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1.  Abnormal Changes of Multidimensional Surface Features Using Multivariate Pattern Classification in Amnestic Mild Cognitive Impairment Patients 
The Journal of Neuroscience  2014;34(32):10541-10553.
Previous studies have suggested that amnestic mild cognitive impairment (aMCI) is associated with changes in cortical morphological features, such as cortical thickness, sulcal depth, surface area, gray matter volume, metric distortion, and mean curvature. These features have been proven to have specific neuropathological and genetic underpinnings. However, most studies primarily focused on mass-univariate methods, and cortical features were generally explored in isolation. Here, we used a multivariate method to characterize the complex and subtle structural changing pattern of cortical anatomy in 24 aMCI human participants and 26 normal human controls. Six cortical features were extracted for each participant, and the spatial patterns of brain abnormities in aMCI were identified by high classification weights using a support vector machine method. The classification accuracy in discriminating the two groups was 76% in the left hemisphere and 80% in the right hemisphere when all six cortical features were used. Regions showing high weights were subtle, spatially complex, and predominately located in the left medial temporal lobe and the supramarginal and right inferior parietal lobes. In addition, we also found that the six morphological features had different contributions in discriminating the two groups even for the same region. Our results indicated that the neuroanatomical patterns that discriminated individuals with aMCI from controls were truly multidimensional and had different effects on the morphological features. Furthermore, the regions identified by our method could potentially be useful for clinical diagnosis.
doi:10.1523/JNEUROSCI.4356-13.2014
PMCID: PMC4122798  PMID: 25100588
aMCI; cortical surface feature; entorhinal; MRI; multivariate classification
2.  Reversal of Multidrug Resistance by the Chinese Medicine Yiqi Jianpi Huaji Decoction and the Mechanism of Action in Human Gastric Cancer SGC7901/VCR Cells 
Yiqi Jianpi Huaji Decoction (YJHD), a traditional Chinese medicinal formula composed of twelve ingredients, has recently been reported to have a good clinical curative effect. The purpose of the present study was to evaluate the effects of YJHD on SGC7901/VCR gastric cancer cells and to elucidate the possible mechanism of action. First, the effects of a low dose of YJHD in combination with chemotherapeutic agents on SGC7901/VCR cells were assessed using the CCK-8 assay and flow cytometry, and the effects of YJHD on genes and proteins involved in drug resistance (MDR1, MRP, TUBB3, STMN1, and TS) were evaluated. Furthermore, transfection of SGC7901/VCR cells with siRNAs targeting these genes inhibited their expression, and the efficacy of vincristine against the cells was dramatically improved in vitro when these genes were silenced. These results demonstrate that low-dose YJHD inhibited cell proliferation, induced apoptosis, reversed MDR, and increased sensitivity to chemotherapeutic agents in vitro by downregulating P-gp, MRP, TUBB3, and STMN1 expression. MDR can be reversed by siRNAs targeting genes involved in MDR, and this strategy for cancer treatment should be evaluated in future studies.
doi:10.1155/2015/390812
PMCID: PMC4332981
3.  Abnormal autonomic and associated brain activities during rest in autism spectrum disorder 
Brain  2014;137(1):153-171.
Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.
doi:10.1093/brain/awt294
PMCID: PMC3891443  PMID: 24424916
autism; autonomic nervous system; emotion; skin conductance; resting state
5.  Hyperspectral Imaging for Mapping of Total Nitrogen Spatial Distribution in Pepper Plant 
PLoS ONE  2014;9(12):e116205.
Visible/near-infrared (Vis/NIR) hyperspectral imaging was employed to determine the spatial distribution of total nitrogen in pepper plant. Hyperspectral images of samples (leaves, stems, and roots of pepper plants) were acquired and their total nitrogen contents (TNCs) were measured using Dumas combustion method. Mean spectra of all samples were extracted from regions of interest (ROIs) in hyperspectral images. Random frog (RF) algorithm was implemented to select important wavelengths which carried effective information for predicting the TNCs in leaf, stem, root, and whole-plant (leaf-stem-root), respectively. Based on full spectra and the selected important wavelengths, the quantitative relationships between spectral data and the corresponding TNCs in organs (leaf, stem, and root) and whole-plant (leaf-stem-root) were separately developed using partial least-squares regression (PLSR). As a result, the PLSR model built by the important wavelengths for predicting TNCs in whole-plant (leaf-stem-root) offered a promising result of correlation coefficient (R) for prediction (RP = 0.876) and root mean square error (RMSE) for prediction (RMSEP = 0.426%). Finally, the TNC of each pixel within ROI of the sample was estimated to generate the spatial distribution map of TNC in pepper plant. The achievements of the research indicated that hyperspectral imaging is promising and presents a powerful potential to determine nitrogen contents spatial distribution in pepper plant.
doi:10.1371/journal.pone.0116205
PMCID: PMC4280196  PMID: 25549353
6.  Color Measurement of Tea Leaves at Different Drying Periods Using Hyperspectral Imaging Technique 
PLoS ONE  2014;9(12):e113422.
This study investigated the feasibility of using hyperspectral imaging technique for nondestructive measurement of color components (ΔL*, Δa* and Δb*) and classify tea leaves during different drying periods. Hyperspectral images of tea leaves at five drying periods were acquired in the spectral region of 380–1030 nm. The three color features were measured by the colorimeter. Different preprocessing algorithms were applied to select the best one in accordance with the prediction results of partial least squares regression (PLSR) models. Competitive adaptive reweighted sampling (CARS) and successive projections algorithm (SPA) were used to identify the effective wavelengths, respectively. Different models (least squares-support vector machine [LS-SVM], PLSR, principal components regression [PCR] and multiple linear regression [MLR]) were established to predict the three color components, respectively. SPA-LS-SVM model performed excellently with the correlation coefficient (rp) of 0.929 for ΔL*, 0.849 for Δa*and 0.917 for Δb*, respectively. LS-SVM model was built for the classification of different tea leaves. The correct classification rates (CCRs) ranged from 89.29% to 100% in the calibration set and from 71.43% to 100% in the prediction set, respectively. The total classification results were 96.43% in the calibration set and 85.71% in the prediction set. The result showed that hyperspectral imaging technique could be used as an objective and nondestructive method to determine color features and classify tea leaves at different drying periods.
doi:10.1371/journal.pone.0113422
PMCID: PMC4278674  PMID: 25546335
7.  Imaging Neurodegenerative Diseases: Mechanisms and Interventions 
BioMed Research International  2014;2014:419317.
doi:10.1155/2014/419317
PMCID: PMC4283430  PMID: 25587534
8.  Fabrication of low cost soft tissue prostheses with the desktop 3D printer 
Scientific Reports  2014;4:6973.
Soft tissue prostheses such as artificial ear, eye and nose are widely used in the maxillofacial rehabilitation. In this report we demonstrate how to fabricate soft prostheses mold with a low cost desktop 3D printer. The fabrication method used is referred to as Scanning Printing Polishing Casting (SPPC). Firstly the anatomy is scanned with a 3D scanner, then a tissue casting mold is designed on computer and printed with a desktop 3D printer. Subsequently, a chemical polishing method is used to polish the casting mold by removing the staircase effect and acquiring a smooth surface. Finally, the last step is to cast medical grade silicone into the mold. After the silicone is cured, the fine soft prostheses can be removed from the mold. Utilizing the SPPC method, soft prostheses with smooth surface and complicated structure can be fabricated at a low cost. Accordingly, the total cost of fabricating ear prosthesis is about $30, which is much lower than the current soft prostheses fabrication methods.
doi:10.1038/srep06973
PMCID: PMC4245596  PMID: 25427880
9.  Vaccinia Virus Induces Rapid Necrosis in Keratinocytes by a STAT3-Dependent Mechanism 
PLoS ONE  2014;9(11):e113690.
Rationale
Humans with a dominant negative mutation in STAT3 are susceptible to severe skin infections, suggesting an essential role for STAT3 signaling in defense against cutaneous pathogens.
Methods
To focus on innate antiviral defenses in keratinocytes, we used a standard model of cutaneous infection of severe combined immunodeficient mice with the current smallpox vaccine, ACAM-2000. In parallel, early events post-infection with the smallpox vaccine ACAM-2000 were investigated in cultured keratinocytes of human and mouse origin.
Results
Mice treated topically with a STAT3 inhibitor (Stattic) developed larger vaccinia lesions with higher virus titers and died more rapidly than untreated controls. Cultured human and murine keratinocytes infected with ACAM-2000 underwent rapid necrosis, but when treated with Stattic or with inhibitors of RIP1 kinase or caspase-1, they survived longer, produced higher titers of virus, and showed reduced activation of type I interferon responses and inflammatory cytokines release. Treatment with inhibitors of RIP1 kinase and STAT3, but not caspase-1, also reduced the inflammatory response of keratinocytes to TLR ligands. Vaccinia growth properties in Vero cells, which are known to be defective in some antiviral responses, were unaffected by inhibition of RIP1K, caspase-1, or STAT3.
Conclusions
Our findings indicate that keratinocytes suppress the replication and spread of vaccinia virus by undergoing rapid programmed cell death, in a process requiring STAT3. These data offer a new framework for understanding susceptibility to skin infection in patients with STAT3 mutations. Interventions which promote prompt necroptosis/pyroptosis of infected keratinocytes may reduce risks associated with vaccination with live vaccinia virus.
doi:10.1371/journal.pone.0113690
PMCID: PMC4242661  PMID: 25419841
10.  Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians 
Aging (Albany NY)  2014;6(11):944-951.
Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population.
PMCID: PMC4276788  PMID: 25553725
insulin-like growth factor binding protein 3; longevity; single nucleotide polymorphism
11.  Association of BRCA2 N372H polymorphism with cancer susceptibility: A comprehensive review and meta-analysis 
Scientific Reports  2014;4:6791.
BRCA2 gene plays an important role in homologous recombination. Polymorphic variants in this gene has been suggested to confer cancer susceptibility. Numerous studies have investigated association between BRCA2 N372H polymorphism and risk of several cancers, especially breast cancer. However, the results were inconsistent. We performed a comprehensive meta-analysis to provide a more precise assessment of the association between N372H and cancer risk, following the latest meta-analysis guidelines (PRISMA). Forty six studies involving 36299 cases and 48483 controls were included in our meta-analysis. The crude ORs and the 95% CIs were used to evaluate the strength of the association. The results indicated that the BRCA2 N372H variant was significantly associated with an increased risk of overall cancer (dominant model: OR = 1.07, 95% CI = 1.01–1.13; recessive model: OR = 1.12, 95% CI = 1.02–1.23). Moreover, stratified analyses by the cancer type and source of control observed significantly increased risk associated with BRCA2 N372H in subgroups with ovarian cancer, non-Hodgkin lymphoma and population-based controls, but not breast cancer or hospital-based controls. We also found such association among Africans. Overall, the meta-analysis suggested that BRCA2 N372H may be a cancer susceptibility polymorphism. Well-designed and large-scale studies are needed to substantiate the association between BRCA2 N372H polymorphism and cancer risk.
doi:10.1038/srep06791
PMCID: PMC4210867  PMID: 25348552
12.  The reduction of vascular disease risk mutations contributes to longevity in the Chinese population 
Meta Gene  2014;2:761-768.
Aim
Genetic factors play important roles in determining human lifespan. Although some “longevity genes” have been identified to be implicated in human longevity, many disease-associated variants were also observed in the long-lived individuals. The oldest old and their offspring usually have a lower prevalence of age-related diseases, which is likely attributed to a reduction or an absence of disease risk variants.
Methods and results
To test this hypothesis, 23 disease risk single nucleotide polymorphisms (SNPs), identified by previous genome-wide association studies (GWASs), were selected and genotyped in 1074 samples consisting of 574 longevity subjects (over 90 years old) and 500 younger controls. Our results revealed that 5 SNPs (rs2144300, rs1864163, rs2200733, rs1967017, and rs7193343) displayed significantly lower allelic frequencies and odds ratios (ORs) in the longevity group than that in the control group. The frequencies of homozygous mutation genotypes and corresponding ORs of the rs1864163, rs2200733, rs127430, rs1967017, and rs12413409 were lower in the longevity subjects. Interestingly, most of the abovementioned SNPs convey susceptibility to cardiovascular disease (CVD), which is the leading cause of deaths in old adults but shows a much lower incidence in the longevity individuals and their offspring.
Conclusion
Taking into account the observation that the longevity subjects and their offspring have lower rate of cardiovascular mortality, it is then most plausible that the lack of disease risk variants, especially the CVD, is a genetic contributor to longevity in the Chinese population.
Highlights
•23 disease risk gene polymorphisms were determined in 1074 subjects.•5 polymorphisms displayed lower allelic frequencies in longevity subjects.•Lack of disease risk variants contributes to longevity.
doi:10.1016/j.mgene.2014.09.010
PMCID: PMC4287879  PMID: 25606459
AD, Alzheimer Disease; CHB, Chinese Han Beijing; CVD, cardiovascular disease; GWAS, genome-wide association study; MAF, minor allele frequency; OR, odds ratio; PD, Parkinson Disease; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism.; Cardiovascular disease; Longevity; Heritability; Single nucleotide polymorphism
13.  Telmisartan protects 5/6 Nx rats against renal injury by enhancing nNOS-derived NO generation via regulation of PPARγ signaling 
A 5/6 nephrectomized (Nx) rat model was employed to address the impact of telmisartan on CKD related renal injury and the underlying molecular mechanisms. It was noted that telmisartan provided protection for rats against 5/6 Nx induced lethality. Telmisartan treated 5/6 Nx rats manifested improved renal function as characterized by the higher GFR but lower urinary albumin, BUN and Scr as compared with that of control rats. Telmisartan treatment also significantly decreased systolic blood pressure and alleviated glomerulosclerosis and interstitial fibrosis. Mechanistic studies revealed that telmisartan possesses the capability to increase NO generation in the kidney. Further studies demonstrated that telmisartan promotes PPARγ expression, by which it specifically enhances nNOS expression in the kidneys after 5/6 Nx insult. Particularly, blockade of PPARγ signaling by GW9662 abolished the protective effect conferred by telmisartan, indicating that telmisartan induction of renal nNOS expression along with NO generation is dependent on PPARγ signaling. Together, our data support that telmisartan could be a promising drug for treatment of chronic kidney diseases in diverse clinical settings.
PMCID: PMC4212926  PMID: 25360216
nNOS; PPARγ; 5/6 nephrectomy; telmisartan; CKD
14.  Focus on China: should clinicians engage in research? and lessons from other countries 
Following tremendous economic progress, society in China is also undergoing fundamental changes, as is the healthcare system. Currently the training of Chinese young doctors and their future work placement are all undergoing re-structuring. We compiled some thoughts and opinions on the topic of ‘should clinicians in China engage in research?’, and publish them as a special report in this issue of Quantitative Imaging in Medicine and Surgery (QIMS). The contributors included some editorial members of this journal, and a few personal friends. Besides a few minor linguistic corrections, opinions from the contributors have not been edited, as we want authors’ to write their own independent views. However, it is possible there is a selection bias of the contributors of this paper; more likely those who are interested in the medical research are selected and therefore the views of the contributors may not be generalizable. To compare the structure and funding of China with other countries, authors from UK, The Netherlands, France, and USA are also invited.
doi:10.3978/j.issn.2223-4292.2014.10.07
PMCID: PMC4213419  PMID: 25392826
China; Chinese; doctors; medical research; medical training; research funding
15.  Individual Differences in Impulsivity Predict Head Motion during Magnetic Resonance Imaging 
PLoS ONE  2014;9(8):e104989.
Magnetic resonance imaging (MRI) provides valuable data for understanding the human mind and brain disorders, but in-scanner head motion introduces systematic and spurious biases. For example, differences in MRI measures (e.g., network strength, white matter integrity) between patient and control groups may be due to the differences in their head motion. To determine whether head motion is an important variable in itself, or just simply a confounding variable, we explored individual differences in psychological traits that may predispose some people to move more than others during an MRI scan. In the first two studies, we demonstrated in both children (N  =  245) and adults (N  =  581) that head motion, estimated from resting-state functional MRI and diffusion tensor imaging, was reliably correlated with impulsivity scores. Further, the difference in head motion between children with attention deficit hyperactivity disorder (ADHD) and typically developing children was largely due to differences in impulsivity. Finally, in the third study, we confirmed the observation that the regression approach, which aims to deal with motion issues by regressing out motion in the group analysis, would underestimate the effect of interest. Taken together, the present findings provide empirical evidence that links in-scanner head motion to psychological traits.
doi:10.1371/journal.pone.0104989
PMCID: PMC4141798  PMID: 25148416
16.  An Automated Three-Dimensional Detection and Segmentation Method for Touching Cells by Integrating Concave Points Clustering and Random Walker Algorithm 
PLoS ONE  2014;9(8):e104437.
Characterizing cytoarchitecture is crucial for understanding brain functions and neural diseases. In neuroanatomy, it is an important task to accurately extract cell populations' centroids and contours. Recent advances have permitted imaging at single cell resolution for an entire mouse brain using the Nissl staining method. However, it is difficult to precisely segment numerous cells, especially those cells touching each other. As presented herein, we have developed an automated three-dimensional detection and segmentation method applied to the Nissl staining data, with the following two key steps: 1) concave points clustering to determine the seed points of touching cells; and 2) random walker segmentation to obtain cell contours. Also, we have evaluated the performance of our proposed method with several mouse brain datasets, which were captured with the micro-optical sectioning tomography imaging system, and the datasets include closely touching cells. Comparing with traditional detection and segmentation methods, our approach shows promising detection accuracy and high robustness.
doi:10.1371/journal.pone.0104437
PMCID: PMC4128780  PMID: 25111442
17.  Fever as a first manifestation of advanced gastric adenosquamous carcinoma: A case report 
World Journal of Gastroenterology : WJG  2014;20(29):10193-10201.
Gastric adenosquamous carcinoma (ASC) is a rare type of gastric cancer. It is a mixed neoplasm, consisting of glandular cells and squamous cells. It is often diagnosed at an advanced stage, thus carrying a poor prognosis. We describe a case of a 73-year-old male, who presented with refractory fever and an intra-abdominal mass on imaging. He underwent a laparoscopic exploration followed by a successful totally laparoscopic total gastrectomy with D2 lymphadenectomy for gastric cancer. Postoperative pathology revealed primary gastric ASC (T4aN0M0). The patient received adjuvant radiotherapy and chemotherapy with S1 and is alive 20 mo after surgery without recurrence. This is the first case of advanced gastric ASC with fever as the initial presentation treated with totally laparoscopic total gastrectomy reported in the English literature.
doi:10.3748/wjg.v20.i29.10193
PMCID: PMC4123350  PMID: 25110448
Gastric adenosquamous carcinoma; Advanced gastric cancer; Malignant tumor; Laparoscopic gastrectomy; Totally laparoscopic total gastrectomy
18.  Serial analysis of lumen geometry and hemodynamics in human arteriovenous fistula for hemodialysis using magnetic resonance imaging and computational fluid dynamics 
Journal of biomechanics  2012;46(1):165-169.
The arteriovenous fistula (AVF) is the preferred form of vascular access for maintenance hemodialysis, but it often fails to mature to become clinically usable, likely due to aberrant hemodynamic forces. A robust pipeline for serial assessment of hemodynamic parameters and subsequent lumen cross-sectional area changes has been developed and applied to a data set from contrast-free MRI of a dialysis patient’s AVF collected over a period of months after AVF creation surgery. Black-blood MRI yielded images of AVF lumen geometry, while cine phase-contrast MRI provided volumetric flow rates at the in-flow and out-flow locations. Lumen geometry and flow rates were used as inputs for computational fluid dynamic (CFD) modeling to provide serial wall shear stress (WSS), WSS gradient, and oscillatory shear index profiles. The serial AVF lumen geometries were co-registered at 1-mm intervals using respective lumen centerlines, with the anastomosis as an anatomical landmark. Lumen enlargement was limited at the vein region near the anastomosis and a downstream vein valve, potentially attributed to a physical inhibition of wall expansion at those sites. This work is the first serial and detail study of lumen and hemodynamic changes in human AVF using MRI and CFD. This novel protocol will be used for a multicenter prospective study to identify critical hemodynamic factors that contribute to AVF maturation failure.
doi:10.1016/j.jbiomech.2012.09.005
PMCID: PMC4120947  PMID: 23122945
hemodialysis; arteriovenous fistula; wall shear stress; computational fluid dynamics; magnetic resonance imaging
19.  Nanoscale Size-Selective Deposition of Nanowires by Micrometer Scale Hydrophilic Patterns 
Scientific Reports  2014;4:5943.
Controlling the post-growth assembly of nanowires is an important challenge in the development of functional bottom-up devices. Although various methods have been developed for the controlled assembly of nanowires, it is still a challenging issue to align selectively heterogeneous nanowires at desired spatial positions on the substrate. Here we report a size selective deposition and sequential alignment of nanowires by utilizing micrometer scale hydrophilic/hydrophobic patterned substrate. Nanowires dispersed within oil were preferentially deposited only at a water/oil interface onto the hydrophilic patterns. The diameter size of deposited nanowires was strongly limited by the width of hydrophilic patterns, exhibiting the nanoscale size selectivity of nanowires deposited onto micrometer scale hydrophilic patterns. Such size selectivity was due to the nanoscale height variation of a water layer formed onto the micrometer scale hydrophilic patterns. We successfully demonstrated the sequential alignment of different sized nanowires on the same substrate by applying this size selective phenomenon.
doi:10.1038/srep05943
PMCID: PMC4120308  PMID: 25087699
20.  A modelling approach to evaluate the long-term effect of soil texture on spring wheat productivity under a rain-fed condition 
Scientific Reports  2014;4:5736.
Soil surface texture is an important environmental factor that influences crop productivity because of its direct effect on soil water and complex interactions with other environmental factors. Using 30-year data, an agricultural system model (DSSAT-CERES-Wheat) was calibrated and validated. After validation, the modelled yield and water use (WU) of spring wheat (Triticum aestivum L.) from two soil textures (silt loam and clay) under rain-fed condition were analyzed. Regression analysis showed that wheat grown in silt loam soil is more sensitive to WU than wheat grown in clay soil, indicating that the wheat grown in clay soil has higher drought tolerance than that grown in silt loam. Yield variation can be explained by WU other than by precipitation use (PU). These results demonstrated that the DSSAT-CERES-Wheat model can be used to evaluate the WU of different soil textures and assess the feasibility of wheat production under various conditions. These outcomes can improve our understanding of the long-term effect of soil texture on spring wheat productivity in rain-fed condition.
doi:10.1038/srep05736
PMCID: PMC4115211  PMID: 25074796
21.  An efficient chemical synthesis of carboxylate-isostere analogs of daptomycin 
Organic & biomolecular chemistry  2013;11(28):4680-4685.
Herein we report a direct and efficient method for the synthesis of four new carboxylate-isostere analogs of daptomycin. The side chain carboxylic acid moieties of the aspartic acids (Asp-3, Asp-7 and Asp-9) and β-methyl glutamic acid (MeGlu-12) were all converted into the corresponding carboxylate isosteres using direct synthetic procedures. The present study also describes an esterification protocol to overcome the possible backbone cyclization of the activated side chain carboxylic acid group of either Asp or Glu, onto the backbone amide.
doi:10.1039/c3ob40924d
PMCID: PMC4033608  PMID: 23752953
22.  Cellulose Nanofiber Paper as an Ultra Flexible Nonvolatile Memory 
Scientific Reports  2014;4:5532.
On the development of flexible electronics, a highly flexible nonvolatile memory, which is an important circuit component for the portability, is necessary. However, the flexibility of existing nonvolatile memory has been limited, e.g. the smallest radius into which can be bent has been millimeters range, due to the difficulty in maintaining memory properties while bending. Here we propose the ultra flexible resistive nonvolatile memory using Ag-decorated cellulose nanofiber paper (CNP). The Ag-decorated CNP devices showed the stable nonvolatile memory effects with 6 orders of ON/OFF resistance ratio and the small standard deviation of switching voltage distribution. The memory performance of CNP devices can be maintained without any degradation when being bent down to the radius of 350 μm, which is the smallest value compared to those of existing any flexible nonvolatile memories. Thus the present device using abundant and mechanically flexible CNP offers a highly flexible nonvolatile memory for portable flexible electronics.
doi:10.1038/srep05532
PMCID: PMC4078308  PMID: 24985164
23.  Sex Differences in Behavior and Expression of CGRP-related Genes in a Rodent Model of Chronic Migraine 
Headache  2011;51(5):674-692.
a. Objective
The objectives of this study were to develop a preclinical rodent model that produces migraine-like behaviors based on International Headache Society diagnostic criteria, to determine whether sex differences are present, and to determine whether expression of CGRP and the genes encoding its receptor in trigeminal ganglion or medulla correlates with those behaviors.
b. Background
Few animal studies of migraine have tested behaviors associated with migraine diagnostic criteria. In this study, changes in activity and in mechanical sensitivity of facial regions following application of inflammatory soup (IS) or vehicle (PBS) to the dura were measured to model changes in routine activity and allodynia. Calcitonin gene related peptide (CGRP), an important mediator of migraine pathogenesis, and the three components of its receptor, calcitonin-like receptor (CLR), receptor activity-modifying protein (RAMP1), and receptor component protein (RCP) mRNAs were quantified in the trigeminal ganglion and medulla to identify baseline sex differences and changes associated with application of IS or PBS to the dura.
c. Methods
Male and female Sprague-Dawley rats were implanted with a dural cannula. Groups of rats were treated with 10 or 20 microliter volumes of IS or PBS. Baseline behavioral testing was conducted prior to surgery and again at 7 days postsurgery, and dural application of IS or PBS was performed repeatedly for a total of 8 applications. Locomotor activity was assessed using force plate actimetry during and following application to provide information on distance traveled, bouts of low mobility, spatial confinement, and focused energy. Periorbital and perimasseter sensory testing was performed 20 min post-application to measure allodynia. The rats were sacrificed 30 minutes following the final dural treatment, tissue was dissected and total RNAs were isolated from ipsilateral trigeminal ganglia and ipsilateral medulla. Quantitative real-time polymerase chain reactions were used to measure the expression of amplified constructs using gene-specific primers for CGRP, RAMP1, CLR, and RCP.
d. Results
Both males and females showed behavioral effects of IS application, but there were pronounced sex differences. Females showed effects at the lower dose, and activity changes were present for a longer duration, but males required fewer applications of IS to exhibit behavioral changes. Females showed increased withdrawal responses for periorbital and perimasseter mechanical testing (10 µl IS groups), and males showed increased perimasseter withdrawal responses (20 µl IS group). In the trigeminal ganglion, there were no baseline sex differences in CGRP-encoding mRNA, but females had lower baseline expression of RAMP1, CLR, and RCP-encoding mRNAs. In the medulla, females had higher baseline levels of CGRP-encoding mRNAs and lower baseline levels of RAMP1, CLR, and RCP-encoding mRNAs than males. Both IS and PBS increased expression of mRNAs encoding CGRP, RAMP1, RCP and CLR in the trigeminal ganglion in males, but in females, only CLR and RCP were increased. In the medulla both IS and PBS increased expression of CGRP, CLR in males and CLR and RCP in females. Thus, expression of CGRP related genes did not mirror the behavioral differences between IS and PBS groups. Instead, CGRP related genes were upregulated by both IS and PBS applications.
e. Conclusions
This study demonstrates significant changes in locomotor activity and facial allodynia associated with application of IS to the dura as well as significant sex differences, demonstrating that International Headache Society diagnostic criteria can be used to design a rodent behavioral model of migraine. In addition, there were prominent baseline sex differences in expression of CGRP and its receptor in both the trigeminal ganglion and medulla, but the majority of changes in expression of CGRP and its receptor were present in both the IS and PBS treated rats. This suggests that the CGRP pathway responds to changes in intracranial pressure or meningeal stretch, while migraine-like behaviors occur after meningeal inflammation.
doi:10.1111/j.1526-4610.2011.01882.x
PMCID: PMC4079043  PMID: 21521205
Chronic migraine; inflammatory soup; rat; facial allodynia; trigeminal; locomotor; activity; sex differences; pain; inflammation; dura mater; CGRP
24.  PPM1D is a prognostic marker and therapeutic target in colorectal cancer 
Protein phosphatase, Mg2+/Mn2+ dependent, 1D (PPM1D) has been associated with carcinogenesis. The present study investigated PPM1D expression as a potential biomarker in colorectal cancer (CRC). PPM1D expression was assessed using immunohistochemistry in 368 patients with CRC. The correlation between PPM1D expression, clinicopathological features and prognosis was analyzed. PPM1D small interfering (si)RNA-induced PPM1D silencing was performed in CRC cell lines to assess the effect of PPM1D on tumor cell proliferation and invasion in vitro. A total of 68.48% (252/368) of the CRC samples displayed high PPM1D expression. By contrast, only 9.24% (34/368) of the matched non-cancerous tissue samples exhibited high PPM1D expression. High PPM1D expression was correlated with node metastasis (P=0.0024), distant metastasis (P<0.001) and TNM stage (P=0.0016). Kaplan-Meier survival analysis revealed that patients with low PPM1D expression had significantly longer survival than those with high PPM1D expression (P=0.012). Moreover, multivariate analyses demonstrated that high PPM1D expression was an independent prognostic factor for overall survival (hazard ratio = 0.24; 95% confidence interval, 0.13–0.86; P=0.004). Furthermore, PPM1D gene silencing was found to significantly reduce the proliferation and invasion of CRC cells in vitro. These findings suggest a role for PPM1D as a prognostic marker and potential therapeutic target in CRC.
doi:10.3892/etm.2014.1762
PMCID: PMC4079395  PMID: 25009596
colorectal cancer; PPM1D; prognosis; biomarker
25.  Serological Evidence of Toxoplasma gondii Infection in Five Species of Bats in China 
Abstract
Toxoplasma gondii is an obligate intracellular protozoan parasite that can infect almost all warm-blooded animals and humans with a worldwide distribution. Bats are reservoirs for an increasing number of emerging zoonotic viruses, such as henipaviruses and severe acute respiratory syndrome coronavirus (SARS-CoV). However, little is known of T. gondii infection in bats. The objective of the present study was to determine the seroprevalence of T. gondii infection in bats in China. A total of 217 serum samples from 5 species of bats were collected between April, 2010, and August, 2011, from 4 provinces in China. Antibodies to T. gondii were determined using the modified agglutination test (MAT, 1:25 or higher). Antibodies to T. gondii were found in 26.5% (18/68) Megaderma lyra, 13.6% (12/88) Rousettus leschenaulti, 13.6% (3/22) Cynopterus sphinx, 20% (4/20) Vespertilio superaus, and 15.8% (3/19) Pipistrellus javanicus. Antibody titers ranged from 1:25 to 1:400, with titers of 1:200 detected in 4 of the 5 bat species. The present study suggests the likely occurrence of T. gondii infection in bats in China, and these bats are new putative hosts for T. gondii, which may pose a threat to human health.
doi:10.1089/vbz.2012.1091
PMCID: PMC3669597  PMID: 23473226
Toxoplasma gondii; Toxoplasmosis; Bat; China; Seroprevalence; Modified agglutination test

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