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Lead is a heavy metal commonly found in the environment with known neurotoxicity, hematological and other toxicities. It has been found that lead exposure can disturb partial metal regulatory function in the blood-CSF barrier (BCB). Copper, which play an important role in maintaining normal brain function, can accumulate in brain after lead exposure. The studies of Alzheimer's disease (AD) indicated that abnormal copper homeostasis in cerebrospinal fluid (CSF) may be involved in the pathogenesis. However, the mechanism of copper disturbance in the brain caused by lead is still unknown. This study was designed to investigate copper clearance by the BCB in central nervous system after lead exposure, with focus on copper transporter protein CTR1/ATP7A. Inductively coupled plasma mass spectrometry (ICP-MS) and principal component analysis (PCA) were used to identify the changes of heavy metal level in hippocampus and CSF after lead exposure. It was found that the change in copper level was most pronounced in the brain between 3 to 12 weeks post lead exposure. Ventriculo-cisternal (VC) perfusion in Sprague Dawley (SD) rat suggested that the ability of BCB to deliver copper from the CSF to blood was decreased after lead exposure. Confocal microscope showed evidence of the presence of excess copper in the choroid plexus cells leading to CTR1/ATP7A shifting toward the apical microvilli facing the CSF after lead exposure. Finally, transmission electron microscopy (TEM) was used for observation of the microstructure of choroid plexus showed altered mitochondrial morphology with decreased microvilli after lead exposure. Our data suggested that lead exposure may alter BCB cellular microscopic structure and its copper transport, clearance function that might further cause brain injury.

The strong nuclear interaction between nucleons (protons and neutrons) is the effective force that holds the atomic nucleus together. This force stems from fundamental interactions between quarks and gluons (the constituents of nucleons) that are described by the equations of Quantum Chromodynamics (QCD). However, as these equations cannot be solved directly, physicists resort to describing nuclear interactions using effective models that are well constrained at typical inter-nucleon distances in nuclei but not at shorter distances. This limits our ability to describe high-density nuclear matter such as in the cores of neutron stars. Here we use high-energy electron scattering measurements that isolate nucleon pairs in short-distance, high-momentum configurations thereby accessing a kinematical regime that has not been previously explored by experiments, corresponding to relative momenta above 400 MeV/c. As the relative momentum between two nucleons increases and their separation thereby decreases, we observe a transition from a spin-dependent tensor-force to a predominantly spin-independent scalar-force. These results demonstrate the power of using such measurements to study the nuclear interaction at short-distances and also support the use of point-like nucleons with two- and three-body effective interactions to describe nuclear systems up to densities several times higher than the central density of atomic nuclei., Comment: Total 26 pages, 13 figures. Main text: 8 pages, 3 figures. Methods section: 6 pages. Extended Data: 8 figures, 1 table. Supplementary Materials: 8 pages, 2 figures

The soft coral-derived fungus Trichoderma harzianum (XS-20090075) was found to be a potential strain to produce substantial new compounds in our previous study. In order to explore its potential to produce more metabolites, chemical epigenetic manipulation was used on this fungus to wake its sleeping genes, leading to the significant changes of its secondary metabolites by using a histone deacetylase (HDAC) inhibitor. The most obvious difference was the original main products harziane diterpenoids were changed into cyclonerane sesquiterpenoids. Three new terpenoids were isolated from the fungal culture treated with 10 mM sodium butyrate, including cleistanthane diterpenoid, harzianolic acid A (1), harziane diterpenoid, harzianone E (2), and cyclonerane sesquiterpenoid, 3,7,11-trihydroxy-cycloneran (3), together with 11 known sesquiterpenoids (4-14). The absolute configurations of 1-3 were determined by single-crystal X-ray diffraction, ECD and OR calculations, and biogenetic considerations. This was the first time to obtain cleistanthane diterpenoid and africane sesquiterpenoid from genus Trichoderma, and this was the first chlorinated cleistanthane diterpenoid. These results demonstrated that the chemical epigenetic manipulation should be an efficient technique for the discovery of new secondary metabolites from marine-derived fungi.

Jie Zheng,1,2,* Fuao Cao,3,* Xiaopei Huang,4,* Kuvaneshan Ramen,2 Xiaowen Xu,3 Yan Zhu,5 Wenjun Chang,4 Yunfeng Shan,2 Aizhen Guo1 1Department of General Medicine, Yangpu Hosptial, Tongji University School of Medicine, Shanghai 200090, People’s Republic of China; 2Department of General Surgery, First Affiliated Hospital, Wenzhou Medical University, Zhejiang 325015, People’s Republic of China; 3Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of China; 4Department of Environmental Hygiene, Second Military Medical University, Shanghai 200433, People’s Republic of China; 5Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of China *These authors contributed equally to this work Purpose: Eyes absent homologue 2 (EYA2), which functions as a transcription activator and phosphatase, plays an important role in several types of cancer. However, the impact of EYA2 in colorectal cancer (CRC) remains elusive. Patients and methods: We evaluated the significance of EYA2 expression in the development and progression of CRC in a large cohort, including 922 CRC cases. EYA2 protein expression was determined via immunohistochemistry in colorectal tissues. The correlation between EYA2 expression and CRC occurrence was investigated in tumor tissue and the adjacent normal tissues. Factors contributing to CRC prognosis were evaluated using Kaplan–Meier and Cox model analyses. Results: EYA2 expression was progressively lower in the adjacent normal tissue, adenomas, primary tumor and the metastatic CRC (all P

Zhenhong Fu,1,* Xia Yang,1,* Mingzhi Shen,2,* Hao Xue,1,* Geng Qian,1 Feng Cao,1 Jun Guo,1 Wei Dong,1 Yundai Chen1 1Department of Cardiology, Chinese People’s Liberation Army General Hospital, Beijing, China; 2Department of Cardiology, Hainan Branch of Chinese People’s Liberation Army General Hospital, Sanya, Hainan, China *These authors contributed equally to this work Background and aims: This study sought to evaluate the prognostic powers of combined use of cystatin C (Cys C) and homocysteine (Hcy) at predicting adverse events of patients >80 years old with acute myocardial infarction (AMI).Patients and methods: The analysis involved 753 patients >80 years old undergoing coronary angiography for chest pain in China from January 2006 to December 2012. Kaplan–Meier method was used for survival and major adverse cardiac events (MACE) rates. Multivariate Cox regression was performed to identify mortality predictors. Receiver operating characteristic curve analysis was performed to predict the cutoff values of Cys C and Hcy for all-cause mortality.Results: The duration of follow-up was 40–116 months (median, 63 months; interquartile range, 51–74 months). The long-term survival and event-free survival rates of AMI patients were significantly lower than those of unstable angina pectoris patients (P

Tingting Xu,1,2,* Xiaoyue Xu,1,* Yan Gu,1 Lei Fang,3 Feng Cao1 1School of Pharmacy, China Pharmaceutical University, 2Nanjing Chia Tai Tian Qing Pharmaceutical Co., Ltd, 3Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing, China *These authors contributed equally tothis work Background: To enhance ocular bioavailability, the traditional strategies have focused on prolonging precorneal retention and improving corneal permeability by nano-carriers with positive charge, thiolated polymer, absorption enhancer and so on. Glycylsarcosine (GS) as an active target ligand of the peptide tranpsporter-1 (PepT-1), could specific interact with the PepT-1 on the cornea and guide the nanoparticles to the treating site.Purpose: The objective of the study was to explore the active targeting intercalated nanocomposites based on chitosan-glutathione-glycylsarcosine (CG-GS) and layered double hydroxides (LDH) as novel carriers for the treatment of mid-posterior diseases.Materials and methods: CG-GS-LDH intercalated nanocomposites were prepared by the coprecipitation hydrothermal method. In vivo precorneal retention study, ex vivo fluorescence images, in vivo experiment for distribution and irritation were studied in rabbits. The cytotoxicity and cellular uptake were studied in human corneal epithelial primary cells (HCEpiC).Results: CG-GS-LDH nanocomposites were prepared successfully and characterized by FTIR and XRD. Experiments with rabbits showed longer precorneal retention and higher distribution of fluorescence probe/model drug. In vitro cytological study, CG-GS-LDH nanocomposites exhibited enhanced cellular uptake compared to pure drug solution. Furthermore, the investigation of cellular uptake mechanisms demonstrated that both the active transport by PepT-1 and clathrin-mediated endocytosis were involved in the internalization of CG-GS-LDH intercalated nanocomposites. An ocular irritation study and a cytotoxicity test indicated that these nanocomposites produced no significant irritant effects.Conclusions: The active targeting intercalated nanocomposites could have great potential for topical ocular drug delivery due to the capacity for prolonging the retention on the ocular surface, enhancing the drug permeability through the cornea, and efficiently delivering the drug to the targeted site. Keywords: active targeting, intercalated nanocomposites, peptide transporter-1, layered double hydroxides, glycylsarcosine