Miracle-dz/UniFAR-FTUs huggingface dataset:
G Protein‐Coupled Receptor Endosomal Signaling and Regulation of Neuronal Excitability and Stress Responses: Signaling Options and Lessons From the PAC1 Receptor

Our understanding of G protein coupled receptor (GPCR) mechanisms and functions have evolved considerably. Among the many conceptual realignments, GPCRs can exist in an ensemble of active microstates that have the potential to differentially engage specific downstream signaling events. Furthermore, among GPCR dynamics, GPCR internalization and vesicular trafficking are no longer solely mechanisms for desensitization, but now appreciated to form intricate endosomal signaling complexes that can potentially target second messengers to intracellular compartments with high temporal and spatial resolution. The PACAPergic system is important in the maintenance of physiological homeostasis in the central and peripheral nervous systems and activation of the PACAP‐selective PAC1 receptor can generate differential but coordinate plasma membrane and endosomal signals for cellular responses. The integration of these signals can modulate PACAP‐induced changes in ionic conductances that gate neuronal excitability. PACAP/PAC1 receptor generation of endosomal ERK signals participate in chronic pain and anxiety‐like responses which can be attenuated with endocytosis inhibitors. From the abilities of ligands to stabilize the different GPCR microstates for biased downstream signaling, the development of biased PAC1 receptor agonists and antagonists may provide opportunities to dissociate the homeostatic regulatory signals of PACAP from the maladaptive effects. In particular, the development of biased antagonists to PAC1 receptor‐mediated endosomal signaling may offer therapeutic options for chronic pain and stress‐related disorders. J. Cell. Physiol. 232: 698–706, 2017. © 2016 Wiley Periodicals, Inc.
Airborne Exposure to Trihalomethanes from Tap Water in Homes with Refrigeration-Type and Evaporative Cooling Systems

This study evaluates airborne concentrations of common trihalomethane compounds (THM) in selected living spaces of homes supplied with chlorinated tap water containing >85 ppb total THM. Three small homes in an arid urban area were selected, each having three bedrooms, a full bath, and approximately 1000 square feet; two homes had standard (refrigeration-type) central air conditioning and the third had a central evaporative cooling system (“swamp cooler”). A high-end water-use pattern was used at each home in this exposure simulation. THM were concurrently measured on 4 separate test days in tap water and air in the bathroom, living room, the bedroom closest to the bathroom, and outside using Summa canisters. Chloroform (trichloromethane, TCM), bromodichloromethane (BDCM), and dibromochloromethane (DBCM) concentrations were quantified using U.S. EPA Method TO-14. The apparent volatilization fraction consistently followed the order: TCM >BDCM >DBCM. Relatively low airborne THM concentrations (similar to outdoors) were found in the living room and bedroom samples for the home with evaporative cooling, while the refrigeration-cooled homes showed significantly higher THM levels (three- to fourfold). This differential remained after normalizing the air concentrations based on estimated THM throughput or water concentrations. These findings indicate that, despite higher throughput of THM-containing water in homes using evaporative coolers, the higher air exchange rates associated with these systems rapidly clears THM to levels similar to ambient outdoor concentrations. The data collection and preliminary data analysis were funded by defendants in a toxic tort lawsuit who were attempting to validate the accuracy of modeling assumptions and results that were offered in that litigation. The time and costs of writing this article were borne by the authors. The assistance of Tom Flahive, Gwen Corbett, Rick Hamaker, and Steve Hoyt was greatly appreciated. A poster session including the data described in this report was presented at the Society of Toxicology annual meeting and published in the following abstract: Paustenbach, D. J., Richter, R. O. , Suder, D. , Corbett, G. E. , Flahive, T. P., and Kerger, B. D. 1998. Comparison of measured and model-estimated indoor concentrations of airborne chloroform from use of residential tap water. Toxicological Sciences 42(1-S):40–41.
The Antifibrogenic Potential of PPARγ Ligands in Pulmonary Fibrosis

Pulmonary fibrosis is characterized by the accumulation of fibroblasts, myofibroblasts, collagen, and other extracellular matrix proteins in the interstitium of the lung, with subsequent scarring and destruction of the alveolar capillary interface. In some cases, pulmonary fibrosis is preceded by lung inflammation and can be treated with anti-inflammatory therapies. However, idiopathic pulmonary fibrosis is characterized by a relative paucity of underlying inflammation and currently has no effective treatment. There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays an important role in controlling cell differentiation and that PPARγ ligands can modify inflammatory and fibrotic responses. Peroxisome proliferator-activated receptor γ ligands, including the thiazolidinedione class of antidiabetic drugs and novel triterpenoid compounds derived from oleanic acid, inhibit TGF-β-stimulated profibrotic differentiation of lung fibroblasts in vitro and reduce lung scarring in animal models of fibrosis. The mechanism of action of the PPARγ ligands is under investigation but seems to involve both PPARγ-dependent and PPARγ-independent pathways. These in vitro and in vivo data highlight the potentially exciting role of PPARγ ligands as novel therapies for fibrosis of the lung and other organ systems prone to scarring. Many of the synthetic PPARγ ligands are orally active, and several are currently available and Food Drug Administration approved for use in therapy of type 2 diabetes. Further research is urgently required to more clearly elucidate the mechanism of action of these drugs and to develop more potent antifibrotic agents for patients with scarring diseases for whom there are currently few effective therapies.
Morphological and electrophysiological properties of neurones in the dorsal vagal complex of the rat activated by arterial baroreceptors

This study physiologically identifies and anatomically describes arterial baroreceptive neurones in the nucleus tractus solitarii of the rat. Neurones were recorded using neurobiotin‐containing whole cell patch electrodes in a working heart‐brainstem preparation and characterized physiologically as arterial baroreceptive in response to stimulation of the aortic arch and/or ipsilateral carotid sinus. Fifteen of 84 neurones tested were arterial baroreceptive, 7 of 8 were morphologically identified as located in the solitary tract nucleus (NTS), and 1 of 8 was located in the dorsal vagal nucleus. The seven NTS neurones had a resting membrane potential of −52 ± 3.6 mV and a membrane input resistance of 233 ± 38 MΩ. Action potential height was 62 ± 4.2 mV, width at half amplitude 1.46 ± 0.38 ms, and duration of after‐hyperpolarisation 1.7 ± 2.33 ms. In six of eight neurones labelled there was an invariant excitatory synaptic input (latency 3.95 ± 0.3 ms) to stimulation of the solitary tract. Labelled somata were dorsomedial or medial to the solitary tract from −0.3 mm to +1.5 mm with regard to obex. Neurones had three to eight primary dendrites, and branches often entered the solitary tract and also extended across the ipsilateral NTS. Axons, which were mostly unmyelinated with boutons of the en passant variety, could ramify within the NTS while the main axon exited the NTS (n = 4/6), in the direction of the ipsilateral ventral medulla (n = 5/6). This is the first morphological and localisation data of physiologically characterised arterial baroreceptive NTS neurones in the rat. By comparing labelled cells with each other as well as with other unidentified cells, we conclude that NTS arterially baroreceptive neurones are morphologically and physiologically heterogenous. J. Comp. Neurol. 417:233–249, 2000. ©2000 Wiley‐Liss, Inc.
Apolipoprotein E Genotype in Dyslipidemic Patients and Response of Blood Lipids and Inflammatory Markers to Alpha-Linolenic Acid

The objective of this study was to determine the effect of alpha-linolenic acid (ALA) supplementation on blood lipids and inflammatory markers, in relation to apolipoprotein (apo) E genotype. The diets of 50 dyslipidemic male patients were supplemented with 15 mL of flaxseed oil per day for 12 weeks. Retrospectively, 3 apo E genotype variants were found (ε2/ε3, n=7; ε3/ε3, n=33; ε3/ε4, n=10). No significant differences were found among apo E genotypes in any variables at baseline. ALA supplementation produced a small but significant decrease in high-density lipoprotein cholesterol (from 1.12 to 1.08 mmol/L, 43 to 42 mg/dL; p=0.008) and apo A-I levels (from 1.28 to 1.24 g/L, p=0.036) in the ε3/ε3 homozygotes. In addition, ALA supplementation resulted in a significant decrease in the serum concentration of serum amyloid A (SAA) (p=0.014), C-reactive protein (CRP) (p=0.013), macrophage colony-stimulating factor (MCSF) (p<0.001), and interleukin (IL)-6 (p=0.028). Serum SAA and MCSF were also significantly decreased in the ε3/ε4 group (p=0.005 and p=0.017, respectively). In contrast, ALA produced no effects on any of the inflammatory markers in the ε2/ε3 group. ALA may have beneficial effects on inflammation in dyslipidemic carriers of the apo ε3/ε3 and ε3/ε4 genotypes, but not in carriers of the ε2 allele.
Effects on Growth of Human Osteoblast-Like Cells of Three Nonsteroidal Anti-Inflammatory Drugs

Some nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on bone tissue. The objective of this study was to determine the effect of different doses of dexketoprofen, ketorolac, and metamizole on growth of the osteoblast MG63 cell line. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide spectrophotometry results showed that MG63 cell growth was significantly inhibited after 24 hr of culture with doses of 10, 20, 100, or 1,000 µM of each NSAID and with doses of 0.1, 1, or 5 µM of dexketoprofen and ketorolac but not metamizole. Cell-cycle studies revealed that dexketoprofen and ketorolac treatments significantly arrested the cell cycle in phase G0/G1, increasing the percentage of cells in this phase. Apoptosis/necrosis studies showed significant changes versus control cells, with an increased percentage of cells in apoptosis after treatment with 10, 100, or 1,000 µM of metamizole and after treatment with 1, 10, 100, or 1,000 µM of dexketoprofen or ketorolac. In conclusion, treatment of osteoblast-like cells with high doses of the NSAIDs tested increased not only the percentage of cells in apoptosis but also the percentage of necrotic cells.
Academic Pharmacy: Where is Our Influence?

Objective. To evaluate the talents of fellows from cohorts 1-10 of the Academic Leadership Fellows Program (ALFP). Methods. This was a descriptive analysis of previously collected ALFP cohort data reflecting the talents using the Clifton StrengthsFinder assessment tool. Data consisted of 295 fellows from the first 10 years of the ALFP program. The Clifton StrengthsFinder talents were aggregated and analyzed to determine talents (strengths) distribution and domain. The aggregate of the four domains were compared among ALFP fellows using a chi-square analysis with an a priori alpha of . 05. Results. Lowest frequency of talents was found in the influencing domain (11.2%), while the domains with the largest frequency of talents were strategic thinking (34.4%) and executing (31.1%). When looking at the specific talents within the domains among the ALFP fellows, achiever (in the executing domain) and learner (in the strategic thinking domain) were the most frequent talents, while command (in the influencing domain) and adaptability (in the relationship building domain) were the least frequent talents. Conclusions. Since the profession is deficient in the influencing and relationship building domains (command and adaptability talents, respectively), this could help explain our slow progress in moving the profession from a product-focused role to a provider-based role. Perhaps the profession should be using a strategy better aligned with our signature leadership domains of executing and strategic thinking and focus on being a member of the health care team by aligning with team-based care rather than obtaining provider status.
Analysis of Operative Complications in a Series of 471 Anterior Lumbar Interbody Fusion Procedures

Study Design. This retrospective review compares the intraoperative and perioperative complications associated with the placement of threaded devices and nonthreaded devices used in anterior lumbar interbody fusions. Objective. Anterior lumbar interbody fusion is a common procedure performed with either a nonthreaded device, such as a femoral ring, or a threaded device, such as with a cage or a bone dowel. Summary of Background Data. Many studies have been done detailing the fusion rates and biomechanical properties of both devices. However, few studies have been performed evaluating acute complications between the two device types. Methods. A retrospective chart review was performed of 471 consecutive patients who underwent anterior lumbar interbody fusion: 243 with a nonthreaded interbody device and 228 with a threaded interbody device. Operative notes, anesthesia reports, discharge summaries, and follow-up notes were reviewed from 1992 to June 2002. The patients' demographics, diagnosis, number of levels fused, type of device used, length of hospital stay, and acute complications, either intraoperative or perioperative, were collected and analyzed. Results. Approximately 4.8% of patients with a threaded type interbody device had an intraoperative complication whereas only 0.4% of patients with a nonthreaded type device had an intraoperative complication. There was a significant association between interbody device type (threaded vs. nonthreaded) and occurrence of an intraoperative complication (P = 0.0024). Conclusions. Placement of threaded devices, such as cages or bone dowels, was associated with a higher acute complication rate than was the placement of nonthreaded devices during anterior lumbar interbody fusion.
Synthesis and biological activity of some very hydrophobic superagonist analogues of luteinizing hormone-releasing hormone.

The effect of increased hydrophobicity at position 6 of luteinizing hormone-releasing hormone (LH-RH) has been investigated by the incorporation of a series of 15 very hydrophobic, unnatural D-amino acids at this position. The unnatural amino acids studied can be considered analogues of phenylalanine with carbocyclic aromatic side chains consisting of substituted phenyl (e.g., 2,4,6-trimethylphenyl, p-biphenyl) or polycyclic aromatic (e.g., naphthalene, anthracene) units. When enzymatic resolution (subtilisin Carlsberg) of the most hydrophobic amino acids failed, the racemic amino acids were incorporated, and the diastereomeric LH-RH analogues were resolved by preparative high-performance liquid chromatography. The analogues were synthesized by the solid-phase technique. All of the synthetic compounds were very potent LH-RH superagonists, but [6-(3-(2-naphthyl)-D-alanine)]LH-RH, [6-(3-(2-naphthyl)-D-alanine), 7-(N alpha-methylleucine)]LH-RH and [6-(3-(2,4,6-trimethylphenyl)-D-alanine)]LH-RH appear to be among the most potent LH-RH agonist analogues yet reported when tested in a rat estrus cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds [ED50 approximately 7 x 10(-8) g; twice daily in saline]. These analogues are twice as potent as [D-Trp6,ProNHEt9]LH-RH in this assay system (i.e., approximately 200 times the potency of LH-RH).
Causal links between stressful events, coping style, and adolescent symptomatology.

In a longitudinal study, the causal links between different types of stressors, coping styles and adolescent symptomatology were investigated. A total of 94 adolescents and their mothers participated in three annual assessments of critical life events, daily stressors and coping styles. The longitudinal associations between life events, everyday stressors, a dysfunctional coping style and symptomatology were analyzed via a path-analytic model. Critical life events and daily stressors were found to be strongly related over time; however, the type of stressor was not consistently linked with adolescent symptomatology. In contrast, withdrawal, a form of avoidant coping, emerged as a significant predictor of adolescent symptomatology across all times. Further, emotional and behavioral problems led to a time-lagged increase in withdrawal, creating a vicious circle. The results are discussed with reference to the coping-skill deficit model.
Distinct Protein Kinase A Anchoring Proteins Direct Prostaglandin E2 Modulation of Toll-like Receptor Signaling in Alveolar Macrophages*

Toll-like receptors (TLRs) direct a proinflammatory program in macrophages. One mediator whose generation is induced by TLR ligation is prostaglandin E2 (PGE2), which is well known to increase intracellular cAMP upon G protein-coupled receptor ligation. How PGE2/cAMP shapes the nascent TLR response and the mechanisms by which it acts remain poorly understood. Here we explored PGE2/cAMP regulation of NO production in primary rat alveolar macrophages stimulated with the TLR4 ligand LPS. Endogenous PGE2 synthesis accounted for nearly half of the increment in NO production in response to LPS. The enhancing effect of PGE2 on LPS-stimulated NO was mediated via cAMP, generated mainly upon ligation of the E prostanoid 2 receptor and acting via protein kinase A (PKA) rather than via the exchange protein activated by cAMP. Isoenzyme-selective cAMP agonists and peptide disruptors of protein kinase A anchoring proteins (AKAPs) implicated PKA regulatory subunit type I (RI) interacting with an AKAP in this process. Gene knockdown of potential RI-interacting AKAPs expressed in alveolar macrophages revealed that AKAP10 was required for PGE2 potentiation of LPS-induced NO synthesis. AKAP10 also mediated PGE2 potentiation of the expression of cytokines IL-10 and IL-6, whereas PGE2 suppression of TNF-α was mediated by AKAP8-anchored PKA-RII. Our data illustrate the pleiotropic manner in which G protein-coupled receptor-derived cAMP signaling can influence TLR responses in primary macrophages and suggest that AKAP10 may coordinate increases in gene expression.
Pigeon Paramyxovirus: Association with Common Avian Pathogens in Chickens and Serologic Survey in Wild Birds

Abstract Pigeon paramyxovirus-1 (PPMV-1) was isolated from pigeons from east-central Alabama and used in association with chicken anemia virus (CAV), infectious bursal disease virus (IBDV), or finch Mycoplasma gallisepticum (MG) in specific-pathogen-free chickens to assess clinical disease and pathology. PPMV-1 infection in all groups was conducted at day 10 of age via the ocular route. The low passage PPMV-1 isolate was inoculated into chickens in different groups at 10 days post–CAV infection, 6 days post–IBDV infection, and 6 days post–finch MG infection, respectively. Additionally, to obtain information on the status of paramyxovirus infection in the wild bird population of the region, we used a multispecies competitive enzyme-linked immunosorbent assay kit to assess serum samples from 180 wild birds representing 24 species obtained throughout 2001. Mild respiratory signs characterized by sneezing were observed in PPMV-1–infected chicks. In the brain, PPMV-1 caused disseminated vasculitis in the neuropile and meninges, sometimes with small foci of gliosis. Most brains had only mild lesions. In the upper respiratory tract, lesions were confined to the larynx and proximal trachea as hyperplasia of laryngeal mucosa-associated lymphoid tissue. In the lung, PPMV-1 caused minimal to moderate multifocal interstitial pneumonia. Lymphocytic expansion occurred in the interstitium of the Harderian gland. PPMV-1 in the spleen caused expansion of the white pulp as a result of hypertrophy of the macrophages in the periarteriolar sheaths accompanied by lymphocytic hyperplasia at the periphery. No severe aggravation of either signs or lesions could be attributed to any of the avian pathogens used in association with PPMV-1. The serologic survey in wild birds showed antibody levels that were considered negative or doubtful. Interestingly, significantly (P < 0.05) higher mean titers were observed during the months of October and November 2001, following closely multiple PPMV-1 episodes of mortality in wild collard doves in northwestern Florida.
Nível de corrupção dos países e opacidade dos resultados contábeis

Corruption is a structural problem that deteriorates democracy, country legitimacy and public morality, besides weakening the economy and the accounting system. On the other hand, the earnings management is a phenomenon that denotes the lack of transparency on financial transactions, what results in low accounting quality. These phenomena show evidences of transparency issues and weakness of the accounting system worldwide. The purpose of this study is to discover the real effect of corruption over earnings management level in emerging countries, seeking to provide significant evidence that indicates that a better and more transparent accounting is linked to a less public and private corruption. For a sample of 20 emerging countries, from 2004 to 2013, there will be used control of corruption and rule of law indicators, both extracted from World Bank data. There will also be used indicators of accounting quality, focused on earnings management, from the work of Bhattacharya, Daouk and Welker (2003), which are earnings aggressiveness, loss avoidance and income smoothing. For data analysis was applied, firstly, the Shapiro-Francia test, when the rejection of null hypothesis of data normal distribution, it proceeded to the development of non-parametric tests. In a second moment, it was used the Spearman’s correlation to test the correlation of earnings aggressiveness, loss avoidance, income smoothing, rule of law with control of corruption.
No association of dysbindin with symptom factors of schizophrenia in an Irish case–control sample

Robust associations between the dysbindin gene (DTNBP1) and schizophrenia have been demonstrated in many but not all samples, and evidence that this gene particularly predisposes to negative symptoms in this illness has been presented. The current study sought to replicate the previously reported negative symptom associations in an Irish case–control sample. Association between dysbindin and schizophrenia has been established in this cohort, and a factor analysis of the assessed symptoms yielded three factors, Positive, Negative, and Schneiderian. The sequential addition method was applied using UNPHASED to assess the relationship between these symptom factors and the high‐risk haplotype. No associations were detected for any of the symptom factors indicating that the dysbindin risk haplotype does not predispose to a particular group of symptoms in this sample. Several possibilities, such as differing risk haplotypes, may explain this finding. © 2009 Wiley‐Liss, Inc.