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1.  Eating high fat chow, but not drinking sucrose or saccharin, enhances the development of sensitization to the locomotor effects of cocaine in adolescent female rats 
Behavioural pharmacology  2015;26(3):321-325.
Eating high fat chow accelerates the development of sensitization to cocaine-induced locomotion in female rats. It is not known whether consumption of sucrose or saccharin also increases sensitivity to the behavioral effects of cocaine or whether continuous (or intermittent) access to these feeding conditions is necessary to change sensitivity. Adolescent female Sprague-Dawley rats were assigned to 1 of 7 feeding conditions from post natal day (PND) 25 through 60. Rats ate either high fat (60% kcal from fat) chow and drank water, or standard (17% kcal from fat) chow and drank either water, 10% sucrose solution, or 0.1% saccharin solution. Rats had either continuous access to high fat chow, sucrose or saccharin or they had intermittent access (i.e. 2 days per week) to these substances with access to water and standard chow on other days. As compared with rats eating standard chow, continuous (but not intermittent) access to high fat chow enhanced the development of sensitization to cocaine-induced (1–17.8 mg/kg) locomotion; drinking sucrose or saccharin (continuous or intermittent access) did not alter the development of sensitization to cocaine-induced locomotion. The impact of feeding condition on behavioral effects of cocaine varies between sexes and across dietary composition.
PMCID: PMC4346492  PMID: 25485647
high fat chow; sucrose; saccharin; locomotion; cocaine; sensitization; rat
2.  Association of Subclinical Atherosclerosis Using Carotid Intima-Media Thickness, Carotid Plaque, and Coronary Calcium Score with Left Ventricular Dyssynchrony: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2015;239(2):412-418.
The role of atherosclerosis in the progression of global left ventricular dysfunction and cardiovascular events has been well recognized. Left ventricular (LV) dyssynchrony is a measure of regional myocardial dysfunction. Our objective was to investigate the relationship of subclinical atherosclerosis with mechanical LV dyssynchrony in a population-based asymptomatic multi-ethnic cohort.
Methods and Results
Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) at exam 5 were evaluated using 1.5T cardiac magnetic resonance (CMR) imaging, carotid ultrasound (n=2,062) for common carotid artery (CCA) and internal carotid artery (ICA) intima-media thickness (IMT), and cardiac computed tomography (n=2,039) for coronary artery calcium (CAC) assessment (Agatston method). Dyssynchrony indices were defined as the standard deviation of time to peak systolic circumferential strain (SD-TPS) and the difference between maximum and minimum (max-min) time to peak strain using harmonic phase imaging in 12 segments (3-slices × 4 segments). Multivariable regression analyses were performed to assess associations after adjusting for participant demographics, cardiovascular risk factors, LV mass, and ejection fraction. In multivariable analyses, SD-TPS was significantly related to measures of atherosclerosis, including CCA-IMT (8.7msec/mm change in IMT, p=0.020), ICA-IMT (19.2 msec/mm change in IMT, p<0.001), carotid plaque score (1.2 msec/unit change in score, p<0.001), and log transformed CAC+1 (0.66 msec/unit log-CAC+1, p=0.018). These findings were consistent with other parameter of LV dyssynchrony i.e. max-min.
In the MESA cohort, measures of atherosclerosis are associated with parameters of subclinical LV dyssynchrony in the absence of clinical coronary event and left-bundle-branch block.
PMCID: PMC4361257  PMID: 25682041
Left Ventricular Dyssynchrony; Carotid IMT; Coronary Calcium Score; Atherosclerosis
3.  Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model 
Previous work on vitamin D in the prostate has focused on the prostatic epithelium, from which prostate cancer arises. Prostatic epithelial cells are surrounded by stroma, which has well-established regulatory control over epithelial proliferation, differentiation, and the inflammatory response. Here we examined the regulation of vitamin D-related genes and inflammatory genes by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) in laser-capture microdissected prostate tissue from a vitamin D3 clinical trial and in an in vitro model that facilitates stromal–epithelial crosstalk. Analysis of the trial tissues showed that VDR was present in both cell types, whereas expression of the hydroxylases was the highest in the epithelium. Examination of gene expression by prostatic (1,25(OH)2D) concentrations showed that VDR was significantly lower in prostate tissues with the highest concentration of 1,25(OH)2D, and down-regulation of VDR by 1,25(OH) 2D was confirmed in the primary cell cultures. Analysis of inflammatory genes in the patient tissues revealed that IL-6 expression was the highest in the prostate stroma while PTGS2 (COX2) levels were lowest in the prostate cancer tissues from men in the highest tertile of prostatic 1,25(OH)2D. In vitro, TNF-α, IL-6 and IL-8 were suppressed by 1,25 (OH)2D in the primary epithelial cells, whereas TNF-α and PTGS2 were suppressed by 1,25(OH) 2D in the stromal cells. Importantly, the ability of 1,25(OH)2D to alter pro-inflammatory-induced changes in epithelial cell growth were dependent on the presence of the stromal cells. In summary, whereas both stromal and epithelial cells of the prostate express VDR and can presumably respond to 1,25(OH)2D, which appears to be primarily produced by the prostatic epithelium. Further, while the prostate epithelium was more responsive to the anti-inflammatory activity of 1,25 (OH)2D than stromal cells, stroma–epithelial crosstalk enhanced the phenotypic effects of 1,25(OH)2D and the inflammatory process in the prostate gland.
PMCID: PMC4361379  PMID: 25305352
Prostate epithelium; Prostate stroma; Inflammation; Vitamin D
4.  Serologic and molecular evidence of Brucella ovis infection in ovine and caprine flocks in the State of Minas Gerais, Brazil 
BMC Research Notes  2016;9:190.
Brucella ovis infection is one of the leading causes of sub fertility and infertility in ovine, been characterized mainly by epididymitis, orchitis and testicular atrophy in rams. This study aimed to determine the frequency of B. ovis positivity in rams and goats flocks in the State of Minas Gerais, Brazil, by agarose gel immunodiffusion (AGID), ELISA, Rose Bengal, PCR and bacteriological isolation as diagnostic tools.
Serum and urine samples were collected from properties with sheep or goat flocks, or from properties with mixed flock. Out of 50 sheep flocks, 6 % (3/50) were seropositive by AGID while 4 % (2/50) were positive by urine PCR for B. ovis. Out of five goat farms, 20 % (1/5) were seropositive for B. ovis by AGID. Mixed flock farms had 11.1 % (2/18) of positivity by AGID. By ELISA, 19.5 % (8/41) of sheep properties and 61.1 % (11/18) of the properties with mixed flocks were positive for B. ovis. No samples were positive in the test of Rose Bengal, ruling out exposure to smooth LPS Brucella species (particularly Brucella melitensis) and indicating that the positive in the ELISA was associated with Brucella spp. LPS rough (presumably B. ovis). No urine sample from sheep or goat was positive by bacteriological isolation.
Our results demonstrate serologic or molecular evidence of B. ovis infection in several rams and billy goats from meso-regions of the State of Minas Gerais, Brazil. Also, this study report the indirect ELISA as an important tool for the diagnosis of B. ovis infection, as indirect ELISA in this study demonstrated to be the most sensitive diagnostic method adopted.
PMCID: PMC4808293  PMID: 27017445
Brucellaovis; Rams; Goats; Brucellosis
5.  Development and Validation of an Improved PCR Method Using the 23S-5S Intergenic Spacer for Detection of Rickettsiae in Dermacentor variabilis Ticks and Tissue Samples from Humans and Laboratory Animals 
Journal of Clinical Microbiology  2016;54(4):972-979.
A novel nested PCR assay was developed to detect Rickettsia spp. in ticks and tissue samples from humans and laboratory animals. Primers were designed for the nested run to amplify a variable region of the 23S-5S intergenic spacer (IGS) of Rickettsia spp. The newly designed primers were evaluated using genomic DNA from 11 Rickettsia species belonging to the spotted fever, typhus, and ancestral groups and, in parallel, compared to other Rickettsia-specific PCR targets (ompA, gltA, and the 17-kDa protein gene). The new 23S-5S IGS nested PCR assay amplified all 11 Rickettsia spp., but the assays employing other PCR targets did not. The novel nested assay was sensitive enough to detect one copy of a cloned 23S-5S IGS fragment from “Candidatus Rickettsia amblyommii.” Subsequently, the detection efficiency of the 23S-5S IGS nested assay was compared to those of the other three assays using genomic DNA extracted from 40 adult Dermacentor variabilis ticks. The nested 23S-5S IGS assay detected Rickettsia DNA in 45% of the ticks, while the amplification rates of the other three assays ranged between 5 and 20%. The novel PCR assay was validated using clinical samples from humans and laboratory animals that were known to be infected with pathogenic species of Rickettsia. The nested 23S-5S IGS PCR assay was coupled with reverse line blot hybridization with species-specific probes for high-throughput detection and simultaneous identification of the species of Rickettsia in the ticks. “Candidatus Rickettsia amblyommii,” R. montanensis, R. felis, and R. bellii were frequently identified species, along with some potentially novel Rickettsia strains that were closely related to R. bellii and R. conorii.
PMCID: PMC4809929  PMID: 26818674
6.  Biomechanical evaluation of monosegmental pedicle instrumentation in a calf spine model and the role of fractured vertebrae in screw stability 
Monsegmental pedicle instrumentation (MSPI) has been used to treat thoracolumbar fractures. However, there are few reports about the biomechanical characteristics of MSPI compared with traditional short-segment pedicle instrumentation (SSPI) in management of unstable thoracolumbar fractures, and the influence of vertebral fracture on screw stability is still unclear.
This study was to compare the immediate stability between MSPI and SSPI in management of unstable L1 fracture, and to evaluate the role of fractured vertebrae in screw stability. Two studies were performed: in the first study, sixteen fresh calf spines (T11-L3) were divided into two groups, in which unstable fractures at L1 were produced and then instrumented with MSPI or SSPI respectively. The range of motion (ROM) and lax zone (LZ) of specimens were evaluated with pure moment of 6 Nm loaded. The second study measured and compared the pullout strength of screws inserted in to 16 intact and fractured vertebrae of calf spines (L1-3) respectively. The correlation of pullout strength with load sharing classification (LSC) of fractured vertebrae was analyzed.
No significant difference in the ROM and LZ of the destabilized segments after fixation between MSPI and SSPI, except in axial rotation of ROM (P < 0.05). After fatigue cyclic loading, the MSPI showed a significant increase of ROM during lateral bending and axial rotation (P < 0.05); however, there were no significant differences in the LZ during all loading models between groups (P > 0.05). The mean pullout strength of pedicle screws in fractured vertebrae decreased by 13.7 %, compared with that of intact vertebrae (P > 0.05), and had a low correlation with LSC of the fractured vertebrae (r = 0.293, P > 0.05).
MSPI can provide effective immediate stability for management of unstable thoracolumbar fractures; however, it has less fatigue resistance during lateral bending and axial rotation compared with SSPI. LSC score of fractured vertebrae is not a major influence on the pullout strength of screws.
PMCID: PMC4797180  PMID: 26993472
7.  Dislocation “Bubble-Like-Effect” and the Ambient Temperature Super-plastic Elongation of Body-centred Cubic Single Crystalline Molybdenum 
Scientific Reports  2016;6:22937.
With our recently developed deformation device, the in situ tensile tests of single crystal molybdenum nanowires with various size and aspect ratio were conducted inside a transmission electron microscope (TEM). We report an unusual ambient temperature (close to room temperature) super-plastic elongation above 127% on single crystal body-centred cubic (bcc) molybdenum nanowires with an optimized aspect ratio and size. A novel dislocation “bubble-like-effect” was uncovered for leading to the homogeneous, large and super-plastic elongation strain in the bcc Mo nanowires. The dislocation bubble-like-effect refers to the process of dislocation nucleation and annihilation, which likes the nucleation and annihilation process of the water bubbles. A significant plastic deformation dependence on the sample’s aspect ratio and size was revealed. The atomic scale TEM observations also demonstrated that a single crystal to poly-crystal transition and a bcc to face-centred cubic phase transformation took place, which assisted the plastic deformation of Mo in small scale.
PMCID: PMC4783708  PMID: 26956918
8.  Oxidation Effects in Rare Earth Doped Topological Insulator Thin Films 
Scientific Reports  2016;6:22935.
The breaking of time-reversal symmetry (TRS) in topological insulators is a prerequisite for unlocking their exotic properties and for observing the quantum anomalous Hall effect (QAHE). The incorporation of dopants which exhibit magnetic long-range order is the most promising approach for TRS-breaking. REBiTe3, wherein 50% of the Bi is substitutionally replaced by a RE atom (RE = Gd, Dy, and Ho), is a predicted QAHE system. Despite the low solubility of REs in bulk crystals of a few %, highly doped thin films have been demonstrated, which are free of secondary phases and of high crystalline quality. Here we study the effects of exposure to atmosphere of rare earth-doped Bi2(Se, Te)3 thin films using x-ray absorption spectroscopy. We demonstrate that these RE dopants are all trivalent and effectively substitute for Bi3+ in the Bi2(Se, Te)3 matrix. We find an unexpected high degree of sample oxidation for the most highly doped samples, which is not restricted to the surface of the films. In the low-doping limit, the RE-doped films mostly show surface oxidation, which can be prevented by surface passivation, encapsulation, or in-situ cleaving to recover the topological surface state.
PMCID: PMC4783712  PMID: 26956771
9.  In vitro antimicrosporidial activity of gold nanoparticles against Heterosporis saurida 
Worldwide, there is a need to expand the number of drugs available to treat parasitic infections in aquaculture. One of the new materials being tested is metal nanoparticles, which have unique chemical and physical characteristics owing to their extremely small size and high surface area to volume ratio. We examined the effectiveness of gold nanoparticles against the microsporidian parasite Heterosporis saurida, which causes severe economic losses in lizard fish, Saurida undosquamis aquaculture.
We synthesized gold nanoparticles by chemical reduction of tetrachloroauric acid as a metal precursor. We assessed the antimicrosporidial efficacy of the nanoparticles against H. saurida using an in vitro screening approach, which we had developed previously using the eel kidney cell line EK-1. The number of H. saurida spores produced in EK-1 cells was reduced in a proportional manner to the dosage of gold nanoparticles administered. A cell metabolic activity test (MTT) indicated that the gold nanoparticles did not appear to be toxic to the host cells.
Gold nanoparticles can act as an effective antimicrosporidial agent and hold promise to reduce disease in lizardfish aquaculture. Metal nanoparticles should be considered as an alternate choice for development of new antimicrosporidial drugs to combat disease problems in aquaculture.
PMCID: PMC4778277  PMID: 26939524
Gold nanoparticles; Microsporidia; Heterosporis saurida; Lizardfish; EK-1 cells
10.  Distribution and features of hematological malignancies in Eastern Morocco: a retrospective multicenter study over 5 years 
BMC Cancer  2016;16:159.
Hematological malignancies (HM) are a public health problem. The pattern and distribution of diagnosed hematological cancers vary depending on age, sex, geography, and ethnicity suggesting the involvement of genetic and environmental factors for the development of these diseases. To our knowledge, there is no published report on HM in the case of Eastern Morocco. In this report we present for the first time the overall pattern of HM for this region.
Retrospective descriptive study of patients diagnosed with HM between January 2008 and December 2012 in three centres in Eastern Morocco providing cancer diagnosis, treatment or palliative care services. The FAB (French-American-British) classification system has been taken into account in the analysis of myeloid and lymphoid neoplasms.
In this study, a total of 660 cases of HM were registered between January 2008 and December 2012. Overall, 6075 cases of cancers all sites combined were registered during this study period, indicating that HM account for around 10.9 % (660/6075) of all cancers recorded. Among the 660 registered cases of HM, 53 % were males and 47 % were females, with a male to female ratio of 1.1. Thus, overall, men are slightly more affected with HM than women. By contrast, a female predominance was observed in the case of Hodgkin’s lymphoma (HL), myeloproliferative neoplasms (MPN), acute myeloid leukemia (AML) and the myelodysplastic syndrome (MDS). HM occur at a relatively young age, with an overall median age at diagnosis of 54 years. Non-Hodgkin’s lymphoma (NHL) was the most common HM accounting for 29.7 % of all HM, followed by HL, MPN, multiple myelomas (MM), chronic lymphocytic leukemia (CLL), AML, MDS, acute lymphoblastic leukemia (ALL), and Waldenström macroglobulinemia (WM). The majority of HM cases have been observed among patients aged 60 years and over (40.4 % of HM). Among this age group, NHL was the most common HM. In adolescents, HL was the most frequent HM.
This study provided for the first time the pattern and distribution of HM in Eastern Morocco. Our findings justify the need to establish a regional cancer registry as a first step in blood cancer control in Eastern Morocco.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2205-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4768409  PMID: 26915519
Hematological malignancies; Myeloid neoplasms; Lymphoid neoplasms; Morocco
11.  Near-field engineering of Fano resonances in a plasmonic assembly for maximizing CARS enhancements 
Scientific Reports  2016;6:20777.
Surface enhanced coherent anti-Stokes Raman scattering (SECARS) is a sensitive tool and promising for single molecular detection and chemical selective imaging. However, the enhancement factors (EF) were only 10~100 for colloidal silver and gold nanoparticles usually used as SECARS substrates. In this paper, we present a design of SECARS substrate consisting of three asymmetric gold disks and strategies for maximizing the EF by engineering near-field properties of the plasmonic Fano nanoassembly. It is found that the E-field “hot spots” corresponding to three different frequencies involved in SECARS process can be brought to the same spatial locations by tuning incident orientations, giving rise to highly confined SECARS “hot spots” with the EF reaching single-molecule sensitivity. Besides, an even higher EF of SECARS is achieved by introducing double Fano resonances in this plasmonic nanoassembly via further enlarging the sizes of the constituent disks. These findings put an important step forward to the plasmonic substrate design for SECARS as well as for other nonlinear optical processes.
PMCID: PMC4748302  PMID: 26861192
12.  Emerging Roles of RNA-Binding Proteins in Plant Growth, Development, and Stress Responses 
Molecules and Cells  2016;39(3):179-185.
Posttranscriptional regulation of RNA metabolism, including RNA processing, intron splicing, editing, RNA export, and decay, is increasingly regarded as an essential step for fine-tuning the regulation of gene expression in eukaryotes. RNA-binding proteins (RBPs) are central regulatory factors controlling posttranscriptional RNA metabolism during plant growth, development, and stress responses. Although functional roles of diverse RBPs in living organisms have been determined during the last decades, our understanding of the functional roles of RBPs in plants is lagging far behind our understanding of those in other organisms, including animals, bacteria, and viruses. However, recent functional analysis of multiple RBP family members involved in plant RNA metabolism and elucidation of the mechanistic roles of RBPs shed light on the cellular roles of diverse RBPs in growth, development, and stress responses of plants. In this review, we will discuss recent studies demonstrating the emerging roles of multiple RBP family members that play essential roles in RNA metabolism during plant growth, development, and stress responses.
PMCID: PMC4794599  PMID: 26831454
plant development; RNA-binding protein; RNA chaperone; RNA metabolism; stress response
13.  In vivo anti-LAP mAb enhances IL-17/IFN-γ responses and abrogates anti-CD3-induced oral tolerance 
International Immunology  2014;27(2):73-82.
A new anti-LAP antibody that enhances inflammation in vivo
Regulatory T cells (Tregs) play a critical role in the maintenance of immunological tolerance. The best-characterized Tregs are those expressing the transcription factor Foxp3 and in vivo modulation of Foxp3 Tregs has been employed to study their role in immune homeostasis. Latency-associated peptide (LAP) is a membrane-bound TGF-β complex that has also been shown to play a role in Treg function and oral tolerance. We developed a novel anti-mouse LAP mAb that allowed us to investigate the effect of targeting LAP in vivo on immune function and on anti-CD3-induced oral tolerance. We found that in vivo anti-LAP mAb administration led to a decrease in the number of CD4+LAP+ Tregs in spleen and lymph nodes without affecting CD4+Foxp3+ Tregs. Spleen cells from anti-LAP-injected mice proliferated more in vitro and produced increased amounts of IL-2, IL-17 and IFN-γ. Moreover, injection of anti-LAP antibody abrogated the protective effect of oral anti-CD3 on experimental autoimmune encephalomyelitis (EAE). Finally, in vivo anti-LAP administration prior to myelin oligodendrocyte glycoprotein immunization resulted in severe EAE in the absence of pertussis toxin, which is used for EAE induction. Our findings demonstrate the importance of CD4+LAP+ T cells in the control of immune homeostasis and autoimmunity and provides a new tool for the in vivo investigation of murine LAP+ Tregs on immune function.
PMCID: PMC4303004  PMID: 25194146
experimental autoimmune encephalomyelitis; inflammation; latency-associated peptide; regulatory T cells; TGF-beta
14.  Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I 
Biology Open  2016;5(2):174-177.
The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings) and old (3-5 years of age) minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml). We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I.
Summary: Both leptin and IGF-I are involved in the control of mink ovarian steroid hormone release. Reproductive aging can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I.
PMCID: PMC4823990  PMID: 26794607
Aging; Ovary; Mink; Leptin; IGF-I; Progesterone; Estradiol
15.  Monitoring Local Regional Hemodynamic Signal Changes during Motor Execution and Motor Imagery Using Near-Infrared Spectroscopy 
The aim of this study was to clarify the topographical localization of motor-related regional hemodynamic signal changes during motor execution (ME) and motor imagery (MI) by using near-infrared spectroscopy (NIRS), as this technique is more clinically expedient than established methods (e.g., fMRI). Twenty right-handed healthy subjects participated in this study. The experimental protocol was a blocked design consisting of 3 cycles of 20 s of task performance and 30 s of rest. The tapping sequence task was performed with their fingers under 4 conditions: ME and MI with the right or left hand. Hemodynamic brain activity was measured with NIRS to monitor changes in oxygenated hemoglobin (oxy-Hb) concentration. Oxy-Hb in the somatosensory motor cortex (SMC) increased significantly only during contralateral ME and showed a significant interaction between task and hand. There was a main effect of hand in the left SMC. Although there were no significant main effects or interactions in the supplemental motor area (SMA) and premotor area (PMA), oxy-Hb increased substantially under all conditions. These results clarified the topographical localization by motor-related regional hemodynamic signal changes during ME and MI by using NIRS.
PMCID: PMC4707267  PMID: 26793118
motor imagery; mental practice; motor execution; NIRS; hemodynamic signal changes
16.  Comparison of total, salivary and calculated free cortisol levels in patients with severe sepsis 
The purposes of the study were to compare serum total cortisol (STC), salivary cortisol (SaC) and calculated free cortisol (cFC) levels at baseline and after the adrenocorticotrophic hormone (ACTH) stimulation test in patients with severe sepsis (SS) and determine the suitability of use of SaC and cFC levels instead of STC for the diagnosis of adrenal insufficiency (AI) in patients with SS. And secondary aims of this study were to compare these parameters in patients with SS with healthy controls and check their effects on survival status of the patients.
Thirty patients with SS (15 men and 15 women) were compared with 16 healthy controls. Low-dose (1 μg) ACTH stimulation test was performed to the patients on the first, seventh and 28th days of diagnosis of SS, but in control group, 1 μg ACTH stimulation test was performed only once. STC, SaC and cFC levels were measured during ACTH stimulation test.
Patients were categorized as having low or high baseline STC according to a cut-off level of 10 μg/dL. In high STC group, baseline and peak SaC levels were found to be 2.3 (0.2–9.0) and 3.4 (0.5–17.8) μg/dL on D1 and 1.1 (0.8–4.6) and 2.6 (1.3–2.9) μg/dL on D7, respectively. In the control group, baseline and peak SaC levels were 0.4 (0.1–1.4) and 1.1 (0.4–2.5) μg/dL, respectively. Baseline and peak SaC levels after ACTH stimulation were found to be higher in high STC group than in controls, but they were found to be similar in low STC and control groups. In high STC group, cFC levels were 0.3 (0.1–0.3) and 0.4 (0.3–0.7) μg/dL on D1 and 0.2 (0.1–0.3) and 0.4 (0.1–0.7) μg/dL on D7, respectively. In the control group, baseline and peak cFC levels were 1.7 (0.4–1.9) and 1.8 (1.0–6.6) μg/dL, respectively. cFC levels were found to be lower in patients with SS subgroups than in the control group. Baseline and stimulated STC, SaC and cFC levels did not differ according to the survival status. SaC, cFC and STC levels were found to be correlated with each other.
SS is associated with increased SaC, but decreased cFC levels when baseline STC is assumed to be sufficient. When STC level is assumed to be insufficient, SaC levels remain unchanged, but cFC levels are decreased. Lower STC levels is not associated with increased mortality in patients with SS. More data are needed in order to suggest the use of SaC and cFC instead of STC.
Trial registration No: NCT02589431
PMCID: PMC4706674  PMID: 26753096
ACTH stimulation test; HPA axis; Total cortisol; Salivary cortisol; Calculated free cortisol; Severe sepsis
17.  In silico Screening for Plasmodium falciparum Enoyl-ACP Reductase inhibitors 
The need for novel therapeutics against Plasmodium falciparum is urgent due to recent emergence of multi-drug resistant malaria parasites. Since fatty acids are essential for both the liver and blood stages of the malarial parasite, targeting fatty acid biosynthesis is a promising strategy for combatting P. falciparum. We present a combined computational and experimental study to identify novel inhibitors of enoyl-acyl carrier protein reductase (PfENR) in the fatty acid biosynthesis pathway. A small-molecule database from ChemBridge was docked into three distinct PfENR crystal structures that provide multiple receptor conformations. Two different docking algorithms were used to generate a consensus score in order to rank possible small molecule hits. Our studies led to the identification of five low-micromolar pyrimidine dione inhibitors of PfENR.
PMCID: PMC4278936  PMID: 25344312
18.  Self-reported and P3 event-related potential evaluations of condoms: Does what we say match how we feel? 
Psychophysiology  2009;46(2):420-424.
Research consistently reveals positive self-reported condom evaluations, yet such evaluations often do not predict condom use. Whereas positive self-reports likely reflect social norms regarding prevention of diseases and pregnancy, psychophysiological measures might better assess spontaneous condom evaluations. Here, participants completed a visual oddball task in which condoms and alcoholic beverages were infrequent targets among neutral, positive, and negative context images. Although self-reported condom evaluations were very positive, condom images presented in a negative context produced a smaller P3 than condom images presented in a neutral or positive context, suggesting that spontaneous condom evaluations were more negative than positive. The P3 elicited by alcohol images indicated positive evaluations. The findings underscore the multifaceted nature of evaluations and point to the utility of ERPs for assessing health-related attitudes.
PMCID: PMC4692251  PMID: 19207201
ERPs; P3; Condom; Alcohol; Evaluations; Self-report
19.  Cytotoxicity of glioblastoma cells mediated ex vivo by varicella-zoster virus-specific T cells 
Journal of neurovirology  2011;17(5):448-454.
Clinical or laboratory evidence of varicella-zoster virus (VZV) infection has been consistently associated with lower glioma risk in case–control studies, suggesting a protective effect of VZV against glioma. We formulated the following explanatory hypotheses: reactivated VZV preferentially infects and kills gliomas compared to normal parenchyma; and VZV-specific cytotoxic T lymphocytes (CTL) cross-react with gliomas. We established an ex vivo model of VZV infection, which showed that glioma cell lines and primary astrocytes were equally permissive to VZV infection and had similar 15% average decrease in viability upon infection. In co-cultures, the relative growth of glioma cells and astrocytes was not affected by the VZV infection. However, VZV stimulated, but not mock stimulated, peripheral blood mononuclear cells from VZV-seropositive individuals recognized and killed HLA class I-matched glioma cells (mean±SE decrease in viability of 26±12%, p=0.04), but not matched astrocytes. VZV infection of the glioma cells did not affect the T cell-mediated killing. Taken together, these data suggest that ex vivo VZV infection has similar direct effects on glioma cells and astrocytes. The protective effect of prior VZV infection against the incidence of glioma may be mediated by CTL that recognizes epitopes shared by VZV and glioma cells.
PMCID: PMC4692468  PMID: 21792750
Glioma; Glioblastoma multiforme; Varicella-zoster virus; Cytotoxic T lymphocytes; Astrocytes
20.  Crumbled or mashed feed had no significant effect on the performance of lactating sows or their offspring 
Physical and chemical properties of feedstuffs can be changed by feed processing. Moreover, through various mechanisms, feed processing can affect growth performance and feed efficiency of swine, nutrition value of the feed. Weaning-to service-intervals (WSI), subsequent farrowing rates, and total-born litter sizes were determined by feed intake and metabolic state during lactation.
A total of 20 sows (Landrace × Yorkshire) with an average body weight (BW) of 266.1 kg 4 d before farrowing were used to determine the effect of feed processing on the performance of lactating sows and their offspring. The following two dietary treatments were used: 1) Crumble diet (C); and 2) Mash diet (M). Ten replications were used for each treatment. Back fat thickness of sows was measured 6 cm off the midline at the 10th rib using a real-time ultrasound instrument at 4 d before farrowing, 1 d after farrowing, and during weaning. Sow BW were also checked at 4 d before farrowing, 1 d after farrowing, and during weaning. Fecal score of sows were assessed on d 14. Fecal score of piglets were observed on d 7, 15, and 24. Data were analyzed using t-test procedure of SAS (2014) with sow as experimental unit.
No significant (p > 0.05) difference was observed in the reproduction performance of sows between the two treatments. In addition, there was no significant (p > 0.05) difference in the growth performance of piglets between the two treatments. Fecal score of sows or piglets showed no significant (p > 0.05) difference either.
In conclusion, different feed processing (mash or crumble) did not make any significant difference on the performance of lactation sow or their piglets.
PMCID: PMC4690338  PMID: 26705478
Feed processing; Performance; Piglets; Sow
21.  Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation 
BMC Immunology  2015;16:74.
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells known to modulate the immune system and to promote hematopoiesis. These dual effects make MSCs attractive for use as cellular therapy in hematopoietic cell transplantation (HCT). MSCs can be used peri-HCT or pre-engraftment to modulate immune reconstitution, promoting hematopoietic stem cell (HSC) engraftment and/or preventing graft-versus-host disease (GVHD). Pre-clinical studies have demonstrated that MSCs can potentiate HSC engraftment and prevent GVHD in a variety of animal models. Clinical trials have been small and largely non-randomized but have established safety and early evidence of efficacy, supporting the need for larger randomized trials.
PMCID: PMC4681052  PMID: 26674007
22.  Mechanistic Studies on the Application of DNA Aptamers as Inhibitors of 2-Oxoglutarate-Dependent Oxygenases 
Journal of medicinal chemistry  2012;55(7):3546-3552.
The Escherichia coli (E. coli) AlkB protein and its functional human homologues belong to a subfamily of 2-oxoglutarate (2OG)-dependent oxygenases (2OG oxygenases for simplicity) that enable the repair of cytotoxic methylation damage in nucleic acids and which catalyse t-RNA oxidations. DNA alkylation is a major mechanism of action for cytotoxic anti-cancer drugs. Thus, the inhibition of oxidative demethylation, catalyzed by these enzymes, has the potential to improve the efficacy of chemotherapies. Here we report that oligonucleotide aptamers constitute a new class of potent inhibitors of 2OG oxygenases. DNA aptamers can selectively bind to AlkB, with nanomolar affinity, and efficiently inhibit catalysis. The mechanism of inhibition was studied by capillary electrophoresis (CE) with laser-induced fluorescence (LIF) detection. Inhibition constants of the aptamers were determined and shown to correlate well with Kd values. The results of kinetic analyses imply that the aptamers bind AlkB away from the active site. Our findings should stimulate the development of oligonucleotide aptamers for human homologues of AlkB and further their study as potential enhancers of chemotherapy efficiency.
PMCID: PMC4681096  PMID: 22471443
23.  HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease 
Nucleic Acids Research  2015;44(Database issue):D877-D881.
More than 90% of common variants associated with complex traits do not affect proteins directly, but instead the circuits that control gene expression. This has increased the urgency of understanding the regulatory genome as a key component for translating genetic results into mechanistic insights and ultimately therapeutics. To address this challenge, we developed HaploReg ( to aid the functional dissection of genome-wide association study (GWAS) results, the prediction of putative causal variants in haplotype blocks, the prediction of likely cell types of action, and the prediction of candidate target genes by systematic mining of comparative, epigenomic and regulatory annotations. Since first launching the website in 2011, we have greatly expanded HaploReg, increasing the number of chromatin state maps to 127 reference epigenomes from ENCODE 2012 and Roadmap Epigenomics, incorporating regulator binding data, expanding regulatory motif disruption annotations, and integrating expression quantitative trait locus (eQTL) variants and their tissue-specific target genes from GTEx, Geuvadis, and other recent studies. We present these updates as HaploReg v4, and illustrate a use case of HaploReg for attention deficit hyperactivity disorder (ADHD)-associated SNPs with putative brain regulatory mechanisms.
PMCID: PMC4702929  PMID: 26657631
24.  Acculturation and Perceived Stress in HIV+ Immigrants: Depression Symptomatology in Asian & Pacific Islanders 
AIDS care  2014;26(12):1581-1585.
Asians and Pacific Islanders (API) are among the fastest growing minority groups within the United States, and this growth has been accompanied by an increase in HIV incidence. Between, 2000 and 2010, the API HIV infection rate increased from 4.5% to 8.7%; however, there is a paucity of HIV-related research for this group, and even less is known about the prevalence and correlates of antiretroviral therapy adherence behavior, quality of life, impact of stress, and efficacious self-management among HIV+ API Americans. This paper examines how acculturation and perceived stress affect depression symptomatology and treatment seeking in the HIV+ API population. A series of cross-sectional audio computer-assisted self-interviews (ACASI) were conducted with a convenience sample of 50 HIV+ API (29 in San Francisco and 21 in New York City). The relationship between acculturation and perceived stress was analyzed, and the results indicate that for those HIV+ API who reported low or moderate acculturation (as compared to those who reported high acculturation), stress was significantly mediated by depression symptomology. Interventions to address acculturation and reduce perceived stress among API generally and Asians specifically are therefore needed.
PMCID: PMC4188794  PMID: 25059642
HIV; Asian and Pacific Islander; Immigrants; Perceived Stress; Depression; Acculturation
25.  Transcriptional Dynamics of Bile Salt Export Pump during Pregnancy: Mechanisms and Implications in Intrahepatic Cholestasis of Pregnancy 
Hepatology (Baltimore, Md.)  2014;60(6):1993-2007.
Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate limiting step in the enterohepatic circulation of bile acids and transactivated by nuclear receptor farnesoid x receptor (FXR). Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent disorder among diseases unique to pregnancy and primarily occurs in the third trimester of pregnancy with a hallmark of elevated serum bile acids. Currently, the transcriptional regulation of BSEP during pregnancy and its underlying mechanisms and involvement in ICP are not fully understood. In this study, the dynamics of BSEP transcription in vivo in the same group of pregnant mice before, during and after gestation were established with in vivo imaging system (IVIS). BSEP transcription was markedly repressed in the later stages of pregnancy and immediately recovered after parturition, resembling the clinical course of ICP in human. The transcriptional dynamics of BSEP was inversely correlated with serum 17β-estradiol (E2) levels before, during and after gestation. Further studies showed that E2 repressed BSEP expression in human primary hepatocytes, Huh 7 cells and in vivo in mice. Such transrepression of BSEP by E2 in vitro and in vivo required estrogen receptor α (ERα). Mechanistic studies with chromatin immunoprecipitation (ChIP), protein co-immunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) assays demonstrated that ERα directly interacted with FXR in living cells and in vivo in mice. In conclusion, BSEP expression was repressed by E2 in the late stages of pregnancy through a non-classical E2/ERα transrepressive pathway, directly interacting with FXR. E2-mediated repression of BSEP expression represents an etiological contributing factor to ICP and therapies targeting the ERα/FXR interaction may be developed for prevention and treatment of ICP.
PMCID: PMC4194188  PMID: 24729004
BSEP; Bile acids; 17β-estradiol; FXR; ERα

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