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Zebrafish larvae have classically been used as a high-throughput model with which to test both the bioactivity and toxicity of known and novel compounds, making them a promising whole organism New Approach Method in the context of the international momentum to eliminate animal testing. Larvae are generally exposed to the chemicals being tested in a static environment and the concentration-response patterns are calculated based on the initial bath concentrations of the compounds. This approach rarely takes into account the absorption, distribution, metabolism, and excretion of the compounds being tested, which can have a significant effect on the toxicokinetic profiles of the compounds and thus impact the predictive ability of the model. In this study, we have evaluated the toxicokinetic profile of 5 known toxicants, 3 phenolic compounds, along with thiabendazole and 3,4-dicholoronalanine, at 6, 8, 24, 72, and 120 h postfertilization in order to match the exposure timelines of a standard in vitro fish embryo toxicity test. It was revealed that in addition to bioaccumulation effects, the compounds were all actively metabolized and excreted by the larvae. Importantly, comparisons between the toxicants revealed that the patterns of uptake and metabolism were varied and could often partially explain the differences in their concentration-response patterns. The findings of this study are significant as they highlight the requirement for an assessment of the stability and toxicokinetic profile of chemicals tested using standard zebrafish larval toxicity assays in order to better understand and compare their toxicity profiles.

Background Young people are most vulnerable to suicidal behaviours but least likely to seek help. A more elaborate study of the intrinsic and extrinsic correlates of suicidal ideation and behaviours particularly amid ongoing population-level stressors and the identification of less stigmatising markers in representative youth populations is essential. Methods Participants (n = 2540, aged 15–25) were consecutively recruited from an ongoing large-scale household-based epidemiological youth mental health study in Hong Kong between September 2019 and 2021. Lifetime and 12-month prevalence of suicidal ideation, plan, and attempt were assessed, alongside suicide-related rumination, hopelessness and neuroticism, personal and population-level stressors, family functioning, cognitive ability, lifetime non-suicidal self-harm, 12-month major depressive disorder (MDD), and alcohol use. Results The 12-month prevalence of suicidal ideation, ideation-only (no plan or attempt), plan, and attempt was 20.0, 15.4, 4.6, and 1.3%, respectively. Importantly, multivariable logistic regression findings revealed that suicide-related rumination was the only factor associated with all four suicidal outcomes (all p < 0.01). Among those with suicidal ideation (two-stage approach), intrinsic factors, including suicide-related rumination, poorer cognitive ability, and 12-month MDE, were specifically associated with suicide plan, while extrinsic factors, including coronavirus disease 2019 (COVID-19) stressors, poorer family functioning, and personal life stressors, as well as non-suicidal self-harm, were specifically associated with suicide attempt. Conclusions Suicide-related rumination, population-level COVID-19 stressors, and poorer family functioning may be important less-stigmatising markers for youth suicidal risks. The respective roles played by not only intrinsic but also extrinsic factors in suicide plan and attempt using a two-stage approach should be considered in future preventative intervention work.

How striatal dopamine synthesis capacity (DSC) contributes to the pathogenesis of negative symptoms in first-episode schizophrenia (SZ) and delusional disorder (DD) has seldom been explored. As negative symptoms during active psychotic episodes can be complicated by secondary influences, such as positive symptoms, longitudinal investigations may help to clarify the relationship between striatal DSC and negative symptoms and differentiate between primary and secondary negative symptoms.A longitudinal study was conducted to examine whether baseline striatal DSC would be related to negative symptoms at 3 months in first-episode SZ and DD patients.Twenty-three first-episode age- and gender-matched patients (11 DD and 12 SZ) were consecutively recruited through an early intervention service for psychosis in Hong Kong. Among them, 19 (82.6%) patients (9 DD and 10 SZ) were followed up at 3 months. All patients received anBaseline striatal DSC (KThese findings highlight the role of striatal DSC in negative symptoms upon resolution of active psychotic episodes among first-episode SZ patients. Baseline striatal dopamine activity may inform future symptom expression with important treatment implications.

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Purpose: To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease.Experimental Design: The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log-rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan–Meier analysis. RACGAP1-targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes.Results: Kaplan–Meier analysis showed that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of postresection recurrent HCC (P < 0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using Ingenuity Pathway Analysis, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1, and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts was analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly upregulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results.Conclusions: siRNA-silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC. Clin Cancer Res; 17(18); 6040–51. ©2011 AACR.

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While chest radiograph (CXR) is the first-line imaging investigation in patients with respiratory symptoms, differentiating COVID-19 from other respiratory infections on CXR remains challenging. We developed and validated an AI system for COVID-19 detection on presenting CXR.A deep learning model (RadGenX), trained on 168,850 CXRs, was validated on a large international test set of presenting CXRs of symptomatic patients from 9 study sites (US, Italy, and Hong Kong SAR) and 2 public datasets from the US and Europe. Performance was measured by area under the receiver operator characteristic curve (AUC). Bootstrapped simulations were performed to assess performance across a range of potential COVID-19 disease prevalence values (3.33 to 33.3%). Comparison against international radiologists was performed on an independent test set of 852 cases.RadGenX achieved an AUC of 0.89 on 4-fold cross-validation and an AUC of 0.79 (95%CI 0.78-0.80) on an independent test cohort of 5,894 patients. Delong's test showed statistical differences in model performance across patients from different regions (p0.01), disease severity (p0.001), gender (p0.001), and age (p = 0.03). Prevalence simulations showed the negative predictive value increases from 86.1% at 33.3% prevalence, to greater than 98.5% at any prevalence below 4.5%. Compared with radiologists, McNemar's test showed the model has higher sensitivity (p0.001) but lower specificity (p0.001).An AI model that predicts COVID-19 infection on CXR in symptomatic patients was validated on a large international cohort providing valuable context on testing and performance expectations for AI systems that perform COVID-19 prediction on CXR.• An AI model developed using CXRs to detect COVID-19 was validated in a large multi-center cohort of 5,894 patients from 9 prospectively recruited sites and 2 public datasets. • Differences in AI model performance were seen across region, disease severity, gender, and age. • Prevalence simulations on the international test set demonstrate the model's NPV is greater than 98.5% at any prevalence below 4.5%.

Emotions are not necessarily universal across different languages and cultures. Mental lexicons of emotions depend strongly on contextual factors, such as language and culture. The Chinese language has unique linguistic properties that are different from other languages. As a main variant of Chinese, Cantonese has some emotional expressions that are only used by Cantonese speakers. Previous work on Chinese emotional vocabularies focused primarily on Mandarin. However, little is known about Cantonese emotion vocabularies. This is important since both language variants might have distinct emotional expressions, despite sharing the same writing system. To explore the structure and organization of Cantonese-label emotion words, we selected 79 highly representative emotion cue words from an ongoing large-scale Cantonese word association study (SWOW-HK). We aimed to identify the categories of these emotion words and non-emotion words that related to emotion concepts. Hierarchical cluster analysis was used to generate word clusters and investigate the underlying emotion dimensions. As the cluster quality was low in hierarchical clustering, we further constructed an emotion graph using a network approach to explore how emotions are organized in the Cantonese mental lexicon. With the support of emotion knowledge, the emotion graph defined more distinct emotion categories. The identified network communities covered basic emotions such as love, happiness, and sadness. Our results demonstrate that mental lexicon graphs constructed from free associations of Cantonese emotion-label words can reveal fine categories of emotions and their relevant concepts.

Purpose NUF2 has been implicated in multiple cancers recently, suggesting NUF2 may play a role in the common tumorigenesis process. In this study, we aim to perform comprehensive meta-analysis of NUF2 expression in the cancer types included in the Cancer Genome Atlas (TCGA). Materials and methods RNA-sequencing data in 31 cancer types in the TCGA data and 11 independent datasets were used to examine NUF2 expression. Silencing NUF2 using targeting shRNAs in hepatocellular carcinoma cell lines was used to evaluate NUF2's role in hepatocellular carcinoma (HCC) in vitro and in vivo. Results NUF2 up-regulation is significantly observed in 23 out of the 31 cancer types in the TCGA datasets and validated in 13 major cancer types using 11 independent datasets. NUF2 overexpression was clinically important as high NUF2 was significantly associated with tumor stages in eight different cancers. High NUF2 was also associated with significantly poorer patient overall survival and disease-free survival in eight and six cancers, respectively. We proceeded to validate NUF2 overexpression and its negative association with overall survival at the protein level in an independent cohort of 40 HCC patients. Compared to the non-targeting controls, NUF2 knockdown cells showed significantly reduced ability to grow, migrate into a scratch wound and invade the 8 μm porous membrane in vitro. Moreover, NUF2 knockdown cells also formed significantly smaller tumors than control cells in mouse xenograft assays in vivo. Conclusion NUF2 up-regulation is a common feature of many cancers. The prognostic potential and functional impact of NUF2 up-regulation warrant further studies.

Polar lipids were extracted from residual biomass of hemp (Cannabis sativa L.) by-products with EtOH and partitioned into aqueous and chloroform fractions. The chloroform fractions were studied for their lipid composition using solid-phase extraction (SPE) followed by UHPLC/HRMS and NMR analyses. The 1H NMR and gravimetric yield of SPE indicated triacylglycerols covered ≥ 51.3% of the chloroform fraction of hemp seed hulls and hemp cake. UHPLC/HRMS analyses of remaining polar lipids led to the identification of nine diacylglycerols (DAGs), six lysophosphatidylcholines (LPCs), five lysophosphatidylethanolamines (LPEs), eight phosphatidylethanolamines (PEs), and thirteen phosphatidylcholines (PCs) for the first time from hemp seed hulls. The regiospecificity of fatty acyl substitutes in glycerol backbone of individual phospholipids were assigned by analyzing the diagnostic fragment ions and their intensities. The heat-map analysis suggested that DAG 18:2/18:2, 1-LPC 18:2, 1-LPE 18:2, PE 18:2/18:2, and PC 18:2/18:2 were the predominant molecules within their classes, supported by the fact that linoleic acid was the major fatty acid covering > 41.1% of the total fatty acids determined by GC-FID analysis. The 31P NMR analysis confirmed the identification of phospholipids and suggested PC covers ≥ 37.9% of the total phospholipid present in hemp by-products. HPLC purification led to the isolation of 1,2-dilinoleoylphosphatidylcholine and 1-palmitoyl-2-linoleoylphosphatidylcholine. These two major PCs further confirmed the UHPLC/HRMS finding.

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that has been shown to interact with many organisms throughout the domains of life, including plants. How this broad-host-range bacterium interacts with each of its diverse hosts, especially the metabolites that mediate these interactions, is not completely known. In this work, we used a liquid culture root infection system to collect plant and bacterial metabolites on days 1, 3 and 5 post- P . aeruginosa (strain PA14) infection of the oilseed plant, canola (Brassica napus). Using MS-based metabolomics approaches, we identified the overproduction of quorum sensing (QS)-related (both signalling molecules and regulated products) metabolites by P. aeruginosa while interacting with canola plants. However, the P. aeruginosa infection induced the production of several phytoalexins, which is a part of the hallmark plant defence response to microbes. The QS system of PA14 appears to only mediate part of the canola–P. aeruginosa metabolomic interactions, as the use of isogenic mutant strains of each of the three QS signalling branches did not significantly affect the induction of the phytoalexin brassilexin, while induction of spirobrassinin was significantly decreased. Interestingly, a treatment of purified QS molecules in the absence of bacteria was not able to induce any phytoalexin production, suggesting that active bacterial colonization is required for eliciting phytoalexin production. Furthermore, we identified that brassilexin, the only commercially available phytoalexin that was detected in this study, demonstrated a MIC of 400 µg ml−1 against P. aeruginosa PA14. The production of phytoalexins can be an effective component of canola innate immunity to keep potential infections by the opportunistic pathogen P. aeruginosa at bay.

Study Objectives No study has yet examined the prevalence of frequent nightmares in representative youth populations in Asia and how they may contribute to future mental health risks. We aimed to fill this gap using data from a large-scale household-based youth sample in Hong Kong. Methods Participants were consecutively recruited from a large-scale epidemiological youth mental health study in Hong Kong (n = 3132). A subset of participants were invited for a follow-up assessment after 1 year (n = 1154 in the final analyses). Frequent nightmares (≥1/week during the past month) were assessed using an item from the Pittsburgh Sleep Quality Index. Univariate analyses and multivariable logistic regression models were applied to examine the contribution of frequent nightmares at baseline to moderate-to-severe depressive and anxiety symptoms, post-traumatic stress disorder symptoms, and 30-day major depressive episode (MDE) or generalized anxiety disorder (GAD), both at baseline and follow-up. The long-term functional implications of frequent nightmares were also examined. Results The prevalence of frequent nightmares was 16.3%. Females were more likely to experience frequent nightmares (20.4%) compared to males (12.1%), p < 0.001. Baseline frequent nightmares were significantly associated with all four mental health outcomes at 1 year. Notably, their prospective associations with depressive and anxiety symptoms and 30-day MDE/GAD remained significant even after adjusting for external stressors, resilience, and sociodemographic characteristics. Frequent nightmares were also significantly associated with both current and 1-year functional impairments. Conclusions Frequent nightmares have significant long-term implications on mental health and functioning. Identifying young adults with frequent nightmares can improve early risk detection and intervention in the population.

Polar lipids were extracted from residual biomass of hemp (

Chenzhe Gao,1,2,* Shen Yu,2,* Xiaonan Zhang,3 Yanxin Dang,2,4 Dan-dan Han,2 Xin Liu,2,5 Janchun Han,1 Mizhou Hui1 1Food Science College, Northeast Agricultural University, Harbin, People’s Republic of China; 2Department of Pharmaceutical Engineering, School of Materials Science and Chemical Engineering, Key Laboratory of Green Chemical Engineering in Heilongjiang Province, Harbin University of Science and Technology, Harbin, People’s Republic of China; 3College of Biological and Food Engineering, Guangdong University of Petrochemical Technology, Maoming, People’s Republic of China; 4Pharmacy Department, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China; 5Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut, USA*These authors contributed equally to this workCorrespondence: Xin LiuDepartment of Pharmaceutical Engineering, School of Materials Science and Chemical Engineering, Key Laboratory of Green Chemical Engineering in Heilongjiang Province, Harbin University of Science and Technology, Harbin, 150040, People’s Republic of ChinaTel +86 451-86392728Fax +86 451-86392710Email xinliu98@126.comJanchun HanFood Science College, Northeast Agricultural University, Harbin, 150030, People’s Republic of ChinaTel/Fax +86 451-55190716Email hanjianchun@neau.edu.cnAim: Iridoid glycosides (IG) as the major active fraction of Syringa oblata Lindl. has a proven anti-inflammatory effect for ulcerative colitis (UC). However, its current commercial formulations are hampered by low bioavailability and unable to reach inflamed colon. To overcome the limitation, dual functional IG-loaded nanoparticles (DFNPs) were prepared to increase the residence time of IG in colon. The protective mechanism of DFNPs on DSS-induced colonic injury was evaluated in rats.Materials and Methods: We prepared DFNPs using the oil-in-water emulsion method. PLGA was selected as sustained-release polymer, and ES100 and EL30D-55 as pH-responsive polymers. The morphology and size distribution of NPs were measured by SEM and DLS technique. To evaluate colon targeting of DFNPs, DiR, was encapsulated as a fluorescent probe into NPs. Fluorescent distribution of NPs were investigated. The therapeutic potential and in vivo transportation of NPs in gastrointestinal tract were evaluated in a colitis model.Results: SEM images and zeta data indicated the successful preparation of DFNPs. This formulation exhibited high loading capacity. Drug release results suggested DFNPs released less than 20% at the first 6 h in simulated gastric fluid (pH1.2) and simulated small intestine fluid (pH6.8). A high amount of 84.7% sustained release from NPs in simulated colonic fluid (pH7.4) was beyond 24 h. DiR-loaded NPs demonstrated a much higher colon accumulation, suggesting effective targeting due to functionalization with pH and time-dependent polymers. DFNPs could significantly ameliorate the colonic damage by reducing DAI, macroscopic score, histological damage and cell apoptosis. Our results also proved that the potent anti-inflammatory effect of DFNPs is contributed by decrease of NADPH, gene expression of COX-2 and MMP-9 and the production of TNF-α, IL-17, IL-23 and PGE2.Conclusion: We confirm that DFNPs exert protective effects through inhibiting the inflammatory response, which could be developed as a potential colon-targeted system.Keywords: iridoid glycoside, ulcerative colitis, Syringa oblata Lindl., pH-sensitive and time-dependent, colon-targeted nanoparticles

Graphical abstract, Highlights • Brusatol affects migration and invasion ability of HCC cells. • Brusatol affects EMT process through modulation of STAT3 activation pathway. • Brusatol mitigates tumorigenesis and metastasis in HCC preclinical model., Introduction Epithelial-mesenchymal transition (EMT) is a process of transdifferentiation where epithelial cells attain mesenchymal phenotype to gain invasive properties and thus, can contribute to metastasis of tumor cells. Objectives The antimetastatic and antitumor efficacy of brusatol (BT) was investigated in a hepatocellular carcinoma (HCC) model. Methods We evaluated the action of BT on EMT process using various biological assays in HCC cell lines and its effect on tumorigenesis in an orthotopic mouse model. Results We found that BT treatment restored the expression of Occludin, E-cadherin (epithelial markers) while suppressing the levels of different mesenchymal markers in HCC cells and tumor tissues. Moreover, we observed a decline in the expression of transcription factors (Snail, Twist). Since the expression of these two factors can be regulated by STAT3 signaling, we deciphered the influence of BT on modulation of this pathway. BT suppressed the phosphorylation of STAT3Y705 and STAT3 depletion using siRNA resulted in the restoration of epithelial markers. Importantly, BT (1mg/kg) reduced the tumor burden in orthotopic mouse model with a concurrent decline in lung metastasis. Conclusions Overall, our results demonstrate that BT interferes with STAT3 induced metastasis by altering the expression of EMT-related proteins in HCC model.

This study applies OLS, panel regression and Granger causality test to investigate the impact of the Coronavirus disease 2019 (Covid-19) outbreak on the global equity markets during the early stage of the pandemic. We find that the Covid-19 outbreak has a significant negative impact on the overall equity index return of the eight economies even at 0.1% significance level. Furthermore, the pandemic has a more significant impact on the European countries than on the East Asian economies. The results have three main implications. Firstly, policy makers should react fast to mitigate the impact of a crisis. Secondly, investors should be aware of an outbreak of disease or other risks and adjust their investments accordingly. Furthermore, the Covid-19 outbreak results in a shift of power from the west to the east.

Hong Kong's existing mental health services are inadequate in addressing young people's needs. The LevelMind@JC project established an early intervention platform of community-based youth-specific mental health centres involving youth workers, cross-disciplinary professionals, and young people. The project intends to (1) pilot a community platform that incorporates a youth-friendly early screening tool with preventative intervention capabilities, (2) set up a state-of-the-art training system for youth mental health workers, (3) establish a community clinical support team and (4) develop a timely evaluation system to monitor the service and evaluate its outcome and cost-effectiveness against generic youth services.Six hundred LevelMind@JC service users will be assessed alongside 600 young people visiting generic youth centres and 100 young people in the community. Participants will be matched according to age, gender, years of education, socioeconomic status, and level of distress. Assessments, administered at baseline and at 3, 6 and 12 months, will cover demographic characteristics, psychological distress, quality of life, depressive and anxiety symptoms, functioning, physical health and lifestyle, personality and social measures, cognitive measures and health economics. Mixed-model ANOVAs will be used to indicate interactions between services and between time points.Built upon a community-based support model, LevelMind@JC aims to promote positive mental health in young people through the collaboration of cross-disciplinary mental health professionals. If efficacy and cost-effectiveness are established, the project could be scaled up, implicating a wider reach of care. We anticipate its success to be critical in combatting mental health issues stemming from both personal and population-level stressors.

Background Whole-plant cannabis extracts are consumed by the public for medical and non-medical (“recreational”) purposes but are poorly researched compared to pure cannabinoids. There is emerging evidence that cannabis extracts comprising complex mixtures of cannabinoids may have different biological effects from that of pure cannabinoids. In the current study, we sought to assess the effect of whole-plant cannabis extracts produced from different chemotypes of cannabis on the normal behavior of zebrafish larvae. Methods Three cannabis plant chemotypes were used in this study that contained either high amounts of THC, high amounts of CBD, high but equal amounts of THC and CBD, or low but equal amounts of THC and CBD. Following solvent extraction, liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) was performed for the detection and quantitation of target cannabinoids. Larval zebrafish behavioral models were subsequently used to assess the effect of the four different whole-plant cannabis extracts on the normal larval behavior using the DanioVision behavioral tracking systems and software. To compare, changes in the behavior activity levels for 30 min periods were compared to controls using 2-way ANOVA with multiple comparisons followed by a Bonferroni post hoc test. Results It was found that the whole-plant extracts that contained high levels of THC had similar effects on larval behavior, while the high CBD and low THC:CBD extracts produced distinct effects on normal larval behavior. Exposure of larvae to concentration-matched levels of THC and CBD found in the extracts revealed that a subset of the cannabis extracts tested had similar behavioral profiles to the pure cannabinoids while others did not. Conclusions To our knowledge, this is the first study to test and compare the bioactivity of different whole-plant cannabis extracts in larval zebrafish. This work will provide a framework for future studies of distinct cannabis extracts and will be useful for comparing the bioactivity of extracts from different cannabis chemotypes as well as extracts made through various heating processes. It will also act as the first stage of assessment before testing the extracts against zebrafish models of toxicity and disease.

Pseudoalteromonas is a globally distributed marine-associated genus that can be found in a broad range of aquatic environments, including in association with macroalgal surfaces where they may take advantage of these rich sources of polysaccharides. The metabolic systems that confer the ability to metabolize this abundant form of photosynthetically fixed carbon, however, are not yet fully understood. Through genomics, transcriptomics, microbiology, and specific structure-function studies of pathway components we address the capacity of newly isolated marine pseudoalteromonads to metabolize the red algal galactan carrageenan. The results reveal that the κ/ι-carrageenan specific polysaccharide utilization locus (CarPUL) enables isolates possessing this locus the ability to grow on this substrate. Biochemical and structural analysis of the enzymatic components of the CarPUL promoted the development of a detailed model of the κ/ι-carrageenan metabolic pathway deployed by pseudoalteromonads, thus furthering our understanding of how these microbes have adapted to a unique environmental niche., Hettle et al. investigate the ability of marine Pseudoalteromonas sp. to metabolise carrageenan, a polysaccharide abundant in red algae. They isolate and characterise previously unstudied strains and find that the recently identified κ/ι-carrageenan specific polysaccharide utilization locus (CarPUL) is required for growth on carrageenan, and biochemically map out many of the steps.

Hepatocellular carcinoma (HCC) is a common and deadly cancer with limited treatment options. Through genome-wide growth depletion screens using clustered regularly interspaced short palindromic repeats and expression profiling of primary HCC tumors, we identified 13 clinically relevant target genes with therapeutic potential. Subsequent functional annotation analysis revealed significant enrichment of these 13 genes in the cell cycle, cell death, and survival pathways. Non–structural maintenance of chromosomes condensin I complex subunit G (NCAPG) was ranked the highest among the depletion screens and multiple HCC expression datasets. Transient inhibition of NCAPG using specific small interfering RNAs resulted in a significant reduction in cell growth, migration, and the down-regulation of mitochondrial gene expression in vitro. Small homologous RNA–mediated knockdown of NCAPG significantly impaired cell viability, caused aberrant mitotic division, fragmented the mitochondrial network, and increased cell death in vitro. HCC cells with a reduced expression of NCAPG formed significantly smaller xenograft tumors in vivo. Importantly, high NCAPG expression was significantly associated with poorer overall and disease-free survival in HCC patients. High NCAPG expression is a novel prognostic biomarker to predict HCC early recurrence after surgical resection. In conclusion, NCAPG is an essential gene for HCC tumor cell survival. It represents a promising novel target for treating HCC and a prognostic biomarker for clinical management of HCC.—Wang, Y., Gao, B., Tan, P. Y., Handoko, Y. A., Sekar, K., Deivasigamani, A., Seshachalam, V. P., OuYang, H.-Y., Shi, M., Xie, C., Goh, B. K. P., Ooi, L. L., Hui, K. M. Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth.

The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review.

Early tumor recurrence after curative surgical resection poses a great challenge to the clinical management of hepatocellular carcinoma (HCC). We conducted whole genome expression microarrays on 64 primary HCC tumors with clinically defined recurrence status and cross-referenced with RNA-seq data from 18 HCC tumors in the Cancer Genome Atlas project. We identified a 77-gene signature, which is significantly associated with early recurrent (ER) HCC tumors. This ER-associated signature shows significant enrichment in genes involved in cell cycle pathway. We performed receiver operating characteristic (ROC) analysis to evaluate the prognostic biomarker potential of these 77 genes and Pearson correlation analysis to identify 11 close clusters. The one gene with the best area under the ROC curve in each of the 11 clusters was selected for validation using reverse-transcription quantitative PCR in an independent cohort of 24 HCC tumors. NUF2 was identified to be the minimal biomarker sufficient to discriminate ER tumors from LR tumors. NUF2 in combination with liver cirrhosis could significantly improve the detection of ER tumors with an AUROC of 0.82 and 0.85 in the test and validation cohort, respectively. In conclusion, NUF2 in combination with liver cirrhosis is a promising prognostic biomarker for early HCC recurrence.

本文报道PKLR 基因新突变致红细胞丙酮酸激酶缺乏症一例。患者男性26岁，表现为重度黄疸、脾大、胆囊结石、血红蛋白水平正常。UTG1A1基因及全外显子突变检测排除Gilbert综合征等先天性胆红素代谢性疾病，考虑存在慢性代偿性溶血继发黄疸，全外显子测序证实为PKLR基因复合杂合突变导致的红细胞丙酮酸激酶缺乏症（pyruvate kinase deficiency，PKD）。肝穿刺活检提示PKD患者肝脏含铁血黄素沉积可导致慢性肝损害。PKLR基因变异Exon6 c.758AG（p.Asn253Ser）为本例首次报道。.

Prostate cancer (PCa) is a common disease among men especially in the old age. The deregulated activation of oncogenic and pro-survival transcription factors has been linked with tumor progression in PCa patients. The consequence of diosgenin treatment on NF-κB/STAT3 activation in PCa cells as well as transgenic mouse model was determined. We also validated the hypothesis of targeting these transcription factors using in silico proteomics simulation model. Diosgenin abrogated NF-κB/STAT3 activation and this action was caused as a result of suppression of protein kinases and reporter gene activity that led to a substantial reduction in the expression of various tumorigenic gene products. In vivo, diosgenin (2% w/w) when mixed in diet and fed to mice abrogated tumor progression in transgenic mice. Diosgenin was also detected in serum and was well absorbed orally. Overall, our data highlights the promising efficacy of diosgenin in PCa therapy.

Cytokinesis, the final step of mitosis, is critical for maintaining the ploidy level of cells. Cytokinesis is a complex, highly regulated process and its failure can lead to genetic instability and apoptosis, contributing to the development of cancer. Human hepatocellular carcinoma is often accompanied by a high frequency of aneuploidy and the DNA ploidy pattern observed in human hepatocellular carcinoma results mostly from impairments in cytokinesis. Many key regulators of cytokinesis are abnormally expressed in human hepatocellular carcinoma, and their expression levels are often correlated with patient prognosis. Moreover, preclinical studies have demonstrated that the inhibition of key cytokinesis regulators can suppress the growth of human hepatocellular carcinoma. Here, we provide an overview of the current understanding of the signaling networks regulating cytokinesis, the key cytokinesis regulators involved in the initiation and development of human hepatocellular carcinoma, and their applications as potential diagnostic and therapeutic biomarkers.

Cosmological Gamma-Ray Bursts (GRBs) are known to arise from distinct progenitor channels: short GRBs mostly from neutron star mergers and long GRBs from a rare type of core-collapse supernova (CCSN) called collapsars. Highly magnetized neutron stars called magnetars also generate energetic, short-duration gamma-ray transients called Magnetar Giant Flares (MGFs). Three have been observed from the Milky Way and its satellite galaxies and they have long been suspected to contribute a third class of extragalactic GRBs. We report the unambiguous identification of a distinct population of 4 local ($$99.9% confidence. These properties, the host galaxies, and non-detection in gravitational waves all point to an extragalactic MGF origin. Despite the small sample, the inferred volumetric rates for events above $4\times10^{44}$ erg of $R_{MGF}=3.8_{-3.1}^{+4.0}\times10^5$ Gpc$^{-3}$ yr$^{-1}$ place MGFs as the dominant gamma-ray transient detected from extragalactic sources. As previously suggested, these rates imply that some magnetars produce multiple MGFs, providing a source of repeating GRBs. The rates and host galaxies favor common CCSN as key progenitors of magnetars., Comment: Accepted for publication in ApJL. Updated versions fix typos in the table and updates citations to published versions

Aims Brief measurements of the subjective experience of stress with good predictive capability are important in a range of community mental health and research settings. The potential for large-scale implementation of such a measure for screening may facilitate early risk detection and intervention opportunities. Few such measures however have been developed and validated in epidemiological and longitudinal community samples. We designed a new single-item measure of the subjective level of stress (SLS-1) and tested its validity and ability to predict long-term mental health outcomes of up to 12 months through two separate studies. Methods We first examined the content and face validity of the SLS-1 with a panel consisting of mental health experts and laypersons. Two studies were conducted to examine its validity and predictive utility. In study 1, we tested the convergent and divergent validity as well as incremental validity of the SLS-1 in a large epidemiological sample of young people in Hong Kong (n = 1445). In study 2, in a consecutively recruited longitudinal community sample of young people (n = 258), we first performed the same procedures as in study 1 to ensure replicability of the findings. We then examined in this longitudinal sample the utility of the SLS-1 in predicting long-term depressive, anxiety and stress outcomes assessed at 3 months and 6 months (n = 182) and at 12 months (n = 84). Results The SLS-1 demonstrated good content and face validity. Findings from the two studies showed that SLS-1 was moderately to strongly correlated with a range of mental health outcomes, including depressive, anxiety, stress and distress symptoms. We also demonstrated its ability to explain the variance explained in symptoms beyond other known personal and psychological factors. Using the longitudinal sample in study 2, we further showed the significant predictive capability of the SLS-1 for long-term symptom outcomes for up to 12 months even when accounting for demographic characteristics. Conclusions The findings altogether support the validity and predictive utility of the SLS-1 as a brief measure of stress with strong indications of both concurrent and long-term mental health outcomes. Given the value of brief measures of mental health risks at a population level, the SLS-1 may have potential for use as an early screening tool to inform early preventative intervention work.

We present the systematic spectral analyses of gamma-ray bursts (GRBs) detected by the Fermi Gamma-Ray Burst Monitor during its first ten years of operation. This catalog contains two types of spectra: time-integrated spectral fits and spectral fits at the brightest time bin, from 2297 GRBs, resulting in a compendium of over 18,000 spectra. The four different spectral models used for fitting the spectra were selected based on their empirical importance to the shape of many GRBs. We describe in detail our procedure and criteria for the analyses, and present the bulk results in the form of parameter distributions both in the observer frame and in the GRB rest frame. 941 GRBs from the first four years have been refitted using the same methodology as that of the 1356 GRBs in years five through ten. The data files containing the complete results are available from the High-Energy Astrophysics Science Archive Research Center.

A new dihydrophenanthrene derivative namely 9,10-dihydro-5-hydroxy-2, 3,6-trimethoxyphenanthrene-1,4-dione (1) was isolated from commercial cannabis product together with 4,5-dihydroxy-2,3,6-trimethoxy-9,10-dihydrophenanthrene (2), 4-hydroxy-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrene (3), combretastatin B-2 (4) and isocannbispiradienone (5). Structure elucidation of the isolated compounds were done based on the interpretation of the mass spectrometry (MS) and nuclear magnetic resonance (NMR) data. New dihydrophenanthrene derivative (1) was tested for its effect on zebrafish larval behaviour. Preliminary results suggested that the new dihydrophenanthrene derivative (1) exhibits similar effect on zebrafish larval behaviour as cannabidiol (CBD), a biologically active component of Cannabis.

Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. The centromere proteins (CENPs) are critical for the mitosis-related protein complex and are involved in kinetochore assembly and spindle checkpoint signaling during mitosis. However, the clinical significance of CENPs in the recurrence and progression of HCC remains poorly understood. Here, we examined the expression of all CENPs and their association with recurrence and survival of HCC patients using the global gene expression profile dataset established in our laboratory. The effect of silencing CENPF on cell viability, migration, and epithelial-mesenchymal transition (EMT) were detected using CCK-8, transwell, and western blot, respectively. RT-qPCR and western blot were performed to confirm the silencing of CENPF and the relationship between STAT5A and CENPF, while tumorigenesis was tested using the HCC Huh7 xenograft mouse model. Most of the CENPs is overexpressed in HCC, and overexpression of CENPF was significantly associated with the poor survival of HCC patients. CENPF promoted HCC cell lines migration and EMT progression. Knockdown CENPF inhibited cell growth activity against human HCC cells in vitro and xenograft tumors in vivo. Bioinformatics analysis revealed that CENPF genes are enriched in the cell cycle. Silencing CENPF arrested cell cycle at the G2/M phase and inhibited Cyclin B1 and Cyclin E1 expressions. Meanwhile, silencing CENPF prohibited phosphorylation of ERK and the expression of NEK2. Additionally, we found that STAT5A down-regulated CENPF expression and inhibited cancer cell growth viability. In conclusion, our data suggested that CENPF could be potentially developed into a theranostic biomarker to tackle HCC progression.

Mannitol is abundant in a wide range of organisms, playing important roles in biotic and abiotic stress responses. Nonetheless, mannitol is not produced by a vast majority of plants, including many important crop plants. Mannitol-producing transgenic plants displayed improved tolerance to salt stresses though mannitol production was rather low, in the &micro, M range, compared to mM range found in plants that innately produce mannitol. Little is known about the molecular mechanisms underlying salt tolerance triggered by low concentrations of mannitol. Reported here is the production of mannitol in Arabidopsis thaliana, by expressing two mannitol biosynthesis genes from the brown alga Ectocarpus sp. strain Ec32. To date, no brown algal genes have been successfully expressed in land plants. Expression of mannitol-1-phosphate dehydrogenase and mannitol-1-phosphatase genes was associated with the production of 42.3&ndash, 52.7 nmol g&minus, 1 fresh weight of mannitol, which was sufficient to impart salinity and temperature stress tolerance. Transcriptomics revealed significant differences in the expression of numerous genes, in standard and salinity stress conditions, including genes involved in K+ homeostasis, ROS signaling, plant development, photosynthesis, ABA signaling and secondary metabolism. These results suggest that the improved tolerance to salinity stress observed in transgenic plants producing mannitol in &micro, M range is achieved by the activation of a significant number of genes, many of which are involved in priming and modulating the expression of genes involved in a variety of functions including hormone signaling, osmotic and oxidative stress, and ion homeostasis.

Rationale: Protein kinases are critical therapeutic targets for curing hepatocellular carcinoma (HCC). As a serine/threonine kinase, the potential roles of serine/threonine kinase 39 (STK39) in HCC remain to be explored. Methods: The expression of STK39 was examined by RT-qPCR, western blotting and immunohistochemistry. Cell proliferation and apoptosis were detected by CCK8 and TUNEL kit. Cell migration and invasion assays were performed using a transwell system with or without Matrigel. RNA-seq, mass spectrometry and luciferase reporter assays were used to identify STK39 binding proteins. Results: Here, we firstly report that STK39 was highly overexpressed in clinical HCC tissues compared with adjacent tissues, high expression of STK39 was induced by transcription factor SP1 and correlated with poor patient survival. Gain and loss of function assays revealed that overexpression of STK39 promoted HCC cell proliferation, migration and invasion. In contrast, the depletion of STK39 attenuated the growth and metastasis of HCC cells. Moreover, knockdown of STK39 induced the HCC cell cycle arrested in the G2/M phase and promoted apoptosis. In mechanistic studies, RNA-seq revealed that STK39 positively regulated the ERK signaling pathway. Mass spectrometry identified that STK39 bound to PLK1 and STK39 promoted HCC progression and activated ERK signaling pathway dependent on PLK1. Conclusions: Thus, our study uncovers a novel role of STK39/PLK1/ERK signaling axis in the progress of HCC and suggests STK39 as an indicator for prognosis and a potential drug target of HCC.

The High Altitude Water Cherenkov observatory (HAWC) is an air shower array devised for TeV gamma-ray astronomy. HAWC is located at an altitude of 4100 m a.s.l. in Sierra Negra, Mexico. HAWC consists of 300 Water Cherenkov Detectors, each instrumented with 4 photomultiplier tubes (PMTs). HAWC re-uses the Front-End Boards from the Milagro experiment to receive the PMT signals. These boards are used in combination with Time to Digital Converters (TDCs) to record the time and the amount of light in each PMT hit (light flash). A set of VME TDC modules (128 channels each) is operated in a continuous (dead time free) mode. The TDCs are read out via the VME bus by Single-Board Computers (SBCs), which in turn are connected to a gigabit Ethernet network. The complete system produces ~ 500 MB/s of raw data. A high-throughput data processing system has been designed and built to enable real-time data analysis. The system relies on off-the-shelf hardware components, an open-source software technology for data transfers (ZeroMQ) and a custom software framework for data analysis (AERIE). Multiple trigger and reconstruction algorithms can be combined and run on blocks of data in a parallel fashion, producing a set of output data streams which can be analyzed in real time with minimal latency (< 5 s). This paper provides an overview of the hardware set-up and an in-depth description of the software design, covering both the TDC data acquisition system and the real-time data processing system. The performance of these systems is also discussed., 14 pages, 3 figures, submitted to Nucl. Instrum. Meth. A