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Different scenarios of precipitation, that lead to such phenomena as droughts and floods are influenced by concurrent multiple teleconnection factors. However, the multivariate relationship between precipitation indices and teleconnection factors, including large-scale atmospheric circulations and sea surface temperature signals in China, is rarely explored. Understanding this relationship is crucial for drought early warning systems and effective response strategies. In this study, we comprehensively investigated the combined effects of multiple large-scale atmospheric circulation patterns on precipitation changes in China. Specifically, Pearson correlation analysis and Partial Wavelet Coherence (PWC) were used to identify the primary teleconnection factors influencing precipitation dynamics. Furthermore, we used the cross-wavelet method to elucidate the temporal lag and periodic relationships between multiple teleconnection factors and their interactions. Finally, the multiple wavelet coherence analysis method was used to identify the dominant two-factor and three-factor combinations shaping precipitation dynamics. This analysis facilitated the quantification and determination of interaction types and influencing pathways of teleconnection factors on precipitation dynamics, respectively. The results showed that: (1) the Atlantic Multidecadal Oscillation (AMO), EI Niño-Southern Oscillation (ENSO), East Asia Summer Monsoon (EASM), and Indian Ocean Dipole (IOD) were dominant teleconnection factors influencing Standardized Precipitation Index (SPI) dynamics; (2) significant correlation and leading or lagging relationships at different timescales generally existed for various teleconnection factors, where AMO was mainly leading the other factors with positive correlation, while ENSO and Southern Oscillation (SO) were mainly lagging behind other factors with prolonged correlations; and (3) the interactions between teleconnection factors were quantified into three types: enhancing, independent and offsetting effects. Specifically, the enhancing effect of two-factor combinations was stronger than the offsetting effect, where AMO + NAO (North Atlantic Oscillation) and AMO + AO (Atlantic Oscillation) had a larger distribution area in southern China. Conversely, the offsetting effect of three-factor combinations was more significant than that of the two-factor combinations, which was mainly distributed in northeast and northwest regions of China. This study sheds new light on the mechanisms of modulation and pathways of influencing various large-scale factors on seasonal precipitation dynamics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) cell-intrinsic programmed death 1 (PD-1) promotes tumor progression. However, the mechanisms that regulate its expression are unclear. This study investigated the impact of alpha-fetoprotein (AFP) on HCC cell-intrinsic PD-1 expression., Methods: The expression of PD-1 and AFP at the gene and protein levels was detected using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). Proteins interacting with AFP were examined by co-immunoprecipitation (CO-IP). Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were used to identify transcription-enhanced association domain 1 (TEAD1) binding to the promoter of PD-1., Results: The expression of HCC cell-intrinsic PD-1 was positively correlated with AFP. Mechanistically, AFP inhibited the phosphorylation of large tumor suppressor 2 (LATS2) and yes-associated protein (YAP). As a result, YAP is transferred to the nucleus and forms a transcriptional complex with TEAD1, promoting PD-1 transcription by binding to its promoter., Conclusion: AFP is an upstream regulator of the HCC cell-intrinsic PD-1 and increases PD-1 expression via the LATS2/YAP/TEAD1 axis., General: Our findings provide insight into the mechanisms of HCC development and offer new ideas for further in-depth studies of HCC., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest regarding the publication of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have no interests to declare.

Background: The fully phosphorothioate-modified oligonucleotide (OGN) nusinersen has low ionization efficiency in the negative ion mode, resulting in a low mass spectrometry response. There have been no relevant reports on developing a LC-MS method for the determination of nusinersen by optimizing mobile phase composition. Materials & methods: Mobile phase additives comprised of 15 mM triethylamine/25 mM 1,1,1,3,3,3-hexafluoro-2-propanol with a pH of 9.6. Nusinersen was extracted from plasma using Oasis ® HLB solid-phase extraction (Waters, MA, USA). Results & conclusion: By adjusting the pH of the mobile phase to 9.6 by optimizing the type and concentration of ion-pair reagents, a high mass spectrometry response was obtained. The developed method was applied to nusinersen and met the requirements for the pharmacokinetic study of nusinersen in rabbits.

Oxytocin is a pleiotropic neuropeptide that plays roles in biological processes ranging from birth, lactation, and social bonding to immune function, cardiovascular repair, and regulation of appetite. Although measurements of endogenous oxytocin concentrations have been performed for more than 50 years, the ability to measure oxytocin accurately poses notable challenges. One potential solution for overcoming these challenges involves measurement of oxytocin's carrier molecule - neurophysin I (NP-1) - as a surrogate biomarker. NP-1 is secreted in equimolar concentrations with oxytocin but has a longer half-life, circulates in higher concentrations, and can be measured using a sandwich immunoassay. We report experiments that 1) analytically validate a commercially available NP-1 sandwich immunoassay for use with human plasma and urine samples, 2) confirm the specificity of this assay, based on detection of NP-1 in plasma from wild-type but not oxytocin knockout mice, 3) demonstrate that NP-1 concentrations are markedly elevated in late pregnancy, consistent with studies showing substantial increases in plasma oxytocin throughout gestation, and 4) establish strong correlation between NP-1 and plasma oxytocin concentrations when oxytocin is measured in extracted (but not non-extracted) plasma. The NP-1 assay used in this study has strong analytical properties, does not require time-intensive extraction protocols, and the assay itself can be completed in < 2 h (compared to 16-24 h for a competitive oxytocin immunoassay). Our findings suggest that much like copeptin has become a useful surrogate biomarker in studies of vasopressin, measurements of NP-1 have similar potential to advance oxytocin research., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The development of drought has spatial and temporal synchronization. Previous studies usually explore the spatial and temporal evolution of drought separately. Moreover, existing approaches are based on a fixed overlapping area and do not consider the variable drought cluster area during development. This study proposes an improved and simple approach to derive dynamic overlapping area threshold for 3-dimensional droughts extraction. Based on the one monthly Nonparametric Standardized Precipitation Index (NSPI), this improved approach was applied for investigating the migration characteristics of meteorological drought events in the Loess Plateau of China. Then, Random Forest and Extreme Gradient Boosting model with Shapley additive explanation values were used to quantify the importance of driving factors on the dynamics of drought characteristics. The results showed that: (1) the improved approach has a better performance on identifying prolonged droughts than the method using a fixed overlap area threshold; (2) spatially, meteorological drought events with high severity (DS), long duration (DD), large effected area (DA) and fast migration velocity (DV) mainly occur in the central region; (3) temporally, droughts are expected to aggravate with significantly increased DS and DA which are mainly caused by increased temperature and vegetation; and (4) meteorological droughts have a preferred westward migration direction and three dominant migration paths, which are crucial for local drought prevention and control. The findings of this study provide new perspectives on drought migration characteristics, which are important for the exploration of drought-driven mechanisms, risk assessment and future prediction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Soil texture is one of the most important indicators of soil physical properties, which has traditionally been measured through laborious procedures. Approaches utilizing visible near-infrared spectroscopy, with their advantages in efficiency, eco-friendliness and non-destruction, are emerging as potent alternatives. Nevertheless, these approaches often suffer from limitations in classification accuracy, and the substantial impact of spectral preprocessing, model integration, and sample matrix effect is commonly disregarded. Here a novel 11-class soil texture classification strategy that address this challenge by combining Multiplicative Scatter Correction (MSC) with Residual Network (ResNet) models was presented, resulting in exceptional classification accuracy. Utilizing the LUCAS dataset, collected by the Land Use and Cover Area frame Statistical Survey project, we thoroughly evaluated eight spectral preprocessing methods. Our findings underscored the superior performance of MSC in reducing spatial complexity within spectral data, showcasing its crucial role in enhancing model precision. Through comparisons of three 1D CNN models and two ResNet models integrated with MSC, we established the superior performance of the MSC-incorporated ResNet model, achieving an overall accuracy of 98.97 % and five soil textures even reached 100.00 %. The ResNet model demonstrated a marked superiority in classifying datasets with similar features, as observed by the confusion matrix analysis. Moreover, we investigated the potential benefit of pre-categorization based on land cover type of the soil samples in enhancing the accuracy of soil texture classification models, achieving overall classification accuracies exceeding 99.39 % for woodland, grassland, and farmland with the 2-layer ResNet model. The proposed work provides a pioneering and efficient strategy for rapid and precise soil texture identification via visible near-infrared spectroscopy, demonstrating unparalleled accuracy compared to existing methods, thus significantly enhancing the practical application prospects in soil, agricultural and environmental science., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Geng Leng reports financial support was provided by National Natural Science Foundation of China. Geng Leng reports financial support was provided by Sichuan Science and Technology Program. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Biofilm dispersal contributes to bacterial spread and disease transmission. However, its exact mechanism, especially that in the pathogen Mycobacterium tuberculosis , is unclear. In this study, the cellulase activity of the M. tuberculosis Rv0062 protein was characterized, and its effect on mycobacterial biofilm dispersal was analyzed by observation of the structure and components of Rv0062-treated biofilm in vitro. Meanwhile, the metabolite factors that induced cellulase-related biofilm dispersal were also explored with metabolome analysis and further validations. The results showed that Rv0062 protein had a cellulase activity with a similar optimum pH (6.0) and lower optimum temperature (30 °C) compared to the cellulases from other bacteria. It promoted mycobacterial biofilm dispersal by hydrolyzing cellulose, the main component of extracellular polymeric substrates of mycobacterial biofilm. A metabolome analysis revealed that 107 metabolites were significantly altered at different stages of M. smegmatis biofilm development. Among them, a decrease in gamma-aminobutyric acid (GABA) promoted cellulase-related biofilm dispersal, and this effect was realized with the down-regulation of the bacterial signal molecule c-di-GMP. All these findings suggested that cellulase promotes mycobacterial biofilm dispersal and that this process is closely associated with biofilm metabolite alterations.

There are complex bidirectional feedback relationships among different types of droughts (e.g., meteorological and agricultural droughts). As agricultural drought intensifies, meteorological drought response to agricultural drought may be changed from negative to positive feedback. Nevertheless, the negative-positive feedback transition thresholds of meteorological drought in response to agricultural drought and their dynamics have remained unsolved. Herein, we proposed a new quantitative method to characterize the mutual feedback between meteorological drought and agricultural drought based on the vine copula function for the first time in this study. The negative-positive feedback transition threshold and the sensitivity of the feedback were quantified under certain drought conditions. In order to investigate the feedback relationship dynamics under a changing environment, the total study period was evenly divided into two stages: stage 1 (1982-1999) and stage 2 (2000-2018). Finally, the random forest method was used to explore the dominant factors on the transition threshold. Results indicate that: (1) the negative-positive feedback transition thresholds in August is generally lower than June and July in mainland China, the basin with large threshold is the Southwest River Basin; (2) the sensitivity of meteorological drought in response to agricultural drought was higher in positive feedback than in negative feedback; (3) the transition thresholds of stage 2 was mostly reduced, while the feedback sensitivity of positive feedback was mostly increased; and (4) compared with the single factor, the land-meteorological coupling strength (the correlation between precipitation and soil moisture) dominants the negative-positive feedback transition threshold. This study sheds new insights into droughts feedback., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Accommodations with shared washing facilities increase the risks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for people experiencing rough sleeping and evidence on what interventions are effective in reducing these risks needs to be understood., Methods: Systematic review, search date 6 December 2022 with methods published a priori. Electronic searches were conducted in MEDLINE, PubMed, Cochrane Library, CINAHL and the World Health Organization (WHO) COVID-19 Database and supplemented with grey literature searches, hand searches of reference lists and publication lists of known experts. Observational, interventional and modelling studies were included; screening, data extraction and risk of bias assessment were done in duplicate and narrative analyses were conducted., Results: Fourteen studies from five countries (USA, England, France, Singapore and Canada) were included. Ten studies were surveillance reports, one was an uncontrolled pilot intervention, and three were modelling studies. Only two studies were longitudinal. All studies described the effectiveness of different individual or packages of mitigation measures., Conclusions: Despite a weak evidence base, the research suggests that combined mitigation measures can help to reduce SARS-CoV-2 transmission but are unlikely to prevent outbreaks entirely. Evidence suggests that community prevalence may modify the effectiveness of mitigation measures. More longitudinal research is needed., Systematic Review Registration: PROSPERO CRD42021292803., (© The Author(s) 2023. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Agricultural drought posing a significant threat to agricultural production is subject to the complex influence of ocean, terrestrial and meteorological multi-factors. Nevertheless, which factor dominating the dynamics of agricultural drought characteristics and their dynamic impact remain equivocal. To address this knowledge gap, we used ERA5 soil moisture to calculate the standardized soil moisture index (SSI) to characterize agricultural drought. The extreme gradient boosting model was then adopted to fully examine the influence of ocean, terrestrial and meteorological multi-factors on agricultural drought characteristics and their dynamics in China. Meanwhile, the Shapley additive explanation values were introduced to quantify the contribution of multiple drivers to drought characteristics. Our analysis reveals that the drought frequency, severity and duration in China ranged from 5-70, 2.15-35.02 and 1.76-31.20, respectively. Drought duration is increasing and drought intensity is intensifying in southeast, north and northwest China. In addition, potential evapotranspiration is the most significant driver of drought characteristics at the basin scale. Regarding the dynamic evolution of drought characteristics, the percentages of raster points for drought duration and severity with evapotranspiration as the dominant factor are 30.7 % and 32.7 %, and the percentages with precipitation are 35.3 % and 35.0 %, respectively. Precipitation in northern regions has a positive effect on decreasing drought characteristics, while in southern regions, evapotranspiration dominates the dynamics in drought characteristics due to increasing vegetation transpiration. Moreover, the drought severity is exacerbated by the Atlantic Multidecadal Oscillation in the Yangtze and Pearl River basins, while the contribution of the North Atlantic Oscillation to the drought duration evolution is increasing in the Yangtze River basin. Generally, this study sheds new insights into agricultural drought evolution and driving mechanism, which are beneficial for agricultural drought early warning and mitigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Healthy lung microbiota plays an important role in preventing Mycobacterium tuberculosis (Mtb) infections by activating immune cells and stimulating production of T-helper cell type 1 cytokines. The dynamic stability of lung microbiota relies mostly on lung homeostasis. In our previous studies, we found that Mtb virulence factor, Rv1987 protein, can mediate host immune response and enhance mycobacterial survival in host lung. However, the alteration of lung microbiota and the contribution of lung microbiota dysbiosis to mycobacterial evasion in this process are not clear so far., Methods: M. smegmatis which does not contain the ortholog of Rv1987 protein was selected as a model strain to study the effects of Rv1987 on host lung microbiota. The lung microbiota, immune state and metabolites of mice infected by M. smegmatis overexpressing Rv1987 protein (MS1987) were detected and analyzed., Results: The results showed that Rv1987 inhibited inflammatory response in mouse lung and anaerobic bacteria and Proteobacteria , Bacteroidota , Actinobacteriota and Acidobacteriota bacteria were enriched in the lung tissues correspondingly. The immune alterations and microbiota dysbiosis affected host metabolic profiles, and some of significantly altered bacteria in MS1987-infected mouse lung, such as Delftia acidovorans , Ralstonia pickettii and Escherichia coli , led to anti-inflammatory responses in mouse lung. The secretory metabolites of these altered bacteria also influenced mycobacterial growth and biofilm formation directly., Conclusion: All these results suggested that Rv1987 can attenuate inflammatory response and alter microbiota in the lung, which in turn facilitates mycobacterial survival in the host., 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 © 2023 Liu, Zhang, Leng, Hu, Wang, Deng, Ma and Sha.)

The promise of electrochemically reducing excess anthropogenic carbon dioxide into useful chemicals and fuels has gained significant interest. Recently, indium-copper (In-Cu) alloys have been recognized as prospective catalysts for the carbon dioxide reduction reaction (CO 2 RR), although they chiefly yield carbon monoxide. Generating further reduced C 1 species such as methane remains elusive due to a limited understanding of how In-Cu alloying impacts electrocatalysis. In this work, we investigated the effect of alloying In with Cu for CO 2 RR to form methane through first-principles simulations. Compared with pure copper, In-Cu alloys suppress the hydrogen evolution reaction while demonstrating superior initial CO 2 RR selectivity. Among the alloys studied, In 7 Cu 10 exhibited the most promising catalytic potential, with a limiting potential of -0.54 V versus the reversible hydrogen electrode. Analyses of adsorbed geometries and electronic structures suggest that this decreased overpotential arises primarily from electronic perturbations around copper and indium ions and carbon-oxygen bond stability. This study outlines a rational strategy to modulate metal alloy compositions and design synergistic CO 2 RR catalysts possessing appreciable activity and selectivity., 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 © 2023 Hao, Duan, Leng, Liu, Li, Wang and Qu.)

With the rapid development of the LED industry, gallium (Ga)-bearing waste generated is regarded as one of the most hazardous as it typically contains heavy metals and combustible organics. Traditional technologies are characterized by long processing routes, complex metal separation processes and significant secondary pollution emission. In this study, we proposed an innovative and green strategy to selectively recovery Ga from Ga-bearing waste by using a quantitative phase-controlling transition process. In the phase-controlling transition process, the gallium nitride (GaN) and indium (In) are converted to alkali-soluble gallium (III) oxide (Ga 2 O 3 ) and alkali-insoluble indium oxides (In 2 O 3 ) by oxidation calcination, while nitrogen is converted into diatomic nitrogen gas instead of ammonia/ammonium (NH 3 /NH 4 + ). By selective leaching with NaOH solution, nearly 92.65% of Ga can be recycled with a leaching selectivity of 99.3%, while little emissions of NH 3 /NH 4 + . Ga 2 O 3 with a purity of 99.97% was obtained from the leachate which is also economy promising by economic assessment. Therefore, the proposed methodology compared to the conventional acid and alkali leaching methods is potentially greener and more efficient process for extracting valuable metals from nitrogen-bearing solid waste., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

4-methylbenzylidene camphor (4-MBC) is used as a UV-B filter in cosmetics. Two oxidized metabolites of 4-MBC - 3-(4-carboxybenzylidene)camphor (cx-MBC) and 3-(4-carboxybenzylidene)-6-hydroxycamphor (cx-MBC-OH) - were analyzed in 250 24-h urine samples from young adults in Germany. The samples were from the German Environmental Specimen Bank (ESB) and represented exposure in the years 1995, 2005, 2010, 2015 and 2019. A UHPLC-MS/MS method enabled the sensitive determination of both metabolites, with limits of quantification at 0.15 μg L -1 (cx-MBC) and 0.30 μg L -1 (cx-MBC-OH), respectively. A temporal trend of the internal exposure to 4-MBC was clearly noticeable. The metabolite cx-MBC was frequently quantifiable at the beginning of the period: in 70% of the samples in 1995, and 56% in 2005. After 2005, urinary concentrations and detection rates of cx-MBC dropped to reach very low levels. In 2015 and 2019, the detection rate was only 2% and 0%, respectively. A similar trend was observed for cx-MBC-OH, though overall, this metabolite was detected less often and at lower concentration levels than cx-MBC. Nowadays, measurable levels of urinary 4-MBC metabolites are an extremely rare occurrence in Germany. These trends are consistent with the history of 4-MBC use by the cosmetic industry. The highest measured individual concentration of 16.20 μg L -1 (in a sample of the year 2005) was still more than 30 times below the health-based guidance value (HBM-I). An investigation of the ratios between both metabolites uncovered several features of the 4-MBC metabolism which have been essentially overlooked until now. In particular, stereochemical aspects should be explored in future studies. As urine was collected in autumn/winter in Northwestern Germany, the 4-MBC metabolites measured probably do not arise from sunscreen products in a narrow sense. They rather may reveal the use of other skin care products containing 4-MBC for UV protection as an added feature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In the present experiments, we tested the conclusion from previous electrophysiological experiments that gavage of sweet food and systemically applied insulin both stimulate oxytocin secretion. To do so, we measured oxytocin secretion from urethane-anaesthetised male rats, and demonstrated a significant increase in secretion in response to gavage of sweetened condensed milk but not isocaloric cream, and a significant increase in response to intravenous injection of insulin. We compared the measurements made in response to sweetened condensed milk with the predictions from a computational model, which we used to predict plasma concentrations of oxytocin from the published electrophysiological responses of oxytocin cells. The prediction from the computational model was very closely aligned to the levels of oxytocin measured in rats in response to gavage., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Poly (lactic-co-glycolic acid) (PLGA) microspheres have been one of the most successful products for slow drug release. While distribution of drugs in microspheres might be a fundamental factor affecting drug release, it has been often overlooked. Indeed, very few studies are available on the distribution of drugs in microspheres with complex morphology like golf ball-shaped microspheres. In this paper, the distribution of rotigotine in golf ball-shaped microspheres (GSRM) was investigated by argon ion milling, combined with scanning electron microscopy and energy dispersive X-ray spectroscopy (AIM-SEM-EDS). Rotigotine in GSRM was clearly observed in two forms, respectively in an aggregated state and as a molecular dispersion. The distribution of palmitic acid in the microspheres (used as an additive to reduce burst release) was also demonstrated: 10% was found on the microspheres' surface while 90% separated from the polymer to form small particles inside the microspheres onto which rotigotine aggregated through hydrogen bonding interactions. In in-vitro release studies we observed that first the phase-separated palmitic acid/rotigotine particles dissolved and released the drug, followed by the release of the molecularly dispersed rotigotines by osmosis. We also found that rotigotine accelerated the degradation and reduced the glass transition temperature of PLGA, which played an important role as well in the release of the drug from GSRM. Finally, two linear Level A in vitro-in vivo correlations were established and validated, indicating that the in vitro release testing could be a meaningful predictor for the in vivo performance of GSRM. Our work demonstrates the importance of studying drug distribution in complex microspheres to understand drug release., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Neutrophil Extracellular Traps (NETs) are fibrous networks made of DNA-histone complexes and proteins protruded from activated neutrophils. Accumulating evidences have highlighted the vital role of NETs in tumor progression and diffusion. However, limited systematic studies regarding the role of NETs in LUAD have been performed. Methods: Differentially expressed NETs-related genes and their mutation landscape were identified with TCGA database. Consensus clustering analysis was performed to determine the NETs-related subtypes of LUAD. LASSO algorithm was employed to construct a prognostic signature. Moreover, GSE30219 and GSE31210 were used as independent validation. We also constructed a lncRNA-miRNA-mRNA regulatory axis with several miRNA and lncRNA databases. Results: Consensus clustering identified two NETs-related clusters in LUAD. High NETs score was correlated with a favorable overall survival, abundant immune cell infiltration, and high activity of immune response signal pathways. Six NET-related genes (G0S2, KCNJ15, S100A12, AKT2, CTSG, and HMGB1) with significant prognostic value were screened to develop a prognostic signature. LUAD patients with low-risk had a significantly favorable overall survival both in the training set and validation set. Moreover, NETs-related risk score and clinical stage could act as an independent prognostic factor for LUAD patients. Significant correlation was obtained between risk score and tumor immune microenvironment. We also identified lncRNA BCYRN1/miR-3664-5p/CTSG regulatory axis that may be involved in the progression of LUAD. Conclusion: We developed two molecular subtypes and a prognostic signature for LUAD based on NETs-related genes. This stratification could provide more evidences for estimating the prognosis and immunotherapy of LAUD patients., 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 © 2023 Zuo, Leng and Leng.)

Tumour cells change their metabolic patterns to support high proliferation rates and cope with oxidative stress. The lncRNA ELFN1-AS1 is highly expressed in a wide range of cancers and is essential to the proliferation and apoptosis of tumour cells. Nevertheless, its function in the metabolic reprogramming of tumour cells is unclear. Here we show that ELFN1-AS1 promotes glucose consumption as well as lactate and NADPH production. Database searching, bioinformatics analysis, RNA immunoprecipitation (RIP) and RNA pull-down assays show that ELFN1-AS1 enhances glucose-6-phosphate dehydrogenase ( G6PD ) expression and activates the pentose phosphate pathway (PPP) by promoting TP53 degradation. In addition, luciferase reporter assay and chromatin immunoprecipitation (ChIP) show that YY1 binds to the ELFN1-AS1 promoter to promote transcriptional activation of ELFN1-AS1 . Consistent with the in vitro experiments, knockdown of ELFN1-AS1 impedes the growth of tumours transplanted into mice by inhibiting the expression of G6PD . In conclusion, this study reveals that ELFN1-AS1 activates the PPP, and validates the regulatory role of the YY1 / ELFN1-AS1 / TP53 / G6PD axis in colorectal cancer.

Technical grade branched nonylphenol (NP) was determined in human urine by online solid phase extraction-ultra high-performance liquid chromatography-tandem mass spectrometry (SPE-UHPLC-MS/MS). Prior to analysis, urine specimens were simply diluted and enzymatically deconjugated. The run time of the chromatography, including SPE and re-equilibration, was 9 min per injection. The enzymatic cleavage of NP conjugates was optimised with incurred sample material from a human metabolism study: the highest recoveries were obtained with β-glucuronidase from E. coli K 12 in 0.1 M ammonium acetate at pH 6.5, within a minimal hydrolysis time of 30 to 60 min. Using sodium acetate instead of ammonium acetate led to systematically decreased recovery rates. The analytical method was validated regarding its precision (coefficients of variation: 2.9-7.4%), accuracy (relative recovery rates: 93-105%), robustness (relative recovery rates in individual urine matrices: 92-117%), selectivity, and limit of quantification (1.0 μg L -1 ). Fundamental aspects in the analysis of technical product mixtures such as NP, comprising various isomers and homologues, were considered. Validation results, an exposure scenario and the application of the procedure to real samples, show that it enables a rugged monitoring of NP exposures above, at, and significantly below health-based guidance values, corresponding to daily NP intakes in the low μg kg -1 d -1 range. On the other hand, background levels in non-specifically exposed populations cannot be detected with this method. Hence, while alternative approaches should be pursued for NP analysis at environmental trace level, the speed and simplicity of our method are ideal for high-throughput human biomonitoring in occupational medicine., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Oxytocin, a neuropeptide known for its role in reproduction and socioemotional processes, may hold promise as a therapeutic agent in treating social impairments in patient populations. However, research has yet to uncover precisely how to manipulate this system for clinical benefit. Moreover, inconsistent use of standardized and validated oxytocin measurement methodologies-including the design and study of hormone secretion and biochemical assays-present unresolved challenges. Human studies measuring peripheral (i.e., in plasma, saliva, or urine) or central (i.e., in cerebrospinal fluid) oxytocin concentrations have involved very diverse methods, including the use of different assay techniques, further compounding this problem. In the present review, we describe the scientific value in measuring human endogenous oxytocin concentrations, common issues in biochemical analysis and study design that researchers face when doing so, and our recommendations for improving studies using valid and reliable methodologies., (© 2022. The Author(s).)

Cordycepin is an essential nucleoside antibiotic with a broad spectrum of physiological functions, which is currently produced by the fermentation of Cordyceps militaris. Even though numerous efforts were made to enhance cordycepin production, the cordycepin yield is still limited. High-cordycepin-yielding strains are still a prerequisite for industrial cordycepin production in large amounts. Screening high-cordycepin-yielding strains from other sources may break new grounds for cordycepin. In this study, Cordyceps hawkesii Gray, with high homology to C. militaris, was selected as the source to screen the cordycepin manufacturing endophytic fungi. Four isolates capable of cordycepin production were successfully obtained among all isolated endophytic fungi. One of the four with better cordycepin yield was identified as Irpex lacteus CHG05, which belongs to the Phlebia species. The response surface methodology was applied to optimize the culture conditions for cordycepin fermentation. 162.05 mg/L of cordycepin with a 53.1% improvement was achieved compared to the original conditions. This study indicates that the endophytic fungi from C. hawkesii Gray could produce cordycepin and served as the first report for cordycepin by the white-rot fungus of I. lacteus. Even though the yield is low compared to C. militaris, this strain provided another choice for enhanced cordycepin in the future., (© 2022. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Objective: Acne is a significant problem in young people. At present, most acne treatment products are topically applied cosmetics, whose efficacy is limited by the stratum corneum. The dissolving microneedle technique can effectively deliver drug molecules into the body. In this study, dissolving microneedles containing anti-acne ingredients were tested for human efficacy and safety., Methods: We conducted a 28-day clinical efficacy and safety trial on 30 individuals with visible facial acne. During the trial, anti-acne microneedle (AA-DMN) patches were applied to designated skin areas once daily for 28 consecutive days. Skin pigmentation was measured using a Courage + Khazaka skin melanin and hemoglobin test probe Mexameter MX18. Acne volume was measured using a Canfieldsci skin rapid optical imaging system PRIMOS. In addition, skin irritation was evaluated via self-report and dermatologist's examination., Results: The AA-DMN patches showed good efficacy including improvement of skin pigmentation and reduced acne volume. Acne volume was reduced by 12.34% after 3 days of patch use and further reduced by 10.01% after 7 continuous days of use. After 28 days of treatment, skin melanin decreased by 5.88% and heme decreased by 7.83%. No adverse reactions were observed in any of the participants., Conclusions: Anti-acne microneedle patches showed an excellent effect in reducing acne and post-inflammatory hyperpigmentation (PIH), without adverse skin reactions. The novel AA-DMN patch is a safe and effective anti-acne treatment., (© 2022 Wiley Periodicals LLC.)

Licoricidin, a type of isoflavonoid, is extracted from the root of Glycyrrhiza glabra . It has been widely proven that licoricidin possesses multiple biological activities, including anti-cancer effects and a powerful antimicrobial effect against Helicobacter pylori ( H. pylori ). However, the exact mechanism of licoricidin against gastric cancer remains unclear. In this study, we comprehensively explored the effects of licoricidin on MGC-803 gastric cancer cells in vitro and in vivo and further elucidated its mechanism of action. Our results revealed that licoricidin exhibited multiple anti-gastric cancer activities, including suppressing proliferation, inducing apoptosis, arresting the cell cycle in G 0 /G 1 phase, and inhibiting the migration and invasion abilities of MGC-803 gastric cancer cells. In addition to this, a total of 5861 proteins were identified by quantitative proteomics research strategy of TMT labeling, of which 19 differential proteins (two upregulated and 17 downregulated) were screened out. Combining bioinformatics analyses and the reported roles in cancer progression of the 19 proteins, we speculated that isoprenyl carboxyl methyltransferase (ICMT) was the most likely target of licoricidin. Western blot assays and IHC assays subsequently proved that licoricidin significantly downregulated the expression of ICMT, both in MGC-803 cells and in xenograft tumors. Moreover, licoricidin effectively reduced the level of active Ras-GTP and blocked the phosphorylation of Raf and Erk, which may be involved in its anti-gastric cancer effects. In summary, we first demonstrated that licoricidin exerted favorable anti-gastric cancer activities via the ICMT/Ras pathway, which suggests that licoricidin, as a natural product, could be a novel candidate for the management of gastric cancer., 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 © 2022 Ma, Wu, Bai, Wang, Ma, Guo, Liu, Leng, Kong and Zhang.)

Autism spectrum disorders (ASDs) are prevalent in children and adolescents and disproportionately affect males, and the main contributing factors underlying male vulnerability remain widely unknown. Pesticide use is widely reported to be associated with ASD risk, and the cases of pesticide poisoning incidence in rural areas are remarkably higher than those in the urban areas while the prevalence of ASDs in rural areas was higher than that in urban areas and the rate of male pesticide poisoning was significantly higher than female. Thus, pesticide usage may be an important contributing factor for causing sex-specific differences of ASD incidence. ASD burden was analyzed by using the data of ASD number, ASD rate (ASD cases per 100,000 persons) and disability-adjusted life years (DALYs) from 1990 to 2019. The changes from 1990 to 2030 were predicted using autoregressive integrated moving average (ARIMA) in time series forecasting based on the small values of Akaike information criterion and Bayesian information criterion. Finally, the relationship between ASD rate and pesticide usage risk index (PURI) was analyzed via Pearson's correlation coefficient. ASD number, ASD rate and DALYs will be reduced by 45.5% ± 8.2% ( t = 9.100 and p = 0.0119), 56.6% ± 10.2% ( t = 9.111 and p = 0.0118), and 44.9% ± 7.0% ( t = 20.90 and p = 0.0023) from 1990 to 2030 in China. PURI has a strong relationship with ASD rate (rho = 0.953 to 0.988 and p < 0.0001). Pesticide poisoning incidence in males is up to 2-fold higher than that in females. ASD number and DALYs in males are 4-fold higher than those in females. Furthermore, there is growing evidence supporting that males are more susceptible than females to pesticides with sex differences in neurotoxicogenetics. Therefore, pesticide poisoning may be a contributing factor for causing the sex differences of ASD. Much work still needs to be done to confirm that., 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 © 2022 Hai and Leng.)

In this paper, we analyse the claim that oxytocin is a 'social neuropeptide'. This claim originated from evidence that oxytocin was instrumental in the initiation of maternal behaviour and it was extended to become the claim that oxytocin has a key role in promoting social interactions between individuals. We begin by considering the structure of the scientific literature on this topic, identifying closely interconnected clusters of papers on particular themes. We then analyse this claim by considering evidence of four types as generated by these clusters: (i) mechanistic studies in animal models, designed to understand the pathways involved in the behavioural effects of centrally administered oxytocin; (ii) evidence from observational studies indicating an association between oxytocin signalling pathways and social behaviour; (iii) evidence from intervention studies, mainly involving intranasal oxytocin administration; and (iv) evidence from translational studies of patients with disorders of social behaviour. We then critically analyse the most highly cited papers in each segment of the evidence; we conclude that, if these represent the best evidence, then the evidence for the claim is weak. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.

Objectives: There is a lack of clinical research in the Chinese market concerning dissolving microarray (DMA) patches in cosmetic applications. In this study, the clinical efficacy and safety tests of DMA patch technology were performed on Chinese consumers., Methods: A 4-week clinical efficacy and safety evaluation was conducted on 30 Chinese female subjects with crow's feet and eye bags. DMA patches loaded with hyaluronic acid (HA-DMA) were applied under the eyes and corners of the eyes of the subjects three times a week over four consecutive weeks. Skin firmness and dermal layer strength were measured using ultrasound, and changes in skin wrinkles were detected using VISIA-CR and Primos Lite. Eye bag ratings were evaluated by professional dermatologists based on the 0-6 grades of eye bags in the "Skin Aging Atlas Volume 2: Asian Type.", Results: HA-DMA patches produced good clinical improvements on both crow's feet and eye bags in the study participants. HA-DMA effectively increased skin firmness while reducing the number, area, and volume of crow's feet, along with reducing eye bag ratings. The reductions in all metrics were statistically significant with positive effects evident in as little as 1 week of treatment. There were no adverse effects related to the treatments observed during the test period., Conclusions: In a clinical efficacy trial of 30 Chinese female subjects, HA-DMA showed excellent therapeutic benefits without adverse effects while reducing crow's feet and eye bags. HA-DMA is expected to be a safe, effective, and novel cosmetic for improving the appearance of aging skin., (© 2021 Wiley Periodicals LLC.)

Background: Till now, no experiment has been performed to detect programmed death ligand 1 (PD-L1)/programmed death 1 (PD-1), soluble PD-L1/soluble PD-1 simultaneously in perioperative patients of gastric carcinoma. Our experiment aims at determining the clinical significance and possible mechanism of soluble PD-L1/soluble PD-1 in gastric carcinoma., Methods: Thirty patients undergone gastrectomy were selected as the experimental group. Tissue's programmed death ligand 1 and peripheral programmed death 1 were detected using immunofluorescence and flow cytometry. Soluble PD-L1 and soluble PD-1 were detected using enzyme-linked immunosorbent assay., Results: First, preoperative programmed death 1 was higher than control group and decreased to normal post-operatively. Preoperatively ,elevated levels of programmed death 1 on cluster of differentiation (CD)4 T cells indicated less lymphatic metastasis (P < 0.01) and small tumor volume (P < 0.01); elevated programmed death 1 of CD8 T cells indicated big tumor volume (P < 0.01) and well histological differentiation (P < 0.01). Second, preoperative soluble PD-L1 and soluble PD-1 are lower than in control group. Post-operatively, the soluble PD-1 rose to normal, but the soluble PD-L1 showed no change. Third, programmed death ligand 1 can be observed in carcinoma tissue. Fourth, the area under the curve of soluble PD-1 (0.675) for diagnosis was worse than that of soluble PD-L1 (0.885). Kaplan-Meier analysis showed that soluble PD-1 < 245.26 pg/ml in post-operative serum predicted a poor prognosis (overall survival percentage: 60%) at 2 years (P < 0.05). Multivariate analysis revealed that carcinoembryonic antigen (>5 ng/l) and soluble PD-1 after gastrectomy (>245.26 pg/ml) were independent prognostic factors for overall survival (hazard ratio: 20.812, 95% confidence interval: 1.217-355.916, P = 0.036; hazard ratio: 0.028, 95% confidence interval: 0.001-0.786, P = 0.036, respectively)., Conclusions: We propose that soluble PD-1 combined with programmed death ligand 1 are effective not only in protecting T cells from the adhesion by programmed death ligand 1 but also in preventing the occurrence and the development of tumor as well. Through multivariate analysis, we found that soluble PD-1 was an independent protective factor for post-operative prognosis of gastric carcinoma patients, which indirectly verified the vital function of soluble PD-1. Soluble PD-1 might be promising predictive biomarkers for the diagnosis and prognosis of gastric carcinoma patients., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

What Is Known and Objective: An increasing number of targeted drugs have been used to treat advanced or metastatic gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, the optimal treatment efficacy of these drugs is still controversial. The aims of this study are to systematically summarize the efficacy and safety of current targeted drugs for advanced or metastatic GC and GEJC., Methods: PubMed, EmBase, Cochrane Library, Web of Science and ClinicalTrials were searched for double-blind randomized controlled trials (RCTs) on GC and GEJC up to December 2019. Additionally, we updated the literature search from Jan, 1, 2020 to September 30, 2021. Narrative and quantitative analysis were performed to analyse the efficacy and safety. STATA 15.1 was used to identify publication bias, and the SUCRA (surface under the cumulative ranking) curve was conducted to rank the treatments for each outcome., Results: A total of 27 RCTs with 9295 GC and GEJC patients treated by 19 drugs were included. SUCRA showed that regorafenib was the most likely to improve patients' progression-free survival (96.4%), followed by apatinib (90.7%), nivolumab (82.4%), everolimus (76.5%) and pertuzumab (68.5%). Meanwhile, apatinib (92.4%) was most likely to improve overall survival, followed by nivolumab (87.9%), regorafenib (72.5%), olaparib (67.7%) and lapatinib (63.2%). Additionally, neutropenia, diarrhoea and fatigue were the most common adverse events caused by these drugs, followed by pain, nausea, decreased appetite, anaemia and vomiting., What Is New and Conclusion: Regorafenib and nivolumab have higher efficacy and tolerability and are the most advantageous for advanced GC and GEJC. Moreover, apatinib has higher efficacy but lower tolerability. Everolimus and pertuzumab combined with chemotherapy have best secondary higher efficacy for progression-free survival and good tolerability. Lapatinib and olaparib combined with chemotherapy have moderate efficacy for overall survival and good tolerability., (© 2021 John Wiley & Sons Ltd.)

As a natural organic compound secreted by arbuscular mycorrhizal fungi (AMF), glomalin-related soil protein (GRSP) is an important part in soil, affecting the bioavailability of polycyclic aromatic hydrocarbons (PAHs) in it. Previous research have demonstrated that GRSP could enhance the availability of PAHs in the soil and favor their accumulation in plant roots. However, a scarcity of research exists on the different molecular weights of GRSP interacting with PAHs due to their complexation and heterogeneity. In this research, the extracted GRSP in soil was divided into three molecular weight (Mw) fractions of GRSP (<3,000, 3,000-10,000, and >10,000 Da), whose characteristics and binding capacity of PAHs were conducted by using UV-visible absorption, quenching fluorometry and, Fourier transform infrared spectroscopy. The results showed that the GRSP was composed of abundant compounds, it has a wide distribution of molecular weight, and the >10,000 Da Mw fraction was dominant. For three Mw fractions of GRSP, they have some difference in spectral features, for example, the >10,000 Da fraction showed higher dissolved organic carbon (DOC) contents, more phenolic hydroxyl groups, and stronger UV adsorption capacity than the low and middle Mw fractions. In addition, the interaction between GRSP and phenanthrene is related to the characteristics of the Mw fractions, especially the phenolic hydroxyl group, which has a significantly positive correlation with a binding coefficient of K A ( k = 0.992, p < 0.01). Simultaneously, hydrophobic, NH-π, and H-bound also played roles in the complexation of phenanthrene with GRSP. These findings suggested that different GRSP Mw fractions could influence the fate, availability, and toxicity of PAHs in soil by their interaction., 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 © 2022 Zhou, Wang, Jiang, Leng, Vasilyeva, Waigi and Gao.)

Background and Aim: Long non-coding RNA (lncRNA) TNK2 AS1 is a noncoding RNA with the capability of affecting microRNAs (miRNAs) levels and gene expression. The study was designed to investigate the mechanism of TNK2 AS1 in gastric cancer., Methods: The loss and gain of function of TNK2 AS1 were investigated by analyzing the malignant behavior of AGS cells including the abilities of migration, invasion, and epithelial-mesenchymal transition (EMT) process via wound healing and transwell assay, as well as western blot. The targeting relationship of LncRNA TNK2 AS1 was analyzed through searching bioinformatics database, luciferase reporter assay, and RNA immunoprecipitation (RIP) assay. Tumor-bearing experiment in nude mice was performed to further confirm the regulatory role of TNK2 AS1 in vivo. Immunofluorescence assay for Ki67 expression was carried out in tumor tissues of mice model., Results: The results showed that TNK2 AS1 overexpression promoted the malignant behaviors of AGS cells, which could be weakened by miR-125a-5p mimic addition. In addition, Jumonji, At-rich interaction domain (JARID2), and phosphatidylinositol 3 kinase (PI3K)/AKT pathway were regulated by TNK2-AS1/miR-125a-5p axis. In vivo, TNK2 AS1/miR-125a-5p axis promoted tumor growth and led to increases in green fluorescence intensity and vimentin expression and a decrease in E-cadherin level, which could be mediated by JARID2 and PI3K/AKT pathway., Conclusion: Therefore, a conclusion was drawn that TNK2-AS1/miR-125a-5p promoted the progression of gastric cancer., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Recent reduction of sea ice may have contributed to vegetation growth over the Arctic through albedo feedback effects to atmospheric warming. Understanding the varying response of vegetation to sea ice dynamics is critical for predicting future climate change over the Arctic and middle-high latitudes. Instead of looking at the direct response characteristics, we perform a systematic analysis of the time-lag and time-cumulation responses of vegetation to sea ice dynamics, using a long-term Arctic Normalized Difference Vegetation Index (NDVI) dataset and three sea ice indices (sea ice concentration (SIC), sea ice area (SIA) and sea ice extent (SIE)) from 1982 to 2015. The results show that annual NDVI in the Arctic has exhibited a significant (p < 0.05) increase during 1982 to 2015, while a significant (p < 0.05) decrease is detected for annual SIC, SIA and SIE. The results of a regression analysis on NDVI identify a lag time of 7-months, 8-months and 9-months for vegetation response to SIC, SIA and SIE in February, March and April, respectively, while no evident lag response is observed in summer except for August. For the cumulation response, NDVI in February, March and April shows the largest response to the previous 5, 7 and 9 months of sea ice variations, respectively, while a short cumulation response of 1 to 3 months is found in summer. The differences in the spatial patterns of lagged time are usually not statistically significant in autumn and winter. A shorter lag response (1-3 month) is found in the Yamalia region in June. Further analysis suggests that vegetation response to sea ice dynamics depends on bio - climatic characteristics and soil pH, with vegetation responding faster to sea ice changes in acidic soil. This study provides observational evidences on the varying response of vegetation to sea ice dynamics over the Arctic, which has great implications for predicting vegetation-climate feedback and climate change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Nonylphenol (NP) is an endocrine-disrupting anthropogenic chemical that is ubiquitous in the environment. Human biomonitoring data and knowledge on internal NP exposure are still sparse, and its human metabolism is largely unknown. Therefore, in this study, we investigated human metabolism and urinary excretion of NP. Three male volunteers received a single oral dose of 1 mg 13 C 6 -labeled NP (10.6-11.7 μg/kg body weight). Consecutive full urine voids were collected for 48 h. A metabolite screening identified nine ring- and/or side chain-oxidized metabolites. We chose the most promising hits, the alkyl chain-oxidized metabolites hydroxy-NP (OH-NP) and oxo-NP, for quantitative investigation next to the parent NP. For this purpose, we newly synthesized specific n - 1-oxidized monoisomeric analytical standards. Quantification of the polyisomeric metabolites was performed via online-solid phase extraction-LC-MS/MS with stable isotope dilution using a previously published consensus method. Alkyl chain hydroxylation (OH-NP) constituted the major metabolism pathway representing 43.7 or 62.2% (depending on the mass transition used for quantification) of the NP dose excreted in urine. The urinary excretion fraction ( F UE ) for oxo-NP was 6.0 or 9.3%. The parent NP, quantified via an analogous isomeric 13 C 6 -NP standard, represented 6.6%. All target analytes were excreted predominately as glucuronic acid conjugates. Excretion was rather quick, with concentration maxima in urine 2.3-3.4 h after dosing and biphasic elimination kinetics (elimination half-times first phase: 1.0-1.5 h and second phase: 5.2-6.8 h). Due to its high F UE and insusceptibility to external contamination (contrary to parent NP), OH-NP represents a robust and sensitive novel exposure biomarker for NP. The novel F UE s enable to robustly back-calculate the overall NP intakes from urinary metabolite levels in population samples for a well-informed cumulative exposure and risk assessment.

Our understanding of the oxytocin system has been built over the last 70 years by the work of hundreds of scientists, reported in thousands of papers. Here, we construct a map to that literature, using citation network analysis in conjunction with bibliometrics. The map identifies ten major 'clusters' of papers on oxytocin that differ in their particular research focus and that densely cite papers from the same cluster. We identify highly cited papers within each cluster and in each decade, not because citations are a good indicator of quality, but as a guide to recognising what questions were of wide interest at particular times. The clusters differ in their temporal profiles and bibliometric features; here, we attempt to understand the origins of these differences., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

The increase in extreme climate events such as flooding and droughts predicted by the general circulation models (GCMs) is expected to significantly affect hydrological processes, erosive dynamics, and their associated nonpoint source (NPS) pollution, resulting in a major challenge to water availability for human life and ecosystems. Using the Hydrological Simulation Program-Fortran model, we evaluated the synergistic effects of droughts and rainfall events on hydrology and water quality in an upstream catchment of the Miyun Reservoir based on the outputs of five GCMs. It showed substantial increases in air temperature, precipitation intensity, frequency of heavy rains and rainstorms, and drought duration, as well as sediment and nutrient loads in the RCP 8.5 scenario. Sustained droughts followed by intense precipitation could cause complex interactions and mobilize accumulated sediment, nutrients and other pollutants into surface water that pose substantial risks to the drinking water security, with the comprehensive effects of soil water content, antecedent drought duration, precipitation amount and intensity, and other climate characteristics, although the effects varied greatly under different rainfall patterns. The Methods and findings of this study evidence the synergistic impacts of droughts and heavy rainfall on watershed system and the significant effects of initial soil moisture conditions on water quantity and quality, and help to guide a robust adaptive management system for future drinking water supply., (© 2021. The Author(s).)

Climbazole is a preservative and an anti-dandruff ingredient with applications in various cosmetic products. The general population is therefore exposed to this chemical, and exposure monitoring is desirable. We have postulated a pathway for the human metabolism of climbazole, leading to two specific metabolites which can be excreted via urine. An analytical method for the determination of these metabolites in human urine was developed and validated. The sample preparation includes an enzymatic hydrolysis protocol. The measurement as such is based on online solid phase extraction (SPE), coupled to ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Intra- and inter-series coefficients of variation (CV) were determined in the concentration range from 1 µg/l to 100 µg/l with spiked pooled urine samples, and they were consistently below 15%, mostly below 10%. The corresponding accuracies (mean relative recovery rates) in spiked pooled urine varied from 97% to 103%. The robustness of the method was estimated by spiking individual urine samples. At 1 µg/l, the robustness was rather limited due to interfering matrix peaks in several samples, but excellent results were obtained at 10 µg/l and 100 µg/l, with CVs between 7% and 14% and accuracies from 101% to 110%. Matrix interferences often seemed to be associated with higher creatinine contents (≥2.0 g/l) of the samples. We subsequently applied the method to urine specimens from a human metabolism study involving documented climbazole exposures. We were able to identify and quantify the postulated metabolites in those real samples, thus validating our metabolism hypothesis. We also investigated the precision and accuracy of the enzymatic deconjugation with the real samples. The deconjugation step was found to be highly repeatable and largely quantitative. Both metabolites formed glucuronides, though varying fractions were also excreted in unconjugated (free) forms. Phase II conjugates other than glucuronides did not seem to be produced in significant amounts. With our method, both climbazole metabolites can be reliably quantified in the range between about 1.5 µg/l (depending on matrix interferences in individual samples) and at least 500 µg/l., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Livestock production has significant impacts on the environment, including due to the use of water. In this study, we provide a spatially explicit estimation of livestock blue water use, by analyzing feed crop water use and livestock drinking water. For the past four decades, livestock water use has increased from 145 km 3 /year in 1971 to 270 km 3 /year in 2012 with an increasing trend of 1.36%/year. The proportion of livestock drinking water use has remained relatively stable at around 10% of total water use attributable to livestock production. Several hotspots of water use, including eastern China, northern India, US high plains, are identified in terms of the long-term averages, while South America and Central Africa show the most rapidly increasing trends. In USA, climate change is found to contribute most to the changes in water use attributable to livestock, while feed cropping intensity and land use change are the dominant driver in China and India, respectively. Though, in total, livestock water use makes a relatively modest contribution to the Planetary Boundary (PB) that has been proposed for anthropogenic water use (4000 km 3 /year), we argue that this aggregate number is not particularly meaningful, so we identify places where livestock is a major contributor to the unsustainable use of water, in northern India, part of the Middle East, Northern China and Central US. 7% of rivers where excessive water withdrawals mean that there is insufficient residual flow to sustain the aquatic environment (which we take to be the local manifestation of a PB) have been tipped over that boundary because of livestock farming, whilst in a further 34% of rivers, livestock farming on its own exceeds the water PB. Our results provide new and more geographically specific evidence about the impact that the meat industry makes on the PB for water., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Intérêts concurrents: Diane Kelsall a été rédactrice en chef intérimaire du CMAJ jusqu’en octobre 2019; elle est actuellement rédactrice en chef du CMAJ Open et conseillère éditoriale pour le CMAJ. Gillian Leng est chef de la direction du National Institute for Health and Care Excellence, qui a une politique sur la déclaration et la gestion des conflits d’intérêts, et présidente du Guidelines International Network, qui propose des conseils sur la gestion des conflits d’intérêts potentiels. Brett Thombs, Ainsley Moore et Navindra Persaud sont respectivement président, viceprésidente et membre du Groupe d’étude canadien sur les soins de santé préventifs, qui élabore des guides de pratique clinique et a une politique sur la déclaration et la gestion des conflits d’intérêts. Navindra Persaud a reçu du financement des Instituts de recherche en santé du Canada, de l’Unité de soutien de la SRAP de l’Ontario et du Programme des chaires de recherche du Canada, indépendamment des travaux soumis. Holger Schünemann est membre du groupe de travail GRADE, principal auteur des principes sur la divulgation des intérêts du Guidelines International Network et auteur de correspondance de l’article sur l’outil PANELVIEW. Rachel Rodin et Marcello Tonelli ont reçu du financement des Instituts de recherche en santé du Canada pour la tenue de l’échange Meilleurs cerveaux mentionné dans l’article. Elie Akl a contribué à plusieurs études sur les conflits d’intérêts. G. Michael Allan a participé à la rédaction de lignes directrices. Il a reçu du soutien aux déplacements, des honoraires de conférencier et du soutien à la recherche. Ce financement été accordé par des sources sans but lucratif. Le Dr Allan n’a reçu aucun financement de l’industrie pharmaceutique. Isabelle Ganache a reçu des honoraires personnels de l’Institut national d’excellence santé et en services sociaux (INESSS) à titre de directrice du Bureau — Méthodologies et éthique (responsable des politiques institutionnelles sur la déclaration et la gestion des conflits d’intérêts) durant la réalisation de ce projet. Quinn Grundy a reçu des fonds du Conseil de recherches en sciences humaines et une bourse de recherche (Connaught New Research Award) de l’Université de Toronto, indépendamment des travaux soumis. Aucun autre intérêt concurrent n’a été déclaré. Déclarations d’intérêts: Diane Kelsall est conseillère éditoriale et Navindra Persaud, rédacteur associé pour le CMAJ. Ils n’ont toutefois pas participé au processus ayant mené au choix de cet article.

The elevated atmospheric carbon dioxide concentration (CO 2 ), as a key variable linking human activities and climate change, seriously affects the watershed hydrological processes. However, whether and how atmospheric CO 2 influences the watershed water-energy balance dynamics at multiple time scales have not been revealed. Based on long-term hydrometeorological data, the variation of non-stationary parameter n series in the Choudhury's equation in the mainstream of the Wei River Basin (WRB), the Jing River Basin (JRB) and Beiluo River Basin (BLRB), three typical Loess Plateau regions in China, was examined. Subsequently, the Empirical Mode Decomposition method was applied to explore the impact of CO 2 on watershed water-energy balance dynamics at multiple time scales. Results indicate that (1) in the context of warming and drying condition, annual n series in the WRB displays a significantly increasing trend, while that in the JRB and BLRB presents non-significantly decreasing trends; (2) the non-stationary n series was divided into 3-, 7-, 18-, exceeding 18-year time scale oscillations and a trend residual. In the WRB and BLRB, the overall variation of n was dominated by the residual, whereas in the JRB it was dominated by the 7-year time scale oscillation; (3) the relationship between CO 2 concentration and n series was significant in the WRB except for 3-year time scale. In the JRB, CO 2 concentration and n series were significantly correlated on the 7- and exceeding 7-year time scales, while in the BLRB, such a significant relationship existed only on the 18- and exceeding 18-year time scales. (4) CO 2 -driven temperature rise and vegetation greening elevated the aridity index and evaporation ratio, thus impacting watershed water-energy balance dynamics. This study provided a deeper explanation for the possible impact of CO 2 concentration on the watershed hydrological processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: Diane Kelsall was the interim editor-in-chief of CMAJ until October 2019, and is currently editor for CMAJ Open and consulting editor for CMAJ. Gillian Leng is an executive director of the National Institute for Health and Care Excellence, which also has a policy on declaring and managing conflicts of interest, and is the chair of the Guidelines International Network, which provides advice on managing potential conflicts of interest. Brett Thombs, Ainsley Moore and Navindra Persaud are, respectively, chair, vice-chair and a member of the Canadian Task Force on Preventive Healthcare, which develops clinical practice guidelines and also has a policy on declaring and managing conflicts of interests. Navindra Persaud reports receiving research funding from the Canadian Institutes of Health Research, the Ontario SPOR Support Unit, and the Canada Research Chairs program, outside of the submitted work. Holger Schünemann is a member of the GRADE working group and was the lead author on the Guidelines International Network principles for disclosure of interests, and is the corresponding author on the manuscript describing the PANELVIEW instrument. Rachel Rodin and Marcello Tonelli report receiving funding from the Canadian Institutes of Health Research to host the Best Brains Exchange referred to in the article. Elie Akl reports contributing to a number of studies on conflicts of interest. G. Michael Allan reports being an author of guidelines, who has received travel support, honoraria for speaking at conferences, and research support. The supports have been from nonprofit sources. Dr. Allan has received no funding from the pharmaceutical industry. Isabelle Ganache reports receiving personal fees from Institut national d’excellence santé et en services sociaux (INESSS), as director of the Bureau – Methodologies and Ethics (which is responsible for the institutional policy on declaring and managing conflicts of interest), during the conduct of the study. Quinn Grundy reports receiving grants from the Social Science and Humanities Research Council and a Connaught New Research Award from the University of Toronto, outside of the submitted work. No other competing interests were declared.

The UV filter 4-methylbenzylidene camphor (4-MBC), used in cosmetics, the antioxidant butylated hydroxytoluene (BHT), used inter alia as a food additive and in cosmetics, and the plasticizer tris(2-ethylhexyl) trimellitate (TOTM), used mainly in medical devices as substitute for di-(2-ethylhexyl) phthalate (DEHP), are suspected to have endocrine disrupting effects. Human biomonitoring methods that allow for assessing the internal exposure of the general population to these substances were recently developed in a German cooperation to enhance the use of human biomonitoring. First-morning void urine samples from 3- to 17-year-old children and adolescents living in Germany were analysed for metabolites of 4-MBC (N = 447), BHT (N = 2091), and TOTM (N = 431) in the population-representative German Environmental Survey on Children and Adolescents 2014-2017 (GerES V). 4-MBC metabolites were found in quantifiable amounts only in single cases and exposure levels remained well below health-based guidance values. In contrast, ubiquitous exposure to BHT became evident with a geometric mean (GM) urinary concentration of the metabolite BHT acid of 2.346 μg/L (1.989 μg/g creatinine ) and a maximum concentration of 248 μg/L (269 μg/g crea ). The highest GM concentration was found in young children aged 3-5 years, yet no specific sources of exposure could be identified. Also, TOTM metabolites were found in quantifiable amounts only in very few samples. None of these findings could be related to previous hospital treatment or exposure via house dust. The presented results will be the basis to derive reference values for exposure of children and adolescents in Germany to BHT and will facilitate to identify changing exposure levels in the general population., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dimethyl sulfide (DMS) is the major biogenic volatile sulfur compound in surface seawater. Good quality DMS data with high temporal and spatial resolution are desirable for understanding reduced sulfur biogeochemistry. Here we present a fully automated and novel "microslug" gas-liquid segmented flow-chemiluminescence (MSSF-CL) based method for the continuous in-situ measurement of DMS in natural waters. Samples were collected into a flow tank and DMS transferred from the aqueous phase to the gas phase using a vario-directional coiled flow, in which microvolume liquid and gas slugs were interspersed. The separated DMS was reacted with ozone in a reaction cell for CL detection. The analytical process was automated, with a sample throughput of 6.6 h -1 . Using MSSF for DMS separation was more effective and easily integrated with CL detection compared with the commonly used bubbling approach. Key parameters of the proposed method were investigated. The linear range for the method was 0.05-500 nM (R 2  = 0.9984) and the limit of detection (3 x S/N) was 0.015 nM, which is comparable to the commonly used gas chromatography (GC) method and sensitive enough for direct DMS measurement in typical aquatic environments. Reproducibility and recovery were assessed by spiking natural water samples (river, lake, reservoir and pond) with different concentrations of DMS (10, 20 and 50 nM), giving relative standard deviations (RSDs) ≤1.75% (n = 5) and recoveries of 94.4-107.8%. This fully automated system is reagent free, easy to assemble, simple to use, portable (weight ~5.1 kg) and can be left in the field for several hours of unattended operation. The instrumentation can provide high quality DMS data for natural waters with an environmentally relevant temporal resolution of ~9 min., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Effect biomarkers can be used to elucidate relationships between exposure to environmental chemicals and their mixtures with associated health outcomes, but they are often underused, as underlying biological mechanisms are not understood. We aim to provide an overview of available effect biomarkers for monitoring chemical exposures in the general and occupational populations, and highlight their potential in monitoring humans exposed to chemical mixtures. We also discuss the role of the adverse outcome pathway (AOP) framework and physiologically based kinetic and dynamic (PBK/D) modelling to strengthen the understanding of the biological mechanism of effect biomarkers, and in particular for use in regulatory risk assessments. An interdisciplinary network of experts from the European chapter of the International Society for Exposure Science (ISES Europe) and the Organization for Economic Co-operation and Development (OECD) Occupational Biomonitoring activity of Working Parties of Hazard and Exposure Assessment group worked together to map the conventional framework of biomarkers and provided recommendations for their systematic use. We summarized the key aspects of this work here, and discussed these in three parts. Part I, we inventory available effect biomarkers and promising new biomarkers for the general population based on the H2020 Human Biomonitoring for Europe (HBM4EU) initiative. Part II, we provide an overview AOP and PBK/D modelling use that improved the selection and interpretation of effect biomarkers. Part III, we describe the collected expertise from the OECD Occupational Biomonitoring subtask effect biomarkers in prioritizing relevant mode of actions (MoAs) and suitable effect biomarkers. Furthermore, we propose a tiered risk assessment approach for occupational biomonitoring. Several effect biomarkers, especially for use in occupational settings, are validated. They offer a direct assessment of the overall health risks associated with exposure to chemicals, chemical mixtures and their transformation products. Promising novel effect biomarkers are emerging for biomonitoring of the general population. Efforts are being dedicated to prioritizing molecular and biochemical effect biomarkers that can provide a causal link in exposure-health outcome associations. This mechanistic approach has great potential in improving human health risk assessment. New techniques such as in silico methods (e.g. QSAR, PBK/D modelling) as well as 'omics data will aid this process. Our multidisciplinary review represents a starting point for enhancing the identification of effect biomarkers and their mechanistic pathways following the AOP framework. This may help in prioritizing the effect biomarker implementation as well as defining threshold limits for chemical mixtures in a more structured way. Several ex vivo biomarkers have been proposed to evaluate combined effects including genotoxicity and xeno-estrogenicity. There is a regulatory need to derive effect-based trigger values using the increasing mechanistic knowledge coming from the AOP framework to address adverse health effects due to exposure to chemical mixtures. Such a mechanistic strategy would reduce the fragmentation observed in different regulations. It could also stimulate a harmonized use of effect biomarkers in a more comparable way, in particular for risk assessments to chemical mixtures., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This article covers recently published National Institute for Health and Care Excellence (NICE) guidance relevant to public health and a review of evidence published since we released the NICE guidance on unintentional injury prevention in under 15 year olds. The article features some of this evidence that was found to reinforce published recommendations on safety in the home and on the roads, indicating the guidance remains up to date and relevant. In addition, it importantly highlights that there is great opportunity to prevent future unintentional injury through integrated and coordinated, evidence and intelligence-informed approaches., (© The Author(s) 2019. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This article covers recent National Institute for Health and Care Excellence guidance and standards relevant to public health with a focus on behaviour change. The article summarizes recommendations for local commissioners and providers to help them tackle a range of behaviours including smoking, poor eating patterns, lack of physical activity and alcohol misuse., (© The Author(s) 2019. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This article covers recent National Institute for Health and Care Excellence guidance relevant to public health with a focus on suicide prevention. The article concentrates on the 'Preventing suicide in community and custodial settings' guideline that underpins the recently published 'Suicide prevention' quality standard. The article includes actions that local organizations can take together to prevent suicide and to help people affected by suicide., (© The Author(s) 2019. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fulvestrant ('Faslodex'), an estrogen receptor antagonist, is available for the treatment of advanced breast cancer. The oil-based vehicle of Faslodex can lead to various adverse effects. A novel fulvestrant microcrystal (aqueous suspension) was developed in this study to eliminate these adverse effects. A sensitive and robust liquid chromatography tandem mass spectrometry method was developed and validated for the determination of fulvestrant in rat plasma using supported-liquid extraction. The separation of fulvestrant was achieved on an Agilent SB-C 18 column (2.1 × 50 mm, 3.5 μm) with isocratic elution using fulvestrant-d3 as internal standard. Mass spectrometric detection was conducted in negative multiple reaction monitoring mode. Ion transitions were at m/z 605.5 → 427.5 for fulvestrant and m/z 608.5 → 430.5 for fulvestrant-d3. The excellent linearity was demonstrated over the range 0.05-100.0 ng/ml (r 2  = 0.99). The lower limit of quantitation was 0.05 ng/ml, which was superior to that reported in literature The method validation was evaluated by selectivity, accuracy, precision, recovery and matrix effect in agreement with the US Food and Drug Administration guidance. The method was successfully applied to a pharmacokinetic study of a novel fulvestrant microcrystal in rats after intramuscular administration. It revealed that the rate of absorption increases and the extent of absorption is constant with a decrease in microcrystal diameter., (© 2020 John Wiley & Sons, Ltd.)