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1.  Analysis of computed tomography and pathological observations of non-Hodgkin lymphomas with peritoneal, omental and mesenteric involvement 
The aim of the present study was to evaluate the association between computed tomography (CT) images and the pathological observations of non-Hodgkin lymphoma (NHL) patients with peritoneal, omental and mesenteric involvement. In total, 26 patients suffering from an NHL with peritoneal, omental or mesenteric involvement were reviewed retrospectively, and the observed CT scan characteristics were analyzed. In addition, associations among the CT scan characteristics and the NHL subtypes, including diffuse large B-cell, mantle cell, follicular cell and T-cell lymphoma, were evaluated. The CT scan characteristics of the NHLs with peritoneal, omental and mesenteric involvement included peritoneal cord-like thickening, peritoneal omental nodular and swelling thickening, omental cake-like thickening and mesenteric mass. The probability of peritoneal linear, omental nodular and swelling thickening was found to be higher in diffuse large B-cell lymphoma cases compared with cases of other NHL subtypes (P<0.05). However, the probability of omental cake-like thickening and mesenteric mass was not found to be significantly different among the NHL subtypes (P>0.05). Signs of peritoneal, omental and mesenteric involvement were observed in the CT scans of all the NHL subtypes, particularly in diffuse large B-cell lymphoma cases. Therefore, linear, omental nodular and swelling thickening were characteristic of diffuse large B-cell lymphoma, while omental cake-like thickening and mesenteric mass were observed in all NHL subtypes.
PMCID: PMC4316982  PMID: 25667648
abdomen; non-Hodgkin lymphoma; X-ray; computed tomography
2.  Common Clinical Conditions – Age, Low BMI, Ritonavir Use, Mild Renal Impairment - Affect Tenofovir Pharmacokinetics in a Large Cohort of HIV-Infected Women 
AIDS (London, England)  2014;28(1):59-66.
Tenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world setting are unknown.
Intensive pharmacokinetic (PK) studies of tenofovir in a large, diverse cohort of HIV-infected women over 24-hours at steady-state were performed and factors that influenced exposure (assessed by areas-under-the-time-concentration curves, AUCs) identified
HIV-infected women (n=101) on tenofovir-based therapy underwent intensive 24-hour PK sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight and body mass index (BMI) were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFR) prior to starting tenofovir were estimated by the CKD-EPI equation using both creatinine and cystatin-C measures
The median (range) of tenofovir AUCs was 3350 (1031–13,911) ng x h/mL. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, p 0.002), increasing age (1.21-fold increase per decade, p=0.0007) and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR <70mL/min, p=0.0075).
Concomitant ritonavir use, increasing age, decreasing BMI and lower GFR prior to tenofovir initiation as estimated by cystatin C were all associated with elevated tenofovir exposure in a diverse cohort of HIV-infected women. Clinicians treating HIV-infected women should be aware of common clinical conditions that affect tenofovir exposure when prescribing this medication.
PMCID: PMC3956315  PMID: 24275255
Tenofovir; pharmacokinetics; HIV-infected women; diverse populations; GFR; cystatin C
3.  Short Communication: A Low-Cost Method for Analyzing Nevirapine Levels in Hair as a Marker of Adherence in Resource-Limited Settings 
The measurement of antiretroviral concentrations in hair is emerging as an important technology to objectively quantify adherence to combination antiretroviral therapy. Hair levels of antiretrovirals are the strongest independent predictor of virologic success in large prospective cohorts of HIV-infected patients and surpass self-report in predicting outcomes. Hair is easy to collect and store, but validated methods to analyze antiretroviral levels in hair using liquid chromatography tandem mass spectrometry (LC-MS/MS) are expensive. We report here on the development of a thin-layer chromatography (TLC) assay for the semiquantitative analysis of nevirapine in hair. TLC assay results from 11 samples were consistent with results using LC-MS/MS [Spearman correlation coefficient 0.99 (95% CI 0.95–0.996)]. This simple, low-cost method of analyzing nevirapine concentrations in hair may provide a novel monitoring tool for antiretroviral adherence in resource-limited settings and merits further study in clinical settings.
PMCID: PMC3887402  PMID: 24164410
4.  The Immunologic Effects of Mesalamine in Treated HIV-Infected Individuals with Incomplete CD4+ T Cell Recovery: A Randomized Crossover Trial 
PLoS ONE  2014;9(12):e116306.
The anti-inflammatory agent, mesalamine (5-aminosalicylic acid) has been shown to decrease mucosal inflammation in ulcerative colitis. The effect of mesalamine in HIV-infected individuals, who exhibit abnormal mucosal immune activation and microbial translocation (MT), has not been established in a placebo-controlled trial. We randomized 33 HIV-infected subjects with CD4 counts <350 cells/mm3 and plasma HIV RNA levels <40 copies/ml on antiretroviral therapy (ART) to add mesalamine vs. placebo to their existing regimen for 12 weeks followed by a 12 week crossover to the other arm. Compared to placebo-treated subjects, mesalamine-treated subjects did not experience any significant change in the percent CD38+HLA-DR+ peripheral blood CD4+ and CD8+ T cells at week 12 (P  = 0.38 and P  = 0.63, respectively), or in the CD4+ T cell count at week 12 (P  = 0.83). The percent CD38+HLA-DR+ CD4+ and CD8+ T cells also did not change significantly in rectal tissue (P  = 0.86, P  = 0.84, respectively). During the period of mesalamine administration, plasma sCD14, IL-6, D-dimer, and kynurenine to tryptophan ratio were not changed significantly at week 12 and were similarly unchanged at week 24. This study suggests that, at least under the conditions studied, the persistent immune activation associated with HIV infection is not impacted by the anti-inflammatory effects of mesalamine.
Trial Registration NCT01090102
PMCID: PMC4283685  PMID: 25545673
5.  Acetylcholine Induces Mesenchymal Stem Cell Migration via Ca2+/PKC/ERK1/2 Signal Pathway 
Journal of cellular biochemistry  2012;113(8):2704-2713.
Acetylcholine (ACh) plays an important role in neural and non-neural function, but its role in mesenchymal stem cell (MSC) migration remains to be determined. In the present study, we have found that ACh induces MSC migration via muscarinic acetylcholine receptors (mAChRs). Among several mAChRs, MSCs express mAChR subtype 1 (m1AChR). ACh induces MSC migration via interaction with mAChR1. MEK1/2 inhibitor PD98059 blocks ERK1/2 phosphorylation while partially inhibiting the ACh-induced MSC migration. InsP3Rs inhibitor 2-APB that inhibits MAPK/ERK phosphorylation completely blocks Ach-mediated MSC migration. Interestingly, intracellular Ca2+ ATPase specific inhibitor thapsigargin also completely blocks ACh-induced MSC migration through the depletion of intracellular Ca2+ storage. PKCα or PKCβ inhibitor or their siRNAs only partially inhibit ACh-induced MSC migration, but PKC-ζ siRNA completely inhibits ACh-induced MSC migration via blocking ERK1/2 phosphorylation. These results indicate that ACh induces MSC migration via Ca2+, PKC and ERK1/2 signal pathways.
PMCID: PMC4263956  PMID: 22441978
Mesenchymal stem cell; Acetylcholine; Migration; Protein kinase C; Ras mitogen-activated protein kinase; Calcium; Muscarinic receptors; ERK1/2
6.  Soil nitric oxide emissions from terrestrial ecosystems in China: a synthesis of modeling and measurements 
Scientific Reports  2014;4:7406.
Soils are among the major sources of atmospheric nitric oxide (NO), which play a crucial role in atmospheric chemistry. Here we systematically synthesized the modeling studies and field measurements and presented a novel soil NO emission inventory of terrestrial ecosystems in China. The previously modeled inventories ranged from 480 to 1375 and from 242.8 to 550 Gg N yr−1 for all lands and croplands, respectively. Nevertheless, all the previous modeling studies were conducted based on very few measurements from China. According to the current synthesis of field measurements, most soil NO emission measurements were conducted at croplands, while the measurements were only conducted at two sites for forest and grassland. The median NO flux was 3.2 ng N m−2 s−1 with a fertilizer induced emission factor (FIE) of 0.04% for rice fields, and was 7.1 ng N m−2 s−1 with an FIE of 0.67% for uplands. A novel NO emission inventory of 1226.33 (ranging from 588.24 to 2132.05) Gg N yr−1 was estimated for China's terrestrial ecosystems, which was about 18% of anthropogenic emissions. More field measurements should be conducted to cover more biomes and obtain more representative data in order to well constrain soil NO emission inventory of China.
PMCID: PMC4261933  PMID: 25490942
7.  Mycorrhizal-induced calmodulin mediated changes in antioxidant enzymes and growth response of drought-stressed trifoliate orange 
Trifoliate orange [Poncirus trifoliata (L) Raf.] is considered highly arbuscular mycorrhizal (AM) dependent for growth responses through a series of signal transductions in form of various physiological responses. The proposed study was carried out to evaluate the effect of an AM fungus (Funneliformis mosseae) on growth, antioxidant enzyme (catalase, CAT; superoxide dismutase, SOD) activities, leaf relative water content (RWC), calmodulin (CaM), superoxide anion (O2•−), and hydrogen peroxide (H2O2) concentrations in leaves of the plants exposed to both well-watered (WW) and drought stress (DS) conditions. A 58-day of DS significantly decreased mycorrhizal colonization by 60% than WW. Compared to non-AM seedlings, AM seedlings displayed significantly higher shoot morphological properties (plant height, stem diameter, and leaf number), biomass production (shoot and root fresh weight) and leaf RWC, regardless of soil water status. AM inoculation significantly increased CaM and soluble protein concentrations and CAT activity, whereas significantly decreased O2•− and H2O2 concentration under both WW and DS conditions. The AM seedlings also exhibited significantly higher Cu/Zn-SOD and Mn-SOD activities than the non-AM seedlings under DS but not under WW, which are triggered by higher CaM levels in AM plants on the basis of correlation studies. Further, the negative correlation of Cu/Zn-SOD and Mn-SOD activities with O2•− and H2O2 concentration showed the DS-induced ROS scavenging ability of CaM mediated SODs under mycorrhization. Our results demonstrated that AM-inoculation elevated the synthesis of CaM in leaves and up-regulated activities of the antioxidant enzymes, thereby, repairing the possible oxidative damage to plants by lowering the ROS accumulation under DS condition.
PMCID: PMC4257356  PMID: 25538696
CaM; Cu/Zn-SOD; drought stress; Mn-SOD; mycorrhizal fungi; ROS; trifoliate orange
8.  MEMS-Based Handheld Fourier Domain Doppler Optical Coherence Tomography for Intraoperative Microvascular Anastomosis Imaging 
PLoS ONE  2014;9(12):e114215.
To demonstrate the feasibility of a miniature handheld optical coherence tomography (OCT) imager for real time intraoperative vascular patency evaluation in the setting of super-microsurgical vessel anastomosis.
A novel handheld imager Fourier domain Doppler optical coherence tomography based on a 1.3-µm central wavelength swept source for extravascular imaging was developed. The imager was minimized through the adoption of a 2.4-mm diameter microelectromechanical systems (MEMS) scanning mirror, additionally a 12.7-mm diameter lens system was designed and combined with the MEMS mirror to achieve a small form factor that optimize functionality as a handheld extravascular OCT imager. To evaluate in-vivo applicability, super-microsurgical vessel anastomosis was performed in a mouse femoral vessel cut and repair model employing conventional interrupted suture technique as well as a novel non-suture cuff technique. Vascular anastomosis patency after clinically successful repair was evaluated using the novel handheld OCT imager.
With an adjustable lateral image field of view up to 1.5 mm by 1.5 mm, high-resolution simultaneous structural and flow imaging of the blood vessels were successfully acquired for BALB/C mouse after orthotopic hind limb transplantation using a non-suture cuff technique and BALB/C mouse after femoral artery anastomosis using a suture technique. We experimentally quantify the axial and lateral resolution of the OCT to be 12.6 µm in air and 17.5 µm respectively. The OCT has a sensitivity of 84 dB and sensitivity roll-off of 5.7 dB/mm over an imaging range of 5 mm. Imaging with a frame rate of 36 Hz for an image size of 1000(lateral)×512(axial) pixels using a 50,000 A-lines per second swept source was achieved. Quantitative vessel lumen patency, lumen narrowing and thrombosis analysis were performed based on acquired structure and Doppler images.
A miniature handheld OCT imager that can be used for intraoperative evaluation of microvascular anastomosis was successfully demonstrated.
PMCID: PMC4256419  PMID: 25474742
9.  A city park as a potential epidemic site of scrub typhus: a case–control study of an outbreak in Guangzhou, China 
Parasites & Vectors  2014;7(1):513.
Scrub typhus is an important public health problem in China, especially in Guangzhou city. Typical outbreaks of scrub typhus have been previously reported in rural areas, affecting mainly farmers. We describe an atypical outbreak of the disease with case fatalities, from a park in Haizhu District, Guangzhou, that could turn out to be a potential scrub typhus epidemic site.
From May 2012 to June 2012, a case–control study was conducted to identify source and risk factors of this outbreak. Reported cases of scrub typhus in Xiaogang Park were confirmed by Weil–Felix test or a nested polymerase chain reaction (NPCR). Controls were matched with their neighbors by gender and age. Multivariate conditional logistic regression was used to identify risk factors and protective factors.
A total of 29 cases were confirmed by Weil–Felix test, including 4 deaths by both Weil–Felix test and NPCR. All patients presented with fever (100%), while 28 (96.6%) cases had eschars, 10 (34.5%) headache, 10 (34.5%) chills, 6 (20.7%) lymphadenopathy, 5 (17.2%) rash, 2 (6.9%) vomiting and 1 (3.5%) presented with conjunctival congestion. The proportion of cases with activity history in Xiaogang Park was much higher than the control group (72.4% vs 24.1%, P < 0.001), and morning exercise in park or field was also as a risk factor for scrub typhus (adjusted OR = 3.0, 95% CI: 1.1 - 8.2). Four factors were significantly associated with the risk of developing scrub typhus: sitting on the lawn (adjusted OR = 8.0, 95% CI: 1.4 - 44.5), close contact with rats (adjusted OR = 3.3, 95% CI: 1.2 -9.6), sitting near the rat holes (OR = 6.8, 95% CI: 1.2 - 38.1) and wearing long-sleeved clothing when outside (adjusted OR = 0.3, 95% CI: 0.1 - 0.7).
We confirmed an atypical outbreak of scrub typhus in a park in Guangzhou city, which has the potential to develop into an important epidemic site. This public health risk should not be neglected and requires more attention from authorities.
PMCID: PMC4240828  PMID: 25403988
City; Park; Scrub typhus; Epidemiology
10.  Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase 
Science translational medicine  2013;5(183):183ra56-11.
Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.
PMCID: PMC4220792  PMID: 23636092
11.  Multi-Enhanced-Phonon Scattering Modes in Ln-Me-A Sites co-substituted LnMeA11O19 Ceramics 
Scientific Reports  2014;4:6823.
Authors reported an effective path to decrease the thermal conductivity while to increase the coefficient of thermal expansion, thus enhancing the thermo-physical properties of the LnMeA11O19-type magnetoplumbite LaMgAl11O19 by simultaneously substituting La3+, Mg2+ and Al3+ ions with large ionic radius Ba2+, Zn2+ and Ti4+, respectively. The mechanism behind the lowered thermal conductivity was mainly due to the multi-enhanced-phonon scattering modes in Ln-Me-A sites co-substituted LnMeA11O19 ceramics. These modes involve the following four aspects, namely, point defect mechanism, the intrinsic scattering in the complex crystal cell and materials with stepped surface to localize phonon vibrational modes, as well as nano-platelet-like structure to incorporate additional grain boundary scattering. This study provides novel thoughts for promising candidate materials of even lower thermal conductivity for the next generation thermal barrier coatings.
PMCID: PMC4212246  PMID: 25351166
12.  Neuroprotective effect of RYGB in Zucker fatty diabetic rats 
The aim of this study is to explore the therapeutic potential of RYGB, a common used bariatric surgery, on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic rats. In animal model experiments, rats were made diabetic by STZ administration, and after 12 weeks of diabetes, two groups were studied: RYGB and sham surgery control (PF). Change in oral glucose tolerance, insulin sensitivity, and the plasma concentrations of insulin, glucagon, glucagon-like peptide-1 (GLP-1) were measured. Peripheral nerve function was determined by the current perception threshold. Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated. The results indicated that glucose tolerance and insulin sensitivity were significantly improved in the RYGB group. Fasting total GLP-1 were increased in the RYGB group. The increase seen in current perception threshold vales in RYGB group was reduced. The decreased IENFDs in sole skins of RYGB group were ameliorated by RYGB. In conclusion, the findings indicate that RYGB ameliorates the severity of DPN, which may be associated with increased GLP-1 and improved insulin sensitivity/action.
PMCID: PMC4238512  PMID: 25419361
Roux-en-Y gastric bypass; diabetes; glucagon-like peptide-1; insulin sensitivity
13.  Volumetric (3D) compressive sensing spectral domain optical coherence tomography 
Biomedical Optics Express  2014;5(11):3921-3934.
In this work, we proposed a novel three-dimensional compressive sensing (CS) approach for spectral domain optical coherence tomography (SD OCT) volumetric image acquisition and reconstruction. Instead of taking a spectral volume whose size is the same as that of the volumetric image, our method uses a sub set of the original spectral volume that is under-sampled in all three dimensions, which reduces the amount of spectral measurements to less than 20% of that required by the Shan-non/Nyquist theory. The 3D image is recovered from the under-sampled spectral data dimension-by-dimension using the proposed three-step CS reconstruction strategy. Experimental results show that our method can significantly reduce the sampling rate required for a volumetric SD OCT image while preserving the image quality.
PMCID: PMC4242027  PMID: 25426320
(170.4500) Optical coherence tomography; (100.3010) Image reconstruction techniques
14.  Genome-wide DNA Methylation Profiles and Their Relationships with mRNA and the microRNA Transcriptome in Bovine Muscle Tissue (Bos taurine) 
Scientific Reports  2014;4:6546.
DNA methylation is a key epigenetic modification in mammals and plays important roles in muscle development. We sampled longissimus dorsi muscle (LDM) from a well-known elite native breed of Chinese Qinchuan cattle living within the same environment but displaying distinct skeletal muscle at the fetal and adult stages. We generated and provided a genome-wide landscape of DNA methylomes and their relationship with mRNA and miRNA for fetal and adult muscle studies. Integration analysis revealed a total of 77 and 1,054 negatively correlated genes with methylation in the promoter and gene body regions, respectively, in both the fetal and adult bovine libraries. Furthermore, we identified expression patterns of high-read genes that exhibit a negative correlation between methylation and expression from nine different tissues at multiple developmental stages of bovine muscle-related tissue or organs. In addition, we validated the MeDIP-Seq results by bisulfite sequencing PCR (BSP) in some of the differentially methylated promoters. Together, these results provide valuable data for future biomedical research and genomic and epigenomic studies of bovine skeletal muscle that may help uncover the molecular basis underlying economically valuable traits in cattle. This comprehensive map also provides a solid basis for exploring the epigenetic mechanisms of muscle growth and development.
PMCID: PMC4194443  PMID: 25306978
15.  Fenobam Sulfate Inhibits Cocaine-Taking and Cocaine-Seeking Behavior in Rats: Implications for Addiction Treatment in Humans 
Psychopharmacology  2013;229(2):253-265.
The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be critically involved in drug reward and addiction. Because the mGluR5 negative allosteric modulators (NAMs) MPEP and MTEP significantly inhibit addictive-like behaviors of cocaine and other drugs of abuse in experimental animals, it has been suggested that mGluR5 NAMs may have translational potential for treatment of addiction in humans. However, neither MPEP nor MTEP have been evaluated in humans due to their off-target actions and rapid metabolism.
Herein, we evaluate a potential candidate for translational addiction research: a new sulfate salt formulation of fenobam, a selective mGluR5 NAM that has been investigated in humans.
In rats, fenobam sulfate had superior pharmacokinetics compared to the free base, with improved Cmax (maximal plasma concentration) and longer half life. Oral (p.o.) administration of fenobam sulfate (30 or 60 mg/kg) inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Fenobam sulfate also inhibited oral sucrose self-administration and sucrose-induced reinstatement of sucrose-seeking behavior, but had no effect on locomotion.
This study provides additional support for the role of mGluR5 signaling in cocaine addiction and suggests that fenobam sulfate may have translational potential in medication development for the treatment of cocaine addiction in humans.
PMCID: PMC4191672  PMID: 23615919
Cocaine; fenobam; self-administration; reinstatement; cocaine-seeking behavior; incubation of cocaine craving; mGluR5
16.  Approach of the treatment for pneumothorax 
Journal of Thoracic Disease  2014;6(Suppl 4):S416-S420.
Pneumothorax can occur in several situations such as; chronic obstructive pulmonary disease (COPD) where emphysema is observed or due to a biopsy for malignancy suspicion. In any case it is a dangerous situation that requires immediate attention and treatment. Pneumothorax can be divided in primary and secondary. Staging of pneumothorax is also very important. In our current editorial we summarize etiology and treatment of pneumothorax from a panel of pulmonary physicians, oncologists and thoracic surgeons.
PMCID: PMC4203983  PMID: 25337397
Pneumothorax; medical thoracoscopy; intervention
17.  Transbronchial lung biopsy and pneumothorax 
Journal of Thoracic Disease  2014;6(Suppl 4):S443-S447.
Mini-interventional procedures are used in the everyday clinical practice by pulmonary physicians and radiologists. Fine needle aspiration and biopsy forceps are the tools mostly used. During these procedures pneumothorax can occur and immediate treatment is necessary. In our current work, we will focus on minimal invasive techniques for biopsy and pneumothorax treatment.
PMCID: PMC4203985  PMID: 25337401
Pneumothorax; intervention; bronchoscope; transbronchial needle aspiration; electromagnetic navigation bronchoscopy (ENB); endobronchial ultrasonic (EBUS)
18.  Weak base pairing in both seed and 3′ regions reduces RNAi off-targets and enhances si/shRNA designs 
Nucleic Acids Research  2014;42(19):12169-12176.
The use of RNA interference is becoming routine in scientific discovery and treatment of human disease. However, its applications are hampered by unwanted effects, particularly off-targeting through miRNA-like pathways. Recent studies suggest that the efficacy of such off-targeting might be dependent on binding stability. Here, by testing shRNAs and siRNAs of various GC content in different guide strand segments with reporter assays, we establish that weak base pairing in both seed and 3′ regions is required to achieve minimal off-targeting while maintaining the intended on-target activity. The reduced off-targeting was confirmed by RNA-Seq analyses from mouse liver RNAs expressing various anti-HCV shRNAs. Finally, our protocol was validated on a large scale by analyzing results of a genome-wide shRNA screen. Compared with previously established work, the new algorithm was more effective in reducing off-targeting without jeopardizing on-target potency. These studies provide new rules that should significantly improve on siRNA/shRNA design.
PMCID: PMC4231738  PMID: 25270879
19.  Peripheral Blood Mononuclear Cell Gene Expression Profiles Predict Poor Outcome in Idiopathic Pulmonary Fibrosis 
Science translational medicine  2013;5(205):205ra136.
We aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) by performing microarray experiments of PBMCs in discovery and replication cohorts of IPF patients. Microarray analyses identified 52 genes associated with transplant-free survival (TFS) in the discovery cohort. Clustering the microarray samples of the replication cohort using the 52-gene outcome-predictive signature distinguished two patient groups with significant differences in TFS. We studied the pathways associated with TFS in each independent microarray cohort and identified decreased expression of “The costimulatory signal during T cell activation” Biocarta pathway and, in particular, the genes CD28, ICOS, LCK, and ITK, results confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A proportional hazards model, including the qRT-PCR expression of CD28, ICOS, LCK, and ITK along with patient’s age, gender, and percent predicted forced vital capacity (FVC%), demonstrated an area under the receiver operating characteristic curve of 78.5% at 2.4 months for death and lung transplant prediction in the replication cohort. To evaluate the potential cellular source of CD28, ICOS, LCK, and ITK expression, we analyzed and found significant correlation of these genes with the PBMC percentage of CD4+CD28+ T cells in the replication cohort. Our results suggest that CD28, ICOS, LCK, and ITK are potential outcome biomarkers in IPF and should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.
PMCID: PMC4175518  PMID: 24089408
20.  N-n-butyl haloperidol iodide inhibits H2O2-induced Na+/Ca2+-exchanger activation via the Na+/H+ exchanger in rat ventricular myocytes 
N-n-butyl haloperidol iodide (F2), a novel compound, has shown palliative effects in myocardial ischemia/reperfusion (I/R) injury. In this study, we investigated the effects of F2 on the extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/Na+/H+ exchanger (NHE)/Na+/Ca2+ exchanger (NCX) signal-transduction pathway involved in H2O2-induced Ca2+ overload, in order to probe the underlying molecular mechanism by which F2 antagonizes myocardial I/R injury. Acute exposure of rat cardiac myocytes to 100 μM H2O2 increased both NHE and NCX activities, as well as levels of phosphorylated MEK and ERK. The H2O2-induced increase in NCX current (INCX) was nearly completely inhibited by the MEK inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis[o-aminophenylmercapto] butadiene), but only partly by the NHE inhibitor 5-(N,N-dimethyl)-amiloride (DMA), indicating the INCX increase was primarily mediated by the MEK/mitogen-activated protein kinase (MAPK) pathway, and partially through activation of NHE. F2 attenuated the H2O2-induced INCX increase in a concentration-dependent manner. To determine whether pathway inhibition was H2O2-specific, we examined the ability of F2 to inhibit MEK/ERK activation by epidermal growth factor (EGF), and NHE activation by angiotensin II. F2 not only inhibited H2O2-induced and EGF-induced MEK/ERK activation, but also completely blocked both H2O2-induced and angiotensin II-induced increases in NHE activity, suggesting that F2 directly inhibits MEK/ERK and NHE activation. These results show that F2 exerts multiple inhibitions on the signal-transduction pathway involved in H2O2-induced INCX increase, providing an additional mechanism for F2 alleviating intracellular Ca2+ overload to protect against myocardial I/R injury.
PMCID: PMC4166912  PMID: 25246767
N-n-butyl haloperidol; hydrogen peroxide; Na+/Ca2+ exchanger; Na+/H+ exchanger
21.  Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8) 
Journal of pharmaceutical sciences  2013;102(9):3451-3457.
Organic anion transporter 3 (OAT3, SLC22A8), a transporter expressed on the basolateral membrane of the proximal tubule, plays a critical role in the renal excretion of organic anions including many therapeutic drugs. The goal of this study was to evaluate the in vivo effects of the OAT3-Ile305Phe variant (rs11568482), present at 3.5% allele frequency in Asians, on drug disposition with a focus on cefotaxime, a cephalosporin antibiotic. In HEK293- Flp-In cells, the OAT3-Ile305Phe variant had a lower maximum cefotaxime transport activity, Vmax, [159 ± 3 nmol*(mg protein)−1/min (mean ± SD)] compared with the reference OAT3 [305 ± 28 nmol*(mg protein)−1/min, (mean ± SD), p < 0.01], whereas the Michaelis-Menten constant values (Km) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CLR; mean ± SD: 84.8 ± 32.1 mL/min, n = 5) compared with volunteers that were homozygous for the reference allele (158 ± 44.1 mL/min, n = 10; p = 0.006). Furthermore, the net secretory component of cefotaxime renal clearance (CLsec) was reduced in volunteers heterozygous for the variant allele [33.3 ± 31.8 mL/min (mean ± SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0 ± 42.2 mL/min (mean ± SD), p = 0.01]. In summary, our study suggests that a low-frequency reduced-function polymorphism of OAT3 associates with reduced cefotaxime CLR and CLsec.
PMCID: PMC4151246  PMID: 23649425
Organic anion transporter; cefotaxime; tubular secretion; OAT3; polymorphisms; pharmacogenomics; pharmacokinetics; renal clearance
22.  Insights from ecological niche modeling on the taxonomic distinction and niche differentiation between the black-spotted and red-spotted tokay geckoes (Gekko gecko) 
Ecology and Evolution  2014;4(17):3383-3394.
The black-spotted tokay and the red-spotted tokay are morphologically distinct and have largely allopatric distributions. The black-spotted tokay is characterized by a small body size and dark skin with sundry spots, while the red-spotted tokay has a relatively large body size and red spots. Based on morphological, karyotypic, genetic, and distribution differences, recent studies suggested their species status; however, their classifications remain controversial, and additional data such as ecological niches are necessary to establish firm hypotheses regarding their taxonomic status. We reconstructed their ecological niches models using climatic and geographic data. We then performed niche similarity tests (niche identity and background tests) and point-based analyses to explore whether ecological differentiation has occurred, and whether such differences are sufficient to explain the maintenance of their separate segments of environmental ranges. We found that both niche models of the black- and the red-spotted tokay had a good fit and a robust performance, as indicated by the high area under the curve (AUC) values (“black” = 0.982, SD = ± 0.002, “red” = 0.966 ± 0.02). Significant ecological differentiation across the entire geographic range was found, indicating that the involvement of ecological differentiation is important for species differentiation. Divergence along the environmental axes is highly associated with climatic conditions, with isothermality being important for the “black” form, while temperature seasonality, precipitation of warmest quarter, and annual temperature range together being important for the “red” form. These factors are likely important factors in niche differentiation between the two forms, which result in morphological replacement. Overall, beside morphological and genetic differentiation information, our results contribute to additional insights into taxonomic distinction and niche differentiation between the black- and the red-spotted tokay.
PMCID: PMC4228613  PMID: 25535555
Climate; ecological speciation; Gekko gecko; Gekko reevesii; MaxEnt; niche divergence; taxonomy
23.  Oxymatrine Improves Intestinal Epithelial Barrier Function Involving NF-κB-Mediated Signaling Pathway in CCl4-Induced Cirrhotic Rats 
PLoS ONE  2014;9(8):e106082.
Accumulating evidence suggests that intestinal epithelial barrier dysfunction plays an important role in the pathogenesis of hepatic cirrhosis and its complications such as gastrointestinal injury and hepatic encephalopathy. To date, there is no cure for cirrhosis-associated intestinal mucosal lesion and ulcer. This study aimed to investigate the effect of oxymatrine on intestinal epithelial barrier function and the underlying mechanism in carbon tetrachloride (CCl4)-induced cirrhotic rats. Thirty CCl4-induced cirrhotic rats were randomly divided into treatment group, which received oxymatrine treatment (63 mg/kg), and non-treatment group, which received the same dose of 5% glucose solution (vehicle). The blank group (n = 10 healthy rats) received no treatment. Terminal ileal samples were collected for histopathological examination. The expression level of nuclear factor-κB (NF-κB) p65 in ileal tissue was evaluated by immunohistochemistry. The gene and protein expression levels of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in ileal tissues were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Additionally, plasma endotoxin level was determined. In comparison to the blank group, a significant alteration in the morphology of intestinal mucosal villi in the non-treatment group was observed. The intestinal mucosal villi were atrophic, shorter, and fractured, and inflammatory cells were infiltrated into the lamina propria and muscular layer. Besides, serious swell of villi and loose structure of mucous membrane were observed. Oxymatrine reversed the CCl4-induced histological changes and restored intestinal barrier integrity. Moreover, oxymatrine reduced the protein expression level of NF-κB p65, TNF-α, and IL-6, which were elevated in the vehicle-treated group. In addition, the serum endotoxin level was significantly decreased after oxymatrine treatment in CCl4-induced cirrhotic rats. The results indicate that oxymatrine improves intestinal barrier function via NF-κB-mediated signaling pathway and may be used as a new protecting agent for cirrhosis-associated intestinal mucosal damage.
PMCID: PMC4149463  PMID: 25171482
24.  Recognition of Bungarus multicinctus Venom by a DNA Aptamer against β-Bungarotoxin 
PLoS ONE  2014;9(8):e105404.
Antibody-based technology is the main method for diagnosis and treatment of snake bite envenoming currently. However, the development of an antibody, polyclonal or monoclonal, is a complicated and costly procedure. Aptamers are single stranded oligonucleotides that recognize specific targets such as proteins and have shown great potential over the years as diagnostic and therapeutic agents. In contrast to antibodies, aptamers can be selected in vitro without immunization of animals, and synthesized chemically with extreme accuracy, low cost and high degree of purity. In this study we firstly report on the identification of DNA aptamers that bind to β-bungarotoxin (β-BuTx), a neurotoxin from the venom of Bungarus multicinctus. A plate-SELEX method was used for the selection of β-BuTx specific aptamers. After 10 rounds of selection, four aptamer candidates were obtained, with the dissociation constant ranged from 65.9 nM to 995 nM measured by fluorescence spectroscopy. Competitive binding assays using both the fluorescently labeled and unlabeled aptamers revealed that the four aptamers bound to the same binding site of β-BuTx. The best binder, βB-1, bound specifically to β-BuTx, but not to BSA, casein or α-Bungarotoxin. Moreover, electrophoretic mobility shift assay and enzyme-linked aptamer assay demonstrated that βB-1 could discriminate B. multicinctus venom from other snake venoms tested. The results suggest that aptamer βB-1 can serve as a useful tool for the design and development of drugs and diagnostic tests for β-BuTx poisoning and B. multicinctus bites.
PMCID: PMC4140777  PMID: 25144237
25.  Hair and Plasma Data Show that Lopinavir, Ritonavir and Efavirenz All Transfer from Mother to Infant in Utero, but only Efavirenz Transfers via Breastfeeding 
As efforts intensify to eliminate perinatal HIV transmission, understanding kinetics of maternal-to-child transfer of antiretrovirals during pregnancy and breastfeeding is critical. Antiretroviral levels in plasma, cord blood and breastmilk reflect exposure over short intervals. Hair concentrations reflect cumulative exposure and can uniquely quantify in-utero transfer of maternal medications to infants. We measured plasma and hair antiretroviral levels in HIV-infected Ugandan mothers and their infants at delivery and during breastfeeding to assess transfer.
HIV-infected pregnant women were randomized to lopinavir/ritonavir- or efavirenz-based therapy in a larger trial (PROMOTE). At 0, 8 and 12 weeks postpartum, plasma antiretroviral levels were measured in 117 mother-infant pairs; hair levels were assayed at 12 weeks. Ratios and correlations of infant:maternal concentrations were calculated.
By 12 weeks, 90.4% of mothers reported exclusive breastfeeding. Hair and plasma levels over time suggest moderate (47%) to extensive (87%) in-utero transfer of lopinavir and ritonavir, respectively, but negligible transfer of either via breastfeeding. Moderate transfer of efavirenz occurs during pregnancy and breastfeeding (40% cumulative; 15% during breastfeeding). Despite differences in exposure, no infant seroconversions or correlations between infant hair/plasma antiretroviral levels and adverse effects were observed.
Using a unique approach combining hair and plasma data, we found that different antiretrovirals had distinct kinetics of mother-to-infant transfer. Efavirenz transfers during both pregnancy and breastfeeding, whereas lopinavir and ritonavir transfer only in-utero. Further study of the degree and timing of maternal-to-child transfer by antiretroviral will help optimize strategies that protect infants and minimize toxicities during periods of risk.
PMCID: PMC3800282  PMID: 24135775

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