Melatonin inhibits Gram-negative pathogens by targeting citrate synthase

Bacterial infections caused by Gram-negative pathogens represent a growing burden for public health worldwide. Despite the urgent need for new antibiotics that effectively fight against pathogenic bacteria, very few compounds are currently under development or approved in the clinical setting. Repurposing compounds for other uses offers a productive strategy for the development of new antibiotics. Here we report that the multifaceted melatonin effectively improves survival rates of mice and decreases bacterial loads in the lung during infection. Mechanistically, melatonin specifically inhibits the activity of citrate synthase of Gram-negative pathogens through directly binding to the R300, D363, and H265 sites, particularly for the notorious Pasteurella multocida. These findings highlight that usage of melatonin is a feasible and alternative therapy to tackle the increasing threat of Gram-negative pathogen infections via disrupting metabolic flux of bacteria.

     

Cryo-EM structures reveal the dynamic transformation of human alpha-2-macroglobulin working as a protease inhibitor

Science China Life Sciences - Human alpha-2-macroglobulin is a well-known inhibitor of a broad spectrum of proteases and plays important roles in immunity, inflammation, and infections. Here, we...     

Engineering Saccharomyces cerevisiae-based biosensors for copper detection

Heavy metals, that is Cu(II), are harmful to the environment. There is an increasing demand to develop inexpensive detection methods for heavy metals. Here, we developed a yeast biosensor with reduced-noise and improved signal output for potential on-site copper ion detection. The copper-sensing circuit was achieved by employing a secondary genetic layer to control the galactose-inducible (GAL) system in Saccharomyces cerevisiae. The reciprocal control of the Gal4 activator and Gal80 repressor under copper-responsive promoters resulted in a low-noise and sensitive yeast biosensor for copper ion detection. Furthermore, we developed a betaxanthin-based colorimetric assay, as well as 2-phenylethanol and styrene-based olfactory outputs for the copper ion detection. Notably, our engineered yeast sensor confers a narrow range switch-like behaviour, which can give a ‘yes/no’ response when coupled with a betaxanthin-based visual phenotype. Taken together, we envision that the design principle established here might be applicable to develop other sensing systems for various chemical detections.     

Coloration and phenology manifest nutrient variability in senesced leaves of 46 temperate deciduous woody species

颜色和物候表明46种温带落叶木本植物衰老叶片的养分变异 不同共生植物的叶片养分含量差异显著,反映了不同的叶片养分利用策略。然而,衰老叶片养分的种间变异及其驱动因素尚不清楚。本研究旨在探讨衰老叶片养分的种间变异及其驱动因素。我们在中国东北的帽儿山森林生态系统研究站测定了46种共存温带落叶木本植物新鲜落叶的碳、氮、磷浓度。 采用随机森林模型量化10个生物因素(菌根类型、固氮类型、生长形态、耐阴性、叶片质地、变色程度、变色类型、叶片变色峰期、落叶峰期和落叶末期)的相对重要性。研究结果表明,落叶氮浓度种间变化为4倍,磷浓度变化达9倍。较高的氮和磷平均浓度(15.38和1.24 mg g⁻¹)表明该森林氮和磷限制较弱。功能群仅对特定养分及其比值有显著影响。磷浓度、氮磷比与外生菌根树种的落叶高峰日和落叶结束日呈负相关。颜色鲜艳的叶片(红色＞棕色＞黄色＞黄绿色＞绿色)倾向于比绿色叶片氮和磷浓度更低而碳氮比和碳磷比较高。随机森林模型表明,秋季叶变色和落叶物候贡献了80%的种间变异解释量。这些结果增加了我们对温带森林木本植物营养策略之衰老叶片养分变异性的理解。     

Probiotic Therapy (BIO-THREE) Mitigates Intestinal Microbial Imbalance and Intestinal Damage Caused by Oxaliplatin

Probiotics and Antimicrobial Proteins - Gastrointestinal mucositis associated with the use of chemotherapeutic drugs can seriously affect the quality of life of patients. In this study, a probiotic...     

肿瘤转移的分子机制及靶向干预研究新进展

肿瘤转移是一个多阶段的恶性进展过程,涉及肿瘤细胞从原发部位逃逸,侵入脉管系统并在其中存活,随循环系统到达远处靶器官并穿出脉管系统播散定植,最终克隆性生长形成转移瘤。转移过程的每一阶段与肿瘤细胞本身遗传和表观遗传改变以及微环境中诸多因素的综合调控密切相关。本综述概要介绍了恶性肿瘤转移多步骤过程中所涉的分子调控机制以及肿瘤转移靶向干预新措施等方面的研究进展;同时,就未来肿瘤转移研究相关的新技术和新方向作一简单的展望。     

Spectroscopic and molecular modeling studies of the interaction between cytidine and human serum albumin and its analytical application

In this study, the interaction between cytidine and human serum albumin (HSA) was investigated for the first time by fluorescence spectroscopy in combination with UV absorption spectrum and molecular modeling under simulative physiological conditions. Experimental results indicated that cytidine had a strong ability to quench the intrinsic fluorescence of human serum albumin. The binding constants (K) at different temperatures, thermodynamic parameter enthalpy changes (DeltaH) and entropy changes (DeltaS) of HSA-cytidine had been calculated according to the relevant fluorescence data, which indicated that the hydrophobic and electrostatic interactions played a major role, which was in agreement with the results of molecular modeling study. In addition, the effects of other ions on the binding constants were also studied. Furthermore, synchronous fluorescence technology was successfully applied to the determination of human serum albumin added into the cytidine solution.     

Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood-brain barrier

Neurotrophins, such as brain derived neurotrophic factor (BDNF), do not cross the blood-brain barrier (BBB). Certain monoclonal antibodies (MAb) to the human insulin receptor (HIR) do cross the BBB via receptor-mediated transport, and can act as a molecular Trojan horse to ferry across the BBB an attached drug. A genetically engineered fusion protein was produced whereby the amino terminus of human BDNF is fused to the carboxyl terminus of the heavy chain of a chimeric HIRMAb. The HIRMAb-BDNF fusion protein reacted equally with antibodies to human IgG and BDNF. The bi-functionality of the fusion protein was retained as the affinity of the fusion protein for the HIR was identical to that of the chimeric HIRMAb, and the affinity of the fusion protein for the trkB receptor was identical to that of BDNF. The fusion protein was equi-potent with BDNF in a neuroprotection assay in human neural cells. The pharmacokinetics (PK) of the fusion protein was examined in the adult Rhesus monkey. The mean residence time (MRT) of the fusion protein in blood was >100-fold longer than the MRT of BDNF. Therapeutic levels of BDNF were produced in primate brain following the intravenous administration of the fusion protein. A fusion protein tandem vector was engineered that allowed for isolation of a CHO cell line that produced the fusion protein at high levels in serum free medium. Neurotrophins, such as BDNF, can be re-formulated to enable these molecules to cross the human BBB, and such fusion proteins represent a new class of human neurotherapeutics.