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To investigate the association of attention-deficit/hyperactivity disorder (ADHD) with the 48-base pair (bp) variable number of tandem repeats (VNTR) in exon 3 of the dopamine receptor D4 (DRD4) gene, we genotyped 240 ADHD patients and their parents from Hong Kong. The 4R allele was most common, followed by 2R. We examined association between the 2R allele (relative to 4R) and ADHD by Transmission Disequilibrium Test (TDT). The odds ratio (OR) (95% confidence interval) was 0.90 (0.64-1.3). The p-value was 0.6. Examining subgroups revealed nominally significant association of 2R with inattentive ADHD: OR = 0.33 (0.12-0.92) and p = 0.03. Because our study used TDT analysis, we meta-analyzed the association of 2R with ADHD in Asians (1329 patient alleles), revealing results similar to ours: OR = 0.97 (0.80-1.2) and p = 0.8. To examine the association of 2R with inattentive ADHD, we meta-analyzed all studies (regardless of analysis type or ethnicity, in order to increase statistical power): 702 patient alleles, 1420 control alleles, OR = 0.81 (0.57-1.1) and p = 0.2. Overall, there is no evidence of association between ADHD and the 2R allele, but the suggestive association with the inattentive type warrants further investigation., (© 2024 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)

Voltage-gated sodium channel 1.7 (Nav1.7) remains one of the most promising drug targets for pain relief. In the current study, we conducted a high-throughput screening of natural products in our in-house compound library to discover novel Nav1.7 inhibitors, then characterized their pharmacological properties. We identified 25 naphthylisoquinoline alkaloids (NIQs) from Ancistrocladus tectorius to be a novel type of Nav1.7 channel inhibitors. Their stereostructures including the linkage modes of the naphthalene group at the isoquinoline core were revealed by a comprehensive analysis of HRESIMS, 1D, and 2D NMR spectra as well as ECD spectra and single-crystal X-ray diffraction analysis with Cu Kα radiation. All the NIQs showed inhibitory activities against the Nav1.7 channel stably expressed in HEK293 cells, and the naphthalene ring in the C-7 position displayed a more important role in the inhibitory activity than that in the C-5 site. Among the NIQs tested, compound 2 was the most potent with an IC 50 of 0.73 ± 0.03 µM. We demonstrated that compound 2 (3 µM) caused dramatical shift of steady-state slow inactivation toward the hyperpolarizing direction (V 1/2 values were changed from -39.54 ± 2.77 mV to -65.53 ± 4.39 mV, which might contribute to the inhibition of compound 2 against the Nav1.7 channel. In acutely isolated dorsal root ganglion (DRG) neurons, compound 2 (10 μM) dramatically suppressed native sodium currents and action potential firing. In the formalin-induced mouse inflammatory pain model, local intraplantar administration of compound 2 (2, 20, 200 nmol) dose-dependently attenuated the nociceptive behaviors. In summary, NIQs represent a new type of Nav1.7 channel inhibitors and may act as structural templates for the following analgesic drug development., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Introduction: Water-assisted colonoscopy increases left colon mucus production; however, the effect of saline on mucus production is unclear. We tested the hypothesis that saline infusion may reduce mucus production in a dose-related manner., Methods: In a randomized trial, patients were assigned to colonoscopy with CO 2 insufflation, water exchange (WE) with warm water, 25% saline, or 50% saline. The primary outcome was the Left Colon Mucus Scale (LCMS) score (5-point scale). Blood electrolytes were measured before and after saline infusion., Results: A total of 296 patients with similar baseline demographics were included. The mean LCMS score for WE with water was significantly higher than that for WE with saline and CO 2 (1.4 ± 0.8 [WE water] vs 0.7 ± 0.6 [WE 25% saline] vs 0.5 ± 0.5 [WE 50% saline] vs 0.2 ± 0.4 [CO 2 ]; overall P < 0.0001), with no significant difference between the 25% and 50% saline groups. The left colon adenoma detection rate (ADR) was highest in the 50% saline group, followed by the 25% saline and the water groups (25.0% vs 18.7% vs 13.3%), but the difference was not significant. Logistic regression showed water infusion as the only predictor of moderate mucus production (odds ratio 33.3, 95% confidence interval 7.2-153.2). No acute electrolyte abnormalities were documented indicating a safe modification., Discussion: The use of 25% and 50% saline significantly inhibited mucus production and numerically increased ADR in the left colon. Evaluation of the impact of mucus inhibition by saline on ADR may refine the outcomes of WE., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Objective: To explore the clinical characteristics and treatment options of keratoacanthoma (KA) of the penis., Methods: We report the diagnosis and treatment of a case of penile keratoacanthoma in our hospital and review the literature., Results: The patient was admitted due to the discovery of a "new lesion on the glans for 4 months," diagnosed with a penile tumor, underwent tumor resection surgery, with histopathological examination revealing squamous epithelial hyperplasia, thickening, and excessive keratinization. The postoperative pathological diagnosis was penile keratoacanthoma. There was no recurrence or metastasis during follow-up., Conclusion: KA is a relatively rare benign tumor with potential malignant transformation, and close follow-up is necessary postoperatively.

Objective: To investigate the clinical features of distant metastatic penile cancer (DMPC) and the factors influencing its prognosis., Methods: We searched the Surveillance, Epidemiology and End Results Database for cases of DMPC diagnosed between 2004 and 2019, analyzed their clinical characteristics and the cancer-specific survival (CSS) rates relating to different factors using the Kaplan-Meier method and the differences among the variables by log-rank test. We determined the variables independently associated with CSS by Cox regression analysis., Results: According to the inclusion criteria, 108 cases of DMPC were identified. The patients were mainly married White people, with a median CSS of 9 months, and 1-, 2- and 3-year CSS rates of 36.4%, 17.8% and 13.5%, respectively. Pairwise comparison showed no statistically significant differences in the median overall CSS among the patients in the surgery, chemotherapy and surgery + chemotherapy groups (8 mo vs 9 mo vs 13 mo, P > 0.05). Race was an independent factor affecting the prognosis of CSS., Conclusion: Distant metastatic penile cancer is a rare malignancy with poor prognosis, for which there have been no existing ideal treatment options.

This work examines six structures ( P 4̅3 m , P 4 2 nm , R 3 m , P 2 1 / c , R 3̅ m , and C 2/ m ) of alkaline earth metal cyanide A(CN) 2 (A = Be, Mg, Ca, Sr, and Ba) using first-principles calculations. The symmetries of P 4̅3 m , P 4 2 nm , and R 3 m reflect a variation of Pn 3̅ m , previously reported as occurring on Be(CN) 2 and Mg(CN) 2 in X-ray diffraction studies, while the symmetries of P 2 1 / c , R 3̅ m , and C 2/ m were selected from the P 3̅ m 1 symmetry found using Mg(OH) 2 as the initial structures, with -OH being replaced by -CN. The band structure, density of states, and phonon properties of all A(CN) 2 structures were then investigated using density functional theory (DFT), with a generalized gradient approximation (GGA) applied for the exchange and correlation energy values. The simulation results for the phonon spectra indicate that the stable structures are Be(CN) 2 ( P 4̅3 m , P 4 2 nm , and C 2/ m ), Mg(CN) 2 ( P 4̅3 m , P 4 2 nm , and C 2/ m ), Ca(CN) 2 ( P 2 1 / c ), Sr(CN) 2 ( P 2 1 / c and R 3̅ m ), and Ba(CN) 2 ( R 3̅ m ) at 0 GPa. For the effects of high pressure, Ca(CN) 2 and Sr(CN) 2 were thus found to be stable as C 2/ m at pressures above 10 and 3 GPa, respectively, while Ca(CN) 2 is as stable as R 3̅ m above 15 GPa. In the calculated band structures, all of the compounds with the C 2/ m structure demonstrated good conductivity, while the other structures have a band gap range of 2.83-6.33 eV., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Using a deep learning algorithm in the development of a computer-aided system for colon polyp detection is effective in reducing the miss rate. This study aimed to develop a system for colon polyp detection and classification. We used a data augmentation technique and conditional GAN to generate polyp images for YOLO training to improve the polyp detection ability. After testing the model five times, a model with 300 GANs (GAN 300) achieved the highest average precision (AP) of 54.60% for SSA and 75.41% for TA. These results were better than those of the data augmentation method, which showed AP of 53.56% for SSA and 72.55% for TA. The AP, mAP, and IoU for the 300 GAN model for the HP were 80.97%, 70.07%, and 57.24%, and the data increased in comparison with the data augmentation technique by 76.98%, 67.70%, and 55.26%, respectively. We also used Gaussian blurring to simulate the blurred images during colonoscopy and then applied DeblurGAN-v2 to deblur the images. Further, we trained the dataset using YOLO to classify polyps. After using DeblurGAN-v2, the mAP increased from 25.64% to 30.74%. This method effectively improved the accuracy of polyp detection and classification.

As a promising source of biologically active substances, the Artemisia species from Kazakhstan have not been investigated efficiently. Considering the rich history, medicinal values, and availability of the Artemisia plants, systematic investigations of two Artemisia species growing in the East Kazakhstan region were conducted. In this study, one new germacrane-type sesquiterpene lactone ( 11 ), together with 10 known sesquiterpenes and its dimer, were characterized from A. nitrosa Weber. Additionally, one new chromene derivative ( 1 ') with another 12 known compounds, including coumarins, sesquiterpene diketones, phenyl propanoids, polyacetylenics, dihydroxycinnamic acid derivatives, fatty acids, naphthalene derivatives, flavones, and caffeic acid derivatives were isolated from A. marschalliana Spreng. All compounds were isolated and identified for the first time from these two Artemisia species. The structures of new compounds ( 11 , 1 ') were established by using UV, TOFMS, LC-MS, 1D and 2D NMR spectroscopic analyses. The cytotoxicity of all isolated compounds was evaluated. As a result, all compounds did not show significant inhibition against HL-60 and A-549 cell lines. The sesquiterpenoids isolated from A. nitrosa were tested for their inhibitory activity against the LPS-induced NO release from the RAW624.7 cells, and neither of them exhibited significant activity.

Background and Aims: Water exchange (WE) improves lesion detection but misses polyps because of human limitations. Computer-aided detection (CADe) identifies additional polyps overlooked by the colonoscopist. Additional polyp detection rate (APDR) is the proportion of patients with at least 1 additional polyp detected by CADe. The number of false positives (because of feces and air bubble) per colonoscopy (FPPC) is a major CADe limitation, which might be reduced by salvage cleaning with WE. We compared the APDR and FPPC by CADe between videos of WE and air insufflation in the right-sided colon., Methods: CADe used a convolutional neural network with transfer learning. We edited and coded withdrawal-phase videos in a randomized controlled trial that compared right-sided colon findings between air insufflation and WE. Two experienced blinded endoscopists analyzed the CADe-overlaid videos and identified additional polyps by consensus. An artifact triggered by CADe but not considered a polyp by the reviewers was defined as a false positive. The primary outcome was APDR., Results: Two hundred forty-five coded videos of colonoscopies inserted with WE (n = 123) and air insufflation (n = 122) methods were analyzed. The APDR in the WE group was significantly higher (37 [30.1%] vs 15 [12.3%], P = .001). The mean [standard deviation] FPPC related to feces (1.78 [1.67] vs 2.09 [2.09], P = .007) and bubbles (.53 [.89] vs 1.25 [2.45], P = .001) in the WE group were significantly lower., Conclusions: CADe showed significantly higher APDR and lower number of FPPC related to feces and bubbles in the WE group. The results support the hypothesis that the strengths of CADe and WE complement the weaknesses of each other in optimizing polyp detection., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. All rights reserved.)

Adult mammals have limited potential for cardiac regeneration after injury. In contrast, neonatal mouse heart, up to 7 days post birth, can completely regenerate after injury. Therefore, identifying the key factors promoting the proliferation of endogenous cardiomyocytes (CMs) is a critical step in the development of cardiac regeneration therapies. In our previous study, we predicted that mitogen-activated protein kinase (MAPK) interacting serine/threonine-protein kinase 2 (MNK2) has the potential of promoting regeneration by using phosphoproteomics and iGPS algorithm. Here, we aimed to clarify the role of MNK2 in cardiac regeneration and explore the underlying mechanism. In vitro, MNK2 overexpression promoted, and MNK2 knockdown suppressed cardiomyocyte proliferation. In vivo, inhibition of MNK2 in CMs impaired myocardial regeneration in neonatal mice. In adult myocardial infarcted mice, MNK2 overexpression in CMs in the infarct border zone activated cardiomyocyte proliferation and improved cardiac repair. In CMs, MNK2 binded to eIF4E and regulated its phosphorylation level. Knockdown of eukaryotic translation initiation factor (eIF4E) impaired the proliferation-promoting effect of MNK2 in CMs. MNK2-eIF4E axis stimulated CMs proliferation by activating cyclin D1. Our study demonstrated that MNK2 kinase played a critical role in cardiac regeneration. Over-expression of MNK2 promoted cardiomyocyte proliferation in vitro and in vivo, at least partly, by activating the eIF4E-cyclin D1 axis. This investigation identified a novel target for heart regenerative therapy., (Copyright © 2022. Published by Elsevier Ltd.)

Colonoscopy is the gold standard to detect colon polyps prematurely. Early detection, characterization and resection of polyps decrease colon cancer incidence. Colon polyp missing rate remains high despite novel methods development. Narrowed-band imaging (NBI) is one of the image enhance techniques used to boost polyp detection and characterization, which uses special filters to enhance the contrast of the mucosa surface and vascular pattern of the polyp. However, the single-button-activated system is not convenient for a full-time colonoscopy operation. We selected three methods to simulate the NBI system: Color Transfer with Mean Shift (CTMS), Multi-scale Retinex with Color Restoration (MSRCR), and Gamma and Sigmoid Conversions (GSC). The results show that the classification accuracy using the original images is the lowest. All color transfer methods outperform the original images approach. Our results verified that the color transfer has a positive impact on the polyp identification and classification task. Combined analysis results of the mAP and the accuracy show an excellent performance of the MSRCR method.

Small-molecule kinase inhibitors represent a major group of cancer therapeutics, but tumor responses are often incomplete. To identify pathways that modulate kinase inhibitor response, we conducted a genome-wide knockout (KO) screen in glioblastoma cells treated with the pan-ErbB inhibitor neratinib. Loss of general control nonderepressible 2 (GCN2) kinase rendered cells resistant to neratinib, whereas depletion of the GADD34 phosphatase increased neratinib sensitivity. Loss of GCN2 conferred neratinib resistance by preventing binding and activation of GCN2 by neratinib. Several other Food and Drug Administration (FDA)-approved inhibitors, such erlotinib and sunitinib, also bound and activated GCN2. Our results highlight the utility of genome-wide functional screens to uncover novel mechanisms of drug action and document the role of the integrated stress response (ISR) in modulating the response to inhibitors of oncogenic kinases., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Dicarabrols B and C (1 and 2), two new carabrane sesquiterpenoid dimers, along with one new carabrane sesquiterpenoid (3) were isolated from the whole plant of Carpesium abrotanoides L. Their full structures were established by extensive analysis of HR-ESI-MS and NMR spectroscopic data, and time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. Dicarabrol B possesses a novel C 30 skeleton featuring a methylene-tethered bridge between two sesquiterpene moieties, while dicarabrol C presents the unique linkage of a cyclopentane ring in the molecule. Dicarabrol C exhibited potent inhibitory effects on HL-60 cells with an IC 50 value of 3.7 μmol·L -1 ., (Copyright © 2021 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Colonoscopies reduce the incidence of colorectal cancer through early recognition and resecting of the colon polyps. However, the colon polyp miss detection rate is as high as 26% in conventional colonoscopy. The search for methods to decrease the polyp miss rate is nowadays a paramount task. A number of algorithms or systems have been developed to enhance polyp detection, but few are suitable for real-time detection or classification due to their limited computational ability. Recent studies indicate that the automated colon polyp detection system is developing at an astonishing speed. Real-time detection with classification is still a yet to be explored field. Newer image pattern recognition algorithms with convolutional neuro-network (CNN) transfer learning has shed light on this topic. We proposed a study using real-time colonoscopies with the CNN transfer learning approach. Several multi-class classifiers were trained and mAP ranged from 38% to 49%. Based on an Inception v2 model, a detector adopting a Faster R-CNN was trained. The mAP of the detector was 77%, which was an improvement of 35% compared to the same type of multi-class classifier. Therefore, our results indicated that the polyp detection model could attain a high accuracy, but the polyp type classification still leaves room for improvement.

A phytochemical investigation was carried out on the extract of a medicinal plant Callicarpa nudiflora, resulting in the characterization of five new 3, 4-seco-isopimarane (1-5) and one new 3, 4-seco-pimarane diterpenoid (6), together with four known compounds. The structures of the new compounds were fully elucidated by extensive analysis of MS, 1D and 2D NMR spectroscopic data, and time-dependent density functional theory (TDDFT) calculation of electronic circular dichroism (ECD) spectra, and DFT calculations for NMR chemical shifts and optical rotations., (Copyright © 2021 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Randomized control trials and meta-analyses comparing colonoscopies with and without computer-aided detection (CADe) assistance showed significant increases in adenoma detection rates (ADRs) with CADe. A major limitation of CADe is its false positives (FPs), ranked 3rd in importance among 59 research questions in a modified Delphi consensus review. The definition of FPs varies. One commonly used definition defines an FP as an activation of the CADe system, irrespective of the number of frames or duration of time, not due to any polypoid or nonpolypoid lesions. Although only 0.07 to 0.2 FPs were observed per colonoscopy, video analysis studies using FPs as the primary outcome showed much higher numbers of 26 to 27 per colonoscopy. Most FPs were of short duration (91% < 0.5 s). A higher number of FPs was also associated with suboptimal bowel preparation. The appearance of FPs can lead to user fatigue. The polypectomy of FPs results in increased procedure time and added use of resources. Re-training the CADe algorithms is one way to reduce FPs but is not practical in the clinical setting during colonoscopy. Water exchange (WE) is an emerging method that the colonoscopist can use to provide salvage cleaning during insertion. We discuss the potential of WE for reducing FPs as well as the augmentation of ADRs through CADe.

Background: Recent findings indicated a high comorbidity between attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), as well as shared genetic influences on them. The latter might contribute at least partly to the former clinical scenario. This study aimed at investigating whether SHANK genes were potential pleiotropic genes to the two said disorders, underlying their genetic overlap. Methods: This study recruited 298 boys with ADHD (including 256 family trios of 1 ADHD boy and his 2 biological parents), 134 boys with ASD, 109 boys with both ADHD and ASD, and 232 typically developing boys as community controls. They were aged between 6 and 11 years old. Results: There was no significant difference in allele frequency of a number of single nucleotide polymorphisms (SNPs) in SHANK2 / SHANK3 between the three clinical groups (ADHD, ASD, and ADHD + ASD) and between the two control groups (community controls and pseudo-controls), respectively. The three clinical groups and the two control groups were thus, respectively, combined. A comparison between the two aggregated samples identified significant evidence of disease association for three SHANK2 SNPs with both ADHD and ASD, even after multiple testing correction: rs11236616 ( OR = 0.762, permuted p = 0.0376), rs7106631 ( OR = 0.720, permuted p = 0.0034), and rs9888288 ( OR = 0.770, permuted p = 0.0407). Comparisons among individual groups pointed to a similar trend of findings. Conclusion: SHANK2 could be considered a potential pleiotropic gene underlying the genetic overlap between ADHD and ASD. This might contribute partly to their high comorbidity in the afflicted children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ma, Chen, Lee, Lai, Hung, Tang, Ho, Shea, Mo, Mak, Sham and Leung.)

Water exchange (WE) and artificial intelligence (AI) have made critical advances during the past decade. WE significantly increases adenoma detection and AI holds the potential to help endoscopists detect more polyps and adenomas. We performed an electronic literature search on PubMed using the following keywords: water-assisted and water exchange colonoscopy, adenoma and polyp detection, artificial intelligence, deep learning, neural networks, and computer-aided colonoscopy. We reviewed relevant articles published in English from 2010 to May 2020. Additional articles were searched manually from the reference lists of the publications reviewed. We discussed recent advances in both WE and AI, including their advantages and limitations. AI may mitigate operator-dependent factors that limit the potential of WE. By increasing bowel cleanliness and improving visualization, WE may provide the platform to optimize the performance of AI for colonoscopies. The strengths of WE and AI may complement each other in spite of their weaknesses to maximize adenoma detection., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Tzu Chi Medical Journal.)

During eukaryotic DNA replication, DNA polymerase alpha/primase (Pol α) initiates synthesis on both the leading and lagging strands. It is unknown whether leading- and lagging-strand priming are mechanistically identical, and whether Pol α associates processively or distributively with the replisome. Here, we titrate cellular levels of Pol α in S. cerevisiae and analyze Okazaki fragments to study both replication initiation and ongoing lagging-strand synthesis in vivo. We observe that both Okazaki fragment initiation and the productive firing of replication origins are sensitive to Pol α abundance, and that both processes are disrupted at similar Pol α concentrations. When the replisome adaptor protein Ctf4 is absent or cannot interact with Pol α, lagging-strand initiation is impaired at Pol α concentrations that still support normal origin firing. Additionally, we observe that activation of the checkpoint becomes essential for viability upon severe depletion of Pol α. Using strains in which the Pol α-Ctf4 interaction is disrupted, we demonstrate that this checkpoint requirement is not solely caused by reduced lagging-strand priming. Our results suggest that Pol α recruitment for replication initiation and ongoing lagging-strand priming are distinctly sensitive to the presence of Ctf4. We propose that the global changes we observe in Okazaki fragment length and origin firing efficiency are consistent with distributive association of Pol α at the replication fork, at least when Pol α is limiting., Competing Interests: The authors have declared that no competing interests exist.

Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as a promising therapeutic target for the treatment of malignant tumors characterized by dysregulated tryptophan metabolism. However, the antitumor efficacy of existing small-molecule IDO1 inhibitors is still unsatisfactory, and the underlying mechanism remains largely undefined. To identify novel IDO1 inhibitors, an in-house natural product library of 2000 natural products was screened for inhibitory activity against recombinant human IDO1. High-throughput fluorescence-based screening identified 79 compounds with inhibitory activity > 30% at 20 μM. Nine natural products were further confirmed to inhibit IDO1 activity by > 30% using Ehrlich's reagent reaction. Compounds 2, 7, and 8 were demonstrated to inhibit IDO1 activity in a cellular context. Compounds 2 and 7 were more potent against IDO1 than TDO2 in the enzymatic assay. The kinetic studies showed that compound 2 exhibited noncompetitive inhibition, whereas compounds 7 and 8 were graphically well matched with uncompetitive inhibition. Compounds 7 and 8 were found to bind to the ferric-IDO1 enzyme. Docking stimulations showed that the naphthalene ring of compound 8 formed "T-shaped" π-π interactions with Phe-163 and that the 6-methyl-naphthalene group formed additional hydrophobic interactions with IDO1. Compound 8 was identified as a derivative of tanshinone, and preliminary SAR analysis indicated that tanshinone derivatives may be promising hits for the development of IDO1 inhibitors. This study provides new clues for the discovery of IDO1/TDO2 inhibitors with novel scaffolds.

Objective: We examined adulthood diagnostic, functioning, and social outcomes of childhood ADHD in a Hong Kong Chinese clinical sample. Method: We identified from the central registry 499 Chinese adults clinically diagnosed with ADHD aged 6 to 12 in 2002-2005 in four Hong Kong child psychiatric centers. Assessments included ADHD Clinical Diagnostic Scale (ACDS), Structured Clinical Interview for DSM Disorders (SCID), and World Health Organization Disability Assessment Schedule (WHO-DAS). Results: Eligible participants = 499. One hundred forty-five completed assessments, two deceased, six incarcerated, 100 had invalid contact, 83 declined, 34 emigrated, and 129 unable to attend. Mean follow-up duration = 14.9 years. Nonrespondents were slightly younger (19.78 vs. 20.53, p < .001). In all, 83.1% of all participants currently met Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5 ) ADHD criteria (36.8% inattentive subtype (IA), 43% combined, 3.3% hyperactive/impulsive subtype (H/I) ). One third of persistent ADHD participants currently received care. ADHD persistence was associated with significantly increased psychiatric comorbidity (49.5% vs. 22.7%, p = .02) and poor academic and social outcomes. ADHD persistence and comorbidity independently predicted impairment. Conclusion: Adulthood-persistence of clinically presented childhood ADHD is common and impairing in Hong Kong Chinese.

Numerous mobile apps have been developed for making our lives more convenient and improving our quality of life. Health apps are among them. These types of apps are designed to help users for recording their health-related behaviors and to give advice about improving users' physical conditions. However, users frequently do not continue to use these health apps. As a result, the companies of health apps have paid the development cost but cannot get back the benefit from the apps they launch. To find out the reason, this study conducts an empirical investigation and develops a trade-off dual-factor model to dissect the reason why users discontinue use of health apps. The research model is based on the perspectives of information disclosure and expectation-confirmation theory. Users may worry about the disclosure of individual health privacy; however, on the other hand, they enjoy the functions of health apps, proffering various kinds of health-related assistance. The decision of whether or not to continue using this kind of app turns into a trade-off issue. To delve into the determinants, we conduct an online survey and collect 242 qualified responses as our research samples. Structural equation modeling is employed to analyze the samples in this study. The result reveals that our research model explains 31% of the variance. The findings and implications can serve as references for researchers and practitioners., (Copyright © 2019 Elsevier Inc. All rights reserved.)

One new dimeric (1) and two monomeric sesquiterpene lactones (5 and 13), together with 10 known compounds (2-4, 6-12), were isolated from Artemisia heptapotamica collected in Almaty region of Kazakhstan. All compounds were isolated from this plant for the first time. The structures of the new compounds were mainly achieved by extensive analysis of MS, 1D and 2D NMR spectroscopic data, and ECD spectrum as well. The inhibitory activities of all isolates against activation of NF-κB induced by LPS were assessed on a THP1-Dual cell model. Some of them showed strong inhibitory activity with IC 50 values ranging from 2 to 25 μmol·L -1 ., (Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Hao Jia Xu Re Qing Granules (HJ), is an effective clinically used antipyretic based on traditional Chinese medicine. Although its antipyretic therapeutic effectiveness is obvious, its therapeutic mechanism has not been comprehensively explored yet. In this research, we first identified potential biomarkers which may be relevant for the antipyretic effect of HJ based on urine metabolomics using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). A rat model of fever was established using the yeast-induced febrile response. Total-ion-current metabolic profiles of different groups were acquired and the data were processed by multivariate statistical analysis-partial least-squares discriminant analysis. As envisioned, the results revealed changes of urine metabolites related to the antipyretic effect. Fourteen potential biomarkers were selected from the urine samples based on the results of Student's t-test, "shrinkage t", variable importance in projection and partial least-squares discriminant analysis. N-Acetylleucine, kynurenic acid, indole-3-ethanol, nicotinuric acid, pantothenic acid and tryptophan were the most significant biomarkers found in the urine samples, and may be crucially related to the antipyretic effect of HJ. Consequently, we propose the hypothesis that the significant antipyretic effect the HJ may be related to the inhibition of tryptophan metabolism. This research thus provides strong theoretical support and further direction to explain the antipyretic mechanism of HJ, laying the foundation for future studies., (© 2018 John Wiley & Sons, Ltd.)

Background: colorectal cancer (CRC) is the second leading cause of cancer and cancer-related death in the world. Noninvasive biomarkers for early diagnosis of CRC are highly demanded., Objective: The up-regulation of specific microRNAs (miRNAs) in serum has been considered a promising biomarker of CRC and miR-24-2 may be a potential biomarker in the diagnosis the progression of CRC., Methods: Sixty-eighty healthy subjects and 228 CRC patients were divided into six groups: control group, CRC 0, CRC I, CRC II, CRC III, CRC IV and CRC V. Serum level of miR-24-2 was measured by real-time qPCR. Serum lipid profiles and oxidative-related molecules were also measured., Results: Serum levels of miR-24-2 in CRC patients were significantly higher than healthy subjects (p< 0.05). In addition, the expression level of the miR-24-2 was decreased with the progression of CRC and reached the lowest level in CRC V. Spearman Rank Correlation analysis showed that miR-24-2 level was negatively related to the levels of superoxide dismutase (SOD) and reduced glutathione (GSH), aspartate transaminase (AST), alanine transaminase (ALT), cholesterol and triglyceride (p< 0.05)., Conclusions: Serum miR-24-2 is a potential negative biomarker in the diagnosis of the progression of CRC patients and associated with biochemical indices.

Objective: To investigate the protective effects of Chinese medicine formulation Chaihu Shugan San (, CHSGS) on nonalcoholic fatty liver disease (NAFLD) in rats with insulin resistance (IR) and its molecular mechanisms., Methods: Male Sprague-Dawley rats were randomly divided into six groups: the control group, the model group, Dongbao Gantai group (, DBGT, 0.09 g methionine/kg), CHSGS high-dose group (CHSG-H, 12.6 g crude drug/kg), CHSGS medium-dose group (CHSG-M, 6.3 g crude drug/kg), and CHSGS low-dose group (CHSG-L, 3.15 g crude drug/kg). After establishing the NAFLD rat model and treatment for 8 weeks, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), free fatty acid (FFA), fasting blood glucose (FBG), fasting insulin (FINS) contents in blood serum, and TC, TG contents in the hepatic homogenate were measured by an automatic biochemical analyzer, and a homeostasis model assessment was applied to assess the status of IR, insulin sensitivity index (ISI), and homeostasis model assessment for insulin secretion (HOMA-IS). The expression levels of adiponectin and leptin mRNA in liver tissue were analyzed by reverse transcription polymerase chain reaction. Pathological changes of livers were observed by hematoxylin-eosin staining of paraffin section., Results: Compared with the model group, the serum levels of TC, TG, FFA, FBG, FINS, IRI, ISI, and the liver levels of TC and TG in CHSG-H, CHSG-M, CHSG-L groups showed significant declines (P<0.01 or P<0.05); the serum levels of HDL-C, HOMA-IS were significantly increased (P<0.01 or P<0.05); the expression of leptin mRNA was dramatically decreased and the expression of adiponectin mRNA was increased in the hepatic tissue (P<0.01 or P<0.05). The fatty deposition of liver cells could also be alleviated., Conclusion: CHSGS could up-regulate the expression of adiponectin mRNA and down-regulate the expression of leptin mRNA on the liver, suggesting the CHSGS had positive therapeutic effect on NAFLD in rats with IR.

Interleukin-8 (IL-8), which is secreted by cancer cells undergoing epithelial-mesenchymal transition (EMT), can promote EMT in adjacent epithelial-like cells. MicroRNAs (miRNAs/miRs) can affect the expression of target genes via binding to their 3'-untranslated regions (3'-UTRs), which may subsequently affect the biological behaviors of cancer cells. In our previous study, miR-520c-3p was predicted to directly target the 3'-UTR of IL-8. Therefore, the present study was carried out to investigate whether miR-520c-3p can interact with the IL-8 gene and regulate the EMT of breast cancer cells. Web-based prediction algorithms were used to identify miRNAs that potentially target the IL-8 transcript. Luciferase reporter assays were used to confirm the targeting of IL-8 by miR-520c-3p. Reverse transcription-quantitative PCR and western blot analyses were used to examine the levels of IL-8 and EMT-related genes in breast cancer cells. The functional impact of miR-520c-3p on EMT phenotype was evaluated using Transwell and wound-healing assays, and rescue experiments were conducted by overexpressing IL-8 to determine its effect on cell properties. miR-520c-3p was predicted by all three databases, which strongly suggested its interaction with the 3'-UTR of IL-8. The relative Renilla luciferase activity of luciferase reporter construct containing the wild-type 3'-UTR of IL-8 was markedly decreased by miR-520c-3p transfection when compared with scrambled miRNA control transfection (P<0.001). In addition, compared with the scrambled miRNA control transfection, the overexpression of miR-520c-3p significantly reduced the expression of IL-8, and resulted in increased E-cadherin and decreased vimentin and fibronectin levels in MCF-7 and T47D cells (all P<0.001). Introduction of miR-520c-3p inhibited the invasion and migration of MCF-7 and T47D cells (all P<0.001). By contrast, the rescue of IL-8 expression led to the recovery of EMT-related protein expression patterns and cell motility and invasion capabilities. In conclusion, aberrant miR-520c-3p expression may lead to reduced IL-8 expression and promote the mesenchymal phenotype in breast cancer cells, thereby increasing invasive growth.

Background: Methylphenidate (MPH) has been found to be an effective medication for attention-deficit/hyperactivity disorder (ADHD). However, there are neither consistent nor sufficient findings on whether psychiatric comorbidities and associated cognitive functions of ADHD are related to treatment response to MPH in ADHD children., Objectives: This study investigated whether psychiatric comorbidities, IQ, and neurocognitive deficits are related to treatment response to MPH in ADHD children. In some ways, it is preferable to have a drug that the effectiveness of which to a disorder is not affected by its associated cognitive functions and psychiatric comorbidities. On the other hand, it is likely that the baseline symptom severity of ADHD is associated with the effectiveness of MPH treatment on the symptoms post treatment., Methods: A total of 149 Chinese boys (aged 6-12 years) with ADHD, combined type, and normal IQ participated in this study. Assessment of ADHD symptom severity was conducted pre and post MPH treatment, while assessment of psychiatric comorbidities, IQ, and neurocognitive deficits was performed in a non-medicated condition. Treatment response was defined as the ADHD symptom severity post MPH treatment., Results: Results indicated that MPH treatment was effective, significantly improving the ADHD condition. Yet, comorbid disorders, IQ, and neurocognitive deficits were not related to MPH treatment response on ADHD symptoms. These findings indicated that the effectiveness of MPH was not affected by psychiatric comorbidities and associated cognitive functions of ADHD. Instead, as expected, it was the baseline symptom severity that was mainly related to the treatment response, ie, the milder the baseline condition, the better the treatment response., Conclusion: The current findings positively endorse the widespread clinical use of MPH for treating ADHD. It improves the behavioral symptoms of ADHD regardless of varying psychiatric comorbidities, IQ, and neurocognitive deficits., Competing Interests: Disclosure The authors report no conflicts of interests in this work.

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.

Phytochemical investigation of the twigs of Podocarpus nagi (Podocarpaceae) led to the isolation of two new abietane-type diterpenoids, named 1β,16-dihydroxylambertic acid (1) and 3β,16-dihydroxylambertic acid (2), along with two new ent-pimarane-type diterpenoids, named ent-2β,15,16,18-tetrahydroxypimar-8(14)-ene (3) and ent-15-oxo-2β,16,18-trihydroxypimar-8(14)-ene (4). Their respective structures were elucidated on the basis of spectroscopic analyses, including 1D- and 2D-NMR, IR, CD, and HR-ESI-MS. This is the first time ent-pimarane-type diterpenoids from the genus Podocarpus has been reported. All four new compounds were tested for cytotoxic activity. The MTT assay results showed that compounds 3 and 4 significantly inhibited the proliferation of human cervical cancer Hela cells, human lung cancer A549 cells, and human breast cancer MCF-7 cells at a concentration of 10 μM. Furthermore, using the lipopolysaccharide (LPS)-stimulated RAW264.7 cells, compounds 2 and 4 were found to significantly inhibit nitrogen oxide (NO) production with IC50 values of 26.5 ± 6.1 and 17.1 ± 1.5 μM, respectively.

Long non-coding RNAs (lncRNAs) have been identified to be critical mediators in various tumors associated with cancer progression. Long non-coding RNA activated by TGF-β (lncRNA-ATB) is a stimulator of epithelial-mesenchymal transition (EMT) and serves as a novel prognostic biomarker for hepatocellular carcinoma. However, the biological role and clinical significance of lncRNA-ATB in human prostate cancer have yet to be fully elucidated. The present study was designed to explore the expression of lncRNA-ATB in human prostate cancer patients and the role of lncRNA-ATB in prostate cancer cells. We showed that lncRNA-ATB expression was significantly upregulated in tumor tissues in patients with prostate cancer in comparison with adjacent non-tumor tissues. Further analysis indicted that high lncRNA-ATB expression may be an independent prognostic factor for biochemical recurrence (BCR)-free survival in prostate cancer patients. Overexpression of lncRNA-ATB promoted, and knockdown of lncRNA-ATB inhibited the growth of prostate cancer cells via regulations of cell cycle regulatory protein expression levels. In addition, lncRNA-ATB stimulated epithelial-mesenchymal transition (EMT) associated with ZEB1 and ZNF217 expression levels via ERK and PI3K/AKT signaling pathways. These results indicated that lncRNA-ATB may be considered as a new predictor in the clinical prognosis of patients with prostate cancer. Overexpression of lncRNA-ATB exerts mitogenic and EMT effects of prostate cancer via activation of ERK and PI3K/AKT signaling pathways.

Background: The long-term outcome of never-treated patients with schizophrenia is unclear., Aims: To compare the 14-year outcomes of never-treated and treated patients with schizophrenia and to establish predictors for never being treated., Method: All participants with schizophrenia (n = 510) in Xinjin, Chengdu, China were identified in an epidemiological investigation of 123 572 people and followed up from 1994 to 2008., Results: The results showed that there were 30.6%, 25.0% and 20.4% of patients who received no antipsychotic medication in 1994, 2004 and 2008 respectively. Compared with treated patients, those who were never treated in 2008 were significantly older, had significantly fewer family members, had higher rates of homelessness, death from other causes, being unmarried, living alone, being without a caregiver and poor family attitudes. Partial and complete remission in treated patients (57.3%) was significantly higher than that in the never-treated group (29.8%). Predictors of being in the never-treated group in 2008 encompassed baseline never-treated status, being without a caregiver and poor mental health status in 1994., Conclusions: Many patients with schizophrenia still do not receive antipsychotic medication in rural areas of China. The 14-year follow-up showed that outcomes for the untreated group were worse. Community-based mental healthcare, health insurance and family intervention are crucial for earlier diagnosis, treatment and rehabilitation in the community., (© The Royal College of Psychiatrists 2015.)

Knowledge of the precise rigidity dependence of the helium flux is important in understanding the origin, acceleration, and propagation of cosmic rays. A precise measurement of the helium flux in primary cosmic rays with rigidity (momentum/charge) from 1.9 GV to 3 TV based on 50 million events is presented and compared to the proton flux. The detailed variation with rigidity of the helium flux spectral index is presented for the first time. The spectral index progressively hardens at rigidities larger than 100 GV. The rigidity dependence of the helium flux spectral index is similar to that of the proton spectral index though the magnitudes are different. Remarkably, the spectral index of the proton to helium flux ratio increases with rigidity up to 45 GV and then becomes constant; the flux ratio above 45 GV is well described by a single power law.

A precise measurement of the proton flux in primary cosmic rays with rigidity (momentum/charge) from 1 GV to 1.8 TV is presented based on 300 million events. Knowledge of the rigidity dependence of the proton flux is important in understanding the origin, acceleration, and propagation of cosmic rays. We present the detailed variation with rigidity of the flux spectral index for the first time. The spectral index progressively hardens at high rigidities.

We present a measurement of the cosmic ray (e^{+}+e^{-}) flux in the range 0.5 GeV to 1 TeV based on the analysis of 10.6 million (e^{+}+e^{-}) events collected by AMS. The statistics and the resolution of AMS provide a precision measurement of the flux. The flux is smooth and reveals new and distinct information. Above 30.2 GeV, the flux can be described by a single power law with a spectral index γ=-3.170±0.008(stat+syst)±0.008(energy scale).

A precision measurement by AMS of the positron fraction in primary cosmic rays in the energy range from 0.5 to 500 GeV based on 10.9 million positron and electron events is presented. This measurement extends the energy range of our previous observation and increases its precision. The new results show, for the first time, that above ∼200  GeV the positron fraction no longer exhibits an increase with energy.

Precision measurements by the Alpha Magnetic Spectrometer on the International Space Station of the primary cosmic-ray electron flux in the range 0.5 to 700 GeV and the positron flux in the range 0.5 to 500 GeV are presented. The electron flux and the positron flux each require a description beyond a single power-law spectrum. Both the electron flux and the positron flux change their behavior at ∼30  GeV but the fluxes are significantly different in their magnitude and energy dependence. Between 20 and 200 GeV the positron spectral index is significantly harder than the electron spectral index. The determination of the differing behavior of the spectral indices versus energy is a new observation and provides important information on the origins of cosmic-ray electrons and positrons.

To against the emergence of drug-resistent candidiasis, the studys of synergism of natural compounds combine with antifungal agents in vitro showed a continuous growth in recent years. The paper reviewed recent progresses to compare the synergetic effect by FICI method, and to conclude the synergetic mechanisms which have been confirmed as a reference for futher study.

Six new triterpenoids, meliasenins S-X (1-6, resp.), were isolated from the stem bark of Melia toosendan. Their structures were elucidated by mass spectrometry, NMR experiments, and comparison with the known compounds. Particularly, the absolute configuration at C(24) in new compounds was determined through their CD spectra of the [Pr(FOD)3 ] complex (fod=1,1,1,2,2,3,3,7,7,7-decafluoroheptane-4,6-dione) in CCl4 , as well as by using Mosher's method., (Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.)

Nine new, uncommon humulane-type sesquiterpenoids (1, 2, 4, 6-11), together with two known derivatives, were isolated from extracts of the plant Pilea cavaleriei subsp. crenata. The structures of these compounds were fully elucidated by extensive analyses of spectroscopic data (MS, 1D- and 2D-NMR), use of the Mosher method, and by X-ray crystallographic analysis, in combination with chemical conversions. An ene reaction was discovered during the chemical transformations, which might provide an explanation for the wide distribution of the allylic hydroperoxide group in natural products.

A precision measurement by the Alpha Magnetic Spectrometer on the International Space Station of the positron fraction in primary cosmic rays in the energy range from 0.5 to 350 GeV based on 6.8 × 10(6) positron and electron events is presented. The very accurate data show that the positron fraction is steadily increasing from 10 to ∼ 250  GeV, but, from 20 to 250 GeV, the slope decreases by an order of magnitude. The positron fraction spectrum shows no fine structure, and the positron to electron ratio shows no observable anisotropy. Together, these features show the existence of new physical phenomena.

This article reviews the progress made by Chinese scientists in the field of natural products chemistry in 2011. Selected compounds with unique structural features and/or promising bioactivities are described herein on the basis of structural types., (Copyright © 2013 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Objective: To examine the antifungal effect of different extract of Dryopteris fragrans (L.) Schott. in vitro, and screen the effective fraction from those extracts., Methods: Separated the Dryopteris fragrans extract and got four parts by refluxing extraction,and determined the contents of total phloroglucinol. Disc agar diffusion method and solid agar dilution method were used to determine inhibitory effect. Minimum inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) of different parts of Dryopteris fragrans extract against four strains of common clinical dermatophytes were investigated., Results: The data showed that the contents sequence of total phloroglucinol was in the following order: 95% -ethanol extract > water extract > diethyl ether extract > petroleum ether extract, and the antimicrobial activities against the four dermatophytes were as following order: 95% -ethanol extract > water extract > di-ethyl ether extract > petroleum ether extract., Conclusion: The contents of total phloroglucinol in 95% -ethanol extract of Dryopteris fragrans is the highest, and the antifungal activity against dermatophytes in vitro is the strongest. The effective fraction of Dryopteris fragrans is the 95%-ethanol extract.

Objective: To study the effect of HGD on diabetic cardiomyopathy and its mechanism., Methods: The T2-DM rats model was established by combining high fat diet with STZ. The blood glucose, insulin, myocardial fibrosis and TGF-beta1/Smad3 signaling pathway were observed; TGF-beta1 and Smad3 mRNA expression were detected by RT-PCR method, protein expression detected by immunohistochemical method., Results: HGD obviously reduced fasting blood glucose, insulin, improved insulin resistance, reduced myocardial hydroxyproline contents, lowered cardiac index, significantly inhibited over-expression of TGF-beta1/SMAD3 mRNA and protein in diabetic rats cardiac., Conclusion: HGD can obviously prevent experimental diabetic myocardial fibrosis through the regulation effect on TGFbeta1/Smad3 signaling pathway.

Two unprecedented dimeric diterpenoids, with a 2,3-dihydrofuran ring fusing an abietane and a 4,5-seco-abietane diterpene, were isolated from Cunninghamia lanceolata. Their structures were elucidated by spectroscopic measurements, and their absolute configurations were determined by quantum chemical TDDFT ECD calculations, chemical transformations, and Mosher's method. The Mosher method carried out with MPA and MTPA esters of the sterically hindered sec-hydroxyl group gave contradictory results, while MPA afforded the correct absolute configuration., (© 2011 American Chemical Society)