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1.  Phylogeny, Systematics and Biogeography of the Genus Panolis (Lepidoptera: Noctuidae) Based on Morphological and Molecular Evidence 
PLoS ONE  2014;9(3):e90598.
The genus Panolis is a small group of noctuid moths with six recognized species distributed from Europe to East Asia, and best known for containing the widespread Palearctic pest species P. flammea, the pine beauty moth. However, a reliable classification and robust phylogenetic framework for this group of potentially economic importance are currently lacking. Here, we use morphological and molecular data (mitochondrial genes cytochrome c oxidase subunit I and 16S ribosomal RNA, nuclear gene elongation factor-1 alpha) to reconstruct the phylogeny of this genus, with a comprehensive systematic revision of all recognized species and a new one, P. ningshan sp. nov. The analysis results of maximum parsimony, maximum likelihood and Bayesian inferring methods for the combined morphological and molecular data sets are highly congruent, resulting in a robust phylogeny and identification of two clear species groups, i.e., the P. flammea species group and the P. exquisita species group. We also estimate the divergence times of Panolis moths using two conventional mutation rates for the arthropod mitochondrial COI gene with a comparison of two molecular clock models, as well as reconstruct their ancestral areas. Our results suggest that 1) Panolis is a young clade, originating from the Oriental region in China in the Late Miocene (6–10Mya), with an ancestral species in the P. flammea group extending northward to the Palearctic region some 3–6 Mya; 2) there is a clear possibility for a representative of the Palearctic clade to become established as an invasive species in the Nearctic taiga.
PMCID: PMC3946178  PMID: 24603596
2.  Exposure to the Polybrominated Diphenyl Ether Mixture DE-71 Damages the Nigrostriatal Dopamine System: Role of Dopamine Handling in Neurotoxicity 
Experimental neurology  2012;241:138-147.
In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson’s disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity. Using an in vitro model system we found DE-71 effectively caused cell death in a dopaminergic cell line as well as reducing the number of TH+ neurons isolated from VMAT2 WT and LO animals. Assessment of DE-71 neurotoxicity in vivo demonstrated significant deposition of PBDE congeners in the brains of mice, leading to reductions in striatal dopamine and dopamine handling, as well as reductions in the striatal dopamine transporter (DAT) and VMAT2. Additionally, DE-71 elicited a significant locomotor deficit in the VMAT2 WT and LO mice. However, no change was seen in TH expression in dopamine terminal or in the number of dopamine neurons in the substantia nigra pars compacta (SNpc). To date, these are the first data to demonstrate that exposure to PBDEs disrupts the nigrostriatal dopamine system. Given their similarities to PCBs, additional laboratory and epidemiological research should be considered to assess PBDEs as a potential risk factor for PD and other neurological disorders.
PMCID: PMC3600580  PMID: 23287494
Polybrominated diphenyl ethers; dopamine; striatum; vesicular monoamine transporter 2; DE-71; Parkinson’s disease
3.  Chronic Arsenic Exposure and Angiogenesis in Human Bronchial Epithelial Cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway 
Environmental Health Perspectives  2014;122(3):255-261.
Background: Environmental and occupational exposure to arsenic is a major public health concern. Although it has been identified as a human carcinogen, the molecular mechanism underlying the arsenic-induced carcinogenesis is not well understood.
Objectives: We aimed to determine the role and mechanisms of miRNAs in arsenic-induced tumor angiogenesis and tumor growth.
Methods: We utilized an in vitro model in which human lung epithelial BEAS-2B cells were transformed through long-term exposure to arsenic. A human xenograft tumor model was established to assess tumor angiogenesis and tumor growth in vivo. Tube formation assay and chorioallantoic membranes assay were used to assess tumor angiogenesis.
Results: We found that miR-199a-5p expression levels were more than 100-fold lower in arsenic-transformed cells than parental cells. Re-expression of miR-199a-5p impaired arsenic-induced angiogenesis and tumor growth through its direct targets HIF-1α and COX-2. We further showed that arsenic induced COX-2 expression through HIF-1 regulation at the transcriptional level. In addition, we demonstrated that reactive oxygen species are an upstream event of miR-199a-5p/ HIF-1α/COX-2 pathway in arsenic-induced carcinogenesis.
Conclusion: The findings establish critical roles of miR-199a-5p and its downstream targets HIF-1/COX-2 in arsenic-induced tumor growth and angiogenesis.
Citation: He J, Wang M, Jiang Y, Chen Q, Xu S, Xu Q, Jiang BH, Liu LZ. 2014. Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway. Environ Health Perspect 122:255–261;
PMCID: PMC3948041  PMID: 24413338
4.  miR-100 Induces Epithelial-Mesenchymal Transition but Suppresses Tumorigenesis, Migration and Invasion 
PLoS Genetics  2014;10(2):e1004177.
Whether epithelial-mesenchymal transition (EMT) is always linked to increased tumorigenicity is controversial. Through microRNA (miRNA) expression profiling of mammary epithelial cells overexpressing Twist, Snail or ZEB1, we identified miR-100 as a novel EMT inducer. Surprisingly, miR-100 inhibits the tumorigenicity, motility and invasiveness of mammary tumor cells, and is commonly downregulated in human breast cancer due to hypermethylation of its host gene MIR100HG. The EMT-inducing and tumor-suppressing effects of miR-100 are mediated by distinct targets. While miR-100 downregulates E-cadherin by targeting SMARCA5, a regulator of CDH1 promoter methylation, this miRNA suppresses tumorigenesis, cell movement and invasion in vitro and in vivo through direct targeting of HOXA1, a gene that is both oncogenic and pro-invasive, leading to repression of multiple HOXA1 downstream targets involved in oncogenesis and invasiveness. These findings provide a proof-of-principle that EMT and tumorigenicity are not always associated and that certain EMT inducers can inhibit tumorigenesis, migration and invasion.
Author Summary
Induction of epithelial-mesenchymal transition (EMT) in epithelial tumor cells has been shown to enhance migration, invasion and cancer ‘stemness’. Here we demonstrate that a miRNA downregulated in human breast tumors, miR-100, can simultaneously induce EMT and inhibit tumorigenesis, migration and invasion through direct targeting of distinct genes. This is the first report of an EMT inducer that suppresses cell movement and tumor invasion, which indicates that EMT is not always associated with increased tumorigenesis, migration and invasion, and that all EMT inducers are not equal: while some of them can promote tumorigenicity, motility and invasiveness, others inhibit these properties owing to their ability to concurrently target both EMT-repressing genes and oncogenic/pro-invasive genes. These findings provide new insights into the complex roles of EMT inducers.
PMCID: PMC3937226  PMID: 24586203
5.  Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids 
OncoTargets and therapy  2014;7:353-363.
Celecoxib, an inhibitor of cyclooxygenase-2 (COX2), was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs), as well as elucidate the underlying mechanisms.
The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway.
MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 μmol/L) plus 5-fluorouracil (8.1 × 10−3 g/L) or sorafenib (4.4 μmol/L) increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR) and phosphorylated (p)-AKT expression. Gefitinib (5 μmol/L), which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 μmol/L) plus celecoxib (21.8 μmol/L) increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited.
Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2 MCSs. Our results provided molecular evidence to support celecoxib combination-treatment strategies for patients with human hepatocellular carcinoma. MCSs provided a good model to evaluate the interaction of anticancer drugs.
PMCID: PMC3938498  PMID: 24591842
hepatocellular carcinoma; celecoxib; multicellular spheroids; 5-fluorouracil; sorafenib; gefitinib
6.  NMDA Receptors Subserve Persistent Neuronal Firing During Working Memory In Dorsolateral Prefrontal Cortex 
Neuron  2013;77(4):736-749.
Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPAR) contributed background depolarization to sustain network firing. In contrast, many Response cells -which likely predominate in rodent PFC- were sensitive to AMPAR blockade and increased firing following systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer’s Disease profoundly impair cognition.
PMCID: PMC3584418  PMID: 23439125
7.  Whole-Exome Sequencing as a diagnostic tool in a child with Atypical Episodic Muscle Weakness 
Clinical genetics  2012;83(5):457-461.
The advent of whole-exome next-generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical application of WES has remained relatively unexplored. We describe our experience with WES as a diagnostic tool in a three-year old female patient with a two-year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work-up. WES was performed on the proband and her two parents. Parental exome data was used to filter de novo genomic events in the proband and suspected mutations were confirmed using di-deoxy sequencing. WES revealed a de novo non-synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband’s original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.
PMCID: PMC3926310  PMID: 22901280
Hypokalemic periodic paralysis; CACNA1S; next generation sequencing; hypotonia
8.  Comparison of Drip, Pipe and Surge Spring Root Irrigation for Jujube (Ziziphus jujuba Mill.) Fruit Quality in the Loess Plateau of China 
PLoS ONE  2014;9(2):e88912.
Loess Plateau is a typical rain-fed farming region, facing the threat of drought. Irrigation method is among the most important factors affecting jujube quality. This study investigated the response of Ziziphus jujuba Mill. cv. Lizao quality to three different irrigation methods (drip-, pipe- and surge spring root irrigation) combining two water levels (20 m3/hm2 and 120 m3/hm2). The effects of the trials were evaluated by taking into account the physical-chemical characteristics of jujubes and the antioxidant activity. Concomitant to this, the concentration of some taste-related (viz. glucose, fructose, TSS and malic acid) and health-related compounds/parameters (viz. catechin and epicatechin) were generally much greater in jujube fruit treated with drip irrigation (120 m3/hm2). Different irrigation treatments had no significant effects on antioxidant capacity, total phenolics and proanthocyanidins (except for pipe irrigation 20 m3/hm2). The best compromise between quality and irrigation of jujube fruit was achieved with drip irrigation (120 m3/hm2).
PMCID: PMC3925179  PMID: 24551188
9.  YgaE Regulates Out Membrane Proteins in Salmonella enterica Serovar Typhi under Hyperosmotic Stress 
The Scientific World Journal  2014;2014:374276.
Salmonella enterica serovar Typhi (S. Typhi) is a human-specific pathogen that causes typhoid fever. In this study, we constructed ΔygaE mutant and a microarray was performed to investigate the role of ygaE in regulation of gene expression changes in response to hyperosmotic stress in S. Typhi. qRT-PCR was performed to validate the microarray results. Our data indicated that ygaE was the repressor of gab operon in S. Typhi as in Escherichia coli (E. coli), though the sequence of ygaE is totally different from gabC (formerly ygaE) in E. coli. OmpF, OmpC, and OmpA are the most abundant out membrane proteins in S. Typhi. Here we report that YgaE is a repressor of both OmpF and OmpC at the early stage of hyperosmotic stress. Two-dimensional electrophoresis was applied to analyze proteomics of total proteins in wild-type strain and ΔygaE strain and we found that YgaE represses the expression of OmpA at the late stage of hyperosmotic stress. Altogether, our results implied that YgaE regulates out membrane proteins in a time-dependent manner under hyperosmotic stress in S. Typhi.
PMCID: PMC3921978  PMID: 24592164
10.  Vitamin D and the Immune System from the Nephrologist's Viewpoint 
ISRN Endocrinology  2014;2014:105456.
Vitamin D and its analogues are widely used as treatments by clinical nephrologists, especially when treating chronic kidney disease (CKD) patients with secondary hyperparathyroidism. As CKD progresses, the ability to compensate for elevations in parathyroid hormone (PTH) and fibroblast growth factor-23 and for decreases in 1,25(OH)2D3 becomes inadequate, which results in hyperphosphatemia, abnormal bone disorders, and extra-skeletal calcification. In addition to its calciotropic effect on the regulation of calcium, phosphate, and parathyroid hormone, vitamin D has many other noncalciotropic effects, including controlling cell differentiation/proliferation and having immunomodulatory effects. There are several immune dysregulations that can be noted when renal function declines. Physicians need to know well both the classical and nonclassical functions of vitamin D. This review is an analysis from the nephrologist's viewpoint and focuses on the relationship between the vitamin D and the immune system, together with vitamin's clinical use to treat kidney diseases.
PMCID: PMC3920624  PMID: 24587915
11.  Correlation of Interleukin-17-Producing Effector Memory T Cells and CD4+CD25+Foxp3 Regulatory T Cells with the Phosphate Levels in Chronic Hemodialysis Patients 
The Scientific World Journal  2014;2014:593170.
Background and Objectives. Hyperparathyroidism and hyperphosphatemia contribute to the inflammatory effects in chronic hemodialysis (HD) patients. Interleukin-17-producing CD4+ effector memory T (Th17) cells and CD4+CD25+Foxp3 regulatory T (Treg) cells both play critical roles in immune activation and inflammation. We investigated the relationship between the Treg and Th17 cells and the phosphate level in chronic HD patients. Methods. 105 patients aged ≥35 years on chronic HD over 3 months were enrolled. The peripheral blood mononuclear cells were collected, cultured, and stimulated by phytohemagglutinin-L, phorbol myristate acetate, and ionomycin at different time points for T cell differentiation. Results. The T cell differentiation was as follows: Th17 cells (mean ± standard deviation (SD): 25.61% ± 10.2%) and Treg cells (8.45% ± 4.3%). The Th17 cell differentiation was positively correlated with the phosphate and albumin levels and negatively correlated with age. The Treg cell differentiation was negatively correlated with albumin level and age. In the nondiabetes group (n = 53), the Th17 cell differentiation was predominantly correlated with the phosphate and iPTH (intact parathyroid hormone) levels as well as the dialysis vintage. Conclusion. Higher phosphate and iPTH levels and longer dialysis duration may increase Th17 cell differentiation, especially in the nondiabetic chronic HD patients.
PMCID: PMC3914580  PMID: 24558316
12.  The RNA Chaperone Hfq Is Involved in Stress Tolerance and Virulence in Uropathogenic Proteus mirabilis 
PLoS ONE  2014;9(1):e85626.
Hfq is a bacterial RNA chaperone involved in the riboregulation of diverse genes via small noncoding RNAs. Here, we show that Hfq is critical for the uropathogenic Proteus mirabilis to effectively colonize the bladder and kidneys in a murine urinary tract infection (UTI) model and to establish burned wound infection of the rats. In this regard, we found the hfq mutant induced higher IL-8 and MIF levels of uroepithelial cells and displayed reduced intra-macrophage survival. The loss of hfq affected bacterial abilities to handle H2O2 and osmotic pressures and to grow at 50°C. Relative to wild-type, the hfq mutant had reduced motility, fewer flagella and less hemolysin expression and was less prone to form biofilm and to adhere to and invade uroepithelial cells. The MR/P fimbrial operon was almost switched to the off phase in the hfq mutant. In addition, we found the hfq mutant exhibited an altered outer membrane profile and had higher RpoE expression, which indicates the hfq mutant may encounter increased envelope stress. With the notion of envelope disturbance in the hfq mutant, we found increased membrane permeability and antibiotic susceptibilities in the hfq mutant. Finally, we showed that Hfq positively regulated the RpoS level and tolerance to H2O2 in the stationary phase seemed largely mediated through the Hfq-dependent RpoS expression. Together, our data indicate that Hfq plays a critical role in P. mirabilis to establish UTIs by modulating stress responses, surface structures and virulence factors. This study suggests Hfq may serve as a scaffold molecule for development of novel anti-P. mirabilis drugs and P. mirabilis hfq mutant is a vaccine candidate for preventing UTIs.
PMCID: PMC3893223  PMID: 24454905
13.  Association Study of Serotonin Transporter SLC6A4 Gene with Chinese Han Irritable Bowel Syndrome 
PLoS ONE  2014;9(1):e84414.
Irritable bowel syndrome (IBS) is a common clinical gastrointestinal dysfunction disorders. 5-sertonon (5-hydroxytryptamine, 5-HT) is a very important neurotransmitter, which is involved in gastrointestinal motion and sensation. Solute carrier family 6 member 4 (SLC6A4) gene encode serotonin transporter (SERT) which function is to rapidly reuptake the most of 5-HT. Therefore, it is needed to explore the association between SLC6A4 gene polymorphisms and IBS.
119 patients and 238 healthy controls were administrated to detect the SLC6A4 gene polymorphisms including 5-HT-transporter-gene-linked polymorphic region (5-HTTLPR), variable number of tandem repeats (VNTRs) and three selected tag Single Nucleotide Polymorphisms (SNPs) rs1042173, rs3794808, rs2020936 by using polymerase chain reaction (PCR) and TaqMan® SNP Genotyping.
There were significant difference for 5-HTTLPR between IBS and control groups (X2 = 106.168, P<0.0001). In control group, genotypes were mainly L/L (58.4%), however, the genotypes in IBS were S/S (37.8%). The significant difference was shown in D-IBS subjects when compared to the controls (X2 = 50.850, P<0.0001) for 5-HTTLPR. For STin2 VNTR, rs1042173, rs3794808, and rs2020936 polymorphisms, there were no any significant differences between IBS and control groups. There were no statistical significantly haplotypes for 5-HTTLPR, VNTRs and the three SNPs between IBS and controls.
The S allele in 5-HTTLPR was a susceptible allele with Chinese Han IBS, but other associations of VNTRs, three selected Tag SNPs and positive haplotype with IBS were not found. It is indicated that much research are needed to study the relationship between other polymorphisms in SLC6A4 gene and IBS.
PMCID: PMC3879322  PMID: 24392134
15.  LipL41, a Hemin Binding Protein from Leptospira santarosai serovar Shermani 
PLoS ONE  2013;8(12):e83246.
Leptospirosis is one of the most widespread zoonotic diseases in the world. It is caused by the pathogen Leptospira that results in multiple-organ failure, in particular of the kidney. Outer membrane lipoprotein is the suspected virulence factor of Leptospira. In Leptospira spp LipL41 is one major lipoprotein and is highly conserved. Previous study suggests that LipL41 bears hemin-binding ability and might play a possible role in iron regulation and storage. However, the characterization of hemin-binding ability of LipL41 is still unclear. Here the hemin-binding ability of LipL41 was examined, yielding a Kd = 0.59 ± 0.14 μM. Two possible heme regulatory motifs (HRMs), C[P/S], were found in LipL41 at 140Cys-Ser and 220Cys-Pro. The mutation study indicates that Cys140 and Cys220 might be cooperatively involved in hemin binding. A supramolecular assembly of LipL41 was determined by transmission electron microscopy. The LipL41 oligomer consists of 36 molecules and folds as a double-layered particle. At the C-terminus of LipL41, there are two tetratricopeptide repeats (TPRs), which might be involved in the protein-protein interaction of the supramolecular assembly.
PMCID: PMC3861479  PMID: 24349474
16.  Clinicopathologic significance of claudin-6, occludin, and matrix metalloproteinases −2 expression in ovarian carcinoma 
Diagnostic Pathology  2013;8:190.
Tight junctions (TJs) are mainly composed of claudins, occludin, and tight junction adhesion molecules (JAM). The invasive and metastatic phenotype of highly invasive cancer cells has been related to abnormal structure and function of TJs, and with expression of activated matrix metalloproteinases (MMPs). The relevance of these mechanisms responsible for the invasion and metastasis of ovarian carcinoma is unclear. Similarly, it is not known if the expression of claudin-6, occludin and MMP2 is related with the clinical properties of these tumors.
Expression of claudin-6, occludin, and MMP2 was detected in samples of human ovarian cancer tissues by immunohistochemistry and correlated with the clinical properties of the tumors.
The positive expression rates of claudin-6 and MMP-2 were higher in ovarian papillary serous carcinomas than n ovarian serous adenomas (P < 0.05). There were no differences in the expression of occludin (P > 0.05). The expression of claudin-6 and occludin in ovarian cancer was not correlated with patient age, pathological grade, clinical stage, and metastasis (P > 0.05). MMP-2 expression was enhanced with increased clinical stage and metastasis (P < 0.05), but was unrelated to patient age or tumor grade (P > 0.05). There were no apparent correlations between expression of claudin-6, occludin and MMP-2 in ovarian cancer tissue (P > 0.05).
Our data suggest, for the first time, that the claudin-6 and MMP-2 are up-regulated in ovarian papillary serous carcinomas, MMP-2 expression was enhanced with increased clinical stage and metastasis. Claudin-6 and MMP-2 may play a positive role in the invasion and metastasis of ovarian cancer.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3866569  PMID: 24245968
Tight junctions; Ovarian cancer; Claudin-6; Occludin; MMP-2
17.  Synthesis of Photoresponsive Dual NIR Two-Photon Absorptive [60]Fullerene Triads and Tetrads 
Molecules (Basel, Switzerland)  2013;18(8):10.3390/molecules18089603.
Broadband nonlinear optical (NLO) organic nanostructures exhibiting both ultrafast photoresponse and a large cross-section of two-photon absorption throughout a wide NIR spectrum may make them suitable for use as nonlinear biophotonic materials. We report here the synthesis and characterization of two C60-(antenna)x analogous compounds as branched triad C60(>DPAF-C18)(>CPAF-C2M) and tetrad C60(>DPAF-C18)(>CPAF-C2M)2 nanostructures. These compounds showed approximately equal extinction coefficients of optical absorption over 400–550 nm that corresponds to near-IR two-photon based excitation wavelengths at 780–1,100 nm. Accordingly, they may be utilized as potential precursor candidates to the active-core structures of photosensitizing nanodrugs for 2γ-PDT in the biological optical window of 800–1,050 nm.
PMCID: PMC3830959  PMID: 23941881
C60-(antenna)x nanostructures; ultrafast intramolecular energy-transfer; NIR two-photon absorption; 2γ-photodynamic therapeutic agent; photosensitizer
18.  Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2 
Brain  2013;137(1):44-56.
Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.
PMCID: PMC3891447  PMID: 24253200
childhood neuronopathy; Brown-Vialetto-Van Laere syndrome; riboflavin therapy; RFVT2; SLC52A2
19.  Fecal microbiota transplantation for severe enterocolonic fistulizing Crohn’s disease 
The concept of fecal microbiota transplantation (FMT) has been used in traditional Chinese medicine at least since the 4th century. Evidence from recent human studies strongly supports the link between intestinal bacteria and inflammatory bowel disease. We proposed that standardized FMT might be a promising rescue therapy for refractory inflammatory bowel disease. However, there were no reports of FMT used in patients with severe Crohn’s disease (CD). Here, we report the successful treatment of standardized FMT as a rescue therapy for a case of refractory CD complicated with fistula, residual Barium sulfate and formation of intraperitoneal large inflammatory mass. As far as we know, this is the first case of severe CD treated using FMT through mid-gut.
PMCID: PMC3819561  PMID: 24222969
Fecal microbiota transplantation; Crohn’s disease; Rescue therapy; Inflammatory bowel disease; Fistula
20.  Relationship of personal health experiences with interest in health careers among youth from an underserved area 
Journal of allied health  2013;42(3):135-140.
Only 10% of health professionals are from racial/ethnic minority groups, and much research has been focused on encouraging minorities to enter a health career. The lack of health workforce diversity has many implications for the effective delivery of care to an increasingly diverse US population. The goal of this analysis is to examine the influence of personal health experiences on interest in a health career. “Personal Health Experiences” is a newly created scaled variable that assesses the influence of direct and indirect health experiences of respondents. In a sample of 134 predominantly minority 10th graders from underprivileged neighborhoods, the scale had adequate psychometric properties (range = 1 to 7; mean = 4.44, s.d. = 1.46, median=4.60, Cronbach's alpha = 0.72), and multivariate regression modeling revealed that “Personal Health Experiences” predicted increased “Interest in Health Careers" (B=0.47, s.e.=0.10). Future research is needed to determine the role that personal health experiences play in career choices and one's success in health career decisions. Such information could, for example, help to refine health profession recruitment strategies.
PMCID: PMC3768001  PMID: 24013242
21.  Primary Care Physicians’ Cancer Screening Recommendation Practices and Perceptions of Cancer Risk of Asian Americans 
Asian Americans experience disproportionate incidence and mortality rates of certain cancers, compared to other racial/ethnic groups. Primary care physicians are a critical source for cancer screening recommendations and play a significant role in increasing cancer screening of their patients. This study assessed primary care physicians’ perceptions of cancer risk in Asians and screening recommendation practices. Primary care physicians practicing in New Jersey and New York City (n=100) completed a 30-question survey on medical practice characteristics, Asian patient communication, cancer screening guidelines, and Asian cancer risk. Liver cancer and stomach cancer were perceived as higher cancer risks among Asian Americans than among the general population, and breast and prostate cancer were perceived as lower risks. Physicians are integral public health liaisons who can be both influential and resourceful toward educating Asian Americans about specific cancer awareness and screening information.
PMCID: PMC3800694  PMID: 23679307
Asian Americans; cancer; primary care physician; health disparities
22.  The Prevalence and Awareness of Cardiometabolic Risk Factors in Southern Chinese Population with Coronary Artery Disease 
The Scientific World Journal  2013;2013:416192.
Background. Cardiometabolic risk factors significantly accelerate the progression of coronary artery disease (CAD); however, whether CAD patients in South China are aware of the prevalence of these risk factors is not clear yet. Methods. The study consisted of 2312 in-admission CAD patients from 2008 to 2011 in South China. Disease history including hypertension, dyslipidemia, and diabetes was relied on patients' self-reported records. Physical and clinical examinations were tested to assess the real prevalence of the cardiometabolic risk factors. Results. 57.9% of CAD patients had more than 3 cardiometabolic risk factors in terms of the metabolic syndrome. The self-known and real prevalence of hypertension, diabetes, and dyslipidemia were 56.6%, 28.3%, and 25.1% and 91.3%, 40.9%, and 92.0%, respectively. The awareness rates were 64.4%, 66.3%, and 28.5% for hypertension, diabetes, and dyslipidemia. The prevalence of cardiometabolic risk factors was significantly different among gender and among disease status. Conclusions. Most CAD patients in South China had more than three cardiometabolic risk factors. However, the awareness rate of cardiometabolic diseases was low, especially for dyslipidemia. Strategies of routine physical examination programs are needed for the early detection and treatment of cardiometabolic risk factors in order to prevent CAD progression and prognosis.
PMCID: PMC3810187  PMID: 24222736
23.  Correction: Norcantharidin Inhibits Renal Interstitial Fibrosis by Blocking the Tubular Epithelial-Mesenchymal Transition 
PLoS ONE  2013;8(10):10.1371/annotation/84e623b5-d1a7-47b7-96d7-4f5464b6f4b3.
PMCID: PMC3794066  PMID: 24115993
24.  Neuromodulation of Thought: Flexibilities and Vulnerabilities in Prefrontal Cortical Network Synapses 
Neuron  2012;76(1):223-239.
In this review, we discuss how working memory prefrontal cortical (PFC) circuits are modulated differently than plastic changes in sensory/motor and subcortical circuits. Working memory arises from recurrent excitation within layer III PFC pyramidal cell NMDA circuits, which are afflicted in aging and schizophrenia. Neuromodulators rapidly and flexibly alter the efficacy of these synaptic connections, while leaving the synaptic architecture unchanged, a process called Dynamic Network Connectivity (DNC). Increases in calcium-cAMP signaling open ion channels in long, thin spines, gating network connections. Inhibition of calcium-cAMP signaling, e.g. by noradrenergic α2A-adrenoceptor stimulation on spines, strengthens synaptic efficacy and increases network firing, while optimal levels of dopamine D1 receptor stimulation sculpt network inputs to refine mental representation. Generalized increases in calcium-cAMP signaling during fatigue or stress disengage dlPFC recurrent circuits, reduce firing and impair top-down cognition. Impaired DNC regulation contributes to age-related cognitive decline, while genetic insults to DNC proteins are commonly linked to schizophrenia.
PMCID: PMC3488343  PMID: 23040817
25.  An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway 
Activated protein C (APC) is a protease with anticoagulant and cell-signaling activities. In the central nervous system, APC and its analogs with reduced anticoagulant activity but preserved cell signaling activities, such as 3K3A-APC, exert neuroprotective, vasculoprotective and anti-inflammatory effects. Murine APC promotes subependymal neurogenesis in rodents in vivo after ischemic and traumatic brain injury. Whether human APC can influence neuronal production from resident progenitor cells in humans is unknown. Here we show that 3K3A-APC, but not S360A-APC (an enzymatically inactive analog of APC), stimulated neuronal mitogenesis and differentiation from fetal human neural stem and progenitor cells (NPCs). 3K3A-APC’s effects on proliferation and differentiation were comparable to those respectively obtained with fibroblast growth factor and brain-derived growth factor. Its promoting effect on neuronal differentiation was accompanied by inhibition of astroglial differentiation. In addition, 3K3A-APC exerted modest anti-apoptotic effects during neuronal production. These effects appeared mediated through specific protease activated (PAR) and sphingosine-1-phosphate (S1PR) receptors, in that siRNA-mediated inhibition of PARs 1–4 and S1PRs 1–5 revealed that PAR1, PAR3 and S1PR1 are required for the neurogenic effects of 3K3A-APC. 3K3A-APC activated Akt, a downstream target of S1PR1, which was inhibited by S1PR1, PAR1 and PAR3 silencing. Adenoviral transduction of NPCs with a kinase-defective Akt mutant abolished the effects of 3K3A-APC on NPCs, confirming a key role of Akt activation in 3K3A-APC-mediated neurogenesis. Thus, APC and its pharmacological analogues, by influencing PAR and S1PR signals in resident neural progenitor cells, may be potent modulators of both development and repair in the human CNS.
PMCID: PMC3707621  PMID: 23554499

Results 1-25 (253)