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1.  The superior aspect of the perirenal space: could it be depicted by dual-source CT in vivo in adults 
The British Journal of Radiology  2014;88(1045):20140480.
Objective:
This study aims to observe whether the renal fascias could be effectively shown by dual-source CT (DSCT) and to explore the superior communication of the perirenal space (PS) in vivo in adults.
Methods:
275 cases were included in the normal group and 124 cases in the acute pancreatitis group in this study; all images obtained by DSCT were observed; the superior adherence of the renal fascias and the pattern of superior communication of the PS were judged; and the consistency between the two groups was compared.
Results:
The superior adherence of the renal fascias was reliably displayed in 57.8% of the normal group and 69.4% of the acute pancreatitis group, the anterior renal fascia (ARF) did not fuse with the posterior renal fascia superiorly. The left ARF fused with the posterior parietal peritoneum in 57.9% of the normal group and 45.3% of the pancreatitis group, where the left PS communicated with the subdiaphragmatic retroperitoneal space (SDRS). The left ARF fused with the peritoneum laterally and simultaneously with the inferior phrenic fascia medially in 42.1% and 54.7% of each group, respectively, where the left PS was open towards the SDRS laterally but sealed off from the SDRS medially. The right ARF fused with the peritoneum in all cases; and the right PS was open towards the bare area of the liver.
Conclusion:
To some extent, DSCT can display renal fascia and its superior adherence and reflect the superior communication of the PS.
Advances in knowledge:
This study was conducted in vivo in adults by high-resolution DSCT, and more samples could be provided.
doi:10.1259/bjr.20140480
PMCID: PMC4277382  PMID: 25411900
2.  mGluR5 positive allosteric modulation and its effects on MK-801 induced set-shifting impairments in a rat operant delayed matching/non-matching-to-sample task 
Psychopharmacology  2014;232(1):251-258.
Rationale
Positive allosteric modulators (PAMs) of type 5 metabotropic glutamate receptors (mGluR5) exert pro-cognitive effects in animal models of various neuropsychiatric diseases. However, few studies to date have examined ability of mGluR5 PAMs to reverse cognitive deficits in operant delayed matching/non-matching-to-sample (DMS/DNMS) tasks.
Objectives
To determine the ability of the mGluR5 PAM 3-cyano-N-1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) to reverse set-shifting deficits induced by the NMDA receptor antagonist MK-801.
Methods
Male Sprague-Dawley rats were initially trained to lever press for sucrose reinforcement under either DMS or DNMS conditions. Following successful acquisition of the task, reinforcement conditions were reversed (DNMS→DMS or DMS→DNMS). In Experiment 1, rats were treated daily prior to each session with either vehicle/vehicle, vehicle/MK-801 (0.06 mg/kg) simultaneously, CDPPB (20 mg/kg)/MK-801 simultaneously, or CDPPB 30 min prior to MK-801. In Experiment 2, rats were treated with either vehicle/vehicle, vehicle/MK-801, or CDPPB 30 min prior to MK-801 only prior to sessions that followed task reversal.
Results
In Experiment 1, no group differences in initial task acquisition were observed. Rats treated with vehicle+MK−801 showed significant set-shifting impairments following task reversal, which were partially attenuated by simultaneous administration of CDPPB/MK-801, and completely precluded by administration of CDPPB 30 min prior to MK-801. In Experiment 2, MK-801 did not impair reversal learning and no other group differences were observed.
Conclusions
MK-801 induced deficits in operant set-shifting ability were prevented by pretreatment with CDPPB. MK-801 did not produce deficits in initial task learning or when treatment was initiated following task reversal.
doi:10.1007/s00213-014-3653-8
PMCID: PMC4278949  PMID: 24973895
operant set-shifting; type 5 metabotropic glutamate receptor; N-methyl-D-aspartate receptor; cognitive impairment; match-to-sample; schizophrenia
3.  Thyroid Autoantibodies in the Cerebrospinal Fluid of Subjects with and without Thyroid Disease: Implications for Hashimoto's Encephalopathy 
Journal of Thyroid Research  2015;2015:819072.
Introduction. Plasma antithyroid peroxidase (anti-TPO) and anti-thyroglobulin antibodies (anti-Tg) are widely used in the diagnosis of autoimmune thyroiditis. No research has compared anti-TPO and anti-Tg both in plasma and cerebrospinal fluid (CSF) of healthy individuals vis-à-vis patients with thyroid disease. Methods. We measured anti-TPO and anti-Tg antibodies in plasma and CSF in nine subjects (mean age ± SD: 73 ± 6 years) with hypothyroidism and nine subjects (mean age ± SD: 73 ± 8 years) without thyroid disease. Results. The concentration of anti-TPO autoantibodies in CSF was very low compared to plasma in both subjects with thyroid and without thyroid disease (P = 0.007). CSF anti-Tg autoantibodies titers were very low compared to the plasma in subjects with thyroid disease (P = 0.004), whereas, in subjects without thyroid disease, this difference did not reach statistical significance (P = 0.063). Conclusions. Thyroid autoantibodies levels were low in plasma and CSF; we did not observe any transfer of thyroid autoantibodies from the peripheral blood to the CSF. Therefore, regarding Hashimoto's encephalopathy, where elevated antithyroid autoantibodies are often measured in blood, it is more likely that thyroiditis and encephalopathy represent nonspecific, but distinct, events of an aggressive immune system.
doi:10.1155/2015/819072
PMCID: PMC4698931  PMID: 26798549
4.  Optimizing biologic treatment in IBD: objective measures, but when, how and how often? 
BMC Gastroenterology  2015;15:178.
Background
The advent of biologic agents for the treatment of inflammatory bowel disease (IBD) was accompanied in parallel with emerging understanding of persisting underlying inflammation and ensuing bowel damage that can occur even in patients with seeming clinical remission. This lead to the concepts of mucosal healing and deep remission gaining acceptance as the more desired goals for therapy within an ambitious disease-control therapeutic approach, namely, treat-to-target strategy. However, how to practically monitor IBD patients, which objective measures to follow, at what time-points and whether to act upon results in asymptomatic patients are all questions that remain disputed.
Methods and result
In this concise review we aim to provide an overview of objective measures for monitoring of IBD patients, focusing on the challenging group of patients treated by infliximab, adalimumab, vedolizumab and other biologics. These objective measures are discussed in the context of the different common clinical scenarios wherein the clinician may contemplate their use. Specifically, we will delineate the role of objective parameters to be monitored during induction phase of treatment, during maintenance therapy, at loss of response and after elective cessation of therapy in patients in remission.
Conclusion
Coupled with the non-negligible costs of therapy, and the over-all worse prognosis of moderate-severe patients who are the usual recipients of biologic therapies, this challenging patients seem to be the first candidates for this more proactive strategy combining inflammatory and pharmacokinetic monitoring of objective inflammatory and pharmacokinetic measures. More data is still desirable to better define the exact parameters to be followed and their optimal thresholds, and to delineate the optimal cost-effective interventions for these patients.
doi:10.1186/s12876-015-0408-x
PMCID: PMC4683713  PMID: 26678147
5.  Multi-responsive Hydrogels Derived from the Self-assembly of Tethered Allyl-functionalized Racemic Oligopeptides 
A multi-responsive triblock hydrogelator oligo(dl-allylglycine)-block-poly(ethylene glycol)-block-oligo(dl-allylglycine) (ODLAG-b-PEG-b-ODLAG) was synthesized facilely by ring-opening polymerization (ROP) of DLAG N-carboxyanhydride (NCA) with a diamino-terminated PEG as the macroinitiator. This system exhibited heat-induced sol-to-gel transitions and either sonication- or enzyme-induced gel-to-sol transitions. The β-sheeting of the oligopeptide segments was confirmed by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and wide-angle X-ray scattering (WAXS). The β-sheets further displayed tertiary ordering into fibrillar structures that, in turn generated a porous and interconnected hydrogel matrix, as observed via transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The reversible macroscopic sol-to-gel transitions triggered by heat and gel-to-sol transitions triggered by sonication were correlated with the transformation of nanostructural morphologies, with fibrillar structures observed in gel and spherical aggregates in sol, respectively. The enzymatic breakdown of the hydrogels was also investigated. This allyl-functionalized hydrogelator can serve as a platform for the design of smart hydrogels, appropriate for expansion into biological systems as bio-functional and bio-responsive materials.
doi:10.1039/C4TB00909F
PMCID: PMC4255538  PMID: 25485113
6.  Atlas Assimilation Patterns in Different Types of Adult Craniocervical Junction Malformations 
Spine  2015;40(22):1763-1768.
Study Design.
This is a cross-sectional analysis of resonance magnetic images of 111 patients with craniocervical malformations and those of normal subjects.
Objective.
To test the hypothesis that atlas assimilation is associated with basilar invagination (BI) and atlas's anterior arch assimilation is associated with craniocervical instability and type I BI.
Summary of Background Data.
Atlas assimilation is the most common malformation in the craniocervical junction. This condition has been associated with craniocervical instability and BI in isolated cases.
Methods.
We evaluated midline Magnetic Resonance Images (MRIs) (and/or CT scans) from patients with craniocervical junction malformation and normal subjects. The patients were separated into 3 groups: Chiari type I malformation, BI type I, and type II. The atlas assimilations were classified according to their embryological origins as follows: posterior, anterior, and both arches assimilation.
Results.
We studied the craniometric values of 111 subjects, 78 with craniocervical junction malformation and 33 without malformations. Of the 78 malformations, 51 patients had Chiari type I and 27 had BI, of whom 10 presented with type I and 17 with type II BI. In the Chiari group, 41 showed no assimilation of the atlas. In the type I BI group, all patients presented with anterior arch assimilation, either in isolation or associated with assimilation of the posterior arch. 63% of the patients with type II BI presented with posterior arch assimilation, either in isolation or associated with anterior arch assimilation. In the control group, no patients had atlas assimilation.
Conclusion.
Anterior atlas assimilation leads to type I BI. Posterior atlas assimilation more frequently leads to type II BI. Separation in terms of anterior versus posterior atlas assimilation reflects a more accurate understanding of the clinical and embryological differences in craniocervical junction malformations.
Level of Evidence: N/A
doi:10.1097/BRS.0000000000001045
PMCID: PMC4671914  PMID: 26165213
atlas assimilation; basilar invagination; cervical atlas; Chiari malformation
7.  Association of Paraoxonase 1 Gene Polymorphisms With the Risk of Hepatitis B Virus-related Liver Diseases in a Guangxi Population 
Medicine  2015;94(48):e2179.
Abstract
Paraoxonase 1 (PON1), a liver-induced glycoprotein enzyme responsible for antioxidant defense against reactive oxygen species and anti-inflammatory, has been linked to various cancers. The objective of this study was to explore the association of PON1 rs662 and rs705382 with the risk of chronic hepatitis B (CHB), hepatitis B virus-related liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in patients living in the Guangxi region of southern China.
The PON1 rs662 and rs705382 single-nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) in 99 CHB patients, 84 LC patients, 258 HCC patients, and 221 healthy controls.
Significant associations with CHB risk were observed for the rs705382 SNP after adjusting for sex, age, ethnicity, smoking, alcohol consumption, and body mass index. When stratified by sex and age, this positive association was significantly strengthened among men and individuals over 40 years old. Moreover, a decreased risk of LC was associated with the rs705382 CG and the combined GG + CG genotypes among women, with borderline statistical significance. In haplotype analyses, the haplotype GA was associated with a 1.68-fold increase in the risk of HCC.
Our results showed that the PON1 rs705382 SNP might be a risk factor for CHB in Guangxi populations.
doi:10.1097/MD.0000000000002179
PMCID: PMC4674207  PMID: 26632904
8.  The clustered protocadherin endolysosomal trafficking motif mediates cytoplasmic association 
BMC Cell Biology  2015;16:28.
Background
Clustered protocadherins (Pcdhs) are a large family of neural cadherin-like proteins encoded by individual exons located within three gene clusters. Each exon codes an extracellular, transmembrane, and proximal cytoplasmic domain. These “variable” regions may be spliced to a constant cytoplasmic moiety encoded at the end of a cluster. Pcdh extracellular domains mediate homophilic cell-cell binding but their cytoplasmic domains cause intracellular retention and may negatively regulate Pcdh cell-cell binding. Pcdhs can be found at the cell surface in neurons and other cells but are also, unlike classical cadherins, prominently trafficked to the endolysosome system. It was previously found that a segment within the variable portion of the Pcdh-γA3 cytoplasmic domain (VCD) was shown to be necessary for endolysosomal trafficking.
Results
Here it is shown that this same VCD segment can mediate cytoplasmic association among Pcdhs from the different clusters. Internal deletions within this VCD region (termed here the VCD motif) that disrupt the association altered trafficking of Pcdh-γA3 in the endolysosomal system while deletions outside VCD motif did not affect trafficking.
Conclusions
The results show that Pcdhs associate cytoplasmically via a motif within the VCD and that this is critical for Pcdh trafficking. Given that truncation at the VCD motif alters endolysosomal trafficking of Pcdhs, the VCD interaction described here may provide new insights into the dynamic nature of Pcdh mediated cell-cell interactions.
doi:10.1186/s12860-015-0074-4
PMCID: PMC4660814  PMID: 26608278
Protocadherins; Adhesion; Cadherin; Endosome; Trafficking; Electron microscopy
9.  High-throughput screening for modulators of cellular contractile force† 
When cellular contractile forces are central to pathophysiology, these forces comprise a logical target of therapy. Nevertheless, existing high-throughput screens are limited to upstream signalling intermediates with poorly defined relationships to such a physiological endpoint. Using cellular force as the target, here we report a new screening technology and demonstrate its applications using human airway smooth muscle cells in the context of asthma and Schlemm's canal endothelial cells in the context of glaucoma. This approach identified several drug candidates for both asthma and glaucoma. We attained rates of 1000 compounds per screening day, thus establishing a force-based cellular platform for high-throughput drug discovery.
doi:10.1039/c5ib00054h
PMCID: PMC4657543  PMID: 25953078
10.  Tracking single-particle rotation during macrophage uptake† 
Soft matter  2015;11(26):5346-5352.
We investigated the rotational dynamics of single microparticles during their internalization by macrophage cells. The microparticles used were triblock patchy particles that display two fluorescent patches on their two poles. The optical anisotropy made it possible to directly visualize and quantify the orientation and rotation of the particles. We show that particles exhibit a mixture of fast and slow rotation as they are uptaken by macrophages and transiently undergo directional rotation during their entry into the cell. The size of the particles and the surface presentation of ligands exerted a negligible influence on this heterogeneity of particle rotation.
doi:10.1039/c5sm00893j
PMCID: PMC4657870  PMID: 26059797
11.  Minnelide effectively eliminates CD133+ side population in pancreatic cancer 
Molecular Cancer  2015;14:200.
Background
Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease hallmarked by limited patient survival. Resistance to chemotherapy, a major cause of treatment failure in PDAC patients, is often attributed to Cancer Stem Cells (CSCs). Pancreatic CSCs are a small subset of quiescent cells within a tumor represented by surface markers like CD133. These cells are responsible not only for tumor recurrence, but also poor prognosis based on their “stem-like” characteristics. At present, conventional therapy is directed towards rapidly dividing PDAC cells and thus fails to target the CSC population.
Methods
MIA PaCa-2, S2-013 and AsPC-1 were treated with 12.5 nM triptolide (12 T cells) for 7 days. The surviving cells were recovered briefly in drug-free growth media and then transferred to Cancer Stem cell Media (CSM). As a control, untreated cells were also transferred to CSM media (CSM). The 12 T and CSM cells were tested for stemness properties using RNA and protein markers. Low numbers of CSM and 12 T cells were implanted subcutaneously in athymic nude mice to study their tumorigenic potential. 12 T and CSM cells were sorted for CD133 expression and assayed for their colony forming ability and sphere forming ability. Invasiveness of 12 T cells, CSM and MIA PaCa-2 were compared using Boyden chamber assays.
Results
Treated 12 T cells displayed increased expression of the surface marker CD133 and the drug transporter ABCG2 compared to untreated cells (CSM cells). Both 12 T and CSM cells formed subcutaneous tumors in mice confirming their tumor-initiating properties. When tested for invasion, 12 T cells had increased invasiveness compared to CSM cells. CD133+ cells in both CSM and 12 T showed greater colony and sphere forming ability compared to CD133− cells from each group. Consistent with these data, when injected subcutaneously in mice, CD133− cells from CSM or 12 T did not form any tumors whereas CD133+ cells from both groups showed tumor formation at a very low cell number. Despite pre-exposure to triptolide in 12 T CD133+ cells, treatment of tumors formed by these cells with Minnelide, a triptolide pro-drug, showed significant tumor regression.
Conclusion
Our results indicated that triptolide enhanced and enriched the “stemness” in the PDAC cell lines at a low dose of 12.5 nM, but also resulted in the regression of tumors derived from these cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-015-0470-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12943-015-0470-6
PMCID: PMC4657383  PMID: 26597727
12.  Being lonely or using substances with friends? A cross-sectional study of Hungarian adolescents’ health risk behaviours 
BMC Public Health  2015;15:1107.
Background
Studying adolescents’ health risk behaviours is oddly significant in Central and Eastern European countries, where the prevalence of smoking and drinking among 14–18 year old students is significantly high. The goal of our study is to examine the role of social psychological and social behavioural variables in health risk behaviours among Hungarian adolescents.
Methods
Our sample was comprised of three high schools of Debrecen (the second largest city of Hungary). In all, 501 students filled in the questionnaire from 22 classes (14–22 years old). Students aged above 18 years were excluded for the purpose of the study, giving a total sample size of 471 high school students. Descriptive statistics and binary logistic regression analyses were conducted.
Results
According to our results (1) social behavioural factors (namely, smoking and alcohol use of the best friend and peer group) proved to be better predictors of adolescents’ health risk behaviours as compared to the included social psychological attributes (2); among the latter ones, loneliness and shyness were negatively related with both smoking and drinking, while competitiveness was a predictor of drinking prevalence among boys.
Conclusions
The findings suggest that social behavioural factors, including smoking and drinking of friends, are oddly important predictors of Hungarian adolescents’ health risk behaviours. According to our results, health policy should pay more attention to peer norms related to smoking and drinking during school health promotion. Developing health protective social norms may be an indispensable component of effective health promotion in high schools.
doi:10.1186/s12889-015-2474-y
PMCID: PMC4637146  PMID: 26547688
Adolescent; Smoking; Drinking; Social behavioural factors; Psychological attributes
13.  The Human Gut Microbiome as a Screening Tool for Colorectal Cancer 
Recent studies have suggested that the gut microbiome may be an important factor in the development of colorectal cancer (CRC). Abnormalities in the gut microbiome have been reported in patients with CRC; however, this microbial community has not been explored as a potential screen for early stage disease. We characterized the gut microbiome in patients from three clinical groups representing the stages of CRC development: health, adenoma, and carcinoma. Analysis of the gut microbiome from stool samples revealed both an enrichment and depletion of several bacterial populations associated with adenomas and carcinomas. Combined with known clinical risk factors of CRC (e.g. BMI, age, race), data from the gut microbiome significantly improved the ability to differentiate between healthy, adenoma, and carcinoma clinical groups relative to risk factors alone. Using Bayesian methods, we determined that using gut microbiome data as a screening tool improved the pre-test to post-test probability of adenoma over 50-fold. For example, the pre-test probability in a 65 year-old was 0.17% and, after using the microbiome data, this increased to 10.67% (1 in 9 chance of having an adenoma). Taken together the results of our study demonstrate the feasibility of using the composition of the gut microbiome to detect the presence of precancerous and cancerous lesions. Furthermore, these results support the need for more cross sectional studies with diverse populations and linkage to other stool markers, dietary data, and personal health information.
doi:10.1158/1940-6207.CAPR-14-0129
PMCID: PMC4221363  PMID: 25104642
14.  Perceived threat predictor of calcium-rich foods in the women of premenopausal age Isfahan - Iran in 2013-2014 
Background:
During women lives, frequently face the challenge of calcium reduction and absorption. Decreased calcium absorption followed by a decrease in estrogen at perimenopausal ages, low average per capita calcium intake among women, wrong nutritional behavior, household income reductions and make them more susceptible to osteoporosis and related complications. The aim of this study was to evaluate the relationship between the health belief model constructs and consuming calcium-rich foods in menopausal age women.
Materials and Methods:
This study was descriptive-correlation study. The questionnaires were completed by 210 menopausal women who had referred to health centers. The research data were analyzed using: Frequency distribution, mean score, Pearson correlation coefficients and multivariate regression. Significant level of P < 0/05 were considered.
Results:
The mean and standard deviation of the scores for perceived susceptibility and severity of the threats of consumption and complications of inadequate intake were respectively: (62.1 and 38.9, and 60.2 and 39.9) and (59.6 and 37.9 and 56.3 and 36.5). The relationship between the number of units of calcium intake with perceived susceptibility and severity calcium intake and complications caused by the inadequate intake of calcium were (P < 0.001, r = 0.581, r = 0.651) and (P < 0.001, r = 0.634, r = 0.567).
Conclusions:
The obtained results indicate that perceived threat is the prognostic factor for the intake of calcium-rich foods and the increase of perceived threat in the health promotion programs may be associated with the increase in the consumption of calcium-rich foods in the women of premenopausal age.
doi:10.4103/1735-9066.170006
PMCID: PMC4700686  PMID: 26793252
Calcium; food; health belief model; menopause
15.  Development and validation of the Australian Aboriginal racial identity and self-esteem survey for 8–12 year old children (IRISE_C) 
Introduction
In Australia, there is little empirical research of the racial identity of Indigenous children and youth as the majority of the current literature focuses on adults. Furthermore, there are no instruments developed with cultural appropriateness when exploring the identity and self-esteem of the Australian Aboriginal population, especially children. The IRISE_C (Racial Identity and Self-Esteem of children) inventory was developed to explore the elements of racial identity and self-esteem of urban, rural and regional Aboriginal children. This paper describes the development and validation of the IRISE_C instrument with over 250 Aboriginal children aged 8 to 12 years.
Methods
A pilot of the IRISE C instrument was combined with individual interviews and was undertaken with 35 urban Aboriginal children aged 8–12 years. An exploratory factor analysis was performed to refine the survey and reduce redundant items in readiness for the main study. In the main study, the IRISE C was employed to 229 Aboriginal children aged 6–13 years across three sites (rural, regional and urban) in Western Australia. An exploratory factor analysis using Principal axis factoring was used to assess the fit of items and survey structure. A confirmatory factor analysis was then employed using LISREL (diagonally weighted least squares) to assess factor structures across domains. Internal consistency and reliability of subscales were assessed using Cronbach’s co-efficient alpha.
Results
The pilot testing identified two key concepts - children’s knowledge of issues related to their racial identity, and the importance, or salience, that they attach to these issues. In the main study, factor analyses showed two clear factors relating to: Aboriginal culture and traditions; and a sense of belonging to an Aboriginal community. Principal Axis Factoring of the Knowledge items supported a 2-factor solution, which explained 38.7 % of variance. Factor One (Aboriginal culture) had a Cronbach’s alpha of 0.835; Factor 2 (racial identity) had a Cronbach’s alpha of 0.800, thus demonstrating high internal reliability of the scales.
Conclusion
The IRISE_C has been shown to be a valid instrument useful of exploring the development of racial identity of Australian Aboriginal children across the 8–12 year old age range and across urban, rural and regional geographical locations.
doi:10.1186/s12939-015-0234-3
PMCID: PMC4619330  PMID: 26499852
Instrument development; Racial identity; Self-esteem; Australian Aboriginal children
16.  Poly(lactic-co-glycolic) acid microspheres encapsulated in Pluronic F-127 prolong Hirudin delivery and improve functional recovery from a demyelination lesion 
Biomaterials  2014;35(31):8895-8902.
Components of the blood have been proposed as potential therapeutic targets for improving cellular regeneration after injury and neurodegenerative disease. In this work, thrombin is shown to increase endogenous neural progenitor proliferation in the intact murine spinal cord. A local injection of heparin before a spinal cord injury reduces cell proliferation and astrogliogenesis associated with scarring. We sought to create depot-formulations of PLGA microsphere and Pluronic F-127 for sustained local delivery of two thrombin inhibitors, heparin and hirudin. Each hydrogel depot-formulation showed delayed drug release compared to microspheres or hydrogel alone. Animals with a lateral demyelination lesion showed a reduction in CD68+ macrophages when treated with hirudin-loaded PLGA/F-127 gels compared to control and heparin-treated animals. Moreover, hirudin-loaded materials showed an accelerated recovery in coordinated stepping and increased oligodendrocyte densities. Together, these data demonstrate that controlled delivery of hirudin accelerates functional recovery from a demyelination lesion in the spinal cord.
doi:10.1016/j.biomaterials.2014.06.051
PMCID: PMC4136545  PMID: 25064804
Drug Release; Hydrogel; Poly(lactic-co-glycolic) acid microspheres; Pluronic; thrombin; oligodendrocyte; spinal cord; gliosis; progenitor cell
17.  AlGaN/GaN Metal-Oxide-Semiconductor High-Electron-Mobility Transistor with Polarized P(VDF-TrFE) Ferroelectric Polymer Gating 
Scientific Reports  2015;5:14092.
Effect of a polarized P(VDF-TrFE) ferroelectric polymer gating on AlGaN/GaN metal-oxide-semiconductor high-electron-mobility transistors (MOS-HEMTs) was investigated. The P(VDF-TrFE) gating in the source/drain access regions of AlGaN/GaN MOS-HEMTs was positively polarized (i.e., partially positively charged hydrogen were aligned to the AlGaN surface) by an applied electric field, resulting in a shift-down of the conduction band at the AlGaN/GaN interface. This increases the 2-dimensional electron gas (2-DEG) density in the source/drain access region of the AlGaN/GaN heterostructure, and thereby reduces the source/drain series resistance. Detailed material characterization of the P(VDF-TrFE) ferroelectric film was also carried out using the atomic force microscopy (AFM), X-ray Diffraction (XRD), and ferroelectric hysteresis loop measurement.
doi:10.1038/srep14092
PMCID: PMC4568540  PMID: 26364872
18.  FRET-Based Nanobiosensors for Imaging Intracellular Ca2+ and H+ Microdomains 
Sensors (Basel, Switzerland)  2015;15(9):24662-24680.
Semiconductor nanocrystals (NCs) or quantum dots (QDs) are luminous point emitters increasingly being used to tag and track biomolecules in biological/biomedical imaging. However, their intracellular use as highlighters of single-molecule localization and nanobiosensors reporting ion microdomains changes has remained a major challenge. Here, we report the design, generation and validation of FRET-based nanobiosensors for detection of intracellular Ca2+ and H+ transients. Our sensors combine a commercially available CANdot®565QD as an energy donor with, as an acceptor, our custom-synthesized red-emitting Ca2+ or H+ probes. These ‘Rubies’ are based on an extended rhodamine as a fluorophore and a phenol or BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid) for H+ or Ca2+ sensing, respectively, and additionally bear a linker arm for conjugation. QDs were stably functionalized using the same SH/maleimide crosslink chemistry for all desired reactants. Mixing ion sensor and cell-penetrating peptides (that facilitate cytoplasmic delivery) at the desired stoichiometric ratio produced controlled multi-conjugated assemblies. Multiple acceptors on the same central donor allow up-concentrating the ion sensor on the QD surface to concentrations higher than those that could be achieved in free solution, increasing FRET efficiency and improving the signal. We validate these nanosensors for the detection of intracellular Ca2+ and pH transients using live-cell fluorescence imaging.
doi:10.3390/s150924662
PMCID: PMC4610457  PMID: 26404317
quantum dot nanobiosensors; nanoparticle surface chemistry; FRET-based Ca2+ and H+ probes; red-emitting indicator; intracellular Ca2+ and H+ fluorometry; cell-penetrating peptide; concentration microdomain
19.  Histone hypoacetylation-activated genes are repressed by acetyl-CoA- and chromatin-mediated mechanism 
Biochimica et biophysica acta  2014;1839(9):751-763.
Transcriptional activation is typically associated with increased acetylation of promoter histones. However, this paradigm does not apply to transcriptional activation of all genes. In this study we have characterized a group of genes that are repressed by histone acetylation. These histone hypoacetylation-activated genes (HHAAG) are normally repressed during exponential growth, when the cellular level of acetyl-CoA is high and global histone acetylation is also high. The HHAAG are induced during diauxic shift, when the levels of acetyl-CoA and global histone acetylation decrease. The histone hypoacetylation-induced activation of HHAAG is independent of Msn2/Msn4. The repression of HSP12, one of the HHAAG, is associated with well-defined nucleosomal structure in the promoter region, while histone hypoacetylation-induced activation correlates with delocalization of positioned nucleosomes or with reduced nucleosome occupancy. Correspondingly, unlike the majority of yeast genes, HHAAG are transcriptionally upregulated when expression of histone genes is reduced. Taken together, these results suggest a model in which histone acetylation is required for proper positioning of promoter nucleosomes and repression of HHAAG.
doi:10.1016/j.bbagrm.2014.05.029
PMCID: PMC4136683  PMID: 24907648
Histone acetylation; transcription; acetyl-CoA; chromatin; HSP12
20.  Biologic Activity of Porphyromonas endodontalis complex lipids 
Journal of endodontics  2014;40(9):1342-1348.
Introduction
Periapical infections secondary to pulpal necrosis are associated with bacterial contamination of the pulp. Porphyromonas endodontalis, a Gram-negative organism, is considered to be a pulpal pathogen. P. gingivalis is phylogenetically related to P. endodontalis and synthesizes several classes of novel complex lipids that possess biological activity, including the capacity to promote osteoclastogenesis and osteoclast activation. The purpose of this study was to extract and characterize constituent lipids of P. endodontalis, and evaluate their capacity to promote pro-inflammatory secretory responses in the macrophage cell line, RAW 264.7, as well as their capacity to promote osteoclastogenesis and inhibit osteoblast activity.
Methods
Constituent lipids of both organisms were fractionated by HPLC and were structurally characterized using electrospray-mass spectrometry (ESI-MS) or ESI-MS/MS. The virulence potential of P. endodontalis lipids was then compared with known biologically active lipids isolated from P. gingivalis.
Results
P. endodontalis total lipids were shown to promote TNF-α secretion from RAW 264.7 cells and the serine lipid fraction appeared to account for the majority of this effect. P. endodontalis lipid preparations also increased osteoclast formation from RAW 264.7 cells but osteoblast differentiation in culture was inhibited and appeared to be dependent on TLR2 expression.
Conclusions
These effects underscore the importance of P. endodontalis lipids in promoting inflammatory and bone cell activation processes that could lead to periapical pathology.
doi:10.1016/j.joen.2014.02.017
PMCID: PMC4143668  PMID: 25146013
Osteoclastogenesis; Osteoblast; RAW 264.7 cells; P. endodontalis; Electrospray-MS
21.  Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold 
Scientific Reports  2015;5:12974.
The constitutively active tyrosine kinase BCR-ABL is the underlying cause of chronic myeloid leukemia (CML). Current CML treatments rely on the long-term use of tyrosine kinase inhibitors (TKIs), which target the ATP binding site of BCR-ABL. Over the course of treatment, 20–30% of CML patients develop TKI resistance, which is commonly attributed to point mutations in the drug-binding region. We design a new class of peptide inhibitors that target the substrate-binding site of BCR-ABL by grafting sequences derived from abltide, the optimal substrate of Abl kinase, onto a cell-penetrating cyclotide MCoTI-II. Three grafted cyclotides show significant Abl kinase inhibition in vitro in the low micromolar range using a novel kinase inhibition assay. Our work also demonstrates that a reengineered MCoTI-II with abltide sequences grafted in both loop 1 and 6 inhibits the activity of [T315I]Abl in vitro, a mutant Abl kinase harboring the “gatekeeper” mutation which is notorious for being multidrug resistant. Results from serum stability and cell internalization studies confirm that the MCoTI-II scaffold provides enzymatic stability and cell-penetrating properties to the lead molecules. Taken together, our study highlights that reengineered cyclotides incorporating abltide-derived sequences are promising substrate-competitive inhibitors for Abl kinase and the T315I mutant.
doi:10.1038/srep12974
PMCID: PMC4532999  PMID: 26264857
22.  Multifunctional luminescent nanomaterials from NaLa(MoO4)2:Eu3+/Tb3+ with tunable decay lifetimes, emission colors, and enhanced cell viability 
Scientific Reports  2015;5:11844.
A facile, but effective, method has been developed for large-scale preparation of NaLa(MoO4)2 nanorods and microflowers co-doped with Eu3+ and Tb3+ ions (abbreviated as: NLM:Ln3+). The as-synthesized nanomaterials possess a pure tetragonal phase with variable morphologies from shuttle-like nanorods to microflowers by controlling the reaction temperature and the amount of ethylene glycol used. Consequently, the resulting nanomaterials exhibit superb luminescent emissions over the visible region from red through yellow to green by simply changing the relative doping ratios of Eu3+ to Tb3+ ions. Biocompatibility study indicates that the addition of NLM:Ln3+ nanomaterials can stimulate the growth of normal human retinal pigment epithelium (ARPE-19) cells. Therefore, the newly-developed NaLa(MoO4)2 nanomaterials hold potentials for a wide range of multifunctional applications, including bioimaging, security protection, optical display, optoelectronics for information storage, and cell stimulation.
doi:10.1038/srep11844
PMCID: PMC4531290  PMID: 26259515
23.  Explaining, not just predicting, drives interest in personal genomics 
Genome Medicine  2015;7(1):74.
Background
There is a widespread assumption that risk prediction is the major driver of customer interest in personal genomic testing (PGT). However, some customers may also be motivated by finding out whether their existing diseases have a genetic etiology. We evaluated the impact of an existing medical diagnosis on customer interest in condition-specific results from PGT.
Methods
Using a prospective online survey of PGT customers, we measured customer interest prior to receiving PGT results for 11 health conditions, and examined the association between interest and personal medical history of these conditions using logistic regression.
Results
We analyzed data from 1,538 PGT customers, mean age 48.7 years, 61 % women, 90 % White, and 47 % college educated. The proportion of customers who were ‘very interested’ in condition-specific PGT varied considerably, from 28 % for ulcerative colitis to 68% for heart disease. After adjusting for demographic and personal characteristics including family history, having a diagnosis of the condition itself was significantly associated with interest in genetic testing for risk of that condition, with odds ratios ranging from 2.07 (95 % CI 1.28-3.37) for diabetes to 19.99 (95 % CI 4.57-87.35) for multiple sclerosis.
Conclusions
PGT customers are particularly interested in genetic markers for their existing medical conditions, suggesting that the value of genetic testing is not only predictive, but also explanatory.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-015-0188-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13073-015-0188-5
PMCID: PMC4533947  PMID: 26269719
24.  Discovery of novel virus sequences in an isolated and threatened bat species, the New Zealand lesser short-tailed bat (Mystacina tuberculata) 
The Journal of General Virology  2015;96(Pt 8):2442-2452.
Bats harbour a diverse array of viruses, including significant human pathogens. Extensive metagenomic studies of material from bats, in particular guano, have revealed a large number of novel or divergent viral taxa that were previously unknown. New Zealand has only two extant indigenous terrestrial mammals, which are both bats, Mystacina tuberculata (the lesser short-tailed bat) and Chalinolobus tuberculatus (the long-tailed bat). Until the human introduction of exotic mammals, these species had been isolated from all other terrestrial mammals for over 1 million years (potentially over 16 million years for M. tuberculata). Four bat guano samples were collected from M. tuberculata roosts on the isolated offshore island of Whenua hou (Codfish Island) in New Zealand. Metagenomic analysis revealed that this species still hosts a plethora of divergent viruses. Whilst the majority of viruses detected were likely to be of dietary origin, some putative vertebrate virus sequences were identified. Papillomavirus, polyomavirus, calicivirus and hepevirus were found in the metagenomic data and subsequently confirmed using independent PCR assays and sequencing. The new hepevirus and calicivirus sequences may represent new genera within these viral families. Our findings may provide an insight into the origins of viral families, given their detection in an isolated host species.
doi:10.1099/vir.0.000158
PMCID: PMC4681071  PMID: 25900137
25.  Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis 
BMC Gastroenterology  2015;15:94.
Background
The NF-kB signaling, regulated by IKK1-p52/RelB and IKK2-p65, is activated by various stresses to protect or damage the liver, in context-specific manners. Two previous studies of liver-specific expression of constitutive active IKK2 (IKK2ca) showed that strong activation of IKK2-NF-kB in mouse livers caused inflammation, insulin resistance, and/or fibrosis. The purpose of this study was to understand how moderate activation of IKK2-NF-kB in adult mouse livers alters hepatic gene expression and pathophysiology.
Method
We generated mice with adult hepatocyte-specific activation of Ikk2 (Liv-Ikk2ca) using Alb-cre mice and Ikk2ca Rosa26 knockin mice in which a moderate expression of Ikk2ca transgene was driven by the endogenous Rosa26 promoter.
Results
Surprisingly, compared to wild-type mice, adult male Liv-Ikk2ca mice had higher hepatic mRNA expression of Ikk2 and classical NF-kB targets (e.g. Lcn2 and A20), as well as IKK1, NIK, and RelB, but no changes in markers of inflammation or fibrosis. Blood levels of IL-6 and MCP-1 remained unchanged, and histology analysis showed a lack of injury or infiltration of inflammatory cells in livers of Liv-Ikk2ca mice. Moreover, Liv-Ikk2ca mice had lower mRNA expression of prooxidative enzymes Cyp2e1 and Cyp4a14, higher expression of antioxidative enzymes Sod2, Gpx1, and Nqo1, without changes in key enzymes for fatty acid oxidation, glucose utilization, or gluconeogenesis. In parallel, Liv-Ikk2ca mice and wild-type mice had similar levels of hepatic reduced glutathione, endogenous reactive oxygen species, and lipid peroxidation. Additionally, Liv-Ikk2ca mice had higher Cyp3a11 without down-regulation of most drug processing genes. Regarding nuclear proteins of NF-kB subunits, Liv-Ikk2ca mice had moderately higher p65 and p50 but much higher RelB. Results of ChIP-qPCR showed that the binding of p50 to multiple NF-kB-target genes was markedly increased in Liv-Ikk2ca mice. Additionally, Liv-Ikk2ca mice had moderate increase in triglycerides in liver, which was associated with higher lipogenic factors Pparγ, Lxr, Fasn, Scd1, and CD36.
Conclusion
In summary, moderate activation of IKK2-NF-kB in unstressed adult mouse hepatocytes produces a cytoprotective gene expression profile and induces lipogenesis without apparent signs of inflammation or fibrosis, likely due to strong activation of the anti-inflammatory IKK1-RelB alternative NF-kB pathway as well as the Lxr.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0325-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0325-z
PMCID: PMC4518658  PMID: 26219821
IKK2; IKK1; NF-kB; RelB; Lxr; Liver; Mice; Lipogenesis; Inflammation; Fibrosis

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