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1.  Elevated cyclin D1 expression is predictive for a benefit from TPF induction chemotherapy in oral squamous cell carcinoma patients with advanced nodal disease 
Molecular cancer therapeutics  2013;12(6):1112-1121.
Induction chemotherapy is likely to be effective for biologically distinct subgroups of cancer patients with biomarker detection. In order to investigate the prognostic and predictive values of cyclin D1 expression in patients with oral squamous cell carcinoma(OSCC) who were treated in a prospective, randomized, phase 3 trial evaluating standard treatment with surgery and post-operative radiotherapy preceded or not by induction docetaxel, cisplatin and 5-fluorouracil(TPF). Immunohistochemical staining for cyclin D1 was performed in pretreatment biopsy specimens of 232 out of 256 clinical stage III/IVA OSCC patients randomized to the clinical trial. Cyclin D1 index was estimated as the proportion of tumor cells with cyclin D1 nuclear staining. A low cyclin D1 expression predicted significantly better overall survival(P=0.001), disease-free survival(P=0.005), locoregional recurrence-free survival(P=0.003) and distant metastasis-free survival(P=0.002) compared to high cyclin D1 expression. Cyclin D1 expression levels were not predictive of benefit from induction TPF in the population overall. However, patients with nodal stage cN2 whose tumors had high cyclin D1 expression treated with TPF had significantly greater overall survival(P=0.025) and distant metastasis-free survival(P=0.025) when compared to high cyclin D1 cN2 patients treated with surgery upfront. Patients with low cyclin D1 level or patients with cN0 or cN1 disease did not benefit from induction chemotherapy. This study indicates that cN2 OSCC patients with high cyclin D1 expression can benefit from the addition of TPF induction chemotherapy to standard treatment. Cyclin D1 expression could be used as a biomarker in further validation studies to select cN2 patients that could benefit from induction therapy.
doi:10.1158/1535-7163.MCT-12-1013
PMCID: PMC5247265  PMID: 23515614
Cyclin D1; Oral squamous cell carcinoma; Induction chemotherapy; Predictive biomarker; Prognostic biomarker
2.  Identification, Characterization, and Application of the Replicon Region of the Halophilic Temperate Sphaerolipovirus SNJ1 
Journal of Bacteriology  2016;198(14):1952-1964.
ABSTRACT
The temperate haloarchaeal virus SNJ1 displays lytic and lysogenic life cycles. During the lysogenic cycle, the virus resides in its host, Natrinema sp. strain J7-1, in the form of an extrachromosomal circular plasmid, pHH205. In this study, a 3.9-kb region containing seven predicted genes organized in two operons was identified as the minimal replicon of SNJ1. Only RepA, encoded by open reading frame 11-12 (ORF11-12), was found to be essential for replication, and its expression increased during the lytic cycle. Sequence analysis suggested that RepA is a distant homolog of HUH endonucleases, a superfamily that includes rolling-circle replication initiation proteins from various viruses and plasmids. In addition to RepA, two genetic elements located within both termini of the 3.9-kb replicon were also required for SNJ1 replication. SNJ1 genome and SNJ1 replicon-based shuttle vectors were present at 1 to 3 copies per chromosome. However, the deletion of ORF4 significantly increased the SNJ1 copy number, suggesting that the product of ORF4 is a negative regulator of SNJ1 abundance. Shuttle vectors based on the SNJ1 replicon were constructed and validated for stable expression of heterologous proteins, both in J7 derivatives and in Natrinema pallidum JCM 8980T, suggesting their broad applicability as genetic tools for Natrinema species.
IMPORTANCE Archaeal viruses exhibit striking morphological diversity and unique gene content. In this study, the minimal replicon of the temperate haloarchaeal virus SNJ1 was identified. A number of ORFs and genetic elements controlling virus genome replication, maintenance, and copy number were characterized. In addition, based on the replicon, a novel expression shuttle vector has been constructed and validated for protein expression and purification in Natrinema sp. CJ7 and Natrinema pallidum JCM 8980T. This study not only provided mechanistic and functional insights into SNJ1 replication but also led to the development of useful genetic tools to investigate SNJ1 and other viruses infecting Natrinema species as well as their hosts.
doi:10.1128/JB.00131-16
PMCID: PMC4936101  PMID: 27137505
3.  Reversibly Extracellular pH Controlled Cellular Uptake and Photothermal Therapy by PEGylated Mixed-Charge Gold Nanostars 
Shielding nanoparticles from nonspecific interactions with normal cells/tissues before they reach and after they leave tumors is crucial for the selective delivery of NPs into tumor cells. By utilizing the reversible protonation of weak electrolytic groups to pH changes, long-chain amine/carboxyl-terminated polyethylene glycol (PEG) decorated gold nanostars (GNSs) are designed, exhibiting reversible, significant, and sensitive response in cell affinity and therapeutic efficacy to the extracellular pH (pHe) gradient between normal tissues and tumors. This smart nanosystem shows good dispersity and unimpaired photothermal efficacy in complex bioenvironment at pH 6.4 and 7.4 even when their surface charge is neutral. One PEGylated mixed-charge GNSs with certain surface composition, GNS-N/C 4, exhibits high cell affinity and therapeutic efficacy at pH 6.4, and low affinity and almost “zero” damage to cells at pH 7.4. Remarkably, this significant and sensitive response in cell affinity and therapeutic efficacy is reversible as local pH alternated. In vivo, GNS-N/C 4 shows higher accumulation in tumors and improved photothermal therapeutic efficacy than pH-insensitive GNSs. This newly developed smart nanosystem, whose cell affinity reversibly transforms in response to pHe gradient with unimpaired biostability, provides a novel effective means of tumor-selective therapy.
doi:10.1002/smll.201403248
PMCID: PMC5227651  PMID: 25565411
4.  Critical Roles of STAT3 in β-Adrenergic Functions in the Heart 
Circulation  2015;133(1):48-61.
Background
β-adrenergic receptors (βARs) play paradoxical roles in the heart. On one hand, βARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of βARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing heart in both the human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function.
Methods and Results
We observed that STAT3 can be directly activated in cardiomyocytes by β-adrenergic agonists. To follow up this finding, we analyzed βAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute βAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic β-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gαs and Src kinases are required for βAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of βAR pathway, including β1AR and PKA, and T-type Ca2+ channels.
Conclusions
Our data demonstrates for the first time that STAT3 has a fundamental role in βAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for βAR-mediated cardiac stress adaption, pathological remodelling and heart failure.
doi:10.1161/CIRCULATIONAHA.115.017472
PMCID: PMC4698100  PMID: 26628621
GPCR; βAR signaling; STAT3; heart failure
5.  Casticin induces apoptosis and G0/G1 cell cycle arrest in gallbladder cancer cells 
Background
Casticin, the flavonoid extracted from Vitex rotundifolia L, exerts various biological effects, including anti-inflammatory and anti-cancer activity. The aim of this study is to investigate the effects and mechanisms of casticin in human gallbladder cancer cells.
Methods
Human NOZ and SGC996 cells were used to perform the experiments. CCK-8 assay and colony formation assay were performed to evaluate cell viability. Cell cycle analyses and annexin V/PI staining assay for apoptosis were measured using flow cytometry. Western blot analysis was used to evaluate the changes in protein expression, and the effect of casticin treatment in vivo was experimented with xenografted tumors.
Results
In this study, we found that casticin significantly inhibited gallbladder cancer cell proliferation in a dose- and time-dependent manner. Casticin also induced G0/G1 arrest and mitochondrial-related apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase expression, and by downregulating Bcl-2 expression. Moreover, casticin induced cycle arrest and apoptosis by upregulating p27 and downregulating cyclinD1/cyclin-dependent kinase4 and phosphorylated protein kinase B. In vivo, casticin inhibited tumor growth.
Conclusion
Casticin induces G0/G1 arrest and apoptosis in gallbladder cancer, suggesting that casticin might represent a novel and effective agent against gallbladder cancer.
doi:10.1186/s12935-016-0377-3
PMCID: PMC5217413  PMID: 28070171
Casticin; Gallbladder cancer; Akt signaling pathway; G0/G1 arrest; Apoptosis
6.  Effects of the −791(C→T) mutation in the promoter for tumor necrosis factor alpha on gene expression and resistance of Large White pigs to enterotoxigenic Escherichia coli F18 
Tumor necrosis factor alpha (TNF-α) plays an important role in the immune system. In this study, TNF-α expression was analyzed in 11 tissues of 8 piglets resistant to enterotoxigenic Escherichia coli (ETEC) F18 and 8 ETEC F18-susceptible piglets from the Large White breed. The expression levels of TNF-α were high in immune organs (spleen, lung, thymus, and lymph nodes). The levels were higher in ETEC F18-resistant piglets than in ETEC F18-susceptible piglets, with significant differences in spleen, kidney, thymus, lymph node, and duodenum (P < 0.05). The mutation TNF-α −791(C→T) and 3 genotypes (CC, CT, and TT) were identified. The TNF-α expression levels in the spleen, kidney, lymph nodes, and duodenum were significantly higher in the TT pigs than in the CC pigs (P < 0.05). Thus, TNF-α −791(C→T) has significant effects on mRNA expression and may regulate ETEC F18 resistance of weaning piglets. Therefore, the −791(C→T) mutation of the TNF-α gene could be considered an important potential genetic marker of ETEC F18 resistance.
PMCID: PMC4924554  PMID: 27408333
7.  Movement analysis of free-grazing domestic ducks in Poyang Lake, China: a disease connection 
Previous work suggests domestic poultry are important contributors to the emergence and transmission of highly pathogenic avian influenza throughout Asia. In Poyang Lake, China, domestic duck production cycles are synchronized with arrival and departure of thousands of migratory wild birds in the area. During these periods, high densities of juvenile domestic ducks are in close proximity to migratory wild ducks, increasing the potential for the virus to be transmitted and subsequently disseminated via migration. In this paper, we use GPS dataloggers and dynamic Brownian bridge models to describe movements and habitat use of free-grazing domestic ducks in the Poyang Lake basin and identify specific areas that may have the highest risk of H5N1 transmission between domestic and wild birds. Specifically, we determine relative use by free-grazing domestic ducks of natural wetlands, which are the most heavily used areas by migratory wild ducks, and of rice paddies, which provide habitat for resident wild ducks and lower densities of migratory wild ducks. To our knowledge, this is the first movement study on domestic ducks, and our data show potential for free-grazing domestic ducks from farms located near natural wetlands to come in contact with wild waterfowl, thereby increasing the risk for disease transmission. This study provides an example of the importance of movement ecology studies in understanding dynamics such as disease transmission on a complicated landscape.
doi:10.1080/13658816.2015.1065496
PMCID: PMC5042146  PMID: 27695384
domestic poultry; disease transmission; dynamic Brownian bridge movement model
8.  LINE-1 Cultured Cell Retrotransposition Assay 
Summary
The Long INterspersed Element-1 (LINE-1 or L1) retrotransposition assay has facilitated the discovery and characterization of active (i.e., retrotransposition-competent) LINE-1 sequences from mammalian genomes. In this assay, an engineered LINE-1 containing a retrotransposition reporter cassette is transiently transfected into a cultured cell line. Expression of the reporter cassette, which occurs only after a successful round of retrotransposition, allows the detection and quantification of the LINE-1 retrotransposition efficiency. This assay has yielded insight into the mechanism of LINE-1 retrotransposition. It also has provided a greater understanding of how the cell regulates LINE-1 retrotransposition and how LINE-1 retrotransposition impacts the structure of mammalian genomes. Below, we provide a brief introduction to LINE-1 biology and then detail how the LINE-1 retrotransposition assay is performed in cultured mammalian cells.
doi:10.1007/978-1-4939-3372-3_10
PMCID: PMC5070806  PMID: 26895052
LINE-1; Alu; retrotransposition assay; trans-complementation assay; mammalian cultured cells
9.  A novel matrine derivate inhibits differentiated human hepatoma cells and hepatic cancer stem-like cells by suppressing PI3K/AKT signaling pathways 
Acta Pharmacologica Sinica  2016;38(1):120-132.
Matrine is an alkaloid extracted from a Chinese herb Sophora flavescens Ait, which has shown chemopreventive potential against various cancers. In this study, we evaluated the anticancer efficacy of a novel derivative of matrine, (6aS, 10S, 11aR, 11bR, 11cS)-10- methylamino-dodecahydro- 3a,7a-diazabenzo (de) (MASM), against human hepatocellular carcinoma (HCC) cells and their corresponding sphere cells in vitro and in vivo. Human HCC cell lines (Hep3B and Huh7) were treated with MASM. Cell proliferation was assessed using CCK8 and colony assays; cell apoptosis and cell cycle distributions were examined with flow cytometry. The expression of cell markers and signaling molecules was detected using Western blot and qRT-PCR analyses. A sphere culture technique was used to enrich cancer stem cells (CSC) in Hep3B and Huh7 cells. The in vivo antitumor efficacy of MASM was evaluated in Huh7 cell xenograft model in BALB/c nude mice, which were administered MASM (10 mg·kg−1·d−1, ig) for 3 weeks. After the treatment was completed, tumor were excised and weighed. A portion of tumor tissue was enzymatically dissociated to obtain a single cell suspension for the spheroid formation assays. MASM (2, 10, 20 μmol/L) dose-dependently inhibited the proliferation of HCC cells, and induced apoptosis, which correlated with a reduction in Bcl-2 expression and an increase in PARP cleavage. MASM also induced cell cycle arrest in G0/G1 phase, which was accompanied by increased p27 and decreased Cyclin D1 expression. Interestingly, MASM (2, 10, and 20 μmol/L) drastically reduced the EpCAM+/CD133+ cell numbers, suppressed the sphere formation, inhibited the expression of stem cell marker genes and promoted the expression of mature hepatocyte markers in the Hep3B and Huh7 spheroids. Additionally, MASM dose-dependently suppressed the PI3K/AKT/mTOR and AKT/GSK3β/β-catenin signaling pathways in Hep3B and Huh7 cells. In Huh7 xenograft bearing nude mice, MASM administration significantly inhibited Huh7 xenograft tumor growth and markedly reduced the number of surviving cancer stem-like cells in the tumors. MASM administration also reduced the expression of stem cell markers while increasing the expression of mature hepatocyte markers in the tumor tissues. The novel derivative of matrine, MASM, markedly suppresses HCC tumor growth through multiple mechanisms, and it may be a promising candidate drug for the treatment of hepatocellular carcinoma.
doi:10.1038/aps.2016.104
PMCID: PMC5220537  PMID: 27773936
matrine; MASM; hepatocellular carcinoma; Hep3B cells; Huh7 cells; cancer stem cells; xenograft nude mouse model; PI3K/AKT pathway
10.  Study of in vitro RBCs membrane elasticity with AOD scanning optical tweezers 
Biomedical Optics Express  2016;8(1):384-394.
The elasticity of red cell membrane is a critical physiological index for the activity of RBC. Study of the inherent mechanism for RBCs membrane elasticity transformation is attention-getting all along. This paper proposes an optimized measurement method of erythrocytes membrane shear modulus incorporating acousto-optic deflector (AOD) scanning optical tweezers system. By use of this method, both membrane shear moduli and sizes of RBCs with different in vitro times were determined. The experimental results reveal that the RBCs membrane elasticity and size decline with in vitro time extension. In addition, semi quantitative measurements of S-nitrosothiol content in blood using fluorescent spectrometry during in vitro storage show that RBCs membrane elasticity change is positively associated with the S-nitrosylation level of blood. The analysis considered that the diminished activity of the nitric oxide synthase makes the S-nitrosylation of in vitro blood weaker gradually. The main reason for worse elasticity of the in vitro RBCs is that S-nitrosylation effect of spectrin fades. These results will provide a guideline for further study of in vitro cells activity and other clinical applications.
doi:10.1364/BOE.8.000384
PMCID: PMC5231307
(000.1430) Biology and medicine; (350.4855) Optical tweezers or optical manipulation
11.  Human Induced Pluripotent Stem Cell NEUROG2 Dual Knockin Reporter Lines Generated by the CRISPR/Cas9 System 
Stem Cells and Development  2015;24(24):2925-2942.
Human induced pluripotent stem cell (hiPSC) technologies are powerful tools for modeling development and disease, drug screening, and regenerative medicine. Faithful gene targeting in hiPSCs greatly facilitates these applications. We have developed a fast and precise clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) technology-based method and obtained fluorescent protein and antibiotic resistance dual knockin reporters in hiPSC lines for neurogenin2 (NEUROG2), an important proneural transcription factor. Gene targeting efficiency was greatly improved in CRISPR/Cas9-mediated homology directed recombination (∼33% correctly targeted clones) compared to conventional targeting protocol (∼3%) at the same locus. No off-target events were detected. In addition, taking the advantage of the versatile applications of the CRISPR/Cas9 system, we designed transactivation components to transiently induce NEUROG2 expression, which helps identify transcription factor binding sites and trans-regulation regions of human NEUROG2. The strategy of using CRISPR/Cas9 genome editing coupled with fluorescence-activated cell sorting of neural progenitor cells in a knockin lineage hiPSC reporter platform might be broadly applicable in other stem cell derivatives and subpopulations.
doi:10.1089/scd.2015.0131
PMCID: PMC4683556  PMID: 26414932
12.  Beclin-1- mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice 
Background
Diabetes is the most common metabolic disease with many chronic complications, and cognitive disorders are one of the common complications in patients with diabetes. Previous studies have showed that autophagy played important roles in the progression of metabolic syndrome, diabetes and other diseases. So we investigated whether aged diabetic mice are prone to be associated with the cognitive and affective disorders and whether Beclin-1-mediated autophagy might be involved in thepahological process.
Methods
High-fat diet/streptozotocin (STZ) injection-induced diabetic C57 mice were adopted in this study. Cognitive disorders were detected by Morris water maze and fear conditional test. Affective disorders were detected by tail suspension test and forced swimming test. Magnetic resonance imaging was applied to observe changes of morphology and metabolism in the brain. The 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used to assess metabolism changes in the brain of aged diabetic mice. Autophagy were evaluated by Beclin- 1, LC3II/I and P62, which were detected by western blot analysis and observed by electron microscopy.
Results
1. Compared with control group, diabetes mice showed significantly decreasing abilities in spatial memory and conditioned fear memory (all P < 0.05), and increasing tendency of depression (P < 0.05). 2. MRI showed that the majority of elderly diabetic mice were associated with multiple cerebral small vessel disease. Some even showed hippocampal atrophy, ventricular dilatation and leukoaraiosis. 3. FDG-PET-CT discovered that the glucose metabolism in the amygdala and hippocampus was significantly decreased compared with normal aged mice (P < 0.05). 4. Electron microscopy found that, although autophagy bodies was not widespread, and there was no significant difference between the two groups, yet compared with normal aged mice, apparent cell edema, myelinated tow reduction and intracellular lipofuscin augmentation existed in elderly diabetic mice brain. 5. The level of p62 was increased in the STZ-induced diabetic mice hippocampus and striatum, and beclin1 protein expression were significantly decreased in diabetic mice hippocampus compared with normal aged mice (P < 0.05). There was a upward trend of the ratio of LC3II/I in hippocampus, cortex and striatum, but no statistically difference between the two groups.
Conclusion
Compared with normal aged mice, diabetic aged mice were apt to cerebral small vessel disease and associated with cognitive and affective disorders, which may be related to the significantly reduced glucose metabolism in hippocampus and amygdala. Beclin1 mediated autophagy in hippocampus probably played an important role in cognitive and affective disorders of STZ-induced aged diabetic mice.
doi:10.1186/s40035-016-0070-4
PMCID: PMC5154026  PMID: 27999666
13.  Association of diabetic vascular complications with poor sleep complaints 
Background
Literatures reported that poor sleep complaints were associated with a great deal of health outcomes. However, there are few studies on the association of poor sleep complaints with diabetic vascular complications.
Methods
Aiming on the association, a cross-sectional survey was conducted among 1220 diabetic patients in this study. Poor sleep complaints were composed of difficulty falling asleep, early final awakening, short sleep and long sleep. The diabetic vascular complications involved in the study were diagnosed according to the Standards of Medical Care in Diabetes (ADA 2016).
Results
Our findings indicated that short sleep remained independently associated with diabetic kidney disease (DKD) (OR > 1, P < 0.05) after the adjustments; long sleep independently associated with diabetic retinopathy (DR) (OR > 1, P < 0.05); early final awakening and short sleep independently associated with cardiovascular disease (OR > 1, P < 0.05); short sleep independently associated with peripheral arterial disease (OR > 1, P < 0.05); there was no association between poor sleep complaints and neuropathy (P > 0.05).
Conclusions
The study suggests that the poor sleep complaints were distinguishably associated with diabetic vascular complications. Clinicians should take poor sleep complaints into account in diabetes treatment.
doi:10.1186/s13098-016-0195-8
PMCID: PMC5146879  PMID: 27980688
Poor sleep complaints; Diabetic kidney disease (DKD); Neuropathy; Diabetic retinopathy (DR); Cardiovascular disease (CVD); Peripheral arterial disease (PAD)
15.  Identification of feature genes for smoking-related lung adenocarcinoma based on gene expression profile data 
OncoTargets and therapy  2016;9:7397-7407.
This study aimed to identify the genes and pathways associated with smoking-related lung adenocarcinoma. Three lung adenocarcinoma associated datasets (GSE43458, GSE10072, and GSE50081), the subjects of which included smokers and nonsmokers, were downloaded to screen the differentially expressed feature genes between smokers and nonsmokers. Based on the identified feature genes, we constructed the protein–protein interaction (PPI) network and optimized feature genes using closeness centrality (CC) algorithm. Then, the support vector machine (SVM) classification model was constructed based on the feature genes with higher CC values. Finally, pathway enrichment analysis of the feature genes was performed. A total of 213 down-regulated and 83 up-regulated differentially expressed genes were identified. In the constructed PPI network, the top ten nodes with higher degrees and CC values included ANK3, EPHA4, FGFR2, etc. The SVM classifier was constructed with 27 feature genes, which could accurately identify smokers and nonsmokers. Pathways enrichment analysis for the 27 feature genes revealed that they were significantly enriched in five pathways, including proteoglycans in cancer (EGFR, SDC4, SDC2, etc.), and Ras signaling pathway (FGFR2, PLA2G1B, EGFR, etc.). The 27 feature genes, such as EPHA4, FGFR2, and EGFR for SVM classifier construction and cancer-related pathways of Ras signaling pathway and proteoglycans in cancer may play key roles in the progression and development of smoking-related lung adenocarcinoma.
doi:10.2147/OTT.S114230
PMCID: PMC5153289  PMID: 27994470
lung adenocarcinoma; feature genes; support vector machine (SVM) classification; pathway
16.  A 3′ poly(A) tract is required for LINE-1 retrotransposition 
Molecular cell  2015;60(5):728-741.
Summary
L1 retrotransposons express proteins (ORF1p and ORF2p) that preferentially mobilize their encoding RNA in cis, but they also can mobilize Alu RNA and, more rarely, cellular mRNAs in trans. Although these RNAs differ in sequence, each ends in a 3′ polyadenosine (poly(A)) tract. Here, we replace the L1 polyadenylation signal with sequences derived from a non-polyadenylated long noncoding RNA (MALAT1), which can form a stabilizing triple helix at the 3′ end of an RNA. L1/MALAT RNAs accumulate in cells, lack poly(A) tails, and are translated; however, they cannot retrotranspose in cis. Remarkably, the addition of a 16 or 40 base poly(A) tract downstream of the L1/MALAT triple helix restores retrotransposition in cis. The presence of a poly(A) tract also allows ORF2p to bind and mobilize RNAs in trans. Thus, a 3′ poly(A) tract is critical for the retrotransposition of sequences that comprise approximately one billion base pairs of human DNA.
doi:10.1016/j.molcel.2015.10.012
PMCID: PMC4671821  PMID: 26585388
17.  Non-Contact Strain Measurement in the Mouse Forearm Loading Model Using Digital Image Correlation (DIC) 
Bone  2015;81:593-601.
This study investigates the use of a non-contact method known as Digital Image Correlation (DIC) to measure strains in the mouse forearm during axial compressive loading. A two camera system was adapted to analyze the medial and lateral forearm displacements simultaneously, and the derived DIC strain measurements were compared to strain gage readings from both the ulna and radius. Factors such as region-of-interest (ROI) location, lens magnification, noise, and out-of-plane motion were examined to determine their influence on the DIC strain measurements. We confirmed that our DIC system can differentiate ROI locations since it detected higher average strains in the ulna compared to the radius and detected compressive strains on medial bone surfaces vs. tensile strains on lateral bone surfaces. Interestingly, the DIC method also captured heterogeneity in surface strain fields which are not detectable by strain gage based methods. A separate analysis of the noise intrinsic to the DIC system also revealed that the noise constituted less than 4.5% of all DIC strain measurements. Furthermore, finite element (FE) simulations of the forearm showed that out-of-plane motion was not a significant factor that influenced DIC measurements. Finally, we observed that average DIC strain measurements can be up to 1.5–2 times greater than average strain gage readings on the medial bone surfaces. These findings suggest that strain experienced in the mouse forearm model by loading is better captured through DIC as opposed to strain gages, which as a result of being glued to the bone surface artificially stiffen the bone and lead to an underestimation of the strain response.
doi:10.1016/j.bone.2015.09.007
PMCID: PMC4640949  PMID: 26388521
Strain; digital image correlation; forearm; ulna; radius
18.  Abnormal eating behavior in video-recorded meals in anorexia nervosa 
Eating behaviors  2015;19:28-32.
Objective
Eating behavior during meals in anorexia nervosa (AN) has long been noted to be abnormal, but little research has been done carefully characterizing these behaviors. These eating behaviors have been considered pathological, but are not well understood. The current study sought to quantify ingestive and non-ingestive behaviors during a laboratory lunch meal, compare them to the behaviors of healthy controls (HC), and examine their relationships with caloric intake and anxiety during the meal.
Method
A standardized lunch meal was video-recorded for 26 individuals with AN and 10 HC. Duration, frequency, and latency of 16 mealtime behaviors were coded using computer software. Caloric intake, dietary energy density (DEDS), and anxiety were also measured.
Results
Nine mealtime behaviors were identified that distinguished AN from HC: staring at food, tearing food, nibbling/picking, dissecting food, napkin use, inappropriate utensil use, hand fidgeting, eating latency, and nibbling/picking latency. Among AN, a subset of these behaviors were related to caloric intake and anxiety.
Discussion
These data demonstrate that the mealtime behaviors of patients with AN and HC differ significantly, and some of these behaviors may be associated with food intake and anxiety. These mealtime behaviors may be important treatment targets to improve eating behavior in individuals with AN.
doi:10.1016/j.eatbeh.2015.06.005
PMCID: PMC4644429  PMID: 26164671
anorexia nervosa; eating disorders; anxiety; food intake; eating behavior; video assessment
19.  Expression Profiling of Ascorbic Acid–Related Transporters in Human and Mouse Eyes 
Purpose
Ascorbic acid (AsA) is an important antioxidant in the eye. Ascorbic acid is usually transported by sodium-dependent AsA transporters (SVCTs), and dehydroascorbic acid (DHA) by glucose transporters (GLUTs). This study investigates these AsA-related transporters in human compared with mouse eyes.
Methods
Five pairs of human donor eyes and 15 pairs of mouse eyes were collected. Immunofluorescence and in situ hybridization were performed to detect SVCTs and GLUTs expression in the ciliary epithelium, retina, and lens epithelial cells (LECs). These tissues were isolated with laser microdissection followed by extraction of total RNA. Quantitative PCR (qPCR) was performed to examine the mRNA level of SVCTs and GLUTs in human and mouse ocular tissues.
Results
Immunofluorescence and in situ hybridization showed SVCT2 and GLUT1 expression in human ciliary epithelium with varied distributions. Sodium-dependent AsA transporter 2 is expressed only in the pigmented epithelium (PE), and GLUT1 is predominately expressed in the nonpigmented epithelium (NPE). However, SVCT2 was not identified in mouse ciliary epithelium, whereas GLUT1 expressed in both PE and NPE. Laser microdissection and qPCR revealed high levels of SVCT2 mRNA in human RPE cells and murine neural retina. Sodium-dependent AsA transporter 1 mRNA could be detected only in human and murine LECs. Glucose transporter 3 and GLUT4 mRNA could not be detected in either the human or mouse ciliary processes or in the lens epithelium.
Conclusions
These fundamental findings indicate AsA transporter expression in eyes of humans is significantly different compared with mice. This may explain why human aqueous and vitreous humors contain higher AsA levels compared with other animals.
doi:10.1167/iovs.16-19162
PMCID: PMC4961060  PMID: 27367512
ascorbic acid; transporters; SVCT2; GLUT1
20.  Infusion with Human Bone Marrow-derived Mesenchymal Stem Cells Improves β-cell Function in Patients and Non-obese Mice with Severe Diabetes 
Scientific Reports  2016;6:37894.
Mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for type 1 diabetes (T1D). However, little is known on whether MSC transplantation can benefit T1D patients with ketoacidosis and its potential actions. Here, we show that infusion with bone marrow MSCs preserves β-cell function in some T1D patients with ketoacidosis by decreasing exogenous insulin requirement and increasing plasma C-peptide levels up to 1–2 years. MSC transplantation increased plasma and islet insulin contents in non-obese diabetic (NOD) mice with severe diabetes. In comparison with severe diabetes controls, MSC infusion reduced insulitis, decreased pancreatic TNF-α, and increased IL-10 and TGF-β1 expression in NOD mice. MSC infusion increased the percentages of splenic Tregs and levels of plasma IL-4, IL-10 and TGF-β1, but reduced the percentages of splenic CD8+ T and levels of plasma IFN-γ, TNF-α and IL-17A in NOD mice. Finally, infused MSCs predominantly accumulated in pancreatic tissues at 28 days post infusion. The effects of MSCs on preserving β-cell function and modulating inflammation tended to be dose-dependent and multiple doses of MSCs held longer effects in NOD mice. Hence, MSC transplantation preserved β-cell function in T1D patients and NOD mice with severe diabetes by enhancing Treg responses.
doi:10.1038/srep37894
PMCID: PMC5131346  PMID: 27905403
21.  Characterization of community-associated Staphylococcus aureus from skin and soft-tissue infections: a multicenter study in China 
Emerging Microbes & Infections  2016;5(12):e127-.
We evaluated the epidemiological and molecular features of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and methicillin-sensitive S. aureus (MSSA) from children and adult patients with skin and soft-tissue infections (SSTIs) in China. Prospective community-acquired S. aureus SSTI surveillance was conducted in 23 hospitals over a 24-month period. Susceptibility to 16 antimicrobials was evaluated using the agar dilution method. StatApriori was used to determine statistically significant association trends. The genotypic characteristics of CA-MRSA isolates were tested by staphylococcal cassette chromosome mec (SCCmec) typing, staphylococcal protein A (spa) typing, and multilocus sequence typing. The presence of Panton–Valentine leukocidin (pvl) genes was determined. Overall, 71.6% (1946/2716) of cases were community-associated S. aureus. CA-MRSA accounted for 2.6% (51). Out of 1895 methicillin-sensitive S. aureus strains, 97.3% were resistant to erythromycin, 96.6% to penicillin and 89.1% to clindamycin. No S. aureus strains were resistant to vancomycin. Thirteen sequence types (STs) and 17 spa types were detected among the CA-MRSA strains. The most prevalent sequence type was ST121 (19/51, 37.3%), followed by ST59 (13/51, 25.5%). In addition, t437 was predominant, accounting for 43.1% (22/51). Only five (9.8%) of the CA-MRSA strains harbored pvl genes. There were no significant differences in antibiotic sensitivity profiles between ST121 and non-ST121 MRSA isolates. However, ST121 strains tended to be more resistant to cefazolin, whereas non-ST121 strains were more resistant to chloramphenicol. In conclusion, CA-MRSA infections are rare among Chinese SSTI patients. MRSA strains in China have diverse genetic backgrounds, with ST121 being the predominant clone. Fusidic acid and mupirocin remain effective for topical treatment.
doi:10.1038/emi.2016.128
PMCID: PMC5180372  PMID: 27999423
methicillin-resistant Staphylococcus aureus; China; molecular epidemiology; skin and soft-tissue infection; Staphylococcus aureus
22.  The complete chloroplast genome sequence of Helwingia himalaica (Helwingiaceae, Aquifoliales) and a chloroplast phylogenomic analysis of the Campanulidae 
PeerJ  2016;4:e2734.
Complete chloroplast genome sequences have been very useful for understanding phylogenetic relationships in angiosperms at the family level and above, but there are currently large gaps in coverage. We report the chloroplast genome for Helwingia himalaica, the first in the distinctive family Helwingiaceae and only the second genus to be sequenced in the order Aquifoliales. We then combine this with 36 published sequences in the large (c. 35,000 species) subclass Campanulidae in order to investigate relationships at the order and family levels. The Helwingia genome consists of 158,362 bp containing a pair of inverted repeat (IR) regions of 25,996 bp separated by a large single-copy (LSC) region and a small single-copy (SSC) region which are 87,810 and 18,560 bp, respectively. There are 142 known genes, including 94 protein-coding genes, eight ribosomal RNA genes, and 40 tRNA genes. The topology of the phylogenetic relationships between Apiales, Asterales, and Dipsacales differed between analyses based on complete genome sequences and on 36 shared protein-coding genes, showing that further studies of campanulid phylogeny are needed.
doi:10.7717/peerj.2734
PMCID: PMC5131622  PMID: 27917320
Asterids; Campanulidae; Phylogeny; Plastomes; Yunnan
23.  A Novel Method for N-terminal Acetylation Prediction 
The NetAcet method has been developed to make predictions of N-terminal acetylation sites, but more information of the data set could be utilized to improve the performance of the model. By employing a new way to extract patterns from sequences and using a sample balancing mechanism, we obtained a correlation coefficient of 0.85, and a sensitivity of 93% on an independent mammalian data set. A web server utilizing this method has been constructed and is available at http://166.111.24.5/acetylation.html.
doi:10.1016/S1672-0229(04)02032-7
PMCID: PMC5187419  PMID: 15901254
N-terminal acetylation; support vector machine (SVM)
24.  Association between the Achievement of Target Range CKD-MBD Markers and Mortality in Prevalent Hemodialysis Patients in Taiwan by Using the Kidney Disease: Improving Global Outcomes Clinical Guidelines 
BioMed Research International  2016;2016:1523124.
Background. This study evaluated the association between achieving target chronic kidney disease-mineral and bone disorder (CKD-MBD) marker levels and mortality in Taiwanese hemodialysis (HD) patients. Target levels were based on the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Methods. We performed a retrospective medical record review of 1126 HD patients between 2009 and 2013. A logistic regression model was used to evaluate the relationship between achieving target marker levels and the risk for all-cause and cardiovascular (CV) mortality. Reference target ranges were 7.9 ≤ calcium (Ca) ≤ 9.9 mg/dL, 2.4 ≤ phosphate (P) ≤ 4.7 mg/dL, and 144 ≤ intact parathyroid hormone (iPTH) ≤ 648 pg/mL. Results. Achievement of target P levels was associated with a lower risk for all-cause mortality compared to achievement of either target Ca or iPTH levels. Achieving target P + iPTH levels (OR 1.32) was associated with a lower odds ratio for all-cause mortality compared to achieving target Ca + P (OR 1.66) and Ca + iPTH (OR 1.43) levels. Similar trends were observed for CV mortality risk. Conclusions. The present study demonstrated that achieving serum P levels within the KDIGO target range is the most important factor for lowering mortality in HD patients.
doi:10.1155/2016/1523124
PMCID: PMC5149608  PMID: 28003998
25.  Annexin A3 Knockdown Suppresses Lung Adenocarcinoma 
Our previous study identified an elevated abundance of annexin A3 (Anxa3) as a novel prognostic biomarker of lung adenocarcinoma (LADC) through quantitative proteomics analysis. However, the biological functions of Anxa3 in LADC are not fully clear. In this study, in vitro and in vivo assays were performed to investigate the effects of Anxa3 downregulation on the growth, migration, invasion, metastasis, and signaling pathway activation of LADC cells. After Anxa3 downregulation, the growth of A549 and LTEP-a2 LADC cells was slowed and they showed decreased migration and invasion in vitro. Anxa3 knockdown significantly inhibited tumor formation by A549 cells in vivo; while many metastases were formed by control A549 cells, there were obvious reductions in the numbers of lung, liver, and brain metastases formed by Anxa3 knockdown in A549 cells. Furthermore, Anxa3 knockdown significantly decreased MMP-2 and N-cadherin expression and increased E-cadherin expression both in cell lines in vitro and in tumor nodules examined during in vivo tumorigenesis assays. Interestingly, Anxa3 downregulation reduced the phosphorylated levels of MEK and ERK. In summary, Anxa3 knockdown inhibited the growth, migration, invasion, and metastasis of LADC, decreased the activation of the MEK/ERK signaling pathway, and modulated the expression of MMP-2, E-cadherin, and N-cadherin.
doi:10.1155/2016/4131403
PMCID: PMC5138443  PMID: 27995049

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