Proteomics analysis indicates the involvement of immunity and inflammation in the onset stage of SOD1-G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease, and the pathogenic mechanism that underlies ALS is still unclear. We analyzed the differentially expressed proteins (DEPs) in the spinal cord between SOD1-G93A transgenic mice at the onset stage and non-transgenic (NTG) littermates based on 4D label-free quantitative proteomics (4D-LFQ) with liquid chromatography-tandem mass spectrometry (LC-MS/MS). In our study, 189 DEPs were screened, of which 166 were up-regulated and 23 down-regulated. Clusters of Orthologous Groups (COG)/ EuKaryotic Orthologous Groups (KOG) classification, subcellular localization annotation, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, clustering analysis and protein-protein interaction (PPI) network analyses were performed. Parallel reaction monitoring (PRM) analysis validated 48 proteins from immunity and inflammation-related pathways of KEGG. We described the function and distribution of DEPs, most of which were involved in the following pathways: complement and coagulation cascades, antigen processing and presentation, NF-kappa B signaling pathway, Retinoic acid-inducible gene I (RIG) -I-like receptor signaling pathway, the extracellular matrix-receptor (ECM-receptor) interaction, focal adhesion, phagosome and lysosome. PPI network analysis identified Fn1, Fga, Serpina1e and Serpina3n as potential biomarkers. Our discoveries broaden the view and expand our understanding of immunity and inflammation in ALS. SIGNIFICANCE: This study gives a comprehensive description of DEPs in the spinal cord proteomics of SOD1-G93A mice at the onset period. Compared with a previous study focusing on progressive stage, we showed that immunity and inflammation play an important role at the onset stage of ALS. Several pathways validated by PRM bring new insight to the pathological mechanisms of ALS. The participation of RIG-I-like signaling pathway in ALS and potential biomarkers Fga, Fn1, Serpina1e and Serpina3n are supplements to existing knowledge.

Azo-Enhanced Raman Scattering for Enhancing the Sensitivity and Tuning the Frequency of Molecular Vibrations.

Raman scattering provides stable narrow-banded signals that potentially allow for multicolor microscopic imaging. The major obstacle for the applications of Raman spectroscopy and microscopy is the small cross section of Raman scattering that results in low sensitivity. Here, we report a new concept of azo-enhanced Raman scattering (AERS) by designing the intrinsic molecular structures using resonance Raman and concomitant fluorescence quenching strategies. Based on the selection of vibrational modes and the enhancing unit of azobenzenes, we obtained a library of AERS molecules with specific Raman signals in the fingerprint and silent frequency regions. The spectral characterization and molecular simulation revealed that the azobenzene unit conjugated to the vibrational modes significantly enhanced Raman signals due to the mechanism of extending the conjugation system, coupling the electronic-vibrational transitions, and improving the symmetry of vibrational modes. The nonradiative decay of azobenzene from the excited state quenched the commitment fluorescence, thus providing a clean background for identifying Raman scattering. The most sensitive AERS molecules produced Raman signals of more than 4 orders of magnitude compared to 5-ethynyl-2'-deoxyuridine (EdU). In addition, a frequency tunability of 10 distinct Raman bands was achieved by selecting different types of vibrational modes. This methodology of AERS allows for designing small-molecule Raman probes to visualize various entities in complex systems by multicolor spontaneous Raman imaging. It will open new prospects to explore innovative applications of AERS in interdisciplinary research fields.

Super-capacity information-carrying systems encoded with spontaneous Raman scattering.

Optical multiplex barcode systems have been significantly boosting the throughput of scientific discovery. A high volume of barcodes can be made from combinations of distinct spectral bands and intensity levels. However, the practical capacity often reaches a ceiling due to the overlaps of signal frequencies or intensities when massive information is written on individual carriers. In this paper, we built super-capacity information-carrying systems by tuning vibrational signals into octal numeral intensities in multiple bands of Raman-silent regions. This novel approach experimentally yielded the largest capacity of distinct optical barcodes to date. The experiments of encoding ASCII and Unicode systems to write and read languages indicate that the Raman coding method provides a new strategy for super-capacity data storage. In addition, multiplex screening of a cell-binding ligand was implemented to demonstrate the feasibility of this technology for fast and in situ high-throughput bio-discovery. These information-carrying systems may open new scenarios for the development of high-throughput screening, diagnostics and data storage.

Liver Enzymes, Fatty Liver and Type 2 Diabetes Mellitus in a Jinchang Cohort: A Prospective Study in Adults.

OBJECTIVES: It is unclear whether liver enzymes or the interactions of various liver enzymes is a predictor of type 2 diabetes mellitus (T2DM), which is independent of fatty liver. METHODS: A total of 48,001 subjects participated in baseline examinations. Among the subjects, 33,355 were followed for an average of 2.2 years. Cox proportional hazard models were used to examine the adjusted associations of AST, GGT and ALT with T2DM. RESULTS: The cumulative incidence of T2DM was 8.05% to 9.02% for fatty liver and 2.25% to 4.10% for non-fatty liver, both showing statistically significant differences. Compared with the normal liver enzyme levels in the group with fatty liver, the adjusted incident hazard ratios in T2DM were: ALT 1.23 (95% CI 1.10 to 1.50); AST 1.30 (95% CI 1.07-1.59); and GGT 1.34 (95% CI 1.08 to 1.65). In addition, compared with the normal liver enzyme levels in the group with non-fatty liver, the adjusted incident hazard ratios in type 2 diabetes were: ALT 1.27 (95% CI 1.02 to 1.59); AST 1.33 (95% CI 1.02 to 1.59); and GGT 1.53 (95% CI 1.19 to 1.98). There are significant interactions of T2DM hazard ratios between GGT and ALT and between GGT and AST in addition to ALT and AST. CONCLUSIONS: Our results suggest that the incidence of T2DM in the group with fatty liver is significantly higher than that in the normal population, and the rise of serum AST, GGT and ALT levels are risk factors independent of fatty liver for the development of T2DM after adjusting for confounding factors.

Effectiveness of Screening Modalities in Colorectal Cancer: A Network Meta-Analysis.

The aim of the study was to evaluate on the effectiveness of screening modalities in the prevention of colorectal cancer (CRC) occurrence and deaths. General meta-analysis was performed to produce pooled estimates of the effect of CRC incidence and mortality using a search of PubMed, Web of Science, and the Cochrane Library for eligible studies from January 1992 to March 2016. A network meta-analysis was performed to synthetically compare the effectiveness of 5 frequently used screening modalities. A total of 44 studies with a focus on mortality from CRC using different screening methods were included. General meta-analysis showed that fecal immunohistochemical testing (FIT), flexible sigmoidoscopy (FS), colonoscopy, combination of fecal occult blood testing and FS screening respectively reduced CRC mortality by 59% (relative risk [RR], 0.41; 95% confidence interval [CI], 0.29-0.59), 33% (RR, 0.67; 95% CI, 0.58-0.78), 61% (RR, 0.39; 95% CI, 0.31-0.50), 38% (RR, 0.62; 95% CI, 0.42-0.91) compared with no screening, whereas guaiac fecal occult blood testing (gFOBT) reduced CRC-related mortality by 14% (RR, 0.86; 95% CI, 0.82-0.90). Subgroup analysis showed that summary estimates of reduction in distal CRC mortality and proximal CRC mortality were 26% (95% CI, 62%-89%) and 10% (95% CI, 83%-98%). A network meta-analysis revealed rank probability analysis in which the colonoscopy had a 94.6% probability of being the most effective examination to reduce CRC mortality. In addition, the network meta-analysis estimated odds ratio, which was a 79% reduction (95% CI, 0.09-0.60) in CRC mortality when screening with FIT was compared with annual or biennial gFOBT and colonoscopy was approximately 80% more effective than gFOBT for reducing CRC mortality (RR, 0.25; 95% CI, 0.13-0.54). Analysis of the effects of different screening methods showed that there was a significant reduction in the incidence of colon cancer, excluding gFOBT. This meta-analysis confirmed that gFOBT, FIT, FS, and colonoscopy were all effective in preventing CRC deaths and a major reduction in distal but not proximal CRC mortality was found. In addition, they were more effective in preventing CRC incidence in addition to gFOBT. The network meta-analysis suggests that colonoscopy is the most effective screening for preventing CRC deaths.

In vitro and in vivo tumor suppressive activity induced by human telomerase transcriptase-targeting antisense oligonucleotides mediated by cationic liposomes.

The objective of this study was to investigate the in vitro and in vivo influence of cationic liposomes on the tumor suppressive effect of antisense telomerase oligodeoxynucleotides to human cervical adenocarcinoma cells (HeLa). Antisense oligodeoxynucleotides (ASODN) against the human telomerase transcriptase (hTERT) served as telomerase inhibitors. The cholesterol derivative, 3beta [N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol), was synthesized, and cationic liposomes (CL) were prepared using DC-Chol and dioleoylphosphatidylethanolamine (DOPE). The in vitro IC50 of the CL-ASODN complex was 1.88 mumol/l, while the IC50 of the cells treated with free ASODNs or CL alone was 25.24 mumol/l and 55.18 mumol/l, respectively. The CL-ASODN complex inhibited HeLa cell growth for at least 120 h. In vivo, the CL-ASODN complex inhibited the tumor growth rate by 55.11%, which increased to 89.47% when CL-ASODN was combined with 5-fluorouracil treatment. ASODNs alone failed to induce tumor-suppressive activity, suggesting that CL prepared from DOPE and DC-Chol can significantly enhance the growth inhibitory effect of ASODN on tumor cells both in vitro and in vivo.