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1.  Predictive performance of ‘Diprifusor’ TCI system in patients during upper abdominal surgery under propofol/fentanyl anesthesia*  
Objective: To evaluate the predictive performance of ‘Diprifusor’ TCI (target-controlled infusion) system for its better application in clinical anesthesia. Methods: The predictive performance of a ‘Diprifusor’ TCI system was investigated in 27 Chinese patients (16 males and 11 females) during upper abdominal surgery under total intravenous anesthesia (TIVA) with propofol/fentanyl. Measured arterial propofol concentrations were compared with the values predicted by the TCI infusion system. Performance was determined by the median performance error (MDPE), the median absolute performance error (MDAPE), the divergence (the percentage change of the absolute PE with time), and the wobble (the median absolute deviation of each PE from the MDPE). Results: The median (range) values of 14.9% (−21.6%~42.9%) for MDPE, 23.3% (6.9%~62.5%) for MDAPE, −1.9% h−1 (−32.7%~23.0% h−1) for divergence, and 18.9% (4.2%~59.6%) for wobble were obtained from 227 samples from all patients. For the studied population, the PE did not increase with time but with increasing target propofol concentration, particularly following induction. Conclusions: The control of depth of anaesthesia was good in all patients undergoing upper abdominal surgical operation and the predictive performance of the ‘Diprifusor’ target controlled infusion system was considered acceptable for clinical purposes. But the relatively bigger wobble showed that the pharmacokinetic model is not so suitable and requires improvement.
PMCID: PMC1390758  PMID: 15593391
Target-controlled infusion (TCI); ‘Diprifusor’ TCI system; Predictive performance assessment; Wobble; Infusion
2.  Dual-energy CT imaging of thoracic malignancies 
Cancer Imaging  2013;81-91.
Computed tomography (CT) plays a pivotal role in the detection, characterization, and staging of lung cancer and other thoracic malignancies. Since the introduction of clinically viable dual-energy CT techniques, substantial evidence has accumulated on the use of this modality for imaging chest malignancies. This article describes the principles of dual-energy CT along with suitable image acquisition, reconstruction, and postprocessing strategies for oncologic applications in the chest. The potential of dual-energy CT techniques for the detection, characterization, staging, and surveillance of chest malignancy, as well as the limitations of this modality are discussed.
PMCID: PMC3596838  PMID: 23470989
Lung cancer; dual energy; dual source; X-ray computed tomography
3.  Differential regulation of the hmsCDE operon in Yersinia pestis and Yersinia pseudotuberculosis by the Rcs phosphorelay system 
Scientific Reports  2015;5:8412.
Yersinia pestis, the agent of plague, forms a biofilm in its flea vector to enhance transmission. Y. pestis biofilm development is positively regulated by hmsT and hmsD, encoding diguanylate cyclases (DGCs) involved in synthesis of the bacterial second messenger c-di-GMP. rcsA, encoding an auxiliary protein in Rcs phosphorelay, is nonfunctional in Y. pestis, while in Yersinia pseudotuberculosis, rcsA is functional and represses biofilms. Previously we showed that Rcs phosphorelay negatively regulates transcription of hmsT in Y. pestis and its ancestor Yersinia pseudotuberculosis. In this study, we show that Rcs positively regulates hmsCDE operon (encoding HmsD) in Y. pestis; while in the presence of functional rcsA, Rcs represses hmsCDE operon in Y. pseudotuberculosis. Loss of rcsA's function in Y. pestis not only causes derepression of hmsT but also causes activation of hmsD, which may account for the increased biofilm formation in Y. pestis. In addition, differential regulation of the two DGCs, HmsT and HmsD by Rcs may help Y. pestis to adapt to different environment.
PMCID: PMC4325325  PMID: 25672461
4.  Utility of the diffusion-weighted imaging for activity evaluation in Crohn’s disease patients underwent magnetic resonance enterography 
BMC Gastroenterology  2015;15:12.
Cross-sectional imaging techniques as magnetic resonance enterography (MRE) may offer additional information on transmural inflammation, stricturing and fistulising complications in Crohn’s disease (CD). The purpose of our study was to evaluate the diagnostic accuracy of Magnetic Resonance Imaging (MRI) combined with Diffusion-weighted Imaging (DWI) and MRE for determination of inflammation in small bowel CD.
MR imaging examination was performed with a GE Signa EXCITE 3.0 T MRI scanner. The optimal b value in DWI with a learning cohort of patients was determined. The diagnostic accuracy for active lesions and disease activity were accessed by MRE combined with DWI.
The b value 800 s/mm2 group showed the highest diagnostic sensitivity (74.19%) for diagnostic assessment of active Crohn’s lesions on DWI. MRE combined with DWI showed the highest sensitivity (93.55%), specificity (89.47%) and diagnostic accuracy (92%) compared with MRE or DWI alone. The segmental MR score (MR-score-S) showed a significantly positive correlation with the Capsule Endoscopy Crohn’s Disease Activity Index Score (CECDAI-S) (r = 0.717, p < 0.01). The total MR score (MR-score-T) showed significant association with C-reactive protein (CRP) (r = 0.445, p = 0.019) and erythrocyte sedimentation rate (ESR) (r = 0.688, p < 0.01).
MRE combined with DWI improves the diagnostic accuracy for active lesions and correlates the endoscopic disease activity. MRE with DWI could represent a non-invasive tool in assessing active inflammation in CD.
PMCID: PMC4323053  PMID: 25653007
5.  In vivo monitoring of dihydroartemisinin-piperaquine sensitivity in Plasmodium falciparum along the China-Myanmar border of Yunnan Province, China from 2007 to 2013 
Malaria Journal  2015;14:47.
Artemisinin-based combination therapy (ACT) is the recommended first-line treatment of falciparum malaria in all endemic countries. Artemisinin resistance in Plasmodium falciparum has been confirmed in the Greater Mekong subregion (GMS). Dihydroartemisinin-piperaquine (DAPQ) is the most commonly used ACT in China. To understand the DAPQ sensitivity of P. falciparum, DAPQ resistance was monitored in vivo along the China-Myanmar border from 2007 to 2013.
Eligible patients with mono-infections of P. falciparum were recruited to this study after obtaining full informed consent. DAPQ tablets for different categories of kg body weight ranges were given once a day for three days. Patients were followed up for 42 days. Polymerase chain reaction (PCR) was conducted to distinguish between re-infection and recrudescence, to confirm the Plasmodium species. The data were entered and analysed by the Kaplan-Meier method. Treatment outcome was assessed according to the WHO recommended standards.
243 patients were completed valid follow-up. The fever clearance time (FCT) and asexual parasite clearance times (APCT) were, respectively, 36.5 ± 10.9 and 43.5 ± 11.8 hours, and there was an increasing trend of both FCT (F = 268.41, P < 0.0001) and APCT (F = 88.6, P < 0.0001) from 2007 to 2013. Eight (3.3%, 95% confidence interval, 1.4–6.4%) patients present parasitaemia on day three after medication; however they were spontaneous cure on day four. 241 (99.2%; 95% CI, 97.1–99.9%) of the patients were adequate clinical and parasitological response (ACPR) and the proportions of ACPR had not changed significantly from 2007 to 2013 (X2 = 2.81, P = 0.7288).
In terms of efficacy, DAPQ is still an effective treatment for falciparum malaria. DAPQ sensitivity in P. falciparum had not significantly changed along the China-Myanmar border of Yunnan Province, China. However more attentions should be given to becoming slower fever and parasite clearance.
PMCID: PMC4333884  PMID: 25652213
Plasmodium falciparum; Dihydroartemisinin-piperaquine; In vivo test; Resistance; China-Myanmar border
6.  Hypoxia-induced MTA1 promotes MC3T3 osteoblast growth but suppresses MC3T3 osteoblast differentiation 
Bone fracture is one of the most common physical injuries in which gene expression and the microenvironment are reprogramed to facilitate the recovery process.
By specific siRNA transfection and MTT assay, we evaluated the effects of metastasis-associated gene 1 (MTA1) in osteoblast growth. To show the role of MTA1 in osteoblast under hypoxia conditions, by overexpressing and silencing MTA1 expression, we performed mineral deposition and alkaline phosphatase activity assay to observe the differentiation status of osteoblast cells. Real-time PCR and Western blot assays were adopted to detect the expression of certain target genes.
Here, we reported that hypoxia-induced MTA1 expression through hypoxia-induced factor 1 alpha (HIF-1α) and stimulated the growth of osteoblast MC3T3 cells. Silencing of MTA1 through specific siRNA suppressed MC3T3 cell growth and elicited cell differentiation and induced alkaline phosphatase activation and the upregulation of bone morphogenetic protein-2 and osteocalcin.
We found that MTA1 was regulated by HIF-1α in hypoxia circumstance to suppress osteoblast differentiation. These findings provide new insights for bone fracture healing and new strategies to develop potential targets to promote fracture healing.
Electronic supplementary material
The online version of this article (doi:10.1186/s40001-015-0084-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4324858  PMID: 25644400
Bone fracture; Fracture healing; Hypoxia-induced MTA1; Osteoblast cell growth; Osteoblast differentiation
7.  Max-AUC Feature Selection in Computer-Aided Detection of Polyps in CT Colonography 
We propose a feature selection method based on a sequential forward floating selection (SFFS) procedure to improve the performance of a classifier in computerized detection of polyps in CT colonography (CTC). The feature selection method is coupled with a nonlinear support vector machine (SVM) classifier. Unlike the conventional linear method based on Wilks' lambda, the proposed method selected the most relevant features that would maximize the area under the receiver operating characteristic curve (AUC), which directly maximizes classification performance, evaluated based on AUC value, in the computer-aided detection (CADe) scheme. We presented two variants of the proposed method with different stopping criteria used in the SFFS procedure. The first variant searched all feature combinations allowed in the SFFS procedure and selected the subsets that maximize the AUC values. The second variant performed a statistical test at each step during the SFFS procedure, and it was terminated if the increase in the AUC value was not statistically significant. The advantage of the second variant is its lower computational cost. To test the performance of the proposed method, we compared it against the popular stepwise feature selection method based on Wilks' lambda for a colonic-polyp database (25 polyps and 2624 nonpolyps). We extracted 75 morphologic, gray-level-based, and texture features from the segmented lesion candidate regions. The two variants of the proposed feature selection method chose 29 and 7 features, respectively. Two SVM classifiers trained with these selected features yielded a 96% by-polyp sensitivity at false-positive (FP) rates of 4.1 and 6.5 per patient, respectively. Experiments showed a significant improvement in the performance of the classifier with the proposed feature selection method over that with the popular stepwise feature selection based on Wilks' lambda that yielded 18.0 FPs per patient at the same sensitivity level.
PMCID: PMC4283828  PMID: 24608058
Colonic polyps; computer-aided detection (CADe); feature selection; support vector machines (SVMs)
8.  Polycomb repressive complex 2 regulates hematopoietic stem cell maintenance and differentiation in a developmental stage-specific manner 
Cell stem cell  2013;14(1):68-80.
Recent studies point to a pivotal role of polycomb repressive complex 2 (PRC2) in stem cell function and cancer. Loss of function approaches targeting individual PRC2 subunits have however generated findings that are difficult to reconcile. Here, we prevent assembly of both Ezh1- and Ezh2-containing PRC2 complexes by conditional deletion of Eed, a core subunit, and assess hematopoiesis. We find that deletion of Eed exhausts adult bone marrow HSCs, although fetal liver HSCs are produced in normal numbers. Eed null neonatal HSCs express HSC signature genes, but are defective in maintenance and differentiation. Comparative gene expression profiling revealed that neonatal and adult HSCs lacking Eed upregulated gene sets of conflicting pathways. Deletion of Cdkn2a, a PRC2 target gene, in Eed null mice enhances HSPC survival but fails to restore HSC functions. Taken together, our findings define developmental stage-specific requirements for canonical PRC2 complexes in normal HSC function.
PMCID: PMC3947409  PMID: 24239285
9.  Chitosan oligosaccharides block LPS-induced O-GlcNAcylation of NF-κB and endothelial inflammatory response 
Carbohydrate polymers  2013;99:10.1016/j.carbpol.2013.08.082.
It is known that chitosan oligosaccharides (COS) suppress LPS-induced vascular endothelial inflammatory response by mechanism involving NF-κB blockade. It remains unknown how COS inhibit NF-κB. We provided evidence both in cultured endothelial cells and mouse model supporting a new mechanism. Regardless of the endothelial cell types, the LPS-induced NF-κB-dependent inflammatory gene expression was suppressed by COS, which was associated with reduced NF-κB nucleus translocation. LPS enhanced O-GlcNAc modification of NF-κB/p65 and activated NF-κB pathway, which could be prevented either by siRNA knockdown of O-GlcNAc transferase (OGT) or pretreatment with COS. Inhibition of either mitogen-activated protein kinase or superoxide generation abolishes LPS-induced NF-κB O-GlcNAcylation. Consistently, aortic tissues from LPS-treated mice presented enhanced NF-κB/p65 O-GlcNAcylation in association with upregulated gene expression of inflammatory cytokines in vascular tissues; however, pre-administration of COS prevented these responses. In conclusion, COS decreased OGT-dependent O-GlcNAcylation of NF-κB and thereby attenuated LPS-induced vascular endothelial inflammatory response.
PMCID: PMC3843148  PMID: 24274545
Chitosan oligosaccharides; LPS (Lipopolysaccharides); Endothelial cells; O-GlcNAcylation; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells); Inflammatory response
10.  Single segment of posterior lumbar interbody fusion for adult isthmic spondylolisthesis: reduction or fusion in situ 
European Spine Journal  2013;23(1):172-179.
We prospectively compared surgical reduction or fusion in situ with posterior lumbar interbody fusion (PLIF) for adult isthmic spondylolisthesis in terms of surgical invasiveness, clinical and radiographical outcomes, and complications.
From January 2006 to June 2008, 88 adult patients with isthmic spondylolisthesis who underwent surgical treatment in our unit were randomized to reduced group (group 1, n = 45) and in situ group (group 2, n = 43), and followed up for average 32.5 months (range 24–54 months). The clinical and radiographical outcomes were compared between the two groups.
The average operative time and blood loss during surgery showed insignificant difference (p > 0.05) between two groups. The radiological outcomes were significantly better in group 1, but there was no significant difference between two groups of clinical outcomes, depicting as VAS, ODI, JOA and patients’ satisfaction surveys. Incident rate of surgical complications was similar in two groups, but in group 1 the complication seemed more severe because of two patients with neurological symptoms.
For the adult isthmic spondylolisthesis without degenerative disease in adjacent level, single segment of PLIF with pedicle screw fixation is an effective and safe surgical procedure regardless of whether additional reduction had been conducted or not. Better radiological outcome does not mean better clinical outcome.
PMCID: PMC3897824  PMID: 23764766
Isthmic spondylolisthesis; Surgical reduction; Single segment; Sagittal balance; PLIF
11.  Clinical trial with traditional Chinese medicine intervention ''tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment'' for chronic hepatitis B-associated liver failure 
World Journal of Gastroenterology : WJG  2014;20(48):18458-18465.
AIM: To study the clinical efficacy of traditional Chinese medicine (TCM) intervention “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) for treating liver failure due to chronic hepatitis B.
METHODS: We designed the study as a randomized controlled clinical trial. Registration number of Chinese Clinical Trial Registry is ChiCTR-TRC-12002961. A total of 144 patients with liver failure due to infection with chronic hepatitis B virus were enrolled in this randomized controlled clinical study. Participants were randomly assigned to the following three groups: (1) a modern medicine control group (MMC group, 36 patients); (2) a “tonifying qi and detoxification” (“TQD”) group (72 patients); and (3) a “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) group (36 patients). Patients in the MMC group received general internal medicine treatment; patients in the “TQD” group were given a TCM formula “tonifying qi and detoxification” and general internal medicine treatment; patients in the “TTK” group were given a TCM formula of “TTK” and general internal medicine treatment. All participants were treated for 8 wk and then followed at 48 wk following their final treatment. The primary efficacy end point was the patient fatality rate in each group. Measurements of various virological and biochemical indicators served as secondary endpoints. The one-way analysis of variance and the t-test were used to compare patient outcomes in the different treatment groups.
RESULTS: At the 48-wk post-treatment time point, the patient fatality rates in the MMC, “TQD”, and “TTK” groups were 51.61%, 35.38%, and 16.67%, respectively, and the differences between groups were statistically significant (P < 0.05). However, there were no significant differences in the levels of hepatitis B virus DNA or prothrombin activity among the three groups (P > 0.05). Patients in the “TTK” group had significantly higher levels of serum total bilirubin compared to MMC subjects (339.40 μmol/L ± 270.09 μmol/L vs 176.13 μmol/L ± 185.70 μmol/L, P = 0.014). Serum albumin levels were significantly increased in both the “TQD” group and “TTK” group as compared with the MMC group (31.30 g/L ± 4.77 g/L, 30.72 g/L ± 2.89 g/L vs 28.57 g/L ± 4.56 g/L, P < 0.05). There were no significant differences in levels of alanine transaminase among the three groups (P > 0.05). Safety data showed that there was one case of stomachache in the “TQD” group and one case of gastrointestinal side effect in the “TTK” group.
CONCLUSION: Treatment with “TTK” improved the survival rates of patients with liver failure due to chronic hepatitis B. Additionally, liver tissue was regenerated and liver function was restored.
PMCID: PMC4277987  PMID: 25561817
Clinical study; “Tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”); Liver regeneration; Treatment with integrated traditional and Western medicine; Chronic hepatitis B-associated liver failure
12.  Upregulation of Unc-51-Like Kinase 1 by Nitric Oxide Stabilizes SIRT1, Independent of Autophagy 
PLoS ONE  2014;9(12):e116165.
SIRT1 is central to the lifespan and vascular health, but undergoes degradation that contributes to several medical conditions, including diabetes. How SIRT1 turnover is regulated remains unclear. However, emerging evidence suggests that endothelial nitric oxide synthase (eNOS) positively regulates SIRT1 protein expression. We recently identified NO as an endogenous inhibitor of 26S proteasome functionality with a cellular reporter system. Here we extended this finding to a novel pathway that regulates SIRT1 protein breakdown. In cycloheximide (CHX)-treated endothelial cells, NONOate, an NO donor, and A23187, an eNOS activator, significantly stabilized SIRT1 protein. Similarly, NO enhanced SIRT1 protein, but not mRNA expression, in CHX-free cells. NO also stabilized an autophagy-related protein unc-51 like kinase (ULK1), but did not restore SIRT1 protein levels in ULK1-siRNA-treated cells or in mouse embryonic fibroblasts (MEF) from Ulk1−/− mice. This suggests that ULK1 mediated the NO regulation of SIRT1. Furthermore, adenoviral overexpression of ULK1 increased SIRT1 protein expression, while ULK1 siRNA treatment decreased it. Rapamycin-induced autophagy did not mimic these effects, suggesting that the effects of ULK1 were autophagy-independent. Treatment with MG132, a proteasome inhibitor, or siRNA of β-TrCP1, an E3 ligase, prevented SIRT1 reduction induced by ULK1-siRNA. Mechanistically, ULK1 negatively regulated 26S proteasome functionality, which was at least partly mediated by O-linked-GlcNAc transferase (OGT), probably by increased O-GlcNAc modification of proteasomal subunit Rpt2. The NO-ULK1-SIRT1 axis was likely operative in the whole animal: both ULK1 and SIRT1 protein levels were significantly reduced in tissue homogenates in eNOS-knockout mice (lung) and in db/db mice where eNOS is downregulated (lung and heart). Taken together, the results show that NO stabilizes SIRT1 by regulating 26S proteasome functionality through ULK1 and OGT, but not autophagy, in endothelial cells.
PMCID: PMC4277463  PMID: 25541949
13.  Bacteria can mobilize nematode-trapping fungi to kill nematodes 
Nature Communications  2014;5:5776.
In their natural habitat, bacteria are consumed by bacterivorous nematodes; however, they are not simply passive preys. Here we report a defensive mechanism used by certain bacteria to mobilize nematode-trapping fungi to kill nematodes. These bacteria release urea, which triggers a lifestyle switch in the fungus Arthrobotrys oligospora from saprophytic to nematode–predatory form; this predacious form is characterized by formation of specialized cellular structures or ‘traps’. The bacteria significantly promote the elimination of nematodes by A. oligospora. Disruption of genes involved in urea transport and metabolism in A. oligospora abolishes the urea-induced trap formation. Furthermore, the urea metabolite ammonia functions as a signal molecule in the fungus to initiate the lifestyle switch to form trap structures. Our findings highlight the importance of multiple predator–prey interactions in prey defense mechanisms.
Certain soil fungi form specialized cellular structures or 'traps' to feed on nematodes, which in turn eat bacteria. Here, the authors show that urea released from bacteria induces trap formation in the fungi and this promotes nematode elimination.
PMCID: PMC4275587  PMID: 25514608
14.  KRAS mutations in tumor tissue and plasma by different assays predict survival of patients with metastatic colorectal cancer 
The optimal laboratory assay for detecting KRAS mutations in different biospecimens from patients with metastatic colorectal cancer (mCRC), and the clinical relevance of these gene alterations is still in question. We analyzed the prognostic–predictive relevance of KRAS status, determined in tumor and plasma DNA by two different assays, in a large mono-institutional series of mCRC patients.
DNA sequencing and peptide-nucleic-acid-mediated-polymerase chain reaction clamping (PNA-PCR) were used to determine KRAS status in 416 tumor and 242 matched plasma DNA samples from mCRC patients who received chemotherapy only. Relationships with outcomes were analyzed with respect to the different assays and tissue types.
PNA-PCR was significantly more sensitive in detecting KRAS mutations than sequencing (41% vs. 30%, p < 0.001). KRAS mutations were more frequent in tumor tissue than in plasma (sequencing, 38% vs. 17%, p < 0.001; PNA-PCR, 47% vs. 31%, p < 0.001). Median OS was consistently shorter in KRAS-mutated patients than KRAS wild-type patients, independent from the assay and tissue tested; the largest difference was in plasma samples analyzed by PNA-PCR (KRAS mutated vs. wild-type: 15.7 vs. 19.1 months, p = 0.009). No association was observed between KRAS status and other outcomes. When tumor and plasma results were considered together, median OS in patients categorized as tissue/plasma KRAS negative/negative, tissue/plasma KRAS discordant, and tissue/plasma KRAS positive/positive were 21.0, 16.9 and 15.4 months, respectively (p = 0.008).
KRAS mutation status is of prognostic relevance in patients with mCRC. KRAS mutations in both tumor tissue and plasma are a strong prognostic marker for poor outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-014-0104-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4272803  PMID: 25491325
Kras; Colorectal cancer; Prognosis
15.  Genetically Targeted Binary Labeling of Retinal Neurons 
The Journal of Neuroscience  2014;34(23):7845-7861.
A major stumbling block to understanding neural circuits is the extreme anatomical and functional diversity of interneurons. Subsets of interneurons can be targeted for manipulation using Cre mouse lines, but Cre expression is rarely confined to a single interneuron type. It is essential to have a strategy that further restricts labeling in Cre driver lines. We now describe an approach that combines Cre driver mice, recombinant adeno-associated virus, and rabies virus to produce sparse but binary labeling of select interneurons—frequently only a single cell in a large region. We used this approach to characterize the retinal amacrine and ganglion cell types in five GABAergic Cre mouse (Mus musculus) lines, and identified two new amacrine cell types: an asymmetric medium-field type and a wide-field type. We also labeled several wide-field amacrine cell types that have been previously identified based on morphology but whose connectivity and function had not been systematically studied due to lack of genetic markers. All Cre-expressing amacrine cells labeled with an antibody to GABA. Cre-expressing RGCs lacked GABA labeling and included classically defined as well as recently identified types. In addition to the retina, our technique leads to sparse labeling of neurons in the cortex, lateral geniculate nucleus, and superior colliculus, and can be used to express optogenetic tools such as channelrhodopsin and protein sensors such as GCaMP. The Cre drivers identified in this study provide genetic access to otherwise hard to access cell types for systematic analysis including anatomical characterization, physiological recording, optogenetic and/or chemical manipulation, and circuit mapping.
PMCID: PMC4044247  PMID: 24899708
amacrine cell; Cre recombinase; ganglion cell; rabies virus; retina
16.  Striatal-enriched protein tyrosine phosphatase - STEPs toward understanding chronic stress-induced activation of CRF neurons in the rat BNST 
Biological psychiatry  2013;74(11):10.1016/j.biopsych.2013.07.032.
STEP is a brain-specific protein tyrosine phosphatase that opposes the development of synaptic strengthening and the consolidation of fear memories. In contrast, stress facilitates fear memory formation, potentially by activating corticotrophin releasing factor (CRF) neurons in the anterolateral cell group of the bed nucleus of the stria terminalis (BNSTALG).
Here, using dual-immunofluorescence, single-cell RT-PCR, quantitative RT-PCR, Western blot, and whole cell patch-clamp electrophysiology, we examined the expression and role of STEP in regulating synaptic plasticity in rat BNSTALG neurons, and its modulation by stress.
STEP was selectively expressed in CRF neurons in the oval nucleus of the BNSTALG. Following repeated restraint stress (RRS), animals displayed a significant increase in anxiety-like behavior, which was associated with a down-regulation of STEP mRNA and protein expression in the BNSTALG as well as selectively enhanced magnitude of long-term potentiation (LTP) induced in Type III, putative CRF neurons. To determine if the changes in STEP expression following RRS were mechanistically related to the facilitation of synaptic strengthening, we examined the effects of intracellular application of STEP on the induction of LTP. STEP completely blocked the RRS-induced facilitation of LTP in BNSTALG neurons.
Hence, STEP acts to buffer CRF neurons against excessive activation, while down-regulation of STEP after chronic stress may result in pathological activation of CRF neurons in the BNSTALG and contribute to prolonged states of anxiety. Thus, targeted manipulations of STEP activity might represent a novel treatment strategy for stress-induced anxiety disorders.
PMCID: PMC3818357  PMID: 24012328
striatal-enriched protein tyrosine phosphatase; STEP; corticotrophin releasing factor; CRF; bed nucleus of the stria terminalis; BNST; chronic stress; anxiety
17.  Stability switches and double Hopf bifurcation in a two-neural network system with multiple delays 
Cognitive Neurodynamics  2013;7(6):505-521.
Time delay is an inevitable factor in neural networks due to the finite propagation velocity and switching speed. Neural system may lose its stability even for very small delay. In this paper, a two-neural network system with the different types of delays involved in self- and neighbor- connection has been investigated. The local asymptotic stability of the equilibrium point is studied by analyzing the corresponding characteristic equation. It is found that the multiple delays can lead the system dynamic behavior to exhibit stability switches. The delay-dependent stability regions are illustrated in the delay-parameter plane, followed which the double Hopf bifurcation points can be obtained from the intersection points of the first and second Hopf bifurcation, i.e., the corresponding characteristic equation has two pairs of imaginary eigenvalues. Taking the delays as the bifurcation parameters, the classification and bifurcation sets are obtained in terms of the central manifold reduction and normal form method. The dynamical behavior of system may exhibit the quasi-periodic solutions due to the Neimark- Sacker bifurcation. Finally, numerical simulations are made to verify the theoretical results.
PMCID: PMC3825147  PMID: 24427223
Neural network; Multiple delays; Stability switches; Double Hopf bifurcation; Quasi-periodic behavior
19.  GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia 
Leukemia  2013;28(6):1259-1270.
Transient leukemia (TL) is evident in 5–10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1-mutations (GATA1s). Here we report that TL cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s-mutation as sorted TL-blasts, consistent with their clonal origin. TL-blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34+-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. While GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. ChIP-seq indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1Δe2 knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.
PMCID: PMC4047213  PMID: 24336126
Down syndrome; eosinophilia; GATA1s; MYC; E2F
20.  Posterior tibialis tendon transfer via the circumtibial route: a cadaveric limb analysis 
Studies have yet to determine the optimal height at which the posterior tibial tendon (PTT) can be re-routed and the tendon length discrepancy at different height levels in terms of PTT transfer via the circumtibial route. This cadaveric study was conducted to determine the optimal height of PTT subcutaneous transfer and to compare tendon length discrepancies at different heights.
Materials and methods
Twenty-five fresh normal cadaveric lower legs were used for measurements. PTT was exposed and then isolated. An incision along the calf was made to re-route PTT outside the fascia. The upper edge of the incision was classified as point “a.” The distal tip of the tendon was classified as point “b.” The midpoints of the intermediate cuneiform, the lateral cuneiform, and the cuboid were defined as points “c,” “d,” and “e,” respectively. The lengths of “ab,” “ac,” “ad,” and “ae” were measured and compared at different height levels above the distal tip of the medial malleolus. Angles α, β, and γ between the tendon outside the fascia connecting to different bones and the tendon inside the fascia were also measured as tendons were transferred at different bones and different height levels. Experimental data were collected and analyzed.
At a height of ≥5 cm, all of the PTTs could reach the midpoints of the three bones. The lengths of ac, ad, and ae were significantly less than the length of ab (p < 0.05). At a height of 10 cm, angles α, β, and γ were 177° ± 2.1°, 170° ± 3.1°, and 164° ± 3.7°, respectively. These angles were not significantly different from those at a height of 11 cm (p >0.05).
PTT transfer via the subcutaneous route could achieve an adequate length to be transferred to the intermediate cuneiform, the lateral cuneiform, and the cuboid from a height of 5 cm above the distal tip of the medial malleolus. A height of 10 cm could be optimal for PTT transfer in the three bones via the subcutaneous route.
PMCID: PMC4255935  PMID: 25471044
21.  An fMRI Study of Neuronal Specificity in Acupuncture: The Multiacupoint Siguan and Its Sham Point 
Clarifying the intrinsic mechanisms of acupuncture's clinical effects has recently been gaining popularity. Here, we choose the Siguan acupoint (a combination of bilateral LI4 and Liv3) and its sham point to evaluate multiacupoint specificity. Thirty-one healthy volunteers were randomly divided into real acupoint (21 subjects) and sham acupoint (10 subjects) groups. Our study used a single block experimental design to avoid the influence of posteffects. Functional magnetic resonance imaging data were acquired during acupuncture stimulation. Results showed extensive increase in neuronal activities with Siguan acupuncture and significant differences between stimulation at real and sham points. Brain regions that were activated more by real acupuncture stimulation than by sham point acupuncture included somatosensory cortex (the superior parietal lobule and postcentral gyrus), limbic-paralimbic system (the calcarine gyrus, precuneus, cingulate cortex, and parahippocampal gyrus), visual-related cortex (the fusiform and occipital gyri), basal ganglia, and the cerebellum. In this way, our study suggests Siguan may elicit specific activities in human brain.
PMCID: PMC4265514  PMID: 25525442
22.  Molecular mechanisms of epithelial–mesenchymal transition 
The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial–mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.
PMCID: PMC4240281  PMID: 24556840
23.  Diffuse alveolar hemorrhage after erlotinib combined with concurrent chemoradiotherapy in a patient with esophageal carcinoma 
Diffuse alveolar hemorrhage (DAH) is a life-threatening clinical pathologic syndrome caused by a variety of diseases. We report a case of DAH related to combination therapy of chemoradiotherapy and erlotinib. As to know, DAH following chemoradiotherapy was only reported among hematopoietic stem cell transplant recipients with hematologic malignancies till now. DAH associated with chemoradiotherapy for oesophageal carcinoma has not been reported. This is the first DAH report on erlotinib-combined chemoradiotherapy for esophageal cancer. The authors believe epidermal growth factor receptor tyrosine kinase inhibitor erlotinib increased the lung injury. Molecular targeted drugs are gradually applied to be combined with chemoradiation, whether this combination will cause the increase of serious adverse reactions need further study. This case can provide certain reference for erlotinib in the treatment. Meanwhile, after long term hormone therapy for DAH, the patient was diagnosed with pneumocystis carinii pneumonia. It reminds us to attach importance to the immunosuppressive diseases after long-term hormone treatment.
PMCID: PMC4276233  PMID: 25550975
Diffuse alveolar hemorrhage; chemoradiotherapy; erlotinib; esophageal carcinoma
24.  Delineation of Early and Later Adult Onset Depression by Diffusion Tensor Imaging 
PLoS ONE  2014;9(11):e112307.
Due to a lack of evidence, there is no consistent age of onset to define early onset (EO) versus later onset (LO) major depressive disorder (MDD). Fractional anisotropy (FA), derived from diffusion tensor imaging (DTI), has been widely used to study neuropsychiatric disorders by providing information about the brain circuitry, abnormalities of which might facilitate the delineation of EO versus LO MDD.
In this study, 61 pairs of untreated, non-elderly, first-episode MDD patients and healthy controls (HCs) aged 18–45 years old received DTI scans. The voxel-based analysis method (VBM), classification analysis, using the Statistical Package for the Social Sciences (SPSS), and regression analyses were used to determine abnormal FA clusters and their correlations with age of onset and clinical symptoms.
Classification analysis suggested in the best model that there were two subgroups of MDD patients, delineated by an age of onset of 30 years old, by which MDD patients could be divided into EO (18–29 years old) and LO (30–45 years old) groups. LO MDD was characterized by decreased FA, especially in the white matter (WM) of the fronto-occipital fasciculus and posterior limb of internal capsule, with a negative correlation with the severity of depressive symptoms; in marked contrast, EO MDD showed increased FA, especially in the WM of the corpus callosum, corticospinal midbrain and inferior fronto-occipital fasciculus, while FA of the WM near the midbrain had a positive correlation with the severity of depressive symptoms.
Specific abnormalities of the brain circuitry in EO vs. LO MDD were delineated by an age of onset of 30 years old, as demonstrated by distinct abnormal FA clusters with opposite correlations with clinical symptoms. This DTI study supported the evidence of an exact age for the delineation of MDD, which could have broad multidisciplinary importance.
Trial Registration NCT00703742
PMCID: PMC4231105  PMID: 25393297
25.  The unified transform method for the Sasa–Satsuma equation on the half-line 
We implement the unified transform method to the initial-boundary value (IBV) problem of the Sasa–Satsuma equation on the half line. In addition to presenting the basic Riemann–Hilbert formalism, which linearizes this IBV problem, we also analyse the associated general Dirichlet to Neumann map using the so-called global relation.
PMCID: PMC3780815  PMID: 24204181
Riemann–Hilbert problem; Sasa–Satsuma equation; initial-boundary value problem

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