Miracle-dz/UniFAR-FTUs huggingface dataset:
Gemfibrozil, a Lipid-lowering Drug, Inhibits the Induction of Nitric-oxide Synthase in Human Astrocytes*

Gemfibrozil, a lipid-lowering drug, inhibited cytokine-induced production of NO and the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astrocytes. Similar to gemfibrozil, clofibrate, another fibrate drug, also inhibited the expression of iNOS. Inhibition of human iNOS promoter-driven luciferase activity by gemfibrozil in cytokine-stimulated U373MG astroglial cells suggests that this compound inhibits the transcription of iNOS. Since gemfibrozil is known to activate peroxisome proliferator-activated receptor-α (PPAR-α), we investigated the role of PPAR-α in gemfibrozil-mediated inhibition of iNOS. Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of ΔhPPAR-α, the dominant-negative mutant of human PPAR-α. However, ΔhPPAR-α was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR-α. The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-γ (IFN-γ) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to γ-activation site (GAS), nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein β (C/EBPβ); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors. The combination of interleukin (IL)-1β and IFN-γ induced the activation of NF-κB, AP-1, C/EBPβ, and GAS but not that of ISRE, suggesting that IRF-1 may not be involved in cytokine-induced expression of iNOS in human astrocytes. Interestingly, gemfibrozil strongly inhibited the activation of NF-κB, AP-1, and C/EBPβ but not that of GAS in cytokine-stimulated astroglial cells. These results suggest that gemfibrozil inhibits the induction of iNOS probably by inhibiting the activation of NF-κB, AP-1, and C/EBPβ and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in neuroinflammatory diseases.
Biliary Secretion of Glutathione in Estradiol 17β-d-Glucuronide-Induced Cholestasis

Estradiol-17β-d-glucuronide (E2-17G) induces an acute but reversible inhibition of bile flow after its intravenous administration to rats, due in part to the endocytic retrieval of the canalicular multidrug resistance-associated transporter protein 2 and the bile salt export pump, transporters that contribute to bile flow. Decreased bile salt-independent bile flow (BSIF) is also involved and persists during the phase of recovery from cholestasis. Because glutathione and \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{HCO}_{3}^{-}\) \end{document} are major contributors to BSIF, we evaluated changes in their biliary excretion and the hepatic content of total glutathione during E2-17G-induced cholestasis. E2-17G acutely decreased bile flow and biliary excretion of total glutathione by about 80%; glutathione excretion was still inhibited at 80 min and 120 min, even though bile flow was partially and totally restored, respectively. Neither liver glutathione content nor the proportions of oxidized glutathione in bile and liver were affected by E2-17G at any time. \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{HCO}_{3}^{-}\) \end{document} concentrations in bile were unchanged, so that secretion paralleled variations in bile flow. In the isolated perfused liver, addition of E2-17G decreased both bile flow and the biliary concentration of glutathione, whereas addition of its noncholestatic isomer estradiol-3-d-glucuronide (E2-3G) did not inhibit bile flow, but significantly reduced the concentration of glutathione in bile. The bile:liver concentration ratios of glutathione were significantly decreased in vivo by E2-17G and in the perfused liver by E2-17G and E2-3G. These data indicate that E2-17G cis-inhibits the canalicular transport of glutathione and thus contributes to the cholestatic effect by inhibiting BSIF.
Micromagnetic Studies of Co/Pt Multilayers With Perpendicular Anisotropy

Two micromagnetic models, Model A with the polycrystalline microstructure and Model B with just regular mesh, are set up to simulate the hysteresis loops of Co/Pt multilayers with perpendicular anisotropy. In both models, a defect region on a scale of 100 nm is introduced in any Co film with only two atomic layers, which plays a key role in this simulation. The magnetic anisotropy constant K of cells in the defect region is weakened compare to the K out of the defect. The simulated M-H loops express the characteristics of the experiments well. The loops of a series of [Co/Pt]n multilayers with different repetition period also agree with experiment well. Moreover, the movement of reversed domain wall during magnetization reversal is observed in this simulation.
Effect of C-Terminal Protein Tags on Pentitol and l-Arabinose Transport by Ambrosiozyma monospora Lat1 and Lat2 Transporters in Saccharomyces cerevisiae

ABSTRACT Functional expression in heterologous hosts is often less successful for integral membrane proteins than for soluble proteins. Here, two Ambrosiozyma monospora transporters were successfully expressed in Saccharomyces cerevisiae as tagged proteins. Growth of A. monospora on l-arabinose instead of glucose caused transport activities of l-arabinose, l-arabitol, and ribitol, measured using l-[1-3H]arabinose, l-[14C]arabitol, and [14C]ribitol of demonstrated purity. A. monospora LAT1 and LAT2 genes were cloned earlier by using their ability to improve the growth of genetically engineered Saccharomyces cerevisiae on l-arabinose. However, the l-arabinose and pentitol transport activities of S. cerevisiae carrying LAT1 or LAT2 are only slightly greater than those of control strains. S. cerevisiae carrying the LAT1 or LAT2 gene fused in frame to the genes for green fluorescent protein (GFP) or red fluorescent protein (mCherry) or adenylate kinase (AK) exhibited large (>3-fold for LAT1; >20-fold for LAT2) increases in transport activities. Lat1-mCherry transported l-arabinose with high affinity (Km ≈ 0.03 mM) and l-arabitol and ribitol with very low affinity (Km ≥ 75 mM). The Lat2-GFP, Lat2-mCherry, and Lat2-AK fusion proteins could not transport l-arabinose but were high-affinity pentitol transporters (Km s ≈ 0.2 mM). The l-arabinose and pentitol transport activities of A. monospora could not be completely explained by any combination of the observed properties of tagged Lat1 and Lat2, suggesting either that tagging and expression in a foreign membrane alters the transport kinetics of Lat1 and/or Lat2 or that A. monospora contains at least one more l-arabinose transporter.
Deletion of the nicotinic acetylcholine receptor subunit gene Dα1 confers insecticide resistance, but at what cost?

ABSTRACT Nicotinic acetylcholine receptors (nAChRs) have vital functions in processes of neurotransmission that underpin key behaviors. These pentameric ligand-gated ion channels have been used as targets for insecticides that constitutively activate them, causing the death of insect pests. In examining a knockout of the Dα1 nAChR subunit gene, our study linked this one subunit with multiple traits. We were able to confirm previous work that had identified Dα1 as a target of the neonicotinoid class of insecticides. Further, we uncovered roles for the gene in influencing mating behavior and patterns of sleep. The knockout mutant was also observed to have a significant reduction in longevity. This study highlighted the severe fitness costs that appear to be associated with the loss of function of this gene in natural populations in the absence of insecticides targeting the Dα1 subunit. Such a fitness cost could explain why target site resistances to neonicotinoids in pest insect populations have been associated specific amino acid replacement mutations in nAChR subunits, rather than loss of function. That mutant phenotypes were observed for the two behaviors examined indicates that the functions of Dα1, and other nAChR subunits, need to be explored more broadly. It also remains to be established whether these phenotypes were due to loss of the Dα1 receptor and/or to compensatory changes in the expression levels of other nAChR subunits.
Divergent Signaling Pathways Link Focal Adhesion Kinase to Mitogen-activated Protein Kinase Cascades

Stimulation of a number of cell surface receptors, including integrins and G protein-coupled receptors, results in the activation of a non-receptor tyrosine kinase known as focal adhesion kinase (FAK). In turn, this kinase is believed to play a critical role in signaling to intracellular kinase cascades controlling gene expression such as extracellular signal-regulated kinases (ERKs), by a yet poorly defined mechanism. Furthermore, whether this tyrosine kinase also mediates the activation of other mitogen-activated protein kinase family members, such as c-Jun NH2-terminal kinases (JNKs), is still unclear. We show here that the activation of FAK by anchoring to the cell membrane is itself sufficient to stimulate potently both ERK and JNK. These effects were found to be phosphatidylinositol 3-kinase-independent, as FAK effectively stimulated Akt, and wortmannin suppressed Akt but not ERK or JNK activation. As previously reported by others, activation of ERK correlated with the ability of FAK to induce tyrosine phosphorylation of Shc. Surprisingly, however, stimulation of JNK was not dependent on the kinase activity of FAK or on the ability to induce tyrosine phosphorylation of FAK substrates. Instead, we provide evidence that FAK may stimulate JNK through a novel pathway involving the recruitment of paxillin to the plasma membrane and the subsequent activation of a biochemical route dependent on small GTP-binding proteins of the Rho family.
Combined Stimulation of Toll-Like Receptor 5 and NOD1 Strongly Potentiates Activity of NF-κB, Resulting in Enhanced Innate Immune Reactions and Resistance to Salmonella enterica Serovar Typhimurium Infection

ABSTRACT Pathogen recognition receptors (PRRs) are essential components of host innate immune systems that detect specific conserved pathogen-associated molecular patterns (PAMPs) presented by microorganisms. Members of two families of PRRs, transmembrane Toll-like receptors (TLRs 1, 2, 4, 5, and 6) and cytosolic NOD receptors (NOD1 and NOD2), are stimulated upon recognition of various bacterial PAMPs. Such stimulation leads to induction of a number of immune defense reactions, mainly triggered via activation of the transcription factor NF-κB. While coordination of responses initiated via different PRRs sensing multiple PAMPS present during an infection makes clear biological sense for the host, such interactions have not been fully characterized. Here, we demonstrate that combined stimulation of NOD1 and TLR5 (as well as other NOD and TLR family members) strongly potentiates activity of NF-κB and induces enhanced levels of innate immune reactions (e.g., cytokine production) both in vitro and in vivo. Moreover, we show that an increased level of NF-κB activity plays a critical role in formation of downstream responses. In live mice, synergy between these receptors resulting in potentiation of NF-κB activity was organ specific, being most prominent in the gastrointestinal tract. Coordinated activity of NOD1 and TLR5 significantly increased protection of mice against enteroinvasive Salmonella infection. Obtained results suggest that cooperation of NOD and TLR receptors is important for effective responses to microbial infection in vivo.
Identification of the authentic varicella‐zoster virus gB (gene 31) initiating methionine overlapping the 3′ end of gene 30

The varicella‐zoster virus (VZV) gB sequence was re‐examined in light of recent knowledge about unusually long gB signal peptides in other herpesviral gB homologs. Through mutational analysis, the discovery was made that the authentic initiating methionine for VZV gB is a codon beginning at genome nucleotide 56,819. The total length for the VZV gB primary translation product was 931 amino acids (aa) with a 71‐aa signal sequence. Considering the likely signal sequence cleavage site to be located between Ser 71 and Val 72, the length of the mature VZV gB polypeptide would then be 860 amino acids prior to further internal endoproteolytic cleavage between amino acids Arg 494 and Ser 495. In this report, we also produced a full‐length gB and demonstrated its association with VZV gE, suggesting a possible gE‐gB interaction during gB trafficking before its cleavage in the Golgi. J. Med. Virol. 70:S64–S70, 2003. © 2003 Wiley‐Liss, Inc.
Analysis of Desert Dust Outbreaks Over Southern Europe Using CALIOP Data and Ground-Based Measurements

Saharan dust outbreaks are one of the major aerosol sources in Southern Europe. Dust affects the radiative balance of the Earth-atmosphere system and impacts health. The assessment of Saharan outbreaks requires information about the vertical distribution of dust in the atmosphere, usually obtained from lidar measurements, such as the ones performed by the spaceborne Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) sensor. In this paper, we have used CALIOP level-1 daytime data in combination with aerosol optical depth (AOD) measurements from Aerosol Robotic Network (AERONET) ground-based photometers to obtain aerosol profiles during 23 dust outbreaks over Southern Europe. These profiles are used for two main purposes: analyzing the lidar ratio values and vertical distribution of dust and evaluating the performance of version 3 of CALIOP algorithms. The mean lidar ratio obtained from the synergic method ranged between 47.7 and 49.0 sr, depending on the criterion used to average CALIOP signal. The dust layers traveled at a wide range of altitudes, from surface level up to 7.6 km. We found that the AOD values retrieved from CALIOP level 2 (version 3) and AERONET were not correlated (r <; 0.2). In addition, we observed that the mean AOD obtained by satellite retrievals, between 0.16 and 0.18, was lower than the mean AERONET value, i.e., 0.33, by 50%. These differences in the AOD were found to be caused by two main reasons: misclassification of dense dust layers as clouds by CALIOP algorithms, mainly over 4 km, and limitations of CALIOP algorithms to detect weak aerosol layers, particularly between 1.5 and 2.5 km.
Negative Correlation Between Hepatitis C Virus (HCV) and Let-7 MicroRNA Family in Transplanted Livers: The Role of rs868 Single-Nucleotide Polymorphism

Background Genetic alterations of TGF-β pathway members, including its transmembrane receptor, TGFBR1, may influence the course of HCV infection. Rs868 is a single-nucleotide polymorphism of the 3′UTR region of TGFBR1, located in a binding site for the conserved let-7/miR98 microRNA family. Previously, we demonstrated a favorable course of hepatitis C recurrence after liver transplantation in rs868 AG genotype of the transplanted liver when compared to rs868 AA. The aim of the present study was to confirm the biological effect of rs868. Material/Methods HepG2 cell line was transfected with luciferase vectors cloned with 3′UTR of TGFBR1 gene encompassing different rs868 alleles. Post-transplant liver biopsies from 61 patients with HCV-related end-stage liver disease were evaluated histopathologically and analyzed for the expression of TGFBR1 mRNA, let-7/miR98 microRNAs, HCV RNA load, and rs868 genotype. Results Luciferase expression was significantly lower in the A allele-containing vector. TGFBR1 mRNA and HCV RNA load were correlated negatively with let-7/miR98 microRNAs and this correlation was significantly stronger for rs868 AG compared to AA genotype. A strong positive correlation was demonstrated between TGFBR1 and HCV in both genotypes. In AG heterozygotes, let-7/miR98 microRNAs showed a strong negative correlation with periportal or periseptal interface hepatitis (Ishak A score). Conclusions There is a negative correlation between let-7/miR98 microRNAs and HCV viral load and TGFBR1 mRNA after liver transplantation. In the rs868 AG heterozygotes, this correlation was stronger and there was a negative correlation between let-7/miR98 and Ishak A score, which is in concordance with the previously demonstrated protective role of this genotype in post-transplant hepatitis C recurrence.
Candidate gene polymorphisms and the risk for pregnancy‐related venous thrombosis

Venous thrombosis (VT) is one of the leading causes of maternal death in the western world, but the genetic causes of pregnancy‐related VT are insufficiently understood. The aim of this study was to investigate the association between common genetic variations in candidate genes and pregnancy‐related VT. We undertook a hospital based case–control study of women with VT during pregnancy or puerperium; controls were women giving birth without having VT. Single nucleotide polymorphisms (SNPs) were selected in 49 pre‐specified candidate genes involved in coagulation, inflammation, and hormonal metabolism in 313 cases and 353 controls. We found new associations between SNPs and total pregnancy‐related VT in the genes encoding coagulation factors V and VIII, and p‐selectin. Additional new associations between SNPs and antenatal VT were found in the genes encoding the epidermal growth factor receptor, the pregnane X receptor, and protein S. Of 21 SNPs previously associated with thrombotic disease, rs2289252 in F11 and rs3917643 in F3 were associated with pregnancy‐related VT, while rs4524 in F5 was associated with antenatal VT.
Melatonin suppresses migration and invasion via inhibition of oxidative stress pathway in glioma cells

Abstract: Melatonin, an indolamine produced and secreted predominately by the pineal gland, exhibits a variety of physiological functions, possesses antioxidant and antitumor properties. In this study, we have shown that pharmacologic concentration (1 mm) of melatonin significantly reduced cell migration and invasion of T98G and U251 glioma cells after 24‐hr treatment and inhibited expression of matrix metalloproteinase 2 (MMP 2) and MMP 9. The melatonin inhibition of cell migration and invasion was associated with its reduction of intracellular basal free radical generation. Melatonin at pharmacologic concentration also inhibited the constitutive activation of the reactive oxygen species downstream transcription factor nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB). Furthermore, pyrrolidine dithiocarbamate, a NF‐κB‐specific inhibitor, at 10 μm displayed anti‐migration and invasion effects and inhibition of MMP 2 and MMP 9 expression resembling that of melatonin. Taken together, it is concluded that inhibition of migration and invasion of glioma cells by melatonin is associated with the latter in its inhibition of oxidative stress pathway. This suggests a potential therapeutic application of melatonin in the treatment of glioma.
Study of Antiretroviral Drug–Resistant HIV-1 Genotypes in Northern Thailand: Role of Mutagenically Separated Polymerase Chain Reaction as a Tool for Monitoring Zidovudine-Resistant HIV-1 in Resource-Limited Settings

Summary:As the number of HIV-1–infected individuals receiving antiretroviral drugs has been rapidly increasing in developing countries, there is an urgent need for drug resistance genotype information of non-B subtype HIV-1 and for the establishment of a practical system of monitoring drug-resistant viruses. This study first sequenced the reverse transcriptase region of HIV-1 in 112 infected individuals who had been treated with zidovudine (AZT)/didanosine or AZT/zalcitabine as dual therapy at a government hospital in northern Thailand and then compared the above sequence method with mutagenically separated polymerase chain reaction (MS-PCR) for detecting M41L and K70R mutations. Concordant rates of detecting M41L and K70R mutations by the 2 methods were 96.9% (93/96) and 92.7% (89/96), respectively. The M41L and K70R MS-PCR could detect 86.4% of AZT-resistant strains with any resistance mutation, which was determined by the sequencing method. Then 292 drug-naive individuals were screened for the presence of drug-resistant HIV-1 by the MS-PCR assay and it was found that 2 individuals (0.7%) carried viruses with either the M41L or K70R mutation. It is feasible to test a large number of samples with MS-PCR, which is sensitive, cheap, and easy to perform and does not require sophisticated equipment. The M41L and K70R MS-PCR is potentially a useful tool to monitor the spread of AZT-resistant HIV-1 in resource-limited countries.
Developing capacity-building activities for mental health system strengthening in low- and middle-income countries for service users and caregivers, service planners, and researchers

There is increasing international recognition of the need to build capacity to strengthen mental health systems. This is a fundamental goal of the ‘Emerging mental health systems in low- and middle-income countries’ (Emerald) programme, which is being implemented in six low- and middle-income countries (LMICs) (Ethiopia, India, Nepal, Nigeria, South Africa, Uganda). This paper discusses Emerald's capacity-building approaches and outputs for three target groups in mental health system strengthening: (1) mental health service users and caregivers, (2) service planners and policy-makers, and (3) mental health researchers. When planning the capacity-building activities, the approach taken included a capabilities/skills matrix, needs assessments, a situational analysis, systematic reviews, qualitative interviews and stakeholder meetings, as well as the application of previous theory, evidence and experience. Each of the Emerald LMIC partners was found to have strengths in aspects of mental health system strengthening, which were complementary across the consortium. Furthermore, despite similarities across the countries, capacity-building interventions needed to be tailored to suit the specific needs of individual countries. The capacity-building outputs include three publicly and freely available short courses/workshops in mental health system strengthening for each of the target groups, 27 Masters-level modules (also open access), nine Emerald-linked PhD students, two MSc studentships, mentoring of post-doctoral/mid-level researchers, and ongoing collaboration and dialogue with the three groups. The approach taken by Emerald can provide a potential model for the development of capacity-building activities across the three target groups in LMICs.