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1.  Effects of chronic sleep deprivation on bone mass and bone metabolism in rats 
Background
This study aimed to assess the effects of chronic sleep deprivation (CSD) on bone mass and bone metabolism in rats.
Methods
Twenty-four rats were randomly divided into CSD and control (CON) groups. Rats were subjected to CSD by using the modified multiple platform method (MMPM) to establish an animal model of CSD. Biochemical parameters such as levels of serum N-terminal propeptide of type I procollagen (PINP), N-terminal cross-linking telopeptide of type I collagen (NTX), growth hormone (GH), estradiol (E2), serum 25(OH)D, and calcium (Ca) were evaluated at 0, 1, 2, and 3 months. After 3 months, each fourth lumbar vertebra and the distal femoral metaphysis of the left extremity of rats were harvested for micro-computed tomography scans and histological analysis, respectively, after the rats were sacrificed under an overdose of pentobarbital sodium.
Results
Compared with rats from the CON group, rats from the CSD group showed significant decreases in bone mineral density (BMD), bone volume over total volume, trabecular bone thickness, and trabecular bone number and significant increases in bone surface area over bone volume and trabecular bone separations (P < 0.05). Bone histomorphology studies showed that rats in the CSD group had decreased osteogenesis, impaired mineralization of newly formed bones, and deteriorative trabecular bone in the secondary spongiosa zone. In addition, they showed significantly decreased levels of serum PINP (1 month later) and NTX (3 months later) (P < 0.05). The serum 25(OH)D level of rats from the CSD group was lower than that of rats from the CON group after 1 month (P < 0.05).
Conclusions
CSD markedly affects bone health by decreasing BMD and 25(OH)D, deteriorating the bone microarchitecture, and decreasing bone formation and bone resorption markers.
doi:10.1186/s13018-016-0418-6
PMCID: PMC4970273  PMID: 27485745
Chronic sleep deprivation; Bone mineral density; Bone microstructure; Bone turnover; Vitamin D
2.  Effects of chronic sleep deprivation on glucose homeostasis in rats 
Sleep and Biological Rhythms  2016;14(4):321-328.
Epidemiological studies have shown that chronic sleep disturbances resulted in metabolic disorders. The purpose of this study was to assess the relationship between chronic sleep deprivation (CSD) and the glucose homeostasis in rats. Twenty-four rats were randomly divided into CSD group and control (CON) group. The CSD rats were intervened by a modified multiple platform method (MMPM) to establish an animal model of chronic sleep disturbances. After 3-month intervention, all rats were subjected to an intraperitoneal glucose tolerance test (IPGTT) and an insulin tolerance test (ITT), and the body weight, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, lipid profile group, and homeostasis model assessment-IR (HOMA-IR) were measured. Both the CSD and CON groups had an attenuation of weight gain after 3-month intervention. The plasma glucose level of CSD group was higher than that of the CON group during the IPGTT (P < 0.01). The CSD rats showed a marked increase in HOMA-IR and ITT compared with the CON group (P < 0.01). There were no significant differences of AST, ALT, creatinine, and most lipid parameters between the CSD and CON groups (P > 0.05). The CSD has a marked effect on glucose homeostasis, comprising glucose intolerance and insulin resistance.
doi:10.1007/s41105-016-0061-y
PMCID: PMC5037153  PMID: 27738407
Chronic sleep deprivation; Glucose intolerance; Insulin resistance; Body weight
3.  Genome sequences of two closely related strains of Escherichia coli K-12 GM4792 
Escherichia coli lab strains K-12 GM4792 Lac+ and GM4792 Lac- carry opposite lactose markers, which are useful for distinguishing evolved lines as they produce different colored colonies. The two closely related strains are chosen as ancestors for our ongoing studies of experimental evolution. Here, we describe the genome sequences, annotation, and features of GM4792 Lac+ and GM4792 Lac-. GM4792 Lac+ has a 4,622,342-bp long chromosome with 4,061 protein-coding genes and 83 RNA genes. Similarly, the genome of GM4792 Lac- consists of a 4,621,656-bp chromosome containing 4,043 protein-coding genes and 74 RNA genes. Genome comparison analysis reveals that the differences between GM4792 Lac+ and GM4792 Lac- are minimal and limited to only the targeted lac region. Moreover, a previous study on competitive experimentation indicates the two strains are identical or nearly identical in survivability except for lactose utilization in a nitrogen-limited environment. Therefore, at both a genetic and a phenotypic level, GM4792 Lac+ and GM4792 Lac-, with opposite neutral markers, are ideal systems for future experimental evolution studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s40793-015-0114-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s40793-015-0114-x
PMCID: PMC4675052  PMID: 26664654
Escherichia coli K12; GM4792; Lactose; Gram-negative; Genome comparison; Experimental evolution; Variant analysis
4.  Correlation between bone mineral density and serum trace element contents of elderly males in Beijing urban area 
Trace element levels are associated with the incidence of osteoporotic fractures, but related mechanisms remain unknown. Trace elements may interfere with growth, development and maintenance of bones. Therefore, we investigated whether plasma trace element levels are associated with bone mineral density in elderly males in Beijing. After epidemiologically investigating 91 elderly males with age ranging from 50 years to 80 years, we obtained a total of 30 healthy (group 1), 31 osteopoenic (group 2) and 30 osteoporotic (group 3) subjects. Blood was collected, and serum concentrations of trace elements were detected. Elderly males in the three groups were carefully matched in terms of body mass index. Iron, manganese, zinc, copper, selenium, cadmium and lead were analysed by inductively coupled plasma-mass spectrometry. Bone mineral density (BMD) was measured by QDR-2000 dual-energy X-ray absorptiometry. Correlation between BMD and serum element contents was analysed using SPSS16.0. The plasma levels of manganese, zinc, copper, selenium and lead were similar in all of the groups (P>0.05). Cadmium was significantly and negatively correlated with BMD of the lumbar vertebrae (P<0.05). Moreover, cadmium and iron contents significantly differed in osteoporotic and healthy groups. These elements may directly and correlatively affect BMD in elderly males. Many trace elements may directly and correlatively influence BMD. Future studies should be conducted to evaluate serum and bone levels of these trace elements to determine the relationship of these trace elements with osteoporosis.
PMCID: PMC4694461  PMID: 26770561
Osteoporosis; bone mineral density; element
5.  Renoprotective effects of olmesartan medoxomil on diabetic nephropathy in streptozotocin-induced diabetes in rats 
Biomedical Reports  2013;2(1):24-28.
Olmesartan medoxomil (OM) is one of the newest members of the angiotensin receptor blocker (ARB) family. The renoprotective effects of the angiotensin II type 1 receptor antagonist OM was investigated in a streptozotocin (STZ)-induced diabetic rat model. In this study, we investigated whether OM was able to ameliorate diabetic nephropathy (DN). Thirty male Sprague Dawley rats were assigned to 3 groups: the non-diabetic (group A, n=10), the untreated STZ-induced DN control (group B, n=10) and the STZ-induced DN treated with OM (group C, n=10). Blood pressure (BP) and glucose, creatinine (Cr), blood urea nitrogen (BUN), superoxide dismutase (SOD), malondialdehyde (MDA) microalbumin and urinary protein concentrations were measured. In STZ diabetic rats, BP, glucose, Cr, BUN, MDA and urinary protein levels were significantly increased compared to the non-diabetic control group. OM significantly improved the biological indices in the DN rats. The renal pathological changes were also observed under a light microscope. Our results suggested that OM exerted renoprotective effects on rats with STZ-induced diabetes.
doi:10.3892/br.2013.183
PMCID: PMC3917007  PMID: 24649063
renoprotective effects; olmesartan medoxomil; diabetic nephropathy
6.  Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits 
Pankratz, Nathan | Schick, Ursula M | Zhou, Yi | Zhou, Wei | Ahluwalia, Tarunveer Singh | Allende, Maria Laura | Auer, Paul L | Bork-Jensen, Jette | Brody, Jennifer A | Chen, Ming-Huei | Clavo, Vinna | Eicher, John D | Grarup, Niels | Hagedorn, Elliott J | Hu, Bella | Hunker, Kristina | Johnson, Andrew D | Leusink, Maarten | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Manichaikul, Ani | Marioni, Riccardo E | Nalls, Mike A | Pazoki, Raha | Smith, Albert Vernon | van Rooij, Frank J A | Yang, Min-Lee | Zhang, Xiaoling | Zhang, Yan | Asselbergs, Folkert W | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Cushman, Mary | de Bakker, Paul I W | Deary, Ian J | Dong, Liguang | Feitosa, Mary F | Floyd, James S | Franceschini, Nora | Franco, Oscar H | Garcia, Melissa E | Grove, Megan L | Gudnason, Vilmundur | Hansen, Torben | Harris, Tamara B | Hofman, Albert | Jackson, Rebecca D | Jia, Jia | Kähönen, Mika | Launer, Lenore J | Lehtimäki, Terho | Liewald, David C | Linneberg, Allan | Liu, Yongmei | Loos, Ruth J F | Nguyen, Vy M | Numans, Mattijs E | Pedersen, Oluf | Psaty, Bruce M | Raitakari, Olli T | Rich, Stephen S | Rivadeneira, Fernando | Di Sant, Amanda M Rosa | Rotter, Jerome I | Starr, John M | Taylor, Kent D | Thuesen, Betina Heinsbæk | Tracy, Russell P | Uitterlinden, Andre G | Wang, Jiansong | Wang, Judy | Dehghan, Abbas | Huo, Yong | Cupples, L Adrienne | Wilson, James G | Proia, Richard L | Zon, Leonard I | O’Donnell, Christopher J | Reiner, Alex P | Ganesh, Santhi K
Nature genetics  2016;48(8):867-876.
Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. Erythrocyte and WBC phenotypes were analyzed with Illumina HumanExome BeadChip genotypes in 52,531 individuals (37,775 of European ancestry; 11,589 African Americans; 3,167 Hispanic Americans) from 16 population-based cohorts. We then performed replication analyses of novel discoveries in 18,018 European American women and 5,261 Han Chinese. We identified and replicated four novel erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six novel WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC (MYB). The novel association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments of S1pr4 in mouse and zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
doi:10.1038/ng.3607
PMCID: PMC5145000  PMID: 27399967
7.  Hydrochloric acid-enhanced radiofrequency ablation for treating a large hepatocellular carcinoma with spontaneous rapture: a case report 
Background
A ruptured hepatocellular carcinoma (HCC) is often fatal. In addition to surgery and transarterial embolization, radiofrequency ablation (RFA) might be another option for treating a ruptured HCC. Unfortunately, conventional RFA has a limited ablation zone; as such, it is rarely used to treat ruptured tumors.
Case presentation
This case was a 60-year-old man who had a large, ruptured HCC in which hydrochloric acid (HCl)-enhanced RFA successfully controlled the bleeding and made the tumor completely necrotic.
Conclusion
Considering the effectiveness of HCl-enhanced RFA in achieving hemostasis and tumor ablation, it might be a new option for treating large, ruptured HCCs.
doi:10.1186/s40880-016-0161-8
PMCID: PMC5219733  PMID: 28061892
Hydrochloric acid; Radiofrequency ablation; Spontaneous rupture; Hepatocellular carcinoma
8.  Hydroxycinnamic acid amides from Scopolia tangutica inhibit the activity of M1 muscarinic acetylcholine receptor in vitro 
Fitoterapia  2015;108:9-12.
Scopolia tangutica Maxim (S. Tangutica) extracts have been traditionally used as antispasmodic, sedative, and analgesic agents in Tibet and in the Qinghai province of China. Their active compositions are however poorly understood. We have recently isolated five new hydroxycinnamic acid (HCA) amides along with two known HCA amides, one cinnamic acid amide from these extracts. In this study, we evaluate their abilities to inhibit carbacol-induced activity of M1 muscarinic acetylcholine receptor along with the crude extracts. Chinese hamster ovary cells stably expressing the recombinant human M1 receptor (CHO-M1 cells) were employed to evaluate the anticholinergic potentials. Intracellular Ca2+ changes were monitored using the FLIPR system. Five HCA amides as well as the crude S. Tangutica extract displayed dose-dependent inhibitory effects against M1 receptor. These findings demonstrate that HCA amides are part of the M1 receptor-inhibiting principles of S. tangutica. Since blockade of parasympathetic nerve impulse transmission through the inhibition of the M1 receptor lessens smooth muscle spasms, our findings provided a molecular explanation for the traditional use of S. Tangutica against spasm.
Graphical abstract
doi:10.1016/j.fitote.2015.11.007
PMCID: PMC4698058  PMID: 26586621
Scopolia tangutica Maxim; hydroxycinnamic acid amides; M1 muscarinic acetylcholine receptor
9.  Disrupted-in-Schizophrenia-1 Attenuates Amyloid-β Generation and Cognitive Deficits in APP/PS1 Transgenic Mice by Reduction of β-Site APP-Cleaving Enzyme 1 Levels 
Neuropsychopharmacology  2015;41(2):440-453.
Disrupted-in-Schizophrenia-1 (DISC1) is a genetic risk factor for a wide range of major mental disorders, including schizophrenia, major depression, and bipolar disorders. Recent reports suggest a potential role of DISC1 in the pathogenesis of Alzheimer's disease (AD), by referring to an interaction between DISC1 and amyloid precursor protein (APP), and to an association of a single-nucleotide polymorphism in a DISC1 intron and late onset of AD. However, the function of DISC1 in AD remains unknown. In this study, decreased levels of DISC1 were observed in the cortex and hippocampus of 8-month-old APP/PS1 transgenic mice, an animal model of AD. Overexpression of DISC1 reduced, whereas knockdown of DISC1 increased protein levels, but not mRNA levels of β-site APP-Cleaving Enzyme 1 (BACE1), a key enzyme in amyloid-β (Aβ) generation. Reduction of BACE1 protein levels by overexpression of DISC1 was accompanied by an accelerating decline rate of BACE1, and was blocked by the lysosomal inhibitor chloroquine, rather than proteasome inhibitor MG-132. Moreover, overexpression of DISC1 in the hippocampus with an adeno-associated virus reduced the levels of BACE1, soluble Aβ40/42, amyloid plaque density, and rescued cognitive deficits of APP/PS1 transgenic mice. These results indicate that DISC1 attenuates Aβ generation and cognitive deficits of APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. Our findings provide new insights into the role of DISC1 in AD pathogenesis and link a potential function of DISC1 to the psychiatric symptoms of AD.
doi:10.1038/npp.2015.164
PMCID: PMC5130120  PMID: 26062786
10.  Cell surface‐anchored syndecan‐1 ameliorates intestinal inflammation and neutrophil transmigration in ulcerative colitis 
Abstract
Syndecan‐1 (SDC1), with a variable ectodomain carrying heparan sulphate (HS) chains between different Syndecans, participates in many steps of inflammatory responses. In the process of proteolysis, the HS chains of the complete extracellular domain can be shed from the cell surface, by which they can mediate most of SDC1's function. However, the exact impact on SDC1 which anchored on the cell surface has not been clearly reported. In our study, we established the models by transfection with the cleavable resistant SDC1 mutant plasmid, in which SDC1 shedding can be suppressed during stimulation. Role of membrane SDC1 in inflammatory pathway, pro‐inflammatory cytokine secretion as well as neutrophil transmigration, and how suppressing its shedding will benefit colitis were further investigated. We found that the patients suffered ulcerative colitis had high serum SDC1 levels,presented with increased levels of P65, tumour necrosis factor alpha (TNF‐α) and IL‐1β and higher circulating neutrophils. NF‐κB pathway was activated, and secretion of TNF‐α, interleukin‐1beta (IL‐1β), IL‐6 and IL‐8 were increased upon lipopolysaccharide stimuli in intestinal epithelial cells. Syndecan‐1, via its anchored ectodomain, significantly lessened these up‐regulation extents. It also functioned in inhibiting transmigration of neutrophils by decreasing CXCL‐1 secretion. Moreover, SDC1 ameliorated colitis activity and improved histological disturbances of colon in mice. Taken together, we conclude that suppression of SDC1 shedding from intestinal epithelial cells relieves severity of intestinal inflammation and neutrophil transmigration by inactivating key inflammatory regulators NF‐κB, and down‐regulating pro‐inflammatory cytokine expressions. These indicated that compenstion and shedding suppression of cytomembrane SDC1 might be the optional therapy for intestinal inflammation.
doi:10.1111/jcmm.12934
PMCID: PMC5192823  PMID: 27558380
ectodomain shedding; intestinal inflammation; NF‐κB pathway; neutrophil transmigration; pro‐inflammatory cytokine; syndecan‐1
11.  Identified molecular mechanism of interaction between environmental risk factors and differential expression genes in cartilage of Kashin–Beck disease 
Medicine  2016;95(52):e5669.
Supplemental Digital Content is available in the text
Abstract
As environmental risk factors (ERFs) play an important role in the pathogenesis of Kashin–Beck disease (KBD), it is important to identify the interaction between ERFs and differentially expression genes (DEGs) in KBD. The environmental response genes (ERGs) were analyzed in cartilage of KBD in comparison to normal controls.
We searched 5 English and 3 Chinese databases from inception to September 2015, to identify case–control studies that examined ERFs for KBD using integrative meta-analysis and systematic review. Total RNA was isolated from articular cartilage of KBD patients and healthy controls. Human whole genome microarray chip (Agilent) was used to analyze the amplified, labeled, and hybridized total RNA, and the validated microarray data were partially verified using real-time quantitative polymerase chain reaction (qRT-PCR). The ERGs were derived from the Comparative Toxicogenomics Database. The identified ERGs were subjected to KEGG pathway enrichment, biological process (BP), and interaction network analyses using the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.7, and STRING.
The trace elements (selenium and iodine), vitamin E, and polluted grains (T-2 toxin/HT-2 toxin, deoxynivalenol, and nivalenol) were identified as the ERFs for KBD using meta-analysis and review. We identified 21 upregulated ERGs and 7 downregulated ERGs in cartilage with KBD compared with healthy controls, which involved in apoptosis, metabolism, and growth and development. KEGG pathway enrichment analysis found that 2 significant pathways were involved with PI3K-Akt signaling pathway and P53 signaling pathway, and gene ontology function analysis found 3 BPs involved with apoptosis, death, and cell death in KBD cartilage.
According to previous results and our own research, we suggest that the trace element selenium and vitamin E induce PI3K-Akt signaling pathway and the mycotoxins (T-2 toxin/HT-2 toxin and DON) induce P53 signaling pathway, contributing to the development of KBD, and chondrocyte apoptosis and cell death.
doi:10.1097/MD.0000000000005669
PMCID: PMC5207552  PMID: 28033256
differentially expressed genes; environmental risk factors; Kashin–Beck disease
12.  Sodium selenate regulates the brain ionome in a transgenic mouse model of Alzheimer’s disease 
Scientific Reports  2016;6:39290.
Many studies have shown that imbalance of mineral metabolism may play an important role in Alzheimer’s disease (AD) progression. It was recently reported that selenium could reverse memory deficits in AD mouse model. We carried out multi-time-point ionome analysis to investigate the interactions among 15 elements in the brain by using a triple-transgenic mouse model of AD with/without high-dose sodium selenate supplementation. Except selenium, the majority of significantly changed elements showed a reduced level after 6-month selenate supplementation, especially iron whose levels were completely reversed to normal state at almost all examined time points. We then built the elemental correlation network for each time point. Significant and specific elemental correlations and correlation changes were identified, implying a highly complex and dynamic crosstalk between selenium and other elements during long-term supplementation with selenate. Finally, we measured the activities of two important anti-oxidative selenoenzymes, glutathione peroxidase and thioredoxin reductase, and found that they were remarkably increased in the cerebrum of selenate-treated mice, suggesting that selenoenzyme-mediated protection against oxidative stress might also be involved in the therapeutic effect of selenate in AD. Overall, this study should contribute to our understanding of the mechanism related to the potential use of selenate in AD treatment.
doi:10.1038/srep39290
PMCID: PMC5180247  PMID: 28008954
13.  Transcriptional analysis of degenerate strain Clostridium beijerinckii DG-8052 reveals a pleiotropic response to CaCO3-associated recovery of solvent production 
Scientific Reports  2016;6:38818.
Degenerate Clostridium beijerinckii strain (DG-8052) can be partially recovered by supplementing CaCO3 to fermentation media. Genome resequencing of DG-8052 showed no general regulator mutated. This study focused on transcriptional analysis of DG-8052 and its response to CaCO3 treatment via microarray. The expressions of 5168 genes capturing 98.6% of C. beijerinckii NCIMB 8052 genome were examed. The results revealed that with addition of CaCO3 565 and 916 genes were significantly up-regulated, and 704 and 1044 genes significantly down-regulated at acidogenic and solventogenic phase of DG-8052, respectively. These genes are primarily responsible for glycolysis to solvent/acid production (poR, pfo), solventogensis (buk, ctf, aldh, adh, bcd) and sporulation (spo0A, sigE, sigma-70, bofA), cell motility and division (ftsA, ftsK, ftsY, ftsH, ftsE, mreB, mreC, mreD, rodA), and molecular chaperones (grpE, dnaK, dnaJ, hsp20, hsp90), etc. The functions of some altered genes in DG-8052, totalling 5.7% at acidogenisis and 8.0% at sovlentogenisis, remain unknown. The response of the degenerate strain to CaCO3 was suggested significantly pleiotropic. This study reveals the multitude of regulatory function that CaCO3 has in clostridia and provides detailed insights into degeneration mechanisms at gene regulation level. It also enables us to develop effective strategies to prevent strain degeneration in future.
doi:10.1038/srep38818
PMCID: PMC5155275  PMID: 27966599
14.  Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux 
Cell Reports  2016;17(11):2811-2818.
Summary
Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (TSCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the TSCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of TSCM cells in vivo using stable isotope labeling with heavy water. The data indicate that TSCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, TSCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that TSCM cells exist in a state of perpetual flux throughout the human lifespan.
Graphical Abstract
Highlights
•Human stem cell-like memory T (TSCM) cells proliferate extensively in vivo•Human TSCM cells express high levels of Ki67•Human TSCM cells have long telomeres•Human TSCM cells display high levels of telomerase activity
Stem cell-like memory T (TSCM) cells are multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. Ahmed et al. find that human TSCM cells are maintained by ongoing proliferation and display limited telomere length erosion coupled with high expression levels of active telomerase and Ki67.
doi:10.1016/j.celrep.2016.11.037
PMCID: PMC5186732  PMID: 27974195
adaptive immunity; memory T cells; stem cell-like memory T cells; CD4+ T cells; CD8+ T cells; in vivo heavy water labeling; proliferation; telomere length; telomerase activity; memory T cell maintenance
15.  A d-Amino Acid-Containing Neuropeptide Discovery Funnel 
Analytical Chemistry  2016;88(23):11868-11876.
A receptor binding class of d-amino acid-containing peptides (DAACPs) is formed in animals from an enzymatically mediated post-translational modification of ribosomally translated all-l-amino acid peptides. Although this modification can be required for biological actions, detecting it is challenging because DAACPs have the same mass as their all-l-amino acid counterparts. We developed a suite of mass spectrometry (MS) protocols for the nontargeted discovery of DAACPs and validated their effectiveness using neurons from Aplysia californica. The approach involves the following three steps, with each confirming and refining the hits found in the prior step. The first step is screening for peptides resistant to digestion by aminopeptidase M. The second verifies the presence of a chiral amino acid via acid hydrolysis in deuterium chloride, labeling with Marfey’s reagent, and liquid chromatography–mass spectrometry to determine the chirality of each amino acid. The third involves synthesizing the putative DAACPs and comparing them to the endogenous standards. Advantages of the method, the d-amino acid-containing neuropeptide discovery funnel, are that it is capable of detecting the d-form of any common chiral amino acid, and the first two steps do not require peptide standards. Using these protocols, we report that two peptides from the Aplysia achatin-like neuropeptide precursor exist as GdYFD and SdYADSKDEESNAALSDFA. Interestingly, GdYFD was bioactive in the Aplysia feeding and locomotor circuits but SdYADSKDEESNAALSDFA was not. The discovery funnel provides an effective means to characterize DAACPs in the nervous systems of animals in a nontargeted manner.
doi:10.1021/acs.analchem.6b03658
PMCID: PMC5144109  PMID: 27788334
16.  Cerebrospinal Fluid IL-10 and IL-10/IL-6 as Accurate Diagnostic Biomarkers for Primary Central Nervous System Large B-cell Lymphoma 
Scientific Reports  2016;6:38671.
Early diagnosis of primary central nervous system lymphoma (PCNSL) represents a challenge, and cerebrospinal fluid (CSF) cytokines may be diagnostic biomarkers for PCNSL. We used an electrochemiluminescence immunoassay to measure interleukin (IL)-10, IL-6, IL-8 and tumor necrosis factor α (TNF-α) in the CSF of 22 B cell PCNSL patients and 80 patients with other CNS diseases. CSF IL-10 was significantly higher in PCNSL patients than in the control group (median 74.7 pg/ml vs < 5.0 pg/ml, P < 0.000). Using a CSF IL-10 cutoff value of 8.2 pg/ml, the diagnostic sensitivity and specificity were 95.5% and 96.1%, respectively (AUC, 0.957; 95% CI, 0.901–1.000). For a CSF IL-10/IL-6 cutoff value of 0.72, the sensitivity was 95.5%, and the specificity was 100.0% (AUC, 0.976; 95% CI, 0.929–1.000). An increased CSF IL-10 level at diagnosis and post-treatment was associated with poor Progression free survival (PFS) for patients with PCNSL (P = 0.0181 and P = 0.0002, respectively). A low diagnostic value for PCNSL was found with CSF IL-8 or TNF-α. In conclusion, increased CSF IL-10 was a reliable diagnostic biomarker for large B cell PCNSL, and an IL-10/IL-6 ratio facilitates differentiation from other conditions, especially a CNS infection.
doi:10.1038/srep38671
PMCID: PMC5141427  PMID: 27924864
17.  Identification and functional analysis of long intergenic noncoding RNA genes in porcine pre-implantation embryonic development 
Scientific Reports  2016;6:38333.
Genome-wide transcriptome studies have identified thousands of long intergenic noncoding RNAs (lincRNAs), some of which play important roles in pre-implantation embryonic development (PED). Pig is an ideal model for reproduction, however, porcine lincRNAs are still poorly characterized and it is unknown if they are associated with porcine PED. Here we reconstructed 195,531 transcripts in 122,007 loci, and identified 7,618 novel lincRNAs from 4,776 loci based on published RNA-seq data. These lincRNAs show low exon number, short length, low expression level, tissue-specific expression and cis-acting, which is consistent with previous reports in other species. By weighted co-expression network analysis, we identified 5 developmental stages specific co-expression modules. Gene ontology enrichment analysis of these specific co-expression modules suggested that many lincRNAs are associated with cell cycle regulation, transcription and metabolism to regulate the process of zygotic genome activation. Futhermore, we identified hub lincRNAs in each co-expression modules, and found two lincRNAs TCONS_00166370 and TCONS_00020255 may play a vital role in porcine PED. This study systematically analyze lincRNAs in pig and provides the first catalog of lincRNAs that might function as gene regulatory factors of porcine PED.
doi:10.1038/srep38333
PMCID: PMC5138625  PMID: 27922056
18.  Diagnostic Accuracy of Contrast-Enhanced Ultrasound Enhancement Patterns for Thyroid Nodules 
Background
The aim of this study was to investigate the accuracy of contrast-enhanced ultrasound (CEUS) enhancement patterns in the assessment of thyroid nodules.
Material/Methods
A total of 158 patients with suspected thyroid cancer underwent conventional ultrasound (US) and CEUS examinations. The contrast enhancement patterns of the lesions, including the peripheries of the lesions, were assessed by CEUS scans. The relationship between the size of the lesions and the degree of enhancement was also studied. US- and/or CEUS-guided biopsy was used to obtain specimens for histopathological diagnosis.
Results
The final data included 148 patients with 157 lesions. Seventy-five patients had 82 malignant lesions and 73 patients had 75 benign lesions. Peripheral ring enhancement was seen in 40 lesions. The differences of enhancement patterns and peripheral rings between benign and malignant nodules were significant (p=0.000, 0.000). The diagnostic sensitivity, specificity, and accuracy for malignant were 88%, 65.33%, and 88.32%, respectively, for CEUS, whereas they were 98.33%, 42.67%, and 71.97%, respectively, for TC by conventional US. The misdiagnosis rate by conventional US was 57.33% and 34.67% by CEUS (p=0.005). With regard to the size of lesions, a significant difference was found between low-enhancement, iso-enhancement, high-enhancement, iso-enhancement with no-enhancement area and no-enhancement (p=0.000).
Conclusions
In patients with suspicious US characteristics, CEUS had high specificity and contributed to establishing the diagnosis. Therefore, CEUS could avoid unnecessary biopsy.
doi:10.12659/MSM.899834
PMCID: PMC5154710  PMID: 27916971
Contrast Media; Thyroid Neoplasms; Ultrasonography, Doppler
19.  Lycopene Ameliorates Transplant Arteriosclerosis in Vascular Allograft Transplantation by Regulating the NO/cGMP Pathways and Rho-Associated Kinases Expression 
Objective. Transplant arteriosclerosis is considered one of the major factors affecting the survival time of grafts after organ transplantation. In this study, we proposed a hypothesis of whether lycopene can protect grafted vessels through regulating key proteins expression involved in arteriosclerosis. Methods. Allogeneic aortic transplantation was performed using Brow-Norway rats as donors and Lewis rats as recipients. After transplantation, the recipients were divided into two groups: the allograft group and the lycopene group. Negative control rats (isograft group) were also established. Histopathological staining was performed to observe the pathological changes, and the expression levels of Ki-67, caspase-3, Rho-associated kinases, intercellular adhesion molecules (ICAM-1), and eNOS were assessed. Western blotting analysis and real-time PCR were also performed for quantitative analysis. Results. The histopathological staining showed that vascular stenosis and intimal thickening were not evident after lycopene treatment. The Ki-67, ROCK1, ROCK2, and ICAM-1 expression levels were significantly decreased. However, eNOS expression in grafted arteries and plasma cGMP concentration were increased after lycopene treatment. Conclusions. Lycopene could alleviate vascular arteriosclerosis in allograft transplantation via downregulating Rho-associated kinases and regulating key factor expression through the NO/cGMP pathways, which may provide a potentially effective method for transplant arteriosclerosis in clinical organ transplantation.
doi:10.1155/2016/3128280
PMCID: PMC5165158  PMID: 28050227
20.  Regulator of G‐protein signalling 5 protects against atherosclerosis in apolipoprotein E‐deficient mice 
British Journal of Pharmacology  2015;172(23):5676-5689.
Background and Purpose
Atherosclerosis is a chronic inflammatory disease, in which ‘vulnerable plaques’ have been recognized as the underlying risk factor for coronary disease. Regulator of G‐protein signalling (RGS) 5 controls endothelial cell function and inflammation. In this study, we explored the effect of RGS5 on atherosclerosis and the potential underlying mechanisms.
Experimental Approach
RGS5−/− apolipoprotein E (ApoE)−/− and ApoE −/− littermates were fed a high‐fat diet for 28 weeks. Total aorta surface and lipid accumulation were measured by Oil Red O staining and haematoxylin–eosin staining was used to analyse the morphology of atherosclerotic lesions. Inflammatory cell infiltration and general inflammatory mediators were examined by immunofluorescence staining. Apoptotic endothelial cells and macrophages were assayed with TUNEL. Expression of RGS5and adhesion molecules, and ERK1/2 phosphorylation were evaluated by co‐staining with CD31. Expression of mRNA and protein were determined by quantitative real‐time PCR and Western blotting respectively.
Key Results
Atherosclerotic phenotypes were significantly accelerated in RGS5−/− ApoE −/− mice, as indicated by increased inflammatory mediator expression and apoptosis of endothelial cells and macrophages. RGS5 deficiency enhanced instability of vulnerable plaques by increasing infiltration of macrophages in parallel with the accumulation of lipids, and decreased smooth muscle cell and collagen content. Mechanistically, increased activation of NF‐κB and MAPK/ERK 1/2 could be responsible for the accelerated development of atherosclerosis in RGS5‐deficient mice.
Conclusions and Implications
RGS5 deletion accelerated development of atherosclerosis and decreased the stability of atherosclerotic plaques partly through activating NF‐κB and the MEK‐ERK1/2 signalling pathways.
Linked Articles
This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
doi:10.1111/bph.12991
PMCID: PMC4667852  PMID: 25363362
21.  Oestrogen inhibits BMP4‐induced BMP4 expression in cardiomyocytes: a potential mechanism of oestrogen‐mediated protection against cardiac hypertrophy 
British Journal of Pharmacology  2015;172(23):5586-5595.
Background and Purpose
Oestrogen inhibits cardiac hypertrophy and bone morphogenetic protein‐4 (BMP4) induces cardiac hypertrophy. Here we have studied the inhibition by oestrogen of BMP4 expression in cardiomyocytes.
Experimental Approach
Cultures of neonatal rat cardiomyocytes were used in in vitro experiments. Bilatαl ovariectomy (OVX) was carried out in female Kunming mice and cardiac hypertrophy was induced by transverse aortic constriction (TAC).
Key Results
Oestrogen inhibited BMP4‐induced cardiomyocyte hypertrophy and BMP4 expression in vitro. The inhibition of BMP4‐induced BMP4 protein expression by oestrogen was prevented by the inhibitor of oestrogen receptor‐β, PHTPP, but not by the inhibitor of oestrogen receptor‐α MPP. BMP4 induced smad1/5/8 activation, which was not affected by oestrogen in cardiomyocytes. BMP4 induced JNK but not ERK1/2 and p38 activation, and activated JNK was inhibited by oestrogen. Treatment with the p38 inhibitor SB203580 or the JNK inhibitor SP600125 inhibited BMP4‐induced BMP4 expression in cardiomyocytes, but the ERK1/2 inhibitor U0126 increased BMP4‐induced BMP4 expression, indicating that JNK, ERK1/2 and p38 MAPKs were all involved, although only JNK activation contributed to the inhibition of BMP4‐induced BMP4 expression by oestrogen. TAC induced significant heart hypertrophy in OVX mice in vivo and oestrogen replacement inhibited TAC‐induced heart hypertrophy in OVX mice. In parallel with the data of heart hypertrophy, oestrogen replacement significantly reduced the increased BMP4 protein expression in TAC‐treated OVX mice.
Conclusions and Implications
Oestrogen treatment inhibited BMP4‐induced BMP4 expression in cardiomyocytes through stimulating oestrogen receptor‐β and inhibiting JNK activation. Our results provide a novel mechanism underlying oestrogen‐mediated protection against cardiac hypertrophy.
Linked Articles
This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
doi:10.1111/bph.12983
PMCID: PMC4667872  PMID: 25323043
23.  Influence of WeChat on sleep quality among undergraduates in Chongqing, China: a cross-sectional study 
SpringerPlus  2016;5(1):2066.
Background
Previous studies showed that social media is associated with sleep quality. WeChat (a native social media in China) is very popular in China, especially among the youth. In the second quarter of 2016, Tencent’s WeChat had 806 million monthly active users. The study sought to identify the influence of WeChat on the sleep quality among undergraduate students.
Methods
A cross-sectional survey adopted a multi-stage stratified sampling survey to investigate undergraduates in Chongqing, China. Data were collected on 1979 eligible adults, aged 20.27 (SD: 1.26) years old, using Pittsburgh Sleep Quality Index (PSQI) to measure sleep quality.
Results
Respondents aged 20.27 ± 1.26 years included 535 (27.0%) males, and 1311 (66.3%) reported as having poor sleep quality. Of the 1979 participants, 1320 (66.70%) were WeChat users. In multivariable analyses, gender, grade, nationality, living costs, the student leader, the only child, type of university, WeChat usage was associated with domains of PSQI among undergraduates (p < 0.05 for all). Compared with non-users, WeChat users had a lower score of subjective quality of sleep, sleep latency, use of sleeping medication, daytime dysfunction, and global PSQI score (p < 0.05 for all).
Conclusions
WeChat users may have better sleep quality than non-WeChat users among undergraduates. To determine causal relationships, further longitudinal studies will be required to test for the association between WeChat users and sleep quality. This study may also provide some implications for health promotion on sleep quality of undergraduate students.
doi:10.1186/s40064-016-3730-z
PMCID: PMC5133219  PMID: 27995043
WeChat; Sleep quality; Undergraduates; Social media; China
24.  Enhanced pro‐protein convertase subtilisin/kexin type 9 expression by C‐reactive protein through p38MAPK‐HNF1α pathway in HepG2 cells 
Abstract
Plasma C‐reactive protein (CRP) concentration is associated positively with cardiovascular risk, including dyslipidemia. We suggested a regulating role of CRP on pro‐protein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low‐density lipoprotein (LDL) metabolism, and demonstrated the PCSK9 as a pathway linking CRP and LDL regulation. Firstly, experiments were carried out in the presence of human CRP on the protein and mRNA expression of PCSK9 and LDL receptor (LDLR) in human hepatoma cell line HepG2 cells. Treatment with CRP (10 μg/ml) enhanced significantly the mRNA and protein expression of PCSK9 and suppressed the expression of LDLR. Of note, a late return of LDLR mRNA levels occurred at 12 hrs, while the LDLR protein continued to decrease at 24 hrs, suggesting that the late decrease in LDLR protein levels was unlikely to be accounted for the decrease in LDL mRNA. Secondly, the role of PCSK9 in CRP‐induced LDLR decrease and the underlying pathways were investigated. As a result, the inhibition of PCSK9 expression by small interfering RNA (siRNA) returned partly the level of LDLR protein and LDL uptake during CRP treatment; CRP‐induced PCSK9 increase was inhibited by the p38MAPK inhibitor, SB203580, resulting in a significant rescue of LDLR protein expression and LDL uptake; the pathway was involved in hepatocyte nuclear factor 1α (HNF1α) but not sterol responsive element‐binding proteins (SREBPs) preceded by the phosphorylation of p38MAPK. These findings indicated that CRP increased PCSK9 expression by activating p38MAPK‐HNF1α pathway, with a certain downstream impairment in LDL metabolism in HepG2 cells.
doi:10.1111/jcmm.12931
PMCID: PMC5134380  PMID: 27633999
C‐reactive protein; pro‐protein convertase subtilisin/kexin type 9; mitogen‐activated protein kinase
25.  Dental pulp stem cells express tendon markers under mechanical loading and are a potential cell source for tissue engineering of tendon-like tissue 
Postnatal mesenchymal stem cells have the capacity to differentiate into multiple cell lineages. This study explored the possibility of dental pulp stem cells (DPSCs) for potential application in tendon tissue engineering. The expression of tendon-related markers such as scleraxis, tenascin-C, tenomodulin, eye absent homologue 2, collagens I and VI was detected in dental pulp tissue. Interestingly, under mechanical stimulation, these tendon-related markers were significantly enhanced when DPSCs were seeded in aligned polyglycolic acid (PGA) fibre scaffolds. Furthermore, mature tendon-like tissue was formed after transplantation of DPSC-PGA constructs under mechanical loading conditions in a mouse model. This study demonstrates that DPSCs could be a potential stem cell source for tissue engineering of tendon-like tissue.
doi:10.1038/ijos.2016.33
PMCID: PMC5168414  PMID: 27811845
dental pulp stem cells; in vivo model; mechanical loading; tendon engineering

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