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1.  Salvage Intensity-Modulated Radiation Therapy (IMRT) for Locally Recurrent Nasopharyngeal Cancer after Definitive IMRT: A Novel Scenario of the Modern Era 
Scientific Reports  2016;6:32883.
Locally recurrent nasopharyngeal carcinoma (rNPC) after definitive IMRT occurs in 10% of all cases and represents a distinct clinical entity that has been selectively enriched by radio-resistant cancer cells. Therefore, we report of the outcomes of 77 patients who had repeat salvage-IMRT for rNPC after only a definitive course of IMRT. Various clinical outcomes were measured. Log-rank tests were used to detect differences in the survival outcomes between factor-defined subgroups. Multivariable analysis was performed using the Cox proportional hazard model. The median follow-up time was 25.7 months (range 3.0–75.7 months), measured from the time of recurrence. The median OS time and PFS time of the entire cohort was 37.0 and 20.5 months, respectively. Thirty-four patients (44.2%) died. Approximately 35% of these patients died from disease progression, but 53% were from treatment-induced severe adverse effects (SAEs) without evidence of disease progression. Higher T-classification of the recurrent tumor and the development of SAEs were found to be the only independent and significant adverse prognostic factors on multivariable analysis. These outcomes underscore the particularly virulent characteristics of rNPC after definitive IMRT. Concerning is the impact of re-irradiation toxicity on patient mortality.
doi:10.1038/srep32883
PMCID: PMC5018695  PMID: 27616024
2.  Wnt5a and Ror2 expression associate with the disease progress of primary thyroid lymphoma 
Tumour Biology  2015;37(5):6085-6090.
Primary thyroid lymphoma (PTL) is a rare malignant thyroid tumor; its pathogenesis is closely related to chronic lymphocytic thyroiditis. The different pathological subtypes and stages of PTL have distinct clinical characteristics and prognosis, but the specific reasons are not clear. Wnt5a is a representative protein of non-canonical Wnt signaling. It plays an important role in many different types of tumors. This study is to explore the changes of Wnt5a and its receptor Ror2 in PTL development process and the clinical significance of their represent. We collected 22 PTL patient tumor specimens and clinical data. We observed the expression of Wnt5a and Ror2 in PTL tumor tissues by immunohistochemistry. Wnt5a was expressed positively in 12 (54.5 %) cases, and Ror2 was expressed positively in 18 (81.8 %) cases. The expression of Wnt5a had a significant difference in different pathological subtypes of PTL (P < 0.05). Wnt5a and Ror2 expression were associated with local invasion and clinical stage, respectively (P < 0.05), and had no significant correlation with age, gender, and tumor size. Although, no significant difference in overall survival was found between positive and negative groups of Wnt5a (P = 0.416) or Ror2 (P = 0.256), respectively. We still consider that Wnt5a and Ror2 play a complex and subtle role in the pathogenesis and progression of PTL and may become potential biomarkers and therapeutic targets of PTL.
doi:10.1007/s13277-015-4471-2
PMCID: PMC4875128  PMID: 26608372
Primary thyroid lymphoma; Wnt5a; Ror2; Immunohistochemistry
3.  Reduced prefrontal activation during working and long-term memory tasks and impaired patient-reported cognition among cancer survivors post-chemotherapy compared with healthy controls 
Cancer  2015;122(2):258-268.
Background
Patients receiving adjuvant chemotherapy have reported cognitive impairments, which may last years after completion of treatment. Working memory- and long-term memory-related changes in this population are not well understood. In this study we aimed to demonstrate that cancer-related cognitive impairments are associated with under recruitment brain regions involved in working and recognition memory compared to controls.
Method
Oncology patients (n=15) receiving adjuvant chemotherapy with evidence of cognitive impairment by neuropsychological testing and self-report and age/education group-matched, cognitively normal controls (n=14) underwent functional magnetic resonance imaging (fMRI). During fMRI scanning, participants performed a non-verbal n-back working memory task and a visual recognition task.
Results
On the working memory task, when 1-back and 2-back data were averaged and contrasted with 0-back data, significantly reduced activation was observed in the right dorsolateral prefrontal cortex for oncology patients versus controls. On the recognition task, oncology patients displayed decreased activity of left-middle hippocampus compared to controls. Neuroimaging results were not associated with patient-reported cognition.
Conclusion
Decreased recruitment of brain regions associated with working and recognition memory encoding were observed in the oncology group. These results suggest reduced neural functioning post-chemotherapy and corroborate patient-reported cognitive difficulties following cancer treatment, though a direct association was not observed.
doi:10.1002/cncr.29737
PMCID: PMC4707984  PMID: 26484435
fMRI; Cancer-related cognitive impairment (CRCI); working memory; recognition memory; patient-reported outcomes (PRO)
4.  An End-to-End Examination of Geometric Accuracy of IGRT Using a New Digital Accelerator Equipped with On-Board Imaging System 
Physics in medicine and biology  2012;57(3):757-769.
The Varian’s new digital linear accelerator (LINAC), TrueBeam™ STx, is equipped with high dose rate flattening filter free (FFF) mode (6 MV and 10 MV), high definition multileaf collimator (HDMLC) (2.5 mm leaf width), as well as onboard imaging (OBI) capabilities. A series of end-to-end phantom tests were performed TrueBeam-based IGRT to determine the geometric accuracy of image-guided setup and dose delivery process for all beam modalities delivered using IMRT and RapidArc™. In these tests, an anthropomorphic phantom with a Ball Cube II insert and the analysis software (FilmQA™ (3cognition)) were used to evaluate the accuracy of TrueBeam™ image-guided setup and dose delivery. Laser cut EBT2 films with 0.15 mm accuracy were embedded into the phantom. The phantom with the film inserted was first scanned with a GE Discovery-ST CT scanner, and the images were then imported to the planning system. Plans with steep dose fall off surrounding hypothetical targets of different sizes were created using RapidArc and IMRT with FFF and WFF (with flattening filter) beams. Four RapidArc plans (6 MV and 10 MV FFF) and five IMRT plans (6 MV and 10 MV FFF; 6 MV, 10 MV and 15 MV WFF) were studied. The RapidArc plans with 6 MV FFF were planned with target diameters of 1 cm (0.52 cc), 2 cm (4.2 cc), and 3 cm (14.1 cc), and all other plans were planned with a target diameter of 3 cm. Both onboard planar and volumetric imaging procedures were used for phantom setup and target localization. The IMRT and RapidArc plans were then delivered, and the film measurements were compared with the original treatment plans using a Gamma criteria of 3%/1 mm and 3%/2 mm. The shifts required in order to align the film measured dose with the calculated dose distributions was attributed to be the targeting error. Targeting accuracy of image-guided treatment using TrueBeam™ was found to be within 1 mm. For irradiation of the 3 cm target, the Gammas (3%, 1 mm) were found to be above 90% in all plan deliveries. For irradiations of smaller targets (2 cm and 1 cm), similar accuracy was achieved for 6 MV and 10 MV beams. Slightly degraded accuracy was observed for irradiations with higher energy beam (15 MV). In general, Gammas (3%, 2 mm) were found to be above 97% for all the plans. Our end-to-end tests showed an excellent relative dosimetric agreement and sub millimeter targeting accuracy for 6 and 10 MV beams, using both FFF and WFF delivery methods. However, increased deviations in spatial and dosimetric accuracy were found when treating lesions smaller than 2 cm or with 15 MV beam.
doi:10.1088/0031-9155/57/3/757
PMCID: PMC5233463  PMID: 22252134
IGRT; image guided delivery; Flattening Filter Free field; film dosimetry; end-to-end test
5.  Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells 
Background
Metformin is a widely used biguanide drug for the treatment of type 2 diabetes. It has been revaluated as a potential anti-cancer drug with promising activity in various tumors. However, the precise mechanisms underlying the suppression of cancer cells by metformin remain not well understood.
Material/Methods
In this study, human renal cell carcinoma cell line ACHN was used to investigate the anti-proliferation effect of metformin. A cell counting kit-8 assay was used to detect the cell viability. The cell cycle distribution and apoptosis were analyzed by flow cytometry. The expression of cyclin D1 and p27KIP1 was detected by Western blot. The underlying mechanism involving miRNA34a was further investigated by quantitative RT-PCR and transfection with miRNA inhibitor specific for miRNA34a in ACHN, 769-P, and A498 cells.
Results
Metformin could significantly inhibit the proliferation of ACHN cells in a dose- and time-dependent manner. In addition, the results showed that metformin induced G0/G1 phase arrest and delayed entry into S phase in ACHN cells. It was shown that metformin downregulates the expression of cyclin D1 and increases the p27KIP1 level. Furthermore, metformin increased ACHN cell death. Lastly, miRNA34a was found to be upregulated by metformin in ACHN, 769-P, and A498 cells. Subsequently, it was demonstrated that inhibition of miRNA34a could partially attenuate the suppressive effect of metformin on renal cancer cell proliferation.
Conclusions
The study data revealed that metformin induced cell growth inhibition and cell cycle arrest partially by upregulating miRNA34a in renal cancer cells.
doi:10.12659/MSM.898710
PMCID: PMC5226302  PMID: 28045889
Cell Cycle; Cell Proliferation; Kidney Neoplasms; Metformin; MicroRNAs
6.  Methylseleninic acid super-activates p53-senescence cancer progression barrier in prostate lesions of Pten-knockout mouse 
Monomethylated selenium (MM-Se) forms that are precursors of methylselenol such as methylseleninic acid (MSeA) differ in metabolism and anti-cancer activities in preclinical cell and animal models from seleno-methionine that had failed to exert preventive efficacy against prostate cancer (PCa) in North American men. Given that human PCa arises from precancerous lesions such as high-grade prostatic intraepithelial neoplasia (HG-PIN) which frequently have lost PTEN tumor suppressor permitting AKT oncogenic signaling, we tested the efficacy of MSeA to inhibit HG-PIN progression in Pten prostate specific knockout (KO) mice and assessed the mechanistic involvement of p53-mediated cellular senescence and of the androgen receptor (AR). We observed that short-term (4 weeks) oral MSeA treatment significantly increased expression of P53 and P21Cip1 proteins and senescence-associated-β-galactosidase staining, and reduced Ki-67 cell proliferation index in Pten KO prostate epithelium. Long-term (25 weeks) MSeA administration significantly suppressed HG-PIN phenotype, tumor weight, and prevented emergence of invasive carcinoma in Pten KO mice. Mechanistically, the long-term MSeA treatment not only sustained P53-mediated senescence, but also markedly reduced AKT phosphorylation and AR abundance in the Pten KO prostate. Importantly, these cellular and molecular changes were not observed in the prostate of wild type littermates which were similarly treated with MSeA. Since p53 signaling is likely to be intact in HG-PIN compared to advanced PCa, the selective super-activation of p53-mediated senescence by MSeA suggests a new paradigm of cancer chemoprevention by strengthening a cancer progression barrier through induction of irreversible senescence with additional suppression of AR and AKT oncogenic signaling.
doi:10.1158/1940-6207.CAPR-15-0236
PMCID: PMC4706786  PMID: 26511486
senescence; monomethylated selenium; cancer chemoprevention
7.  SchizConnect: Mediating Neuroimaging Databases on Schizophrenia and Related Disorders for Large-Scale Integration 
NeuroImage  2015;124(0 0):1155-1167.
SchizConnect (www.schizconnect.org) is built to address the issues of multiple data repositories in schizophrenia neuroimaging studies. It includes a level of mediation—translating across data sources—so that the user can place one query, e.g. for diffusion images from male individuals with schizophrenia, and find out from across participating data sources how many datasets there are, as well as downloading the imaging and related data. The current version handles the Data Usage Agreements across different studies, as well as interpreting database-specific terminologies into a common framework. New data repositories can also be mediated to bring immediate access to existing datasets. Compared with centralized, upload data sharing models, SchizConnect is a unique, virtual database with a focus on schizophrenia and related disorders that can mediate live data as information are being updated at each data source. It is our hope that SchizConnect can facilitate testing new hypotheses through aggregated datasets, promoting discovery related to the mechanisms underlying schizophrenic dysfunction.
doi:10.1016/j.neuroimage.2015.06.065
PMCID: PMC4651768  PMID: 26142271
Data mediation and integration; neuroinformatics; mega analysis; schizophrenia databases
8.  The Northwestern University Neuroimaging Data Archive (NUNDA) 
NeuroImage  2015;124(0 0):1131-1136.
The Northwestern University Neuroimaging Data Archive (NUNDA), an XNAT-powered data archiving system, aims to facilitate secure data storage; centralized data management; automated, standardized data processing; and simple, intuitive data sharing. NUNDA is a federated data archive, wherein individual project owners regulate access to their data. NUNDA supports multiple methods of data import, enabling data collection in a central repository. Data in NUNDA are available by project to any authorized user, allowing coordinated data management and review across sites. With NUNDA pipelines, users capitalize on existing procedures or standardize custom routines for consistent, automated data processing. NUNDA can be integrated with other research databases to simplify data exploration and discovery. And data on NUNDA can be confidently shared for secure collaboration.
doi:10.1016/j.neuroimage.2015.05.060
PMCID: PMC4651782  PMID: 26032888
Neuroinformatics; data storage; data processing and analysis; data sharing; XNAT
9.  A human monoclonal antibody against small envelope protein of hepatitis B virus with potent neutralization effect 
mAbs  2015;8(3):468-477.
ABSTRACT
Hepatitis B virus (HBV) produces large (L), middle (M), and small (S) envelope proteins, alternatively referred to as hepatitis B surface antigen (HBsAg). Currently, yeast-derived S protein serves as the preventive vaccine, while hepatitis B immune globulin (HBIG) concentrated from pooled plasma of vaccine recipients is employed for post-exposure prophylaxis. However, only a small proportion of the antibodies in HBIG are HBV specific. In the present study, a human monoclonal anti-S antibody (G12) was developed, produced under GLP conditions, and subjected to a panel of functional assays. In vitro results demonstrated high affinity of G12 for the S protein (KD = 7.56 nM). It reacted with envelope proteins of all 7 HBV genotypes tested (A-F, H) by immunofluorescent staining, and more than 97% of HBsAg-positive patient serum samples by enzyme-linked immunosorbent assay. G12 recognized a conformational epitope, although the exact sequence remains unknown. Strikingly, G12 was at least 1,000-fold more potent than HBIG in neutralizing HBV infectivity in both HepaRG cell line and HepG2 cells reconstituted with the HBV receptor. In a transgenic mouse model of HBV persistence, a single peritoneal injection of G12 markedly diminished serum HBsAg titers in all 7 mice, which was sustained for the observation period of 144 d in mice with low pre-treatment levels. While the therapeutic potential of G12 warrants further investigation using a large number of animals, G12 is a potent neutralizing human monoclonal antibody and a promising candidate to replace or supplement HBIG in the prevention of HBV infection.
doi:10.1080/19420862.2015.1134409
PMCID: PMC4966830  PMID: 26713590
Anti-S; hepatitis B immune globulin; hepatitis B virus; human monoclonal antibody; neutralization; small envelope protein; transgenic mice
10.  Structural mechanism for the arginine sensing and regulation of CASTOR1 in the mTORC1 signaling pathway 
Cell Discovery  2016;2:16051-.
The mTOR complex I (mTORC1) signaling pathway controls many metabolic processes and is regulated by amino acid signals, especially arginine. CASTOR1 has been identified as the cytosolic arginine sensor for the mTORC1 pathway, but the molecular mechanism of how it senses arginine is elusive. Here, by determining the crystal structure of human CASTOR1 in complex with arginine, we found that an exquisitely tailored pocket, carved between the NTD and the CTD domains of CASTOR1, is employed to recognize arginine. Mutation of critical residues in this pocket abolished or diminished arginine binding. By comparison with structurally similar aspartate kinases, a surface patch of CASTOR1-NTD on the opposite side of the arginine-binding site was identified to mediate direct physical interaction with its downstream effector GATOR2, via GATOR2 subunit Mios. Mutation of this surface patch disrupted CASTOR1’s recognition and inhibition of GATOR2, revealed by in vitro pull-down assay. Normal mode (NM) analysis revealed an ‘open’-to-‘closed’ conformational change for CASTOR1, which is correlated to the switching between the exposing and concealing of its GATOR2-binding residues, and is most likely related to arginine binding. Interestingly, the GATOR2-binding sites on the two protomers of CASTOR1 dimer face the same direction, which prompted us to propose a model for how dimerization of CASTOR1 relieves the inhibition of GATOR1 by GATOR2. Our study thus provides a thorough analysis on how CASTOR1 recognizes arginine, and describes a possible mechanism of how arginine binding induces the inter-domain movement of CASTOR1 to affect its association with GATOR2.
doi:10.1038/celldisc.2016.51
PMCID: PMC5187391  PMID: 28066558
mTORC1 signaling pathway; arginine; CASTOR1; GATOR2; GATOR1; crystal structure
11.  Cloning, Expression, and Characterization of Prophenoloxidases from Asian Corn Borer, Ostrinia furnacalis (Gunée) 
Journal of Immunology Research  2016;2016:1781803.
Insect phenoloxidase (PO) belongs to the type 3 copper protein family and possesses oxidoreductase activities. PO is typically synthesized as a zymogen called prophenoloxidase (PPO) and requires the proteolytic activation to function. We here cloned full-length cDNA for 3 previously unidentified PPOs, which we named OfPPO1a, OfPPO1b, and OfPPO3, from Asian corn borer, Ostrinia furnacalis (Gunée), in addition to the previously known OfPPO2. These conceptual PPOs and OfPPO2 all contain two common copper-binding regions, two potential proteolytic activation sites, a plausible thiol-ester site, and a conserved C-terminal region but lack a secretion signal peptide sequence at the N-terminus. O. furnacalis PPOs were highly similar to other insect PPOs (42% to 79% identity) and clustered well with other lepidopteran PPOs. RT-PCR assay showed the transcripts of the 4 OfPPOs were all detected at the highest level in hemocytes and at the increased amounts after exposure to infection by bacteria and fungi. Additionally, we established an Escherichia coli (E. coli) expression system to produce recombinant O. furnacalis PPO proteins for future use in investigating their functions. These insights could provide valuable information for better understanding the activation and functioning mechanisms of O. furnacalis PPOs.
doi:10.1155/2016/1781803
PMCID: PMC5203920  PMID: 28078308
12.  Characterization of the Complete Mitochondrial Genome of Leucoma salicis (Lepidoptera: Lymantriidae) and Comparison with Other Lepidopteran Insects 
Scientific Reports  2016;6:39153.
The complete mitochondrial genome (mitogenome) of Leucoma salicis (Lepidoptera: Lymantriidae) was sequenced and annotated. It is a circular molecule of 15,334 bp, containing the 37 genes usually present in insect mitogenomes. All protein-coding genes (PCGs) are initiated by ATN codons, other than cox1, which is initiated by CGA. Three of the 13 PCGs had an incomplete termination codon, T or TA, while the others terminated with TAA. The relative synonymous codon usage of the 13 protein-coding genes (PCGs) was consistent with those of published lepidopteran sequences. All tRNA genes had typical clover-leaf secondary structures, except for the tRNASer (AGN), in which the dihydrouridine (DHU) arm could not form a stable stem-loop structure. The A + T-rich region of 325 bp had several distinctive features, including the motif ‘ATAGA’ followed by an 18 bp poly-T stretch, a microsatellite-like (AT)7 element, and an 11-bp poly-A present immediately upstream of tRNAMet. Relationships among 32 insect species were determined using Maximum Likelihood (ML), Neighbor Joining (NJ) and Bayesian Inference (BI) phylogenetic methods. These analyses confirm that L. salicis belongs to the Lymantriidae; and that Lymantriidae is a member of Noctuoidea, and is a sister taxon to Erebidae, Nolidae and Noctuidae, most closely related to Erebidae.
doi:10.1038/srep39153
PMCID: PMC5156926  PMID: 27974854
13.  Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion 
PLoS ONE  2016;11(12):e0168418.
In high grade glioma (HGG), extensive tumor cell infiltration of normal brain typically precludes identifying effective margins for surgical resection or irradiation. Pertussis toxin (PT) is a multimeric complex that inactivates diverse Gi/o G-protein coupled receptors (GPCRs). Despite the broad continuum of regulatory events controlled by GPCRs, PT may be applicable as a therapeutic. We have shown that the urokinase receptor (uPAR) is a major driver of HGG cell migration. uPAR-initiated cell-signaling requires a Gi/o GPCR, N-formyl Peptide Receptor 2 (FPR2), as an essential co-receptor and is thus, PT-sensitive. Herein, we show that PT robustly inhibits migration of three separate HGG-like cell lines that express a mutated form of the EGF Receptor (EGFR), EGFRvIII, which is constitutively active. PT also almost completely blocked the ability of HGG cells to invade Matrigel. In the equivalent concentration range (0.01–1.0 μg/mL), PT had no effect on cell survival and only affected proliferation of one cell line. Neutralization of EGFRvIII expression in HGG cells, which is known to activate uPAR-initiated cell-signaling, promoted HGG cell migration. The increase in HGG cell migration, induced by EGFRvIII neutralization, was entirely blocked by silencing FPR2 gene expression or by treating the cells with PT. When U87MG HGG cells were cultured as suspended neurospheres in serum-free, growth factor-supplemented medium, uPAR expression was increased. HGG cells isolated from neurospheres migrated through Transwell membranes without loss of cell contacts; this process was inhibited by PT by >90%. PT also inhibited expression of vimentin by HGG cells; vimentin is associated with epithelial-mesenchymal transition and worsened prognosis. We conclude that PT may function as a selective inhibitor of HGG cell migration and invasion.
doi:10.1371/journal.pone.0168418
PMCID: PMC5158192  PMID: 27977780
14.  Inflammation induced oxidative stress mediates gene fusion formation in prostate cancer 
Cell reports  2016;17(10):2620-2631.
Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene, TMPRSS2, to the oncogenic ETS transcription factor, ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks facilitate the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli leads to the development of prostate cancer.
eTOC
While there is considerable evidence in the literature linking inflammation to the development of prostate cancer, there are few direct links to recurrent driver gene mutations. Mani et al. find a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions.
doi:10.1016/j.celrep.2016.11.019
PMCID: PMC5147555  PMID: 27926866
15.  Profiling and Identification of Novel Immunogenic Proteins of Staphylococcus hyicus ZC-4 by Immunoproteomic Assay 
PLoS ONE  2016;11(12):e0167686.
Staphylococcus hyicus has caused great losses in the swine industry by inducing piglet exudative epidermitis (EE), sow mastitis, metritis, and other diseases and is a threat to human health. The pathogenesis of EE, sow mastitis, and metritis involves the interaction between the host and virulent protein factors of S. hyicus, however, the proteins that interact with the host, especially the host immune system, are unclear. In the present study, immunoproteomics was used to screen the immunogenic proteins of S. hyicus strain ZC-4. The cellular and secreted proteins of S. hyicus strain ZC-4 were obtained, separated by 2D gel electrophoresis, and further analyzed by western blot with S. hyicus strain ZC-4-infected swine serum. Finally, 28 specific immunogenic proteins including 15 cellular proteins and 13 secreted proteins, 26 of which were novel immunogenic proteins from S. hyicus, were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. To further verify their immunogenicity, two representative proteins (acetate kinase [cellular] and enolase [secreted]) were chosen for expression, and the resultant recombinant proteins could react with S. hyicus ZC-4-infected swine serum. In mice, both acetate kinase and enolase activated the immune response by increasing G-CSF and MCP-5 expression, and acetate kinase further activated the immune response by increasing IL-12 expression. Enolase can confer better protection against S.hycius than acetate kinase in mice. For the first time to our knowledge, our results provide detailed descriptions of the cellular and secreted proteins of S. hyicus strain ZC-4. These immunogenic proteins may contribute to investigation and elucidation of the pathogenesis of S. hyicus and provide new candidates for subunit vaccines in the future.
doi:10.1371/journal.pone.0167686
PMCID: PMC5145190  PMID: 27930728
16.  A Comparison of Referred Sexual Partners to Their Community Recruited Counterparts in The BROTHERS Project (HPTN 061) 
AIDS and behavior  2015;19(12):2214-2223.
The BROTHERS Project (HPTN 061) was established to determine the feasibility and acceptability of a multi-component intervention among African American MSM to reduce HIV incidence. The goal of this analysis was to determine if the sexual partner referral approach used in HPTN 061 broadened the reach of recruitment with regards to characteristics associated with higher infection rates and barriers to quality health care. Overall, referred sexual partners had notable structural barrier differences in comparison to community-recruited participants: lower income, less education, higher unemployment, HIV positive diagnosis, incarceration history, and no health insurance. The study’s findings pose implications for utilizing the sexual partner referral approach in reaching African American MSM who may not be accessed by traditional recruitment methods or who are well-integrated in health care systems.
doi:10.1007/s10461-015-1005-2
PMCID: PMC4532644  PMID: 25874753
HIV; African American MSM; Referrals; Recruitment
17.  A Polarization-Dependent Normal Incident Quantum Cascade Detector Enhanced Via Metamaterial Resonators 
The design, fabrication, and characterization of a polarization-dependent normal incident quantum cascade detector coupled via complementary split-ring metamaterial resonators in the infrared regime are presented. The metamaterial structure is designed through three-dimensional finite-difference time-domain method and fabricated on the top metal contact, which forms a double-metal waveguide together with the metallic ground plane. With normal incidence, significant enhancements of photocurrent response are obtained at the metamaterial resonances compared with the 45° polished edge coupling device. The photocurrent response enhancements exhibit clearly polarization dependence, and the largest response enhancement factor of 165% is gained for the incident light polarized parallel to the split-ring gap.
doi:10.1186/s11671-016-1749-2
PMCID: PMC5133221  PMID: 27910073
Infrared; Photodetectors; Polarization-selective devices; Metamaterials
18.  Comparison of Transcriptome Between Type 2 Diabetes Mellitus and Impaired Fasting Glucose 
Background
The aim of this study was to compare the transcriptome between impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), and further research their molecular mechanisms.
Material/Methods
The original microarray GSE21321, including miRNA and mRNA expression profiles, was downloaded from the GEO database. Data preprocessing was processed by limma package, and differentially expressed genes (DGs) and miRNA (DMs) were screened. Then, the regulatory relationships among miRNA, TF, and genes were screened and the regulatory network was constructed. Finally, DAVID was used for KEGG enrichment analysis.
Results
There were 11 upregulated IFG-related DMs and five upregulated T2DM-related DMs. Three of the DMs overlapped. In addition, there were eight downregulated IFG-related DMs and two downregulated T2DM-related DMs. Only one downregulated DM overlapped. Similarly, there were 264 upregulated IFG-related DGs and 331 upregulated T2DM-related DGs; and 196 overlapping genes were obtained. In addition, there were 400 downregulated IFG-related DMs and 568 downregulated T2DM-related DMs. A total of 326 downregulated DMs were overlapped. The overlapped DGs were enriched in various pathways, including hematopoietic cell lineage, Fc gamma R-mediated phagocytosis, and MAPK signaling pathway. TAF1 (upregulated gene) and MAFK (downregulated gene) were hub nodes both in IFG- and T2DM-related miRNA-TF-gene regulatory network. In addition, miRNAs, including hsa-miR-29a, hsa-miR-192, and hsa-miR-144, were upregulated hub nodes in the two regulatory networks.
Conclusions
Genes including TAF1 and MAFK, and miRNAs including hsa-miR-29a, hsa-miR-192, and hsa-miR-144 might be potential target genes and important miRNAs for IFG and T2DM.
doi:10.12659/MSM.896772
PMCID: PMC5147684  PMID: 27906902
Blood Glucose; Diabetes Mellitus, Type 2; Transcriptome
19.  Prevalence of metabolic syndrome and its risk factors among rural adults in Nantong, China 
Scientific Reports  2016;6:38089.
The prevalence of metabolic syndrome (MS) varies worldwide due to genetic and environmental factors. A population-based cross-sectional study, with 37,582 participants recruited in Nantong, China in 2007-2008 (stage I) and 2013 (stage II). Socio-demographic, lifestyle factors, disease history and fasting blood sample were collected. The prevalence of MS was much higher in 2013 (42.6%) than that in 2007-2008 (21.6%), which was significantly higher in older people in both stages. Participants with two or more familial history of diseases were associated with a higher MS prevalence compared to those who didn’t have familial history of diseases. Total physical activity (PA) was associated with 24 and 19% decreased risk of MS in men and women. Occupational PA in moderate and vigorous intensity was associated with a 25%-45% decreased risk of MS. Female smokers who smoked more than 10 cigarettes per day or over 25 years were associated with 96 and 74% increased MS risk, respectively. The highest quartile of rice wine consumption was associated with a lower risk of MS with OR of 0.63 in women, compared with female non-drinkers. These findings indicated that PA and rice wine are two protective factors in MS prevention in rural areas of East China.
doi:10.1038/srep38089
PMCID: PMC5128865  PMID: 27901076
20.  Narrowing the spread in CMIP5 model projections of air-sea CO2 fluxes 
Scientific Reports  2016;6:37548.
Large spread appears in the projection of air-sea CO2 fluxes using the latest simulations from the Coupled Model Intercomparison Project Phase 5 (CMIP5). Here, two methods are applied to narrow this spread in 13 CMIP5 models. One method involves model selection based on the ability of models to reproduce the observed air-sea CO2 fluxes from 1980 to 2005. The other method involves constrained estimation based on the strong relationship between the historical and future air-sea CO2 fluxes. The estimated spread of the projected air-sea CO2 fluxes is effectively reduced by using these two approaches. These two approaches also show great agreement in the global ocean and three regional oceans of the equatorial Pacific Ocean, the North Atlantic Ocean and the Southern Ocean, including the average state and evolution characteristics. Based on the projections of the two approaches, the global ocean carbon uptake will increase in the first half of the 21st century then remain relatively stable and is projected to be 3.68–4.57 PgC/yr at the end of 21st century. The projections indicate that the increase in the CO2 uptake by the oceans will cease at the year of approximately 2070.
doi:10.1038/srep37548
PMCID: PMC5124959  PMID: 27892473
21.  Robustness and Vulnerability of Networks with Dynamical Dependency Groups 
Scientific Reports  2016;6:37749.
The dependency property and self-recovery of failure nodes both have great effects on the robustness of networks during the cascading process. Existing investigations focused mainly on the failure mechanism of static dependency groups without considering the time-dependency of interdependent nodes and the recovery mechanism in reality. In this study, we present an evolving network model consisting of failure mechanisms and a recovery mechanism to explore network robustness, where the dependency relations among nodes vary over time. Based on generating function techniques, we provide an analytical framework for random networks with arbitrary degree distribution. In particular, we theoretically find that an abrupt percolation transition exists corresponding to the dynamical dependency groups for a wide range of topologies after initial random removal. Moreover, when the abrupt transition point is above the failure threshold of dependency groups, the evolving network with the larger dependency groups is more vulnerable; when below it, the larger dependency groups make the network more robust. Numerical simulations employing the Erdős-Rényi network and Barabási-Albert scale free network are performed to validate our theoretical results.
doi:10.1038/srep37749
PMCID: PMC5125273  PMID: 27892940
22.  Long-Term Application of Bioorganic Fertilizers Improved Soil Biochemical Properties and Microbial Communities of an Apple Orchard Soil 
Soil biochemical properties and microbial communities are usually considered as important indicators of soil health because of their association with plant nutrition. In this study, we investigated the impact of long-term application of bioorganic fertilizer (BOF) on soil biochemical properties and microbial communities in the apple orchard soil of the Loess Plateau. The experiment included three treatments: (1) control without fertilization (CK); (2) chemical fertilizer application (CF); and (3) bioorganic fertilizer application (BOF). The high throughput sequencing was used to examine the bacterial and fungal communities in apple orchard soil. The results showed that the BOF treatment significantly increased the apple yield during the experimental time (2009–2015). The application of BOF significantly increased the activities of catalase and invertase compared to those in CK and CF treatments. The high throughput sequencing data showed that the application of BOF changed the microbial community composition of all soil depths considered (0–20 cm, 20–40 cm, and 40–60 cm), e.g., the relative abundance of bio-control bacteria (Xanthomonadales, Lysobacter, Pseudomonas, and Bacillus), Proteobacteria, Bacteroidetes, Ohtaekwangia, Ilyonectria, and Lecanicillium was increased while that of Acidobacteria, Chloroflexi, Gp4, Gp6 and Sphaerobacter was decreased. The increase in apple yield after the application of BOF might be due to increase in organic matter, total nitrogen and catalase and invertase activities of soil and change in the bacterial community composition by enriching Bacillus, Pseudomonas, Lysobacter, and Ohtaekwangia. These results further enhance the understanding on how BOFs alter soil microbial community composition to stimulate soil productivity.
doi:10.3389/fmicb.2016.01893
PMCID: PMC5125012  PMID: 27965631
bioorganic fertilizers; soil microbes; apple yield; soil depth; composition
23.  Cerebral Targeting of Acupuncture at Combined Acupoints in Treating Essential Hypertension: An Rs-fMRI Study and Curative Effect Evidence 
The study attempted to explore that the synergistic effect of acupoints combination is not a simple superposition of single acupoint's effect by comparing and analyzing the changes of blood pressure (BP), SF-36, and brain regions after acupuncture treatment. 47 patients were randomly divided into LR3+KI3 group, LR3 group, and KI3 group. Subjects received Rs-fMRI scan, BP measurement, and SF-36 questionnaires before and after treatment and short-term acupuncture treatment. After treatment, there were no significant differences in BP and SF-36 among 3 groups, compared to the case before treatment, SBP of 3 groups decreased, and DBP significantly decreased while vitality and mental health significantly increased in LR3+KI3 group. Both number and scopes of changes of brain regions in LR3+KI3 group were the largest, which mainly included BAs 3, 4, 8, 19, 21, 24, 32, 44, and 45. In conclusion, acupuncture at LR3+KI3 may auxiliarily reduce BP and improve the vitality and mental health of patients, and the changes of brain regions were related to somatesthesia, movement, vision, audition, emotion and mood, language, memory, etc. BAs 4, 9, 10, 24, 31, 32, and 46 may be the targeting brain areas of acupuncture in assisting hypotension. It is suggested that acupoints combination of LR3+KI3 maybe generates a synergistic effect, and it is not simple sum of single acupoint effect.
doi:10.1155/2016/5392954
PMCID: PMC5149687  PMID: 28003850
24.  Role for the IFT-A complex in selective transport to the primary cilium 
Cell reports  2016;17(6):1505-1517.
Summary
Intraflagellar transport sub-complex A (IFT-A) is known to regulate retrograde IFT in the cilium. To rigorously assess its other possible roles, we knocked out an IFT-A subunit, IFT121/WDR35, in mammalian cells and screened the localization of more than 50 proteins. We found that Wdr35 regulates cilium assembly by selectively regulating transport of distinct cargoes. Beyond its role in retrograde transport, we show that Wdr35 functions in fusion of Rab8 vesicles at the nascent cilium, protein exit from the cilium, and centriolar satellite organization. Further, we show that Wdr35 is essential for entry of many membrane proteins into the cilium through robust interactions with cargoes and other IFT-A subunits, but the actin network functions to dampen this transport. Wdr35 is mutated in several ciliopathies, and we find that certain disease mutations impair interactions with cargo and other IFT-A subunits. Together, our data link defects in IFT-A mediated cargo transport with disease.
eTOC Blurb
Fu et al. find that Wdr35-containing intraflagellar transport sub-complex A (IFT-A) regulates selective transport of distinct cargoes for primary cilium assembly. Wdr35 is essential for entry of many membrane proteins into the cilium.
doi:10.1016/j.celrep.2016.10.018
PMCID: PMC5123888  PMID: 27806291
25.  Hedgehog signaling promotes basal progenitor expansion and the growth and folding of the neocortex 
Nature neuroscience  2016;19(7):888-896.
The unique mental abilities of humans are rooted in the immensely expanded and folded neocortex, which reflects the expansion of neural progenitors, especially basal progenitors including basal radial glia (bRGs, also called outer RGs) and intermediate progenitor cells (IPCs). Here, we show that constitutively active Shh signaling expanded bRGs and IPCs and induced folding in the otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreased the number of bRGs and IPCs and the size of the neocortex. SHH signaling was strongly active in the human fetal neocortex but not in the mouse embryonic neocortex, and blocking SHH signaling in human cerebral organoids decreased the number of bRGs. Mechanistically, Shh signaling increased the initial generation and self-renewal of bRGs as well as increasing IPC proliferation. Thus, robust SHH signaling in the human fetal neocortex may contribute to bRG and IPC expansion and neocortical growth and folding.
doi:10.1038/nn.4307
PMCID: PMC4925239  PMID: 27214567

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