An extinct north American porcupine with a South American tail.

New World porcupines (Erethizontinae) originated in South America and dispersed into North America as part of the Great American Biotic Interchange (GABI) 3-4 million years ago.1 Extant prehensile-tailed porcupines (Coendou) today live in tropical forests of Central and South America.2,3 In contrast, North American porcupines (Erethizon dorsatum) are thought to be ecologically adapted to higher-latitude temperate forests, with a larger body, shorter tail, and diet that includes bark.4,5,6,7 Limited fossils8,9,10,11,12,13 have hindered our understanding of the timing of this ecological differentiation relative to intercontinental dispersal during the GABI and expansion into temperate habitats.14,15,16,17,18 Here, we describe functionally important features of the skeleton of the extinct Erethizon poyeri, the oldest nearly complete porcupine skeleton documented from North America, found in the early Pleistocene of Florida. It differs from extant E. dorsatum in having a long, prehensile tail, grasping foot, and lacking dental specializations for bark gnawing, similar to tropical Coendou. Results from phylogenetic analysis suggest that the more arboreal characteristics found in E. poyeri are ancestral for erethizontines. Only after it expanded into temperate, Nearctic habitats did Erethizon acquire the characteristic features that it is known for today. When combined with molecular estimates of divergence times, results suggest that Erethizon was ecologically similar to a larger species of Coendou when it crossed the Isthmus of Panama by the early Pleistocene. It is likely that the range of this more tropically adapted form was limited to a continuous forested biome that extended from South America through the Gulf Coast.

Virtual endocast of late Paleocene Niptomomys (Microsyopidae, Euarchonta) and early primate brain evolution.

Paleogene microsyopid plesiadapiforms are among the oldest euarchontans known from relatively complete crania. While cranial endocasts are known for larger-bodied Eocene microsyopine microsyopids, this study documents the first virtual endocast for the more diminutive uintasoricine microsyopids, derived from a specimen of Niptomomys cf. Niptomomys doreenae (USNM 530198) from the late Paleocene of Wyoming. Size estimates of smaller-bodied uintasoricines are similar to those inferred for the common ancestor of Primates, so the virtual endocast of Niptomomys may provide a useful model to study early primate brain evolution. Due to the broken and telescoped nature of the neurocranium of USNM 530198, a µCT scan of the specimen was used to create a 3D model of multiple bone fragments that were then independently isolated, repositioned, and merged to form a cranial reconstruction from which a virtual endocast was extracted. The virtual endocast of Niptomomys has visible caudal colliculi, suggesting less caudal expansion of the cerebrum compared to that of euprimates, but similar to that of several other plesiadapiforms. The part of the endocast representing the olfactory bulbs is larger relative to overall endocast volume in Niptomomys (8.61%) than that of other known plesiadapiforms (∼5%) or euprimates (<3.5%). The petrosal lobules (associated with visual stabilization) are relatively large for a Paleocene placental mammal (1.66%). The encephalization quotient of Niptomomys is relatively high (range = 0.35-0.85) compared to that of Microsyops (range = 0.32-0.52), with the upper estimates in the range of values calculated for early euprimates. However, this contrast likely relates in part to the small size of the taxon, and is not associated with evidence of neocortical expansion. These findings are consistent with a model of shifting emphasis in primate evolution toward functions of the cerebrum and away from olfaction with the origin of euprimates.

[Reversal of direct oral anticoagulants: what about new treatments available?] / Réversibilité des anticoagulants oraux directs†: quid des nouveaux traitements disponibles†?

In cases of severe bleeding on direct oral anticoagulant (DOAC) therapy, several hemostatic agents can be used with varying levels of evidence, including fresh frozen plasma and prothrombin complex concentrates. Recently, we have seen the emergence of specific antidotes to DOAC, such as idarucizumab and andexanet alfa, effective on anti-II and anti-Xa DOAC respectively. These new molecules have shown excellent biological efficacy, hence supporting their use in clinical practice, however they are not routinely used, mainly due to limited availability and high cost. Ciraparantag, an antagonist of DOAC and heparins currently in phase III trials, could become a key molecule in the future considering encouraging preliminary results.

En cas d'hémorragie sévère sous traitement par un anticoagulant oral direct (ACOD), plusieurs agents hémostatiques peuvent être utilisés avec un niveau d'évidence variable, notamment le plasma frais congelé et les concentrés de complexe prothrombinique. Récemment, nous avons vu l'émergence d'antidotes spécifiques aux ACOD, comme l'idarucizumab et l'andexanet alfa, neutralisant les ACOD anti-II et anti-Xa respectivement. Ces nouvelles molécules ont montré une bonne efficacité biologique justifiant leur utilisation en pratique mais leur administration n'est pas encore systématique, en raison notamment d'une disponibilité restreinte et d'un coût élevé. Le ciraparantag, antagoniste des ACOD et des héparines, en cours d'étude de phase III, pourrait devenir une molécule clé à l'avenir au vu de résultats préliminaires encourageants.

Microevolutionary variation in molar morphology of Onychomys leucogaster decoupled from genetic structure.

In neutral models of quantitative trait evolution, both genetic and phenotypic divergence scale as random walks, producing a correlation between the two measures. However, complexity in the genotype-phenotype map may alter the correlation between genotypic and phenotypic divergence, even when both are evolving neutrally or nearly so. Understanding this correlation between phenotypic and genetic variation is critical for accurately interpreting the fossil record. This study compares the geographic structure and scaling of morphological variation of the shape of the first lower molar of 77 individuals of the northern grasshopper mouse Onychomys leucogaster to genome-wide SNP variation in the same sample. We found strong genetic structure but weak or absent morphological structure indicating that the scaling of each type of variation is decoupled from one another. Low PST values relative to FST values are consistent with a lack of morphological divergence in contrast to genetic divergence between groups. This lack of phenotypic structure and the presence of notable within-sample phenotypic variance are consistent with uniform selection or constraints on molar shape across a wide geographic and environmental range. Over time, this kind of decoupling may result in patterns of phenotypic stasis masking underlying genetic patterns.

Domestic cat embryos reveal unique transcriptomes of developing incisor, canine, and premolar teeth.

Division of the dentition into morphologically distinct classes of teeth (incisors, canines, premolars, and molars) and the acquisition of tribosphenic molars facilitated precise occlusion between the teeth early in mammal evolution. Despite the evolutionary and ecological importance of distinct classes of teeth with unique cusp, crest, and basin morphologies, relatively little is known about the genetic basis for the development of different tooth classes within the embryo. Here we investigated genetic differences between developing deciduous incisor, canine, and premolar teeth in the domestic cat (Felis catus), which we propose to be a new model for tooth development. We examined differences in both developmental timing and crown morphology between the three tooth classes. Using RNA sequencing of early bell stage tooth germs, we showed that each of the three deciduous tooth classes possess a unique transcriptional profile. Three notable groups of genes emerged from our differential expression analysis; genes involved in the extracellular matrix (ECM), Wnt pathway signaling, and members of multiple homeobox gene families (Lhx, Dlx, Alx, and Nkx). Our results suggest that ECM genes may play a previously under-appreciated role in shaping the surface of the tooth crown during development. Differential regulation of these genes likely underlies differences in tooth crown shape and size, although subtle temporal differences in development between the tooth germs could also be responsible. This study provides foundational data for future experiments to examine the function of these candidate genes in tooth development to directly test their potential effects on crown morphology.

Palaeoproteomics resolves sloth relationships.

The living tree sloths Choloepus and Bradypus are the only remaining members of Folivora, a major xenarthran radiation that occupied a wide range of habitats in many parts of the western hemisphere during the Cenozoic, including both continents and the West Indies. Ancient DNA evidence has played only a minor role in folivoran systematics, as most sloths lived in places not conducive to genomic preservation. Here we utilize collagen sequence information, both separately and in combination with published mitochondrial DNA evidence, to assess the relationships of tree sloths and their extinct relatives. Results from phylogenetic analysis of these datasets differ substantially from morphology-based concepts: Choloepus groups with Mylodontidae, not Megalonychidae; Bradypus and Megalonyx pair together as megatherioids, while monophyletic Antillean sloths may be sister to all other folivorans. Divergence estimates are consistent with fossil evidence for mid-Cenozoic presence of sloths in the West Indies and an early Miocene radiation in South America.

Skeletal morphology of the early Paleocene plesiadapiform Torrejonia wilsoni (Euarchonta, Palaechthonidae).

Plesiadapiforms, like other Paleogene mammals, are known mostly from fossil teeth and jaw fragments. The several families of plesiadapiforms known from partial skeletons have all been reconstructed as arborealists, but differences in postcranial morphology among these taxa indicate a diversity of positional behaviors. Here we provide the first detailed descriptions and comparisons of a dentally associated partial skeleton (NMMNH P-54500) and of the most complete dentary with anterior teeth (NMMNH P-71598) pertaining to Torrejonia wilsoni, from the early Paleocene (late Torrejonian To3 interval zone) of the Nacimiento Formation, San Juan Basin, New Mexico, USA. NMMNH P-54500 is the oldest known partial skeleton of a plesiadapiform and the only known postcrania for the Palaechthonidae. This skeleton includes craniodental fragments with all permanent teeth fully erupted, and partial forelimbs and hind limbs with some epiphyses unfused, indicating that this individual was a nearly fully-grown subadult. Analysis of the forelimb suggests mobile shoulder and elbow joints, a habitually flexed forearm, and capacity for manual grasping. The hip joint allowed abduction and lateral rotation of the thigh and provides evidence for frequent orthograde postures on large diameter supports. Other aspects of the hind limb suggest a habitually flexed thigh and knee with no evidence for specialized leaping, and mobile ankle joints capable of high degrees of inversion and eversion. Although it is likely that some variability exists within the group, analysis of this skeleton suggests that palaechthonids are most like paromomyids among plesiadapiforms, but retain more plesiomorphic postcranial features than has been documented for the Paromomyidae. These observations are congruent with craniodental evidence supporting palaechthonids and paromomyids as closely related within the Paromomyoidea. The skeleton of T. wilsoni also demonstrates that many regions of the postcranium were already well adapted for arboreality within the first few million years of the diversification of placental mammals following the Cretaceous-Paleogene extinction event.

New fossils, systematics, and biogeography of the oldest known crown primate Teilhardina from the earliest Eocene of Asia, Europe, and North America.

Omomyiform primates are among the most basal fossil haplorhines, with the oldest classified in the genus Teilhardina and known contemporaneously from Asia, Europe, and North America during the Paleocene-Eocene Thermal Maximum (PETM) ∼56 mya. Characterization of morphology in this genus has been limited by small sample sizes and fragmentary fossils. A new dental sample (n = 163) of the North American species Teilhardina brandti from PETM strata of the Bighorn Basin, Wyoming, documents previously unknown morphology and variation, prompting the need for a systematic revision of the genus. The P4 of T. brandti expresses a range of variation that encompasses that of the recently named, slightly younger North American species 'Teilhardina gingerichi,' which is here synonymized with T. brandti. A new partial dentary preserving the alveoli for P1-2 demonstrates that T. brandti variably expresses an unreduced, centrally-located P1, and in this regard is similar to that of T. asiatica from China. This observation, coupled with further documentation of variability in P1 alveolar size, position, and presence in the European type species T. belgica, indicates that the original diagnosis of T. asiatica is insufficient at distinguishing this species from either T. belgica or T. brandti. Likewise, the basal omomyiform 'Archicebus achilles' requires revision to be distinguished from Teilhardina. Results from a phylogenetic analysis of 1890 characters scored for omomyiforms, adapiforms, and other euarchontan mammals produces a novel clade including T. magnoliana, T. brandti, T. asiatica, and T. belgica to the exclusion of two species previously referred to Teilhardina, which are here classified in a new genus (Bownomomys americanus and Bownomomys crassidens). While hypotheses of relationships and inferred biogeographic patterns among species of Teilhardina could change with the discovery of more complete fossils, the results of these analyses indicate a similar probability that the genus originated in either Asia or North America.

Oldest evidence for grooming claws in euprimates.

Euprimates are unusual among mammals in having fingers and toes with flat nails. While it seems clear that the ancestral stock from which euprimates evolved had claw-bearing digits, the available fossil record has not yet contributed a detailed understanding of the transition from claws to nails. This study helps clarify the evolutionary history of the second pedal digit with fossils representing the distal phalanx of digit two (dpII), and has broader implications for other digits. Among extant primates, the keratinized structure on the pedal dpII widely varies in form. Extant strepsirrhines and tarsiers have narrow, distally tapering, dorsally inclined nails (termed a 'grooming claws' for their use in autogrooming), while extant anthropoids have more typical nails that are wider and lack distal tapering or dorsal inclination. At least two fossil primate species thought to be stem members of the Strepsirrhini appear to have had grooming claws, yet reconstructions of the ancestral euprimate condition based on direct evidence from the fossil record are ambiguous due to inadequate fossil evidence for the earliest haplorhines. Seven recently discovered, isolated distal phalanges from four early Eocene localities in Wyoming (USA) closely resemble those of the pedal dpII in extant prosimians. On the basis of faunal associations, size, and morphology, these specimens are recognized as the grooming phalanges of five genera of haplorhine primates, including one of the oldest known euprimates (∼56 Ma), Teilhardina brandti. Both the phylogenetic distribution and antiquity of primate grooming phalanges now strongly suggest that ancestral euprimates had grooming claws, that these structures were modified from a primitive claw rather than a flat nail, and that the evolutionary loss of 'grooming claws' represents an apomorphy for crown anthropoids.

Semi-supervised determination of pseudocryptic morphotypes using observer-free characterizations of anatomical alignment and shape.

Accurate, quantitative characterization of complex shapes is recognized as a key methodological challenge in biology. Recent development of automated three-dimensional geometric morphometric protocols (auto3dgm) provides a promising set of tools to help address this challenge. While auto3dgm has been shown to be useful in characterizing variation across clades of morphologically very distinct mammals, it has not been adequately tested in more problematic cases where pseudolandmark placement error potentially confounds interpretation of true shape variation. Here, we tested the sensitivity of auto3dgm to the degree of variation and various parameterization settings using a simulation and three microCT datasets that characterize mammal tooth crown morphology as biological examples. The microCT datasets vary in degree of apparent morphological differentiation, with two that include grossly similar morphospecies and one that includes two laboratory strains of a single species. Resulting alignments are highly sensitive to the number of pseudolandmarks used to quantify shapes. The degree to which the surfaces were downsampled and the apparent degree of morphological differentiation across the dataset also influenced alignment repeatability. We show that previous critiques of auto3dgm were based on poorly parameterized alignments and suggest that sample-specific sensitivity analyses should be added to any research protocol including auto3dgm. Auto3dgm is a useful tool for studying samples when pseudolandmark placement error is small relative to the true differences between specimens. This method therefore represents a promising avenue forward in morphometric studies at a wide range of scales, from samples that differ by a single genetic locus to samples that represent multiple phylogenetically diverse clades.

Oldest skeleton of a plesiadapiform provides additional evidence for an exclusively arboreal radiation of stem primates in the Palaeocene.

Palaechthonid plesiadapiforms from the Palaeocene of western North America have long been recognized as among the oldest and most primitive euarchontan mammals, a group that includes extant primates, colugos and treeshrews. Despite their relatively sparse fossil record, palaechthonids have played an important role in discussions surrounding adaptive scenarios for primate origins for nearly a half-century. Likewise, palaechthonids have been considered important for understanding relationships among plesiadapiforms, with members of the group proposed as plausible ancestors of Paromomyidae and Microsyopidae. Here, we describe a dentally associated partial skeleton of Torrejonia wilsoni from the early Palaeocene (approx. 62 Ma) of New Mexico, which is the oldest known plesiadapiform skeleton and the first postcranial elements recovered for a palaechthonid. Results from a cladistic analysis that includes new data from this skeleton suggest that palaechthonids are a paraphyletic group of stem primates, and that T. wilsoni is most closely related to paromomyids. New evidence from the appendicular skeleton of T. wilsoni fails to support an influential hypothesis based on inferences from craniodental morphology that palaechthonids were terrestrial. Instead, the postcranium of T. wilsoni indicates that it was similar to that of all other plesiadapiforms for which skeletons have been recovered in having distinct specializations consistent with arboreality.

The evolutionary radiation of plesiadapiforms.

Very shortly after the disappearance of the non-avian dinosaurs, the first mammals that had features similar to those of primates started appearing. These first primitive forms went on to spawn a rich diversity of plesiadapiforms, often referred to as archaic primates. Like many living primates, plesiadapiforms were small arboreal animals that generally ate fruit, insects, and, occasionally, leaves. However, this group lacked several diagnostic features of euprimates. They also had extraordinarily diverse specializations, represented in eleven families and more than 140 species, which, in some cases, were like nothing seen since in the primate order. Plesiadapiforms are known from all three Northern continents, with representatives that persisted until at least 37 million years ago. In this article we provide a summary of the incredible diversity of plesiadapiform morphology and adaptations, reviewing our knowledge of all eleven families. We also discuss the challenges that remain in our understanding of their ecology and evolution.

First virtual endocasts of adapiform primates.

Well-preserved crania of notharctine adapiforms from the Eocene of North America provide the best direct evidence available for inferring neuroanatomy and encephalization in early euprimates (crown primates). Virtual endocasts of the notharctines Notharctus tenebrosus (n = 3) and Smilodectes gracilis (n = 4) from the middle Eocene Bridger formation of Wyoming, and the late Eocene European adapid adapiform Adapis parisiensis (n = 1), were reconstructed from high-resolution X-ray computed tomography (CT) data. While the three species share many neuroanatomical similarities differentiating them from plesiadapiforms (stem primates) and extant euprimates, our sample of N. tenebrosus displays more variation than that of S. gracilis, possibly related to differences in the patterns of cranial sexual dimorphism or within-lineage evolution. Body masses predicted from associated teeth suggest that N. tenebrosus was larger and had a lower encephalization quotient (EQ) than S. gracilis, despite their close relationship and similar inferred ecologies. Meanwhile, body masses predicted from cranial length of the same specimens suggest that the two species were more similar, with overlapping body mass and EQ, although S. gracilis exhibits a range of EQs shifted upwards relative to that of N. tenebrosus. While associated data from other parts of the skeleton are mostly lacking for specimens included in this study, measurements for unassociated postcrania attributed to these species yield body mass and EQ estimates that are also more similar to each other than those based on teeth. Regardless of the body mass prediction method used, results suggest that the average EQ of adapiforms was similar to that of plesiadapiforms, only overlapped the lower quadrant for the range of extant strepsirrhines, and did not overlap with the range of extant haplorhines. However, structural changes evident in these endocasts suggest that early euprimates relied more on vision than olfaction relative to plesiadapiforms, despite having relatively small endocranial volumes compared to extant taxa.

Internal carotid arterial canal size and scaling in Euarchonta: Re-assessing implications for arterial patency and phylogenetic relationships in early fossil primates.

Primate species typically differ from other mammals in having bony canals that enclose the branches of the internal carotid artery (ICA) as they pass through the middle ear. The presence and relative size of these canals varies among major primate clades. As a result, differences in the anatomy of the canals for the promontorial and stapedial branches of the ICA have been cited as evidence of either haplorhine or strepsirrhine affinities among otherwise enigmatic early fossil euprimates. Here we use micro X-ray computed tomography to compile the largest quantitative dataset on ICA canal sizes. The data suggest greater variation of the ICA canals within some groups than has been previously appreciated. For example, Lepilemur and Avahi differ from most other lemuriforms in having a larger promontorial canal than stapedial canal. Furthermore, various lemurids are intraspecifically variable in relative canal size, with the promontorial canal being larger than the stapedial canal in some individuals but not others. In species where the promontorial artery supplies the brain with blood, the size of the promontorial canal is significantly correlated with endocranial volume (ECV). Among species with alternate routes of encephalic blood supply, the promontorial canal is highly reduced relative to ECV, and correlated with both ECV and cranium size. Ancestral state reconstructions incorporating data from fossils suggest that the last common ancestor of living primates had promontorial and stapedial canals that were similar to each other in size and large relative to ECV. We conclude that the plesiomorphic condition for crown primates is to have a patent promontorial artery supplying the brain and a patent stapedial artery for various non-encephalic structures. This inferred ancestral condition is exhibited by treeshrews and most early fossil euprimates, while extant primates exhibit reduction in one canal or another. The only early fossils deviating from this plesiomorphic condition are Adapis parisiensis with a reduced promontorial canal, and Rooneyia and Mahgarita with reduced stapedial canals.

Cranial anatomy of Paleogene Micromomyidae and implications for early primate evolution.

Paleogene micromomyids are small (∼10-40 g) euarchontan mammals with primate-like molars and postcrania suggestive of committed claw-climbing positional behaviors, similar to those of the extant arboreal treeshrew, Ptilocercus. Based primarily on evidence derived from dental and postcranial morphology, micromomyids have alternately been allied with plesiadapiforms, Dermoptera (colugos), or Primatomorpha (Primates + Dermoptera) within Euarchonta. Partial crania described here of Paleocene Dryomomys szalayi and Eocene Tinimomys graybulliensis from the Clarks Fork Basin of Wyoming are the first known for the family Micromomyidae. The cranium of D. szalayi exhibits a distinct, small groove near the lateral extreme of the promontorium, just medial to the fenestra vestibuli, the size of which suggests that the internal carotid artery was non-functional, as has been inferred for paromomyid and plesiadapid plesiadapiforms, but not for Eocene euprimates, carpolestids, and microsyopids. On the other hand, D. szalayi is similar to fossil euprimates and plesiadapoids in having a bullar morphology consistent with an origin that is at least partially petrosal, unlike that of paromomyids and microsyopids, although this interpretation will always be tentative in fossils that lack exhaustive ontogenetic data. Micromomyids differ from all other known plesiadapiforms in having an inflated cochlear part of the bony labyrinth and a highly pneumatized squamosal and mastoid region with associated septa. Cladistic analyses that include new cranial data, regardless of how bullar composition is coded in plesiadapiforms, fail to support either Primatomorpha or a close relationship between micromomyids and dermopterans, instead suggesting that micromomyids are among the most primitive known primates.

First North American fossil monkey and early Miocene tropical biotic interchange.

New World monkeys (platyrrhines) are a diverse part of modern tropical ecosystems in North and South America, yet their early evolutionary history in the tropics is largely unknown. Molecular divergence estimates suggest that primates arrived in tropical Central America, the southern-most extent of the North American landmass, with several dispersals from South America starting with the emergence of the Isthmus of Panama 3-4 million years ago (Ma). The complete absence of primate fossils from Central America has, however, limited our understanding of their history in the New World. Here we present the first description of a fossil monkey recovered from the North American landmass, the oldest known crown platyrrhine, from a precisely dated 20.9-Ma layer in the Las Cascadas Formation in the Panama Canal Basin, Panama. This discovery suggests that family-level diversification of extant New World monkeys occurred in the tropics, with new divergence estimates for Cebidae between 22 and 25 Ma, and provides the oldest fossil evidence for mammalian interchange between South and North America. The timing is consistent with recent tectonic reconstructions of a relatively narrow Central American Seaway in the early Miocene epoch, coincident with over-water dispersals inferred for many other groups of animals and plants. Discovery of an early Miocene primate in Panama provides evidence for a circum-Caribbean tropical distribution of New World monkeys by this time, with ocean barriers not wholly restricting their northward movements, requiring a complex set of ecological factors to explain their absence in well-sampled similarly aged localities at higher latitudes of North America.