Miracle-dz/UniFAR-FTUs huggingface dataset:
Regional and differential expression of gelatinases in rat brain after systemic kainic acid or bicuculline administration

Indirect evidence from in vitro studies implicates a functional role for matrix metalloproteinases (MMPs) in the central nervous system (CNS), including induction of neuronal migration during development and enhancement of neurite extension. Few reports have documented the expression of these enzymes in the brain, especially after injury in vivo. The objective of this study was to determine whether MMPs are expressed in various regional areas of rat brain after administration of the neurotoxin, kainic acid. Limbic motor seizures and neuronal degeneration were induced in Sprague–Dawley rats by systemic administration of kainate (10 mg/kg). Rats were subsequently divided into convulsive and non‐convulsive groups, after observing their behaviour in response to the drug. Animals were killed 6, 12, 24, 72 and 168 h (7 days) after injection of kainate. Gelatinases were extracted from various brain regions and assayed by gelatin‐substrate zymography. Levels of glial fibrillary acidic protein (GFAP) in corresponding regions were measured by ELISA. In the absence of treatment, MMP‐2 and MMP‐9 activities were expressed differentially in various brain regions with the highest levels in the hippocampus and the lowest in the cerebellum. In areas from convulsive rats, MMP‐9 activity was markedly elevated at 6 h, and reached a maximum at 12 h after injection of kainate (8.1‐fold hippocampus, 7.7‐fold diencephalon, 7.2‐fold striatum, 5.7‐fold frontal cortex, 5.5‐fold cerebellum, 2.6‐fold midbrain). MMP‐2 activity was induced more than two‐fold in the hippocampus, diencephalon and striatum, to a lesser extent in the frontal cortex and midbrain, and was unchanged in the cerebellum, 72 h after injection. Neither MMP activity was altered in any brain region derived from non‐convulsive rats. Treatment with the GABAA antagonist, bicuculline, resulted in increased levels of MMP‐9, 12 h after drug administration, but no change in levels of MMP‐2 up to 3 days following treatment. GFAP levels were induced 3 days after kainic acid injection in brain regions where MMP‐2 was elevated. Nissl staining displayed the classical, regional neurodegeneration in kainate‐treated animals that exhibited seizures. No obvious degeneration was detected in kainate‐treated, non‐convulsive rats or bicuculline‐treated animals. These data demonstrate that MMP‐9 and MMP‐2 are differentially expressed with respect to time after kainic acid injection, and suggest that they are regulated by convulsion and/or neurodegenerative‐associated mechanisms, respectively. Although similar in catalytic activity, MMP‐9 and MMP‐2 may play different roles in response to kainic acid‐induced seizure and neuronal degeneration.
Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed α‐helix

The macrophage infectivity potentiator protein from Trypanosoma cruzi (TcMIP) is a major virulence factor secreted by the etiological agent of Chagas' disease. It is functionally involved in host cell invasion. We have determined the three‐dimensional crystal structure of TcMIP at 1.7 Å resolution. The monomeric protein displays a peptidyl‐prolyl cis–trans isomerase (PPIase) core, encompassing the characteristic rotamase hydrophobic active site, thus explaining the strong inhibition of TcMIP by the immunosuppressant FK506 and related drugs. In TcMIP, the twisted β‐sheet of the core is extended by an extra β‐strand, preceded by a long, exposed N‐terminal α‐helix, which might be a target recognition element. An invasion assay shows that the MIP protein from Legionella pneumophila (LpMIP), which has an equivalent N‐terminal α‐helix, can substitute for TcMIP. An additional exposed α‐helix, this one unique to TcMIP, is located in the C‐terminus of the protein. The high‐resolution structure reported here opens the possibility for the design of new inhibitory drugs that might be useful for the clinical treatment of American trypanosomiasis.
Effect of Indomethacin on the Regulation of Cerebral Blood Flow during Respiratory Alkalosis in Newborn Piglets

ABSTRACT: The effect of cyclooxygenase inhibition by indomethacin on regional cerebral blood flow (CBF) during hypocapnia induced by hyperventilation and during hypercapnia induced by CO2 inhalation was examined. CBF was measured in 27 anesthetized, ventilated piglets (2-8 d) using microspheres in control and indomethacin treated animals (5 mg/kg) after hyperventilation or inhalation of 6% CO2. In the control group (n=6), CBF decreased significantly (p<0.05) to all regions of the brain after hyperventilation with a 32% decrease in the cerebral cortex. In the indomethacin-treated group (n=6), blood flow significantly decreased by 35 to 49% in all regions of the brain, except the cerebral white matter, during normocapnia with no further decrease in flow during subsequent hypocapnia. Although CBF increased significantly after indomethacin treatment during hypercapnia the response was markedly attenuated with blood flow to the cerebral gray matter, hippocampus and pons rising only 42, 25, and 42% in contrast to 108, 75, and 225% in the control group. Since indomethacin decreased resting CBF, unilateral sympathetic nerve stimulation at 15 Hz was used to test the specificity of indomethacin on hypocapnic vasoconstriction (n=5). Unilateral sympathetic nerve stimulation caused a further statistically significant decrease in CBF on the stimulated side after hyperventilation with indomethacin (12%), which was comparable to that which occurred during normocapnia (16%). The data demonstrate that indomethacin attenuates the cerebrovascular sensitivity to both increases and decreases in CO2/H+ and implicate a possible role for vasoactive prostanoids in mediating the response of CBF to fluctuations in CO2 in newborn piglets.
Insider Trading with Different Market Structures

The recent theoretical research on the informational effect of insider trading in the spirit of Kyle (1985) and Jain and Mirman (1999) was mainly interested in the interaction between the financial and real decisions of the insider, taking into consideration different market structures in both the real and financial markets. However, none investigated the importance of the competition structure in the financial market modeled alone, on the dissemination of information. In this paper, we highlight the effect of the competition structure in the financial market on information revelation. For this purpose, we first extend Jain and Mirman (1999) to incorporate: (i) Cournot competition among the insiders (Model I) and (ii) Stackelberg competition between the insiders (Model II). We then add a real market to Model II, where the publicly-owned firm is a quantity-setting monopolist (Model III). The last model allows to investigate where does the real market interfere relatively to Model II. We show how the equilibrium outcomes are affected by each of the market structure and we perform a comparative statics analysis between the models.
The Role of E6AP in the Regulation of p53 Protein Levels in Human Papillomavirus (HPV)-positive and HPV-negative Cells*

The E6 protein encoded by the oncogenic human papillomaviruses (HPVs) targets p53 for ubiquitin-dependent proteolysis. E6-mediated p53 degradation requires the 100-kDa cellular protein E6-associated protein (E6AP). E6AP and E6 together provide the E3-ubiquitin protein ligase activity in the transfer of ubiquitin to p53. In vitro studies have shown that E6AP can form a high energy thiolester bond with ubiquitin and, in the presence of E6, transfer ubiquitin to p53. In this study we have addressed the role of E6AP in vivo in the degradation of p53. Overexpression of wild-type E6AP in HeLa cells, which are HPV18-positive and express E6, resulted in a decreased steady state level of p53 and a decrease in the half-life of p53. Mutant forms of E6AP proteins were identified that were catalytically incapable of participating in E6-dependent ubiquitination of p53 and functioned in a dominant-negative manner in that they inhibited the E6-mediated ubiquitination of p53 by the wild-type E6AP in vitro. Transient transfection of one of these dominant negative (dn) mutants resulted in an increase in both the steady state level and half-life of p53 in vivo in HeLa cells. Consistent with this observation, overexpression of the dn E6AP resulted in a marked G1 shift in the cell cycle profile. In contrast, dn E6AP had no effect on p53 levels in U2OS cells, an HPV-negative cell line that contains wild-type p53. These studies provide evidence for the involvement of E6AP in E6-mediated p53 degradation in vivoand also indicate that E6AP may not be involved in the regulation of p53 ubiquitination in the absence of E6.
Glomerular targeting of acidic fibroblast growth factor-1 in renal transplanted rats1

Background. Acidic fibroblast growth factor (FGF-1) functions as a potent hormonal inducer of wound repair mechanisms in vivo. In addition, the involvement of FGF-1 in a number of pathophysiological conditions, including chronic human renal allograft rejection, has been described. Consequently, there is an increasing need to monitor FGF-1 pharmacokinetics and distribution for both therapeutic and diagnostic opportunities. We now describe in vivo imaging and targeting of FGF-1 in renal transplanted rats. Methods. Sham-operated, syngeneic renal transplanted, and allogeneic renal transplanted rats were imaged using an Anger gamma camera. Renal function was evaluated first by dynamic 99mTc-MAG3 imaging, and subsequently, 99mTc-labeled FGF-1 (99mTc-FGF-1) was imaged after i.v. injection. Microautoradiography of harvested kidneys determined the compartmental localization of 99mTc-FGF-1. Results. 99mTc-MAG3 renal scans were grossly abnormal in the allogeneic renal transplanted rats. In this group, a significant reduction in 99mTc-FGF-1 renal binding was measured by imaging analyses, as compared with renal binding in the sham-operated and syngeneic renal transplanted groups, which were not significantly different. Both groups of renal transplanted rats showed a redistribution of FGF-1 to the glomerular compartment. Conclusions. 99mTc-FGF-1 serves as a new radiotracer to measure in vivo targeting of the growth factor. Reduced renal binding of 99mTc-FGF-1 in the allogeneic transplanted kidney was consistent with decreased blood flow. Unique glomerular targeting of 99mTc-FGF-1 in the transplanted kidney provides additional evidence supporting a role for this growth factor in the pathogenesis of chronic rejection.
Blockade of CD40-Mediated Signaling Is Sufficient for Inducing Islet But Not Skin Transplantation Tolerance 1

Treatment of mice with a single donor-specific transfusion (DST) plus a brief course of anti-CD154 mAb to block CD40-mediated signaling uniformly induces donor-specific transplantation tolerance. Survival of islet allografts in treated mice is permanent, but skin grafts eventually fail unless recipients are thymectomized. The nature of the cellular mechanisms involved and the basis for the difference in survival of islet vs skin allografts are not known. In this study, we used CD40 knockout mice to investigate the role of CD40-mediated signaling in each component of the tolerance induction protocol: the DST, the graft, and the host. When CD40-mediated signaling was eliminated in only the DST or the graft, islet allografts were rapidly rejected. However, when CD40 signaling was eliminated in the host, ∼40% of the islet allografts survived. When CD40 signaling was eliminated in the DST, the graft, and the host, islet grafts survived long term (>84 days), whereas skin allografts were rapidly rejected (∼13 days). We conclude that transplantation tolerance induction in mice treated with DST and anti-CD154 mAb requires blockade of CD40-mediated signaling in the DST, the graft, and the host. Blockade of CD40-mediated signaling is necessary and sufficient for inducing islet allograft tolerance and is necessary but not sufficient for long-term skin allograft survival. We speculate that a requirement for regulatory CD4+ T cells in skin allograft recipients could account for this differential response to tolerance induction.
Relative contribution of hemopoietic and pulmonary parenchymal cells to lung inducible nitric oxide synthase (inos) activity in murine endotoxemia.

Acute lung injury is an important feature of sepsis and increased iNOS expression and NO production contribute to the pathogenesis of this syndrome. We generated bone marrow-transplanted chimeric mice with iNOS expression limited to either inflammatory or pulmonary parenchymal cells, and assessed pulmonary iNOS activity and systemic levels of NO metabolites in an endotoxemic model of sepsis. We found that while both pulmonary parenchymal cells and inflammatory cells contribute to the increased lung iNOS activity in endotoxemia, pulmonary parenchymal cells contribute to a significantly greater degree. Using measurement of plasma NO(-)(x), whole body NO production was assessed in this model. We found that the main source of NO(-)(x) was again, parenchymal cells and not inflammatory cells. This is the first study to demonstrate that most of the increased NO production in this model of endotoxemic sepsis derives from parenchymal cells rather than inflammatory cells.
Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial.

OBJECTIVE In a recent crossover trial, methylphenidate treatment decreased apathy in Alzheimer's disease. We further assessed this finding in the Apathy in Dementia Methylphenidate Trial (ADMET). METHOD Six-week, randomized, double-blind, placebo-controlled multicenter trial enrolling Alzheimer's disease participants (NINCDS-ADRDA criteria) with apathy assigned to methylphenidate 20 mg daily or placebo, conducted from June 2010 to December 2011. Primary outcomes were change in Apathy Evaluation Scale (AES) score and modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGI-C). Secondary outcomes included change in Neuropsychiatric Inventory (NPI) apathy score, Mini-Mental State Examination (MMSE) score, and safety. RESULTS 60 participants were randomly assigned (29 methylphenidate, 31 placebo). At baseline, mean (SD) age = 76 (8) years, MMSE score = 20 (5), AES score = 51 (12), NPI total score = 16 (8), and 62% of the participants (n = 37) were female. After 6 weeks' treatment, mean (SD) change in AES score was -1.9 (1.5) for methylphenidate and 0.6 (1.4) for placebo (P = .23). Odds ratio for improvement in ADCS-CGI-C was 3.7 (95% CI, 1.3 to 10.8) (P = .02), with 21% of methylphenidate versus 3% of placebo rated as moderately or markedly improved. NPI apathy score improvement was 1.8 points (95% CI, 0.3 to 3.4) greater on methylphenidate than on placebo (P = .02). MMSE trended toward improvement on methylphenidate (P = .06). There were trends toward greater anxiety and weight loss > 2% in the methylphenidate-treated group. CONCLUSIONS Methylphenidate treatment of apathy in Alzheimer's disease was associated with significant improvement in 2 of 3 efficacy outcomes and a trend toward improved global cognition with minimal adverse events, supporting the safety and efficacy of methylphenidate treatment for apathy in Alzheimer's disease. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01117181.
Double-Circuit Transmission-Line Fault Location Utilizing Synchronized Current Phasors

Fault location is considered as one of the essential techniques enabling a smart grid. This paper presents a novel fault location approach for double-circuit transmission lines. Various existing algorithms usually require measurements recorded from one or two terminals of the faulted line. However, when such measurements are not available, these methods are not applicable. To fill this gap, this paper proposes a fault location method by harnessing current measurements from one or more branches, which may not be necessarily taken from the faulted section. The currents from multiple branches are synchronized and can be obtained from phasor measurement units installed in the system. The bus impedance matrix technique is exploited to develop the new method. The shunt capacitance of the line is fully considered by utilizing the distributed parameter line model. The network data are assumed to be available. When multiple synchronized current measurements are available, an optimal estimator capable of identifying possible bad measurement data and, thus, further enhancing the fault location is also proposed. Quite accurate results have been achieved based on simulation studies.
Interleukin-17 Stimulates C-reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-dependent NF-κB and C/EBPβ Activation*

Elevated systemic levels of the acute phase C-reactive protein (CRP) are predictors of future cardiovascular events. There is evidence that CRP may also play a direct role in atherogenesis. Here we determined whether the proinflammatory interleukin (IL)-17 stimulates CRP expression in hepatocytes (Hep3B cell line and primary hepatocytes) and coronary artery smooth muscle cells (CASMC). Our results demonstrate that IL-17 potently induces CRP expression in Hep3B cells independent of IL-1β and IL-6. IL-17 induced CRP promoter-driven reporter gene activity that could be attenuated by dominant negative IκBα or C/EBPβ knockdown and stimulated both NF-κB and C/EBP DNA binding and reporter gene activities. Targeting NF-κB and C/EBPβ activation by pharmacological inhibitors, small interfering RNA interference and adenoviral transduction of dominant negative expression vectors blocked IL-17-mediated CRP induction. Overexpression of wild type p50, p65, and C/EBPβ stimulated CRP transcription. IL-17 stimulated p38 MAPK and ERK1/2 activation, and SB203580 and PD98059 blunted IL-17-mediated NF-κB and C/EBP activation and CRP transcription. These results, confirmed in primary human hepatocytes and CASMC, demonstrate for the first time that IL-17 is a potent inducer of CRP expression via p38 MAPK and ERK1/2-dependent NF-κB and C/EBPβ activation and suggest that IL-17 may mediate chronic inflammation, atherosclerosis, and thrombosis.
A Comprehensive Model of Stress

Background: In this study, a complex theoretical model regarding the stress-distress relationship was evaluated. The various components in the model included experienced stress (daily hassles), psychological distress, neuroticism, problem-focused coping, avoidant coping, satisfaction with received social support and unassertiveness. On the basis of various previous findings, experienced stress was assumed to have a direct effect on psychological distress. In addition, neuroticism was assumed to have a direct effect on psychological distress as well as an indirect effect through its association with experienced stress, problem-focused coping, avoidant coping, satisfaction with social support and unassertiveness. Further, both problem-focused and avoidant coping were assumed to affect the level of psychological distress directly as well as indirectly through their influence on experienced stress. Similarly, satisfaction with social support was assumed to have a direct beneficial effect on psychological distress in addition to an indirect effect through its association with coping and experienced stress. Finally, unassertiveness was assumed to have a direct effect on psychological distress as well as an indirect effect through its influence on experienced stress and coping. Methods: A covariance path analysis technique (LISREL) was used. Results: A considerable predictive power of the model could be demonstrated. Experienced stress and neuroticism turned out to be most predictive of psychological distress. The effects of social support, coping and unassertiveness on psychological distress were seriously attenuated by their common association with neuroticism. Conclusion: Above all, the present findings underscore the need to investigate all variables that are expected to play a role simultaneously so as to be able to take their interdependency into account. It is argued that although such comprehensive models may be more difficult to interpret as of yet, they are likely to more closely resemble reality.
PCR-RFLP Detection od PAI-2 Gene Variants: Prevelence in Ethnic Groups and Disease Relationship in patients Undergoing corony Angiography

Summary PAI-2 is a fibrinolytic inhibitor produced predominantly by monocytes. Most PAI-2 is intracellular making study in clinical conditions difficult. Abnormalities in production may be associated with inflammation and fibrinolysis at sites of tissue damage such as the atherosclerotic plaque. PAI-2 gene variants have been described: variant A consists of Asn120, Asn404 and Ser413 and variant B consists of Asp120, Lys404 and Cys413. We designed a PCR-RFLP assay using primers spanning the region containing Asn/Lys404 and Ser/Cys413. Variant B contains an Mwol restriction site. We analysed 302 Pima Indians and 286 healthy Caucasian volunteers. To investigate relationships between genotype and vascular disease we analysed 333 Caucasian patients undergoing coronary angiography. Gene variant B was more common in the Pimas than in Caucasians (p <0.0001). There was no significant difference in genotype distribution between the volunteers and patients. In the patients there was no association between genotype and either a history of MI or extent of coronary atheroma.
Effect of spironolactone on patients with resistant hypertension and obstructive sleep apnea

ABSTRACT Objective: To examine whether spironolactone could reduce the severity of obstructive sleep apnea (OSA) and lower blood pressure in patients with resistant hypertension. Methods: This was a blank-controlled, single-center study. Patients with resistant hypertension and moderate-to-severe OSA (apnea–hypopnea index >15 events/h) were enrolled and randomly assigned to the therapy or control group. Patients in the therapy group were administered spironolactone 20 mg once daily (up to 40 mg once daily for 4 weeks, if required) in addition to original antihypertensive medication. Follow-up was 12 weeks. Results: Thirty patients were enrolled (n = 15 per group). After 12 weeks of follow-up, apnea–hypopnea index (21.8 ± 15.7 vs. 1.8 ± 12.8, p < 0.05), hypopnea index (9.8 ± 11.1 vs. −2.7 ± 16.8, p < 0.05), oxygen desaturation index (20.8 ± 15.0 vs. 0.3 ± 16.1, p < 0.05), clinical blood pressure, ambulatory blood pressure, and plasma aldosterone level (9.8 ± 6.3 vs. 2.9 ± 6.7, p < 0.05) were reduced significantly in the therapy group compared with the control group. No side effects were reported. Conclusions: Spironolactone reduced the severity of OSA and reduced blood pressure in resistant hypertension patients with moderate-to-severe OSA. These findings may assist in the treatment of OSA in patients with resistant hypertension.