The Association Between Child Abuse and Internet Addiction: A Three-Level Meta-Analysis.

Child abuse is an important factor for Internet addiction. Despite numerous researches had observed there was a positive correlation between child abuse and Internet addiction, the strength of this association differed considerably in the previous studies. This study aims to obtain reliable estimates for effect sizes and investigate the potential moderator of the association between child abuse and Internet addiction. Thirty-one studies reported the association between child abuse and Internet addiction (273 effect sizes and 55,585 participants) through a systematic literature search. Based on Preferred Reporting Items for Systematic Review and Meta-Analysis approach, a three-level model was employed to conduct a three-level meta-analysis. The current meta-analysis found that child abuse was significantly positively correlated with Internet addiction. Besides, the study found that the type of child abuse and publication year had significant moderating effects on the association between child abuse and Internet addiction. This study suggested child abuse was a risk factor for Internet addiction. Moreover, child abuse is an essential factor should be considered when strengthening interventions for individuals' Internet addiction.

Synthesis of peptidomimetics as antibiotic adjuvants for combination with aztreonam to combat MDR Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the multipledrug-resistant (MDR) Gram-negative pathogens with few drugs available for treatment. Antibiotic adjuvant approach provides an alternative and complementary strategy. In this study, the stereo-structure-activity relationship of monobactams against MDR Gram-negative organisms was extended. Meanwhile, a series of novel peptidemimetic derivatives as antibiotic adjuvants was synthesized and evaluated for their synergistic effects with aztreonam (AZT) against P. aeruginosa, using dipeptide PAßN as the lead. Among the analogues, compound 22j showed a significant synergistic effect against MDR P. aeruginosa in vitro and in vivo, presumably through the mechanism of affecting the permeability of outer membrane. Thus, we identified 22j as a novel peptidemimetic lead compound to potentiate the activity of AZT against MDR P. aeruginosa, which is worthy of further development as antibiotic adjuvant candidates.

PHT427 as an effective New Delhi metallo-ß-lactamase-1 (NDM-1) inhibitor restored the susceptibility of meropenem against Enterobacteriaceae producing NDM-1.

Introduction: With the increasingly serious problem of bacterial drug resistance caused by NDM-1, it is an important strategy to find effective inhibitors to assist ß-lactam antibiotic treatment against NDM-1 resistant bacteria. In this study, PHT427 (4-dodecyl-N-1,3,4-thiadiazol-2-yl-benzenesulfonamide) was identified as a novel NDM-1 inhibitor and restored the susceptibility of meropenem against Enterobacteriaceae producing NDM-1. Methods: We used a high throughput screening model to find NDM-1 inhibitor in the library of small molecular compounds. The interaction between the hit compound PHT427 and NDM-1 was analyzed by fluorescence quenching, surface plasmon resonance (SPR) assay, and molecular docking analysis. The efficacy of the compound in combination with meropenem was evaluated by determining the FICIs of Escherichia coli BL21(DE3)/pET30a(+)-bla NDM-1 and Klebsiella pneumoniae clinical strain C1928 (producing NDM-1). In addition, the mechanism of the inhibitory effect of PHT427 on NDM-1 was studied by site mutation, SPR, and zinc supplementation assays. Results: PHT427 was identified as an inhibitor of NDM-1. It could significantly inhibit the activity of NDM-1 with an IC50 of 1.42 µmol/L, and restored the susceptibility of meropenem against E. coli BL21(DE3)/pET30a(+)-bla NDM-1 and K. pneumoniae clinical strain C1928 (producing NDM-1) in vitro. The mechanism study indicated that PHT427 could act on the zinc ions at the active site of NDM-1 and the catalytic key amino acid residues simultaneously. The mutation of Asn220 and Gln123 abolished the affinity of NDM-1 by PHT427 via SPR assay. Discussion: This is the first report that PHT427 is a promising lead compound against carbapenem-resistant bacteria and it merits chemical optimization for drug development.

The role of OFDI in home-country pollution: insights from LMDI and 3SLS approaches.

Under the global climate crisis, harnessing investment for sustainable development is a practical and effective measure for international society. Based on the logarithmic mean Divisia index (LMDI) decomposition and three-stage least squares (3SLS) structural approaches, this study explores the home-country pollution reduction effect of Chinese OFDI activities using the city-level panel data from 2007 to 2019. The findings of this study indicate that (1) China has made a remarkable achievement in PM2.5 pollution reduction and governance, especially from the year 2012. (2) The OFDI activities can significantly decrease the home-country PM2.5 pollution. With every 1% increase in OFDI flows, the overall pollution level will decrease by 0.76%. (3) Compared with the scale mechanism, the technology and composition mechanism effects of OFDI flows are more evident in addressing the home-country PM2.5 pollution. With several related policy implications, this study may fill the lacuna of how to play the role of OFDI activities in the home country, thus promoting sustainable development in the next stage.

The health consequences of greenhouse gas emissions: a potential pathway.

Excessive greenhouse gas emissions might be the major culprit for environmental degradation, which have direct and indirect adverse impacts in various ways. As the largest emitter of carbon emissions, China suffered great harm from climate change during the past 40 years. Therefore, it becomes necessary to study the impact of carbon emissions on health issues and their potential mechanism. Using the panel data from 30 provinces in China between 2002 and 2017, this study employes and extends the Stochastic Impacts by Regression on Population, Affluence, and Technology (STIRPAT) model and mediating effect model to analyze the direct and indirect effects of carbon emissions. The main results are as follows: (1) Carbon emissions has a certain negative impact on public health, which would increase with the rise of temperature. (2) The increase in carbon emissions has a more significant negative effect on health with the average temperature exceeding 17.75 °C, indicating that the temperature has a threshold effect. (3) The potential health risks become higher with the development of urbanization, but there is no obvious spillover effect in the health consequences. The results remain robust after controlling other factors. This study supplements the literature of climate governance and human health, potentially contributing to the next stage of high-quality and sustainable development.

Fixed asset changes with carbon regulation: The cases of China.

Carbon regulation might threaten corporate competitiveness and thus guide their production and investment behaviours. Using the difference-in-differences (DID) model, we analyze the impact of China's carbon emission trading (CET) pilots on the fixed asset and its investment. The main findings are as follows: (1) CET reduces the fixed assets value and investment of regulated companies. (2) The decline in the fixed asset and its investment represents more significantly in the economically developed areas, pilots with grandfathering allocation, energy and manufacturing industries, and state-owned enterprises. (3) Potential influence channel estimation indicates that the fixed-asset investment decreases through investment diversion, rather than operation transfer. (4) CET reduces the over-investment in the fixed assets of regulated companies and improves their fixed-asset investment efficiency. This study supplements the literature on carbon regulation and corporate behaviours, potentially contributing to the next stage of climate governance and global decarbonization.

IMB-XMA0038, a new inhibitor targeting aspartate-semialdehyde dehydrogenase of Mycobacterium tuberculosis.

The emergence of drug-resistant tuberculosis (TB) constitutes a major challenge to TB control programmes. There is an urgent need to develop effective anti-TB drugs with novel mechanisms of action. Aspartate-semialdehyde dehydrogenase (ASADH) is the second enzyme in the aspartate metabolic pathway. The absence of the pathway in humans and the absolute requirement of aspartate in bacteria make ASADH a highly attractive drug target. In this study, we used ASADH coupled with Escherichia coli type III aspartate kinase (LysC) to establish a high-throughput screening method to find new anti-TB inhibitors. IMB-XMA0038 was identified as an inhibitor of MtASADH with an IC50 value of 0.59 µg/mL through screening. The interaction between IMB-XMA0038 and MtASADH was confirmed by surface plasmon resonance (SPR) assay and molecular docking analysis. Furthermore, IMB-XMA0038 was found to inhibit various drug-resistant MTB strains potently with minimal inhibitory concentrations (MICs) of 0.25-0.5 µg/mL. The conditional mutant strain MTB::asadh cultured with different concentrations of inducer (10-5 or 10-1 µg/mL pristinamycin) resulted in a maximal 16 times difference in MICs. At the same time, IMB-XMA0038 showed low cytotoxicity in vitro and vivo. In mouse model, it encouragingly declined the MTB colony forming units (CFU) in lung by 1.67 log10 dosed at 25 mg/kg for 15 days. In conclusion, our data demonstrate that IMB-XMA0038 is a promising lead compound against drug-resistant tuberculosis.

Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads.

Polyketide synthase 13 (Pks13) is an essential enzyme in the synthesis of mycolic acids in Mtb. Therefore, Pks13 is a promising drug target for tuberculosis treatment. We used a structure-guided approach to identify novel chemotype inhibitors of Pks13 and assessed them using a Pks13 enzymatic assay and surface plasmon resonance. The structure-activity relationships (SAR) results demonstrated that the substituents at the 2, 5, and 6 positions of the 4H-chromen-4-one scaffold are critical for maintaining the MIC. Compound 6e with 2-hydroxyphenyl at the 2 position of the 4H-chromen-4-one scaffold, exhibited potent activity against Mtb H37Rv (MIC = 0.45 µg/mL) and displayed good Pks13 affinity and inhibition (IC50 = 14.3 µM). This study described here could provide an avenue to explore a novel inhibitor class for Pks13 and aid the further development of antituberculosis drugs.

Do carbon emissions impact the health of residents? Considering China's industrialization and urbanization.

Industrialization and urbanization have aggravated the contradiction between environmental protection and economic growth, leading to health issues. While there are considerable interests in understanding the health effects of carbon emissions in the context of climate change, little is observed at regional scale and by econometric methods. Applying regression analysis on 2002-2017 Chinese provincial-level panel data, this study explores the intermediary mechanisms and regional differences of carbon emissions on residents' health. The results indicate that: (1) Carbon emissions have a long-term adverse impact on residents' health-a 1% rise in carbon emission adds 0.298% more outpatients and 0.162% more inpatients; (2) The rise in carbon emissions impairs residents' health mainly by raising the temperature; (3) In areas with high levels of industrialization and urbanization, increased carbon emissions bring greater health risks; and (4) In terms of China's unique "leading industrialization and lagging urbanization" situation, only by upgrading industrial structure, improving urbanization quality, and promoting coordinated industrialization and urbanization can the harm of carbon emissions to residents' health be reduced. Therefore, the "one-size-fits-all" policy model is not suitable for China's current situation. To address global "climate change" issues, China must act according to local conditions by applying mitigating (adaptive) measures in economically developed (less developed) regions. Simultaneously, the authorities must focus on the interaction and synergy between industrialization and urbanization.

Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-ß-lactamase-1.

New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.

Digging Deeper to Save the Old Anti-tuberculosis Target: D-Alanine-D-Alanine Ligase With a Novel Inhibitor, IMB-0283.

The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) has hampered treatments for tuberculosis, which consequently now require novel agents to overcome such drug resistance. The genetically stable D-alanine-D-alanine ligase A (DdlA) has been deemed as an excellent therapeutic target for tuberculosis. In the present study, a competitive inhibitor (IMB-0283) of DdlA was obtained via high-throughput screening. The minimum inhibitory concentrations (MIC) of IMB-0283 for the standard and clinical drug-resistant Mtb strains ranged from 0.25 to 4.00 µg/mL, whereas the conventional inhibitor of DdlA, D-cycloserine (DCS), only inhibited the growth of the standard Mtb strain at 16 µg/mL. The lethal effect of IMB-0283 on Mtb was found to act intracellularly in a DdlA-dependent manner. Specifically, IMB-0283 prevented the synthesis of neonatal cell walls but did not damage mature cell walls. Compared with those of DCS, IMB-0283 exhibited lower cytotoxicity and a higher selective index (SI). At the same dosages of treatment, IMB-0283 reduced bacterial load (log CFU/mL) in an acute animal model from 5.58 to 4.40, while DCS did not yield any such treatment efficacy. Taken together, the lower cytotoxicity and more efficacious in vivo activity of IMB-0283 suggest that it is a promising lead compound for antituberculosis drug development.

IMB-SD62, a triazolothiadiazoles derivative with promising action against tuberculosis.

One lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole was identified as an inhibitor of shikimate dehydrogenase with antitubercular activity. Following up this compound, we optimized the lead through systematic modification of the 3 and 6 positions. The antitubercular activities in vitro, shikimate dehydrogenase inhibitory activities and cytotoxicity of derivatives were determined. We found IMB-SD62 with lower cytotoxicity and better activity. Thus, we studied the in vivo efficacy of IMB-SD62 against Mycobacterium tuberculosis and pharmacokinetics of IMB-SD62. In vivo acute M. tuberculosis H37Rv infection assay, IMB-SD62 showed antitubercular activity with the mean lung CFU counts decreasing 1.7 lg. The plasma pharmacokinetics study in rats showed that the oral bioavailability of IMB-SD62 was 14% and the half time was 1.05 h. The results of tissue distribution indicated that IMB-SD62 was mainly absorbed by liver and lung. In vitro metabolism study suggested that the metabolic ways of IMB-SD62 were dealkylated, oxidized and demethylated. CYP enzyme inhibition of IMB-SD62 in human liver microsomes was also evaluated. IMB-SD62 showed barely inhibition on CYP3A4 and CYP2D6. The excretion study manifested that IMB-SD62 was mainly eliminated by fecal excretion in rats. We concluded that based on these pharmaceutical properties, IMB-SD62 has the potential to be developed into new TB drug.

Plasmid to generate Mycobacteria mutants.

The generation of conditional mutants has been an effective approach to studying bacteria and validating drug targets, and mutants of Mycobacteria are no exception. However unlike other bacteria, there is still a paucity of available tools for Mycobacteria. We constructed a new plasmid containing tetracycline-repressive expression system (TetRr1.7) and Xer Site-Specific recombinase system to generate label-free controllable expression strains. The plasmid was subsequently used to construct a strain of M. tuberculosis expressing the only copy of D-alanine:D-alanine ligase under the control of the tetracycline-repressive promoter. The results showed that the mutant strain lost the ability of colony formation, became more sensitive to D-cycloserine and the cell wall of the mutant strain was disrupted when anhydrotetracycline was added to the medium. Taken together these observations, confirmed that the expression of D-alanine:D-alanine ligase was tightly controlled by the promoter. In conclusion, the new plasmid is a convenient tool for constructing stable conditional mutant strains in Mycobacteria and can be used for future target identification.

Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains.

Following up the SAR study of triazolothiadiazoles for their antitubercular activities targeting Mt SD in our previous study, on the principle of scaffold hopping, the C3 and C6 positions of triazolothiadiazine were examined systematically to define a preliminary structure-activity relationship (SAR) with respect to biological activity. This study herein highlights the potential of two highly potent advanced leads 6c-3, 6g-3 and several other compounds with comparable potencies as promising new candidates for the treatment of TB (6c-3, MIC-H37Rv=0.25µg/mL; MIC-MDRTB=2.0µg/mL; MIC-RDRTB=0.25µg/mL; Mt SD-IC50=86.39µg/mL; and 6g-3, MIC-H37Rv=1.0µg/mL; MIC-MDRTB=4.0µg/mL; MIC-RDRTB=2.0µg/mL; Mt SD-IC50=73.57µg/mL). Compounds 6c-3 and 6g-3 possessed a para-nitro phenyl at the 6 position showed low Vero and HepG2 cells toxicity, turning out to be two excellent lead candidates for preclinical trials. In addition, in vitro Mt SD inhibitory assay indicates that Mt SD is at least one of the targets for their antitubercular activity. Thus, they may turn out to be promising multidrug-resistance-reversing agents.

Identification of a novel inhibitor of isocitrate lyase as a potent antitubercular agent against both active and non-replicating Mycobacterium tuberculosis.

OBJECTIVE: Screen and identify novel inhibitors of isocitrate lyase (ICL) as potent antitubercular agents against Mycobacterium tuberculosis and determine their inhibitory characteristics, antitubercular activities and mechanisms of action. METHODS: Recombinant ICL of M. tuberculosis was expressed and purified, which was used for high-throughput screening (HTS) and the following experiments. A total of 71,765 compounds were screened to identify ICL inhibitors which were then evaluated for their roles as potent antitubercular agents. To determine the inhibitory characteristics of the agents against latent M. tuberculosis in persistent infections, a macrophage model (mouse J774A.1 cell) infected with Mycobacterium marinum BAA-535 strain was built and assessed. The potent antitubercular agents were identified using the macrophage model. Then, the inhibitory intensity and mode of the agents that exhibit on ICL protein of M. tuberculosis were analyzed, and the interaction mechanisms were preliminarily clarified according to the parameters of enzyme kinetics, circular dichroism experiments, fluorescence quenching assay, and molecular docking. RESULTS: The previously established ICL inhibitor screening model was evaluated to be suitable for HTS assay. Of the 71,765 compounds, 13 of them were identified to inhibit ICL effectively and stably. IMBI-3 demonstrated the most significant inhibitory activity with IC50 of 30.9 µmol/L. Its minimum inhibitory concentration (MIC) for M. tuberculosis, including extensively drug-resistant tuberculosis (XDR-TB) and multidrug-resistant tuberculosis (MDR-TB), were determined in the range of 0.25-1 µg/mL. When IMBI-3 is used in combination with isoniazid, the colony-forming units (CFU) counting of latent M. tuberculosis in J774A.1 macrophage cells decreased significantly as IMBI-3 concentration increased. The inhibition mode of IMBI-3 on ICL was probably competitive inhibition with an inhibition constant (Ki) of approximate 1.85 µmol/L. The interaction between IMBI-3 and ICL of M. tuberculosis was also confirmed by circular dichroism experiments and fluorescence quenching assay. And seven possible active amino acids of ICL of M. tuberculosis were identified in the active site through molecular docking. CONCLUSION: IMBI-3, a novel potent antitubercular agent targeting ICL of M. tuberculosis, was identified and evaluated. It inhibited both log-phase M. tuberculosis in vitro and dormant M. tuberculosis in macrophages. It was the first representative compound of this family with the ICL enzyme inhibition and antimycobacterial activities.

Identification and validation of a novel lead compound targeting 4-diphosphocytidyl-2-C-methylerythritol synthetase (IspD) of mycobacteria.

Tuberculosis is a serious threat to world-wide public health usually caused in humans by Mycobacterium tuberculosis (M. tuberculosis). It exclusively utilizes the methylerythritol phosphate (MEP) pathway for biosynthesis of isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), the precursors of all isoprenoid compounds. The 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (IspD; EC 2.7.7.60) is the key enzyme of the MEP pathway. It is also of interest as a new chemotherapeutic target, as the enzyme is absent in mammals and ispD is an essential gene for growth. A high-throughput screening method was therefore developed to identify compounds that inhibit IspD. This process was applied to identify a lead compound, domiphen bromide (DMB), that may effectively inhibit IspD. The inhibitory action of DMB was confirmed by over-expressing or down-regulating IspD in Mycobacterium smegmatis (M. smegmatis), demonstrating that DMB inhibit M. smegmatis growth additionally through an IspD-independent pathway. This also led to higher levels of growth inhibition when combined with IspD knockdown. This novel IspD inhibitor was also reported to exhibit antimycobacterial activity in vitro, an effect that likely occurs as a result of perturbation of cell wall biosynthesis.

Two streptothricins with a cis-streptolidine lactam moiety from Streptomyces sp. I08A 1776.

Two unique cis-fused streptothricins (1 and 2) were isolated from the culture broth of Streptomyces sp. I08A 1776. Their structures were determined by MS, CD, and 1D and 2D NMR spectroscopic data analysis. Compound 2 showed weak antibacterial activities against Bacillus subtilis and Enterococcus faecalis with MIC values of 32 and 64 µg ml(-1), respectively.

A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition.

Mycobacterium tuberculosis pantothenate synthetase is a potential anti-tuberculosis target, and a high-throughput screening system was previously developed to identify its inhibitors. Using a similar system, we screened a small library of compounds and identified actinomycin D (ActD) as a weak inhibitor of pantothenate synthetase. A new method was established to discover more effective inhibitors by determining the molecular mechanism of ActD inhibition followed by structure-based virtual screening. The molecular interaction of inhibition was determined by circular dichroism and tryptophan fluorescence quenching. The structure-based search and virtual screening were performed using the Molecular Operating Environment (MOE) program and SYBYL 7.5, respectively. Two inhibitors were identified with an IC(50) for pantothenate synthetase that was at least ten times better than that of ActD.

Streptothricin derivatives from Streptomyces sp. I08A 1776.

Five new streptothricin derivatives with a carbamoyl group substituted at C-12 (1-5) and three known analogues have been isolated from the culture broth of Streptomyces sp. I08A 1776 by ion exchange and hydrophilic interaction chromatographic techniques. Their structures were determined by spectroscopic and chemical methods. Compound 3 was a streptothricin derivative possessing a cis-streptolidine moiety. Its absolute configuration was defined by comparison of quantum chemical TDDFT calculated and experimental ECD spectra. Compound 5 and streptothricin E (6) displayed antibacterial and antifungal activity with MIC values in the range 1-64 µg/mL.