Miracle-dz/UniFAR-FTUs huggingface dataset:
G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives

Most evidence indicates that, as for family C G protein–coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand–GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-heteromer selective compounds.
Zebrafish fgf24 functions with fgf8 to promote posterior mesodermal development

Fibroblast growth factor (Fgf) signaling plays an important role during development of posterior mesoderm in vertebrate embryos. Blocking Fgf signaling by expressing a dominant-negative Fgf receptor inhibits posterior mesoderm development. In mice, Fgf8 appears to be the principal ligand required for mesodermal development, as mouse Fgf8 mutants do not form mesoderm. In zebrafish, Fgf8 is encoded by the acerebellar locus, and, similar to its mouse otholog, is expressed in early mesodermal precursors during gastrulation. However, zebrafish fgf8 mutants have only mild defects in posterior mesodermal development, suggesting that it is not the only Fgf ligand involved in the development of this tissue. We report here the identification of an fgf8-related gene in zebrafish, fgf24, that is co-expressed with fgf8 in mesodermal precursors during gastrulation. Using morpholino-based gene inactivation, we have analyzed the function of fgf24 during development. We found that inhibiting fgf24 function alone has no affect on the formation of posterior mesoderm. Conversely, inhibiting fgf24 function in embryos mutant for fgf8 blocks the formation of most posterior mesoderm. Thus, fgf8 and fgf24 are together required to promote posterior mesodermal development. We provide both phenotypic and genetic evidence that these Fgf signaling components interact with no tail and spadetail, two zebrafish T-box transcription factors that are required for the development of all posterior mesoderm. Last, we show that fgf24 is expressed in early fin bud mesenchyme and that inhibiting fgf24 function results in viable fish that lack pectoral fins.
Impacts of Hysteresis and Magnetic Couplings on the Stability Domain of Ferroresonance in Asymmetric Three-Phase Three-Leg Transformers

This paper investigates the stability domain of ferroresonance in asymmetric three-phase three-leg transformers considering magnetic couplings and hysteresis effects of the core. A newly developed and accurate time-domain transformer model capable of simulating dynamic and transient operating conditions is implemented in this study. The model is based on electromagnetic circuit theory and considers dynamic hysteresis effects (major and minor loops) as well as core topology, asymmetry, and magnetic flux cross-coupling interactions of the core legs. Unbalanced switching with series and shunt capacitances, which is known to increase the risk of ferroresonance, is studied with the developed model. The validity of the model under ferroresonant conditions is confirmed by comparisons with extensive experimental data. The main contribution is a new analysis of (a)symmetric three-phase transformer ferroresonance behavior with an accurate core model capable of predicting ferroresonance modes.
Comprehensive screening of genes resistant to an anticancer drug in esophageal squamous cell carcinoma

Drug resistance to chemotherapy is a major issue in esophageal cancer management. Drug resistance may be mediated by genetic changes in the tumor; therefore, the identification of gene mutations may lead to better therapeutic outcomes. We used a novel method involving transposons to screen and identify drug-resistant genes. Transposons are DNA sequences that move from one location on the gene to another. A modified piggyBac transposon was designed as an insertion mutagen, and a cytomegalovirus (CMV) promoter sequence was added to induce strong transcription. When the transposon is inserted to the upstream of a certain gene, the gene will be overexpressed while when intserted down or intragenically, it will be downregulated. After establishing a transposon-tagged cell library, we treated cell lines derived from esophageal squamous cell carcinomas (ESCC) [Tohoku esophagus (TE)] with cisplatin (CDDP). We performed splinkerette PCR and TOPO cloning on the resistant colonies. Bacterial colonies were sequenced, and next-generation sequencing was used to identify the overexpressed/downregulated sequences as candidate genes for CDDP resistance. We established 4 cell lines of transposon-tagged cells, TE4, 5, 9 and 15. We treated the two relatively viable cell lines, TE4 and TE15, with CDDP. We identified 37 candidate genes from 8 resistant colonies. Eight genes were overexpressed whilst 29 were downregulated. Among these genes was Janus kinase 2 (JAK2) that is implicated in the progression of myeloproliferative neoplasms. We identified 37 candidate genes responsible for CDDP resistance in the two cell lines derived from ESCC cells. The method is inexpensive, relatively simple, and capable of introducing activating and de-activating mutations in the genome, allowing for drug-resistant genes to be identified.
Associations Between Traumatic Events and Suicidal Behavior in South Africa

Abstract Research conducted predominantly in the developed world suggests that there is an association between trauma exposure and suicidal behavior. However, there are limited data available investigating whether specific traumas are uniquely predictive of suicidal behavior or the extent to which traumatic events predict the progression from suicide ideation to plans and attempts. A national survey was conducted with 4351 adult South Africans between 2002 and 2004 as part of the World Health Organization World Mental Health Surveys. Data on trauma exposure and subsequent suicidal behavior were collected. Bivariate and multivariate survival models tested the relationship between the type and number of traumatic events and lifetime suicidal behavior. A range of traumatic events are associated with lifetime suicide ideation and attempt; however, after controlling for all traumatic events in a multivariate model, only sexual violence (odds ratio = 4.7; confidence interval, 2.3 to 9.4) and having witnessed violence (odds ratio = 1.8; confidence interval, 1.1 to 2.9) remained significant predictors of lifetime suicide attempts. The disaggregation of the associations between traumatic events and suicide attempts indicates that they are largely caused by traumatic events predicting suicide ideation rather than by the progression from suicide ideation to attempt. This article highlights the importance of traumatic life events in the occurrence of suicidal thoughts and behaviors and provides important information about the nature of this association. Future research is needed to better understand how and why such experiences increase the risk of suicidal outcomes.
Shortwave direct radiative forcing of Saharan dust aerosols over the Atlantic Ocean

Using collocated Visible and Infrared Scanner (VIRS) and Clouds and the Earth's Radiant Energy Budget Scanner (CERES) data on board the Tropical Rainfall Measuring Mission (TRMM) satellite, the instantaneous Shortwave Aerosol Radiative Forcing (SWARF) and daytime diurnally averaged SWARF at the top-of-atmosphere (TOA) are estimated for Saharan dust over the Atlantic Ocean (10° N–25°N, 30° W–15° W) for July 1998. A combination of reflectance thresholds, along with infrared spatial coherence techniques, are used to separate dust aerosols from clouds. Using Mie and Discrete Ordinate Radiative Transfer (DISORT) calculations and the VIRS channel 1 reflectance, dust optical thickness (τ) is retrieved. The average instantaneous direct SWARF of dust aerosols per unit τ is −50 W m−2. The daytime diurnally averaged SWARF of dust aerosols is −15.2±10.9 W m−2 for a mean z of 0.79±0.39. This study demonstrates that the synergistic use of instruments from different parts of the electromagnetic spectrum can be used to study the radiative effects of dust aerosols. This study is also among the first to estimate the diurnal SWARF of dust aerosols using satellite sensor data.
Genotoxic, cytotoxic, and apoptotic effects of Hypogymnia physodes (L.) Nyl. on breast cancer cells

The aim of this study is to determine the chemical composition, and evaluate the genotoxic, and anti‐growth potency of the methanol extracts of lichen species Hypogymnia physodes (L.) Nyl. (HPE). Anti‐growth effect was tested in two different human breast cancer cell lines (MCF‐7 and MDA‐MB‐231) by the MTT and ATP viability assays and apoptosis was assayed by the caspase‐cleaved cytokeratin 18 (M30‐antigen). Genotoxic activity of HPE was studied using chromosome aberration and micronuclei tests in human lymphocytes culture in vitro. The chemical composition of H. physodes was analyzed by using direct thermal desorption method coupled with comprehensive gas chromatography–time of flight mass spectrometry (GCXGC‐TOF/MS). Our results indicate that HPE has an anti‐growth effect at relatively lower concentrations, while relatively higher concentrations are required for genotoxic activity. HPE, therefore, seems to represent a therapeutic potential and poses new challenges for medicinal chemistry. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 804–813, 2014.
The Compact, Conical, Accretion-Disk Warm Absorber of the Seyfert 1 Galaxy NGC 4051 and Its Implications for IGM-Galaxy Feedback Processes

Using a 100 ks XMM-Newton exposure of NGC 4051, we show that the time evolution of the ionization state of the X-ray absorbers in response to the rapid and highly variable X-ray continuum constrains all the main physical and geometrical properties of an AGN "warm absorber" wind. The absorber consists of two different ionization components, with a difference of ≈100 in ionization parameter and ≈5 in column density. By tracking the response in the opacity of the gas to changes in the ionizing continuum, we were able to constrain the electron density of the system. We find ne = (5.8-21.0) × 106 cm-3 for the high-ionization absorber and ne > 8.1 × 107 cm-3 for the low-ionization absorber. These densities require that the high- and low-ionization absorbing components of NGC 4051 must be compact, at distances 0.5-1.0 lt-days (2200RS-4400RS) and <3.5 lt-days (<15,800RS) from the continuum source, respectively. This rules out an origin in the dusty obscuring torus, as the dust sublimation radius is at least an order of magnitude larger (~12 lt-days). An accretion-disk origin for the warm absorber wind is strongly suggested, and an association with the high-ionization, He II emitting, broad emission line region (radius <2 lt-days) is possible. The two detected phases are consistent with pressure equilibrium, which suggests that the absorber consists of a two-phase medium. A radial flow in a spherical geometry is unlikely, and a conical wind geometry is preferred. The implied mass outflow rate from this wind can be well constrained and is 2%-5% of the mass accretion rate. If the mass outflow rate scaling with accretion rate is representative of all quasars, our results imply that warm absorbers in powerful quasars are unlikely to produce important evolutionary effects on their larger environment, unless we are observing the winds before they get fully accelerated. Only in such a scenario can AGN winds be important for cosmic feedback.
Renal molecular mechanisms underlying altered Na+ handling and genesis of hypertension during adulthood in prenatally undernourished rats

In the present study, we investigated the development of hypertension in prenatally undernourished adult rats, including the mechanisms that culminate in dysfunctions of molecular signalling in the kidney. Dams were fed a low-protein multideficient diet throughout gestation with or without α-tocopherol during lactation. The time course of hypertension development followed in male offspring was correlated with alterations in proximal tubule Na+-ATPase activity, expression of angiotensin II (Ang II) receptors, and activity of protein kinases C and A. After the establishment of hypertension, Ang II levels, cyclo-oxygenase 2 (COX-2) and NADPH oxidase subunit expression, lipid peroxidation and macrophage infiltration were examined in renal tissue. Lipid peroxidation in undernourished rats, which was very intense at 60 d, decreased at 90 d and returned to control values by 150 d. During the prehypertensive phase, prenatally undernourished rats exhibited elevated renal Na+-ATPase activity, type 2 Ang II receptor down-regulation and altered protein kinase A:protein kinase C ratio. Stable late hypertension coexisted with highly elevated levels of Ang II-positive cells in the cortical tubulointerstitium, enhanced increase in the expression of p47phox (NADPH oxidase regulatory subunit), marked down-regulation of COX-2 expression, expanded plasma volume and decreased creatinine clearance. These alterations were reduced when the dams were given α-tocopherol during lactation. The offspring of well-nourished dams treated with α-tocopherol exhibited most of the alterations encountered in the offspring of undernourished dams not treated with α-tocopherol. Thus, alterations in proximal tubule Na+ transport, subcellular signalling pathways and reactive oxygen species handling in renal tissue underpin the development of hypertension.
Further investigations into connection repeatability of waveguide devices at frequencies from 750 GHz to 1.1 THz

This paper describes some further investigations into the connection repeatability for waveguide devices in the WM-250 (WR-01) waveguide size over the recommended frequency range of 750 GHz to 1.1 THz. This work follows previous work on this subject that was presented at the 82nd ARFTG conference in November 2013. As with the earlier investigation, three devices have been investigated - an offset short-circuit, a flush short-circuit, and a near-matched load. These devices can be used as calibration standards for Vector Network Analyzers (VNAs), and so can be found in VNA calibration kits. On this occasion, the aperture of each device was inverted (i.e. rotated through 180°) between the repeated disconnection and re-connection of the device to the VNA test port. This provides an experimental evaluation of the effect of the imperfect position of the device's flange alignment pins and holes. As before, the repeatability of the measurements is assessed using statistical techniques, in terms of the experimental standard deviation in both the real and imaginary components of the complex-valued linear reflection coefficient. The results obtained during this investigation are compared with the results obtained from the previous investigation (where flange inversion was not included as part of the disconnection and re-connection procedure for the devices).
Follow-Up on Diagnostic Proficiency of Laboratories Equipped To Perform Orthopoxvirus Detection and Quantification by PCR: the Second International External Quality Assurance Study

ABSTRACT Two years after the first external quality assurance study on bioterrorism-relevant viruses, we have conducted a follow-up study on orthopoxvirus detection by PCR. Thirty-three laboratories (27 European, 4 Austral-Asian, and 2 American) participated. Samples contained 0 to 40,000,000 DNA copies of lyophilized monkeypox, cowpox, and vaccinia virus per ml. Laboratories achieved a >80% detection chance above 56,234 copies per ml. Global sensitivity was not significantly improved over that of the first study. Twenty-seven and 9 participants, respectively, were able to genotype and quantify virus. Four of 27 genotyping results were incorrect. Quantification accuracy was significantly better for vaccinia virus than for the other viruses. False-positive results occurred in 22 (11.8%) of all 186 tests on negative samples, but 18 of these were contributed by only five laboratories. Fifty-five percent of laboratories could appropriately detect PCR inhibition. The use of either real-time PCR or commercial diagnostic kits had significant positive influence on laboratory performance.
Evaluation of Computer-Based Testing for Aniseikonia in Children

Purpose. To evaluate the ability of children to perform computer-based matching and to evaluate the accuracy and reliability of size lens induced aniseikonia measurement using the Aniseikonia Inspector version 1. Methods. Fifty-seven children in grades 1, 3, and 5 (aged 6 to 11 years) completed four trials per each of four conditions: control (associated binocular), dissociated (wearing red/green filters only), and dissociated with 3.5% afocal (size) lens over the right eye and size lens over the left eye (the latter two conditions in predetermined random order). Children adjusted the size of a variable semicircle seen by one eye in 0.5% steps using computer arrow keys to match the size of a nonvariable semicircle seen by the other eye. Testing was performed in the dark using large targets oriented vertically. Results. The repeatability coefficient (sw), based on individual measures, was lowest for the control condition. Repeated measures (mean of four trials) show that adjustments with red/green dissociation only were not significantly different from zero size difference, with narrow confidence limit widths at all ages (0.54, 0.42, and 0.22% at grades 1, 3, and 5, respectively). Repeated measures of induced aniseikonia showed increased confidence limit widths (width for right eye condition was 2.77, 0.71, and 0.82% at grades 1, 3, and 5, respectively). Measured aniseikonia (mean of four adjustments) was less than induced aniseikonia with slopes of regressions lines insignificantly <1.0 for all grades. Conclusions. Children as young as 6 years are capable of making the adjustments necessary to obtain a measure of aniseikonia under dissociated conditions with sufficient accuracy and reliability to be clinically useful using the Aniseikonia Inspector software (version 1 with large targets in the dark). Further study is necessary to show how children with natural aniseikonia respond to testing.
Effect of dentinal surface preparation on the bonding of self-adhesive luting cements

The purpose of the present study was to evaluate the bond strength and the interaction morphology of self-adhesive resin luting cements (SLCs) to dentin prepared with different methods. Four SLCs were used: RelyX U100®, RelyX U200®, Clearfil SA Luting®, and SmartCem2®. A flat dentin surface of 40 human molars was exposed and each tooth was sectioned in four tooth-quarters, which were distributed into four groups according to the SLC used to cement indirect resin composite restorations. The tooth-quarters of each group were then distributed in four subgroups according to the method used for dentin preparation: flat-ended cylindrical fine-grit diamond, flat-ended cylindrical median-grit diamond, flat-ended cylindrical plain-cut tungsten carbide, or abraded with #600-grit SiC paper (control). The restored tooth-quarters were sectioned to obtain beams (0.8 mm2) and submitted to the microtensile bond strength test (n = 10). The results were analyzed using two-way ANOVA/Tukey (α = 0.05). Forty-four additional teeth were used for micromorphological investigation of the SLC/dentin interface and of the topographic aspect of the dentin surfaces after application of the SLCs. Only the bond strength of RelyX U200 was significantly influenced by the surface preparation. No interference was identified on the micromorphological aspect of the bonding interfaces. The topographic investigation of the dentinal surfaces showed that the SLCs were not able to effectively remove the smear layer and etch the underlying dentin, irrespective of the preparation method. So, the interference of the dentin preparation on the bond strength of SLCs is material dependent, but don’t influence the micromorphologic aspect of the interaction zone.
The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

Background/Aims: Rho GTPases are crucial regulators of the actin cytoskeleton, membrane trafficking and cell signaling and their importance in cell migration and invasion is well- established. The human cytomegalovirus (HCMV) is a widespread pathogen responsible for generally asymptomatic and persistent infections in healthy people. Recent evidence indicates that HCMV gene products are expressed in over 90% of malignant type glioblastomas (GBM). In addition, the HCMV Immediate Early-1 protein (IE1) is expressed in >90% of tumors analyzed. Methods: RhoA, RhoB and RhoC were individually depleted in U373MG glioblastoma cells as well as U373MG cells stably expressing the HCMV IE1 protein (named U373MG-IE1 cells) shRNA lentivirus vectors. Cell proliferation assays, migration as well as wound-healing assays were performed in uninfected and HCMV-infected cells. Results: The depletion of RhoA, RhoB and RhoC protein resulted in significant alterations in the morphology of the uninfected cells, which were further enhanced by the cytopathic effect caused by HCMV. Furthermore, in the absence or presence of HCMV, the knockdown of RhoB and RhoC proteins decreased the proliferation rate of the parental and the IE1-expressing glioblastoma cells, whereas the knockdown of RhoA protein in the HCMV infected cell lines restored their proliferation rate. In addition, wound healing assays in U373MG cells revealed that depletion of RhoA, RhoB and RhoC differentially reduced their migration rate, even in the presence or the absence of HCMV. Conclusion: Collectively, these data show for the first time a differential implication of Rho GTPases in morphology, proliferation rate and motility of human glioblastoma cells during HCMV infection, further supporting an oncomodulatory role of HCMV depending on the Rho isoforms' state.