Warm-blooded Vertebrates Research Articles

GC3 biology in corn, rice, sorghum and other grasses

BackgroundThe third, or wobble, position in a codon provides a high degree of possible degeneracy and is an elegant fault-tolerance mechanism. Nucleotide biases between organisms at the wobble position have been documented and correlated with the abundances of the complementary tRNAs. We and others have noticed a bias for cytosine and guanine at the third position in a subset of transcripts within a single organism. The bias is present in some plant species and warm-blooded vertebrates but not in all plants, or in invertebrates or cold-blooded vertebrates.ResultsHere we demonstrate that in certain organisms the amount of GC at the wobble position (GC3) can be used to distinguish two classes of genes. We highlight the following features of genes with high GC3 content: they (1) provide more targets for methylation, (2) exhibit more variable expression, (3) more frequently possess upstream TATA boxes, (4) are predominant in certain classes of genes (e.g., stress responsive genes) and (5) have a GC3 content that increases from 5'to 3'. These observations led us to formulate a hypothesis to explain GC3 bimodality in grasses.ConclusionsOur findings suggest that high levels of GC3 typify a class of genes whose expression is regulated through DNA methylation or are a legacy of accelerated evolution through gene conversion. We discuss the three most probable explanations for GC3 bimodality: biased gene conversion, transcriptional and translational advantage and gene methylation.

Bergmann's rule; a concept cluster?

The science behind ecology has been contested for years, partially because of the misuse and misrepresentation of concepts within ecology. This paper discusses the use of Bergmann's rule, a fundamental rule of biogeography. The rule was proposed by Carl Bergmann in 1847 and was published only in German; therefore, the majority of researchers have relied on a single translation by Mayr suggesting that races from cooler climates tend to be larger in species of warm-blooded vertebrates than races of the same species living in warmer climates. That many scientists cannot go back to the original source of information because it has not been published in English has resulted in relying on others for interpretation and led to several problems, the largest of which is whether the definition of the rule should include the mechanism, which had been proposed by Bergmann. There has been a large field of research on the subject, but few tests of the mechanisms behind the observed phenomenon. We conducted a review of the literature on Bergmann's rule, and from this suggest (1) Bergmann's original rule be maintained (a direct translation is provided), (2) mechanism is inherent in Bergmann's rule and is required for a rule to be of scientific value; patterns should be labelled as trends, not rules, (3) the focus should be on falsifying hypothesized mechanisms rather than simply describing patterns, and (4) to truly evaluate Bergmann's rule in a scientific manner the original German source should be translated and made available to the scientific public.

Life is a huge compromise: Is the complexity of the vertebrate immune-neuroendocrine system an advantage or the price to pay?

Recent advances in comparative immunology have established that invertebrates produce hypervariable molecules probably related to immunity, suggesting the possibility of raising a specific immune response. "Priming" and "tailoring" are terms now often associated with the invertebrate innate immunity. Comparative immunologists contributed to eliminate the idea of a static immune system in invertebrates, making necessary to re-consider the evolutive meaning of immunological memory of vertebrates. If the anticipatory immune system represents a maximally efficient immune system, why can it be observed only in vertebrates, especially in consideration that molecular hypervariability exists also in invertebrates? Using well-established theories concerning the evolution of the vertebrate immunity as theoretical basis we analyze from an Eco-immunology-based perspective why a memory-based immune system may have represented an evolutive advantage for jawed vertebrates. We hypothesize that for cold-blooded vertebrates memory represents a complimentary component that flanks the robust and fundamental innate immunity. Conversely, immunological memory has become indispensable and fully exploited in warm-blooded vertebrates, due to their stable inner environment and high metabolic rate, respectively.

The Dopaminergic System of the Telencephalo-Diencephalic Areas of the Vertebrate Brain in the Organization of the Sleep–Waking Cycle

The aim of the present work was to study the involvement of the dopaminergic system of the telencephalic and diencephalic areas of the vertebrate brain in the organization of the sleep-waking cycle in cold-blooded and warm-blooded vertebrates. Immunohistochemical studies of tyrosine hydroxylase content, this being the key enzyme in dopamine synthesis, in the striatum, supraoptic and arcuate nuclei, and zona incerta of the hypothalamus of sturgeon and mammals (rats) of three age groups (14 and 30 days and adults), in conditions of tactile and sleep-deprivation stressors. In fish, transient stress was followed by the detection of tyrosine hydroxylase-immunoreactive cells in all parts of the brain. In prolonged stress, tyrosine hydroxylase-immunoreactive cells and fibers were not found in the forebrain, though they were well represented in the hypothalamic nuclei. In 14-day-old rat pups, 2-h sleep deprivation increased the tyrosine hydroxylase content of fibers in the caudate nucleus and cells in the zona incerta of the hypothalamus, while 30-day-old animals subjected to 6-h sleep deprivation showed increases in tyrosine hydroxylaseimmunoreactive material contents in cells in the paraventricular nucleus and decreases in the quantity in fibers. In adult rats, the arcuate nucleus and zona incerta showed decreases in the content of tyrosine hydroxylase-immunoreactive material on the background of sleep deprivation, with increases during postdeprivation sleep. These data are discussed in the light of the phylo- and ontogenetic development of the neurosecretory and neurotransmitter functions of the dopaminergic system in the evolutionarily ancient diencephalic and evolutionarily young telencephalic areas of the vertebrate brain as major systems triggering and maintaining the functional states of the body during the sleep-waking cycle.

Isolation and characterization of Malassezia spp. in healthy swine of different breeds

Malassezia spp. genus is represented by several lipophilic yeasts, normally present on the skin of many warm-blooded vertebrates, including man. Swine are one of the less investigated animal species. The aim of the present work was to study the occurrence of Malassezia spp. in the external ear canal of 408 healthy swine of different breeds, under different breeding conditions. For this purpose N. 185 free-ranging wild boars, N. 107 large size pigs and 116 Cinta Senese breed were selected. Animals were of both genders, with age ranging from 8 months to 4 years. The subjects were culturally and molecularly checked for Malassezia spp. Ninety-two out of 408 animals scored positive for Malassezia yeasts (22.5%). Malassezia pachydermatis, Malassezia sympodialis and Malassezia furfur were recognized. M. pachydermatis was the sole species isolated from wild boars (12.9%), Cinta Senese (20.7%) and juvenile large size pigs (13.6%); 88% of large size breeds adult subjects scored positive for M. sympodialis (63.6%) and M. furfur (22.7%), respectively. The study focus on scarcely investigated epidemiological aspects of Malassezia spp. in this animal species.

Dynamic positional fate map of the primary heart-forming region

Here we show the temporal–spatial orchestration of early heart morphogenesis at cellular level resolution, in vivo, and reconcile conflicting positional fate mapping data regarding the primary heart-forming field(s). We determined the positional fates of precardiac cells using a precision electroporation approach in combination with wide-field time-lapse microscopy in the quail embryo, a warm-blooded vertebrate (HH Stages 4 through 10). Contrary to previous studies, the results demonstrate the existence of a “continuous” circle-shaped heart field that spans the midline, appearing at HH Stage 4, which then expands to form a wide arc of progenitors at HH Stages 5–7. Our time-resolved image data show that a subset of these cardiac progenitor cells do not overlap with the expression of common cardiogenic factors, Nkx-2.5 and Bmp-2, until HH Stage 10, when a tubular heart has formed, calling into question when cardiac fate is specified and by which key factors. Sub-groups and anatomical bands (cohorts) of heart precursor cells dramatically change their relative positions in a process largely driven by endodermal folding and other large-scale tissue deformations. Thus, our novel dynamic positional fate maps resolve the origin of cardiac progenitor cells in amniotes. The data also establish the concept that tissue motion contributes significantly to cellular position fate — i.e., much of the cellular displacement that occurs during assembly of a midline heart tube (HH Stage 9) is NOT due to “migration” (autonomous motility), a commonly held belief. Computational analysis of our time-resolved data lays the foundation for more precise analyses of how cardiac gene regulatory networks correlate with early heart tissue morphogenesis in birds and mammals.

Forward Genetics in Toxoplasma gondii Reveals a Family of Rhoptry Kinases That Mediates Pathogenesis

Toxoplasma gondii is a widespread protozoan parasite that commonly infects domestic, wild, and companion animals (8). Like related tissue coccidians, T. gondii has a complex life cycle alternating between a sexual cycle, which occurs only within enterocytes of the small intestines of cats (all members of the Felidae appear to be susceptible), and asexual propagation in a variety of warm-blooded vertebrate hosts (8). The sexual phase culminates with fecal shedding of a spore-like stage called the oocyst, which is diploid and undergoes meiosis in the environment. During the asexual cycle, the parasite interconverts between a fast-growing lytic form known as the tacyhzoite and a slow-growing, semidormant form called the bradyzoite. Tachyzoites propagate rapidly in virtually all types of nucleated cells, including macrophages, while differentiation to bradyzoites is favored in long-lived, terminally differentiated host cells (49). Tachyzoites are adept at direct migration across cellular barriers and also disseminate rapidly within leukocytes, thereby reaching sites of immune privilege such as the central nervous system and the developing fetus, where they are more likely to cause disease (2). The life cycle shows remarkable flexibility between lytic and dormant states, thus facilitating asexual transmission between intermediate hosts. This adaptation may account for the recent spread and emergence of a few dominant clonal groups within North America and Europe (46). Toxoplasma is well adapted to mammalian hosts, being transmitted by ingestion of undercooked meat harboring tissue cysts and through food and water supplies contaminated with oocysts shed from cats (8). Humans are accidental hosts of T. gondii, yet seroprevalence rates indicate high rates of chronic infection in many countries of Europe and Central and South America (16). Infections are often mild or subclinical in healthy adults; however, toxoplasmosis can present as a clinically important infection in immunocompromised patients and the developing fetus (32). In many regions of the world, toxoplasmosis remains a frequent problem in patients infected with human immunodeficiency virus, due to lack of access to effective antiviral therapy (29). Additionally, in regions such as southern Brazil, ocular toxoplasmosis often presents as a clinically severe infection in otherwise healthy adults (18). Although T. gondii is primarily an opportunistic pathogen, it has emerged as a model for study of the biology of apicomplexan parasites, a group that contains Plasmodium spp. (malaria parasites), Cryptosporidium spp., and a variety of animal pathogens. Although the life cycles of these parasites differ substantially, they share common pathways for actin-myosin-based motility, calcium-dependent secretion, and active cell invasion (41). Toxoplasma offers excellent tools for studying molecular and cell biology, forward and reverse genetics, and animal models. Hence, exploration of the molecular basis of complex traits such as pathogenesis has been feasible in this system. This review summarizes recent advances using forward genetics to identify genes involved in pathogenesis, as well as the use of reverse genetics to validate the roles of prospective candidate genes.

Can GC Content at Third-Codon Positions Be Used as a Proxy for Isochore Composition?

The isochore theory depicts the genomes of warm-blooded vertebrates as a mosaic of long genomic regions that are characterized by relatively homogeneous GC content. In the absence of genomic data, the GC content at third-codon positions of protein-coding genes (GC3) was commonly used as a proxy for the GC content of isochores. Oddly, in the postgenomic era, GC3 is still sometimes used as a proxy for the GC composition of isochores. Here, we use genic and genomic sequences from human, chimpanzee, cow, mouse, rat, chicken, and zebrafish to show that GC3 only explains a very small proportion of the variation in GC content of long genomic sequences flanking the genes (GCf), and what little correlation there is between GC3 and GCf was found to decay rapidly with distance from the gene. The coefficient of variation of GC3 was found to be much larger than that of GCf and, therefore, GC3 and GCf values are not comparable with each other. Comparisons of orthologous gene pairs from 1) human and chimpanzee and 2) mouse and rat show strong correlations between their GC3 values, but very weak correlations between their GCf values. We conclude that the GC content of third-codon position cannot be used as stand-in for isochoric composition.

Biased amino acid composition in warm-blooded animals

AbstractAmong eubacteria and archeabacteria, amino acid composition is correlated with habitat temperatures. In particular, species living at high temperatures have proteins enriched in the amino acids E-R-K and depleted in D-N-Q-T-S-H-A. Here, we show that this bias is a proteome-wide effect in prokaryotes, and that the same trend is observed in fully sequenced mammals and chicken compared to cold-blooded vertebrates (Reptilia, Amphibia and fish). Thus, warm-blooded vertebrates likely experienced genome-wide weak positive selection on amino acid composition to increase protein thermostability.

Killing of Gram-Negative Bacteria with Normal Human Serum and Normal Bovine Serum: Use of Lysozyme and Complement Proteins in the Death of Salmonella Strains O48

Serum is an environment in which bacterial cells should not exist. The serum complement system provides innate defense against microbial infections. It consists of at least 35 proteins, mostly in pre-activated enzymatic forms. The activation of complement is achieved through three major pathways: the classical, alternative, and lectin. Lysozyme, widely present in body fluids, catalyzes the hydrolysis of beta 1,4 linkage between N-acetyloglucosamine and N-acetylmuramic acid in the bacterial cell wall and cooperates with the complement system in the bactericidal action of serum. In this study, ten strains of serotype O48 Salmonella, mainly associated with warm-blooded vertebrates and clinically important causing diarrhea in infants and children, were tested. The results demonstrated that the most efficient killing of Salmonella O48 occurred when all the components of normal bovine serum (NBS) and normal human serum (NHS) cooperated. To prove the role of lysozyme in the bactericidal activity of bovine and human serum, the method of serum adsorption onto bentonite (montmorillonite, MMT) was used. In order to investigate structural transitions accompanying the adsorption of serum components, we applied X-ray diffraction methods. The results of this investigation suggested that apart from lysozyme, other proteins (as, e.g., C3 protein or IgG immunoglobulin) were adsorbed on MMT particles. It was also shown that Ca(2+) cations can be adsorbed on bentonite. This may explain the different sensitivities of the serovars belonging to the same O48 Salmonella serotype to NBS and NHS devoid of lysozyme.

Regulation of Iron Homeostasis: Is It All in the HBD?

Regulation of Iron Homeostasis: Is It All in the HBD?

Subspecies IIIa and IIIb Salmonellae Are Defective for Colonization of Murine Models of Salmonellosis Compared to Salmonella enterica subsp. I Serovar Typhimurium

Non-subspecies I salmonellae are commensals of cold-blooded vertebrates and cause sporadic disease in mammals. The reasons why non-subspecies I salmonellae do not circulate in populations of warm-blooded vertebrates, but instead only cause occasional disease in this niche, are unknown. We examined the ability of Salmonella enterica subsp. IIIa (subsp. arizonae) and subsp. IIIb (subsp. diarizonae) isolates to grow competitively with subspecies I (serovar Typhimurium) ATCC 14028 in vitro, to colonize Salmonella-sensitive BALB/c mice, and to persist in the intestine of Salmonella-resistant CBA/J mice in competitive infections. Subspecies IIIa had severely reduced intestinal colonization, intestinal persistence, and systemic spread in mice. Subspecies IIIa is nonmotile on swarming agar and thus may also have reduced motility under viscous conditions in vivo. Surprisingly, subspecies IIIb colonizes the intestinal tract of BALB/c mice normally yet does not spread systemically. Subspecies IIIb colonization of the intestine of CBA/J mice is reduced late in infection. In order to understand why these isolates do not colonize systemic sites, we determined that subspecies IIIa and IIIb are not internalized well and do not replicate in J774-A.1 murine macrophages, despite normal adherence to these cells. We further show that selected effectors of both type III secretion systems 1 and 2 are secreted by subspecies IIIa and IIIb in vitro but that each of these isolates secretes a different combination of effectors. We outline the phenotypic differences between these subspecies and subspecies I and provide a possible explanation for the inability of these strains to spread systemically in murine models.

Bendiocarbamate Toxicity in the Chick Embryo

Carbamate pesticides generally possess low toxicity for warm-blooded vertebrates, but developmental data are scarce. We have therefore evaluated embryotoxicity of choline esterase inhibitor bendiocarbamate in the chick embryo. The pesticide was dissolved in 5% acetone in distilled water and a volume of 200 μl was administered over the embryo through membrana papyracea on embryonic days 2, 3, 4, 5, and 10. Sampling was performed on embryonic day 10, while the embryos treated on embryonic day 10 were sampled on embryonic day 17. The toxicity of bendiocarbamate was fairly low, and LD50 decreased with advancing development from 1 mg/ embryo on embryonic day 2 to 29 mg on embryonic day 5. Malformations in surviving embryos were observed rarely (< 3 %) and occurred in both control and experimental groups. There was a mild but statistically significant dose-dependent reduction in body weight, most pronounced in the treatment on embryonic days 5 and 10, but the maximum difference from controls was below 15 %. A small but not significant increase in the number of positive cells was observed in the eye, limb buds, and the central nervous system of embryos treated on embryonic days 3 and 4 and examined after supravital wholemount staining with Lysotracker Red for apoptosis. In agreement with previously published studies in other vertebrate animals, we conclude that bendiocarbamate does not possess significant toxicity in the avian embryo.

Compositional properties and thermal adaptation of 18S rRNA in vertebrates

In order to investigate the influence of temperature on the GC level of the paired sequences of ribosomal 18S RNAs in vertebrates, we have studied their base composition in cold- and warm-blooded vertebrates using a stem-by-stem comparison. We observed that a number of stems of 18S ribosomal RNAs (rRNAs) are variable among species and that the majority of such stems are GC richer in warm-blooded than in cold-blooded vertebrates. We also constructed the secondary structures of the 18S rRNAs of a polar fish, a marsupial, and a monotreme to compare them with those of temperate/tropical fishes and of eutherians, respectively. In these cases, differences similar to those already mentioned were found. We conclude that there is a correlation between stem stability and body temperature even within the relatively limited temperature range of vertebrates.

A novel rodent papillomavirus isolated from anogenital lesions in its natural host

In the present work we describe both the prevalence and the histopathologic features of a novel papillomavirus (referred as McPV2) that naturally infects the rodent Mastomys coucha. Viral DNA could be isolated not only from anogenital wart-like lesions but also from healthy tissues (e.g. liver, kidney, spleen and intestine) without apparent signs of infection. Our finding of a second papillomavirus infecting M. coucha, phylogenetically very distant from the previously known MnPV, reinforces the growing view of warm-blooded vertebrates as being hosts for a number of different papilloma virus types that are not necessarily closely related. The histological descriptions of McPV2-associated anogenital lesions provided here, together with earlier knowledge on MnPV-associated skin carcinogenesis, define M. coucha as an excellent system where the link between infection towards malignancy can be studied in molecular, histochemical and immunological terms in immunocompetent animals. The availability of such an in vivo model also offers the unique opportunity to address defined questions about prophylactic and therapeutic strategies against different papillomavirus infections in their natural host. To date, McPV2 is the first rodent papillomavirus found in anogenital lesions.

Characterization and phylogeny of two β-cytoskeletal actins fromHemibarbus mylodon(Cyprinidae, Cypriniformes), a threatened fish species in Korea

Complementary DNA and genomic sequences representing two different beta-actins were isolated from a threatened freshwater fish species Hemibarbus mylodon. The beta-actin 1 and 2 encoded an identical number of amino acids (375 aa), and shared 88.8 and 99.7% of identity at coding nucleotide and amino acid levels, respectively. Genomic open reading frame (ORF) sequences of both isoforms contained five translated exons interrupted by four introns with conserved GT/AG exon/intron boundary rule. Semi-quantitative RT-PCR showed that the two isoform mRNAs were ubiquitously detected in all tissues tested, but transcript levels were variable across tissues. Phylogenetic analysis showed that H. mylodon beta-actin 1 and 2 were clustered into two distinct major and minor branches of Cypriniformes, respectively. Comparisons of the 5'-upstream region and 3'-UTR of H. mylodon beta-actin 1 also showed a high degree of homology with those of the major teleost beta-actins and warmblooded vertebrate beta-cytoskeletal actins, suggesting their more recent common origin.

Correlations between coding and contiguous non-coding sequences in isochore families from vertebrate genomes

Many years ago compositional correlations were found to hold between coding and contiguous non-coding sequences. These correlations were essentially studied in whole genomes of mammals, which are characterized by strong compositional heterogeneities. Here we investigated whether these correlations also hold within the much more homogeneous isochore families. This point was checked not only in the case of mammals, but also in that of phylogenetically distant vertebrates, which are characterized by very different compositional patterns. Indeed, these are remarkably different in cold- and warm-blooded vertebrates. Fish genomes, for instance, are much more homogeneous than those of mammals and birds. The compositional correlations between coding sequences and the corresponding introns, or their 5′ and 3′ flanking regions, were studied in the isochore families of the fully sequenced genomes from four fishes ( Brachydanio rerio, Oryzias latipes, Gasterosteus aculeatus and Tetraodon nigroviridis), human and chicken.

Transient expression of LIM‐domain transcription factors is coincident with delayed maturation of photoreceptors in the chicken retina

In the retina of warm-blooded vertebrates, photoreceptors are specified many days before the onset of synaptogenesis and the expression of photopigments. The factors that regulate the maturation of photoreceptors in the developing retina remain unknown. We report here that photoreceptors transiently express LIM-domain transcription factors during the development of the chicken retina. We examined the differentiation of photoreceptors through the normal course of embryonic development and at the far periphery of the postnatal retina, where the differentiation of photoreceptors is slowed and persists across a spatial gradient. In the embryonic retina, we find visinin-positive photoreceptors that transiently express Islet2 and Lim3 starting at E8 and ending around E15, but persisting in far peripheral regions of the retina through the first 2 weeks of postnatal development. During early stages of photoreceptor maturation, there is coincident and transient expression of the LIM-domain factors with axonin1, a cell surface glycoprotein that is a member of the immunoglobulin superfamily. Coincident with the downregulation of Islet2 and Lim3, we find the upregulation of calbindin, red/green opsin, rhodopsin, and a synaptic marker in the outer plexiform layer (OPL; dystrophin). In the periphery of the postnatal retina, photoreceptors that express Islet2, Lim3, and axonin1 do not overlap with photoreceptors that express calbindin, red/green opsin, rhodopsin, and dystrophin. We propose that Islet2 and Lim3 may promote the expression of genes that are involved in the early stages of differentiation but may suppress the expression of genes that are required in the mature photoreceptors.

The neoselectionist theory of genome evolution.

The vertebrate genome is a mosaic of GC-poor and GC-rich isochores, megabase-sized DNA regions of fairly homogeneous base composition that differ in relative amount, gene density, gene expression, replication timing, and recombination frequency. At the emergence of warm-blooded vertebrates, the gene-rich, moderately GC-rich isochores of the cold-blooded ancestors underwent a GC increase. This increase was similar in mammals and birds and was maintained during the evolution of mammalian and avian orders. Neither the GC increase nor its conservation can be accounted for by the random fixation of neutral or nearly neutral single-nucleotide changes (i.e., the vast majority of nucleotide substitutions) or by a biased gene conversion process occurring at random genome locations. Both phenomena can be explained, however, by the neoselectionist theory of genome evolution that is presented here. This theory fully accepts Ohta's nearly neutral view of point mutations but proposes in addition (i) that the AT-biased mutational input present in vertebrates pushes some DNA regions below a certain GC threshold; (ii) that these lower GC levels cause regional changes in chromatin structure that lead to deleterious effects on replication and transcription; and (iii) that the carriers of these changes undergo negative (purifying) selection, the final result being a compositional conservation of the original isochore pattern in the surviving population. Negative selection may also largely explain the GC increase accompanying the emergence of warm-blooded vertebrates. In conclusion, the neoselectionist theory not only provides a solution to the neutralist/selectionist debate but also introduces an epigenomic component in genome evolution.

The power of size: A meta-analysis reveals consistency of allometric regressions

The recent revival of body size relationships in ecology has boosted our understanding of ecosystems. Here, a simple model, based on energy equivalency, integrates rate, age, density and area parameters that are important in ecological modelling. Allometric relationships for quantities as diverse as ingestion, mortality, age at maturity, maximum density, territory size of different species groups and trophic levels are derived from production and some ecological transfer efficiencies. The theory is supported by a meta-analysis of 230 allometric regressions derived from over 100 publications. The relationships are shown to be mutually consistent and fit into the model. Rate constants generally decrease with organism mass at an exponent of −1/4. Age and density parameters increase in the same direction following a slope of 1/4. Differences between plants, invertebrates, cold-blooded vertebrates and warm-blooded vertebrates are reflected in the intercepts and can be anticipated from temperature, trophic position and evolutionary history. Cold-blooded species have lower rate constants but reach higher ages and densities than equally sized warm-blooded organisms. Intercepts of body size distributions tend to decrease with trophic position, at a level that is predicted by ecological efficiencies. Area parameters, such as the territory size and geographic range, tend to decrease with species size, but slopes and intercepts were often different from the expected value. Occasionally, outliers were also noted for rate, time or density parameters. With the model at hand, such deviations can be easily identified and subjected to more extensive empirical and theoretical research. With these restrictions, specific issues can now be addressed by a framework that complies with extensive information on related parameters.