Trace water in a BF3·OEt2 system: a facile access to sulfinyl alkenylsulfones from alkynes and sodium sulfinates.

A highly efficient and operationally simple method for the synthesis of ß-sulfinyl alkenylsulfones through a BF3·OEt2-promoted reaction of alkynes and sodium sulfinates is developed, successfully avoiding the complicated anhydrous treatment before the reaction and greatly simplifying the reaction conditions. As a facile and selective route to the targets, it features good functional group compatibility, mild conditions, easily available starting materials, and excellent yields. Notably, the trace water in solvent plays a key role in promoting the reaction, which provides a more practical pathway for the utilization of the BF3·OEt2 catalytic system.

Preventive Effect of Depolymerized Sulfated Galactans from Eucheuma serra on Enterotoxigenic Escherichia coli-Caused Diarrhea via Modulating Intestinal Flora in Mice.

In this work, the preventive effect of depolymerized sulfated polysaccharides from Eucheuma serra (DESP) on bacterial diarrhea by regulating intestinal flora was investigated in vivo. Based on the enterotoxigenic Escherichia coli (ETEC)-infected mouse diarrhea model, DESP at doses ranging from 50 mg/kg to 200 mg/kg alleviated weight loss and decreased the diarrhea rate and diarrhea index. Serological tests showed that the levels of inflammation-related factors were effectively suppressed. Furthermore, the repaired intestinal mucosa was verified by morphology and pathological tissue section observations. Compared with the model group, the richness and diversity of the intestinal flora in the DESP group increased according to the 16S rRNA high-throughput sequencing of the gut microbiota. Specifically, Firmicutes and Actinobacteria increased, and Proteobacteria decreased after DESP administration. At the family level, DESP effectively improved the abundance of Lactobacillaceae, Bifidobacteriaceae, and Lachnospiraceae, while significantly inhibiting the growth of Enterobacteriaceae. Therefore, the antimicrobial diarrhea function of DESP may be related to the regulation of intestinal microbiota.

Antibacterial Activity of Sulfated Galactans from Eucheuma serra and Gracilari verrucosa against Diarrheagenic Escherichia coli via the Disruption of the Cell Membrane Structure.

Seaweed sulfated polysaccharides have attracted significant attention due to their antibacterial activity. This work investigated the antibacterial activity and mechanism of depolymerized sulfated galactans from Eucheuma serra (E. serra) and Gracilaria verrucosa (G. verrucosa) against enterotoxigenic Escherichia coli (ETEC) K88. The results show that removing the metal ions improves the anti-ETEC K88 activity of the galactans. The fluorescence labeling study confirmed that the sulfated galactans penetrated the cell walls and eventually reached the interior of the ETEC K88. Nucleic acid staining and intracellular protein leakage were also observed, indicating the destruction of permeability and integrity of the cell membrane. Interestingly, the two polysaccharides exhibited no effect on the proliferation of the selected Gram-positive bacteria and yeast. This indicates that the cell wall structure of the microorganisms could influence the bacteriostatic activity of the sulfated polysaccharides, as well. These results suggest that the sulfated seaweed polysaccharides might have potential application value in antibacterial diarrhea.

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models.

The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues to regulate cell growth and survival through various mechanisms. However, how mTORC1 responds to acute inflammatory signals to regulate bowel regeneration is still obscure. In this study, we investigated the role of mTORC1 in acute inflammatory bowel disease. Inhibition of mTORC1 activity by rapamycin treatment or haploinsufficiency of Rheb through genetic modification in mice impaired intestinal cell proliferation and induced cell apoptosis, leading to high mortality in dextran sodium sulfate- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis models. Through bone marrow transplantation, we found that mTORC1 in nonhematopoietic cells played a major role in protecting mice from colitis. Reactivation of mTORC1 activity by amino acids had a positive therapeutic effect in mTORC1-deficient Rheb(+/-) mice. Mechanistically, mTORC1 mediated IL-6-induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity. As mTORC1 is an important therapeutic target for multiple diseases, our findings will have important implications for the clinical usage of mTORC1 inhibitors in patients with acute inflammatory bowel disease.

High-efficiency and heritable gene targeting in mouse by transcription activator-like effector nucleases.

Transcription activator-like effector nucleases (TALENs) are a powerful new approach for targeted gene disruption in various animal models, but little is known about their activities in Mus musculus, the widely used mammalian model organism. Here, we report that direct injection of in vitro transcribed messenger RNA of TALEN pairs into mouse zygotes induced somatic mutations, which were stably passed to the next generation through germ-line transmission. With one TALEN pair constructed for each of 10 target genes, mutant F0 mice for each gene were obtained with the mutation rate ranged from 13 to 67% and an average of ∼40% of total healthy newborns with no significant differences between C57BL/6 and FVB/N genetic background. One TALEN pair with single mismatch to their intended target sequence in each side failed to yield any mutation. Furthermore, highly efficient germ-line transmission was obtained, as all the F0 founders tested transmitted the mutations to F1 mice. In addition, we also observed that one bi-allele mutant founder of Lepr gene, encoding Leptin receptor, had similar diabetic phenotype as db/db mouse. Together, our results suggest that TALENs are an effective genetic tool for rapid gene disruption with high efficiency and heritability in mouse with distinct genetic background.

[Clinical trial data management and quality metrics system].

Data quality management system is essential to ensure accurate, complete, consistent, and reliable data collection in clinical research. This paper is devoted to various choices of data quality metrics. They are categorized by study status, e.g. study start up, conduct, and close-out. In each category, metrics for different purposes are listed according to ALCOA+ principles such us completeness, accuracy, timeliness, traceability, etc. Some general quality metrics frequently used are also introduced. This paper contains detail information as much as possible to each metric by providing definition, purpose, evaluation, referenced benchmark, and recommended targets in favor of real practice. It is important that sponsors and data management service providers establish a robust integrated clinical trial data quality management system to ensure sustainable high quality of clinical trial deliverables. It will also support enterprise level of data evaluation and bench marking the quality of data across projects, sponsors, data management service providers by using objective metrics from the real clinical trials. We hope this will be a significant input to accelerate the improvement of clinical trial data quality in the industry.

Norcantharidin inhibits tumor angiogenesis via blocking VEGFR2/MEK/ERK signaling pathways.

Norcantharidin (NCTD), the demethylated form of Cantharidin, a reagent isolated from blister beetles, has been shown to be an anti-tumor agent capable of inhibiting proliferation as well as inducing apoptosis in many cancer cell lines. However, little is known about the effect of NCTD in tumor angiogenesis. In this study, we demonstrated that NCTD inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, invasion, and capillary tube formation of primary human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. Furthermore, we showed NCTD inhibited tumor growth and angiogenesis of colon cancer cells (LOVO) in vivo. We then mechanistically described that NCTD specifically abrogated the phosphorylation/activation of vascular endothelial growth factor receptor-2 (VEGFR2)/MEK/ERK pathway kinases, with little effect on the phosphorylation of p38 MAPK and Akt, and on Cox-2 expression. In summary, our results indicate that NCTD is a potential inhibitor of tumor angiogenesis by blocking VEGFR2/MEK/ERK signaling.

Multiresidue analysis of nine ß-agonists in animal muscles by LC-MS/MS based on a new polymer cartridge for sample cleanup.

A novel, sensitive, and reliable LC-MS/MS method for multiresidue analysis of nine ß-agonists (salbutamol, terbutaline, cimaterol, fenoterol, clorprenaline, ractopamine, tulobuterol, clenbuterol, and penbuterol) in four farm animal muscles was developed. Muscle matrix was extracted with acetonitrile-10% sodium carbonate solution, and then was subjected to cleanup using a SPE cartridge packed with new polymer synthesized in acetone. Chromatographic separation of the components was performed on a Luna C18 column using 0.1% of formic acid in water and acetonitrile. The mass spectrometer was operated in the positive electrospray mode. Good precision and accuracy were obtained for all analytes (except for fenoterol) at the spiked three levels of 1.0, 10, and 50 µg/kg. The decision limit and detection capability of nine ß-agonists ranged from 0.04 to 0.18 and 0.15 to 0.69 µg/kg, respectively. The method developed was successfully applied to the monitoring of nine ß-agonists in pork, beef, mutton, and chicken from Chinese markets.

Regulating donor-acceptor system toward highly efficient dual-state emission for sensitive response of nitroaromatic explosives.

Dual-state emission luminogens (DSEgens) as fluorophores emit efficiently in solution and solid forms have gained increasing concern in the field of chemical sensing. Recent efforts by our group led to the identification of DSEgens as an easy-to-visualize nitroaromatic explosives (NAEs) detection platform. However, none of the previously studied NAEs probes show effective improvement in sensitivity. Here, we designed a series of benzoxazole-based DSEgens through multiple strategies driven by theoretical calculations, revealing their improved detecting performance on NAEs. Compounds 4a-4e exhibit thermal- and photo-stability, large Stokes shift as well as sensitivity solvatochromism (except for 4a and 4b). A subtle balance between rigid conjugation and distorted conformation endows these D-A type fluorophores 4a-4e with DSE properties. Furthermore, 4d and 4e show aggregation-induced emission phenomenon caused by distorted molecular conformation and restricted intramolecular rotation. Interestingly, DSEgen 4e displays anti-interference and sensitivity towards NAEs with a detection limit of 10-8 M. It can be applied for expedient and distinct visual identification of NAEs not only in solution but also on filter paper and film, supporting this new DSEgen as reliable NAEs chemoprobe.

Fine-tuning benzazole-based probe for the ultrasensitive detection of Hg2+ in water samples and seaweed samples.

Developing potentially toxic metal ion probes is significant for environment and food safety. Although Hg2+ probes have been extensively studied, small molecule fluorophores that can integrate two applications of visual detection and separation into one unit remain challenging to access. Herein, by incorporating triphenylamine (TPA) into tridentate skeleton with an acetylene bridge, 2,6-bisbenzimidazolpyridine-TPA (4a), 2,6-bisbenzothiazolylpyridine-TPA (4b) and 2,6-bisbenzothiazolylpyridine-TPA (4c) were first constructed, expectably showing distinct solvatochromism and dual-state emission properties. Since the diverse emission properties, the fluorescence detection of 4a-4b can be achieved with an ultrasensitive response (LOD = 10-11 M) and efficient removal of Hg2+. More interestingly, 4a-4b can not only be developed into paper/film sensing platform, but also reliably detect Hg2+ in real water and seaweed samples, with recoveries ranging from 97.3% to 107.8% and a relative standard deviation of less than 5%, indicating that they have excellent application potential in the field of environmental and food chemistry.

Cu12@Au30Ag12: a magnetic pentakis icosidodecahedron molecule with core-shell configuration.

A 54-atom trimetallic core-shell Cu12@Au30Ag12 molecule has been identified by using first-principles calculations. This molecule with Ih symmetry consists of an icosahedral 12-atom Cu core (Cu12) coated by a pentakis icosidodecahedral 42-atom Au-Ag shell (Au30Ag12) composed of an icosidodecahedral Au30 and an icosahedral Ag12. Both the molecular dynamics simulations and vibrational frequency analysis demonstrate the high stability of Cu12@Au30Ag12. The analyses for electronic properties indicate that there exists spd hybridization which is crucial to maintain the geometrical configuration of Cu12@Au30Ag12. Moreover, a total spin magnetic moment of Cu12@Au30Ag12 is found to be 4 µB, which chiefly arises from the 6 s states of Au atoms. A new type of sugar gourd-like [Cu12@Au30Ag11]n nanowire is also proposed; the results demonstrate that the nanowire exhibits metallic and magnetic behaviors. The magnetic Cu12@Au30Ag12 molecule and [Cu12@Au30Ag11]n nanowire can be promising candidates of novel magnetic nanomaterials and nanodevices.

Life-Events Mediate the Prediction of Parental Alienation on Depression in Rural Left-Behind Children: A Longitudinal Study.

Objectives: Long-time separation with parents during early life, such as left-behind children (LBC, one or both of whose parents are leaving for work for at least a period of 6 months), may contribute to high alienation toward parents and endanger their mental health (e.g., depression). However, the dynamic status of depression and potential prediction of alienation on depression in LBC remained largely unknown. This study aimed to examine the dynamic status of depression, prediction of alienation toward parents on later depression in rural LBC, and a potential mediation of life-events. Methods: A total of 877 LBC in rural areas of China were recruited and surveyed at five time-points (baseline, T0: 1-month, T1: 3-months, T2: 6-months, T3: 12-months, T4) with the Inventory of Alienation Toward Parents, Childhood Depression Inventory, and Adolescent Self-Rating Life-Events Checklist. The Hierarchical Linear Model (HLM) and Hayes's PROCESS macro model were conducted to estimate the developmental trend and hierarchical predictors of depression. Results: The left-behind children aged 9-years old experienced higher depression than the children with other ages. At baseline, the children in the family atmosphere of frequent quarrels and compulsive parenting style reported a higher level of alienation toward parents, life-events, and depression. Alienation toward parents, life-events, and depression were positively and moderately correlated with each other (r = 0.14 ~ 0.64). The HLM model depicted a linear decline in depression, alienation, and life-events with an average rate of 0.23, 0.24, and 0.86, respectively, during the five time-points. Also, T0 alienation toward parents and T0 life-events positively predicted the developmental trajectory of depression over time, and T0 life-events positively predicted the descendant rate of depression. Notably, life-events mediated the prediction of baseline alienation toward parents on T4 depression in LBC. Conclusion: This study is among the first to reveal that alienation toward parents predicts the developmental trajectory of later depression in LBC. The findings that life-events mediate the prediction of alienation on later depression further suggest the importance of family and social factors in the occurrence of depression in LBC. The findings warrant the necessity to consider the family and social factors when evaluating and reducing risks for mental health problems in LBC, i.e., relationship with parents (especially alienation toward parents) and life-events need further attention.

Remote and adjacent psychological predictors of early-adulthood resilience: Role of early-life trauma, extraversion, life-events, depression, and social-support.

Resilience is important for people to maintain mental health after negative life-events. However, its longitudinal psychological and social predictors are poorly revealed. Based on the ecological system theory model, the current study aimed to determine the longitudinal temporal mechanism underlying the development of early-adulthood resilience using long-term (early-life trauma and personality), medium-term and short-term (life-events, social support, and depression) psychosocial predictors. A total of 505 university students were recruited at baseline (T1), 433 of whom took part in a three-year longitudinal investigation (T2). The results showed that at T1 and T2, the resilience scores of individuals were identically high (72.98 and 73.21, respectively). Pearson correlation analysis showed that early-adulthood resilience was negatively correlated with early-life trauma, psychoticism and neuroticism, depression, ad life-events, and positively correlated with extraversion, social-support, and resilience. Regression and structural equation models showed that extraversion had a direct positive effect on T1 resilience through the mediation of T1 life-events, depression, and social-support, while childhood emotional neglect (EN) had indirect negative effect and extraversion had direct positive effect on T2 resilience through the mediation of T1 resilience, and T2 depression and social-support. In conclusion, this study is among the first to reveal the longitudinal temporal process of the development of early-adulthood resilience using remote and adjacent psychosocial predictors. The findings confirm that childhood EN and extraversion have a remote impact on early-adulthood resilience through recent and current depression and social-support. Our results imply that early-life trauma does not hinder the development of early-adulthood resilience in a linear trend.

Two Potential Probiotic Bacillus with Proteolytic Activity to Dietary Protein from Adult Feces.

　Two Bacillus strains were screened and identified using 16S rRNA gene sequencing the phenotypic tests, and then characterized in vitro for the probiotic characteristics. They were able to tolerate pH 2.5 for 2.5 h, following 0.3% bile salts and 0.1% pancreatin treatment for 5 h. They exhibited good ability to attach to intestinal epithelial cells and were susceptible to most of the antibiotics and being killed by several. Further and more important, they showed good proteolytic activity to food protein as gelatin and milk, with even higher activity than the reference strain. Thus, these two Bacillus strains are considered as potential proteolytic probiotic strains to food proteins.

A Hypothesis of Gender Differences in Self-Reporting Symptom of Depression: Implications to Solve Under-Diagnosis and Under-Treatment of Depression in Males.

The phenomenon of female preponderance in depression has been well-reported, which has been challenged by higher rates of suicide and addictive behaviors in males, and a longer life-span in females. We thus propose an alternative hypothesis "Gender differences in self-reporting symptom of depression," suggesting mild-moderate depression tends to be reported more often by females, and severe depression and suicide tend to be reported more often by males. Potential mechanisms that account for this difference may include three aspects: covariation between estrogen levels and the incidence peak of female depression, gender differences in coping style (e.g., comparative emotional inexpressiveness and non-help-seeking in males), and gender differences in symptom phenotypes (e.g., atypical symptoms in male depression). Our newly presented hypothesis implied the overlooked under-diagnosis and under-treatment of depression in males. For effective diagnoses and timely treatment of male depression, it is critical to incorporate symptoms of depression in males into the relevant diagnostic criteria, encourage males to express negative emotions, and increase awareness of suicidal behavior in males.

Depolymerized sulfated galactans from Eucheuma serra ameliorate allergic response and intestinal flora in food allergic mouse model.

The ameliorative effect of depolymerized sulfated polysaccharides from Eucheuma serra (DESP) on ovalbumin (OVA)-caused induced food allergy was investigated in this work. Results showed that OVA stimulated the secretion of allergy-related cytokines (OVA-specific IgE, mMCP-1, IgA, TNF-α) and led to diarrhea, intestinal epithelial damage, and intestinal microflora dysbiosis in sensitized mice. After the administration of DESP, however, the anaphylactic symptoms (shortness of breath, hypothermia, diarrhea), along with the allergy-related cytokines, were effectively suppressed. Moreover, the reduced intestinal inflammation was discovered in the DESP-treated group. Additionally, 16S rRNA sequencing of fecal samples was performed, and gene count and α-diversity analysis revealed that DESP improved microbial community richness. Taxonomic composition analysis showed that DESP modulated the proportion of Firmicutes and Bacteroidetes/Proteobacteria. Particularly, DESP increased probiotics (Lactobacillaceae, Bifidobacteriaceae and Prevotellaceae) and decreased pathogenic bacteria (Helicobacteraceae and Desulfovibrionaceae). These findings, therefore, suggest that DESP may ameliorate food allergy through the regulation of intestinal microbiota.

Fear in the Chinese Population: Influential Patterns in the Early Stage of the COVID-19 Pandemic.

Major global public health emergencies challenge public mental health. Negative emotions, and especially fear, may endanger social stability. To better cope with epidemics and pandemics, early emotional guidance should be provided based on an understanding of the status of public emotions in the given circumstances. From January 27 to February 11, 2020 (during which the cases of COVID-19 were increasing), a national online survey of the Chinese public was conducted. A total of 132,482 respondents completed a bespoke questionnaire, the Emotion Regulation Questionnaire, and the Berkeley Expressivity Questionnaire (BEQ). Results showed that at the early stage of the COVID-19 epidemic, 53.0% of the Chinese population reported varying degrees of fear, mostly mild. As seen from regression analysis, for individuals who were unmarried and with a relatively higher educational level, living in city or area with fewer confirmed cases, cognitive reappraisal, positive expressivity and negative inhibition were the protective factors of fear. For participants being of older age, female, a patient or medical staff member, risk perception, negative expressivity, positive impulse strength and negative impulse strength were the risk factors for fear. The levels of fear and avoidant behavior tendencies were risk factors for disturbed physical function. Structural equation modeling suggested that fear emotion had a mediation between risk perception and escape behavior and physical function disturbance. The findings help to reveal the public emotional status at the early stage of the pandemic based on a large Chinese sample, allowing targeting of the groups that most need emotional guidance under crisis. Findings also provide evidence of the need for psychological assistance in future major public health emergencies.

Negative Emotions in Chinese Frontline Medical Staff During the Early Stage of the COVID-19 Epidemic: Status, Trend, and Influential Pathways Based on a National Investigation.

Objective: The outbreak of coronavirus disease 2019 (COVID-19), declared as a major public health emergency, has had profound effects on public mental health especially emotional status. Due to professional requirements, medical staff are at a higher risk of infection, which might induce stronger negative emotions. This study aims to reveal the emotional status of Chinese frontline medical staff in the early epidemic period to better maintain their mental health, and provide adequate psychological support for them. Methods: A national online survey was carried out in China at the early stage of the COVID-19 epidemic. In total, 3025 Chinese frontline medical staff took part in this investigation which utilized a general information questionnaire, the Emotion Regulation Questionnaire (ERQ), and the Berkeley Expressivity Questionnaire (BEQ). Results: At the early stage of COVID-19, anxiety was the most common negative emotion of Chinese medical staff, followed by sadness, fear, and anger, mainly at a mild degree, which declined gradually over time. Nurses had the highest level of negative emotions compared with doctors and other healthcare workers. Women experienced more fear than men, younger and unmarried medical staff had more anxiety and fear compared with elders and married ones. Risk perception and emotional expressivity increased negative emotions, cognitive reappraisal reduced negative emotions, while negative emotions led to more avoidant behavior and more physical health disturbances, in which negative emotions mediated the effect of risk perception on avoidant behavior tendency in the model test. Conclusion: Chinese frontline medical staff experienced a mild level of negative emotions at the early stage of COVID-19, which decreased gradually over time. The findings suggest that during the epidemic, nurses' mental health should be extensively attended to, as well as women, younger, and unmarried medical staff. To better ensure their mental health, reducing risk perception and improving cognitive reappraisal might be important, which are potentially valuable to form targeted psychological interventions and emotional guidance under crisis in the future.

High-performance ion exchange chromatography of intact bacterial cells in the manner of molecules: 1. Establishment of methodology.

The feasibility of separating intact bacterial cells by high-performance ion exchange chromatography typical for macromolecular study was investigated. A common HPLC system coupled with a light scattering detector was employed; TOYOPEARL SuperQ-650C, a beaded anion exchanger, was used as the column media; bacterial cell samples were prepared by suspending colonies in the equilibrium buffer. Piperazine-hydrochloric acid buffer (0.02 M, pH 7.0) was chosen to be the equilibrium buffer after screening different buffer systems. The absorbed cells were eluted by a linear gradient of NaCl from 0 to 1.00 M in the equilibrium buffer within 30 min, at a flow rate of 1.0 mL/min. A distinctive chromatographic profile with high reproducibility and accuracy was obtained with all of the six kinds of bacteria tested. The eluted fractions for each sample were confirmed by microscopic analysis and physiological or biochemical identification to the bacterial cells applied. More importantly, the eluted cells retained full viability. It is apparent that living bacteria cells exhibited similar behaviors and properties with molecules in anion exchange chromatography, implying that chromatographic methods can become an effective approach in the studies of intact bacterial cells.

First-principles investigation on cluster-assembled silicon nanotubes with Eu atoms encapsulation.

Two kinds of dimers consisting of two endohedral Eu@Si16 cages, Eu2@Si32 and Eu2@Si28, have been predicted by using density functional theory. The structural stabilities, electronic structures, and magnetic properties have been examined at the DFT-GGA level. The results show that each of the central Eu atoms in Eu2@Si32 and Eu2@Si28 keeps spin magnetic moment of about 6.9 µB, respectively. Analysis of electronic structures shows that sp2-like hybridizations induced by the central Eu atoms arise in Si-Si bonds, which remarkably improve the stabilities of both Si32 and Si28 clusters. Furthermore, two types of assembled Si nanotubes (Eu@SiNT-1 and Eu@SiNT-2) with Eu atoms encapsulated are gained; it is found that both of them are of metallic conductive character and have total magnetic moment of 14 µB. All these structures may be rather tempting for the future spintronic devices and high-density magnetic storage materials. Graphical abstract The electronic and magnetic properties of cluster-assembled Eu@SiNTs.