Miracle-dz/UniFAR-FTUs huggingface dataset:
Adrenomedullin Stimulates Two Signal Transduction Pathways, cAMP Accumulation and Ca2+ Mobilization, in Bovine Aortic Endothelial Cells (*)

The biological action of adrenomedullin, a novel hypotensive peptide, on bovine aortic endothelial cells, was examined. The specific binding of adrenomedullin to these cells was observed, and adrenomedullin was found to induce intracellular cAMP accumulation in a dose-dependent manner. EC50 for the cAMP accumulation was about 100 times lower than the apparent IC50 for the binding assay. Adrenomedullin also induced increase of intracellular free Ca2+ in endothelial cells in a dose-dependent manner. The Ca2+ response to adrenomedullin was biphasic with an initial transient increase due to the release from thapsigargin-sensitive intracellular Ca2+ storage and a prolonged increase by influx through the ion channel on the plasma membrane. This intracellular free Ca2+ increase resulted from phospholipase C activation and inositol 1,4,5-trisphosphate formation, and seemed to cause nitric oxide synthase activation by monitoring intracellular cGMP accumulation. Both cAMP accumulation and Ca2+ increased responses to adrenomedullin were mediated by cholera toxin-sensitive G protein, but the two signal transduction pathways were independent. Thus, the results suggest that adrenomedullin elicits the hypotensive effect through at least two mechanisms, a direct action on vascular smooth muscle cells to increase intracellular cAMP and an action on endothelial cells to stimulate nitric oxide release, with both leading to vascular relaxation.
Memantine in dementia: a review of the current evidence

Introduction: As the world's population ages, the incidence of Alzheimer's disease (AD) is projected to double every 20 years. Understanding the pathogenesis of AD and developing effective treatments is a public health imperative. Memantine is a low- to moderate-affinity, non-competitive NMDA receptor antagonist that is currently approved for the treatment of moderate to severe AD. Areas covered: We discuss the current evidence, emphasizing more recent studies examining the effects of memantine in AD. We also look at the gaps in the current knowledge; the studies that will be required to fill these gaps are also discussed. The present paper reviews: the pharmacology of memantine; evidence for its use in moderate to severe AD, as well as in mild to moderate AD; adverse events related to memantine use; its effects specifically on behaviours including aggression and agitation; the pharmacoeconomics of memantine; and the use of memantine in other dementias. Memantine has shown modest benefits in cognition, function, global and behavioural measures, and has shown little potential for drug-drug interactions. Expert opinion: For the treatment of moderate to severe AD, memantine should be offered as a therapeutic option, either on its own, or in combination with a cholinesterase inhibitor.
Adenovirus infection and childhood intussusception.

OBJECTIVE To investigate the possible relationship between enteric adenovirus types 40 and 41 and intestinal intussusception in children. DESIGN Prospective, case-control patient study. PATIENTS Sixty-three consecutive children suspected clinically of having intestinal intussusception were enrolled in this study. Of these, 25 children (mean age, 1.4 years; range, 3 months to 5 years) had barium enema examination-proved intussusception. Age-matched normal controls (24) and controls with diarrhea (21) were obtained within 1 month of the index case. MEASUREMENTS AND RESULTS Stools were tested for the presence of nonenteric adenovirus and enteric adenovirus using a monoclonal antibody-based enzyme immunoassay. Five (20%) of 25 children with intussusception had nonenteric adenovirus in their stools compared with one (4%) of 24 normal controls, none (0%) of 21 of the controls with diarrhea, and none (0%) of 37 patients suspected of having intussusception who had negative results on barium enema examination. However, no stool samples were positive for enteric adenovirus. CONCLUSIONS Nonenteric adenovirus infection and intestinal intussusception may be associated. However, because enteric adenovirus was not found in any of the groups studied, no conclusions can be made regarding their possible influence on the risk for developing intussusception.
Low levels of 17-β-oestradiol, oestrone and testosterone correlate with severe evaporative dysfunctional tear syndrome in postmenopausal women: a case–control study

Aims To evaluate the role of 17-β-oestradiol, oestrone and total testosterone (TT) deficiency in the pathogenesis of severe evaporative dry eye syndrome (DES), investigating the relationship between tear osmolarity, tear film break-up time (TF-BUT), Schirmer test and serum sex hormones in postmenopausal women. Methods 44 postmenopausal women were recruited for a case–control study: 22 women with severe evaporative DES (Group A) and 22 without DES (Group B). The tests performed included laboratory blood analysis: fasting plasma profile (17-β-oestradiol, oestrone and TT), glucose level and lipid profile. Detailed eye examinations, including corneal and conjunctival staining, tear osmolarity measurement, tear volume and TF-BUT, were performed. The Ocular Surface Disease Index Questionnaire was also administered. Results Values of Schirmer test and TF-BUT in Group A were significantly lower in comparison with Group B (p<0.001). Serum levels of 17-β-oestradiol, oestrone and TT were significantly lower in Group A compared with Group B (p<0.05). In women with severe evaporative DES, the levels of 17-β-oestradiol, oestrone and TT were inversely correlated with the tear film osmolarity (r=−0.7, −0.88, −0.81, respectively). Conclusions In postmenopausal women with severe evaporative DES, sex hormone levels are lower than control and that tear osmolarity is negatively correlated with sex hormone levels.
Investigation of omeprazole and phenacetin first‐pass metabolism in humans using a microscale bioreactor and pharmacokinetic models

A new in vitro microfluidic platform (integrated insert dynamic microfluidic platform, IIDMP) allowing the co‐culture of intestinal Caco‐2 TC7 cells and of human primary hepatocytes was used to test the absorption and first‐pass metabolism of two drugs: phenacetin and omeprazole. The metabolism of these drugs by CYP1A2, CYP2C19 and CYP3A4 was evaluated by the calculation of bioavailabilities and of intrinsic clearances using a pharmacokinetic (PK) model. To demonstrate the usefulness of the device and of the PK model, predictions were compared with in vitro and in vivo results from the literature. Based on the IIDMP experiments, hepatic in vivo clearances of phenacetin and omeprazole in the IIDMP were predicted to be 3.10 ± 0.36 and 1.46 ± 0.25 ml/min/kg body weight, respectively. This appeared lower than the in vivo observed data with values ranging between 11.9–19.6 and 5.8–7.5 ml/min/kg body weight, respectively. Then the calculated hepatic and intestinal clearances led to predicting an oral bioavailability of 0.85 and 0.77 for phenacetin and omeprazole versus 0.92 and 0.78 using separate data from the simple monoculture of Caco‐2 TC7 cells and hepatocytes in Petri dishes. When compared with the in vivo data, the results of oral bioavailability were overestimated (0.37 and 0.71, respectively). The feasibility of co‐culture in a device allowing the integration of intestinal absorption, intestinal metabolism and hepatic metabolism in a single model was demonstrated. Nevertheless, further experiments with other drugs are needed to extend knowledge of the device to predict oral bioavailability and intestinal first‐pass metabolism. Copyright © 2015 John Wiley & Sons, Ltd.
INTEREST RATE TARGETS AND SPECULATIVE ATTACKS ON PUBLIC DEBT

The application of exchange rate target zones modeling to interest rates allows interpreting the puzzles that emerged with the public debt euro area crisis, namely the nonlinear behavior of the interest rates and the fact that some stand-alone countries, not belonging to the euro area, have not been subject to speculative attacks in spite of equally large public debt-to-gross domestic product (GDP) ratios. As a matter of fact, this model shows that in the case of a noncredible upper threshold for the interest rate (that may be due to both the lack of room for increasing further the required government primary surplus and/or the absence of a monetary authority acting as a lender of last resort), the resulting public debt unsustainability determines an interest rate nonlinearity and makes the crisis possible for public debt levels that would be stable in the presence of a credible interest rate target.
Study of pneumatic glass-wall cleaning robots

Through the analysis of glass-wall cleaning robots research status at home and abroad, based on cleaning characteristics and requirements of such kind of smooth surface, a kind of pneumatic glass-wall cleaning robot is presented here. The robot which adopts unique three-position cylinder driving technique and embedded control system can crawl along the glass-wall and clean, and can overcome obstacles in a certain height. Running results show that the robot system has simple structure, low cost, the functions of on-line fault diagnosis, and can provide a new efficient, simple and safe way for the glass-wall cleaning.
Multifunctional periodic cellular metals

Periodic cellular metals with honeycomb and corrugated topologies are widely used for the cores of light weight sandwich panel structures. Honeycombs have closed cell pores and are well suited for thermal protection while also providing efficient load support. Corrugated core structures provide less efficient and highly anisotropic load support, but enable cross flow heat exchange opportunities because their pores are continuous in one direction. Recent advances in topology design and fabrication have led to the emergence of lattice truss structures with open cell structures. These three classes of periodic cellular metals can now be fabricated from a wide variety of structural alloys. Many topologies are found to provide adequate stiffness and strength for structural load support when configured as the cores of sandwich panels. Sandwich panels with core relative densities of 2–10% and cell sizes in the millimetre range are being assessed for use as multifunctional structures. The open, three-dimensional interconnected pore networks of lattice truss topologies provide opportunities for simultaneously supporting high stresses while also enabling cross flow heat exchange. These highly compressible structures also provide opportunities for the mitigation of high intensity dynamic loads created by impacts and shock waves in air or water. By filling the voids with polymers and hard ceramics, these structures have also been found to offer significant resistance to penetration by projectiles.
GABA Mediates Steroid‐Induced Astrocyte Differentiation in the Neonatal Rat Hypothalamus

Our previous work has demonstrated that astrocytes in the developing arcuate nucleus of the rat hypothalamus are sexually dimorphic as a result of differential exposure to oestradiol. Moreover, our experiments in neonatal rats suggest an absence of oestrogen receptors (ER) in arcuate nucleus astrocytes in vivo. This, along with the conspicuous lack of evidence in the literature confirming the presence of ER in arcuate nucleus astrocytes of the neonatal rat brain, led us to question the mechanism by which oestrogen induces changes in arcuate nucleus astrocyte morphology. Based on our previous findings that oestradiol increases γ‐aminobutyric acid (GABA) levels in the neonatal rat arcuate, we hypothesize that GABA is released from neighbouring oestrogen‐sensitive neurones and alters arcuate nucleus astrocyte morphology. Here, we report that in vivo reduction of GABA synthesis in the neonatal rat brain by antisense oligodeoxynucleotides to glutamic acid decarboxylase prevented gonadal steroid‐induced astrocyte differentiation in males and testosterone‐treated females. Conversely, activation of GABAA receptors with the agonist muscimol increased astrocyte differentiation in females in the absence of gonadal steroids. Given that GABA is made only in neurones and that its synthesis is increased by oestradiol, we conclude that it acts as a diffusible factor inducing the differentiation of neighbouring astrocytes.
An Intracellular Trafficking Defect in Type I Cystinuria rBAT Mutants M467T and M467K*

The human rBAT protein elicits sodium-independent, high affinity obligatory exchange of cystine, dibasic amino acids, and some neutral amino acids in Xenopus oocytes (Chillarón, J., Estévez, R., Mora, C., Wagner, C. A., Suessbrich, H., Lang, F., Gelpí, J. L., Testar, X., Busch, A. E., Zorzano, A., and Palacín, M. (1996) J. Biol. Chem 271, 17761-17770). Mutations in rBAT have been found to cause cystinuria (Calonge, M. J., Gasparini, P., Chillarón, J., Chillón, M., Galluci, M., Rousaud, F., Zelante, L., Testar, X., Dallapiccola, B., Di Silverio, F., Barceló, P., Estivill, X., Zorzano, A., Nunes, V., and Palacín, M. (1994) Nat. Genet. 6, 420-426). We have performed functional studies with the most common point mutation, M467T, and its relative, M467K, using the oocyte system. The Km and the voltage dependence for transport of the different substrates were the same in both M467T and wild type-injected oocytes. However, the time course of transport was delayed in the M467T mutant: maximal activity was accomplished 3-4 days later than in the wild type. This delay was cRNA dose-dependent: at cRNA levels below 0.5 ng the M467T failed to achieve the wild type transport level. The M467K mutant displayed a normal Km, but the Vmax was between 5 and 35% of the wild type. The amount of rBAT protein was similar in normal and mutant-injected oocytes. In contrast to the wild type, the mutant proteins remained endoglycosidase H-sensitive, suggesting a longer residence time in the endoplasmic reticulum. We quantified the amount of rBAT protein in the plasma membrane by surface labeling with biotin 2 and 6 days after injection. Most of the M467T and M467K protein was located in an intracellular compartment. The converse situation was found in the wild type. Despite the low amount of M467T protein reaching the plasma membrane, the transport activity at 6 days was the same as in the wild type-injected oocytes. The increase in plasma membrane rBAT protein between 2 and 6 days was completely dissociated from the rise in transport activity. These data indicate impaired maturation and transport to the plasma membrane of the M467T and M467K mutant, and suggest that rBAT alone is unable to support the transport function.
Origin of long lifetime of band-edge charge carriers in organic–inorganic lead iodide perovskites

Significance Hybrid organic–inorganic perovskites (HOIPs) are among the most promising materials for next-generation solar cells that combine high efficiency and low cost. The record efficiency of HOIP-based solar cells has reached above 22%, which is comparable to that of silicon solar cells. HOIP solar cells can be manufactured using simple solution processing methods that can be drastically cheaper than the current commercial solar cell technologies. Despite the progress so far, the microscopic mechanism for the high solar cell efficiency in HOIPs is yet to be understood. Our study shows that rotation of organic molecules in HOIPs extends the lifetime of photoexcited charge carriers, leading to the high efficiency. This insight can guide the progress toward improved solar cell performance. Long carrier lifetime is what makes hybrid organic–inorganic perovskites high-performance photovoltaic materials. Several microscopic mechanisms behind the unusually long carrier lifetime have been proposed, such as formation of large polarons, Rashba effect, ferroelectric domains, and photon recycling. Here, we show that the screening of band-edge charge carriers by rotation of organic cation molecules can be a major contribution to the prolonged carrier lifetime. Our results reveal that the band-edge carrier lifetime increases when the system enters from a phase with lower rotational entropy to another phase with higher entropy. These results imply that the recombination of the photoexcited electrons and holes is suppressed by the screening, leading to the formation of polarons and thereby extending the lifetime. Thus, searching for organic–inorganic perovskites with high rotational entropy over a wide range of temperature may be a key to achieve superior solar cell performance.
Reperfusion injury after critical intestinal ischemia and its correction with perfluorochemical emulsion "perftoran".

AIM To investigate the anti-ischemic properties of perfluorochemical emulsion "perftoran" in mesenteric region. METHODS Experiments were conducted on 146 nonlinear white male rats weighing 200-350 g. Partial critical intestinal ischemia was induced by thorough atraumatic strangulation of 5-6 cm jejunal loop with its mesentery for 90 min. Global critical intestinal ischemia was made by atraumatic occlusion of the cranial mesenteric artery (CMA) for 90 min also. Perftoran (PF, 0.8-1.0 mL per 100 g) in experimental groups or 0.9% sodium chloride in control groups was injected at 75 min of ischemic period. Mean systemic arterial blood pressure (BP(M)) registration, intravital microscopy and morphological examination of ischemic intestine and its mesentery were performed in both groups. RESULTS During 90 min of reperfusion, BP(M) progressively decreased to 27.3+/-7.4% after PF administration vs 38.6+/-8.0% in the control group of rats with partial intestinal ischemia (NS) and to 50.3+/-6.9% vs 53.1+/-5.8% in rats after global ischemia (NS). During the reperfusion period, full restoration of microcirculation was never registered; parts with restored blood flow had leukocyte and erythrocyte stasis and intra-vascular clotting, a typical "non-reflow" phenomenon. The reduction of mesenteric 50-400 mum feeding artery diameter was significantly less in the PF group than in the control group (24+/-5.5% vs 45.2+/-3.6%, P<0.05) 5 min after partial intestinal ischemia. This decrease progressed but differences between groups minimized at the 90(th) min of reperfusion (41.5+/-4.2% and 50.3+/-2.8%, respectively). In reperfusion of rat's intestine, a significant mucosal alteration was registered. Villous height decreased 2.5-3 times and the quantity of crypts decreased more than twice. In the group of rats administered PF, intestinal mucosal layer was protected from irreversible post-ischemic derangement during reperfusion. Saved cryptal epithelial cells were the source of regeneration of the epithelium, which began to cover renewing intestinal villi after 24 h of blood flow restoration. View of morphological alterations was more heterogeneous in CMA groups. CONCLUSION Systemic administration of perftoran promotes earlier and more complete structural regeneration during reperfusion in rats after partial and global critical intestinal ischemia.
Nonlinear Relationships in a Logistic Model of Default for a High-Default Installment Portfolio

This study uses data on consumer credit provided by a German retail and trading company along with generalized additive models to analyze nonlinear relationships and their effect on predicting the probability of default in the context of consumer credit scoring. In particular, this study examines which aspects of the contract and which characteristics of the debtor are nonlinearly related to the probability that specific debtors will default on the loans they are seeking to obtain. The findings of our analysis provide clear empirical evidence that certain contract and debtor characteristics have nonlinear and nonmonotonic effects on the probability that a specific debtor will default on their consumer credit. The results of our analysis and the forms that these nonlinear relationships take are interpreted with regard to their economic relevance. Specifically, the study shows that the nonlinear relationships identified are economically relevant because they take into account the costs of a range of misclassification errors. On the basis of this evidence, the study recommends that analysts include nonlinear relationships in the models they design to predict consumer default, although including such relationships increases the complexity of the models that are applied for this purpose.
Heritability of illicit drug use and transition to dependence in Southwest California Indians

Objective Native Americans have high rates of drug use and dependence yet little is known concerning its etiology or clinical course. These analyses were conducted to describe the heritability of the use of a variety of illicit drugs, as well as the conditional probability of transitioning from use to dependence for each drug class in a community sample of Native American men and women. Methods The sample included 460 participants (190 men and 270 women), recruited through community effort, from eight contiguous Indian reservations in Southern California. Participants were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. The Semi-Structured Assessment for the Genetics of Alcoholism interview retrospectively asks about the initial use and drug dependence of the following illicit drug classes: marijuana, cocaine, stimulants, sedatives, opiates, hallucinogens, and solvents. Heritability of initial use was determined using SOLAR (http://www.sfbr.org/solar/). Results Ninety-one percent of this select Indian population had tried at least one of the illicit drug classes. The most commonly tried substance was marijuana (88%), followed by stimulants (60%), cocaine (44%), hallucinogens (34%), and solvents (20%). The heritability of initiation of drug use ranged from 0.14 for cocaine to 0.59 for marijuana. The conditional probability of transition from initiation to drug dependence ranged from 0.66 for stimulants to 0.06 for hallucinogens. Conclusions These findings suggest that heritability of the initiation of substance use, in Southwest California Indians, may be similar to other population samples. In this population, however, high rates of dependence on marijuana, opiates, and stimulants are seen once initiation of the use of the substance has occurred.
Characterization of AβpN3 deposition in the brains of dogs of various ages and other animal species

Senile plaques (SP) are characteristic histopathological manifestations of Alzheimer's disease (AD), but are also found in normal aging (NA). Recent studies have demonstrated that beta amyloid (Aβ) proteins that have been truncated at the N-terminal position 3 (AβpN3) are the predominant component of SP in AD, but not in NA. The present study revealed that AβpN3 was deposited in an age-dependent manner in canine brains. Moreover, AβpN3 was the main component of the SP that developed in very old dogs. The deposition of AβpN3 increased in accordance with the number of SP, but that of N-terminally intact Aβ (AβN1) did not. In addition, AβpN3 was also deposited in the SP of a Japanese macaque and an American black bear, but not in a feline brain. Focal microvascular cerebral amyloid angiopathy was also observed in the deep cortices and the white matter of the dogs and a woodpecker. Those were always composed of both AβpN3 and AβN1. In conclusion, though non-human animals do not develop full pathology of AD of the human type, AβpN3 is widely deposited in the brains of senescent vertebrates.