Approximate Bayesian conditional copulas

Copula models are flexible tools to represent complex structures of dependence for multivariate random variables. According to Sklar's theorem, any multidimensional absolutely continuous distribution function can be uniquely represented as a copula, i.e. a joint cumulative distribution function on the unit hypercube with uniform marginals, which captures the dependence structure among the vector components. In real data applications, the interest of the analyses often lies on specific functionals of the dependence, which quantify aspects of it in a few numerical values. A broad literature exists on such functionals, however extensions to include covariates are still limited. This is mainly due to the lack of unbiased estimators of the conditional copula, especially when one does not have enough information to select the copula model. Several Bayesian methods to approximate the posterior distribution of functionals of the dependence varying according covariates are presented and compared; the main advantage of the investigated methods is that they use nonparametric models, avoiding the selection of the copula, which is usually a delicate aspect of copula modelling. These methods are compared in simulation studies and in two realistic applications, from civil engineering and astrophysics. (C) 2022 Elsevier B.V. All rights reserved

Default Probability Estimation via Pair Copula Constructions

In this paper we present a novel Bayesian approach for default probability estimation. The methodology is based on multivariate contingent claim analysis and pair copula theory. Balance sheet data are used to asses the rm value and to compute its default probability. The rm pricing function is obtained via a pair copula approach, and Monte Carlo simulations are used to calculate the default probability distribution. The methodology is illustrated through an application to defaulted rms data

Bayesian Multivariate Nonlinear State Space Copula Models

In this paper we propose a flexible class of multivariate nonlinear non-Gaussian state space models, based on copulas. More precisely, we assume that the observation equation and the state equation are defined by copula families that are not necessarily equal. For each time point, the resulting model can be described by a C-vine copula truncated after the first tree, where the root node is represented by the latent state. Inference is performed within the Bayesian framework, using the Hamiltonian Monte Carlo method, where a further D-vine truncated after the first tree is used as prior distribution to capture the temporal dependence in the latent states. Simulation studies show that the proposed copula-based approach is extremely flexible, since it is able to describe a wide range of dependence structures and, at the same time, allows us to deal with missing data. The application to atmospheric pollutant measurement data shows that our approach is suitable for accurate modeling and prediction of data dynamics in the presence of missing values. Comparison to a Gaussian linear state space model and to Bayesian additive regression trees shows the superior performance of the proposed model with respect to predictive accuracy

Intratumor Regulatory Noncytotoxic NK Cells in Patients with Hepatocellular Carcinoma

Previous studies support the role of natural killer (NK) cells in controlling hepatocellular carcinoma (HCC) progression. However, ambiguity remains about the multiplicity and the role of different NK cell subsets, as a pro-oncogenic function has been suggested. We performed phenotypic and functional characterization of NK cells infiltrating HCC, with the corresponding nontumorous tissue and liver from patients undergoing liver resection for colorectal liver metastasis used as controls. We identified a reduced number of NK cells in tumors with higher frequency of CD56(BRIGHT)CD16(-) NK cells associated with higher expression of NKG2A, NKp44, and NKp30 and downregulation of NKG2D. Liver-resident (CXCR6(+)) NK cells were reduced in the tumors where T-bet(hi)Eomes(lo) expression was predominant. HCCs showed higher expression of CD49a with particular enrichment in CD49a(+)Eomes(+) NK cells, a subset typically represented in the decidua and playing a proangiogenic function. Functional analysis showed reduced TNF-alpha production along with impaired cytotoxic capacity that was inversely related to CXCR6(-), T-bet(hi)Eomes(lo), and CD49a(+)Eomes(+) NK cells. In conclusion, we identified a subset of NK cells infiltrating HCC, including non-liver-resident cells that coexpressed CD49a and Eomes and showed reduced cytotoxic potential. This NK cell subset likely plays a regulatory role in proangiogenic function

The Late Pleistocene Po River lowstand wedge in the Adriatic Sea: Controls on architecture variability and sediment partitioning

Although facies and stratal geometries of continental margin successions can be defined in detail based on subsurface and outcrop studies, most studies lack the high-resolution age control needed to constrain the time scale of formation of such successions and infer their external forcing mechanisms. Our work on the Po River Lowstand Wedge (PRLW) indicates that deposition rates are surprisingly high with the entire 350-m-thick succession being deposited in less than 17,000 years, and with individual clinothems recording time periods ranging from 400 to 4700 years. The PRLW preserves a high-resolution record of stacked, deltaic shelf-edge clinothems deposited during the Last Glacial Maximum (31.8–14.4 ky BP) in the Adriatic basin (Mediterranean Sea). We investigated clinothem internal geometry, stacking patterns, and facies distributions to infer the main controls on their growth by integrating seismic reflection data with seismic facies attributes and paleoenvironmental proxies. The stratigraphic framework of the shelf-edge clinothems was then related to major paleoenvironmental shifts during the last glacial cycle and driven by eustatic and climatic changes. Within the PRLW, we recognized three distinctive types of 100's-m-high shelf-edge clinothems, type A, type B and type C, each with diagnostic topset geometries, shelf-edge trajectories, and associated distal basin-fill deposits. These elemental clinothem types stack into two Clinothem Sets. Clinothem Set 1, with essentially flat to slightly descending shelf-edge trajectory, is composed of stacked types A and B clinothems, and records the direct influence of river flux leading to dysoxic conditions on the bottom of the basin. In particular, clinothem accumulation rates were as much as 200 km3/ky in some of the type B clinothems. Clinothem Set 2, showing ascending shelf-edge trajectory, records an aggradational stacking coupled with a retreat of the river-entry points with benthic fauna assemblages that reflect the influence of peaks in freshwater discharge. Whereas Clinothem Set 1 developed under perturbations of river supply linked to the multi-scale waxing and waning of glaciers during an interval dominated by eustatic fall, Clinothem Set 2 reflects the main thawing of glaciers concomitant to the first phase of the eustatic rise. From a sequence stratigraphic perspective, Clinothem Set 1 is interpreted as staked high-frequency sequences, while Clinothem Set 2 represents a stack of high-frequency parasequences. The high-resolution age control from boreholes and seismic data enabled us to relate stratal character to independently constrained environmental proxies: this revealed how the evolution of a shelf-edge system intricately convolves the influences of both global (eustacy) and regional (climate-driven supply fluctuations) controls, both at sub-Milankovitch scales. Finally, the thickness, geometry, and stacking patterns of the centennial to millennial clinothems of the PRLW vary in systematic ways resulting in geometries that closely resemble those of ancient shelf-edge systems, and offering the PRLW as a sub-modern analogue. Our observations also reinforce the focus of the classic sequence-stratigraphic approach on analyzing surfaces and their geometric relations and not on time duration or formation mechanisms

FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle

We report the identification and characterization of a novel 32-kDa protein expressed in skeletal muscle and located in the Z-disc of the sarcomere. We found that this protein binds to three other Z-disc proteins; therefore, we have-named it FATZ, gamma -filamin/ABP-L, alpha -actinin and telethonin binding protein of the Z-disc. From yeast two-hybrid experiments we are able to show that the SR3-SR4 domains of alpha -actinin 2 are required to bind the COOH-terminal region of the FATZ as does gamma -filamin/ABP-L, Furthermore, by using a glutathione S-transferase overlay assay we find that FATZ also binds telethonin. The level of FATZ protein in muscle cells increases during differentiation, being clearly detectable before the onset of myosin, Although FATZ has no known interaction domains, it would appear to be involved in a complex network of interactions with other Z-band components. On the basis of the information known about its binding partners, we could envisage a central role for FATZ in the: myofibrillogenesis, After screening our muscle expressed sequence tag data base and the public expressed sequence tag data bases, we were able to assemble two other muscle transcripts that show a high level of identity with FATZ in two different domains. Therefore, FATZ may be the first member of a small family of novel muscle proteins

Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish

The DNA polymerase gamma (Polg) is a nuclear-encoded enzyme involved in DNA replication in animal mitochondria. In humans, mutations in the POLG gene underlie a set of mitochondrial diseases characterized by mitochondrial DNA (mtDNA) depletion or deletion and multiorgan defects, named POLG disorders, for which an effective therapy is still needed. By applying antisense strategies, ENU- and CRISPR/Cas9-based mutagenesis, we have generated embryonic, larval-lethal and adult-viable zebrafish Polg models. Morphological and functional characterizations detected a set of phenotypes remarkably associated to POLG disorders, including cardiac, skeletal muscle, hepatic and gonadal defects, as well as mitochondrial dysfunctions and, notably, a perturbed mitochondria-to-nucleus retrograde signaling (CREB and Hypoxia pathways). Next, taking advantage of preliminary evidence on the candidate molecule Clofilium tosylate (CLO), we tested CLO toxicity and then its efficacy in our zebrafish lines. Interestingly, at well tolerated doses, the CLO drug could successfully rescue mtDNA and Complex I respiratory activity to normal levels, even in mutant phenotypes worsened by treatment with Ethidium Bromide. In addition, the CLO drug could efficiently restore cardio-skeletal parameters and mitochondrial mass back to normal values. Altogether, these evidences point to zebrafish as a valuable vertebrate organism to faithfully phenocopy multiple defects detected in POLG patients. Moreover, this model represents an excellent platform to screen, at the whole-animal level, candidate molecules with therapeutic effects in POLG disorders