Brief review of the stylophoran debate

The "calcichordate" theory interprets an extinct group of calcite-plated invertebrates, the stylophorans, as chordates. In this theory, cornute stylophorans are interpreted as stem chordates, whereas mitrate stylophorans are primitive members of the acraniates, tunicates, and craniates. However, this theory discounts major synapomorphies between cornutes and mitrates. These groups constitute a natural, monophyletic group which is here argued to lie within the echinoderm radiation. The "calcichordate" theory is, therefore, rejected because it relies on assumption-driven hypotheses of character transformation which are supported by ambiguous, poor, or missing fossil evidence. Stylophorans may lie at the base of the echinoderm clade and primitively lack pentameral symmetry, therefore casting light on the near-ancestral body organization of the phylum.     

A cladistic analysis of the cornutes (stem chordates)

At the root of the calcichordate controversy is the problem of recognizing homologous similarity. Only when a criterion or set of criteria for hypothesizing homologies is established can the calcichordate theory be tested against its main rival—the Stylophoran theory—by applying the principle of parsimony. The criterion of topological similarity is applied to a three-laxon problem involving a mitrate, the crown-group Echinodermata and the crown-group Chordata. The mitrate shares more features with extant chordates than with extant echinoderms and the calcichordate theory is supported by a simple parsimony analysis. In a cladistic analysis of the cornutes, four monophyletic families are recognized (Cothurnocystidae, Scotiaecystidae, Phyllocystidae and Hanusiidae) and their interrelationships resolved using Hennig86 and the successive-weighting procedure of Farris. Because the known fossil record of cornutes and mitrates is very poor, the correlation between the cladogram produced for cornutes and their order of appearance in the geological record is weak. All of the cornute families must have originated in the Lower Cambrian at the latest.     

A phylogenetic test of the calcichordate scenario

The calcichordate scenario of Jefferies and colleagues purports to explain the origin and early evolution of the phyla Echinodermata and Chordata. Calcichordate proponents have argued that echinoderms are the sister group of the chordates and urochordates are the sister group of the craniates. These phylogenetic hypotheses, which differ from the traditional groupings, are derived primarily from morphological interpretations of carpoids (solutes, cornutes, and mitrates), an enigmatic fossil group usually held to be primitive stem-group echinoderms. Although the scenario has received only limited support, it has yet to be falsified. The difficulty with falsifying the calcichordate scenario is proving that the morphological interpretations, for example, that carpoids possessed notochords, dorsal hollow nerve cords, and other typical chordate or craniate characters, are incorrect. Here, rather than argue over the interpretation of fossils, the phylogenetic hypotheses embedded within the scenario are tested. It is found that the calcichordate scenario fails such a test, even if both the Recent and fossils forms are coded according to the calcichordate scenario. It is argued that: (1) the erection of scenarios must follow the construction of a cladogram; and (2) fossils are unable to dictate the relationships among phyla. □ Calcichordate scenario, Carpoidea, Deuterostomia, Echinodermata, Chordata, phylogeny, cladistics.     

In defence of the calcichordates

The cornutes and mitrates, collectively known as stylophorans or calcichordates, are the most controversial members of the traditional group of the 'carpoid echinoderms'. In a recent review, Philip has rejected Ubaghs' interpretation of them as aberrant echinoderms with a single feeding arm, has also rejected my own interpretation of diem as primitive chordates, and has made some tentative proposals of his own. The present paper answers Philip's criticisms of the calcichordate interpretation and discusses his own proposals and his comments on Ubaghs' views.     

A new calcichordate from the Ordovician of Bohemia and its anatomy, adaptations and relationships

The paper describes a new member of a group of Lower Palaeozoic marine fossils which partly bridge the gap between echinoderms and chordates. Evidence suggests that this group included the ancestors of the vertebrates. Its members are traditionally regarded as primitive echinoderms, but are better seen as primitive chordates with echinoderm affinities. They form a basal subphylum of chordates-the Calcichordata Jefferies 1967. The Calcichordata, in accordance with an early suggestion by Gislén, are probably ancestral to all living chordates. The new calcichordate is named Reticulocarpos hanusi gen et sp. nov. It comes from the Lower Ordovician ?árka Formation (Llanvirn) of ?árka near Prague, Czechoslovakia and is placed in the family Amygdalothecidae Ubaghs 1970. It is important because of its position in the Calcichordata. This group is divided into two very different orders–the Cornuta and the Mitrata. The Cornuta are the more primitive order and gave rise to the Mitrata, which had the structure of giant, calcite-plated tunicate tadpoles. Many features show that the new species is a very advanced cornute, closely related to the stock that gave rise to the mitrates. For this reason it is important in the general history of the chordates, since some primitive mitrate was probably the latest common ancestor of the living chordate subphyla i.e. of tunicates, of amphioxus and its allies and of the vertebrates. Being a mitrate-like cornute, the new species allows the cornutes and mitrates to be compared more confidently than before. Four results are especially important. Firstly it is likely that the stem (=tail) of mitrates is equivalent only to the anterior part of the stem of cornutes. This is significant, because traditional views as to which was the upper surface in mitrates have been based on stem homologies now seen as false. Secondly Reticulocarpos hanusi is adapted to stay up on very soft mud, using only the strength of the mud for support. The mitrates, on the other hand, supported themselves on soft mud by a much more reliable method resembling buoyancy. Thirdly, the new form had paired transpharyngeal eyes which are otherwise known only in mitrates, and which are the earliest type of paired eyes in chordates. Fourthly, it becomes possible to homologize the thecal plates of cornutes with those of mitrates. Reticulocarpos hanusi represents an important phase in chordate evolution dominated by the necessity of staying up on mud by a very precarious method. During this phase many pre-adaptations for swimming were acquired. Primitive mitrates, descended from a very similar form, were probably the first chordates that could swim.     

Ichnological evidence on the behaviour of mitrates: two trails associated with the Devonian mitrate Rhenocystis

The mitrates are controversial marine Palaeozoic fossils, assigned either to the chordates or to the echinoderms. This paper describes two trails associated with the mitrate Rhenocystis from the Lower Devonian Hunsrück Slate, Bundenbach, Germany. They indicate that, just before death, the animals were moving tail-first with the flat dorsal surface of the head upward. This behaviour is consistent with the chordate theory of mitrates, rather than with either of the two current echinoderm interpretations.     

Functional Morphology of Stylophoran Echinoderms

The life orientation and mode of life of stylophorans are a subject of much ongoing debate. Examination of the ornamentation occurring both on the arm and theca in several cornutes and mitrates strongly supports the view that the life orientation was similar in all stylophorans and was ‘flat‐surface down’. The presence of an asymmetrical ornamentation adapted to hinder, or minimize, back slippage of the organism in all stylophorans gives strong support to their interpretation as mostly sessile organisms, feeding with the arm facing the current and the theca downstream. The examination of a wide array of thecal morphologies and sculpture patterns displayed by the various groups of cornutes and mitrates allows the identification of three main modes of life in stylophorans: (1) an epibenthic mode of life, with the theca as main anchor to the substrate (e.g. asymmetrical cornutes, Diamphidiocystis); (2) an epibenthic mode of life, with the arm as main anchor to the sediment (e.g. symmetrical cornutes, Peltocystis, primitive Mitrocystitida, some Kirkocystidae); (3) an infaunal mode of life, with the theca buried in a slightly inclined attitude (e.g. some Kirkocystidae, Mitrocystitida with cuesta‐shaped ribs). The partially buried mode of life of Lagynocystis is intermediate between 2 and 3.     

A calcichordate interpretation of the new mitrateeumitrocystella savilli from the ordovician of Morocco

A new mitrate (stem-group craniate sensuJefferies 1979) is described from the Ordovician (Llandeilo) of Morocco and an anatomical and functional interpretation on the basis of the calcichordate theory is given. It is characterized by its small size, marked asymmetry of the anterior part of the head, and extensive resorption of the skeleton.     

ICHNOLOGICAL INSIGHTS INTO MITRATE PALAEOBIOLOGY

Abstract:  Mitrates are a controversial group of extinct deuterostomes; there is little agreement over their affinities, functional morphology or even the orientation of their upper and lower surfaces. Four slabs of slate from the Lower Devonian Hunsrück Slate (Bundenbach, Germany) are here described, showing trace fossils ( Vadichnites transversus igen. et isp. nov.) associated with the mitrate Rhenocystis latipedunculata . These new findings clearly demonstrate that the mitrate appendage was used in locomotion and that this movement took place appendage-first. Such a functional interpretation suggests that mitrates were oriented with the flat body surface upwards in life and argues against a phylogenetic position in the echinoderm crown-group.     

Incidence of Central Diabetes Insipidus in Children Presenting with Polydipsia and Polyuria

Objective: Polydipsia and polyuria are common reasons for referral to the Pediatric Endocrine clinic. In the absence of hyperglycemia, diabetes insipidus (DI) should be considered. The objectives of the study were to determine the prevalence of central DI (CDI) in a group of children presenting for evaluation of polydipsia and polyuria, and to determine if predictive features were present in patients in whom the diagnosis of DI was made.Methods: The study was a retrospective chart review of children presenting to the endocrine clinic with complaints of polydipsia and polyuria over a 5-year period.Results: The charts of 41 patients (mean age 4.9 ± 3.7 years, 28 males) were reviewed. CDI was diagnosed in 8 (20%) children based on abnormal water deprivation test (WDT) results. All but one patient had abnormal magnetic resonance imaging (MRI) findings, the most common being pituitary stalk thickening. Children with DI were older (7.86 ± 4.40 vs. 4.18 ± 3.20 years, P = .01) and had a higher propensity for cold beverages intake and unusual water-seeking behaviors compared to those without DI. Baseline WDT also revealed higher serum sodium (Na) and osmolality.Conclusion: The incidence of CDI in children presenting with polydipsia and polyuria is low. Factors associated with higher likelihood of pathology include older age, propensity for cold beverage intake, and higher baseline serum Na and osmolality on a WDT.Abbreviations:BMI = body mass indexCDI = central diabetes insipidusDI = diabetes insipidusNa = sodiumWDT = water deprivation test     

Benzylidine indane-1,3-diones: As novel urease inhibitors; synthesis,in vitro,and in silico studies

Current study deals with the evaluation of indane-1,3-dione based compounds as new class of urease inhibitors. For that purpose, benzylidine indane-1,3-diones (1–30) were synthesized and fully characterized by different spectroscopic techniques including EI-MS, HREI-MS, ¹H, and ¹³C NMR. All synthetic molecules 1–30 were evaluated for urease inhibitory activity and showed good to moderate inhibitory potential within the range of (IC₅₀ = 11.60 ± 0.3–257.05 ± 0.7 µM) as compared to the standard acetohydroxamic acid (IC₅₀ = 27.0 ± 0.5 µM). Compound 1 (IC₅₀ = 11.60 ± 0.3 µM) was found to be most potent inhibitor amongst all derivatives. The key binding interactions of most active compounds within the enzyme pocket were evaluated through in silico studies.     

Indole acrylonitriles as potential anti-hyperglycemic agents: Synthesis, α-glucosidase inhibitory activity and molecular docking studies

One of the most prevailing metabolic disorder diabetes mellitus has become the global health issue that has to be addressed and cured. Different marketed drugs have been made available for the treatment of diabetes but there is still a need of introducing new therapeutic agents that are economical and have lesser or no side effects. The current study deals with the synthesis of indole acrylonitriles (3–23) and the evaluation of these compounds for their potential for α-glucosidase inhibition. The structures of these synthetic molecules were deduced by using different spectroscopic techniques. Acarbose (IC₅₀ = 2.91 ± 0.02 μM) was used as standard in this study and the synthetic molecules (3–23) have shown promising α-glucosidase inhibitory activity. Compounds 4, 8, 10, 11, 14, 18, and 21 displayed superior inhibition of α-glucosidase enzyme in the range of (IC₅₀ = 0.53 ± 0.01–1.36 ± 0.04 μM) as compared to the standard acarbose. Compound 10 (IC₅₀ = 0.53 ± 0.01 μM) was the most effective inhibitor of this library and displayed many folds enhanced activity in contrast to the standard. Molecular docking of synthetic compounds was performed to verify the binding interactions of ligand with the active site of enzyme. This study had identified a number of potential α-glucosidase inhibitors that can be used for further research to identify a potent therapeutic agent against diabetes.     

Differences in Bone Age Readings Between Pediatric Endocrinologists and Radiologists

Objective: Pediatric endocrinologists (PEs) have historically read their own bone age (BA) X-rays based on the belief that radiologists do not accurately interpret these tests. Whether there are significant differences in BA interpretations between these two groups has not been systematically explored. The objectives of the study were to compare BA readings performed by PEs and radiologists and determine whether clinical variables were associated with discrepancies in readings.Methods: A retrospective chart review of children presenting for initial evaluation of short stature (SS) or precocious puberty (PP) who had a BA X-ray completed was performed. Clinical variables analyzed included age, gender, ethnicity, Tanner stage, body mass index, reason for referral, radiologist location (Children's vs. outside hospital), and PE and radiologist BA readings using the Greulich and Pyle method.Results: Of 103 patients aged 9 ± 3.66 years, there was a discrepancy between the PE and radiologist readings on 70 images (68%). Discrepancy ranged from -1.5 to 3.5 years, with a mean of 4 ± 12 months. Patients referred for PP were more likely to have discrepant interpretations than those referred for SS (8.4 months vs. 0.8 months; P = .007). No differences were seen in interpretations between in-house radiologists and those at outside hospitals.Conclusion: Radiologists interpreted BAs differently than PEs in the majority of images. In patients referred for PP, BAs were interpreted as being older by radiologists than by PEs, perhaps due to bias from the reason for referral. Our results provide support for continued independent BA interpretations by PEs.Abbreviations: BA = bone age; GP = Greulich and Pyle; PE = pediatric endocrinologist; PP = precocious puberty; SS = short stature     

Syntheses,in vitro α-amylase and α-glucosidase dual inhibitory activities of 4-amino-1,2,4-triazole derivatives their molecular docking and kinetic studies

Thirty-three 4-amino-1,2,4-triazole derivatives 1–33 were synthesized by reacting 4-amino-1,2,4-triazole with a variety of benzaldehydes. The synthetic molecules were characterized via ¹H NMR and EI-MS spectroscopic techniques and evaluated for their anti-hyperglycemic potential. Compounds 1–33 exhibited good to moderate in vitro α-amylase and α-glucosidase inhibitory activities in the range of IC₅₀ values 2.01 ± 0.03–6.44 ± 0.16 and 2.09 ± 0.08–6.54 ± 0.10 µM as compared to the standard acarbose (IC₅₀ = 1.92 ± 0.17 µM) and (IC₅₀ = 1.99 ± 0.07 µM), respectively. The limited structure-activity relationship suggested that different substitutions on aryl part of the synthetic compounds are responsible for variable activity. Kinetic study predicted that compounds 1–33 followed mixed and non-competitive type of inhibitions against α-amylase and α-glucosidase enzymes, respectively. In silico studies revealed that both triazole and aryl ring along with different substitutions were playing an important role in the binding interactions of inhibitors within the enzyme pocket. The synthetic molecules were found to have dual inhibitory potential against both enzymes thus they may serve as lead candidates for the drug development and research in the future studies.     

Structures and biological activities of brominated azaphilones produced by Penicillium sclerotiorum E23Y–1A

Two new brominated azaphilones, 5-bromoisorotiorin (1) and penicilazaphilones H (2), along with a known azaphilone, 5-bromosclerotiorin (3) were isolated from the marine-derived fungus Penicillium sclerotiorum E23Y–1A cultivated on the solid rice medium with 3.3%NaBr. The structures of three compounds were elucidated based on 1D and 2D NMR spectra as well as HRESIMS data. Their absolute configurations were determined by ECD spectra analysis. Compounds 1-3 showed moderate antibacterial activities against Staphylococcus aureus ATCC 25923 with diameter of the inhibition zones of 8.08 ± 0.01, 7.50 ± 0.05 and 8.17 ± 0.05 mm, respectively, as well as compound 3 exhibited weak inhibitory activity against AChE.     

Genotype × region and genotype × production level interactions in Holstein cows

The identification of the presence of genotype by environment interaction effects on important traits in Holstein cattle allows for the use of international genetic evaluations and a more efficient design of regional genetic evaluation programmes. The aim of this study was to determine the genotype × environment interaction effects in Chilean Holstein dairy cattle through the analysis of records corresponding to calvings between 1998 and 2015. Herds were classified in the central and southern regions of Chile based on herd location as well as by high and low levels of production environments based on the fat plus protein yield averages per herd within each region. The central region has a Mediterranean climate and a confined production system while the southern region has a humid temperate climate and a production system based on grazing with supplementation. Traits studied were milk yield (MY), fat yield (FY), protein yield (PY), fat content (FC) and protein content (PC) by lactation, age at first calving (AFC) and calving interval (CI). Several four-trait mixed animal models were applied to environmental category data as different traits, which included herd-year-calving season (herd-year-birth season for AFC) and lactation number as fixed effects, and animal additive genetic, sire-herd, permanent environment and residual effects as random effects. Genetic correlations (r_g) for MY, FY, FC, PC and CI were found to decrease as differences between environmental categories increased. The r_g between the most extreme environmental categories considered in this study for AFC (0.26) was the only one found statistically lower than 0.60. Genetic correlation values statistically lower than 0.80 (P < 0.05) were observed for AFC, CI, MY, FY and PY between some environmental categories. If separate genetic evaluations are adopted as practical criteria when the value of r_g is lower than 0.60, the consequence of improving a multi-trait economic breeding objective in this population is likely to be small unless extreme environmental categories are considered. However, a moderate decrease in selection response and re-ranking of selection candidates is expected for AFC, CI and yield traits when selection is performed in different environmental conditions. Genotype × environment interaction effects involving production systems in a Mediterranean climate and confinement vs. Temperate Oceanic climate and grazing with supplementation, and between two fat plus protein yield level categories within each environment, were at most moderate for the studied traits.     

Four new species of musci from the andes of Ecuador and Colombia

Eobruchia ecuatoriana sp. nov. (Bruchiaceae) has the aspect of a diminutiveTrematodon, but is distinctive in having a mitrate calyptra and flexuous seta;Macromitrium perreflexum sp. nov. (Orthotrichaceae) has ramarkably reflexed leaves, unlike any known species;Lepidopilum pulcherrimum sp. nov. (Hookeriaceae) is distinguished by its large size and beautifully undulate leaves;Symphyodon americanus sp. nov. (Symphyodontaceae) is remarkable in being the first American representative of a genus and family previously known only from Asia; it is most closely related toS. echinatus (Mitt.) Jaeg. of the Himalayas and Thailand.     

Partial Hospitalization: An Intervention for Youth with Poorly Controlled Diabetes Mellitus

Objective: To examine the efficacy of an integrated medical/psychiatric partial hospitalization program (PHP) to improve glycemic control in youth with both diabetes mellitus and mental health disorders.Methods: This retrospective chart review is of patients admitted to a PHP between 2005–2015 with concerns about diabetes mellitus care. Clinical characteristics, laboratory data, diabetic ketoacidosis hospitalizations, and outpatient clinic visit frequency were collected from the year prior to the year after PHP admission.Results: A total of 43 individuals met inclusion criteria: 22 (51%) were female, 40 (93%) had type 1 diabetes, the mean age was 15.2 ± 2.3 years, and the mean diabetes mellitus duration was 4.6 ± 3.6 years. Of those individuals, 35 of these patients had hemoglobin A1c (HbA1c) data available at baseline, 6 months, and 1 year after PHP. The average HbA1c before PHP admission was 11.3 ± 2.3% (100.5 ± 25 mmol/mol), and decreased to 9.2 ± 1.3% (76.7 ± 14.8 mmol/mol) within 6 months of PHP admission (P<.001). The average HbA1c 1 year after PHP was 10.7 ± 1.7 % (93.3 ± 19.1 mmol/mol). Overall, 24 patients (68%) had lower HbA1c, and 75% of those with improvement maintained an HbA1c reduction of ≥1% (≥10 mmol/mol) at 1 year compared to before PHP.Conclusion: Most patients demonstrated improved glycemic control within 6 months of PHP admission, and many of those maintained a ≥1% (≥10 mmol/mol) reduction in HbA1c at 1 year following PHP admission. This program may represent a promising intervention that could serve as a model for intensive outpatient management of youth with poorly controlled diabetes mellitus.Abbreviations: ADA = American Diabetes Association; DKA = diabetic ketoacidosis; EMR = electronic medical record; HbA1c = hemoglobin A1c; ICD-9 = International Classification of Diseases, 9^th revision; PHP = partial hospitalization program     

VEGFR-2 inhibiting effect and molecular modeling of newly synthesized coumarin derivatives as anti-breast cancer agents

Twenty five newly synthesized coumarin scaffold based derivatives were assayed for their in vitro anticancer activity against MCF-7 breast and PC-3 prostate cancer cell lines and were further assessed for their in vitro VEGFR-2 kinase inhibitory activity. The in vitro cytotoxic studies revealed that most of the synthesized compounds possessed very promising cytotoxicity against MCF-7, particularly; compounds 4a (IC₅₀ = 1.24 µM) and 3d (IC₅₀ = 1.65 µM) exhibited exceptional activities superior to the positive control staurosporine (IC₅₀ = 8.81 µM). Similarly, the majority of the compounds exhibited higher antiproliferative activities compared to the reference standard with IC₅₀ values ranging from 2.07 to 8.68 µM. The two cytotoxic derivatives 4a and 3d were selected to evaluate their inhibitory potencies against VEGFR-2 kinase. Remarkably, compound 4a, exhibited significant IC₅₀ of 0.36 µM comparable to staurosporine (IC₅₀; 0.33 µM). Moreover, it was capable of inducing preG1 apoptosis, cell growth arrest at G2/M phase and activating caspase-9. On the other hand, insignificant cytotoxic activity was observed for all compounds towards PC-3 cell line. Molecular docking study was carried out for the most active anti-VEGFR-2 derivative 4a, which demonstrated the ability of the tested compound to interact with the key amino acids in the target VEGFR-2 kinase binding site. Additionally, the ADME parameters and physicochemical properties of compound 4a were examined in silico.     

Ultrasound assisted rapid synthesis of mefenamic acid based indole derivatives under ligand free Cu-catalysis: Their pharmacological evaluation

An improved and rapid synthesis of mefenamic acid based indole derivatives has been achieved via the ligand free Cu-catalyzed coupling-cyclization method under ultrasound irradiation. This simple, straightforward and inexpensive one-pot method involved the reaction of a terminal alkyne derived from mefenamic acid with 2-iodosulfanilides in the presence of CuI and K₂CO₃ in PEG-400. The reaction proceeded via an initial CC bond formation (the coupling step) followed by CN bond formation (the intramolecular cyclization) to afford the mefenamic acid based indole derivatives in good to acceptable yields. Several of these compounds showed inhibition of PDE4 in vitro and the SAR (Structure Activity Relationship) within the series is discussed. The compound 3d has been identified as a promising and selective inhibitor of PDE4B (IC₅₀ = 1.34 ± 0.46 µM) that showed TNF-α inhibition in vitro (IC₅₀ = 5.81 ± 0.24 µM) and acceptable stability in the rat liver microsomes.