Search

On-site observations show that several damages have occurred in CRTS II slab-type ballastless track system, such as crack and interface debonding between different structural layers, which will trigger the occurrence of some failure modes of CRTS II track slab. As the damages are the prior for specific failure modes, time-dependent reliability of CRTS II track slab should be conducted considering the uncertainties associated with both the failure mode and the damage, which is defined as the conditional time-dependent reliability in this study. To appropriately express the causal relationship among the failure modes and prior damages, a conditional limit state function (LSF) model is proposed with explicit expressions provided. With the aid of the proposed model, conditional time-dependent reliability of CRTS II track slab for two individual failure modes are investigated, which are the steel yielding failure mode under longitudinal cracking, and the vertical instability failure mode under interface debonding. Furthermore, conditional time-dependent system reliability of the track slab has also been analyzed considering four safety failure modes. The advantage of the proposed method is that prior damages have been accounted in establishing the failure criteria and incorporated in the formulation of time-dependent reliability, which provides a general formwork for structural reliability involving the causal relationship among the failure modes and damages.

To translate the marginal distributions between non-Gaussian and Gaussian processes, a Hermite polynomial model (HPM) based on the first four moments was developed and shown to have high flexibility and efficiency. Due to monotonic limitation, there are some processes that the HPM cannot be applied to. To overcome the monotonic limitation an alternative methodology has been developed, in which the need to identify the transition points between different models makes it inconvenient in practice. Furthermore, the alternative methodology applies inappropriate inverse normal transformation expressions for negatively skewed processes. Therefore, a straightforward HPM is proposed to overcome the monotonic limitation, with explicit expressions deduced and clear applicable ranges provided. The applications of the proposed model in statistical response analysis of the time-domain solution of a tension leg platform and the assessment of the reliability of a hull girder for floating, production, storage and offloading (FPSO) units are investigated via practical examples, which demonstrate that the proposed model can be efficiently applied to marine structures.

Pharmacologically inhibiting nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation results in potent therapeutic effects in a wide variety of preclinical inflammatory disease models. NLRP3 deubiquitination is essential for efficient NLRP3 inflammasome activity, but it remains unclear whether this process can be harnessed for therapeutic benefit. Here, we show that thiolutin (THL), an inhibitor of the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease, blocks NLRP3 inflammasome activation by canonical, noncanonical, alternative, and transcription-independent pathways at nanomolar concentrations. In addition, THL potently inhibited the activation of multiple NLRP3 mutants linked with cryopyrin-associated periodic syndromes (CAPS). Treatment with THL alleviated NLRP3-related diseases in mouse models of lipopolysaccharide-induced sepsis, monosodium urate-induced peritonitis, experimental autoimmune encephalomyelitis, CAPS, and methionine-choline-deficient diet-induced nonalcoholic fatty liver disease. Mechanistic studies revealed that THL inhibits the BRCC3-containing isopeptidase complex (BRISC)-mediated NLRP3 deubiquitination and activation. In addition, we show that holomycin, a natural methyl derivative of THL, displays an even higher inhibitory activity against NLRP3 inflammasome than THL. Our study validates that posttranslational modification of NLRP3 can be pharmacologically targeted to prevent or treat NLRP3-associated inflammatory diseases. Future clinical development of derivatives of THL may provide new therapies for NLRP3-related diseases.

In determining structural responses under random excitation using the Monte Carlo method, simulation of non-Gaussian processes is always a challenge. Various methods have been developed to ...

Probability distributions of basic random variables are essential for the accurate evaluation of structural reliability. In engineering practice, the probability distributions of some random variables are often unknown and the only available information about these may be their statistical moments. To conduct structural reliability analysis without the exclusion of random variables with unknown probability distributions, the fourth-moment normal transformation (FMNT) has been proposed. However, the applicability of expression of the FMNT has not been sufficiently investigated. Furthermore, the monotonic regions of the FMNT are not defined without which the application of the transformation is inconvenient, or even unreliable in reliability analysis. In the present paper, a complete expression of the FMNT including six cases with different combinations of skewness and kurtosis is derived, and the monotonicity of each case of the FMNT expression is confirmed. Literature suggests that the complete monotonic expression of the fourth-moment normal transformation is the first time to be successfully accomplished up to date. Through the numerical examples, the FMNT is found to be quite efficient for normal transformation and to be sufficiently accurate to include random variables with unknown probability distributions in structural reliability analysis.

In our efforts to find potential agents for the treatment of Alzheimer's disease in naturally occurring compounds, a systematic investigation for the active constituents of Flemingia philippinensis was carried out. Four new prenylated isoflavones, philippinone A-D (1-4), together with six known analogues (5-10), were obtained from the roots of Flemingia philippinensis. Their structures were established through extensive physical and spectroscopic data analysis. All the isolates were evaluated for their inhibitory effect of self-induced Aβ aggregation among which compound 5 showed significant Aβ aggregation inhibitory ability with the inhibitory rate of 70.56%. The results of molecular docking experiment for compounds 1 and 6 corresponded to that of the thioflavin-T assay. Moreover, the results further clarified the effects of different substituent group of tested compounds on the Aβ aggregation inhibition. A preliminary structure-activity relationship is further discussed. Our results suggested that the isoflavonoids may mitigate the progression of AD and compounds 2 and 5 may be a candidate in the treatment of AD.

Time-variant reliability evaluation including finite element (FE) analysis requires relatively large computational efforts, as FE analysis is time-consuming and the number of calls to FE analysis in time-variant reliability analysis (TRA) cycle is generally large. In this study, a moment-based PHI2 (MPHI2) method is proposed for evaluating time-variant reliability including FE analysis, based on the statistical moments of the limit state function at successive time instants. Instead of conducting FE analysis repeatedly in TRA cycle, MPHI2 method separates FE analysis from the cycle by representing the associated components in the limit state function as a random variable/process and estimating its statistical characteristics before the TRA cycle. After the separation, time-variant reliability can be evaluated based on the assumed random variable/process with no need to conduct FE analysis, which may significantly reduce the number of calls to the FE analysis and thus improve the computational efficiency. Three numerical and practical examples are presented to illustrate the application and efficiency of the proposed MPHI2 method.

In practical engineering, the probability distributions of some random variables are often unknown, and the only available information about these may be their statistical moments. To conduct structural reliability assessment without the exclusion of random variables with unknown probability distributions, an explicit fourth-moment standardization function has been proposed, and a single expression of its inverse transformation, that is, normal transformation, with limitations of inputting sets of the third and fourth moments (skewness and kurtosis) of random variables was derived. However, the clear definition of the complete expressions of the inverse transformation of fourth-moment standardization function under different combinations of skewness and kurtosis of random variables has not been provided yet. It is in this regard that four criteria are proposed to derive the complete inverse transformation of fourth-moment standardization function, and then the complete expressions of the inverse transformation are formulated. Through the numerical examples presented, the proposed complete expressions are found to be quite efficient for normal transformations and to be sufficiently accurate to include random variables with unknown probability distributions in structural reliability assessment.

Non-Gaussian processes beset many aspects of structural engineering analysis. To estimate non-Gaussian processes, various third-order Hermite polynomial models have been proposed and widely...

The United States financial system can be restructured by giving universal direct access to credit risk-free central bank money. In the 10 years since the financial crisis, technological advancements and regulatory tools have laid the foundation for Central Bank Digital Currencies to emerge as this economic resolution. Our paper analyzes similar economic cases and contends that introducing Central Bank Digital Currencies (CBDCs) can improve financial stability without degrading credit availability in the long term. We illustrate this by focusing on similar market shifts, namely in the U.S. student loan market and the New Zealand agribusiness sector. Our analysis showcases that by introducing CBDCs, market participants can subsequently remove certain market subsidies that promote poor risk practices and improper pricing. This subsidy to financial institutions is both explicit in the form of FDIC deposit insurance and implicit in the stipulation of taxpayer funded bailouts that materialized in 2008. We calculate the effect of introducing CBDCs by focusing on historical market examples when similar fundamental market shifts happened. Our conclusion is that CBDCs diminish credit availability within one-year, but this effect is ameliorated as financial stability improves in subsequent years. Accordingly, we recommend a roadmap for rolling out CBDCs in the least disruptive fashion.