Determinants of Default in P2P Lending

This paper studies P2P lending and the factors explaining loan default. This is an important issue because in P2P lending individual investors bear the credit risk, instead of financial institutions, which are experts in dealing with this risk. P2P lenders suffer a severe problem of information asymmetry, because they are at a disadvantage facing the borrower. For this reason, P2P lending sites provide potential lenders with information about borrowers and their loan purpose. They also assign a grade to each loan. The empirical study is based on loans’ data collected from Lending Club (N = 24,449) from 2008 to 2014 that are first analyzed by using univariate means tests and survival analysis. Factors explaining default are loan purpose, annual income, current housing situation, credit history and indebtedness. Secondly, a logistic regression model is developed to predict defaults. The grade assigned by the P2P lending site is the most predictive factor of default, but the accuracy of the model is improved by adding other information, especially the borrower’s debt level.     

Hydrophobicity in the design of P2/P2' tetrahydropyrimidinone HIV protease inhibitors

As part of an ongoing effort in understanding the role of hydrophobicity in the design of nonpeptidic HIV protease inhibitors, the QSAR study on P2/P2' tetrahydropyrimidinone is presented in this report. Our results suggest that the balance of hydrophobicity and a volume- dependent polarizability term plays a key role in the inhibition of the viral protease by these inhibitors. The size of the substituent of ligands at particular positions that induce steric fit is crucial. The role of hydrophobicity in the design of tetrahydropyrimidinone is discussed. It has been found that a sufficient spread in the data is required to observe the optimum value of ClogP for these inhibitors.     

P2 Receptors for Extracellular Nucleotides in the Central Nervous System: Role of P2X7 and P2Y2 Receptor Interactions in Neuroinflammation

Extracellular nucleotides induce cellular responses in the central nervous system (CNS) through the activation of ionotropic P2X and metabotropic P2Y nucleotide receptors. Activation of these receptors regulates a wide range of physiological and pathological processes. In this review, we present an overview of the current literature regarding P2X and P2Y receptors in the CNS with a focus on the contribution of P2X7 and P2Y(2) receptor-mediated responses to neuroinflammatory and neuroprotective mechanisms.     

Immunolocalisation of P2X and P2Y nucleotide receptors in the rat nasal mucosa

Purinoceptor subtypes were localised to various tissue types present within the nasal cavity of the rat, using immunohistochemical methods. P2X₃ receptor immunoreactivity was localised in the primary olfactory neurones located both in the olfactory epithelium and vomeronasal organs (VNO) and also on subepithelial nerve fibres in the respiratory region. P2X₅ receptor immunoreactivity was found in the squamous, respiratory and olfactory epithelial cells of the rat nasal mucosa. P2X₇ receptor immunoreactivity was also expressed in epithelial cells and colocalised with caspase 9 (an apoptotic marker), suggesting an association with apoptosis and epithelial turnover. P2Y₁ receptor immunoreactivity was found within the respiratory epithelium and submucosal glandular tissue. P2Y₂ receptor immunoreactivity was localised to the mucus-secreting cells within the VNO. The possible functional roles of these receptors are discussed.     

P2 receptors in the thymus: expression of P2X and P2Y receptors in adult rats, an immunohistochemical and in situ hybridisation study

The expression of the seven P2X receptor subtypes and of two P2Y receptors was examined immunohistochemically and by in situ hybridisation in thymi of adult male rats. P2X4, P2Y2 and 4 receptor mRNA colocalisation studies combining in situ hybridisation and immunohistochemistry were also carried out. P2X and P2Y receptors were found on thymocytes. P2X receptors were also abundant in cells of the thymic microenvironment, involved in control of T-cell maturation in vivo. We are the first to describe the expression of P2X4 receptors on thymocytes and confirm the finding of P2X1 and P2Y2 receptors on subpopulations of lymphocytes. P2X1,2,3,4 and 5 receptors were present in blood vessels of the thymus. P2X1,2 and 4 receptors were detected in vascular smooth muscle, while P2X3 receptors appeared to be associated with endothelial cells; some small arteries were positive for P2X5, possibly labelling vascular smooth muscle or fibroblasts in the adventitia. P2X2,3,6 and 7 receptors were found on thymic epithelial cells. P2X2 and 3 receptors were abundant on medullary epithelial cells, whilst P2X6 receptors were prominent in Hassall's corpuscles. P2X2 receptors were found on subcapsular and perivascular epithelial cells. P2X2,6 and 7 receptors were detected in epithelial cells along the thymic septa. Expression of P2X receptors was also investigated by Western blotting of crude thymic tissue extracts under reducing conditions. All seven P2X receptor subtypes were found to be dimers of approximately 70 kDa and 140 kDa molecular weight. ATP-mediated apoptosis and cell proliferation of thymocytes are discussed.     

Comparative Analysis of P2X1, P2X2, P2X3, and P2X4 Receptor Subunits in Rat Nodose Ganglion Neurons

Nodose ganglion (NG) neurons are visceral primary sensory neurons. The transmission and regulation of visceral sensation is mediated mainly by the P2X purinoceptor (P2X receptor). Although the characteristics of different P2X receptor subunits in the NG have been studied previously, comprehensive analyses have not been performed. In this study, we used immunohistochemistry, immunocytochemistry, and whole cell patch clamp techniques to compare the expression and function of P2X1, P2X2, P2X3, and P2X4 receptor subunits in adult rat NG neurons. Polyclonal antibodies against the four P2X subunits labeled different subpopulations of NG neurons. P2X1 and P2X3 were expressed mainly in small-to-medium sized NG neurons, whereas P2X2 and P2X4 were located mostly in medium- and larger-sized NG neurons. Over 36% of NG neurons were P2X3 positive, which was higher than the other three P2X subunits. In addition, different types of currents were recorded from neurons expressing different P2X subunits. The fast type of ATP current was recorded from neurons containing P2X1–4 subunits, the intermediate type of current was recorded from neurons containing the P2X1, P2X3, and P2X4 subunits, the slow type was recorded from neurons expressing P2X1–3, and/or P2X4 subunits, whereas the very slow type was recorded from neurons containing the P2X2 and P2X3 subunits. These comparative results provide an anatomical verification of the different subunits in NG neurons, and offer direct support for the idea that various functional NG populations have distinct responses to ATP, which might be in part due to the different expression profiles of diverse P2X subunits.     

Localization of P2X and P2Y receptors in dorsal root ganglia of the cat.

The distribution of P2X and P2Y receptor subtypes in upper lumbosacral cat dorsal root ganglia (DRG) has been investigated using immunohistochemistry. Intensity of immunoreactivity for six P2X receptors (P2X(5) receptors were immuno-negative) and the three P2Y receptors examined in cat DRG was in the order of P2Y(2) = P2Y(4)>P2X(3)>P2X(2) = P2X(7)>P2X(6)>P2X(1) = P2X(4)>P2Y(1). P2X(3), P2Y(2), and P2Y(4) receptor polyclonal antibodies stained 33.8%, 35.3%, and 47.6% of DRG neurons, respectively. Most P2Y(2), P2X(1), P2X(3), P2X(4), and P2X(6) receptor staining was detected in small- and medium-diameter neurons. However, P2Y(4), P2X(2), and P2X(7) staining was present in large- and small-diameter neurons. Double-labeling immunohistochemistry showed that 90.8%, 32.1%, and 2.4% of P2X(3) receptor-positive neurons coexpressed IB(4), CGRP, and NF200, respectively; whereas 67.4%, 41.3%, and 39.1% of P2Y(4) receptor-positive neurons coexpressed IB(4), CGRP, and NF200, respectively. A total of 18.8%, 16.6%, and 63.5% of P2Y(2) receptor-positive neurons also stained for IB(4), CGRP, and NF200, respectively. Only 30% of DRG neurons in cat were P2X(3)-immunoreactive compared with 90% in rat and in mouse. A further difference was the low expression of P2Y(1) receptors in cat DRG neurons compared with more than 80% of the neurons in rat. Many small-diameter neurons were NF200-positive in cat, again differing from rat and mouse.     

Hetero-oligomerization of the P2Y11 receptor with the P2Y1 receptor controls the internalization and ligand selectivity of the P2Y11 receptor

Nucleotides signal through purinergic receptors such as the P2 receptors, which are subdivided into the ionotropic P2X receptors and the metabotropic P2Y receptors. The diversity of functions within the purinergic receptor family is required for the tissue-specificity of nucleotide signalling. In the present study, hetero-oligomerization between two metabotropic P2Y receptor subtypes is established. These receptors, P2Y1 and P2Y11, were found to associate together when co-expressed in HEK293 cells. This association was detected by co-pull-down, immunoprecipitation and FRET (fluorescence resonance energy transfer) experiments. We found a striking functional consequence of the interaction between the P2Y11 receptor and the P2Y1 receptor where this interaction promotes agonist-induced internalization of the P2Y11 receptor. This is remarkable because the P2Y11 receptor by itself is not able to undergo endocytosis. Co-internalization of these receptors was also seen in 1321N1 astrocytoma cells co-expressing both P2Y11 and P2Y1 receptors, upon stimulation with ATP or the P2Y1 receptor-specific agonist 2-MeS-ADP. 1321N1 astrocytoma cells do not express endogenous P2Y receptors. Moreover, in HEK293 cells, the P2Y11 receptor was found to functionally associate with endogenous P2Y1 receptors. Treatment of HEK293 cells with siRNA (small interfering RNA) directed against the P2Y1 receptor diminished the agonist-induced endocytosis of the heterologously expressed GFP-P2Y11 receptor. Pharmacological characteristics of the P2Y11 receptor expressed in HEK293 cells were determined by recording Ca2+ responses after nucleotide stimulation. This analysis revealed a ligand specificity which was different from the agonist profile established in cells expressing the P2Y11 receptor as the only metabotropic nucleotide receptor. Thus the hetero-oligomerization of the P2Y1 and P2Y11 receptors allows novel functions of the P2Y11 receptor in response to extracellular nucleotides.     

Involvement of P2X and P2Y receptors in microglial activation in vivo

Microglial cells are the primary immune effector cells in the brain. Extracellular ATP, e.g., released after brain injury, may initiate microglial activation via stimulation of purinergic receptors. In the rat nucleus accumbens (NAc), the involvement of P2X and P2Y receptors in the generation of microglial reaction in vivo was investigated. A stab wound in the NAc increased immunoreactivity (IR) for P2X_1,2,4,7 and P2Y_1,2,4,6,12 receptors on microglial cells when visualized with confocal laser scanning microscopy. A prominent immunolabeling of P2X₇ receptors with antibodies directed against the ecto- or endodomain was found on Griffonia simplicifolia isolectin-B4-positive cells. Additionally, the P2X₇ receptor was colocalized with active caspase 3 but not with the anti-apoptotic marker pAkt. Four days after local application of the agonists α,βmeATP, ADPβS, 2MeSATP, and BzATP, an increase in OX 42- and G. simplicifolia isolectin-IR was observed around the stab wound, quantified both densitometrically and by counting the number of ramified and activated microglial cells, whereas UTPγS appeared to be ineffective. The P2 receptor antagonists PPADS and BBG decreased the injury-induced increase of these IRs when given alone and in addition inhibited the agonist effects. Further, the intra-accumbally applied P2X₇ receptor agonist BzATP induced an increase in the number of caspase-3-positive cells. These results indicate that ATP, acting via different P2X and P2Y receptors, is a signaling molecule in microglial cell activation after injury in vivo. The up-regulation of P2X₇-IR after injury suggests that this receptor is involved in apoptotic rather than proliferative effects.     

Neuroprotective roles of the P2Y2 receptor

Purinergic signaling plays a unique role in the brain by integrating neuronal and glial cellular circuits. The metabotropic P1 adenosine receptors and P2Y nucleotide receptors and ionotropic P2X receptors control numerous physiological functions of neuronal and glial cells and have been implicated in a wide variety of neuropathologies. Emerging research suggests that purinergic receptor interactions between cells of the central nervous system (CNS) have relevance in the prevention and attenuation of neurodegenerative diseases resulting from chronic inflammation. CNS responses to chronic inflammation are largely dependent on interactions between different cell types (i.e., neurons and glia) and activation of signaling molecules including P2X and P2Y receptors. Whereas numerous P2 receptors contribute to functions of the CNS, the P2Y(2) receptor is believed to play an important role in neuroprotection under inflammatory conditions. While acute inflammation is necessary for tissue repair due to injury, chronic inflammation contributes to neurodegeneration in Alzheimer's disease and occurs when glial cells undergo prolonged activation resulting in extended release of proinflammatory cytokines and nucleotides. This review describes cell-specific and tissue-integrated functions of P2 receptors in the CNS with an emphasis on P2Y(2) receptor signaling pathways in neurons, glia, and endothelium and their role in neuroprotection.     

Functional characterization of P2Y and P2X receptors in human eosinophils

Activation of purinoceptor by ATP induces in eosinophils various cell responses including calcium transients, actin polymerization, production of reactive oxygen metabolites, CD11b-expression, and chemotaxis. Here, the effect of ion channel-gated P2X and/or G protein-coupled P2Y receptor agonists ATP, ATPgammaS, alpha,beta-meATP, 2-MeSATP, BzATP, ADP, CTP, and UTP on the intracellular Ca(2+)-mobilization, actin polymerization, production of reactive oxygen metabolites, CD11b expression and chemotaxis of human eosinophils were measured and the biological activity was analyzed. Although all tested nucleotides were able to induce all these cell responses, the biological activity of the analyzed nucleotides were distinct. Agonists of the G protein-coupled P2Y receptors such as 2-MeSATP, UTP, and ADP have a higher biological activity for production of reactive oxygen metabolites, actin polymerization and chemotaxis in comparison to the ion channel-gated P2X agonists alphabeta-meATP, BzATP, and CTP. In contrast, P2Y and P2X agonist showed similar potencies in respect to intracellular calcium transient and CD11b up-regulation. This conclusion was further supported by experiments with receptor iso-type antagonist KN62, EGTA or with the G(i) protein-inactivating pertussis toxin. These findings indicate participation of different purinorecptors in the regulation of cell responses in eosinophils.     

P2Y 受体研究进展

P2受体作为一类核苷酸受体,可分为门控离子通道P2X受体和G蛋白偶联P2Y受体。P2Y受体在人体内分布广泛,功能复杂,迄今为止已从人体组织细胞克隆出9种P2Y受体,分别为P2Y1,2,4,6,11,1,13,14,15受体。本文对P2Y受体的结构特征、生理功能、药理特性和临床应用进行综述。     

Role played by P2X and P2Y receptors in evoking the muscle chemoreflex.

The role played by purinergic 2Y receptors in evoking the muscle chemoreflex is not well defined. To shed light on this issue, we compared the pressor responses with popliteal arterial injection of UTP (1 mg/kg), a selective P2Y agonist, with those to popliteal arterial injection of ATP (1 mg/kg), a P2X and P2Y agonist, and to alpha,beta-methylene ATP (50 mug/kg), a selective P2X1 and P2X3 agonist, in decerebrate unanesthetized cats. We found that injection of ATP and alpha,beta-methylene ATP increased mean arterial pressure by 19 +/- 2 and 15 +/- 4 mmHg, whereas UTP had no affect on arterial pressure. In addition, the pressor responses to injection of ATP and alpha,beta-methylene ATP were abolished by section of the sciatic nerve, demonstrating that they were reflex in origin. We conclude that P2Y receptors on thin fiber muscle afferents play no role in evoking the muscle chemoreflex.     

Roles of Peripheral P2X and P2Y Receptors in the Development of Melittin-Induced Nociception and Hypersensitivity

A recent report from our laboratory shows that subcutaneous (s.c.) injection of melittin could induce persistent spontaneous nociception (PSN) and primary thermal or mechanical hyperalgesia. However, the exact peripheral mechanisms underlying melittin-induced multiple pain-related behaviors remain unclear. In this study, behavioral tests combined with pharmacological manipulations were used to explore potential roles of local P2X and P2Y receptors in melittin-induced inflammatory pain and hyperalgesia. Post-treatment of the primary injury site with s.c. injection of A-317491 (a potent P2X₃/P2X_2/3 receptor antagonist) and Reactive Blue 2 (a potent P2Y receptor antagonist) could significantly suppress the development of melittin-evoked PSN and hypersensitivity (thermal and mechanical). Our control experiments demonstrated that local administration of either antagonist into the contralateral hindpaw produced no significant effect on any kind of pain-associated behaviors. Taken together, these data indicate that activation of P2X and P2Y receptors might be essential to the maintenance of melittin-induced primary thermal and mechanical hyperalgesia as well as on-going pain. Z.-M. Lu and F. Xie are contributed equally to the work. Special issue article in honor of Dr. Ji-Sheng Han.     

Involvement of P2X and P2U receptors in the constrictor effect of ATP on the pancreatic vascular bed

The effects of ATP on the pancreatic vascular bed were studied on the isolated rat pancreas perfused at a constant pressure so as any change in the vascular tone induces a modification in the flow rate. This study was performed in two different experimental conditions: 1) In the presence of indomethacin, inhibiting the cyclo-oxygenase and prostacyclin (PGI2) synthesis, ATP (which acts on vasodilatator P2Y receptors and vasoconstrictor P2X and P2U receptors) was used at a concentration (165 microM) which did not modify per se the vascular flow rate. With indomethacin, ATP induced a slight but significant and long lasting decrease in the flow rate. This effect is different from that induced by the stimulation of P2X receptors; it is comparable to that induced by the activation of P2U receptors. 2) In the presence of 2,2'pyridylisatogen tosilate (PIT) used at two different concentrations, the first (5 microM) inhibiting the P2Y effects on insulin secreting B cells and pancreatic vessels, the second (25 microM) inhibiting the P2X effects on pancreatic vessels. The effects of ATP are different according to the concentration of PIT. In both cases, ATP induced only a vasoconstriction. However, the kinetics of the flow rate is totally different: in the presence of 5 microM PIT, an immediate and drastic vasoconstriction was observed, followed by a long lasting vasoconstriction of lesser magnitude, which can be ascribed to P2X and P2U receptor activation, respectively. This hypothesis was confirmed by the results in the presence of PIT at 25 microM. At this concentration this compound completely suppressed the drastic and transient vasoconstriction, so that only a progressive and long lasting vasoconstriction of the P2U type could be observed. From these results, it can be concluded that: 1) PGI2 plays a part in the vasodilatator effects of ATP. 2) At the concentrations used, PIT does not block the vasoconstriction induced by P2U receptors. 3) The effects of ATP on pancreatic vessels is dependent on the balance between its vasodilator effect due to the activation of P2Y receptors and its vasoconstrictor effect which involves two types of receptors: P2X and P2U.     

BAC transgenic mice to study the expression of P2X2 and P2Y1 receptors

Extracellular purines are important signaling molecules involved in numerous physiological and pathological processes via the activation of P2 receptors. Information about the spatial and temporal P2 receptor (P2R) expression and its regulation remains crucial for the understanding of the role of P2Rs in health and disease. To identify cells carrying P2X2Rs in situ, we have generated BAC transgenic mice that express the P2X2R subunits as fluorescent fusion protein (P2X2-TagRFP). In addition, we generated a BAC P2Y₁R TagRFP reporter mouse expressing a TagRFP reporter for the P2RY1 gene expression. We demonstrate expression of the P2X2R in a subset of DRG neurons, the brain stem, the hippocampus, as well as on Purkinje neurons of the cerebellum. However, the weak fluorescence intensity in our P2X2R-TagRFP mouse precluded tracking of living cells. Our P2Y₁R reporter mice confirmed the widespread expression of the P2RY1 gene in the CNS and indicate for the first time P2RY1 gene expression in mouse Purkinje cells, which so far has only been described in rats and humans. Our P2R transgenic models have advanced the understanding of purinergic transmission, but BAC transgenic models appeared not always to be straightforward and permanent reliable. We noticed a loss of fluorescence intensity, which depended on the number of progeny generations. These problems are discussed and may help to provide more successful animal models, even if in future more versatile and adaptable nuclease-mediated genome-editing techniques will be the methods of choice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11302-021-09792-9.     

P2Y2 receptors and water transport in the kidney

The kidneys play a critical role in the maintenance of water homeostasis. This is achieved by the inherent architecture of the nephron along with the expression of various membrane transporters and channels that are responsible for the vectorial transport of salt and water. The collecting duct has become a focus of attention by virtue of its ability to transport water independent of solutes (free-water transport), and its apparent involvement in various water balance disorders. It was originally believed that the water transport capability of the collecting duct was solely under the influence of the circulating hormone, arginine vasopressin (AVP). However, during the past decade, locally produced autocrine and/or paracrine factors have emerged as potent modulators of transport of water by the collecting duct. Recently, much attention has been focused on the purinergic regulation of renal water transport. This review focuses on the role of the P2Y₂ receptor, the predominant purinergic receptor expressed in the collecting duct, in the modulation of water transport in physiological and pathophysiological conditions, and its therapeutic potential as a drug target to treat water balance disorders in the clinic. Studies carried out by us and other investigators are unravelling potent interactions among AVP, prostanoid and purinergic systems in the medullary collecting duct, and the perturbations of these interactions in water balance disorders such as acquired nephrogenic diabetes insipidus. Future studies should address the potential therapeutic benefits of modulators of P2Y₂ receptor signalling in water balance disorders, which are extremely prevalent in hospitalised patients irrespective of the underlying pathology.     

Distribution of immunoreactivity for P2X3, P2X5, and P2X6-purinoceptors in mouse retina

Previous findings have shown that P2X-purinoceptor-mediated signaling pathways regulate the release of ACh in the retina. We previously reported the existence of immunoreactivity for P2X1-, P2X2-, P2X4-, and P2X7-purinoceptors in mouse retina and speculated that P2X2 and P2X7-purinoceptors may modulate the activity of cholinergic amacrine cells. In the present study, we used an immunohistochemical technique to examine whether P2X3-, P2X5, and P2X6-purinoceptors are also important for the modulation of cholinergic amacrine cells in mouse retina. Immunoreactivity for P2X3-, P2X5-, and P2X6-purinoceptors was observed in mouse retina. Immunoreactivity for P2X3- purinoceptors was observed in the dendrites of cholinergic amacrine cells. Immunoreactivity for P2X5-purinoceptors existed in the soma of cholinergic amacrine cells. P2X6-purinoceptor immunoreactivity was not colocalized with the cholinergic amacrine cells. We concluded that, among the three P2X-purinoceptors that were examined, P2X3-purinoceptors seem to affect the function of cholinergic amacrine cells in the mouse retina.