z= -5.271] and ratio of IgG4 + plasma cells/IgG + plasma cells [0.570 (0.500, 0.754) vs. 0.046 (0.000, 0.143), Z= -5.268, all P< 0.05). Among the 10 cases of IgG4-ROD with serological examination, 9 cases showed elevated serum in IgG and IgG4. The ultrasonography and CT findings showed the lacrimal gland lesions in the IgG4-ROD group were mostly spindle or kidney shaped with clear boundaries, while the lesions in non-IgG4-ROD were mostly round or irregular with unclear boundaries. Conclusions: The lacrimal gland lesions of IgG4-ROD are characterized by bilaterally spindle or kidney shaped enlargement with clear boundaries. They are more associates with other systemic diseases. The pathological characteristics are a large number of IgG4 + plasma cells infiltration among the lacrimal gland tissue, interstitial striate fibrosis and a large number of lymphoid follicles. ( Chin J Ophthalmol, 2019, 55: 834-841 ).

BACKGROUND Anaplastic thyroid carcinoma (ATC) is a very rare, highly lethal malignant cancer. Our aim in this study was to develop nomograms that predict survival in ATC patients. MATERIAL AND METHODS ATC incidence and mortality were assessed via joinpoint regression analysis of 567 ATC patients selected from the Surveillance, Epidemiology, and End Results 18 Registries Research database. Predictive models were established via univariate and multivariate Cox regression analysis of potential risk factors and used to produce nomograms. Performance of the nomograms in terms of discrimination ability and calibration was evaluated by determining the concordance index (C-index) and by generating calibration plots, respectively. RESULTS The incidence and mortality rates for ATC increased from 2000 to 2015 according to the collected data (p<0.05). Two nomograms were constructed based on 2 predictive models: nomogram 1 considered age, tumor size, and metastasis (all before surgery), and nomogram 2 considered age, tumor size, metastasis, surgery, and extrathyroidal extension (all after surgery). Both nomogram 1 (C-index, 0.6803; 95% confidence interval, 0.6517-0.7089) and nomogram 2 (C-index, 0.7064; 95% confidence interval, 0.6783-0.7345) had good discrimination ability. The validated C-index values were 0.6783 and 0.7029 for nomogram 1 and 2, respectively. The observed values were in agreement with the calibration curves. CONCLUSIONS Nomogram 1 can assist in preoperative prediction of survival time in ATC patients, whereas nomogram 2 can provide additional outcome-related information.

Objective: To evaluate the efficacy and prognostic factors in core binding factor (CBF) acute myeloid leukemia (AML) under current therapy modalities, therefore optimizing the treatment strategies. Methods: Standard cytological and immune methods including next generation sequencing (NGS) were used for risk stratification. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were assessed by multivariate Logistic and Cox regression models in a total of 206 adults (aged 16-65 years) with CBF-AML, including 152 AML patients with t(8;21) and 54 with inv(16). Results: The CR rate of inv(16) patients after first course was 54/54(100%), significantly higher than that of t(8;21) patients [127/147(86.4%), P= 0.005]. The fusion transcript level and KIT mutation were independent factors related to CR rate in t(8;21) patients ( P= 0.044 and 0.027; respectively). DFS and OS in inv(16) patients tended to be more superior than that in t(8;21) patients ( P= 0.066 for DFS; P= 0.306 for OS; respectively). Multivariate Cox identified negative expression of CD(19) and female gender the independent predictors of inferior DFS in t(8;21) patients ( P= 0.000 for CD(19); P= 0.006 for sex; respectively). Analysis of combining CD(19) with gender indicated that females/CD(1)(9-)subpopulation had significantly poor DFS than did males/CD(19)(+) ones (Bonferroni- P< 0.000 01). The number of mutations in each patient, FLT3-ITD and additional karyotype abnormalities did not affect CR rate and DFS (all P> 0.05). Conclusions: Patients with inv(16) have better induction response than those with t(8;21). High level of fusion transcripts and positive KIT mutation are associated with low CR rate in t(8;21) patients. Negative CD(19) expression and female gender are independent predictors of inferior DFS in t(8;21) patients.

Isorhynchophylline (IRN) has been demonstrated to have distinct anti-Alzheimer's disease (AD) activity in several animal models of AD. In this study, we aimed at evaluating the preventive effect of IRN on the cognitive deficits and amyloid pathology in TgCRND8 mice. Male TgCRND8 mice were administered with IRN (20 or 40 mg/kg) by oral gavage daily for 4 months, followed by assessing the spatial learning and memory functions with the Radial Arm Maze (RAM) test. Brain tissues were determined immunohistochemically or biochemically for changes in amyloid pathology, tau hyperphosphorylation and neuroinflammation. Our results revealed that IRN (40 mg/kg) significantly ameliorated cognitive deficits in TgCRND8 mice. In addition, IRN (40 mg/kg) markedly reduced the levels of Aβ 40 , Aβ 42 and tumor necrosis factor (TNF-α), interleukin 6 (IL-6) and IL-1β, and modulated the amyloid precursor protein (APP) processing and phosphorylation by altering the protein expressions of β-site APP cleaving enzyme-1 (BACE-1), phosphorylated APP (Thr668), presenilin-1 (PS-1) and anterior pharynx-defective-1 (APH-1), as well as insulin degrading enzyme (IDE), a major Aβ-degrading enzyme. IRN was also found to inhibit the phosphorylation of tau at the sites of Thr205 and Ser396. Immunofluorescence showed that IRN reduced the Aβ deposition, and suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the cerebral cortex and hippocampus of TgCRND8 mice. Furthermore, IRN was able to attenuate the ratios of p-c-Jun/c-Jun and p-JNK/JNK in the brains of TgCRND8 mice. IRN also showed marked inhibitory effect on JNK signaling pathway in the Aβ-treated rat primary hippocampus neurons. We conclude that IRN improves cognitive impairment in TgCRND8 transgenic mice via reducing Aβ generation and deposition, tau hyperphosphorylation and neuroinflammation through inhibiting the activation of JNK signaling pathway, and has good potential for further development into pharmacological treatment for AD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: CaoWu (Aconiti Kusnezoffii Radix), well known for its high toxicity leading to fatal ventricular arrhythmias, is detoxified by HeZi (Terminalia Chebula Retz) decoction to prepare ZhiCaoWu (Aconiti Kusnezoffii Radix Preparata) as one part of ingredients of NaRu-3 pill which is used for the treatment of rheumatoid arthritis (RA). Aconitine (AC) is a highly toxic alkaloid of CaoWu and it is used as toxic target marker for the quality control (QC) of ZhiCaoWu. In the traditional processing method, the vanish of astringent or spicy feeling in tongue is the important detoxification indicator of ZhiCaoWu. However, how CaoWu is detoxified to ZhiCaoWu and whether the appropriate content of AC in ZhiCaoWu can be efficiently perceived after the empirical detoxification still lack factual basis., Aim of the Study: The present study aimed to optimize the traditional processing method for precision detoxification of CaoWu through biomimetic linking kinetics and human toxicokinetics (TK) of AC, with a view of providing insights into the changes of toxic target marker., Materials and Methods: CaoWu medicinal slices (Mes) and coarse powder (Cop) were processed by blank HeZi decoction through the soaking method for 7 days. High-performance liquid chromatography (HPLC) was used for the analysis of the samples. The acidity of blank HeZi decoction and HeZi processing decoction was directly determined by pH meter. The non-compartment analysis (NCA) was used to have an intuitive appreciation for AC and pH changes in HeZi processing decoction while the compartment model method was used to build the biomimetic linking kinetics model with the covariate. The inter-species scaling of animal TK parameters was conducted to predict human AC TK profiles. The possible uptake ways of AC (rapid-release or extended-release) for humans were attempted to assess the poisoning risk of AC in NaRu-3 pill. Based on the target content of AC in ZhiCaoWu, the biomimetic linking kinetics model was explored to optimize the traditional processing detoxification method of CaoWu. The assays of determining inflammatory cytokines in lipopolysaccharides (LPS)-induced RAW264.7 cells were performed to investigate the inflammatory modulation effects of AC in vitro., Results: ZhiCaoWu was prepared by eliminating redundant AC in CaoWu through the repeatable replacement of HeZi processing decoction in which its acidity (pH) was affected. AC-pH changes in HeZi processing decoction were adequately depicted by a biomimetic linking kinetics model whose predictive power was determined by comparing the predictions of AC in ZhiCaoWu with the reported data. Rapid-release AC at the converted dose of 111.1 and 417.6 μg (0.011 and 0.042% of AC in NaRu-3 pill) reached maximum blood concentrations of 26.1 and 98.1 ng/mL at 0.3 h, in comparison with minimum human lethal concentration (100 ng/mL). Achieving the target content of AC (0.04%) in ZhiCaoWu or AC (0.011%) in NaRu-3 pill to precisely control the poisoning risk, the potential optimized protocols were that the processing time at 0.2-0.8% of AC in CaoWu was 2.0-4.4 days for Cop and 2.7-6.2 days for Mes. Correspondingly, pH values in HeZi processing decoction were 3.95 and 3.77 for Cop and Mes, respectively. Meanwhile, Lipopolysaccharides (LPS)-induced RAW264.7 cells were exposed to 0, 20, and 200 μM of AC for 12 h and AC at 20 μM enhanced the levels of IL-6, IL-10 and TNF-α., Conclusions: Thus, for the first time, a biomimetic linking kinetics model was built to optimize the traditional detoxification method. Moreover, pH changes could be developed as surrogate endpoint for guiding the processing detoxification of CaoWu. Notably, setting the content limit of AC (0.011%) was very rational to control the poisoning risk of NaRu-3 pill. In addition, it was possible that there existed the more complex mechanisms of AC for inflammatory modulation in vitro., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The ripeness of a grape is critical to berry composition and to the resultant wine. For wineries with a single cultivar occupying an extensive area, the total soluble solid of grapes can range from 22°Brix to 28°Brix. Accordingly, the influence of different harvest dates (ripeness) on berry compositions and on the resultant wine profile was investigated for Vitis vinifera L. cv. 'Cabernet Sauvignon.' Berry dehydration was observed as berry weight and juice yields decreased. Berry anthocyanins were concentrated and methylated anthocyanin levels fluctuated with increasing delays in harvesting. Hexanal and 2-hexenal levels in must decreased significantly as berries ripened. In the resultant wines, 2,3-butanediol levels increased. Wines harvested earlier were lighter, presented lower color intensity (CI) values and higher yellow% levels, and exhibited richer aroma profiles (compounds). Through a principal component analysis and discriminant analysis, the compounds characterizing each harvest date were identified., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To analyze the clinical significance of using hepatic transit time (HTT) to evaluate portal vein pressure in gastroesophageal varices patients., Methods: For the observation group, we enrolled 50 gastroesophageal varices patients who had received esophagogastric variceal embolization in our hospital between January 2015 and February 2018. Patients without liver disease populated the control group and were recruited during the same time period. All patients underwent contrast-enhanced sonography. In the observation group, free portal pressure (FPP) was detected during esophagogastric variceal embolization with ultrasound guidance. Differences in hepatic artery-hepatic vein transit time (HA-HVTT), portal vein-hepatic vein transit time (PV-HVTT), and parenchyma-hepatic vein transit time (PA-HVTT) were compared between groups. Correlations between HA-HVTT, PV-HVTT, PA-HVTT, and FPP in the observation group were analyzed using the Pearson coefficient and linear regression analysis., Results: HA-HVTT (t = 5.078; P < .001), PV-HVTT (t = 12.163; P < .001), and PA-HVTT (t = 2.649; P = .009) within the observation group were significantly lower than those of the control group. The areas under the curve of HTT were 0.771 (HA-HVTT), 0.951 (PV-HVTT), and 0.652 (PA-HVTT), and the sensitivity and specificity of PV-HVTT at 7.99 seconds were 86.0% and 88.0%, respectively. The HA-HVTT (r = -0.799; P < .001), PV-HVTT (r = -0.554; P < .001), and PA-HVTT (r = -0.735; P < .001) negatively correlated to FPP in the observation group. Linear regression analysis showed y = -0.410x + 7.254 (HA-HVTT and FPP), y = -0.335x + 4.983 (PV-HVTT and FPP), and y = -0.566x + 4.997 (PA-HVTT and FPP) in the observation group., Conclusion: Compared with the control patients, the HTT of patients with portal hypertension-esophagogastric varices was significantly shorter, and showed an inverse relationship with FPP., (© 2019 by the American Institute of Ultrasound in Medicine.)

Introduction : The increasing prevalence of comorbid depression and diabetes exerts a heavy burden on global health. Co-occurrence of depression and diabetes is common, affecting 14% to 35.8% of patients with diabetes, leading to a higher mortality and morbidity rate, more micro- and macro-vascular diseases and more cognitive decline. Areas covered : In this paper, the authors address various areas from epidemiology, the association between depression and diabetes, treatment strategies and future directions based on the currently available literature to provide novel insight into the pharmacotherapeutic management of comorbid depression and diabetes. Expert opinion : Pharmacotherapy can help patients with comorbid depression and diabetes by relieving depressive symptoms and improving glycemic control. When combined with psychological therapy, as a collaborative care effort, pharmacological therapy based on selective serotonin reuptake inhibitors (SSRIs) is recommended for comorbid depression with diabetes. Furthermore, studies with larger sample sizes that can help to define different subtypes of diabetes and severity of depression are needed so that clinicians can draw up a precise and applicable management guidelines for the personalized therapy of these diseases.

Background: Hypertension is a leading cause of stroke and the significance of blood pressure lowering treatment strategies for prevention of stroke has been well established. Despite the established and widespread use of BP lowering drugs, which one is better for stroke prevention is still debated. This study aimed to determine the most effective and safest blood pressure lowering treatments for stroke prevention among various single and combined therapies., Methods: A systematic search will be performed in PubMed and the Cochrane Library to identify RCTs and meta analyses of different pharmacological interventions for stroke prevention from January 01, 1966 to December 01, 2018. Primary efficacy outcome will be reduction of stroke incidence and safety outcome will be drug-related side effects withdraw. Study quality will be critically appraised based on the seven-point tool for assessing risk of bias by Cochrane collaboration. Pairwise meta-analyses and Bayesian network meta-analyses will be performed for all related outcome measures. We will conduct subgroup analyses and sensitivity analyses to assess the robustness of our findings., Discussion: This network meta-analysis will summarize the direct and indirect evidence aiming to provide a ranking of various blood pressure lowering strategies for prevention of stroke. The results of this meta-analysis may help the physicians in determining the best treatments for their patients in stroke prevention., Trial Registration: CRD42018118454., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Isorhynchophylline (IRN), an oxindole alkaloid isolated from Uncaria rhynchophylla , elicited distinct antidepressant-like activity in mice. The present study aimed to investigate the antidepressant-like effects of IRN in chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors in mice and to illustrate its possible mechanisms of action. The mice were subjected to CUMS for 6 wk and administered with IRN (20 or 40 mg/kg) daily by oral gavage for 3 wk. The PI3K/protein kinase B (Akt) inhibitor and glycogen synthase kinase-3β (GSK-3β) inhibitors were used to determine the involvement of the PI3K/Akt/GSK-3β pathway in the antidepressant-like effects of IRN in the mice. The results showed that CUMS caused depression-like behaviors in the mice, such as behavioral despair by the forced swim test (FST) and anhedonia by the sucrose preference test. In addition, CUMS could significantly reduce the levels of nerve growth factor and brain-derived neurotrophic factor but markedly increase the release of TNF-α and IL-6 in the hippocampus and cerebral cortex of the mice. Western blotting analysis showed that CUMS markedly suppressed the levels of phosphorylated GSK-3β (Ser9) and phosphorylated Akt (Ser473) but significantly enhanced the translocation of NF-κB p65 from cytosol to nuclei in the hippocampus and cerebral cortex of the mice. CUMS could also significantly increase the NF-κB binding activity in the hippocampus and cerebral cortex of the mice, whereas IRN treatment could significantly reverse the behavioral and biochemical changes induced by CUMS in the mice. Moreover, the antidepressant-like effect of IRN was completely abolished by the PI3K/Akt inhibitor. Combination treatment with IRN and GSK-3β inhibitors in the mice exerted a synergistic anti-immobility action in the FST. The results of mechanistic investigations indicated that the antidepressant-like action of IRN was mediated, at least in part, by enhancing neurotrophins and attenuating neuroinflammation via modulating the PI3K/Akt/GSK-3β pathway.-Xian, Y.-F., Ip, S.-P., Li, H.-Q., Qu, C., Su, Z.-R., Chen, J.-N., Lin, Z.-X. Isorhynchophylline exerts antidepressant-like effects in mice via modulating neuroinflammation and neurotrophins: involvement of the PI3K/Akt/GSK-3β signaling pathway.

Cadmium (Cd) as a widespread toxic heavy metal accumulates in animal food including chicken meat through food chain enrichment and finally threatens human health. Selenium (Se) is an essential mineral and possesses antagonistic effects on Cd-induced multiple organs' toxicity in chickens. The objective of the present study was to reveal the antagonistic mechanisms of Se to Cd from the aspects of oxidative stress, inflammation, and meat quality in chicken breast muscles. Firstly, the results showed that Cd significantly elevated the levels of malondialdehyde (MDA), hydrogen peroxide (H 2 O 2 ), and protein carbonyl, and declined the levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) to trigger oxidative stress in chicken breast muscles. However, Se treatment significantly alleviated Cd-induced oxidative stress by increasing the levels of GSH-Px, SOD, and CAT, and decreasing the levels of MDA, H 2 O 2 , and protein carbonyl. Secondly, Se obviously inhibited the expressions of Cd-activated inflammation-related genes including tumor necrosis factor (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducible nitric oxide synthase (iNOS), prostaglandin-endoperoxide synthase 2 (COX-2), and prostaglandin E synthase (PTGEs) in chicken breast muscles. Thirdly, meat quality-related parameters including pH 45min , ultimate pH (pHu), and drip loss were also detected, and the results showed that Se markedly recovered Cd-induced dropt of pH 45min and increase of drip loss in chicken breast muscles. In brief, these findings demonstrated that Se significantly alleviated Cd-induced oxidative stress and inflammation, and declined meat quality of chicken breast muscles.

Aging is an independent risk factor for vascular diseases. Perivascular adipose tissue (PVAT), an active component of the vasculature, contributes to vascular dysfunction during aging. Identification of underlying cell types and their changes during aging may provide meaningful insights regarding the clinical relevance of aging-related vascular diseases. Here, we take advantage of single-cell RNA sequence to characterize the resident stromal cells in the PVAT (PVASCs) and identified different clusters between young and aged PVASCs. Bioinformatics analysis revealed decreased endothelial and brown adipogenic differentiation capacities of PVASCs during aging, which contributed to neointimal hyperplasia after perivascular delivery to ligated carotid arteries. Mechanistically, in vitro and in vivo studies both suggested that aging-induced loss of peroxisome proliferator-activated receptor-γ coactivator-1 α (PGC1α) was a key regulator of decreased brown adipogenic differentiation in senescent PVASCs. We further demonstrated the existence of human PVASCs (hPVASCs) and overexpression of PGC1α improved hPVASC delivery-induced vascular remodeling. Our finding emphasizes that differentiation capacities of PVASCs alter during aging and loss of PGC1α in aged PVASCs contributes to vascular remodeling via decreased brown adipogenic differentiation., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Eleven new lanthanide complexes based on a bis-tridentate nitronyl nitroxide radical NIT-Pm2Py (2-(4,6-di(pyridin-2-yl)pyrimidin-2-yl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-oxy-3-oxide), namely (NIT-Pm2Py)Ln(hfac) 3 (Ln = Gd (1 Gd ), Tb (2 Tb ), Dy (3 Dy ), Ho (4 Ho ), Er (5 Er ), Yb (6 Yb )), [(NIT-Pm2Py)Ln 2 (hfac) 6 ]·xH 2 O (Ln = Gd (7 Gd ), Tb (8 Tb ), Ho (10 Ho ), x = 0.5 for 7 Gd and 1 for 8 Tb and 10 Ho ) and (NIT-Pm2Py)Ln 2 (hfac) 6 (Ln = Dy (9 Dy ), Er (11 Er )) were prepared and characterized. These complexes can be selectively prepared by controlling the reaction ratio of Ln(hfac) 3 ·2H 2 O to the radical ligand NIT-Pm2Py. Single crystal X-ray crystallographic analyses confirmed that 1 Gd -6 Yb are isostructural 2p-4f Ln III -radical complexes, in which the NIT-Pm2Py radical acts as a terminal tridentate ligand chelating to one Ln III ion. On the other hand, 7 Gd -11 Er are isostructural 4f-2p-4f Ln III -radical-Ln III complexes with the NIT-Pm2Py acting as a bridging ligand between two Ln III ions. 7 Gd -11 Er represent a rare family of complexes showing the NIT bridged 4f-2p-4f three-spin motif. Alternating-current (ac) magnetic susceptibility investigations revealed that complex 6 Yb exhibits field-induced frequency dependence, suggesting a possible field-induced single-molecule magnet behavior. Ab initio calculations were performed on all these complexes. The fitting of the magnetic susceptibilities of these complexes indicates weak antiferromagnetic coupling between the Ln III and NIT radical.

Objectives: (1) To compare the American College of Radiology (ACR) thyroid imaging reporting and data system (TIRADS) and American Thyroid Association (ATA) guidelines for thyroid nodules with regard to diagnostic performance and effectiveness at reducing the number of fine-needle aspiration (FNA) biopsies and to preliminarily discuss the reasons for the differences and (2) to compare the diagnostic performance of the two guidelines in the subgroup of nodules <1 cm in diameter., Materials and Methods: In the present study, 1000 thyroid nodules in 894 consecutive patients with final diagnoses were included; these thyroid nodules were investigated via FNA biopsies in our hospital. The ultrasound (US) features of the thyroid nodules were reviewed and stratified according to the categories defined by the ACR TIRADS and ATA guidelines., Results: Compared with the ACR TIRADS guidelines, the ATA guidelines had a higher sensitivity (93.4% (P < 0.001)) and a larger negative predictive value (NPV) (85.3% (P= 0.034)). Compared with the ATA guidelines, the ACR TIRADS guidelines had a higher specificity (66.0% (P < 0.001)), a greater PPV (73.6% (P= 0.001)), and greater accuracy (75.5% (P= 0.017)). Compared with the ATA guidelines, the ACR TIRADS guidelines resulted in significantly fewer unnecessary FNA biopsies (P= 0.007)., Conclusions: This study suggests that both the ACR TIRADS and ATA guidelines have unique strengths with regard to their diagnostic performance. In terms of reducing the number of FNA biopsies, the ACR TIRADS guidelines were superior to the ATA guidelines.

We present here the syntheses, crystal structures, and thermal and magnetic properties of a series of mononuclear Fe 2+ spin crossover (SCO) complexes of the formula [Fe(bamp) 2 ]·Anion·Solv (Anion = NDS 2- , Solv = 2H 2 O, 1 NDS ; Anion = BPDS 2- , Solv = 4.4H 2 O, 2 BPDS ; Anion = ABDS 2- , Solv = Et 2 O and H 2 O, 3 ABDS ; Anion = DNDS 2- , Solv = MeCN, 4 DNDS ; bamp = 2,6-pyridinedimethanamine, H 2 NDS = 1,5-naphthalenedisulphonic acid, H 2 BPDS = 4,4'-biphenyldisulphonic acid, H 2 ABDS = 4,4'-azobenzenedisulfonic acid, H 2 DNDS = 4,4'-dinitrostilbene-2,2'-disulfonic acid). The structures and SCO properties of these complexes can be finely modified by organodisulfonate couteranions. Single-crystal X-ray analyses revealed that all these compounds are hydrogen-bonded three-dimensional frameworks constructed from the charge-assisted hydrogen bonds between bamp donors, organodisulfonate acceptors, and/or crystallized solvent molecules. SCO behavior was observed in all four complexes and has been evidenced by detailed structural and magnetic investigations. While 1 NDS exhibits a sharp cooperative SCO transition with a transition temperature T 1/2 of 247 K, 2 BPDS , 3 ABDS , and 4 DNDS undergo more gradual SCO transitions with T 1/2 values of 176, 171 and 158 K, respectively. Magneto-structural relationship studies revealed that the tunable SCO properties, including the trend of the transition temperatures and the cooperativity of the SCO transition, are mainly attributable to the size of the organodisulfonate anions. This study shows that in order to exhibit cooperative SCO properties, "efficient" hydrogen bonds directly connecting the SCO centers, rather than those between the SCO centers and the innocent neighboring groups, are preferred.

The effective therapeutic approach of cerebral infarction is limited because of its underlying complexity. Recently, multiple long noncoding RNAs (lncRNAs) have been identified in the pathogenesis of cerebral infarction. Here, the current study aims to explore the interaction among lncRNA cyclin-dependent kinase inhibitor-2B-antisense RNA 1 (CDKN2B-AS1), transcription factor B-cell lymphoma/leukemia 11A (BCL11A), and MAPKK kinase kinase 1 (MAP4K1) and further investigate whether they affect cerebral infarction progression. The expression of CDKN2B-AS1, BCL11A, and MAP4K1 was altered in lymphocytes extracted from patients with cerebral infarction. In order to identify their roles in regulatory T (T reg ) cells, the proliferation and apoptosis of the CD4 + CD25 + T reg cells were examined, and levels of IL-4, IL-10, and TGF-β were determined. Also, the RNA crosstalk among CDKN2B-AS1, BCL11A, and MAP4K1 was validated. Finally, we established a rat model of middle cerebral arterial occlusion to evaluate the neurologic impairment and cerebral infarction volume. The results revealed that lymphocytes in patients with cerebral infarction presented with the up-regulated expression of CDKN2B-AS1. Moreover, BCL11A could specifically bind to CDKN2B-AS1 and MAP4K1 promoter so as to inhibit MAP4K1. Moreover, it was observed that down-regulated CDKN2B-AS1 inhibited CD4 + CD25 + T reg -cell proliferation, reduced levels of IL-4, IL-10, and TGF-β and cerebral infarction volume, and elevated MAP4K1 expression. Collectively, our study provides evidence that CDKN2B-AS1 silencing could increase MAP4K1 expression to inhibit the CD4 + CD25 + T reg -cell proliferation by reducing enrichment of transcription factor BCL11A, thereby protecting against cerebral infarction progression, highlighting a promising therapeutic strategy for treating cerebral infarction.-Lei, J.-J., Li, H.-Q., Mo, Z.-H., Liu, K.-J., Zhu, L.-J., Li, C.-Y., Chen, W.-L., Zhang, L. Long noncoding RNA CDKN2B-AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription.