The first species of Hapalodectes (Mesonychia,Mammalia) from the middle Paleocene of China (Qianshan Basin,Anhui Province) sheds light on the initial radiation of hapalodectids

A lower jaw of the mesonychian Hapalodectes is reported from Nongshanian sediments (Upper Doumu Formation; middle Paleocene) of the Qianshan Basin (Anhui Province, China). The fragmentary mandible is only the third specimen of Hapalodectidae discovered in Paleocene deposits, and the first in south east China; it is moreover the oldest, the two other specimens having been found in Gashatan (late Paleocene) localities. The premolars and molars of the new fossil are morphologically similar to Hapalodectes dux (late Paleocene of Mongolia), which has been considered to be the most primitive hapalodectid, but their relative proportions recall H. paleocenus and the Eocene Hapalodectes species. As a result, the fossil described herein appears to be different from the other previously described species of Hapalodectes in being morphologically intermediate between H. dux and the other Hapalodectes species, notably the Bumbanian Hapalodectes hetangensis and H. huanghaiensis from China; it is thus identified as a new species, Hapalodectes lopatini (possibly a male individual). Its discovery is important because it sheds light on the initial radiation of hapalodectids. The presence of one primitive hapalodectid in Mongolia previously suggested the Mongolian Plateau as the centre of origination of this carnivorous family, but the discovery of H. lopatini in older sediments from south‐east China challenges this hypothesis. In the earliest Eocene, Hapalodectes dispersed from Asia to North America; this event being part of the ‘East of Eden’ dispersals. This event resulted in the geographical separation of two distinct Hapalodectes groups, in North America and south‐eastern China respectively.     

Genetic regulation of fluxes: iron homeostasis of Escherichia coli

Iron is an essential trace-element for most organisms. However, because high concentration of free intracellular iron is cytotoxic, cells have developed complex regulatory networks that keep free intracellular iron concentration at optimal range, allowing the incorporation of the metal into iron-using enzymes and minimizing damage to the cell. We built a mathematical model of the network that controls iron uptake and usage in the bacterium Escherichia coli to explore the dynamics of iron flow. We simulate the effect of sudden decrease or increase in the extracellular iron level on intracellular iron distribution. Based on the results of simulations we discuss the possible roles of the small RNA RyhB and the Fe–S cluster assembly systems in the optimal redistribution of iron flows. We suggest that Fe–S cluster assembly is crucial to prevent the accumulation of toxic levels of free intracellular iron when the environment suddenly becomes iron rich.     

2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization

We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC₅₀ values as low as 19 nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFα production in peripheral human monocytes.     

The dynamics of parental care in Choughs(Pyrrhocorax pyrrhocorax)

Summary The dynamics of parental investment throughout the nestling stage and the factors affecting it were studied in the Chough(Pyrrhocorax pyrrhocorax), a species whose patterns of apportioning parental care are largely unknown. The occurrence of important trade-offs between the sexes, among the different activities of parental care and between parents' survival and current offspring survival were estimated. The parental contributions of both sexes were assessed mainly in terms of food provisioning rate and nest attendance time. Only the female brooded young nestlings while the two sexes contributed equally in food deliveries and nest sanitation. Nestling age greatly affected nest attendance time. The female spent a long time brooding in the first 10 days after hatching. Both sexes increased attendance towards the end of the nestling stage. Conversely, feeding rate and feeding rate per nestling remained approximately constant throughout the nestling period. Nestlings in smaller broods received more feeding visits than those in larger broods. The shape of the per-nestling feeding rate curve was concave-up, supporting Nur's (1984) trade-offs model rather than the Lack-Gibb hypothesis. Maintaining a high feeding frequency in broods already above the modal value might be disadvantageous, implying few benefits and large energy costs (i.e. the reduction of the parents' residual reproductive value). Female brooding time in relation to brood size showed the same decreasing concave-up trend line. Short-term trade-offs proved to be important determinants of the dynamics of parental care. Specifically, the distance from the feeding areas greatly affected the delivery rate: pairs spent a disproportionately longer time foraging in more distant patches than in closer ones. Diurnal variations and changes owing to weather conditions were also examined.

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Die Dynamik elterlicher Investition bei der Alpenkrähe(Pyrrhocorax pyrrhocorax)

Zusammenfassung Der elterliche Aufwand und die geschlechtliche Verteilung des Brutaufwandes bei Alpenkrähen ist weitgehend unbekannt. Ziel der Arbeit war es deshalb, die verschiedenen Aktivitäten der elterlichen Brutversorgung und deren Konsequenzen für die Überlebensverhältnisse der Eltern und des Nachwuchses näher zu untersuchen. Die Fütterung der Brut und die Anwesenheit und Betreuung am Nest standen im Mittelpunkt. Während nur das Weibchen brütete, teilten sich die Eltern die Jungenaufzucht und die Pflege des Nestes etwa gleichmäßig, wobei das Nestlingsalter einen erheblichen Einfluß auf die Nestversorgung hatte. In den ersten 10 Tagen huderte das Weibchen intensiv. Beide Eltern steigerten ihre Brutpflege zum Ende der Nestlingszeit. Dagegen blieben die Fütterungsrate und die Anzahl Fütterungen je Nestling über die gesamte Nestlingszeit in etwa konstant. Junge in kleineren Bruten erhielten mehr Fütterungen als solche in großen. Der Verlauf der Abhängigkeit der Fütterungen je Nestling von der Brutgröße stützt mehr die Hypothese von Nur (1984) als die von Lack und Gibb. Die Aufrechterhaltung einer hohen Fütterungsrate auch bei großen Bruten dürfte nachteilig sein, da sie nur wenig Nutzen bei einem hohen Aufwand (Beeinträchtigung der späteren Brutmöglichkeiten) bringt. Der Huderaufwand des Weibchens zeigt in etwa denselben Zusammenhang mit der Brutgröße. Kurzzeitige elterliche Entscheidungen scheinen eine wichtige Rolle in der Regulation der elterlichen Brutpflege zu spielen. Dabei kommt gerade der räumlichen Lage der Nahrungsplätze eine große Bedeutung zu: an weiter entfernt gelegenen Nahrungsplätzen verbrachten die Eltern unverhältnismäßig mehr Zeit als an nahen Futterplätzen. Daneben haben die Tageszeit und das Wetter einen Einfluß auf die elterliche Brutfürsorge der Alpenkrähen.

     

Maurocalcine and peptide A stabilize distinct subconductance states of ryanodine receptor type 1, revealing a proportional gating mechanism

Maurocalcine (MCa) isolated from Scorpio maurus palmatus venom shares 82% sequence identity with imperatoxin A. Both scorpion toxins are putative mimics of the II-III loop peptide (termed peptide A (pA)) of alpha(1s)-dihydropyridine receptor and are thought to act at a common site on ryanodine receptor type 1 (RyR1) important for skeletal muscle EC coupling. The relationship between the actions of synthetic MCa (sMCa) and pA on RyR1 were examined. sMCa released Ca(2+) from SR vesicles (EC(50) = 17.5 nm) in a manner inhibited by micromolar ryanodine or ruthenium red. pA (0.5-40 microm) failed to induce SR Ca(2+) release. Rather, pA enhanced Ca(2+) loading into SR and fully inhibited Ca(2+)-, caffeine-, and sMCa-induced Ca(2+) release. The two peptides modified single channel gating behavior in distinct ways. With Cs(+)-carrying current, 10 nm to 1 microm sMCa induced long lived subconductances having 48% of the characteristic full open state and occasional transitions to 29% at either positive or negative holding potentials. In contrast, pA stabilized long lived channel closures with occasional burst transitions to 65% (s1) and 86% (s2) of the full conductance. The actions of pA and sMCa were observed in tandem. sMCa stabilized additional subconductance states proportional to pA-induced subconductances (i.e. 43% of pA-modified s1 and s2 substates), revealing a proportional gating mechanism. [(3)H]Ryanodine binding and surface plasmon resonance analyses indicated that the peptides did not interact by simple competition for a single class of mutually exclusive sites on RyR1 to produce proportional gating. The actions of sMCa were also observed with ryanodine-modified channels and channels deficient in immunophilin 12-kDa FK506-binding protein. These results provide evidence that sMCa and pA stabilize distinct RyR1 channel states through distinct mechanisms that allosterically stabilize gating states having proportional conductance.     

MEPE-Derived ASARM Peptide Inhibits Odontogenic Differentiation of Dental Pulp Stem Cells and Impairs Mineralization in Tooth Models of X-Linked Hypophosphatemia

Mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X-chromosome) cause X-linked familial hypophosphatemic rickets (XLH), a disorder having severe bone and tooth dentin mineralization defects. The absence of functional PHEX leads to abnormal accumulation of ASARM (acidic serine- and aspartate-rich motif) peptide − a substrate for PHEX and a strong inhibitor of mineralization − derived from MEPE (matrix extracellular phosphoglycoprotein) and other matrix proteins. MEPE-derived ASARM peptide accumulates in tooth dentin of XLH patients where it may impair dentinogenesis. Here, we investigated the effects of ASARM peptides in vitro and in vivo on odontoblast differentiation and matrix mineralization. Dental pulp stem cells from human exfoliated deciduous teeth (SHEDs) were seeded into a 3D collagen scaffold, and induced towards odontogenic differentiation. Cultures were treated with synthetic ASARM peptides (phosphorylated and nonphosphorylated) derived from the human MEPE sequence. Phosphorylated ASARM peptide inhibited SHED differentiation in vitro, with no mineralized nodule formation, decreased odontoblast marker expression, and upregulated MEPE expression. Phosphorylated ASARM peptide implanted in a rat molar pulp injury model impaired reparative dentin formation and mineralization, with increased MEPE immunohistochemical staining. In conclusion, using complementary models to study tooth dentin defects observed in XLH, we demonstrate that the MEPE-derived ASARM peptide inhibits both odontogenic differentiation and matrix mineralization, while increasing MEPE expression. These results contribute to a partial mechanistic explanation of XLH pathogenesis: direct inhibition of mineralization by ASARM peptide leads to the mineralization defects in XLH teeth. This process appears to be positively reinforced by the increased MEPE expression induced by ASARM. The MEPE-ASARM system can therefore be considered as a potential therapeutic target.     

Active-Site Monovalent Cations Revealed in a 1.55-Å-Resolution Hammerhead Ribozyme Structure

We have obtained a 1.55-Å crystal structure of a hammerhead ribozyme derived from Schistosoma mansoni under conditions that permit detailed observations of Na⁺ ion binding in the ribozyme's active site. At least two such Na⁺ ions are observed. The first Na⁺ ion binds to the N7 of G10.1 and the adjacent A9 phosphate in a manner identical with that previously observed for divalent cations. A second Na⁺ ion binds to the Hoogsteen face of G12, the general base in the hammerhead cleavage reaction, thereby potentially dissipating the negative charge of the catalytically active enolate form of the nucleotide base. A potential but more ambiguous third site bridges the A9 and scissile phosphates in a manner consistent with that of previous predictions. Hammerhead ribozymes have been observed to be active in the presence of high concentrations of monovalent cations, including Na⁺, but the mechanism by which monovalent cations substitute for divalent cations in hammerhead catalysis remains unclear. Our results enable us to suggest that Na⁺ directly and specifically substitutes for divalent cations in the hammerhead active site. The detailed geometry of the pre-catalytic active-site complex is also revealed with a new level of precision, thanks to the quality of the electron density maps obtained from what is currently the highest-resolution ribozyme structure in the Protein Data Bank.     

Phororhacoidea or Phorusrhacoidea? A note on the nomenclature of the “terror birds”

The Phorusrhacidae, a group of large terrestrial carnivorous birds mostly known from the Cenozoic of South America, are often placed in a superfamily, for which the taxon name Phororhacoidea Patterson, 1941 is frequently used. However, according to the International Code of Zoological Nomenclature, Phororhacoidea is not valid. The proper taxon name at the superfamily level is Phorusrhacoidea Ameghino, 1889.     

LTR-Retrotransposons in R. exoculata and Other Crustaceans: The Outstanding Success of GalEa-Like Copia Elements

Transposable elements are major constituents of eukaryote genomes and have a great impact on genome structure and stability. They can contribute to the genetic diversity and evolution of organisms. Knowledge of their distribution among several genomes is an essential condition to study their dynamics and to better understand their role in species evolution. LTR-retrotransposons have been reported in many diverse eukaryote species, describing a ubiquitous distribution. Given their abundance, diversity and their extended ranges in C-values, environment and life styles, crustaceans are a great taxon to investigate the genomic component of adaptation and its possible relationships with TEs. However, crustaceans have been greatly underrepresented in transposable element studies. Using both degenerate PCR and in silico approaches, we have identified 35 Copia and 46 Gypsy families in 15 and 18 crustacean species, respectively. In particular, we characterized several full-length elements from the shrimp Rimicaris exoculata that is listed as a model organism from hydrothermal vents. Phylogenic analyses show that Copia and Gypsy retrotransposons likely present two opposite dynamics within crustaceans. The Gypsy elements appear relatively frequent and diverse whereas Copia are much more homogeneous, as 29 of them belong to the single GalEa clade, and species- or lineage-dependent. Our results also support the hypothesis of the Copia retrotransposon scarcity in metazoans compared to Gypsy elements. In such a context, the GalEa-like elements present an outstanding wide distribution among eukaryotes, from fishes to red algae, and can be even highly predominant within a large taxon, such as Malacostraca. Their distribution among crustaceans suggests a dynamics that follows a “domino days spreading” branching process in which successive amplifications may interact positively.