Correlation between biological activity and binding energy in systems of integrin with cyclic RGD-containing binders: a QM/MM molecular dynamics study

We here report a combined quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) study on the binding interactions between the α(V)β(3) integrin and eight cyclic arginine-glycine-aspartate (RGD) containing peptides. The initial conformation of each peptide within the binding site of the integrin was determined by docking the ligand to the reactive site of the integrin crystal structure with the aid of docking software FRED. The subsequent QM/MM MD simulations of the complex structures show that these eight cyclic RGD-peptides have a generally similar interaction mode with the binding site of the integrin to the cyclo(RGDf-N[M]V) analog found in the crystal structure. Still, there are subtle differences in the interactions of peptide ligands with the integrin, which contribute to the different inhibition activities. The averaged QM/MM protein-ligand interaction energy (IE) is remarkably correlated to the biological activity of the ligand. The IE, as well as a three-variable model which is somewhat interpretable, thus can be used to predict the bioactivity of a new ligand quantitatively, at least within a family of analogs. The present study establishes a helpful protocol for advancing lead compounds to potent inhibitors.     

S-PI对香菇酸性蛋白酶的抑制机理及其促进出菇的生化解释

S-PI对纯化的香菇酸性蛋白酶具有强烈的抑制作用,10μmol／L的S-PI可使酶活降低77％,这种抑制属于可逆竞争抛物线型抑制。经25μmol／L酸性蛋白酶水解6小时后,香菇胞外酸性磷酸酶的活性从24．6单位降低到20．8单位,同时C1酶和Cx酶的活性分别比对照降低了76％和58％,这表明香菇酸性蛋白酶不仅直接左右着香菇发育的氮代谢,同时也间接地影响着碳代谢及能量转换。     

茶叶中总硒含量及其影响因素的研究

茶叶中硒素总量测定结果表明：土壤含硒量的高低是直接影响茶叶中硒的总量。茶树根、茎、叶、果中均有硒元素,叶片是茶硒积累的主要器官,尤其是老叶,其含量是嫩叶的几倍．茶树品种间含量的差异显著,最大差异达10倍以上．毛茶加工的成品茶含硒量受加工技术措施影响较大,其不同等级的含硒量与级别没有线性关系．     

Persister control by leveraging dormancy associated reduction of antibiotic efflux

Persistent bacterial infections do not respond to current antibiotic treatments and thus present a great medical challenge. These conditions have been linked to the formation of dormant subpopulations of bacteria, known as persister cells, that are growth-arrested and highly tolerant to conventional antibiotics. Here, we report a new strategy of persister control and demonstrate that minocycline, an amphiphilic antibiotic that does not require active transport to penetrate bacterial membranes, is effective in killing Escherichia coli persister cells [by 70.8 ± 5.9% (0.53 log) at 100 μg/mL], while being ineffective in killing normal cells. Further mechanistic studies revealed that persister cells have reduced drug efflux and accumulate more minocycline than normal cells, leading to effective killing of this dormant subpopulation upon wake-up. Consistently, eravacycline, which also targets the ribosome but has a stronger binding affinity than minocycline, kills persister cells by 3 logs when treated at 100 μg/mL. In summary, the findings of this study reveal that while dormancy is a well-known cause of antibiotic tolerance, it also provides an Achilles’ heel for controlling persister cells by leveraging dormancy associated reduction of drug efflux.     

Fruit and vegetable consumption,cardiovascular disease,and all-cause mortality in China

Science China Life Sciences - Evidence about the response patterns of fruit and vegetable consumption with the risk of cardiovascular disease (CVD) and all-cause mortality was inconsistent. These...     

Alveolar hypercapnia augments pulmonary C-fiber responses to chemical stimulants: role of hydrogen ion.

To determine whether the excitabilities of pulmonary C fibers to chemical and mechanical stimuli are altered by CO(2)-induced acidosis, single-unit pulmonary C-fiber activity was recorded in anesthetized, open-chest rats. Transient alveolar hypercapnia (HPC) was induced by administering CO(2)-enriched gas mixture (15% CO(2), balance air) via the respirator inlet for 30 s, which rapidly lowered the arterial blood pH from a baseline of 7.40 +/- 0.01 to 7.17 +/- 0.02. Alveolar HPC markedly increased the responses of these C-fiber afferents to several chemical stimulants. For example, the C-fiber response to right atrial injection of the same dose of capsaicin (0.25-1.0 microg/kg) was significantly increased from 3.07 +/- 0.70 impulses/s at control to 8.48 +/- 1.52 impulses/s during HPC (n = 27; P < 0.05), and this enhanced response returned to control within approximately 10 min after termination of HPC. Similarly, alveolar HPC also induced significant increases in the C-fiber responses to right atrial injections of phenylbiguanide (4-8 microg/kg) and adenosine (0.2 mg/kg). In contrast, HPC did not change the response of pulmonary C fibers to lung inflation. Furthermore, the peak response of these C fibers to capsaicin during HPC was greatly attenuated when the HPC-induced acidosis was buffered by infusion of bicarbonate (1.36-1.82 mmol. kg(-1). min(-1) for 35 s). In conclusion, alveolar HPC augments the responses of these afferents to various chemical stimulants, and this potentiating effect of CO(2) is mediated through the action of hydrogen ions on the C-fiber sensory terminals.     

Heterogeneous nanomechanical properties of type I collagen in longitudinal direction

Biomechanics and Modeling in Mechanobiology - Collagen is an abundant structural biopolymer in mammal vertebrates, providing structural support as well as mechanical integrity for connective...     

Design,synthesis, and anti-tumor activities of novel triphenylethylene–coumarin hybrids,and their interactions with Ct-DNA

Novel triphenylethylene–coumarin hybrid derivatives containing different amounts of amino side chains were designed and synthesized in good yields under microwave radiation. The derivatives 5b–d which possessed two amino side chains (except morpholinyl) showed a broad-spectrum and good anti-proliferative activity against five tumor cells and low cytotoxicity in osteoblast. UV–vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 10c, 5c, and 13c bearing amino side chain (except morpholinyl) on 4-phenyl had significant interactions with Ct-DNA by the intercalative mode of binding. Structure–activity relationships (SARs) analysis suggested that the amino alkyl chain would play an important role both in the compounds against tumor cells proliferation and their interactions with DNA.     

Conjugative Transfer and cis-Mobilization of a Genomic Island by an Integrative and Conjugative Element of Streptococcus agalactiae

Putative integrative and conjugative elements (ICEs), i.e., genomic islands which could excise, self-transfer by conjugation, and integrate into the chromosome of the bacterial host strain, were previously identified by in silico analysis in the sequenced genomes of Streptococcus agalactiae (M. Brochet et al., J. Bacteriol. 190:6913–6917, 2008). We investigated here the mobility of the elements integrated into the 3′ end of a tRNA^Lys gene. Three of the four putative ICEs tested were found to excise but only one (ICE_515_tRNA^Lys) was found to transfer by conjugation not only to S. agalactiae strains but also to a Streptococcus pyogenes strain. Transfer was observed even if recipient cell already carries a related resident ICE or a genomic island flanked by attL and attR recombination sites but devoid of conjugation or recombination genes (CIs-Mobilizable Element [CIME]). The incoming ICE preferentially integrates into the 3′ end of the tRNA^Lys gene (i.e., the attR site of the resident element), leading to a CIME-ICE structure. Transfer of the whole composite element CIME-ICE was obtained, showing that the CIME is mobilizable in cis by the ICE. Therefore, genomic islands carrying putative virulence genes but lacking the mobility gene can be mobilized by a related ICE after site-specific accretion.     

Inhibition of the Differentiation of Monocyte-Derived Dendritic Cells by Human Gingival Fibroblasts

We investigated whether gingival fibroblasts (GFs) can modulate the differentiation and/or maturation of monocyte-derived dendritic cells (DCs) and analyzed soluble factors that may be involved in this immune modulation. Experiments were performed using human monocytes in co-culture with human GFs in Transwell® chambers or using monocyte cultures treated with conditioned media (CM) from GFs of four donors. The four CM and supernatants from cell culture were assayed by ELISA for cytokines involved in the differentiation of dendritic cells, such as IL-6, VEGF, TGFβ1, IL-13 and IL-10. The maturation of monocyte-derived DCs induced by LPS in presence of CM was also studied. Cell surface phenotype markers were analyzed by flow cytometry. In co-cultures, GFs inhibited the differentiation of monocyte-derived DCs and the strength of this blockade correlated with the GF/monocyte ratio. Conditioned media from GFs showed similar effects, suggesting the involvement of soluble factors produced by GFs. This inhibition was associated with a lower stimulatory activity in MLR of DCs generated with GFs or its CM. Neutralizing antibodies against IL-6 and VEGF significantly (P<0.05) inhibited the inhibitory effect of CM on the differentiation of monocytes-derived DCs and in a dose dependent manner. Our data suggest that IL-6 is the main factor responsible for the inhibition of DCs differentiation mediated by GFs but that VEGF is also involved and constitutes an additional mechanism.