Four sulfur-containing compounds with anti-colon cancer effect from marine-derived fungus Aspergillus terreus.

Sulfur-containing natural products possess a variety of biological functions including antitumor, antibacterial, anti-inflammatory and antiviral activities. In this study, four previously undescribed sulfur-containing compounds asperteretals L and M, terreins A and B, together with 17 known compounds were obtained from a culture of marine fungus A. terreus supplemented with inorganic sulfur source Na2SO4. Their planar structures and absolute configurations were elucidated by NMR, HRESIMS, and ECD experiments. The in vitro cytotoxicities of compounds 1-21 against HCT-116 and Caco-2 were evaluated by SRB assay. Asperteretal M (2) exhibited activity against HCT-116 with the IC50 value at 30µM. The antiproliferative effect of asperteretal M was confirmed by colony formation assay and cell death staining. Furthermore, the preliminary study on the anti-colon cancer mechanism of asperteretal M was performed by RNA-seq analysis. Western blotting validated that asperteretal M significantly decreased the expression of cell-cycle regulatory proteins CDK1, CDK4, and PCNA in a concentration-dependent manner.

[Clinical and genetic analyses of Joubert syndrome in children]. / 儿童Joubertç»¼åˆå¾ä¸´åºŠåŠé—ä¼ å­¦åˆ†æž.

OBJECTIVES: To study the clinical and genetic features of Joubert syndrome (JS) in children. METHODS: A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022. RESULTS: Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1, RPGRIP1L, MKS1, CC2D2A, CEP120, and AHI1 genes. CONCLUSIONS: For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.

Design, Synthesis and Biological Evaluation of Novel Pleuromutilin Derivatives Containing 6-Chloro-1-R-1H-pyrazolo[3,4-d]pyrimidine-4-amino Side Chain.

Two series of pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). 6-chloro-4-amino-1-R-1H-pyrazolo[3,4-d]pyrimidine or 4-(6-chloro-1-R-1H-pyrazolo[3,4-d]pyrimidine-4-yl)amino-phenylthiol were connected to pleuromutilin. A diverse array of substituents was introduced at the N-1 position of the pyrazole ring. The in vitro antibacterial activities of these semisynthetic derivatives were evaluated against two standard strains, Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300, Staphylococcus aureus (S. aureus), ATCC 29213 and two clinical S. aureus strains (144, AD3) using the broth dilution method. Compounds 12c, 19c and 22c (MIC = 0.25 µg/mL) manifested good in vitro antibacterial ability against MRSA which was similar to that of tiamulin (MIC = 0.5 µg/mL). Among them, compound 22c killed MRSA in a time-dependent manner and performed faster bactericidal kinetics than tiamulin in time-kill curves. In addition, compound 22c exhibited longer PAE than tiamulin, and showed no significant inhibition on the cell viability of RAW 264.7, Caco-2 and 16-HBE cells at high doses (≤8 µg/mL). The neutropenic murine thigh infection model study revealed that compound 22c displayed more effective in vivo bactericidal activity than tiamulin in reducing MRSA load. The molecular docking studies indicated that compound 22c was successfully localized inside the binding pocket of 50S ribosomal, and four hydrogen bonds played important roles in the binding of them.

Lentinuses A-B, two alkaloids from the marine-derived fungus Lentinus sajor-caju with potent anti-pulmonary fibrosis activity.

By adding natural amino acids into the medium as sole nitrogen source, twenty-four compounds, including two new alkaloids lentinuses A-B (1-2) with a rare oxazinone core in marine natural products, one new natural product 3-acetamido-4-phenylfurazan (3), 9ß-ergosterol (22) were firstly discovered from a marine fungus, and twenty known compounds (4-21, 23-24) were isolated from the marine-derived fungus Lentinus sajor-caju. The chemical structures of all these compounds were elucidated by HRMS, NMR spectroscopy and X-ray diffraction. Compounds 1-24 were evaluated for their inhibitory activity against TGF-ß1-induced collagen accumulation in human fetal lung fibroblasts (HFL1). Compounds 2, 3, 12, 22, and 23 showed potent activity against TGF-ß1-induced collagen accumulation and low toxicity to HFL1 cells. The binding mode of lentinus B (2) with TGF-ß1 receptor was then performed by using Schrödinger software, and the result showed that lentinus B possesses a strong binding force such as hydrogen bonding and hydrophobic interactions to the protein, which may provide a theoretical basis to design more potent anti-fibrotic drugs in the future.

Efficacy of Guhong injection versus Butylphthalide and Sodium Chloride Injection for mild ischemic stroke: A multicenter controlled study.

BACKGROUND: Most studies on Guhong injection have involved a single center with a small sample size, and the level of clinical evidence is low. AIM: To assess the safety and efficacy of Guhong injection for mild ischemic stroke (IS). METHODS: A total of 399 IS patients treated at six hospitals from August 2018 to August 2019 were retrospectively analyzed. The patients were given Guhong injection (experimental group) or Butylphthalide and Sodium Chloride Injection (control group). Changes in National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores were observed before treatment and at 1, 2, and 3 wk after treatment in each group. The efficacy and safety of Guhong injection for IS were assessed. Other medications taken by the patients were confounding factors for efficacy assessment. These factors were controlled by propensity score matching, and the results were further analyzed based on the matching. RESULTS: The marked response rates at three follow-up visits were 64.64%, 74.7%, and 66.7% in the experimental group, and 48.26%, 45.4%, and 22.2% in the control group. The marked response rates increased significantly in the experimental group compared with the control group (P < 0.05). The overall response rate at the first visit (days 7 ± 2) did not differ significantly between the two groups, but differed significantly at the second (days 14 ± 2) and third visits (days 21 ± 3) (P < 0.05). The proportion of patients without any symptoms in the experimental group was significant different at the first visit (P < 0.05), but not significantly different at the second visit. The two groups showed no significant difference in the baseline distribution of mRS scores. At the first and second visits, the change in mRS scores was -2 and -1 in the experimental and control groups, respectively, which were significantly different (P < 0.05). After propensity score matching, the overall response rate and marked response rate were 97.29% and 100% in the experimental group (P > 0.05) and 64.0% and 47.7% in the control group (P < 0.05) at the first visit, respectively. The decreased NIHSS scores in the two groups were significant different (P < 0.05). The overall response rate and marked response rate differed significantly between the two groups at the second visit (P < 0.05). There was no significant difference in the incidence of adverse events between the two groups. No severe adverse events occurred in either group. CONCLUSION: Guhong injection is safe and more effective than Butylphthalide and Sodium Chloride Injection for treatment of IS.

The critical role of ferritinophagy in human disease.

Ferritinophagy is a type of autophagy mediated by nuclear receptor activator 4 (NCOA4), which plays a role in inducing ferroptosis by regulating iron homeostasis and producing reactive oxygen species in cells. Under physiological conditions, ferritinophagy maintains the stability of intracellular iron by regulating the release of free iron. Studies have demonstrated that ferritinophagy is necessary to induce ferroptosis; however, under pathological conditions, excessive ferritinophagy results in the release of free iron in large quantities, which leads to lipid peroxidation and iron-dependent cell death, known as ferroptosis. Ferritinophagy has become an area of interest in recent years. We here in review the mechanism of ferritinophagy and its association with ferroptosis and various diseases to provide a reference for future clinical and scientific studies.

ß-Carboline Alkaloids From the Deep-Sea Fungus Trichoderma sp. MCCC 3A01244 as a New Type of Anti-pulmonary Fibrosis Agent That Inhibits TGF-ß/Smad Signaling Pathway.

Pulmonary fibrosis is a scarring disease of lung tissue, which seriously threatens human health. Treatment options are currently limited, and effective strategies are still lacking. In the present study, 25 compounds were isolated from the deep-sea fungus Trichoderma sp. MCCC 3A01244. Among them, two ß-carboline alkaloids, trichocarbolines A (1) and C (4) are new compounds. The chemical structures of these compounds were elucidated based on their HRESIMS, 1D and 2D NMR spectra, optical rotation calculation, and comparisons with data reported in the literature. Trichocarboline B [(+)- and (-)-enantiomers] had previously been synthesized, and this is its first report as a natural product. Their anti-pulmonary fibrosis (PF) activity and cytotoxicity were investigated. Compounds 1, 11, and 13 strongly inhibited TGF-ß1-induced total collagen accumulation and showed low cytotoxicity against the HFL1 cell line. Further studies revealed compound 1 inhibited extracellular matrix (ECM) deposition by downregulating the expression of protein fibronectin (FN), proliferating cell nuclear antigen (PCNA), and α-smooth muscle actin (α-SMA). Mechanistic study revealed that compound 1 decreased pulmonary fibrosis by inhibiting the TGF-ß/Smad signaling pathway. As a newly identified ß-carboline alkaloid, compound 1 may be used as a lead compound for developing more efficient anti-pulmonary fibrosis agents.

Exophilone, a Tetrahydrocarbazol-1-one Analogue with Anti-Pulmonary Fibrosis Activity from the Deep-Sea Fungus Exophiala oligosperma MCCC 3A01264.

A new compound, exophilone (1), together with nine known compounds (2-10), were isolated from a deep-sea-derived fungus, Exophiala oligosperma. Their chemical structures, including the absolute configuration of 1, were elucidated using nuclear magnetic resonance (NMR) spectroscopy, high-resolution electrospray ionization mass spectroscopy (HRESIMS), and electronic circular dichroism (ECD) calculation. Compounds were preliminarily screened for their ability to inhibit collagen accumulation. Compounds 1, 4, and 7 showed weaker inhibition of TGF-ß1-induced total collagen accumulation in compared with pirfenidone (73.14% inhibition rate). However, pirfenidone exhibited cytotoxicity (77.57% survival rate), while compounds 1, 4, and 7 showed low cytotoxicity against the HFL1 cell line. Particularly, exophilone (1) showed moderate collagen deposition inhibition effect (60.44% inhibition rate) and low toxicity in HFL1 cells (98.14% survival rate) at a concentration of 10 µM. A molecular docking study suggests that exophilone (1) binds to both TGF-ß1 and its receptor through hydrogen bonding interactions. Thus, exophilone (1) was identified as a promising anti-pulmonary fibrosis agent. It has the potential to be developed as a drug candidate for pulmonary fibrosis.

Design, synthesis, antibacterial activity evaluation and molecular docking study of pleuromutilin derivatives bearing amide side chains.

A seize of pleuromutilin derivatives containing amide side chains were designed and synthesized as potential antibiotics against Methicillin-resistant Staphylococcus aureus (MRSA). Among all target compounds (compounds 11-30), compound 25 was found to have the strongest antibacterial activity against MRSA (minimum inhibitory concentration = 0.5 µg/ml). The result of the time-kill curves indicated that compound 25 could repress the growth of MRSA in vitro obviously (-3.72 log10 CFU/ml reduction). Furthermore, molecular docking studies demonstrated that compound 25 was localized in the binding pocket of 50S ribosomal subunit (ΔGb = -8.99 kcal/mol). Besides, compound 25 displayed low cytotoxicity to RAW 264.7 cells. The results suggested that compound 25 might be further developed into a novel antimicrobial agent against MRSA.

Semisynthetic pleuromutilin antimicrobials with therapeutic potential against methicillin-resistant Staphylococcus aureus by targeting 50S ribosomal subunit.

A series of pleuromutilin analogs with a substituted 1,2,4-triazole were designed, synthesized and assessed for their in vitro and in vivo antibacterial activity. Initially, the MIC of the synthesized derivatives against five strains of Staphylococcus aureus (MRSA ATCC 43300, S. aureus ATCC 29213, clinical isolation of S. aureus AD3, S. aureus 144 and S. aureus SA17) were tested by the broth dilution method. Compounds 30a, 31b and 32a were the most active antibacterial agents in vitro against MRSA (MIC = 0.0625 µg/mL). The results of the time-kill curves showed that compounds 30a and 32a could reduce the amount of MRSA in vitro quickly (-7.70 log10 CFU/mL and -7.10 log10 CFU/mL reduction). In the experiment to further evaluate the in vivo antibacterial activity of compound 30a against MRSA, compound 30a (-1.71 log10 CFU/g) was effective in reducing MRSA load in thigh infected mice. Compound 30a (survival rate was 50%) displayed superior in vivo efficacy to that of tiamulin (survival rate was 30%) in the mouse systemic model. The results of further pharmacokinetic studies on compound 30a showed that the half-life (t1/2), clearance rate (Cl) and the area under the plasma concentration time curve (AUC0→∞) of compound 30a were 0.37 h, 5.43 L/h/kg and 1.84 µg h/mL, respectively. After affinity measurement by surface plasmon resonance (SPR), compound 30a exhibited high affinity with the 50S ribosome, with KD value of 1.95 × 10-6 M. Furthermore, the results of molecular docking studies revealed that compound 30a was successfully localized inside the binding pocket of 50S ribosomal subunit (ΔGb = -9.40 kcal/mol). Meanwhile, most of these compounds had no significant inhibitory effect on RAW 264.7 cells and 16HBE cells at the concentration of 8 µg/mL. The obtained outcomes showed that compound 30a could be utilized as an encouraging perspective in the development of a new therapeutic candidate for bacterial infection.

Selection of optimal models for predicting growth stress in Artemisia desertorum by comparison of linear regression and multiple neural networks: Take the construction of a green mine in the Bayan Obo mine as an example.

In recent years, more and more countries are focusing on the control of mining sites and the surrounding ecological environment, and the new environmental concept of green mines has been proposed. By investigating the ecological background of a mine site, pollution and ecological imbalances in the mine can be predicted, managed or transformed. This study investigated the effects of rare earth elements on plant growth in the Baotou Bayan Obo Rare Earth Mine and evaluated soil contamination and subsequent remediation through the measured plant height. Using linear regression, BP(Back Propagation) neural networks, GA-BP(Genetic Algorithm- Back Propagation) neural networks, ELM(Extreme Learning Machine) and GA-ELM(Genetic Algorithm- Extreme Learning Machine) model prediction instruments, the different rare earth solution concentrations were set as input values and the heights of Artemisia desertorum, which as the model plant, were set as output values in the prediction. The results showed that the linear regression predicted the standard error of single La(III), Ce(III) solution and compound La(III) + Ce(III) solution for Artemisia desertorum growth stress was on the high side, 7.02%- 8.92%; the efficiency range of each group of models under BP neural network, GA-BP neural network and ELM neural network were 1.15%- 2.53%, 0.85%- 1.28%, 1.76%- 3.53%; while the efficiency range under GA-ELM neural network was 0.59%- 0.68%, with average error values and predicted values close to the true values. Among them, the MAPE of GA-ELM neural network are significantly lower than other models, and the error decreases with increasing concentration of the compound solution. So GA-ELM neural network can be used as an efficient, fast and reasonable optimal model for predicting the growth stress of Artemisia desertorum in Bayan Obo mining area. The experimental results can provide a theoretical basis for assessing the risk of soil rare earth contamination in the area, evaluating the expectation of later remediation, and provide a degree of new ideas for the construction of green mines.

Mechanisms and pharmacological applications of ferroptosis: a narrative review.

OBJECTIVE: We aimed at comprehensively analyzing ferroptosis regulation and its potential role in the treatment of associated diseases. BACKGROUND: Ferroptosis is a recently discovered form of cell death that involves small molecule-induced oxidative cell death. This process is usually accompanied by large amounts of iron accumulation and lipid peroxidation. Ferroptosis inducers directly or indirectly affect glutathione peroxidase (GPXs) through different pathways. Disturbances in GPXs result in suppressed cellular antioxidant capacities, accumulation of lipid reactive oxygen species (ROS) and oxidative cell death. It has been reported that ferroptosis is closely associated with the pathophysiological processes of many diseases, including tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury and iron metabolism diseases among others. METHODS: First, we reviewed the mechanisms of ferroptosis, with emphasis on the characteristics and functions of ferroptosis in multiple pathways. Then, inducers and inhibitors of ferroptosis were reviewed, and their mechanisms of action elucidated. Finally, ferroptosis-associated pathophysiological processes of various diseases were reviewed. CONCLUSIONS: Ferroptosis is associated with the occurrence and development of various diseases. Elucidation of the mechanisms involved in ferroptosis will inform new therapeutic targets and strategies for these diseases.

Changes of the Brain Causal Connectivity Networks in Patients With Long-Term Bilateral Hearing Loss.

It remains poorly understood how brain causal connectivity networks change following hearing loss and their effects on cognition. In the current study, we investigated this issue. Twelve patients with long-term bilateral sensorineural hearing loss [mean age, 55.7 ± 2.0; range, 39-63 years; threshold of hearing level (HL): left ear, 49.0 ± 4.1 dB HL, range, 31.25-76.25 dB HL; right ear, 55.1 ± 7.1 dB HL, range, 35-115 dB HL; the duration of hearing loss, 16.67 ± 4.5, range, 3-55 years] and 12 matched normally hearing controls (mean age, 52.3 ± 1.8; range, 42-63 years; threshold of hearing level: left ear, 17.6 ± 1.3 dB HL, range, 11.25-26.25 dB HL; right ear, 19.7 ± 1.3 dB HL, range, 8.75-26.25 dB HL) participated in this experiment. We constructed and analyzed the causal connectivity networks based on functional magnetic resonance imaging data of these participants. Two-sample t-tests revealed significant changes of causal connections and nodal degrees in the right secondary visual cortex, associative visual cortex, right dorsolateral prefrontal cortex, left subgenual cortex, and the left cingulate cortex, as well as the shortest causal connectivity paths from the right secondary visual cortex to Broca's area in hearing loss patients. Neuropsychological tests indicated that hearing loss patients presented significant cognitive decline. Pearson's correlation analysis indicated that changes of nodal degrees and the shortest causal connectivity paths were significantly related with poor cognitive performances. We also found a cross-modal reorganization between associative visual cortex and auditory cortex in patients with hearing loss. Additionally, we noted that visual and auditory signals had different effects on neural activities of Broca's area, respectively. These results suggest that changes in brain causal connectivity network are an important neuroimaging mark of cognitive decline. Our findings provide some implications for rehabilitation of hearing loss patients.

[Effect of rehabilitation treatment based on the ICF-CY Core Sets on activities of daily living in children with cerebral palsy: a prospective randomized controlled study].

OBJECTIVE: To study the effect of rehabilitation treatment based on the International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY) Core Sets on activities of daily living in children with cerebral palsy. METHODS: The children with cerebral palsy were divided into an observation group (n=63) and a control group (n=59) using a random number table. The children in the observation group were evaluated using the brief ICF-CY Core Sets for children under 6 years to identify intervention targets and develop rehabilitation plans and goals, and then specific methods were selected for rehabilitation treatment. The children in the control group were evaluated and treated with the traditional rehabilitation mode. The scores of the Functional Independence Measure for Children (WeeFIM) and the Infants-Junior Middle School Students' Social-Life Abilities Scale were assessed for both groups before treatment and after three courses of treatment. The intervention of environmental factors was compared between the two groups. RESULTS: There was no significant difference in the scores of the WeeFIM and Social-Life Abilities scales between the two groups before treatment (P > 0.05). After treatment, both groups had significant increases in the scores of the WeeFIM and Social-Life Abilities scales (P < 0.001). The observation group had significantly higher scores of WeeFIM and Social-Life Abilities scales than the control group after treatment (P < 0.05). There was no significant difference in the use rate of orthosis between the two groups (P > 0.05), but the use rate of assistive devices for self-help, transfer and communication, the rate of facility renovation, and the rate of family rehabilitation guidance in the observation group were significantly higher than those in the control group (P < 0.05). CONCLUSIONS: The rehabilitation treatment regimen for cerebral palsy based on the CF-CY Core Sets pays more attention to the influence of environmental factors in the process of rehabilitation and can effectively improve the activities of daily living of children with cerebral palsy.

Design, synthesis and biological evaluation of pleuromutilin-Schiff base hybrids as potent anti-MRSA agents in vitro and in vivo.

A series of pleuromutilin derivatives with 1,2,4-triazole-3-substituted Schiff base structure were designed and synthesized under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against 4 strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus 144 and S.aureus AD3) and 1 strain of E. coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, compound 60 exhibited superior in vitro antibacterial effect against MRSA (MIC = 0.25 µg/mL) than tiamulin (MIC = 0.5 µg/mL), and compound 60 (-2.28 log10 CFU/mL) also displayed superior in vivo antibacterial efficacy than tiamulin (-1.40 log10 CFU/mL) in reducing MRSA load in the mouse thigh infection model. The time-kill study and the post-antibiotic effect study indicated that compound 60 showed a faster bactericidal kinetic and longer PAE time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 4.06 and 4.27 h) against MRSA compared with tiamulin (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.72 and 2.14 h). Meanwhile, most of these compounds had no significant inhibitory effect on RAW 264.7 cells and HepG2 cells at the concentration of 4 µg/mL. Additionally, the development of resistance study showed that MRSA did not easily develop resistance against compound 60 compared with tiamulin after induction for 8 passages.

Autophagy is Involved in Neuroprotective Effect of Alpha7 Nicotinic Acetylcholine Receptor on Ischemic Stroke.

The α7 nicotinic acetylcholine receptor (α7nAChR) belongs to the superfamily of cys loop cationic ligand-gated channels, which consists of homogeneous α7 subunits. Although our lab found that activation of α7nAChR could alleviate ischemic stroke, the mechanism is still unknown. Herein, we explored whether autophagy is involved in the neuroprotective effect mediated by α7nAChR in ischemic stroke. Transient middle cerebral artery occlusion (tMCAO) and oxygen and glucose deprivation (OGD/R) exposure were applied to in vivo and in vitro models of ischemic stroke, respectively. Neurological deficit score and infarct volume were used to evaluate outcomes of tMCAO in the in vivo study. Autophagy-related proteins were detected by Western blot, and autophagy flux was detected by using tandem fluorescent mRFP-GFP-LC3 lentivirus. At 24 h after tMCAO, α7nAChR knockout mice showed worse neurological function and larger infarct volume than wild-type mice. PNU282987, an α7nAChR agonist, protected against OGD/R-induced neuronal injury, enhanced autophagy, and promoted autophagy flux. However, the beneficial effects of PNU282987 were eliminated by 3-methyladenine (3-MA), an autophagy inhibitor. Moreover, we found that PNU282987 treatment could activate the AMPK-mTOR-p70S6K signaling pathway in the in vitro study, while the effect was attenuated by compound C, an AMPK inhibitor. Our results demonstrated that the beneficial effect on neuronal survival via activation of α7nAChR was associated with enhanced autophagy, and the AMPK-mTOR-p70S6K signaling pathway was involved in α7nAChR activation-mediated neuroprotection.

Design, synthesis, in vitro and in vivo evaluation against MRSA and molecular docking studies of novel pleuromutilin derivatives bearing 1, 3, 4-oxadiazole linker.

A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85-110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 µg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.

Design, synthesis and biological evaluation of novel pleuromutilin derivatives as potent anti-MRSA agents targeting the 50S ribosome.

A series of novel pleuromutilin derivatives were designed and synthesized with 1,2,4-triazole as the linker connected to benzoyl chloride analogues under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, AD3 and 144) were tested by the broth dilution method. Most of the synthesized derivatives displayed potent activities, and 22-(3-amino-2-(4-methyl-benzoyl)-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 12) was found to be the most active antibacterial derivative against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed compound 12 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 12 was further evaluated using MRSA infected murine thigh model. Compound 12 exhibited superior antibacterial efficacy than tiamulin. It was also found that compound 12 had no significant inhibitory effect on the proliferation of RAW264.7 cells. Compound 12 was further evaluated in CYP450 inhibition assay and showed moderate inhibitory effect on CYP3A4 (IC50 = 3.95 µM). Moreover, seven candidate compounds showed different affinities with the 50S ribosome by SPR measurement. Subsequently, binding of compound 12 and 20 to the 50S ribosome was further investigated by molecular modeling. Three strong hydrogen bonds were formed through the interaction of compound 12 and 20 with 50S ribosome. The binding free energy of compound 12 and 20 with the ribosome was calculated to be -10.7 kcal/mol and -11.66 kcal/mol, respectively.

[Characteristics and Evaluation of Soil Rare Earth Element Pollution in the Bayan Obo Mining Region of Inner Mongolia].

The Bayan Obo deposit is the largest light rare earth ore deposit in the world, which releases rare earth elements (REEs) to the surrounding environment through long-term mining processes. To inform restoration plans, it is necessary to investigate the concentration, spatial distribution, pollution level, and ecological risk of REEs. Sample analyses showed that the average total concentration of REEs in this area is 6064.95 mg·kg-1, which was higher than the background levels of control soils (207.44 mg·kg-1), Inner Mongolia (150.95 mg·kg-1), and China (184.72 mg·kg-1). Light REEs (LREEs) accounted for 83%-99% of the detected REE, and Ce was the dominant element. Areas with high REE concentrations were mainly located near the source bed, and the distribution was extremely inhomogeneous, being greatly affected by external interference. Chondrite normalized REE patterns of different functional areas were similar and normalized curves inclined to the right, indicating district fractionation between the LREE and heavy REEs (HREEs). Significant negative Eu anomalies and positive Ce anomalies were observed in the soils based on δCe and δEu values. La/Yb, La/Sm, and Gd/Yb ratios all indicated that the soils were LREE-enriched, whereas the LREEs were more fractionated than the HREE. Four methods were employed to evaluate the pollution and ecological risk of the detected soil REEs. The average values of Ce, Nd, Pr, and La reached heavily contaminated levels based the geo-accumulation index (Igeo). The modified degree of contamination method showed that the average mCd values of REEs in different functional areas ranged from 7.14 to 31.38. The tailings pond had a high level of pollution, residential and industrial areas had a very high pollution level, and the mining area and waste dump showed extremely high levels of pollution. Based on the pollution load index, the tailings pond is moderately polluted while all other functional areas are severely polluted. The potential ecological risk index values ranged from 120.99 to 6376.46, with REEs in soils posing high strong risk, very strong risk, strong risk, moderate risk, and low risk in 33%, 16%, 12%, 30%, and 9% of the sampling sites, respectively. Based on these findings, measures for controlling current pollution and potential ecological risks from REE in the soils of the Bayan Obo mining region are urgently needed.

Alterations of Prefrontal-Posterior Information Processing Patterns in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by different levels of repetitive and stereotypic behavior as well as deficits in social interaction and communication. In this current study, we explored the changes in cerebral neural activities in ASD. The purpose of this study is to investigate whether there exists a dysfunction of interactive information processing between the prefrontal cortex and posterior brain regions in ASD. We investigated the atypical connectivity and information flow between the prefrontal cortex and posterior brain regions in ASD utilizing the entropy connectivity (a kind of directional connectivity) method. Eighty-nine patients with ASD and 94 typical developing (TD) teenagers participated in this study. Two-sample t-tests revealed weakened interactive entropy connectivity between the prefrontal cortex and posterior brain regions. This result indicates that there exists interactive prefrontal-posterior underconnectivity in ASD, and this disorder might lead to less prior knowledge being used and updated. Our proposals highlighted that aforementioned atypical change might accelerate the deoptimization of brain networks in ASD.