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1.  Rapid Detection of Mycobacterium tuberculosis and Pyrazinamide Susceptibility Related to pncA Mutations in Sputum Specimens through an Integrated Gene-to-Protein Function Approach 
Journal of Clinical Microbiology  2014;52(1):260-267.
Testing the pyrazinamide (PZA) susceptibility of Mycobacterium tuberculosis isolates is challenging. In a previous paper, we described the development of a rapid colorimetric test for the PZA susceptibility of M. tuberculosis by a PCR-based in vitro-synthesized-pyrazinamidase (PZase) assay. Here, we present an integrated approach to detect M. tuberculosis and PZA susceptibility directly from sputum specimens. M. tuberculosis was detected first, using a novel long-fragment quantitative real-time PCR (LF-qPCR), which amplified a fragment containing the whole pncA gene. Then, the positive amplicons were sequenced to find mutations in the pncA gene. For new mutations not found in the Tuberculosis Drug Resistance Mutation Database (www.tbdreamdb.com), the in vitro PZase assay was used to test the PZA resistance. This approach could detect M. tuberculosis within 3 h with a detection limit of 7.8 copies/reaction and report the PZA susceptibility within 2 days. In an initial testing of 213 sputum specimens, the LF-qPCR found 53 positive samples with 92% sensitivity and 97% specificity compared to the culture test for M. tuberculosis detection. DNA sequencing of the LF-qPCR amplicons revealed that 49 samples were PZA susceptible and 1 was PZA resistant. In the remaining 3 samples, with new pncA mutations, the in vitro PZase assay found that 1 was PZA susceptible and 2 were PZA resistant. This integrated approach provides a rapid, efficient, and relatively low-cost solution for detecting M. tuberculosis and PZA susceptibility without culture.
doi:10.1128/JCM.02285-13
PMCID: PMC3911477  PMID: 24226918
2.  Anti-Retroviral Therapy Decreases but Does Not Normalize Indoleamine 2,3-Dioxygenase Activity in HIV-Infected Patients 
PLoS ONE  2014;9(7):e100446.
Background
Indoleamine 2,3-dioxygenase (IDO), which is mainly expressed in activated dendritic cells, catabolizes tryptophan to kynurenine and other downstream catabolites. It is known to be an immune mediator in HIV pathogenesis. The impact of anti-retroviral therapy on its activity has not been well established.
Methods
We measured systemic IDO activity (the ratio of plasma kynurenine to tryptophan) in HIV-infected patients before and after highly active antiretroviral therapy (HAART) and its association with a microbial translocation marker, soluble CD14 (sCD14).
Results
Among 76 participants, higher baseline IDO activity was associated with lower CD4+ T cell counts (P<0.05) and higher plasma sCD14 levels (P<0.001). After 1 year of HAART, IDO activity decreased significantly (P<0.01), but was still higher than in healthy controls (P<0.05). The baseline IDO activity did not predict CD4+ T cell recovery after 1 year of therapy. The percentages of myeloid and plasmacytoid dendritic cells were not correlated with IDO activity.
Conclusions
IDO activity is elevated in HIV-infected patients, which is partially associated with microbial translocation. HAART reduced, but did not normalize the activity of IDO.
doi:10.1371/journal.pone.0100446
PMCID: PMC4077698  PMID: 24983463
3.  Value of MR diffusion imaging in hepatic fibrosis and its correlations with serum indices 
AIM: To compare apparent diffusion coefficient (ADC) values on diffusion-weighted imaging (DWI) of hepatic fibrosis patients with those of healthy controls and to identify their correlations with serum indices of liver fibrosis.
METHODS: Hyaluronic acid (HA), laminin (LN), type III procollagen (PCIII), and collagen type IV (IV-C) were measured in 54 hepatic fibrosis patients and 23 normal controls, and ADC values were determined on DWI at different b values (b = 300, 500, 700 s/mm2). Correlations between serum indices and ADC values at different liver fibrosis stages were examined, and each index variation of liver fibrosis in different stages were compared, and correlation analysis of each index and the staging of liver fibrosis carried out, and the correlation of each index performed.
RESULTS: With progressive liver fibrosis, HA, PCIII, and IV-C levels increased (P < 0.01). As the b value increased, the ADC value decreased gradually with the hepatic fibrosis stages. In different groups with b values of 500 s/mm2 and 700 s/mm2, the ADC value decreased significantly as liver fibrosis progressed (P < 0.01). With b values of 500 s/mm2 and 700 s/mm2, there were negative correlations between ADC and LN, PCIII, HA, and IV-C. This pattern was observed only for HA and IV-C at a b value of 300 s/mm2.
CONCLUSION: Serum indices of liver fibrosis and ADC values are useful for diagnosing liver fibrosis, with some correlations among them.
doi:10.3748/wjg.v20.i24.7964
PMCID: PMC4069324  PMID: 24976733
Liver cirrhosis; Diffusion-weighted imaging; Hyaluronic acid; Laminin; Biological marker
4.  miR-15b Suppression of Bcl-2 Contributes to Cerebral Ischemic Injury and is Reversed by Sevoflurane Preconditioning 
Ischemic neuroprotection afforded by sevoflurane preconditioning has been previously demonstrated, yet the underlying mechanism is poorly understood and likely affects a wide range of cellular activities. Several individual microRNAs have been implicated in both the pathogenesis of cerebral ischemia and cellular survival, and are capable of affecting a range of target mRNA. Conceivably, sevoflurane preconditioning may lead to alterations in ischemia-induced microRNA expression that may subsequently exert neuroprotective effects. We first examined the microRNA expression profile following transient cerebral ischemia in rats and the impact of sevoflurane preconditioning. Microarray analysis revealed that 3 microRNAs were up-regulated (>2.0 fold) and 9 were down-regulated (< 0.5 fold) following middle cerebral artery occlusion (MCAO) compared to sham controls. In particular, miR-15b was expressed at significantly high levels after MCAO. Preconditioning with sevoflurane significantly attenuated the upregulation of miR-15b at 72h after reperfusion. Bcl-2, an anti-apoptotic gene involved in the pathogenesis of cerebral ischemia, has been identified as a direct target of miR-15b. Consistent with the observed downregulation of miR-15b in sevoflurane-preconditioned brain, post-ischemic Bcl-2 expression was significantly increased by sevoflurane preconditioning. We identified the 3’-UTR of Bcl-2 as the target for miR-15b. Molecular inhibition of miR-15b was capable of mimicking the neuroprotective effect of sevoflurane preconditioning, suggesting that the suppression of miR-15b due to sevoflurane contributes to its ischemic neuroprotection. Thus, sevoflurane preconditioning may exert its anti-apoptotic effects by reducing the elevated expression of miR-15b following ischemic injury, allowing its target proteins, including Bcl-2, to be translated and expressed at the protein level.
PMCID: PMC4071288  PMID: 23469855
Sevoflurane; Preconditioning; Cerebral ischemia; microRNA; Bcl-2
5.  Extreme adaptations for aquatic ectoparasitism in a Jurassic fly larva 
eLife  2014;3:e02844.
The reconstruction of ancient insect ectoparasitism is challenging, mostly because of the extreme scarcity of fossils with obvious ectoparasitic features such as sucking-piercing mouthparts and specialized attachment organs. Here we describe a bizarre fly larva (Diptera), Qiyia jurassica gen. et sp. nov., from the Jurassic of China, that represents a stem group of the tabanomorph family Athericidae. Q. jurassica exhibits adaptations to an aquatic habitat. More importantly, it preserves an unusual combination of features including a thoracic sucker with six radial ridges, unique in insects, piercing-sucking mouthparts for fluid feeding, and crocheted ventral prolegs with upward directed bristles for anchoring and movement while submerged. We demonstrate that Q. jurassica was an aquatic ectoparasitic insect, probably feeding on the blood of salamanders. The finding reveals an extreme morphological specialization of fly larvae, and broadens our understanding of the diversity of ectoparasitism in Mesozoic insects.
DOI: http://dx.doi.org/10.7554/eLife.02844.001
eLife digest
Parasites have been exploiting other organisms for millions of years. However, little is known about ancient parasitic insects, as it is rare to find fossils that are preserved well enough for them to be identified as parasites. This is particularly true for ectoparasitic insects, which live on the skin of their hosts. As a result, the only widely accepted ectoparasitic insect from the Mesozoic era is the giant flea, which infested dinosaurs, pterosaurs or mammals.
Now, Chen, Wang, Engel et al. have discovered a new genus and species of ancient aquatic fly, which may be the earliest currently known aquatic ectoparasitic insect. Named Qiyia jurassica—after the Chinese word for ‘bizarre’ and the Jurassic period when it lived—its larva has a combination of features that mark it out as a parasitic ancestor of modern water snipe flies. In addition, the well-preserved fossilised larvae used to identify Q. jurassica have some more unusual features.
The mouth of Q. jurassica had a structure commonly found in ectoparasites, designed to pierce skin and suck blood. The larva also had several features that were particularly well-adapted for gripping the host animal while underwater. The prolegs—stumpy fleshy structures found on the abdomen—were covered in bristles that pointed upwards, anchoring the larva in place. Q. jurassica also had an unusual sucker on its thorax that would have provided a firm grip that held its head still during feeding. Although many modern aquatic ectoparasites—like leeches—have suckers, the Q. jurassica sucker may be unique amongst insect larvae, as it has six large ridges and is covered in spines. Both features may have provided extra grip.
Chen, Wang, Engel et al. suggest that Q. jurassica feasted on the blood of salamanders, as many salamander fossils have been found in the same region. The larvae could have attached to unexposed areas of the salamander—behind the gills, for example—where feeding would also have been easier due to the rich supply of blood vessels, and the thinner, more easily pierced skin.
The wide range of features found on Q. jurassica suggests that Mesozoic ectoparasitic insects were more diverse than previously thought.
DOI: http://dx.doi.org/10.7554/eLife.02844.002
doi:10.7554/eLife.02844
PMCID: PMC4067894  PMID: 24963142
fossil; Diptera; urassic; China; none
6.  (-)-Phenserine Attenuates Soman-Induced Neuropathology 
PLoS ONE  2014;9(6):e99818.
Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.
doi:10.1371/journal.pone.0099818
PMCID: PMC4067273  PMID: 24955574
7.  Analysis of the Transcriptome of Erigeron breviscapus Uncovers Putative Scutellarin and Chlorogenic Acids Biosynthetic Genes and Genetic Markers 
PLoS ONE  2014;9(6):e100357.
Background
Erigeron breviscapus (Vant.) Hand-Mazz. is a famous medicinal plant. Scutellarin and chlorogenic acids are the primary active components in this herb. However, the mechanisms of biosynthesis and regulation for scutellarin and chlorogenic acids in E. breviscapus are considerably unknown. In addition, genomic information of this herb is also unavailable.
Principal Findings
Using Illumina sequencing on GAIIx platform, a total of 64,605,972 raw sequencing reads were generated and assembled into 73,092 non-redundant unigenes. Among them, 44,855 unigenes (61.37%) were annotated in the public databases Nr, Swiss-Prot, KEGG, and COG. The transcripts encoding the known enzymes involved in flavonoids and in chlorogenic acids biosynthesis were discovered in the Illumina dataset. Three candidate cytochrome P450 genes were discovered which might encode flavone 6-hydroase converting apigenin to scutellarein. Furthermore, 4 unigenes encoding the homologues of maize P1 (R2R3-MYB transcription factors) were defined, which might regulate the biosynthesis of scutellarin. Additionally, a total of 11,077 simple sequence repeat (SSR) were identified from 9,255 unigenes. Of SSRs, tri-nucleotide motifs were the most abundant motif. Thirty-six primer pairs for SSRs were randomly selected for validation of the amplification and polymorphism. The result revealed that 34 (94.40%) primer pairs were successfully amplified and 19 (52.78%) primer pairs exhibited polymorphisms.
Conclusion
Using next generation sequencing (NGS) technology, this study firstly provides abundant genomic data for E. breviscapus. The candidate genes involved in the biosynthesis and transcriptional regulation of scutellarin and chlorogenic acids were obtained in this study. Additionally, a plenty of genetic makers were generated by identification of SSRs, which is a powerful tool for molecular breeding and genetics applications in this herb.
doi:10.1371/journal.pone.0100357
PMCID: PMC4067309  PMID: 24956277
8.  HSP27 Protects the Blood-Brain Barrier Against Ischemia-Induced Loss of Integrity 
Loss of integrity of the blood-brain barrier (BBB) in stroke victims initiates a devastating cascade of events including extravasation of blood-borne molecules, water, and inflammatory cells deep into brain parenchyma. Thus, it is important to identify mechanisms by which BBB integrity can be maintained in the face of ischemic injury in experimental stroke. We previously demonstrated that the phylogenetically conserved small heat shock protein 27 (HSP27) protects against transient middle cerebral artery occlusion (tMCAO). Here we show that HSP27 transgenic overexpression also maintains the integrity of the BBB in mice subjected to tMCAO. Extravasation of endogenous IgG antibodies and exogenous FITC-albumin into the brain following tMCAO was reduced in transgenic mice, as was total brain water content. HSP27 overexpression abolished the appearance of TUNEL-positive profiles in microvessel walls. Transgenics also exhibited less loss of microvessel proteins following tMCAO. Notably, primary endothelial cell cultures were rescued from oxygen-glucose deprivation (OGD) by lentiviral HSP27 overexpression according to four viability assays, supporting a direct effect on this cell type. Finally, HSP27 overexpression reduced the appearance of neutrophils in the brain and inhibited the secretion of five cytokines. These findings reveal a novel role for HSP27 in attenuating ischemia/reperfusion injury - the maintenance of BBB integrity. Endogenous upregulation of HSP27 after ischemia in wild-type animals may exert similar protective functions and warrants further investigation. Exogenous enhancement of HSP27 by rational drug design may lead to future therapies against a host of injuries, including but not limited to a harmful breach in brain vasculature.
PMCID: PMC4061290  PMID: 23469858
endothelial cell; heat shock protein; HSP25; HSPB1; microvessel; stroke; tight junction; vascular
9.  Critical appraisal of pemetrexed in the treatment of NSCLC and metastatic pulmonary nodules 
OncoTargets and therapy  2014;7:937-945.
Pemetrexed, a new multitarget antifolate antineoplastic agent, has significantly improved the overall survival in nonsquamous non-small-cell lung cancer patients. Presently, pemetrexed is recommended for first line treatment in combination with platinum derivatives, for second line treatment as a single agent and, more recently, as maintenance treatment after first line chemotherapy. In this article we critically appraise the status of pemetrexed including pharmacodynamics, pharmacokinetics, toxicity, and the cost effectiveness of pemetrexed, as well as the predictive biomarkers for pemetrexed based chemotherapy.
doi:10.2147/OTT.S45148
PMCID: PMC4057332  PMID: 24944517
chemotherapy; non-small-cell lung cancer; pemetrexed
10.  Pharmacotherapy for acute mania and disconcordance with treatment guidelines: bipolar mania pathway survey (BIPAS) in mainland China 
BMC Psychiatry  2014;14:167.
Background
With the recent attention to evidence-based medicine in psychiatry, a number of treatment guidelines for bipolar disorders have been published. This survey investigated prescribing patterns and predictors for guideline disconcordance in the acute treatment of a manic and mixed episode across mainland China.
Methods
The pharmacological treatments of 2828 patients with a recent hypomanic/manic episode or mixed state were examined. Guidelines disconcordance was determined by comparing the medication(s) patients were prescribed with the recommendation(s) in the guidelines of the Canadian Network for Mood and Anxiety Treatments.
Results
The most common pattern of pharmacological treatments for an acute manic or mixed episode was a mood stabilizer plus an atypical antipsychotic (n = 1345, 47.6%), and the rate of guideline-disconcordant treatments was 11.1%. The patients who were treated in general hospitals were more likely to receive guideline-disconcordant treatments than those who were treated in psychiatric hospitals, with an OR of 1.84 (95% CI 1.44-2.36). Similarly, the patients with a mixed episode at study entry were more likely to receive guideline-disconcordant treatments than those with a manic episode, with an OR of 1.69 (95% CI 1.22-2.35). In contrast, the patients with a longer duration of disease (>5 years) were less likely to receive guideline-disconcordant treatments than those with a short duration, with an OR of 0.47 (95% CI 0.36-0.60).
Conclusions
In mainland China, the disconcordance with treatment guidelines for a most recent acute manic or mixed episode was modest under naturalistic conditions. The higher risk for disconcordance in general hospitals than in psychiatric hospitals suggests that special education based on treatment guidelines to practitioners in general hospitals is necessary in order to reduce the risk for disconcordant treatments.
doi:10.1186/1471-244X-14-167
PMCID: PMC4061451  PMID: 24903426
Bipolar disorder; Mania; Pharmacotherapy; Treatment; Guidelines
11.  Comprehensive clinical and pathological analysis of aggressive renal epithelioid angiomyolipoma: report of three cases 
OncoTargets and therapy  2014;7:823-827.
Renal angiomyolipoma (AML) is recognized as a benign hamartomatous lesion arising in the kidney with no obvious malignant potential. However, epithelioid AML (EAML), a rare variant of AML, is potentially malignant, with aggressive clinical features. It can occur in patients with or without tuberous sclerosis. Because EAML may mimic renal cell carcinoma in imaging studies, differentiation of this tumor from renal cell carcinoma preoperatively is difficult. At times, the lesions may extend into the renal vein and inferior vena cava or metastasize to other organs such as the lung and liver. To clarify the biological nature of EAML, three specific cases that we encountered in clinical practice are analyzed and reported in detail.
doi:10.2147/OTT.S61524
PMCID: PMC4043816  PMID: 24920923
kidney; malignant; inferior vena cava
12.  Surveillance-response systems: the key to elimination of tropical diseases 
Tropical diseases remain a major cause of morbidity and mortality in developing countries. Although combined health efforts brought about significant improvements over the past 20 years, communities in resource-constrained settings lack the means of strengthening their environment in directions that would provide less favourable conditions for pathogens. Still, the impact of infectious diseases is declining worldwide along with progress made regarding responses to basic health problems and improving health services delivery to the most vulnerable populations. The London Declaration on Neglected Tropical Diseases (NTDs), initiated by the World Health Organization’s NTD roadmap, set out the path towards control and eventual elimination of several tropical diseases by 2020, providing an impetus for local and regional disease elimination programmes. Tropical diseases are often patchy and erratic, and there are differing priorities in resources-limited and endemic countries at various levels of their public health systems. In order to identify and prioritize strategic research on elimination of tropical diseases, the ‘First Forum on Surveillance-Response System Leading to Tropical Diseases Elimination’ was convened in Shanghai in June 2012. Current strategies and the NTD roadmap were reviewed, followed by discussions on how to identify and critically examine prevailing challenges and opportunities, including inter-sectoral collaboration and approaches for elimination of several infectious, tropical diseases. A priority research agenda within a ‘One Health-One World’ frame of global health was developed, including (i) the establishment of a platform for resource-sharing and effective surveillance-response systems for Asia Pacific and Africa with an initial focus on elimination of lymphatic filariasis, malaria and schistosomiasis; (ii) development of new strategies, tools and approaches, such as improved diagnostics and antimalarial therapies; (iii) rigorous validation of surveillance-response systems; and (iv) designing pilot studies to transfer Chinese experiences of successful surveillance-response systems to endemic countries with limited resources.
doi:10.1186/2049-9957-3-17
PMCID: PMC4071800  PMID: 24971165
Tropical diseases; Control; Elimination; Surveillance-response system; Global health; China
13.  Haploinsufficiency of Def Activates p53-Dependent TGFβ Signalling and Causes Scar Formation after Partial Hepatectomy 
PLoS ONE  2014;9(5):e96576.
The metazoan liver exhibits a remarkable capacity to regenerate lost liver mass without leaving a scar following partial hepatectomy (PH). Whilst previous studies have identified components of several different signaling pathways that are essential for activation of hepatocyte proliferation during liver regeneration, the mechanisms that enable such regeneration to occur without accompanying scar formation remain poorly understood. Here we use the adult zebrafish liver, which can regenerate within two weeks following PH, as a new genetic model to address this important question. We focus on the role of Digestive-organ-expansion-factor (Def), a nucleolar protein which has recently been shown to complex with calpain3 (Capn3) to mediate p53 degradation specifically in the nucleolus, in liver regeneration. Firstly, we show that Def expression is up-regulated in the wild-type liver following amputation, and that the defhi429/+ heteroozygous mutant (def+/−) suffers from haploinsufficiency of Def in the liver. We then show that the expression of pro-inflammatory cytokines is up-regulated in the def+/− liver, which leads to distortion of the migration and the clearance of leukocytes after PH. Transforming growth factor β (TGFβ) signalling is thus activated in the wound epidermis in def+/− due to a prolonged inflammatory response, which leads to fibrosis at the amputation site. Fibrotic scar formation in def+/− is blocked by the over-expression of Def, by the loss-of-function of p53, and by treatment with anti-inflammation drug dexamethasone or TGFβ-signalling inhibitor SB431542. We finally show that the Def- p53 pathway suppresses fibrotic scar formation, at least in part, through the regulation of the expression of the pro-inflammatory factor, high-mobility group box 1. We conclude that the novel Def- p53 nucleolar pathway functions specifically to prevent a scar formation at the amputation site in a normal amputated liver.
doi:10.1371/journal.pone.0096576
PMCID: PMC4011785  PMID: 24801718
14.  Mite and Booklouse Fauna From Vacuumed Dust Samples From Beijing 
A significant-source of allergens come from house dust that contain particles derived from arthropods, molds, and pet dander. This study evaluated mite and booklouse fauna from vacuumed dust samples in Beijing China (a temperate zone). Our survey was carried out in Beijing in the homes of mite allergic patients who visited our Allergy Department. In total, 38 homes were selected for the collection of dust samples by vacuuming, from December 2008 to January 2010. The flotation method was used to isolate mites from house dust. Permanent slides were prepared for mite specimens and mites were identified and counted under a microscope. In total, 1,798 separate mite and insect specimens were found in 345 dust samples taken from 38 homes. A total of 95 individual Dermatophagoides (D) siboney were detected in 35 dust samples from 19 homes (representing 5.3% of all mite and insect species found in house dust); in addition, this mite was found to co-exist with D. farinae (Hughes, 1961) in 33 dust samples. Our results demonstrated the presence D. siboney that co-existed with D. farinae in house dust in Beijing China (a temperate zone).
doi:10.4168/aair.2014.6.3.257
PMCID: PMC4021245  PMID: 24843802
Dermatophagoides siboney; Dermatophagoides farinae; domestic mites
15.  Inhibition of lung tumor growth in nude mice by siRNACD31 targeting PECAM-1 
Oncology Letters  2014;8(1):33-40.
Small interfering RNA (siRNA) provides a promising therapeutic approach in the silencing of disease-causing genes. In the present study, the use of 2′-O-methyl-modified siRNA-cluster of differentiation 31 (siRNACD31), with cationic liposome RNA interference (RNAi)-mate as a carrier, effectively silenced the platelet endothelial cell molecule 1 (PECAM-1) gene of murine hemangioendothelioma cells in vitro. In vivo, 2′-O-methyl-modified siRNACD31 carried by RNAi-mate was successfully delivered, targeting the PECAM-1 gene in the vasculature of nude mouse lung carcinoma xenografts. The growth of the lung carcinoma xenografts was inhibited by the 2′-O-methyl-modified siRNACD31 and RNAi-mate complexes, and the expression of the PECAM-1 protein was downregulated, with a simultaneous decrease in vascular endothelial growth factor (VEGF) protein in the lung carcinoma xenografts. 2′-O-methyl-modified siRNACD31-RNAi-mate complexes may provide a potential therapeutic strategy in lung carcinoma treatment. The effect of PECAM-1 on VEGF expression may possibly be attributed to the function of PECAM-1 signal transduction.
doi:10.3892/ol.2014.2091
PMCID: PMC4063636  PMID: 24959215
small interfering RNA; platelet endothelial adhesion molecule; vascular endothelial growth factor; carcinoma; tumor microenvironment
16.  Guidelines Disconcordance in Acute Bipolar Depression: Data from the National Bipolar Mania Pathway Survey (BIPAS) in Mainland China 
PLoS ONE  2014;9(4):e96096.
With the recent attention to the importance of evidence-based medicine in psychiatry, a number of treatment guidelines have been published. This survey investigated prescribing pattern and predictors for guideline disconcordance in the acute treatment of bipolar depression across mainland China. Pharmacological treatments of 1078 patients with bipolar depression were examined. Guidelines disconcordance was determined by comparing the medication(s) patients were prescribed with the recommendation(s) in the guidelines of the Canadian Network for Mood and Anxiety Treatments. Predictors for guidelines discordance were analyzed with logistic regression. Of the 1078 patients, 50.2% patients were treated against treatment guidelines recommendations. The patients who were treated in general hospitals (OR = 1.53, 95% CI 1.18–1.97), with a depressive episode (OR = 1.67, 95% CI 1.27–2.19) and an older age at first onset (OR = 1.62, 95% CI 1.15–2.28) were more likely to receive guideline-disconcordant treatment than their counterparts. In contrast, the patients with current mental comorbidity, an older age at study entry, a longer duration of disease, and more frequent episodes in past year were less likely to receive guideline-disconcordant treatments than their counterparts with an OR of 0.43 (95% CI 0.24–0.77), 0.52 (95CI% 0.36–0.75), 0.48 (95% CI 0.36–0.65), and 0.50 (95% CI 0.38–0.64), respectively. Our finding suggested the disconcordance with treatment guidelines in patients with an acute bipolar depression is common under naturalistic conditions in mainland China, and the predicting factors correlated with guidelines disconcordance include both psychiatrist-specific (clinicians from general hospitals) and patient-specific features (a depressive episode at first onset, no current co-morbidity with mental disorders, a younger age at study entry, an older age at first onset, shorter duration of disease, and non-frequent episodes in past year).
doi:10.1371/journal.pone.0096096
PMCID: PMC3999095  PMID: 24763748
17.  Primary diffuse large B-cell lymphoma of the chest wall: a case report 
Reports of primary diffuse large B-cell lymphomas of the chest wall are extremely rare in the literature. We report the case of a 62-year-old Chinese woman presenting with left-sided chest pain. A computed tomography scan showed a solid, round mass in the left anterior chest wall, involving the second and third costal cartilages. Complete resection and reconstruction of the chest wall was performed. The histological and immunohistochemical features of the mass were used to diagnose a primary diffuse large B-cell lymphoma.
doi:10.1186/1477-7819-12-104
PMCID: PMC3999458  PMID: 24755347
Chest wall; Diffuse large B-cell lymphoma
18.  WUSCHEL-related Homeobox genes in Populus tomentosa: diversified expression patterns and a functional similarity in adventitious root formation 
BMC Genomics  2014;15:296.
Background
WUSCHEL (WUS)-related homeobox (WOX) protein family members play important roles in the maintenance and proliferation of the stem cell niche in the shoot apical meristem (SAM), root apical meristem (RAM), and cambium (CAM). Although the roles of some WOXs in meristematic cell regulation have been well studied in annual plants such as Arabidopsis and rice, the expression and function of WOX members in woody plant poplars has not been systematically investigated. Here, we present the identification and comprehensive analysis of the expression and function of WOXs in Populus tomentosa.
Results
A genome-wide survey identified 18 WOX encoding sequences in the sequenced genome of Populus trichocarpa (PtrWOXs). Phylogenetic and gene structure analysis revealed that these 18 PtrWOXs fall into modern/WUS, intermediate, and ancient clades, but that the WOX genes in P. trichocarpa may have expanded differently from the WOX genes in Arabidopsis. In the P. trichocarpa genome, no WOX members could be closely classified as AtWOX3, AtWOX6, AtWOX7, AtWOX10, and AtWOX14, but there were two copies of WOX genes that could be classified as PtrWUS, PtrWOX2, PtrWOX4, PtrWOX5, PtrWOX8/9, and PtrWOX11/12, and three copies of WOX genes that could be classified as PtrWOX1 and PtrWOX13. The use of primers specific for each PtrWOX gene allowed the identification and cloning of 18 WOX genes from P. tomentosa (PtoWOXs), a poplar species physiologically close to P. trichocarpa. It was found that PtoWOXs and PtrWOXs shared very high amino acid sequence identity, and that PtoWOXs could be classified identically to PtrWOXs. We revealed that the expression patterns of some PtoWOXs were different to their Arabidopsis counterparts. When PtoWOX5a and PtoWOX11/12a, as well as PtoWUSa and PtoWOX4a were ectopically expressed in transgenic hybrid poplars, the regeneration of adventitious root (AR) was promoted, indicating a functional similarity of these four WOXs in AR regeneration.
Conclusions
This is the first attempt towards a systematical analysis of the function of WOXs in P. tomentosa. A diversified expression, yet functional similarity of PtoWOXs in AR regeneration is revealed. Our findings provide useful information for further elucidation of the functions and mechanisms of WOXs in the development of poplars.
doi:10.1186/1471-2164-15-296
PMCID: PMC4023605  PMID: 24750781
Adventitious root; Expression; Homeobox; Populus; WOX; Wuschel-related
19.  Geographic Mapping of Crohn's Disease and Its Relation to Affluence in Jiangsu Province, an Eastern Coastal Province of China 
Background. Geographical variation in the incidence of Crohn's disease (CD) has been reported in Europe and North American. However, there are no comparable data in mainland China. Methods. We retrospectively identified incident cases of CD patients registered in Jinling hospital during 2003 to 2012. The standardized incidence ratio (SIR) was calculated for each area of Jiangsu province and a thematic map of CD was made according to the local SIR. The association between incidence and local economic status was revealed by correlation between SIR of CD and different local economic indicators. Results. A total of 653 CD patients (male-to-female ratio, 1.8 : 1) from Jiangsu province were included. A steady increase was observed in the number of CD patients over the period of observation. Disease map of SIR showed a pronounced geographic concentration of CD in the south part of Jiangsu province. Spearman correlation analysis showed a positive correlation between local SIR of CD and local economic indicators. Conclusions. There is a marked geographic variability in CD incidence across Jiangsu province. CD incidence in affluent areas seems to be higher than that in less affluent areas. Further multicenter population-based studies are needed to assess the real disease map of CD.
doi:10.1155/2014/590467
PMCID: PMC4009246  PMID: 24839438
20.  MicroRNA124 regulate cell growth of prostate cancer cells by targeting iASPP 
Protein phosphatase 1, regulatory subunit 13 like PPP1R13L, also coined iASPP, was found high expression in prostate cancer tissues and cell lines. In previous research, in vitro and in vivo RNAi mediated by artificial lentiviral shRNAs which proved that suppression of iASPP decrease the proliferation of cancer cells. Endogenous interference RNAs, microRNAs play key roles in cell proliferation by post-transcriptional regulation of gene expression. Natural base pair matched microRNA for iASPP is mir124, which was found high expression in growth factorloss prostate cancer cell lines. In this study we examined effect of mir124 upon iASPP and proliferation of prostate cells in vitro with lentiviral infection and use artificial shRNA as control. In vitro reporter assay confirmed that mir124 binding the 3’UTR of iASPP and suppress mRNA expression. Lentivirus mediated mir124 expression decreased the proliferation and viability of PC3 while endogenous iASPP were knocked down.
PMCID: PMC4069919  PMID: 24966937
Mir124; iASPP; prostate cancer; cell growth
21.  Acupuncture Promotes Angiogenesis after Myocardial Ischemia through H3K9 Acetylation Regulation at VEGF Gene 
PLoS ONE  2014;9(4):e94604.
Background
Acupuncture exerts cardioprotective effects on several types of cardiac injuries, especially myocardial ischemia (MI), but the mechanisms have not yet been well elucidated. Angiogenesis mediated by VEGF gene expression and its modification through histone acetylation has been considered a target in treating myocardial ischemia. This study aims to exam whether modulation of angiogenesis through H3K9 acetylation regulation at VEGF gene is one possible cardioprotective mechanism of acupuncture.
Results
We generated rat MI models by ligating the left anterior descending coronary artery and applied electroacupuncture (EA) treatment at the Neiguan (PC6) acupoint. Our results showed that acupuncture reversed the S-T segment change, reduced Q-wave area, decreased CK, CK-MB, LDH levels, mitigated myocardial remodeling, and promoted microvessel formation in the MI heart. RNA-seq analysis showed that VEGF-induced angiogenesis signaling was involved in the modulation of EA. Western blot results verified that the protein expressions of VEGF, Ras, phospho-p44/42 MAPK, phospho-p38 MAPK, phospho-SAPK/JNK and Akt, were all elevated significantly by EA treatment in the MI heart. Furthermore, increased H3K9 acetylation was also observed according with the VEGF. ChIP assay confirmed that EA treatment could notably stimulate the recruitment of H3K9ace at the VEGF promoter.
Conclusions
Our study demonstrates for the first time that acupuncture can effectively up-regulate VEGF expression through H3K9 acetylation modification directly at the VEGF promoter and hence activate VEGF-induced angiogenesis in rat MI models. We employed high throughput sequencing in this study and, for the first time, generated genome-wide gene expression profiles both in the rat MI model and in acupuncture treatment.
doi:10.1371/journal.pone.0094604
PMCID: PMC3983235  PMID: 24722278
22.  GGPPS1 predicts the biological character of hepatocellular carcinoma in patients with cirrhosis 
BMC Cancer  2014;14:248.
Background
Hepatocellular carcinoma (HCC) has been associated with diabetes and obesity, but a possible connection with the metabolic syndrome (MetS) and its potential interaction with hepatitis and cirrhosis are open to discussion. Our previous investigations have shown that GGPPS1 plays a critical role during hyperinsulinism. In this report, the expression and distribution of GGPPS1 in liver cancer, and its clinical significance were investigated.
Methods
70 patients with hepatocellular carcinoma (HCC) were included in this study. Three different types of tissues from each HCC patient were assembled immediately after surgical resection: tumor-free tissue >5 cm far from tumor edge (TF), adjacent nonmalignant tissue within 2 cm (AT), and tissue from the tumor (TT). Normal liver tissues from 10 liver transplant donors served as healthy control (HC) while 10 patients with liver cirrhosis as cirrhosis control (CC). The expression and distribution of GGPPS1 were detected by immunohistochemistry, western blots, or real-time PCR. The relationship between the expression of GGPPS1 and clinic pathologic index were analyzed.
Results
We found that GGPPS1 was intensified mainly in the cytoplasm of liver tumor cells. Both the expression of GGPPS1 mRNA and protein were upregulated in TT comparing to AT or TF. Meanwhile, HCC patients with cirrhosis had relative higher expression of GGPPS1. In addition, many pathologic characters show close correlation with GGPPS1, such as tumor stage, vessel invasion, and early recurrence.
Conclusion
GGPPS1 may play a critical role during the development of HCC from cirrhosis and is of clinical significance for predicting biological character of HCC.
doi:10.1186/1471-2407-14-248
PMCID: PMC4028285  PMID: 24716791
23.  Structure-constrained sparse canonical correlation analysis with an application to microbiome data analysis 
Biostatistics (Oxford, England)  2012;14(2):244-258.
Motivated by studying the association between nutrient intake and human gut microbiome composition, we developed a method for structure-constrained sparse canonical correlation analysis (ssCCA) in a high-dimensional setting. ssCCA takes into account the phylogenetic relationships among bacteria, which provides important prior knowledge on evolutionary relationships among bacterial taxa. Our ssCCA formulation utilizes a phylogenetic structure-constrained penalty function to impose certain smoothness on the linear coefficients according to the phylogenetic relationships among the taxa. An efficient coordinate descent algorithm is developed for optimization. A human gut microbiome data set is used to illustrate this method. Both simulations and real data applications show that ssCCA performs better than the standard sparse CCA in identifying meaningful variables when there are structures in the data.
doi:10.1093/biostatistics/kxs038
PMCID: PMC3590923  PMID: 23074263
Dimension reduction; Graph; Phylogenetic tree; Regularization; Variable selection
24.  Modulation of the Cellular Distribution of Human Cytomegalovirus Helicase by Cellular Factor Snapin 
Journal of Virology  2013;87(19):10628-10640.
Controlled regulation of genomic DNA synthesis is a universally conserved process for all herpesviruses, including human cytomegalovirus (HCMV), and plays a key role in viral pathogenesis, such as persistent infections. HCMV UL105 is believed to encode the helicase of the DNA replication machinery that needs to localize in the nuclei, the site of viral DNA synthesis. No host factors that interact with UL105 have been identified. In this study, we show that UL105 specifically interacts with Snapin, a human protein that is predominantly localized in the cytoplasm and associated with cellular vesicles. UL105 was found to interact with Snapin in both the yeast two-hybrid screen and coimmunoprecipitation experiments in HCMV-infected cells. The nuclear and cytoplasmic levels of UL105 were decreased and increased in cells overexpressing Snapin, respectively, while the levels of UL105 in the nuclei and cytoplasm were increased and decreased in cells in which the expression of Snapin was downregulated with anti-Snapin small interfering RNA (siRNA) molecules, respectively. Furthermore, viral DNA synthesis and progeny production were decreased in cells overexpressing Snapin and increased in the anti-Snapin siRNA-treated cells, respectively. Our results provide the first direct evidence to suggest that Snapin interacts with UL105 and alters its cellular distribution, leading to modulation of viral DNA synthesis and progeny production. Our study further suggests that modulation of the cellular distribution of viral helicase by Snapin may represent a possible mechanism for regulating HCMV genomic DNA synthesis, a key step during herpesvirus lytic and persistent infections.
doi:10.1128/JVI.01657-13
PMCID: PMC3807405  PMID: 23885069
25.  Oxidative Stress at High Temperatures in Lactococcus lactis Due to an Insufficient Supply of Riboflavin 
Applied and Environmental Microbiology  2013;79(19):6140-6147.
Lactococcus lactis MG1363 was found to be unable to grow at temperatures above 37°C in a defined medium without riboflavin, and the cause was identified to be dissolved oxygen introduced during preparation of the medium. At 30°C, growth was unaffected by dissolved oxygen and oxygen was consumed quickly. Raising the temperature to 37°C resulted in severe growth inhibition and only slow removal of dissolved oxygen. Under these conditions, an abnormally low intracellular ratio of [ATP] to [ADP] (1.4) was found (normally around 5), which indicates that the cells are energy limited. By adding riboflavin to the medium, it was possible to improve growth and oxygen consumption at 37°C, and this also normalized the [ATP]-to-[ADP] ratio. A codon-optimized redox-sensitive green fluorescent protein (GFP) was introduced into L. lactis and revealed a more oxidized cytoplasm at 37°C than at 30°C. These results indicate that L. lactis suffers from heat-induced oxidative stress at increased temperatures. A decrease in intracellular flavin adenine dinucleotide (FAD), which is derived from riboflavin, was observed with increasing growth temperature, but the presence of riboflavin made the decrease smaller. The drop was accompanied by a decrease in NADH oxidase and pyruvate dehydrogenase activities, both of which depend on FAD as a cofactor. By overexpressing the riboflavin transporter, it was possible to improve FAD biosynthesis, which resulted in increased NADH oxidase and pyruvate dehydrogenase activities and improved fitness at high temperatures in the presence of oxygen.
doi:10.1128/AEM.01953-13
PMCID: PMC3811343  PMID: 23913422

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