Constructing and generalizing multivariate copulas: a generalizing approach

Recently, Liebscher (2006) introduced a general construction scheme of d-variate copulas which generalizes the Archimedean family. Similarly, Morillas (2005) proposed a method to obtain a variety of new copulas from a given d-copula. Both approaches coincide only for the particular subclass of Archimedean copulas. Within this work we present a unifying framework which includes both Liebscher and Morillas copulas as special cases. Above that, more general copulas may be constructed. First examples are given. --construction of d-variate copulas,Archimedean copulas

Chemical defenses of the Caribbean sponges Agelas wiedenmayeri and Agelas conifera

Previous studies have determined that Caribbean reef sponges of the genus Agelas are chemically defended from fish predation by brominated pyrrole alkaloids, and that the compounds responsible for this defense have been elucidated for one species, Agelas clathrodes. In this study, we expand our understanding of chemical defense in this common sponge genus to include the characterization of defensive metabolites in the tissues of Agelas wiedenmayeri and Agelas conifera. Bioassay-directed isolation of defensive metabolites was undertaken using fish feeding assays carried out in laboratory aquaria and in the field. Agelas wiedenmayeri contained the same two major metabolites as Agelas clathrodes, 4,5-dibromopyrrole-2-carboxylic acid (1), and oroidin (2), in addition to a small amount of bromoageliferin (7). The two major metabolites were present at higher concentrations in samples of Agelas wiedenmayeri than in Agelas clathrodes, and their relative concentrations were reversed, with Agelas wiedenmayeri on average containing more 4,5-dibromopyrrole-2-carboxylic acid (1) (2.0 mg/mL) than oroidin (2) (0.8 mg/mL). Agelas conifera contained a mixture of dimeric bromopyrrole alkaloids dominated by sceptrin (3), with <10% each of dibromosceptrin (5), bromoageliferin (7), dibromoageliferin (8), ageliferin (6), and bromosceptrin (4). Mean concentration of sceptrin (3) in sponge tissue was 5.3 mg/mL; this compound deterred feeding of reef fish in aquarium assays at 1.0 mg/mL, the lowest concentration assayed. Sceptrin (3) concentrations were higher in sponges collected in the southern Bahama Islands than those collected in the middle Bahamas, but reasons for this variation remain unclear. The structure-activity relationship of the pyrrole group was investigated by assaying derivatives of the active metabolites. Feeding deterrent activity of the molecule was enhanced by the addition of bromine to the pyrrole group, but not affected by exchange of the heteroatom from N to O or S. Combining an understanding of the structure-activity relationship of Agelas metabolites with an understanding of the variation in these metabolites across the genus may provide insight into the evolution of defensive chemistry in this highly successful taxa of pan-tropical sponges

Multivariate Copula Models at Work: Outperforming the desert island copula?

Since the pioneering work of Embrechts and co-authors in 1999, copula models enjoy steadily increasing popularity in finance. Whereas copulas are well-studied in the bivariate case, the higher-dimensional case still offers several open issues and it is by far not clear how to construct copulas which sufficiently capture the characteristics of financial returns. For this reason, elliptical copulas (i.e. Gaussian and Student-t copula) still dominate both empirical and practical applications. On the other hand, several attractive construction schemes appeared in the recent literature prom sing flexible but still manageable dependence models. The aim of this work is to empirically investigate whether these models are really capable to outperform its benchmark, i.e. the Student-t copula (which is termed by Paul Embrechts as "desert island copula" on account of its excellent fit to financial returns) and, in addition, to compare the fit of these different copula classes among themselves. --KS-copula,Hierarchical Archimedian,Product copulas,Pair-copula decomposition

Bromotyrosine-derived alkaloids from the Caribbean sponge Aplysina lacunosa

Abstract Three new bromotyrosine-derived alkaloids 14-debromo-11-deoxyfistularin-3 (1), aplysinin A (2), and aplysinin B (3), together with 15 known compounds (4-18) were isolated from the sponge Aplysina lacunosa collected from Stirrup Cay, Bahamas. The structures of the isolated compounds were identified on the basis of MS and NMR data analysis. The 13 C NMR assignment of spirocyclohexadienylisoxazoline moieties of 1 and 2 were confirmed by an 1,1-ADEQUATE experiment. Compounds 1 and 2 showed a mild to moderate cytotoxic activities against KB-31 and FS4-LTM cell lines. Only aplysinin A (2) exhibited cytotoxicity against MCF-7 cells. 233

Bioplastics in the Sea: Rapid In-Vitro Evaluation of Degradability and Persistence at Natural Temperatures

The progressive substitution of petroleum-based polymers, such as polyethylene, polyvinylchloride, or polyethylene terephtalate, by so-called bioplastics facilitated the development and production of many new materials. The continuously refined properties of bioplastic compounds and their blends enable various applications. With growing production and utilization of bioplastic products, these materials are increasingly discarded into the environment. Although many of these materials are labeled biodegradable, there is limited information about their degradability under environmental conditions. We tested the enzymatic degradability of five bioplastic compounds with the rapid pH-Stat titration assay at environmentally relevant seawater temperatures between 5 and 30°C and pH 8.2. These plastics, issued from the European Horizon 2020 Project ´Bioplastics Europe´, are based on polylactic acid (PLA), polybutylene succinate (PBS), and poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV). Suspensions of microparticles (< 200 µm) were incubated with each of the three hydrolytic enzymes, protease, lipase, and esterase. A PLA-based compound blended with polybutylene adipate terephthalate (PBAT) showed the highest hydrolysis rate of 30 nmol·min-1 when incubated with lipase at 30°C. All other materials showed low hydrolysis rates of less than 10 nmol·min-1. Below 20°C, hydrolysis almost ceased. Plate clearing assays with the same enzymes at 37°C and pH 5 and pH 8, respectively, largely confirmed the results of the pH-Stat titration assays. Our findings indicate that there is a potential degradation of most of the materials with at least one of these hydrolytic enzymes. Nonetheless, the rate of enzymatic degradation under environmentally relevant conditions is low, which indicates only a marginal degradability of bioplastics in the marine environment

NMR-Based Configurational Assignments of Natural Products: Gibbs Sampling and Bayesian Inference Using Floating Chirality Distance Geometry Calculations

Floating chirality restrained distance geometry (fc-rDG) calculations are used to directly evolve structures from NMR data such as NOE-derived intramolecular distances or anisotropic residual dipolar couplings (RDCs). In contrast to evaluating pre-calculated structures against NMR restraints, multiple configurations (diastereomers) and conformations are generated automatically within the experimental limits. In this report, we show that the "unphysical" rDG pseudo energies defined from NMR violations bear statistical significance, which allows assigning probabilities to configurational assignments made that are fully compatible with the method of Bayesian inference. These "diastereomeric differentiabilities" then even become almost independent of the actual values of the force constants used to model the restraints originating from NOE or RDC data

The Advanced Floating Chirality Distance Geometry Approach ― How Anisotropic NMR Parameters Can Support the Determination of the Relative Configuration of Natural Products

The configurational analysis of complex natural products by NMR spectroscopy is still a challenging task. The assignment of the relative configuration is usually carried out by analysis of interproton distances from NOESY or ROESY spectra (qualitative or quantitative) and scalar (J) couplings. About 15 years ago, residual dipolar couplings (RDCs) were introduced as a tool for the configurational determination of small organic molecules. In contrast to NOEs/ROEs which are local parameters (distances up to 400 pm can be detected for small organic molecules), RDCs are global parameters which allow to obtain structural information also from long-range relationships. RDCs have the disadvantage that the sample needs a setup in an alignment medium in order to obtain the required anisotropic environment. Here, we will discuss the configurational analysis of five complex natural products: axinellamine A (1), tetrabromostyloguanidine (2), 3,7-epi-massadine chloride (3), tubocurarine (4), and vincristine (5). Compounds 1–3 are marine natural products whereas 4 and 5 are from terrestrial sources. The chosen examples will carefully work out the limitations of NOEs/ROEs in the configurational analysis of natural products and will also provide an outlook on the information obtained from RDCs

Case report: Psychosis and catatonia in an adolescent patient with adipsic hypernatremia and autoantibodies against the subfornical organ.

This is the first description of a patient in which adipsic hypernatremia, a rare autoimmune encephalitis, presented in combination with complex psychiatric symptomatology, including psychosis and catatonia. Adipsic hypernatremia is characterized by autoantibodies against the thirst center of the brain. These autoantibodies cause inflammation and apoptosis in key regions of water homeostasis, leading to lack of thirst and highly increased serum sodium. To date, the symptoms of weakness, fatigue and drowsiness have been associated with adipsic hypernatremia, but no psychiatric symptomatology. Here, we showcase the first description of an adolescent patient, in which severe and complex psychiatric symptoms presented along with adipsic hypernatremia. The patient experienced delusion, hallucinations, restlessness and pronounced depression. Further, he showed ritualized, aggressive, disinhibited and sexualized behavior, as well as self-harm and psychomotor symptoms. Due to his severe condition, he was hospitalized on the emergency unit of the child and adolescent psychiatry for 8 months. Key symptoms of the presented clinical picture are: childhood-onset complex and treatment-resistant psychosis/catatonia, pronounced behavioral problems, fatigue, absent thirst perception, hypernatremia and elevated prolactin levels. This case report renders first evidence speaking for a causal link between the autoimmune adipsic hypernatremia and the psychotic disorder. Moreover, it sheds light on a new form of autoimmune psychosis

Modernizing persistence–bioaccumulation–toxicity (PBT) assessment with high throughput animal-free methods

The assessment of persistence (P), bioaccumulation (B), and toxicity (T) of a chemical is a crucial first step at ensuring chemical safety and is a cornerstone of the European Union’s chemicals regulation REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals). Existing methods for PBT assessment are overly complex and cumbersome, have produced incorrect conclusions, and rely heavily on animal-intensive testing. We explore how new-approach methodologies (NAMs) can overcome the limitations of current PBT assessment. We propose two innovative hazard indicators, termed cumulative toxicity equivalents (CTE) and persistent toxicity equivalents (PTE). Together they are intended to replace existing PBT indicators and can also accommodate the emerging concept of PMT (where M stands for mobility). The proposed “toxicity equivalents” can be measured with high throughput in vitro bioassays. CTE refers to the toxic effects measured directly in any given sample, including single chemicals, substitution products, or mixtures. PTE is the equivalent measure of cumulative toxicity equivalents measured after simulated environmental degradation of the sample. With an appropriate panel of animal-free or alternative in vitro bioassays, CTE and PTE comprise key environmental and human health hazard indicators. CTE and PTE do not require analytical identification of transformation products and mixture components but instead prompt two key questions: is the chemical or mixture toxic, and is this toxicity persistent or can it be attenuated by environmental degradation? Taken together, the proposed hazard indicators CTE and PTE have the potential to integrate P, B/M and T assessment into one high-throughput experimental workflow that sidesteps the need for analytical measurements and will support the Chemicals Strategy for Sustainability of the European Union

Modernizing persistence–bioaccumulation–toxicity (PBT) assessment with high throughput animal-free methods

The assessment of persistence (P), bioaccumulation (B), and toxicity (T) of a chemical is a crucial first step at ensuring chemical safety and is a cornerstone of the European Union’s chemicals regulation REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals). Existing methods for PBT assessment are overly complex and cumbersome, have produced incorrect conclusions, and rely heavily on animal-intensive testing. We explore how new-approach methodologies (NAMs) can overcome the limitations of current PBT assessment. We propose two innovative hazard indicators, termed cumulative toxicity equivalents (CTE) and persistent toxicity equivalents (PTE). Together they are intended to replace existing PBT indicators and can also accommodate the emerging concept of PMT (where M stands for mobility). The proposed “toxicity equivalents” can be measured with high throughput in vitro bioassays. CTE refers to the toxic effects measured directly in any given sample, including single chemicals, substitution products, or mixtures. PTE is the equivalent measure of cumulative toxicity equivalents measured after simulated environmental degradation of the sample. With an appropriate panel of animal-free or alternative in vitro bioassays, CTE and PTE comprise key environmental and human health hazard indicators. CTE and PTE do not require analytical identification of transformation products and mixture components but instead prompt two key questions: is the chemical or mixture toxic, and is this toxicity persistent or can it be attenuated by environmental degradation? Taken together, the proposed hazard indicators CTE and PTE have the potential to integrate P, B/M and T assessment into one high-throughput experimental workflow that sidesteps the need for analytical measurements and will support the Chemicals Strategy for Sustainability of the European Union.ISSN:0340-5761ISSN:1432-073