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1.  The effect of Zhangfei/CREBZF on cell growth, differentiation, apoptosis, migration, and the unfolded protein response in several canine osteosarcoma cell lines 
We had previously shown that the bLZip domain-containing transcription factor, Zhangfei/CREBZF inhibits the growth and the unfolded protein response (UPR) in cells of the D–17 canine osteosarcoma (OS) line and that the effects of Zhangfei are mediated by it stabilizing the tumour suppressor protein p53. To determine if our observations with D-17 cells applied more universally to canine OS, we examined three other independently isolated canine OS cell lines—Abrams, McKinley and Gracie.
Like D–17, the three cell lines expressed p53 proteins that were capable of activating promoters with p53 response elements on their own, and synergistically with Zhangfei. Furthermore, as with D–17 cells, Zhangfei suppressed the growth and UPR-related transcripts in the OS cell lines. Zhangfei also induced the activation of osteocalcin expression, a marker of osteoblast differentiation and triggered programmed cell death.
Osteosarcomas are common malignancies in large breeds of dogs. Although there has been dramatic progress in their treatment, these therapies often fail, leading to recurrence of the tumour and metastatic spread. Our results indicate that induction of the expression of Zhangfei in OS, where p53 is functional, may be an effective modality for the treatment of OS.
PMCID: PMC4326286
Canine osteosarcoma; Zhangfei/CREBZF; p53; Apoptosis; Osteocalcin
2.  Repetitive Transcranial Magnetic Stimulation Ameliorates Anxiety-Like Behavior and Impaired Sensorimotor Gating in a Rat Model of Post-Traumatic Stress Disorder 
PLoS ONE  2015;10(2):e0117189.
Repetitive transcranial magnetic stimulation (rTMS) has been employed for decades as a non-pharmacologic treatment for post-traumatic stress disorder (PTSD). Although a link has been suggested between PTSD and impaired sensorimotor gating (SG), studies assessing the effects of rTMS against PTSD or PTSD with impaired SG are scarce.
To assess the benefit of rTMS in a rat model of PTSD.
Using a modified single prolonged stress (SPS&S) rat model of PTSD, behavioral parameters were acquired using open field test (OFT), elevated plus maze test (EPMT), and prepulse inhibition trial (PPI), with or without 7 days of high frequency (10Hz) rTMS treatment of SPS&S rats.
Anxiety-like behavior, impaired SG and increased plasma level of cortisol were observed in SPS&S animals after stress for a prolonged time. Interestingly, rTMS administered immediately after stress prevented those impairment.
Stress-induced anxiety-like behavior, increased plasma level of cortisol and impaired PPI occur after stress and high-frequency rTMS has the potential to ameliorate this behavior, suggesting that high frequency rTMS should be further evaluated for its use as a method for preventing PTSD.
PMCID: PMC4320076  PMID: 25659132
3.  The Role of Abcb5 Alleles in Susceptibility to Haloperidol-Induced Toxicity in Mice and Humans 
PLoS Medicine  2015;12(2):e1001782.
We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.
Methods and Findings
A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.
ABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity.
Gary Peltz and colleagues examine the role of ABCB5 alleles in haloperidol-induced toxicity in a murine genetic model and humans treated with haloperidol.
Editors' Summary
The brain is the control center of the human body. This complex organ controls thoughts, memory, speech, and movement, it is the seat of intelligence, and it regulates the function of many organs. The brain comprises many different parts, all of which work together but all of which have their own special functions. For example, the forebrain is involved in intellectual activities such as thinking whereas the hindbrain controls the body’s vital functions and movements. Messages are passed between the various regions of the brain and to other parts of the body by specialized cells called neurons, which release and receive signal molecules known as neurotransmitters. Like all the organs in the body, blood vessels supply the brain with the oxygen, water, and nutrients it needs to function. Importantly, however, the brain is protected from infectious agents and other potentially dangerous substances circulating in the blood by the “blood-brain barrier,” a highly selective permeability barrier that is formed by the cells lining the fine blood vessels (capillaries) within the brain.
Why Was This Study Done?
Although drugs have been developed to treat various brain disorders, more active and less toxic drugs are needed to improve the treatment of many if not most of these conditions. Unfortunately, relatively little is known about how the blood-brain barrier regulates the entry of drugs into the brain or about the genetic factors that affect the brain’s susceptibility to drug-induced toxicities. It is not known, for example, why about half of patients given haloperidol—a drug used to treat psychotic disorders (conditions that affect how people think, feel, or behave)—develop tremors and other symptoms caused by alterations in the brain region that controls voluntary movements. Here, to improve our understanding of how drugs enter the brain and impact its function, the researchers investigate the genetic factors that affect haloperidol-induced toxicity by genetically analyzing several inbred mouse strains (every individual in an inbred mouse strain is genetically identical) with different susceptibilities to haloperidol-induced toxicity and by undertaking a human genetic association study (a study that looks for non-chance associations between specific traits and genetic variants).
What Did the Researchers Do and Find?
The researchers used a database of genetic variants called single nucleotide polymorphisms (SNPs) and a computational genetic mapping approach to show first that variations within the gene encoding Abcb5 affected susceptibility to haloperidol-induced toxicity (indicated by changes in the length of time taken by mice to move their paws when placed on an inclined wire-mesh screen) among inbred mouse strains. Abcb5 is an ATP-binding cassette transporter, a type of protein that moves molecules across cell membranes. The researchers next showed that Abcb5 is expressed in brain capillaries, which is the location of the blood-brain barrier. Abcb5 was also expressed in cerebellar Purkinje cells, which help to control motor (intentional) movements. They also measured the measured the effect of haloperidol and the haloperidol concentration in brain tissue sections in mice that were genetically engineered to make no Abcb5 (Abcb5 knockout mice). Finally, the researchers investigated whether specific alleles (alternative versions) of ABCB5 are associated with haloperidol-induced toxicity in people. Among a group of 85 patients treated with haloperidol for a psychotic illness, one specific ABCB5 allele was associated with haloperidol-induced toxicity during the first few days of treatment.
What Do These Findings Mean?
These findings indicate that Abcb5 is a component of the blood-brain barrier in mice and suggest that genetic variants in the gene encoding this protein underlie, at least in part, the differences in susceptibility to haloperidol-induced toxicity seen among inbred mice strains. Moreover, the human genetic association study indicates that a specific ABCB5 allele also affects the susceptibility of people to haloperidol-induced toxicity. The researchers note that other ABCB5 alleles or other genetic factors that affect haloperidol-induced toxicity in people might emerge if larger groups of patients were studied. However, based on their findings, the researchers propose a new model for the genetic mechanisms that underlie inter-individual and cell type-specific differences in susceptibility to haloperidol-induced brain toxicity. If confirmed in future studies, this model might facilitate the development of more effective and less toxic drugs to treat a range of brain disorders.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute of Neurological Disorders and Stroke provides information about a wide range of brain diseases (in English and Spanish); its fact sheet “Brain Basics: Know Your Brain” is a simple introduction to the human brain; its “Blueprint Neurotherapeutics Network” was established to develop new drugs for disorders affecting the brain and other parts of the nervous system
MedlinePlus provides links to additional resources about brain diseases and their treatment (in English and Spanish)
Wikipedia provides information about haloperidol, about ATP-binding cassette transporters and about genetic association (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC4315575  PMID: 25647612
4.  Cell Surface Self-Assembly of Hybrid Nanoconjugates via Oligonucleotide Hybridization Induces Apoptosis 
ACS nano  2013;8(1):719-730.
Hybrid nanomaterials composed of synthetic and biological building blocks possess high potential for the design of nanomedicines. The use of self-assembling nanomaterials as “bio-mimics” may trigger cellular events and result in new therapeutic effects. Motivated by this rationale, we designed a therapeutic platform that mimics the mechanism of immune effector cells to crosslink surface receptors of target cells and induce apoptosis. This platform was tested against B-cell lymphomas that highly express the surface antigen CD20. Here, two nanoconjugates were synthesized: (1) an anti-CD20 Fab’ fragment covalently linked to a single-stranded morpholino oligonucleotide (MORF1), and (2) a linear polymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple copies of the complementary oligonucleotide MORF2. We show that the two conjugates self-assemble via MORF1-MORF2 hybridization at the surface of CD20+ malignant B-cells, which crosslinks CD20 antigens and initiates apoptosis. When tested in a murine model of human non-Hodgkin’s lymphoma, the two conjugates, either administered consecutively or as a premixture, eradicated cancer cells and produced long-term survivors. The designed therapeutics contains no small-molecule cytotoxic compounds and is immune-independent, aiming to improve over chemotherapy, radiotherapy and immunotherapy. This therapeutic platform can be applied to crosslink any non-internalizing receptor and potentially treat other diseases.
PMCID: PMC3908873  PMID: 24308267
biorecognition; receptor crosslinking; apoptosis; morpholino oligonucleotide; N-(2-hydroxypropyl)methacrylamide (HPMA); CD20; B-cell lymphoma
5.  Effects of cyclic AMP response element binding protein–Zhangfei (CREBZF) on the unfolded protein response and cell growth are exerted through the tumor suppressor p53 
Cell Cycle  2013;13(2):279-292.
Zhangfei/CREBZF, a basic region-leucine zipper (bLZip) transcription factor, is a potent suppressor of growth and the unfolded protein response (UPR) in some cancer cell lines, including the canine osteosarcoma cell line, D-17. However, the effects of Zhangfei are not universal, and it has no obvious effects on untransformed cells and some cancer cell lines, suggesting that Zhangfei may act through an intermediary that is either not induced or is defective in cells that it does not affect. Here we identify the tumor suppressor protein p53 as this intermediary. We show the following: in cells ectopically expressing Zhangfei, the protein stabilizes p53 and co-localizes with it in cellular nuclei; the bLZip domain of Zhangfei is required for its profound effects on cell growth and interaction with p53. Suppression of p53 by siRNA at least partially inhibits the effects of Zhangfei on the UPR and cell growth. The effects of Zhangfei on D-17 cells is mirrored by its effects on the p53-expressing human osteosarcoma cell line U2OS, while Zhangfei has no effect on the p53-null osteosarcoma cell line MG63. In U2OS cells, Zhangfei displaces the E3 ubiquitin ligase mouse double minute homolog 2 (Mdm2) from its association with p53, suggesting a mechanism for the effects of Zhangfei on p53.
PMCID: PMC3906244  PMID: 24200963
cell cycle; protein domains; p53; osteosarcoma; protein translocation; Zhangfei/CREBZF; unfolded protein response; Mdm2; basic-leucine zipper domain
6.  Sexual dimorphism in rat aortic endothelial function of streptozotocin-induced diabetes: possible involvement of superoxide and nitric oxide production 
Little is known of the interactions between diabetes and sex on vascular function. The objectives of this study were to investigate whether there were sex differences in rat aortic endothelial function one week after the induction of streptozotocin (STZ)-diabetes, and to examine the potential roles of superoxide and nitric oxide (NO) in this sex-specific effect. Endothelium-dependent vasodilatation to acetylcholine (ACh) was measured in rat aortic rings before and after treatment with MnTMPyP (25 μM), a superoxide dismutase. Contractile responses to phenylephrine (PE) were generated before and after treatment with L-NAME (200 μM), a nitric oxide synthase (NOS) inhibitor. The mRNA expression of NADPH oxidase (Nox) and endothelial nitric oxide synthase (eNOS) were also determined. We demonstrated that 1) STZ-diabetes impaired endothelium-dependent vasodilatation to ACh to a greater extent in female than male aortae, 2) inhibition of superoxide enhanced sensitivity to ACh only in diabetic females, and 3) Nox1 and Nox4 mRNA expression was significantly elevated only in aortic tissue of diabetic females. Furthermore, incubation of aortic rings with L-NAME potentiated PE responses in all groups, but aortae from control females showed a greater potentiation of the PE response after NOS inhibition compared with others. STZ-diabetes reduced the extent of PE potentiation after L-NAME and the aortic eNOS mRNA expression in females to the same levels as seen in males. These data suggest that a decrease in NO, resulting from either decreased eNOS or elevated superoxide, may partially contribute to the predisposition of the female aorta to injury early in diabetes.
PMCID: PMC3946273  PMID: 24211329
Sex difference; diabetes; endothelial dysfunction; nitric oxide; superoxide
7.  FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma 
AIM: To investigate the expression of forkhead box protein M1 (FoxM1) in the process of epithelial mesenchymal transition in hepatocellular carcinoma (HCC) and its role in metastasis.
METHODS: FoxM1 and E-cadherin expression in HCC tissue microarray specimens was evaluated by immunohistochemical staining, and statistical methods were applied to analyze the correlation between FoxM1 and epithelial-mesenchymal transition (EMT). Kaplan-Meier analysis of the correlation between the FoxM1 expression level and recurrence or overall survival of HCC patients was performed. The expression of FoxM1, E-cadherin and snail homologue 1 (SNAI1) in HCC cell lines was evaluated by real-time reverse transcription-polymerase chain reaction and Western blot. Hepatocyte growth factor (HGF) was used to induce EMT and stimulate cell migration in HCC cells. The expression of FoxM1 and SNAI1 was regulated by transfection with plasmids pcDNA3.1 and siRNAs in vitro. The occurrence of EMT was evaluated by Transwell assay, morphologic analysis and detection of the expression of EMT markers (E-cadherin and vimentin). Luciferase and chromatin immunoprecipitation assays were used to evaluate whether SNAI1 is a direct transcriptional target of FoxM1.
RESULTS: FoxM1 expression was increased significantly in HCC compared with para-carcinoma (10.7 ± 0.9 vs 8.2 ± 0.7, P < 0.05) and normal hepatic (10.7 ± 0.9 vs 2.7 ± 0.4, P < 0.05) tissues. Overexpression of FoxM1 was correlated with HCC tumor size, tumor number, macrovascular invasion and higher TNM stage, but was negatively correlated with E-cadherin expression in microarray specimens and in cell lines. FoxM1 overexpression was correlated significantly with HCC metastasis and EMT. In vitro, we found that FoxM1 plays a key role in HGF-induced EMT, and overexpression of FoxM1 could suppress E-cadherin expression and induce EMT changes, which were associated with increased HCC cell invasiveness. Next, we confirmed that FOXM1 directly binds to and activates the SNAI1 promoter, and we identified SNAI1 as a direct transcriptional target of FOXM1. Moreover, inhibiting the expression of SNAI1 significantly inhibited FoxM1-mediated EMT.
CONCLUSION: FoxM1 overexpression promotes EMT and metastasis of HCC, and SNAI1 plays a critical role in FoxM1-mediated EMT.
PMCID: PMC4284335  PMID: 25574092
Forkhead box protein M1; Epithelial-mesenchymal transition; Hepatocellular carcinoma; Snail homolog 1; E-cadherin
8.  Toll-interacting protein (Tollip) negatively regulates pressure overload-induced ventricular hypertrophy in mice 
Cardiovascular Research  2013;101(1):87-96.
Toll-interacting protein (Tollip) is a critical regulator of the Toll-like receptor-mediated signalling pathway. However, the role of Tollip in chronic pressure overload-induced cardiac hypertrophy remains unclear. This study aimed to determine the functional significance of Tollip in the regulation of aortic banding-induced cardiac remodelling and its underlying mechanisms.
Methods and results
First, we observed that Tollip was down-regulated in human failing hearts and murine hypertrophic hearts, as determined by western blotting and RT–PCR. Using cultured neonatal rat cardiomyocytes, we found that adenovirus vector-mediated overexpression of Tollip limited angiotensin II-induced cell hypertrophy; whereas knockdown of Tollip by shRNA exhibited the opposite effects. We then generated a transgenic (TG) mouse model with cardiac specific-overexpression of Tollip and subjected them to aortic banding (AB) for 8 weeks. When compared with AB-treated wild-type mouse hearts, Tollip-TGs showed a significant attenuation of cardiac hypertrophy, fibrosis, and dysfunction, as measured by echocardiography, immune-staining, and molecular/biochemical analysis. Conversely, a global Tollip-knockout mouse model revealed an aggravated cardiac hypertrophy and accelerated maladaptation to chronic pressure overloading. Mechanistically, we discovered that Tollip interacted with AKT and suppressed its downstream signalling pathway. Pre-activation of AKT in cardiomyocytes largely offset the Tollip-elicited anti-hypertrophic effects.
Our results provide the first evidence that Tollip serves as a negative regulator of pathological cardiac hypertrophy by blocking the AKT signalling pathway.
PMCID: PMC3968303  PMID: 24285748
Tollip; Cardiac remodelling; Pressure overload; AKT; Cardiomyocyte hypertrophy
9.  miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways 
The Journal of Clinical Investigation  2014;124(10):4489-4502.
Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell–associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance–associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a–dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a–centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.
PMCID: PMC4191031  PMID: 25202981
11.  Attribute-Based Proxy Re-Encryption with Keyword Search 
PLoS ONE  2014;9(12):e116325.
Keyword search on encrypted data allows one to issue the search token and conduct search operations on encrypted data while still preserving keyword privacy. In the present paper, we consider the keyword search problem further and introduce a novel notion called attribute-based proxy re-encryption with keyword search (), which introduces a promising feature: In addition to supporting keyword search on encrypted data, it enables data owners to delegate the keyword search capability to some other data users complying with the specific access control policy. To be specific, allows (i) the data owner to outsource his encrypted data to the cloud and then ask the cloud to conduct keyword search on outsourced encrypted data with the given search token, and (ii) the data owner to delegate other data users keyword search capability in the fine-grained access control manner through allowing the cloud to re-encrypted stored encrypted data with a re-encrypted data (embedding with some form of access control policy). We formalize the syntax and security definitions for , and propose two concrete constructions for : key-policy and ciphertext-policy . In the nutshell, our constructions can be treated as the integration of technologies in the fields of attribute-based cryptography and proxy re-encryption cryptography.
PMCID: PMC4280219  PMID: 25549257
12.  Recombinant Treponema pallidum Protein Tp0965 Activates Endothelial Cells and Increases the Permeability of Endothelial Cell Monolayer 
PLoS ONE  2014;9(12):e115134.
The recombinant Treponema pallidum protein Tp0965 (rTp0965), one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs) with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells) to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis.
PMCID: PMC4267829  PMID: 25514584
13.  Genomes of the rice pest brown planthopper and its endosymbionts reveal complex complementary contributions for host adaptation 
Genome Biology  2014;15(12):521.
The brown planthopper, Nilaparvata lugens, the most destructive pest of rice, is a typical monophagous herbivore that feeds exclusively on rice sap, which migrates over long distances. Outbreaks of it have re-occurred approximately every three years in Asia. It has also been used as a model system for ecological studies and for developing effective pest management. To better understand how a monophagous sap-sucking arthropod herbivore has adapted to its exclusive host selection and to provide insights to improve pest control, we analyzed the genomes of the brown planthopper and its two endosymbionts.
We describe the 1.14 gigabase planthopper draft genome and the genomes of two microbial endosymbionts that permit the planthopper to forage exclusively on rice fields. Only 40.8% of the 27,571 identified Nilaparvata protein coding genes have detectable shared homology with the proteomes of the other 14 arthropods included in this study, reflecting large-scale gene losses including in evolutionarily conserved gene families and biochemical pathways. These unique genomic features are functionally associated with the animal’s exclusive plant host selection. Genes missing from the insect in conserved biochemical pathways that are essential for its survival on the nutritionally imbalanced sap diet are present in the genomes of its microbial endosymbionts, which have evolved to complement the mutualistic nutritional needs of the host.
Our study reveals a series of complex adaptations of the brown planthopper involving a variety of biological processes, that result in its highly destructive impact on the exclusive host rice. All these findings highlight potential directions for effective pest control of the planthopper.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0521-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4269174  PMID: 25609551
14.  Stroke Increases Neural Stem Cells and Angiogenesis in the Neurogenic Niche of the Adult Mouse 
PLoS ONE  2014;9(12):e113972.
The unique cellular and vascular architecture of the adult ventricular-subventricular zone (V/SVZ) neurogenic niche plays an important role in regulating neural stem cell function. However, the in vivo identification of neural stem cells and their relationship to blood vessels within this niche in response to stroke remain largely unknown. Using whole-mount preparation of the lateral ventricle wall, we examined the architecture of neural stem cells and blood vessels in the V/SVZ of adult mouse over the course of 3 months after onset of focal cerebral ischemia. Stroke substantially increased the number of glial fibrillary acidic protein (GFAP) positive neural stem cells that are in contact with the cerebrospinal fluid (CSF) via their apical processes at the center of pinwheel structures formed by ependymal cells residing in the lateral ventricle. Long basal processes of these cells extended to blood vessels beneath the ependymal layer. Moreover, stroke increased V/SVZ endothelial cell proliferation from 2% in non-ischemic mice to 12 and 15% at 7 and 14 days after stroke, respectively. Vascular volume in the V/SVZ was augmented from 3% of the total volume prior to stroke to 6% at 90 days after stroke. Stroke-increased angiogenesis was closely associated with neuroblasts that expanded to nearly encompass the entire lateral ventricular wall in the V/SVZ. These data indicate that stroke induces long-term alterations of the neural stem cell and vascular architecture of the adult V/SVZ neurogenic niche. These post-stroke structural changes may provide insight into neural stem cell mediation of stroke-induced neurogenesis through the interaction of neural stem cells with proteins in the CSF and their sub-ependymal neurovascular interaction.
PMCID: PMC4250076  PMID: 25437857
15.  Good neurological recovery after rescue thrombolysis of presumed pulmonary embolism despite prior 100 minutes CPR 
Journal of Thoracic Disease  2014;6(12):E289-E293.
We reported the case of a 70-year-old man who was admitted to neurologic wards for recurrent syncope for 3 years. Unfortunately, just 2 hours after his admission, he suddenly collapsed and failed to return of spontaneous circulation (ROSC) after a 100-minute standard cardiopulmonary resuscitation (CPR). Fortunately, he was timely suspected to have pulmonary embolism (PE) based on his sedentary lifestyle, elevated D-dimer and markedly enlarged right ventricle chamber on bedside echocardiography. After a rescue thrombolytic alteplase therapy, he was successfully resuscitated and good neurological recovery was achieved.
PMCID: PMC4283306  PMID: 25590010
Cardiac arrest; pulmonary embolism (PE); thrombolysis
Nuclear technology  2013;183(1):101-106.
Monte Carlo simulations are increasingly used to reconstruct dose distributions in radiotherapy research studies. Many studies have used the MCNPX Monte Carlo code with a mesh tally for dose reconstructions. However, when the number of voxels in the simulated patient anatomy is large, the computation time for a mesh tally can become prohibitively long. The purpose of this work was to test the feasibility of using lattice tally instead of mesh tally for whole-body dose reconstructions. We did this by comparing the dosimetric accuracy and computation time of lattice tallies with those of mesh tallies for craniospinal proton irradiation. The two tally methods generated nearly identical dosimetric results, within 1% in dose and within 1 mm distance-to-agreement for 99% of the voxels. For a typical craniospinal proton treatment field, simulation speed was 4 to 17 times faster using the lattice tally than using the mesh tally, depending on the numbers of proton histories and voxels. We conclude that the lattice tally is an acceptable substitute for the mesh tally in dose reconstruction, making it a suitable potential candidate for clinical treatment planning.
PMCID: PMC4244884  PMID: 25435594
dose reconstruction; lattice tally; mesh tally
17.  A marine inducible prophage vB_CibM-P1 isolated from the aerobic anoxygenic phototrophic bacterium Citromicrobium bathyomarinum JL354 
Scientific Reports  2014;4:7118.
A prophage vB_CibM-P1 was induced by mitomycin C from the epipelagic strain Citromicrobium bathyomarinum JL354, a member of the alpha-IV subcluster of marine aerobic anoxygenic phototrophic bacteria (AAPB). The induced bacteriophage vB_CibM-P1 had Myoviridae-like morphology and polyhedral heads (approximately capsid 60–100 nm) with tail fibers. The vB_CibM-P1 genome is ~38 kb in size, with 66.0% GC content. The genome contains 58 proposed open reading frames that are involved in integration, DNA packaging, morphogenesis and bacterial lysis. VB_CibM-P1 is a temperate phage that can be directly induced in hosts. In response to mitomycin C induction, virus-like particles can increase to 7 × 109 per ml, while host cells decrease an order of magnitude. The vB_CibM-P1 bacteriophage is the first inducible prophage from AAPB.
PMCID: PMC4236739  PMID: 25406510
18.  Growth and properties of Li, Ta modified (K,Na)NbO3 lead-free piezoelectric single crystals 
Li, Ta modified (K,Na)NbO3 single crystals with the size of 18 mm × 18 mm × 10 mm were successfully grown by top-seeded solution growth method, with orthorhombic–tetragonal phase transition temperature ~79 °C and Curie temperature ~276 °C. The electromechanical coupling factors k33 and kt were found to be ~88% and ~65%, respectively. The piezoelectric coefficient d33 for the [001]c poled crystals reached 255 pC/N. In addition, the electromechanical coupling factor exhibited high stability over the temperature range of −50 °C to 70 °C, making these lead free crystals good candidates for electromechanical applications.
PMCID: PMC4232956  PMID: 25404953
lead-free; KNN single crystals; electromechanical coupling factor; thermal stability
19.  Seed Dormancy, Seedling Establishment and Dynamics of the Soil Seed Bank of Stipa bungeana (Poaceae) on the Loess Plateau of Northwestern China 
PLoS ONE  2014;9(11):e112579.
Studying seed dormancy and its consequent effect can provide important information for vegetation restoration and management. The present study investigated seed dormancy, seedling emergence and seed survival in the soil seed bank of Stipa bungeana, a grass species used in restoration of degraded land on the Loess Plateau in northwest China. Dormancy of fresh seeds was determined by incubation of seeds over a range of temperatures in both light and dark. Seed germination was evaluated after mechanical removal of palea and lemma (hulls), chemical scarification and dry storage. Fresh and one-year-stored seeds were sown in the field, and seedling emergence was monitored weekly for 8 weeks. Furthermore, seeds were buried at different soil depths, and then retrieved every 1 or 2 months to determine seed dormancy and seed viability in the laboratory. Fresh seeds (caryopses enclosed by palea and lemma) had non-deep physiological dormancy. Removal of palea and lemma, chemical scarification, dry storage (afterripening), gibberellin (GA3) and potassium nitrate (KNO3) significantly improved germination. Dormancy was completely released by removal of the hulls, but seeds on which hulls were put back to their original position germinated to only 46%. Pretreatment of seeds with a 30% NaOH solution for 60 min increased germination from 25% to 82%. Speed of seedling emergence from fresh seeds was significantly lower than that of seeds stored for 1 year. However, final percentage of seedling emergence did not differ significantly for seeds sown at depths of 0 and 1 cm. Most fresh seeds of S. bungeana buried in the field in early July either had germinated or lost viability by September. All seeds buried at a depth of 5 cm had lost viability after 5 months, whereas 12% and 4% seeds of those sown on the soil surface were viable after 5 and 12 months, respectively.
PMCID: PMC4232413  PMID: 25396423
20.  Reporting Quality of Systematic Reviews/Meta-Analyses of Acupuncture 
PLoS ONE  2014;9(11):e113172.
The QUOROM and PRISMA statements were published in 1999 and 2009, respectively, to improve the consistency of reporting systematic reviews (SRs)/meta-analyses (MAs) of clinical trials. However, not all SRs/MAs adhere completely to these important standards. In particular, it is not clear how well SRs/MAs of acupuncture studies adhere to reporting standards and which reporting criteria are generally ignored in these analyses.
To evaluate reporting quality in SRs/MAs of acupuncture studies.
We performed a literature search for studies published prior to 2014 using the following public archives: PubMed, EMBASE, Web of Science, the Cochrane Database of Systematic Reviews (CDSR), the Chinese Biomedical Literature Database (CBM), the Traditional Chinese Medicine (TCM) database, the Chinese Journal Full-text Database (CJFD), the Chinese Scientific Journal Full-text Database (CSJD), and the Wanfang database. Data were extracted into pre-prepared Excel data-extraction forms. Reporting quality was assessed based on the PRISMA checklist (27 items).
Of 476 appropriate SRs/MAs identified in our search, 203, 227, and 46 were published in Chinese journals, international journals, and the Cochrane Database, respectively. In 476 SRs/MAs, only 3 reported the information completely. By contrast, approximately 4.93% (1/203), 8.81% (2/227) and 0.00% (0/46) SRs/Mas reported less than 10 items in Chinese journals, international journals and CDSR, respectively. In general, the least frequently reported items (reported≤50%) in SRs/MAs were “protocol and registration”, “risk of bias across studies”, and “additional analyses” in both methods and results sections.
SRs/MAs of acupuncture studies have not comprehensively reported information recommended in the PRISMA statement. Our study underscores that, in addition to focusing on careful study design and performance, attention should be paid to comprehensive reporting standards in SRs/MAs on acupuncture studies.
PMCID: PMC4232579  PMID: 25397774
21.  DAMGO in the central amygdala alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia 
Neuroscience  2013;252:10.1016/j.neuroscience.2013.08.030.
Pain has sensory-discriminative and emotional-affective dimensions. Recent studies show that the affective component can be assessed with a conditioned place avoidance (CPA) test. We hypothesized that systemic morphine before a post-conditioning test would more potently attenuate the affective aspect compared to the sensory component and that DAMGO, a μ-selective opioid receptor agonist, injected into the central nucleus of the amygdala (CeA) would reduce established CPA. A rat model of inflammatory pain, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a CPA test. Three experiments were performed on adult male Sprague-Dawley rats. Systemic morphine (0.5 or 1.0 mg/kg) in Experiment 1, intrathecal (i.t.) morphine (2.5 μg/rat) in Experiment 2, and intra-CeA DAMGO (7.7-15.4 ng/0.4μl) in Experiment 3 were given to CFA-injected rats (n=6-8/group) prior to a post-conditioning test. Saline-injected rats were used as control. Time spent in a pain-paired compartment was recorded twice, before conditioning and after a post-conditioning test. Paw withdrawal latency (PWL) to a noxious thermal stimulus was measured before experiment at day −1 and after the post-conditioning test; hyperalgesia was defined as a decrease in PWL. The data showed that CFA-injected rats had significantly negative CPA compared to those of saline-injected rats (P<0.05). Low dosage systemic morphine significantly (P<0.05) reduced CFA-induced CPA but had no effect on PWL. I.t. morphine did not inhibit the display of CPA but significantly increased PWL, suppressing hyperalgesia (P<0.05). Intra-CeA DAMGO significantly inhibited the display of CPA compared to saline (P<0.05) but had no effect on PWL. The data demonstrates that morphine attenuates the affective component more powerfully than it does the sensory and suggests that the sensory and the emotional-affective dimensions are underpinned by different mechanisms.
PMCID: PMC3864641  PMID: 23994597
Conditioned place avoidance; pain; opioid; amygdala; spinal cord; hyperalgesia
22.  Reflection-mode in vivo photoacoustic microscopy with subwavelength lateral resolution 
Biomedical Optics Express  2014;5(12):4235-4241.
We developed a reflection-mode subwavelength-resolution photoacoustic microscopy system capable of imaging optical absorption contrast in vivo. The simultaneous high-resolution and reflection-mode imaging capacity of the system was enabled by delicately configuring a miniature high-frequency ultrasonic transducer tightly under a water-immersion objective with numerical aperture of 1.0. At 532-nm laser illumination, the lateral resolution of the system was measured to be ~320 nm. With this system, subcellular structures of red blood cells and B16 melanoma cells were resolved ex vivo; microvessels, including individual capillaries, in a mouse ear were clearly imaged label-freely in vivo, using the intrinsic optical absorption from hemoglobin. The current study suggests that, the optical-absorption contrast, subwavelength resolution, and reflection-mode ability of the developed photoacoustic microscopy may empower a wide range of biomedical studies for visualizing cellular and/or subcellular structures.
PMCID: PMC4285601  PMID: 25574435
(170.5120) Photoacoustic imaging; (180.0180) Microscopy; (170.3880) Medical and biological imaging
23.  Draft Genome Sequence of a Novel SAR11 Clade Species Abundant in a Tibetan Lake 
Genome Announcements  2014;2(6):e01137-14.
SAR11 clade bacteria are abundant and play a key role in the nutrient cycles of marine and, presumably, inland aquatic environments. We report here the draft genome sequence of a novel species in the SAR11 cluster, reconstructed from a metagenomic data set obtained from a Tibetan lake.
PMCID: PMC4223464  PMID: 25377713
24.  Horizontal and Vertical Distribution of Marine Virioplankton: A Basin Scale Investigation Based on a Global Cruise 
PLoS ONE  2014;9(11):e111634.
Despite the fact that marine viruses have been increasingly studied in the last decade, there is little information on viral abundance and distribution on a global scale. In this study, we report on a global-scale survey covering the Pacific, Atlantic, and Indian Oceans on viral distribution using flow cytometry. Viruses were stained with the SYBR Green I, which targets only dsDNA viruses. The average viral abundance was 1.10±0.73×107 ml−1 in global surface oceans and decreased from the areas with high chlorophyll concentration (on average, 1.47±0.78×107 ml−1) to the oligotrophic subtropical gyres (on average, 6.34±2.18×106 ml−1). On a large-spatial-scale, viruses displayed significant relationships with both heterotrophic and autotrophic picoplankton abundance, suggesting that viral distribution is dependent on their host cell abundance. Our study provided a basin scale pattern of marine viral distributions and their relationship with major host cells, indicating that viruses play a significant role in the global marine ecosystem.
PMCID: PMC4218788  PMID: 25365318
25.  Benchmark measurements and simulations of dose perturbations due to metallic spheres in proton beams 
Radiation measurements  2013;58:37-44.
Monte Carlo simulations are increasingly used for dose calculations in proton therapy due to its inherent accuracy. However, dosimetric deviations have been found using Monte Carlo code when high density materials are present in the proton beam line. The purpose of this work was to quantify the magnitude of dose perturbation caused by metal objects. We did this by comparing measurements and Monte Carlo predictions of dose perturbations caused by the presence of small metal spheres in several clinical proton therapy beams as functions of proton beam range, spread-out Bragg peak width and drift space. Monte Carlo codes MCNPX, GEANT4 and Fast Dose Calculator (FDC) were used. Generally good agreement was found between measurements and Monte Carlo predictions, with the average difference within 5% and maximum difference within 17%. The modification of multiple Coulomb scattering model in MCNPX code yielded improvement in accuracy and provided the best overall agreement with measurements. Our results confirmed that Monte Carlo codes are well suited for predicting multiple Coulomb scattering in proton therapy beams when short drift spaces are involved.
PMCID: PMC4136527  PMID: 25147474
Proton beam; multiple Coulomb scattering; dose perturbation; Monte Carlo simulation

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