Estimating Systemic Risk within Financial Networks: A Two-Step Nonparametric Method

CoVaR (conditional value-at-risk) is a crucial measure for assessing financial systemic risk, which is defined as a conditional quantile of a random variable, conditioned on other random variables reaching specific quantiles. It enables the measurement of risk associated with a particular node in financial networks, taking into account the simultaneous influence of risks from multiple correlated nodes. However, estimating CoVaR presents challenges due to the unobservability of the multivariate-quantiles condition. To address the challenges, we propose a two-step nonparametric estimation approach based on Monte-Carlo simulation data. In the first step, we estimate the unobservable multivariate-quantiles using order statistics. In the second step, we employ a kernel method to estimate the conditional quantile conditional on the order statistics. We establish the consistency and asymptotic normality of the two-step estimator, along with a bandwidth selection method. The results demonstrate that, under a mild restriction on the bandwidth, the estimation error arising from the first step can be ignored. Consequently, the asymptotic results depend solely on the estimation error of the second step, as if the multivariate-quantiles in the condition were observable. Numerical experiments demonstrate the favorable performance of the two-step estimator.Comment: 40 page

Staffing under Taylor's Law: A Unifying Framework for Bridging Square-root and Linear Safety Rules

Staffing rules serve as an essential management tool in service industries to attain target service levels. Traditionally, the square-root safety rule, based on the Poisson arrival assumption, has been commonly used. However, empirical findings suggest that arrival processes often exhibit an ``over-dispersion'' phenomenon, in which the variance of the arrival exceeds the mean. In this paper, we develop a new doubly stochastic Poisson process model to capture a significant dispersion scaling law, known as Taylor's law, showing that the variance is a power function of the mean. We further examine how over-dispersion affects staffing, providing a closed-form staffing formula to ensure a desired service level. Interestingly, the additional staffing level beyond the nominal load is a power function of the nominal load, with the power exponent lying between $1/2$ (the square-root safety rule) and $1$ (the linear safety rule), depending on the degree of over-dispersion. Simulation studies and a large-scale call center case study indicate that our staffing rule outperforms classical alternatives.Comment: 55 page

Homotopy Iteration Algorithm for Crack Parameters Identification with Composite Element Method

An approach based on homotopy iteration algorithm is proposed to identify the crack parameters in beam structures. In the forward problem, a fully open crack model with the composite element method is employed for the vibration analysis. The dynamic responses of the cracked beam in time domain are obtained from the Newmark direct integration method. In the inverse analysis, an identification approach based on homotopy iteration algorithm is studied to identify the location and the depth of a cracked beam. The identification equation is derived by minimizing the error between the calculated acceleration response and the simulated measured one. Newton iterative method with the homotopy equation is employed to track the correct path and improve the convergence of the crack parameters. Two numerical examples are conducted to illustrate the correctness and efficiency of the proposed method. And the effects of the influencing parameters, such as measurement time duration, measurement points, division of the homotopy parameter and measurement noise, are studied

Antiviral biflavonoids from Radix Wikstroemiae (Liaogewanggen)

<p>Abstract</p> <p>Background</p> <p><it>Radix Wikstroemiae </it>is a common Chinese herbal medicine. The ethyl acetate fraction of the ethanolic extract of <it>W. indica </it>possesses potent <it>in vitro </it>antiviral activity against respiratory syncytial virus (RSV). This study aims to identify the antiviral components of the active fraction.</p> <p>Methods</p> <p>The active fraction of the <it>Radix Wikstroemiae </it>extract was isolated with chromatographic methods such as silica gel, Sephadex LH-20 and semi-preparative high performance liquid chromatography (HPLC) columns. The structures of the isolated compounds were determined based on spectroscopic analyses. The <it>in vitro </it>antiviral activity of the compounds against RSV was tested with the cytopathic effect (CPE) reduction assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method.</p> <p>Results</p> <p>Four biflavonoids, namely neochamaejasmin B, genkwanol B, genkwanol C and stelleranol, were isolated and characterized. Genkwanol B, genkwanol C and stelleranol, which are stereo isomers of spirobiflavonoids, showed potent anti-RSV activity whereas neochamaejasmin B did not.</p> <p>Conclusion</p> <p>Neochamaejasmin B, genkwanol B, genkwanol C and stelleranol were isolated from <it>Radix Wikstroemiae </it>and the complete absolute configurations of five chiral carbons in stelleranol were substantiated for the first time. Furthermore, the anti-RSV activity of genkwanol B, genkwanol C and stelleranol was reported for the first time.</p

Penduliflaworosin, a Diterpenoid from Croton crassifolius, Exerts Anti-Angiogenic Effect via VEGF Receptor-2 Signaling Pathway

Anti-angiogenesis targeting vascular endothelial growth factor receptor-2 (VEGFR-2) has been considered as an important strategy for cancer therapy. Penduliflaworosin is a diterpenoid isolated from the plant Croton crassifolius. Our previous study showed that this diterpenoid possesses strong anti-angiogenic activity by inhibiting vessel formation in zebrafish. This study was conducted to further investigate the anti-angiogenic activity and mechanism of penduliflaworosin. Results revealed that penduliflaworosin significantly inhibited VEGF-induced angiogenesis processes including proliferation, invasion, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, it notably inhibited VEGF-induced sprout formation of aortic rings and blocked VEGF-induced vessel formation in mice. Western blotting studies showed that penduliflaworosin inhibited phosphorylation of the VEGF receptor-2 and its downstream signaling mediators in HUVECs, suggesting that the anti-angiogenic activity was due to an interference with the VEGF/VEGF receptor-2 pathway. In addition, molecular docking simulation indicated that penduliflaworosin could form hydrogen bonds within the ATP-binding region of the VEGF receptor-2 kinase unit. Finally, cytotoxicity assay showed that penduliflaworosin possessed little toxicity toward both cancer and normal cells. Taken together, our findings demonstrate that penduliflaworosin exerts its anti-angiogenic effect via the VEGF receptor-2 signaling pathway. The anti-angiogenic property and low cytotoxicity of penduliflaworosin suggest that it may be useful in cancer treatments

Carboxyl-terminal residues N478 and V479 required for the cytolytic activity of listeriolysin O play a critical role in Listeria monocytogenes pathogenicity

Listeria monocytogenes is a facultative intracellular pathogen that secretes the cytolysin listeriolysin O (LLO), which enables the bacteria to cross the phagosomal membrane. L. monocytogenes regulates LLO activity in the phagosome and minimizes its activity in the host cytosol. Mutants that fail to compartmentalize LLO activity are cytotoxic and have attenuated virulence. Here, we showed that residues N478 and V479 of LLO are required for LLO hemolytic activity and bacterial virulence. A single N478A mutation (LLON478A) significantly increased the hemolytic activity of LLO at a neutral pH, while no difference was observed at the optimum acidic pH, compared with wild-type LLO. Conversely, the mutant LLOV479A exhibited lower hemolytic activity at the acidic pH, but not at the neutral pH. The double mutant LLON478AV479A showed a greater decrease in hemolytic activity at both the acidic and neutral pHs. Interestingly, strains producing LLON478A or LLOV479A lysed erythrocytes similarly to the wild-type strain. Surprisingly, bacteria-secreting LLON478AV479A had barely detectable hemolytic activity, but exhibited host cell cytotoxicity, escaped from the phagosome, grew intracellularly, and spread cell-to-cell with the same efficiency as the wild-type strain, but were highly attenuated in virulence in mice. These data demonstrate that these two residues are required for LLO hemolytic activity and pathogenicity in mice, but not for escape from the phagosome and cell-to-cell spreading. The finding that the nearly non-hemolytic LLON478AV479A mutant grew intracellularly indicates that mutagenesis of a virulence determinant is a novel approach for the development of live vaccine strains

Rapid detection of traditional Chinese medicine with neuraminidase inhibitory activities based on high-throughput and virtual screening strategy

Background: Oseltamivir, a neuraminidase inhibitor (NAI), is the primary and first-line anti-influenza drug. In recent years, more and more oseltamivir resistant strains appeared frequently. Purpose: To identify anti-influenza candidates to overcome oseltamivir resistance from traditional Chinese medicine. Methods: High-throughput screening platform was used to screen candidates with oseltamivir sensitive and resistant neuraminidase (NA) inhibitory activities from traditional Chinese medicine (TCM) and in validation of potential active components in vitro. Molecular docking is used for virtual screening of TCM compound libraries and analysis of the molecular mechanism of active compounds. Results: Six out of 188 TCM formula granules were screened out with good inhibitory activities in oseltamivir sensitive (H5N1) and resistant NA (H274Y mutant). A compound library containing 679 candidates in the above six plants were docked into binding pockets of H5N1 NA and its H274Y mutant. The results indicated that diverse structural types, including flavonoids glycosides, alkaloids, caffeoylquinic acid derivatives, etc. showed good docking scores on the two NAs. Furthermore, 10 representative compounds tested in vitro showed inhibitory activities in both oseltamivir sensitive and resistant NA. The docking simulations revealed that natural TCM molecules bind with NA in an absolute different mode compared with oseltamivir, which occupy the extra cavities adjacent to the active site of NA, thus might make them non-susceptible to be influenced by mutation around the active sites. Conclusions: The combination of high-throughput screening and molecular docking can efficiently screen out candidates that have the potential to overcome oseltamivir resistance from TCM

Thioredoxin A Is Essential for Motility and Contributes to Host Infection of Listeria monocytogenes via Redox Interactions

Microbes employ the thioredoxin system to defend against oxidative stress and ensure correct disulfide bonding to maintain protein function. Listeria monocytogenes has been shown to encode a putative thioredoxin, TrxA, but its biological roles and underlying mechanisms remain unknown. Here, we showed that expression of L. monocytogenes TrxA is significantly induced in bacteria treated with the thiol-specific oxidizing agent, diamide. Deletion of trxA markedly compromised tolerance of the pathogen to diamide, and mainly impaired early stages of infection in human intestinal epithelial Caco-2 cells. In addition, most trxA mutant bacteria were not associated with polymerized actin, and the rare bacteria that were associated with polymerized actin displayed very short tails or clouds during infection. Deletion or constitutive overexpression of TrxA, which was regulated by SigH, severely attenuated the virulence of the pathogen. Transcriptome analysis of L. monocytogenes revealed over 270 genes that were differentially transcribed in the ΔtrxA mutant compared to the wild-type, especially for the virulence-associated genes plcA, mpl, hly, actA, and plcB. Particularly, deletion of TrxA completely reduced LLO expression, and thereby led to a thoroughly impaired hemolytic activity. Expression of these virulence factors are positively regulated by the master regulator PrfA that was found here to use TrxA to maintain its reduced forms for activation. Interestingly, the trxA deletion mutant completely lacked flagella and was non-motile. We further confirmed that this deficiency is attributable to TrxA in maintaining the reduced intracellular monomer status of MogR, the key regulator for flagellar formation, to ensure correct dimerization. In summary, we demonstrated for the first time that L. monocytogenes thioredoxin A as a vital cellular reductase is essential for maintaining a highly reducing environment in the bacterial cytosol, which provides a favorable condition for protein folding and activation, and therefore contributes to bacterial virulence and motility