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1.  SHIELD: an integrative gene expression database for inner ear research 
The inner ear is a highly specialized mechanosensitive organ responsible for hearing and balance. Its small size and difficulty in harvesting sufficient tissue has hindered the progress of molecular studies. The protein components of mechanotransduction, the molecular biology of inner ear development and the genetic causes of many hereditary hearing and balance disorders remain largely unknown. Inner-ear gene expression data will help illuminate each of these areas. For over a decade, our laboratories and others have generated extensive sets of gene expression data for different cell types in the inner ear using various sample preparation methods and high-throughput genome-wide approaches. To facilitate the study of genes in the inner ear by efficient presentation of the accumulated data and to foster collaboration among investigators, we have developed the Shared Harvard Inner Ear Laboratory Database (SHIELD), an integrated resource that seeks to compile, organize and analyse the genomic, transcriptomic and proteomic knowledge of the inner ear. Five datasets are currently available. These datasets are combined in a relational database that integrates experimental data and annotations relevant to the inner ear. The SHIELD has a searchable web interface with two data retrieval options: viewing the gene pages online or downloading individual datasets as data tables. Each retrieved gene page shows the gene expression data and detailed gene information with hyperlinks to other online databases with up-to-date annotations. Downloadable data tables, for more convenient offline data analysis, are derived from publications and are current as of the time of publication. The SHIELD has made published and some unpublished data freely available to the public with the hope and expectation of accelerating discovery in the molecular biology of balance, hearing and deafness.
Database URL: https://shield.hms.harvard.edu
doi:10.1093/database/bav071
PMCID: PMC4513695  PMID: 26209310
2.  P-glycoprotein, but not Multidrug Resistance Protein 4, Plays a Role in the Systemic Clearance of Irinotecan and SN-38 in Mice 
Drug metabolism letters  2010;4(4):195-201.
The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b−/−, Mrp4−/−, and wild-type mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b genotype was a significant covariate for the clearance of both irinotecan lactone and SN-38 lactone. Exposures to irinotecan lactone and SN-38 lactone after a 40 mg/kg dose were 1.6-fold higher in Mdr1a/b−/− mice compared to wild-type mice. Plasma concentrations of irinotecan lactone, irinotecan carboxylate, and SN-38 lactone in Mrp4−/− mice were similar to the wild-type controls. These results suggest that P-gp plays a role in irinotecan and SN-38 elimination, but Mrp4 does not affect irinotecan or SN-38 plasma pharmacokinetics.
PMCID: PMC4486004  PMID: 20583968
Irinotecan; Multidrug resistance protein 4; Pharmacokinetics; P-glycoprotein; SN-38; Transporter
3.  CNTNAP3 Associated ATG16L1 Expression and Crohn's Disease 
Mediators of Inflammation  2015;2015:404185.
Autophagy is a common physiological process in cell homeostasis and regulation. Autophagy-related gene mutations and autophagy disorders are important in Crohn's disease (CD). The nucleotide oligomerization domain 2–autophagy genes autophagy 16-like 1 (NOD2–ATG16L1) signaling axis disorder contributes to the dysfunction of autophagy. This paper is focused on the relationship between contactin associated protein-like 3 (CNTNAP3) and ATG16L1 expression in Crohn's disease. The results indicated that the expression of ATG16L1 is higher in some CD patients compared to normal controls. ATG16L1 was well correlated with the C-reactive protein (CRP) in some CD patients. In vitro study revealed that CNTNAP3 could upregulate the expression of ATG16L1 and increase autophagy vacuoles.
doi:10.1155/2015/404185
PMCID: PMC4391322  PMID: 25883416
4.  Kaempferol pretreatment modulates systemic inflammation and oxidative stress following hemorrhagic shock in mice 
Chinese Medicine  2015;10:6.
Background
Kaempferol has been reported as beneficial for both acute and chronic inflammatory diseases. This study aims to investigate whether kaempferol affects systemic inflammation and oxidative stress in the heart, lung, and liver after hemorrhagic shock in mice.
Methods
Male C57/BL6 mice underwent hemorrhagic shock (mean arterial pressure of 35 mmHg for 90 min) and were arbitrarily divided into Sham, hemorrhagic shock (HS), and Kae groups (n = 10 in each group). Mice in the Kae groups received a kaempferol (10-mg/kg body weight) injection 12 h prior to (Group Kae PT) or 90 min after (Group Kae T) the initiation of hemorrhagic shock. Plasma proinflammatory cytokines (TNF-α and IL-6), organ myeloperoxidase (MPO) and superoxide dismutase (SOD) activities, and organ malondialdehyde (MDA) concentrations and heme oxygenase-1 (HO-1) expression levels were assessed by enzyme-linked immunosorbent assay (ELISA) or western blot assay.
Results
Compared with the HS group and the Kae T group, pretreatment with kaempferol significantly decreased proinflammatory cytokines TNF-α (P = 0.012 and 0.015, respectively) and IL-6 (P = 0.023 and 0.014, respectively) following hemorrhagic shock. Kae pretreatment reverted MPO, SOD, and MDA to basal levels in the heart, lung, and liver (Ps < 0.05), while the Kae T group showed no significant differences in these biomarkers compared with the HS group (Ps > 0.05). HO-1 expression was significantly increased in the Kae PT group compared with the other groups (P = 0.011 vs. HS group and P = 0.02 vs. Kae T group).
Conclusions
Pretreatment of hemorrhagic shock mice with kaempferol significantly decreased plasma levels of TNF-α and IL-6; reverted MPO, SOD, and MDA in the heart, lung, and liver; and increased expression of HO-1 in the same organs.
doi:10.1186/s13020-015-0035-z
PMCID: PMC4369346  PMID: 25798187
Hemorrhagic shock; Kaempferol; Oxidative stress; Systematic inflammation
5.  Expression and regulation of long noncoding RNAs in TLR4 signaling in mouse macrophages 
BMC Genomics  2015;16(1):45.
Background
Though long non-coding RNAs (lncRNAs) are emerging as critical regulators of immune responses, whether they are involved in LPS-activated TLR4 signaling pathway and how is their expression regulated in mouse macrophages are still unexplored.
Results
By repurposing expression microarray probes, we identified 994 lncRNAs in bone marrow-derived macrophages (BMDMs) and classified them to enhancer-like lncRNAs (elncRNAs) and promoter-associated lncRNAs (plncRNAs) according to chromatin signatures defined by relative levels of H3K4me1 and H3K4me3. Fifteen elncRNAs and 12 plncRNAs are differentially expressed upon LPS stimulation. The expression change of lncRNAs and their neighboring protein-coding genes are significantly correlated. Also, the regulation of both elncRNAs and plncRNAs expression is associated with H3K4me3 and H3K27Ac. Crucially, many identified LPS-regulated lncRNAs, such as lncRNA-Nfkb2 and lncRNA-Rel, locate near to immune response protein-coding genes. The majority of LPS-regulated lncRNAs had at least one binding site among the transcription factors p65, IRF3, JunB and cJun.
Conclusions
We established an integrative microarray analysis pipeline for profiling lncRNAs. Also, our results suggest that lncRNAs can be important regulators of LPS-induced innate immune response in BMDMs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1270-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1270-5
PMCID: PMC4320810  PMID: 25652569
TLR4; LPS; elncRNA; plncRNA; Histone modification
6.  Local bone interaction between renin-angiotensin system and kallikrein-kinin system in diabetic rat 
Objective: This study was performed to investigate bone deteriorations and the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) of male rat in response to the hyperglycemia. Methods: The biomarkers in serum and urine were measured by ELISA kit, and tibias were taken for the measurement on gene, protein expression and histological analysis, feumrs were taken for the measurement on biomechanical parameters and micro-CT. Results: The DM1 showed the decreased level of osteocalcin, testosterone and FGF-23, and the increased level of serum CTX as compared to those of vehicle group. The H&E staining showed remarkable bone deteriorations, including increased disconnections and separation of trabecular bone among growth plate and joint cartilage in DM1 group. Biomechanically, the maximum load, maximum stress, and strain parameter of DM1 group was significantly lower than control group. Type 1 diabetic mice displayed bone loss shown the reduction of bone volume/total volume, trabecular number, trabecular thickness and bone mineral density. The STZ injection significantly up-regulated mRNA expression of AT1R, AGT, renin, renin-receptor, and ACE, and the expression of AT2R, B1R and B2R were down-regulated in tibia of rat in hyperglycemia group. The protein expression of renin, ACE and Ang II were significantly up-regulated, and AT2R, B1R and B2R were down-regulated in DM1 group. Conclusions: The treatment of hyperglycemia was detrimental to bone as compared to the vehicle group, and the underlying mechanism was mediated, at least partially, through down-regulation of KSS activity and up-regulation of RAS activity in local bone.
PMCID: PMC4396287  PMID: 25973045
Renin-angiotensin system; kallikrein-kinin system; hyperglycemia; bone
7.  Structural Insights into the Membrane Fusion Mechanism Mediated by Influenza Virus Hemagglutinin 
Biochemistry  2014;53(5):846-854.
Membrane fusion is involved in many fundamental cellular processes and entry of enveloped viruses into host cells. Influenza type A virus HA has long served as a paradigm for mechanistic studies of protein-mediated membrane fusion via large-scale structural rearrangements induced by acidic pH. Here we report the newly determined crystal structure of influenza B virus HA2 in the postfusion state. Together with a large number of previously determined prefusion structures of influenza A and B virus HA and a postfusion structure of influenza A/H3N2 HA2, we identified conserved features that are shared between influenza A and B virus HA in the conformational transition and documented substantial differences that likely influence the detailed mechanisms of this process. Further studies are needed to dissect the effects of these and other structural differences in HA conformational changes and influenza pathogenicity and transmission, which may ultimately expedite the discovery of novel anti-influenza fusion inhibitors.
doi:10.1021/bi401525h
PMCID: PMC3985705  PMID: 24433110
8.  Insulin-producing cells from embryonic stem cells rescues hyperglycemia via intra-spleen migration 
Scientific Reports  2014;4:7586.
Implantation of embryonic stem cells (ESC)-derived insulin-producing cells has been extensively investigated for treatment of diabetes in animal models. However, the in vivo behavior and migration of transplanted cells in diabetic models remains unclear. Here we investigated the location and migration of insulin-producing cells labeled with superparamagnetic iron oxide (SPIO) using a dynamic MRI tracking method. SPIO labeled cells showed hypointense signal under the kidney subcapsules of diabetic mice on MRI, and faded gradually over the visiting time. However, new hypointense signal appeared in the spleen 1 week after transplantation, and became obvious with the time prolongation. Further histological examination proved the immigrated cells were insulin and C-peptide positive cells which were evenly distributed throughout the spleen. These intra-spleen insulin-producing cells maintained their protective effects against hyperglycemia in vivo, and these effects were reversed upon spleen removal. Transplantation of insulin-producing cells through spleen acquired an earlier blood glucose control as compared with that through kidney subcapsules. In summary, our data demonstrate that insulin-producing cells transplanted through kidney subcapsules were not located in situ but migrated into spleen, and rescues hyperglycemia in diabetic models. MRI may provide a novel tracking method for preclinical cell transplantation therapy of diabetes continuously and non-invasively.
doi:10.1038/srep07586
PMCID: PMC4274503  PMID: 25533571
9.  C-MYC Transcriptionally Amplifies SOX2 Target Genes to Regulate Self-Renewal in Multipotent Otic Progenitor Cells 
Stem Cell Reports  2014;4(1):47-60.
Summary
Sensorineural hearing loss is caused by the loss of sensory hair cells and neurons of the inner ear. Once lost, these cell types are not replaced. Two genes expressed in the developing inner ear are c-Myc and Sox2. We created immortalized multipotent otic progenitor (iMOP) cells, a fate-restricted cell type, by transient expression of C-MYC in SOX2-expressing otic progenitor cells. This activated the endogenous C-MYC and amplified existing SOX2-dependent transcripts to promote self-renewal. RNA-seq and ChIP-seq analyses revealed that C-MYC and SOX2 occupy over 85% of the same promoters. C-MYC and SOX2 target genes include cyclin-dependent kinases that regulate cell-cycle progression. iMOP cells continually divide but retain the ability to differentiate into functional hair cells and neurons. We propose that SOX2 and C-MYC regulate cell-cycle progression of these cells and that downregulation of C-MYC expression after growth factor withdrawal serves as a molecular switch for differentiation.
Graphical Abstract
Highlights
•A single factor, C-MYC, induces self-renewal in SOX2-expressing otic progenitors•C-MYC transcriptionally amplifies SOX2 target genes•SOX2 modulates transcription of cell-cycle genes•Immortalized multipotent otic progenitors can differentiate into otic cell types
In this work, Kwan and colleagues generated an immortalized multipotent otic progenitor (iMOP) cell by transient expression of C-MYC in SOX2-expressing otic progenitor cells. The procedure activated endogenous C-MYC expression in the cells and amplified existing SOX2-dependent transcripts to promote self-renewal. Downregulation of C-MYC expression after growth factor withdrawal resulted in a molecular switch from self-renewal to otic differentiation.
doi:10.1016/j.stemcr.2014.11.001
PMCID: PMC4297878  PMID: 25497456
10.  Transcribed ultraconserved region in human cancers 
RNA Biology  2013;10(12):1771-1777.
Long non-coding RNAs (lncRNAs) are transcripts longer than ~200 nucleotides with little or no protein-coding capacity. Growing evidence shows that lncRNAs present important function in development and are associated with many human diseases such as cancers, Alzheimer disease, and heart diseases. Transcribed ultraconserved region (T-UCR) transcripts are a novel class of lncRNAs transcribed from ultraconserved regions (UCRs). UCRs are absolutely conserved (100%) between the orthologous regions of the human, rat, and mouse genomes. The UCRs are frequently located at fragile sites and at genomic regions involved in cancers. Recent data suggest that T-UCRs are altered at the transcriptional level in human tumorigenesis and the aberrant T-UCRs expression profiles can be used to differentiate human cancer types. The profound understanding of T-UCRs can throw new light on the pathogenesis of human cancers.
doi:10.4161/rna.26995
PMCID: PMC3917980  PMID: 24384562
transcribed ultraconserved regions; long non-coding RNAs; mechanism of regulation; aberrant expression; cancers
11.  Different therapeutic approaches on quality of life in patients with inflammatory bowel disease 
BMC Gastroenterology  2014;14:199.
Background
The chronic nature of inflammatory bowel disease leads to considerable impairment on the health related quality of life (HRQOL). The aims of the present study are to validate the mainland Chinese translation of the Inflammatory Bowel Disease Questionnaire (MCIBDQ), and to evaluate the impact of infliximab treatment on HRQOL in patients with IBD for the first time in China, as compared with other therapies of different levels. Furthermore, the impact of different medical therapies on marriage, employment and economic burden in IBD patients were also evaluated.
Methods
Consecutive patients who met inclusion/exclusion criteria were investigated with MCIBDQ, SF-36, disease activity index (DAI), marriage, employment and economic burden questionnaires before and after treatment.
Results
MCIBDQ showed significant reliability and validity both in CD and UC patients. The scores of total SF-36, total MCIBDQ and all domains were found significantly increased, while both DAI and health transition on general health scores were found significantly decreased after infliximab treatment (all P < 0.001). Scores of SF-36 and MCIBDQ increased significantly more in infliximab group than non-infliximab group (all P < 0.05). Infliximab treatment was suggested to significantly reduce the negative impact on love (P = 0.037), increase work time (P = 0.016) and ease economic burden (P = 0.048).
Conclusions
MCIBDQ was demonstrated to be a reliable and valid scale applied in Chinese IBD patients. Infliximab treatment was found to significantly improve HRQOL in IBD patients in comparison with conventional treatments. Negative impact on marriage, employment, and economic status was found in patients with IBD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-014-0199-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-014-0199-5
PMCID: PMC4271410  PMID: 25421821
Inflammatory bowel disease; Health-related quality of life; Inflammatory bowel disease questionnaire; Infliximab
12.  Serological Investigation of Food Specific Immunoglobulin G Antibodies in Patients with Inflammatory Bowel Diseases 
PLoS ONE  2014;9(11):e112154.
Objective
Dietary factors have been indicated to influence the pathogenesis and nature course of inflammatory bowel diseases (IBD) with their wide variances. The aim of the study was to assess the prevalence and clinical significance of 14 serum food specific immunoglobulin G (sIgG) antibodies in patients with IBD.
Methods
This retrospective study comprised a total of 112 patients with IBD, including 79 with Crohn's disease (CD) and 33 with ulcerative colitis (UC). Medical records, clinical data and laboratory results were collected for analysis. Serum IgG antibodies against 14 unique food allergens were detected by semi-quantitative enzyme linked immunosorbent assay (ELISA).
Results
Food sIgG antibodies were detected in 75.9% (60/79) of CD patients, 63.6% (21/33) of UC patients and 33.1% (88/266) of healthy controls (HC). IBD patients showed the significantly higher antibodies prevalence than healthy controls (CD vs. HC, P = 0.000; UC vs. HC, P = 0.001). However no marked difference was observed between CD and UC groups (P = 0.184). More subjects were found with sensitivity to multiple antigens (≥3) in IBD than in HC group (33.9% vs.0.8%, P = 0.000). Egg was the most prevalent food allergen. There was a remarkable difference in the levels of general serum IgM (P = 0.045) and IgG (P = 0.041) between patients with positive and negative sIgG antibodies. Patients with multiple positive allergens (≥3) were especially found with significant higher total IgG levels compared with sIgG-negative patients (P = 0.003). Age was suggested as a protective factor against the occurrence of sIgG antibodies (P = 0.002).
Conclusions
The study demonstrates a high prevalence of serum IgG antibodies to specific food allergens in patients with IBD. sIgG antibodies may potentially indicate disease status in clinical and be utilized to guide diets for patients.
doi:10.1371/journal.pone.0112154
PMCID: PMC4230978  PMID: 25393003
13.  Endoglin is necessary for angiogenesis in human ovarian carcinoma-derived primary endothelial cells 
Cancer Biology & Therapy  2013;14(10):937-948.
Endoglin (CD105, END) is upregulated in proliferating endothelial cells, suggesting potential therapeutic properties. However, it is not clear whether endoglin mediates an enhanced proliferative rate or may be upregulated as part of a negative feedback loop. To gain insights into context-dependent and cell type-dependent regulatory effects of endoglin, we studied its role properties in human ovarian carcinoma-derived endothelial cells (ODMECs). We isolated and cultured primary ODMECs from epithelial ovarian carcinoma tissue. ODMECs had higher expression of endoglin and VEGFR-2, and also exhibited enhanced spontaneous formation of vessel-like structures in vitro. Transfection of siRNA targeting endoglin in ODMECs cells resulted in the reduction of the proliferation and tube formation. These results indicate that a subset of ODMECs display abnormal angiogenic properties and this phenotype was blocked by decreasing endoglin levels, suggesting endoglin is essential for stimulating angiogenesis, and targeting it may be an attractive approach to anti-angiogenesis therapy for ovarian carcinoma.
doi:10.4161/cbt.25940
PMCID: PMC3926891  PMID: 23917399
ovarian carcinoma; endothelial cells; endoglin; siRNA; ODMEC
14.  Helicobacter pylori regulates TLR4 and TLR9 during gastric carcinogenesis 
Objective: To investigated the influence of H. pylori on TLR4 and TLR9 in gastric mucosa during gastric carcinogenesis. Methods: Gastric biopsy specimens were taken from 148 patients and divided into five groups, including normal group (n = 10), chronic superficial gastritis group (n = 35), atrophy/intestinal metaplasia group (n = 35), dysplasia group (n = 34) and gastric carcinoma group (n = 34). Immunohistochemistry was used to detect the expression of TLR4 and TLR9. Geimsa staining and rapid urea test were used for determine H. pylori infection. Results: TLR4 was detected in gastric epithelium and monocytes/macrophages in superficial gastritis, atrophy/intestinal metaplasia, dysplasia or carcinoma. TLR9 was mainly accentuated in monocytes/macrophages. TLR4 positive cells in epithelium and in monocytes/macrophages with H. pylori infection were much more than those without H. pylori infection. Similar results were also found in TLR9. When gastric epithelium was accompanied with H. pylori infection, TLR4 was significant higher in superficial gastritis and atrophy/intestinal metaplasia groups compared with dysplasia and carcinoma groups. When gastric epithelium was infected by H. pylori, TLR9 was significant higher in carcinoma group compared with superficial gastritis, atrophy/intestinal metaplasia and dysplasia. TLR4 and TLR9 show significant correlation with the severity of inflammation. Conclusions: H. pylori infection was associated with increased expression of TLR4 and TLR9 in gastric mucosa. In superficial gastritis and atrophy/intestinal metaplasia the inflammation was predominately mediated by TLR4, while in gastric cancer the inflammation was mainly mediated by TLR9.
PMCID: PMC4230143  PMID: 25400780
Expression of Toll-like receptor; H. pylori; gastric carcinogenesis
15.  Current concepts in the pathogenesis of traumatic temporomandibular joint ankylosis 
Head & Face Medicine  2014;10:35.
Traumatic temporomandibular joint (TMJ) ankylosis can be classified into fibrous, fibro-osseous and bony ankylosis. It is still a huge challenge for oral and maxillofacial surgeons due to the technical difficulty and high incidence of recurrence. The poor outcome of disease may be partially attributed to the limited understanding of its pathogenesis. The purpose of this article was to comprehensively review the literature and summarise results from both human and animal studies related to the genesis of TMJ ankylosis.
doi:10.1186/1746-160X-10-35
PMCID: PMC4158390  PMID: 25189735
Trauma; Temporomandibular joint; Ankylosis; Pathogenesis; Review
16.  Regional difference in GABA levels between medial prefrontal and occipital cortices 
Purpose
To avoid the confounding effects of variations in tissue composition this study measured regional GABA differences using two voxels with the same tissue composition.
Materials and Methods
Eighteen healthy adult volunteers were scanned using a 3 Tesla GE clinical scanner with a J-coupling based editing sequence. Spectroscopy voxels were placed in the medial prefrontal (MPFC) and occipital lobes (OCC) with essentially the same gray and white matter fractions.
Results
A 16% (p=0.0001) significantly higher GABA to creatine ratio was found in the OCC (0.1103±0.0050) compared with the MPFC (0.0953±0.0041). When normalized to tissue water, GABA concentrations in the OCC were 14% higher than in the MPFC.
Conclusion
A difference in GABA concentration was found between the OCC and MPFC voxels in healthy subjects when controlling for tissue composition.
doi:10.1002/jmri.24009
PMCID: PMC3638064  PMID: 23349060
N-acetylaspartate (NAA); creatine; glutamate + glutamine (Glx); gamma-aminobutyric acid (GABA); prefrontal cortex; occipital cortex; white matter; gray matter
17.  Combination of Multichannel Single-Voxel MRS Signals Using Generalized Least Squares 
Purpose
To propose using the generalized least square (GLS) algorithm for combining multichannel single-voxel MRS signals.
Materials and Methods
Phantom and in vivo brain MRS experiments on a 7 T scanner equipped with a 32-channel receiver coil, as well as Monte Carlo simulations, were performed to compare the coefficient of variation (CV) of the GLS method with those of two recently reported spectral combination methods.
Results
Compared to the two existing methods, the GLS method significantly reduced CV values for the simulation, phantom, and in vivo experiments.
Conclusion
The GLS method can lead to improved precision of peak quantification.
doi:10.1002/jmri.23941
PMCID: PMC3582859  PMID: 23172656
MRS; multichannel coil; SNR; noise correlation; generalized least squares; GLS
18.  Associations between prefrontal γ-aminobutyric acid concentration and the tryptophan hydroxylase isoform 2 gene, a panic disorder risk allele in women 
Interactions between the central serotonergic and γ-aminobutyric acid (GABA) systems play key roles in the prefrontal cortical regulation of emotion and cognition and in the pathophysiology and pharmacotherapy of highly prevalent psychiatric disorders. The goal of this study was to test the effects of common variants of the tryptophan hydroxylase isoform 2 (TPH2) gene on GABA concentration in the prefrontal cortex (PFC) using magnetic resonance spectroscopy. In this study involving 64 individuals, we examined the associations between prefrontal cortical GABA concentration and 12 single nucleotide polymorphisms (SNPs) spanning the TPH2 gene, including rs4570625 (–703 G/T SNP), a potentially functional TPH2 polymorphism that has been associated with decreased TPH2 mRNA expression and panic disorder. Our results revealed a significant association between increased GABA concentration in the PFC and the T-allele frequencies of 2 TPH2 SNPs, namely, rs4570625 (of –703 G/T) and rs2129575 (p ≤ 0.0004) and the C-allele frequency of 1 TPH2 SNP, namely, rs1386491 (p = 0.0003) in female subjects. We concluded that rs4570625 (–703 G/T), rs2129575, and rs1386491 play a significant role in GABAergic neurotransmission and may contribute to the sex-specific dysfunction of the GABAergic system in the PFC.
doi:10.1017/S1461145713000254
PMCID: PMC4025920  PMID: 23552096
GABA; tryptophan hydroxylase 2; magnetic resonance spectroscopy; single nucleotide polymorphisms; genetics
19.  Age-modulated association between prefrontal NAA and the BDNF gene 
Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p=0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant interaction between rs1519480 and age on NAA level (p=0.031) Specifically, the effect of rs1519480 on NAA level became significant at age ≥ 34.17. NAA level decreased with advancing age for genotype TT (p=0.001) but not for genotype CT (p=0.82) or CC (p=0.34). Additional in silico analysis of 142 postmortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to interindividual variation in cognitive performance seen during normal aging, as well as contributing to the risk for developing psychiatric and neurological conditions.
doi:10.1017/S1461145712001204
PMCID: PMC4025926  PMID: 23253771
BDNF; N-acetyl-aspartate; proton magnetic resonance spectroscopy; SNP; genetic variation
20.  Protective Effects of Lipoxin A4 in Testis Injury following Testicular Torsion and Detorsion in Rats 
Mediators of Inflammation  2014;2014:898056.
Purpose. To investigate the protective effects of lipoxin A4 (LXA4) in rat testis injury following testicular torsion/detorsion. Methods. A rat testicular torsion model has been established as described. Rats were randomly divided into 6 groups: sham group, torsion group, torsion/detorsion (T/D) group, and T/D plus LXA4-pretreated groups (3 subgroups). Rats in LXA4-pretreated groups received LXA4 injection (0.1, 1.0, and 10 μg/kg body weight in LXA4-pretreated subgroups 1–3, resp.) at a single dose 1 h before detorsion. Biochemical analysis, apoptosis assessment, and morphologic evaluation were carried out after orchiectomies. Results. GPx and SOD levels significantly increased and MDA levels significantly reduced in LXA4-pretreated groups compared to T/D group. LXA4 also reverted IL-2 and TNF-α to basal levels and improved the expression of IL-4 and IL-10 in LXA4-pretreated groups. Moreover, the expression of NF-κB was downregulated in LXA4-pretreated groups. LXA4 treatment also showed an improved testicular morphology and decreased apoptosis in testes. Conclusion. Lipoxin A4 protects rats against testes injury after torsion/detorsion via modulation of cytokines, oxidative stress, and NF-κB activity.
doi:10.1155/2014/898056
PMCID: PMC4034656  PMID: 24904198
21.  Small nucleolar RNA signatures of lung tumor-initiating cells 
Molecular Cancer  2014;13:104.
Background
Non-small cell lung cancer (NSCLC) is the number one cancer killer. Tumor-initiating cells (TICs) are responsible for tumor progression and recurrence. Emerging evidences suggest that small nucleolar RNAs (snoRNAs) play malfunctioning roles in lung tumorigenesis. This study aims to determine if snoRNAs have important function in lung TICs by: 1) profiling and comparing snoRNA expression patterns in lung ALDH1+/- cells of 28 primary NSCLC tissues to identify new signatures of TICs; 2) determining prognostic significance of the snoRNA signatures by analyzing the expression in 82 NSCLC tissues with different stages and histological types using quantitative PCR; 3) functionally investigating if the snoRNAs contribute to stemness of lung TICs using in vitro and in vivo assays.
Results
Twenty-two snoRNAs were identified whose changes were specific to the TICs. The expression of two snoRNAs (snoRA3 and snoRA42) was inversely associated with survival of NSCLC patients (P = 0.002, p = 0.001, respectively). Functional analysis indicated that snoRA42 was upregulated in CD133+ cells isolated from NSCLC cell lines compared with the CD133- counterparts. snoRA42 knockdown reduced the proliferation and self-renewal of TICs in vitro. However, ectopic expression of snoRA42 in non-TICs enhanced the potentials of cell proliferation and self-renewal. snoRA42 expression was associated with expression of stem cell-core transcription factors in lung TICs. Blocking snoRA42 expression in TIC xenografts decreased tumorigenesis in mice.
Conclusions
The snoRNA signatures of lung TICs provide potential biomarkers for predicting outcome of NSCLC. snoRA42 is one of the important snoRNAs in regulating features of lung TICs, and thus contributes to lung tumorigenesis.
doi:10.1186/1476-4598-13-104
PMCID: PMC4029979  PMID: 24886050
22.  Using cognitive theory to facilitate medical education 
BMC Medical Education  2014;14:79.
Background
Educators continue to search for better strategies for medical education. Although the unifying theme of reforms was “increasing interest in, attention to, and understanding of the knowledge base structures”, it is difficult to achieve all these aspects via a single type of instruction.
Methods
We used related key words to search in Google Scholar and Pubmed. Related search results on this topic were selected for discussion.
Results
Despite the range of different methods used in medical education, students are still required to memorize much of what they are taught, especially for the basic sciences. Subjects like anatomy and pathology carry a high intrinsic cognitive load mainly because of the large volume of information that must be retained. For these subjects, decreasing cognitive load is not feasible and memorizing appears to be the only strategy, yet the cognitive load makes learning a challenge for many students. Cognitive load is further increased when inappropriate use of educational methods occurs, e.g., in problem based learning which demands clinical reasoning, a high level and complex cognitive skill. It is widely known that experts are more skilled at clinical reasoning than novices because of their accumulated experiences. These experiences are based on the formation of cognitive schemata. In this paper we describe the use of cognitive schemata, developed by experts as worked examples to facilitate medical students’ learning and to promote their clinical reasoning.
Conclusion
We suggest that cognitive load theory can provide a useful framework for understanding the challenges and successes associated with education of medical professionals.
doi:10.1186/1472-6920-14-79
PMCID: PMC3989791  PMID: 24731433
Working memory; Cognitive load theory; Schemata; Clinical reasoning; Worked example; Problem based learning; Clinical presentation curriculum
23.  Soft Constraints in Nonlinear Spectral Fitting with Regularized Lineshape Deconvolution 
This paper presents a novel method for incorporating a priori knowledge into regularized nonlinear spectral fitting as soft constraints. Regularization was recently introduced to lineshape deconvolution as a method for correcting spectral distortions. Here, the deconvoluted lineshape was described by a new type of lineshape model and applied to spectral fitting. The non-linear spectral fitting was carried out in two steps that were subject to hard constraints and soft constraints, respectively. The hard constraints step provided a starting point and, therefore, only the changes of the relevant variables were constrained in the soft constraints step and incorporated into the linear sub-steps of the Levenberg-Marquardt algorithm. The method was demonstrated using localized averaged echo time point resolved spectroscopy (PRESS) proton spectroscopy of human brains.
doi:10.1002/mrm.24337
PMCID: PMC3432296  PMID: 22618964
lineshape; deconvolution; regularization; soft constraints; spectral fitting
24.  Swim therapy reduces mechanical allodynia and thermal hyperalgesia induced by chronic constriction nerve injury in rats 
Pain medicine (Malden, Mass.)  2013;14(4):516-525.
Objective
Neuropathic pain is common and often difficult to treat because it generally does not respond well to the currently available pain medications or nerve blocks. Recent studies in both humans and animals have suggested that exercise may induce a transient analgesia and reduce acute pain in normal healthy individuals. We examined whether swim therapy could alleviate neuropathic pain in rats.
Design
Rats were trained to swim over a two week period in warm water. After the rats were trained, neuropathic pain was induced by constricting the right sciatic nerve and regular swimming was resumed. The sensitivity of each hind paw was monitored using the Hargreaves test and von Frey test to evaluate the withdrawal response thresholds to heat and touch.
Results
The paw ipsilateral to the nerve ligation expressed pain-like behaviors including thermal hyperalgesia and mechanical allodynia. Regular swim therapy sessions significantly reduced the mechanical allodynia and thermal hyperalgesia. Swim therapy had little effect on the withdrawal thresholds for the contralateral paw. In addition, swim therapy alone did not alter the thermal or mechanical thresholds of normal rats.
Conclusions
The results suggest that regular exercise, including swim therapy, may be an effective treatment for neuropathic pain caused by nerve injuries. This study, showing that swim therapy reduces neuropathic pain behavior in rats, provides a scientific rationale for clinicians to test the efficacy of exercise in the management of neuropathic pain. It may prove to be a safe and cost-effective therapy in a variety of neuropathic pain states.
doi:10.1111/pme.12057
PMCID: PMC3625453  PMID: 23438327
Exercise; Neuralgia; Pain Management; Rehabilitation Medicine
25.  Association between Faecalibacterium prausnitzii Reduction and Inflammatory Bowel Disease: A Meta-Analysis and Systematic Review of the Literature 
Background. Laboratory data suggests a reduction of Faecalibacterium prausnitzii (F. prausnitzii) is confirmed both in fecal samples in inflammatory bowel disease (IBD) patients. Numerous observational studies have suspected dysbiosis, an imbalance between protective and harmful bacteria to be relevant to the etiology and pathogenesis of IBD. Methods. Medline, EMBASE, Pubmed, and others. were searched by 2 independent reviewers. Of 48 abstracts reviewed, 11 studies met our inclusion criteria (subject N = 1180). Meta-analysis was performed with Review Manager 5.2. Results. The bacterial count of F. prausnitzii in IBD patients was significantly lower (6.7888 ± 1.8875) log10 CFU/g feces than healthy controls (7.5791 ± 1.5812) log10 CFU/g feces; P < 0.0001. The Standardization Mean Difference of F. prausnitzii in IBD patients was −0.94 (95% confidence interval [CI]: −1.07–−0.80). Subgroup analyses revealed a trend toward a greater effect for CD (SMD: −1.13, 95% CI: −1.32–−0.94) when compared to UC (SMD: −0.78, 95% CI: −0.97–−0.60). Conclusions. The abundance of F. prausnitzii was decreased in IBD patients compared with healthy controls. Furthermore, the reduction of F. prausnitzii and misbalance of the intestinal microbiota are particularly higher in CD patients with ileal involvement.
doi:10.1155/2014/872725
PMCID: PMC3985188  PMID: 24799893

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