Reexamination of the morphological evidence for the cohort Epitheria (Mammalia,Eutheria)

Novacek and co-workers recognized a monophyletic clade Epitheria, comprising all eutherians except edentates and the extinct palaeoryctoids, on the basis of two synapomorphies: a stirrupshaped stapes and a foramen ovale enclosed within the alisphenoid. To evaluate this phylogenetic hypothesis, we reexamined the distributions of stapedial morphologies and positions of the foramen ovale across Recent and extinct mammals and nonmammalian cynodonts. The states and distributions of the stapes and forament ovale characters used by Novacek and coworkers were modified by recognizing two stapedial characters (one relating to shape of the crura, the other to the nature of the foramen) and a single, multistate foramen ovale character (within, behind, and lateral to the alisphenoid). The taxon-character matrix used by Novacek (1989, 1992b), substituting our amended stapedial and foramen ovale characters and adding several previously unscored extinct taxa and three new characters, was subjected to a series of PAUP manipulations. Identified among the most parsimonious trees were three major topologies for the base of Eutheria: (1) a polytomy including an Edentata/Ungulata clade, (2) a polytomy with Edentata and Ungulata as separate clades, and (3) Edentata and (when included) Palaeoryctoidea as the successive outgroups to a monophyletic Epitheria. We conclude that topology 2 best reflects the current state of knowledge. An edentate/ungulate clade is supported by three characters (from the mastoid region and subarcuate fossa); however, other morphological studies require modification of the distributions of these characters in xenarthrans and bassal ungulates, thereby eliminating support for this clade. In nearly all manipulations, obtaining a monophyletic Epitheria required that one or two steps be added to the most parsimonious trees. When a monophyletic Epitheria was obtained, it was supported by a triangular stapes and, in some trees, the reappearance of a stapedial artery (lost earlier at the level of Recent therians) and a transpromontorial internal carotid artery. In the most parsimonious trees, a foramen ovale within the alisphenoid was an equivocal synapomorphy of Recent therians or cutherians, and a stapes with strongly convex crura (our state closest to the stirrup-shaped state of Novacek and co-workers) appeared independently within various eutherian lineages. The reduction or loss of the stapedial foramen was identified as an independent event in monotremes and within marsupials and various eutherian lineages.To whom correspondence should be addressed.     

Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU

Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-β signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-β-signaling-deficient mice (Smad4^+/? and Smad4^+/?Sptbn1^+/?), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-β signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-β signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-β pathway in the treatment of CRC or other cancers.     

A traversodont cynodont from the Middle Triassic (Ladinian) of Baden-Württemberg (Germany)

Nanogomphodon wildi n. gen., n. sp. is based on a tiny lower postcanine tooth from the lower Lettenkeuper (Lower Keuper or Erfurt Formation; Ladinian) of Michelbach an der Bilz (Baden-Württemberg). It represents the first record of a traversodont cynodont from the Middle Triassic of Europe and exhibits a distinctive combination of dental features. Along with recent discoveries of other traversodont taxa from the Upper Triassic of eastern North America,Nanogomphodon indicates the existence of a distinct lineage of these cynodonts in the Northern Hemisphere.      

Synonymous codon usage pattern among the S,M, and L segments in Crimean-congo hemorrhagic fever virus

Crimean-Congo hemorrhagic fever (CCHF) virus is one among the major zoonosis viral diseases that use the Hyalomma ticks as their transmission vector to cause viral infection to the human and mammalian community. The fatality of infectious is high across the world especially in Africa, Asia, Middle East, and Europe. This study regarding codon usage bias of S, M, and L segments of the CCHF virus pertaining to the host Homo sapiens, reveals in-depth information about the evolutionary characteristics of CCHFV. Relative Synonymous Codon Usage (RSCU), Effective number of codons (ENC) were calculated, to determine the codon usage pattern in each segment. Correlation analysis between Codon adaptation index (CAI), GRAVY (Hydrophobicity), AROMO (Aromaticity), and nucleotide composition revealed bias in the codon usage pattern. There was no strong codon bias found among any segments of the CCHF virus, indicating both the factors i.e., natural selection and mutational pressure shapes the codon usage bias.     

S1P activates store-operated calcium entry via receptor- and non-receptor-mediated pathways in vascular smooth muscle cells

Sphingosine-1-phosphate (S1P) has been shown to modulate intracellular Ca(2+) through both G protein-coupled receptors and intracellular second messenger pathways. The precise mechanism by which S1P activates store-operated calcium entry (SOCE) in vascular smooth muscle cells (VSMCs) has not been fully characterized. Because sphingolipids and Ca(2+) modulate proliferation and constriction in VSMCs, characterizing the connection between S1P and SOCE may provide novel therapeutic targets for vascular diseases. We found that S1P triggered STIM1 puncta formation and SOCE in VSMCs. S1P-activated SOCE was inhibited by 2-aminoethoxydiphenyl borate (2-APB), diethylstilbestrol (DES), and gadolinium (Gd(3+)). SOCE was observed in VSMCs lacking either S1P(2) or S1P(3) receptors, suggesting that S1P acts via multiple signaling pathways. Indeed, both extracellular and intracellular S1P application increased the total internal reflection fluorescence signal in VSMCs cells transfected with STIM1-yellow fluorescent protein in a 2-APB-sensitive manner. These data, and the fact that 2-APB, DES, and Gd(3+) all inhibited S1P-induced cerebral artery constriction, suggest that SOCE modulates S1P-induced vasoconstriction in vivo. Finally, S1P-induced SOCE was larger in proliferative than in contractile VSMCs, correlating with increases in STIM1, Orai1, S1P(1), and S1P(3) receptor mRNA. These data demonstrate that S1P can act through both receptors and a novel intracellular pathway to activate SOCE. Because S1P-induced SOCE contributes to vessel constriction and is increased in proliferative VSMCs, it is likely that S1P/SOCE signaling in proliferative VSMCs may play a role in vascular dysfunction such as atherosclerosis and diabetes.     

Disease-causing Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator Determine the Functional Responses of Alveolar Macrophages

Alveolar macrophages (AMs) play a major role in host defense against microbial infections in the lung. To perform this function, these cells must ingest and destroy pathogens, generally in phagosomes, as well as secrete a number of products that signal other immune cells to respond. Recently, we demonstrated that murine alveolar macrophages employ the cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel as a determinant in lysosomal acidification (Di, A., Brown, M. E., Deriy, L. V., Li, C., Szeto, F. L., Chen, Y., Huang, P., Tong, J., Naren, A. P., Bindokas, V., Palfrey, H. C., and Nelson, D. J. (2006) Nat. Cell Biol. 8, 933–944). Lysosomes and phagosomes in murine cftr^−/− AMs failed to acidify, and the cells were deficient in bacterial killing compared with wild type controls. Cystic fibrosis is caused by mutations in CFTR and is characterized by chronic lung infections. The information about relationships between the CFTR genotype and the disease phenotype is scarce both on the organismal and cellular level. The most common disease-causing mutation, ΔF508, is found in 70% of patients with cystic fibrosis. The mutant protein fails to fold properly and is targeted for proteosomal degradation. G551D, the second most common mutation, causes loss of function of the protein at the plasma membrane. In this study, we have investigated the impact of CFTR ΔF508 and G551D on a set of core intracellular functions, including organellar acidification, granule secretion, and microbicidal activity in the AM. Utilizing primary AMs from wild type, cftr^−/−, as well as mutant mice, we show a tight correlation between CFTR genotype and levels of lysosomal acidification, bacterial killing, and agonist-induced secretory responses, all of which would be expected to contribute to a significant impact on microbial clearance in the lung.     

The approximate entropy of the electromyographic signals of tremor correlates with the osmotic fragility of human erythrocytes

Background  

The main problem of tremor is the damage caused to the quality of the life of patients, especially those at more advanced ages. There is not a consensus yet about the origins of this disorder, but it can be examined in the correlations between the biological signs of aging and the tremor characteristics.