The virtual brain endocast of Trogosus (Mammalia, Tillodontia) and its relevance in understanding the extinction of archaic placental mammals.

After successfully diversifying during the Paleocene, the descendants of the first wave of mammals that survived the end-Cretaceous mass extinction waned throughout the Eocene. Competition with modern crown clades and intense climate fluctuations may have been part of the factors leading to the extinction of these archaic groups. Why these taxa went extinct has rarely been studied from the perspective of the nervous system. Here, we describe the first virtual endocasts for the archaic order Tillodontia. Three species from the middle Eocene of North America were analyzed: Trogosus hillsii, Trogosus grangeri, and Trogosus castoridens. We made morphological comparisons with the plaster endocast of another tillodont, Tillodon fodiens, as well as groups potentially related to Tillodontia: Pantodonta, Arctocyonidae, and Cimolesta. Trogosus shows very little inter-specific variation with the only potential difference being related to the fusion of the optic canal and sphenorbital fissure. Many ancestral features are displayed by Trogosus, including an exposed midbrain, small neocortex, orbitotemporal canal ventral to rhinal fissure, and a broad circular fissure. Potential characteristics that could unite Tillodontia with Pantodonta, and Arctocyonidae are the posterior position of cranial nerve V3 exit in relation to the cerebrum and the low degree of development of the subarcuate fossa. The presence of large olfactory bulbs and a relatively small neocortex are consistent with a terrestrial lifestyle. A relatively small neocortex may have put Trogosus at risk when competing with artiodactyls for potentially similar resources and avoiding predation from archaic carnivorans, both of which are known to have had larger relative brain and neocortex sizes in the Eocene. These factors may have possibly exacerbated the extinction of Tillodontia, which showed highly specialized morphologies despite the increase in climate fluctuations throughout the Eocene, before disappearing during the middle Eocene.

The origin of placental mammal life histories.

After the end-Cretaceous extinction, placental mammals quickly diversified1, occupied key ecological niches2,3 and increased in size4,5, but this last was not true of other therians6. The uniquely extended gestation of placental young7 may have factored into their success and size increase8, but reproduction style in early placentals remains unknown. Here we present the earliest record of a placental life history using palaeohistology and geochemistry, in a 62 million-year-old pantodont, the clade including the first mammals to achieve truly large body sizes. We extend the application of dental trace element mapping9,10 by 60 million years, identifying chemical markers of birth and weaning, and calibrate these to a daily record of growth in the dentition. A long gestation (approximately 7 months), rapid dental development and short suckling interval (approximately 30-75 days) show that Pantolambda bathmodon was highly precocial, unlike non-placental mammals and known Mesozoic precursors. These results demonstrate that P. bathmodon reproduced like a placental and lived at a fast pace for its body size. Assuming that P. bathmodon reflects close placental relatives, our findings suggest that the ability to produce well-developed, precocial young was established early in placental evolution, and that larger neonate sizes were a possible mechanism for rapid size increase in early placentals.

Brawn before brains in placental mammals after the end-Cretaceous extinction.

Mammals are the most encephalized vertebrates, with the largest brains relative to body size. Placental mammals have particularly enlarged brains, with expanded neocortices for sensory integration, the origins of which are unclear. We used computed tomography scans of newly discovered Paleocene fossils to show that contrary to the convention that mammal brains have steadily enlarged over time, early placentals initially decreased their relative brain sizes because body mass increased at a faster rate. Later in the Eocene, multiple crown lineages independently acquired highly encephalized brains through marked growth in sensory regions. We argue that the placental radiation initially emphasized increases in body size as extinction survivors filled vacant niches. Brains eventually became larger as ecosystems saturated and competition intensified.

Petrosal Anatomy of the Paleocene Eutherian Mammal Deltatherium fundaminis (Cope, 1881).

We describe the tympanic anatomy of the petrosal of Deltatherium fundaminis, an enigmatic Paleocene mammal based on cranial specimens recovered from New Mexico, U.S.A. Although the ear region of Deltatherium has previously been described, there has not been a comprehensive, well-illustrated contribution using current anatomical terminology. The dental and cranial anatomy of Deltatherium is a chimera, with morphological similarities to both 'condylarth' and 'cimolestan' taxa. As such, the phylogenetic relationships of this taxon have remained elusive since its discovery, and it has variably been associated with Arctocyonidae, Pantodonta and Tillodontia. The petrosal of Deltatherium is anteriorly bordered by an open space comprising a contiguous carotid opening and pyriform fenestra. The promontorium features both a small rostral tympanic process and small epitympanic wing but lacks well-marked sulci. A large ventral facing external aperture of the canaliculus cochleae is present and bordered posteriorly by a well-developed caudal tympanic process. The hiatus Fallopii opens on the ventral surface of the petrosal. The tegmen tympani is mediolaterally broad and anteriorly expanded, and its anterior margin is perforated by a foramen for the ramus superior of the stapedial artery. The tympanohyal is small but approximates the caudal tympanic process to nearly enclose the stylomastoid notch. The mastoid is widely exposed on the basicranium and bears an enlarged mastoid process, separate from the paraoccipital process. These new observations provide novel anatomical data corroborating previous hypotheses regarding the plesiomorphic eutherian condition but also reveal subtle differences among Paleocene eutherians that have the potential to help inform the phylogeny of Deltatherium. Supplementary Information: The online version contains supplementary material available at 10.1007/s10914-021-09568-3.

Quantitative assessment of tarsal morphology illuminates locomotor behaviour in Palaeocene mammals following the end-Cretaceous mass extinction.

Mammals exhibit vast ecological diversity, including a panoply of locomotor behaviours. The foundations of this diversity were established in the Mesozoic, but it was only after the end-Cretaceous mass extinction that mammals began to increase in body size, diversify into many new species and establish the extant orders. Little is known about the palaeobiology of the mammals that diversified immediately after the extinction during the Palaeocene, which are often perceived as 'archaic' precursors to extant orders. Here, we investigate the locomotor ecology of Palaeocene mammals using multivariate and disparity analyses. We show that tarsal measurements can be used to infer locomotor mode in extant mammals, and then demonstrate that Palaeocene mammals occupy distinctive regions of tarsal morphospace relative to Cretaceous and extant therian mammals, that is distinguished by their morphological robustness. We find that many Palaeocene species exhibit tarsal morphologies most comparable with morphologies of extant ground-dwelling mammals. Disparity analyses indicate that Palaeocene mammals attained similar morphospace diversity to the extant sample. Our results show that mammals underwent a post-extinction adaptive radiation in tarsal morphology relating to locomotor behaviour by combining a basic eutherian bauplan with anatomical specializations to attain considerable ecomorphological diversity.

A monotreme-like auditory apparatus in a Middle Jurassic haramiyidan.

Among extant vertebrates, mammals are distinguished by having a chain of three auditory ossicles (the malleus, incus and stapes) that transduce sound waves and promote an increased range of audible-especially high-frequencies1. By contrast, the homologous bones in early fossil mammals and relatives also functioned in chewing through their bony attachments to the lower jaw2. Recent discoveries of well-preserved Mesozoic mammals have provided glimpses into the transition from the dual (masticatory and auditory) to the single auditory function for the ossicles, which is now widely accepted to have occurred at least three times in mammal evolution3-6. Here we report a skull and postcranium that we refer to the haramiyidan Vilevolodon diplomylos (dating to the Middle Jurassic epoch (160 million years ago)) and that shows excellent preservation of the malleus, incus and ectotympanic (which supports the tympanic membrane). After comparing this fossil with other Mesozoic and extant mammals, we propose that the overlapping incudomallear articulation found in this and other Mesozoic fossils, in extant monotremes and in early ontogeny in extant marsupials and placentals is a morphology that evolved in several groups of mammals in the transition from the dual to the single function for the ossicles.

Virtual endocranial and inner ear endocasts of the Paleocene 'condylarth' Chriacus: new insight into the neurosensory system and evolution of early placental mammals.

The end-Cretaceous mass extinction allowed placental mammals to diversify ecologically and taxonomically as they filled ecological niches once occupied by non-avian dinosaurs and more basal mammals. Little is known, however, about how the neurosensory systems of mammals changed after the extinction, and what role these systems played in mammalian diversification. We here use high-resolution computed tomography (CT) scanning to describe the endocranial and inner ear endocasts of two species, Chriacus pelvidens and Chriacus baldwini, which belong to a cluster of 'archaic' placental mammals called 'arctocyonid condylarths' that thrived during the ca. 10 million years after the extinction (the Paleocene Epoch), but whose relationships to extant placentals are poorly understood. The endocasts provide new insight into the paleobiology of the long-mysterious 'arctocyonids', and suggest that Chriacus was an animal with an encephalization quotient (EQ) range of 0.12-0.41, which probably relied more on its sense of smell than vision, because the olfactory bulbs are proportionally large but the neocortex and petrosal lobules are less developed. Agility scores, estimated from the dimensions of the semicircular canals of the inner ear, indicate that Chriacus was slow to moderately agile, and its hearing capabilities, estimated from cochlear dimensions, suggest similarities with the extant aardvark. Chriacus shares many brain features with other Paleocene mammals, such as a small lissencephalic brain, large olfactory bulbs and small petrosal lobules, which are likely plesiomorphic for Placentalia. The inner ear of Chriacus also shares derived characteristics of the elliptical and spherical recesses with extinct species that belong to Euungulata, the extant placental group that includes artiodactyls and perissodactyls. This lends key evidence to the hypothesized close relationship between Chriacus and the extant ungulate groups, and demonstrates that neurosensory features can provide important insight into both the paleobiology and relationships of early placental mammals.

The Brain and Inner Ear of the Early Paleocene "Condylarth" Carsioptychus coarctatus: Implications for Early Placental Mammal Neurosensory Biology and Behavior.

Mammals underwent a profound diversification after the end-Cretaceous mass extinction, with placentals rapidly expanding in body size and diversity to fill new niches vacated by dinosaurs. Little is known, however, about the brains and senses of these earliest placentals, and how neurosensory features may have promoted their survival and diversification. We here use computed tomography (CT) to describe the brain, inner ear, sinuses, and endocranial nerves and vessels of Carsioptychus coarctatus, a periptychid "condylarth" that was among the first placentals to blossom during the few million years after the extinction, in the Paleocene. Carsioptychus has a generally primitive brain and inner ear that is similar to the inferred ancestral eutherian/placental condition. Notable "primitive" features include the large, anteriorly expanded, and conjoined olfactory bulbs, proportionally small neocortex, lissencephalic cerebrum, and large hindbrain compared to the cerebrum. An encephalization quotient (EQ) cannot be confidently calculated because of specimen crushing but was likely very small, and comparisons with other extinct placentals reveal that many Paleocene "archaic" mammals had EQ values below the hallmark threshold of modern placentals but within the zone of nonmammalian cynodonts, indicative of small brains and low intelligence. Carsioptychus did, however, have a "conventional" hearing range for a placental, but was not particularly agile, with semicircular canal dimensions similar to modern pigs. This information fleshes out the biology of a keystone Paleocene "archaic" placental, but more comparative work is needed to test hypotheses of how neurosensory evolution was related to the placental radiation. Anat Rec, 302:306-324, 2019. © 2018 Wiley Periodicals, Inc.

The osteology of Periptychus carinidens: A robust, ungulate-like placental mammal (Mammalia: Periptychidae) from the Paleocene of North America.

Periptychus is the archetypal genus of Periptychidae, a clade of prolific Paleocene 'condylarth' mammals from North America that were among the first placental mammals to radiate after the end-Cretaceous extinction, remarkable for their distinctive dental anatomy. A comprehensive understanding of the anatomy of Periptychus has been hindered by a lack of cranial and postcranial material and only cursory description of existing material. We comprehensively describe the cranial, dental and postcranial anatomy of Periptychus carinidens based on new fossil material from the early Paleocene (Torrejonian) of New Mexico, USA. The cranial anatomy of Periptychus is broadly concurrent with the inferred plesiomorphic eutherian condition, albeit more robust in overall construction. The rostrum is moderately elongate with no constriction, the facial region is broad, and the braincase is small with a well-exposed mastoid on the posterolateral corner and tall sagittal and nuchal crests. The dentition of Periptychus is characterized by strongly crenulated enamel, enlarged upper and lower premolars with a tall centralised paracone/protoconid. The postcranial skeleton of Periptychus is that of a robust, medium-sized (~20 Kg) stout-limbed animal that was incipiently mediportal and adopted a plantigrade stance. The structure of the fore- and hindlimb of Periptychus corresponds to that of a typically terrestrial mammal, while morphological features of the forelimb such as the low tubercles of the humerus, long and prominent deltopectoral crest, pronounced medial epicondyle, and hemispherical capitulum indicate some scansorial and/or fossorial ability. Most striking is the strongly dorsoplantarly compressed astragalus of Periptychus, which in combination with the distal crus and calcaneal morphology indicates a moderately mobile cruropedal joint. The anatomy of Periptychus is unique and lacks any extant analogue; it combines a basic early placental body plan with numerous unique specializations in its dental, cranial and postcranial anatomy that exemplify the ability of mammals to adapt and evolve following catastrophic environmental upheaval.

A Digital Endocranial Cast of the Early Paleocene (Puercan) 'Archaic' Mammal Onychodectes tisonensis (Eutheria: Taeniodonta).

Eutherian mammals-placentals and their closest extinct relatives-underwent a major radiation following the end-Cretaceous extinction, during which they evolved disparate anatomy and established new terrestrial ecosystems. Much about the timing, pace, and causes of this radiation remain unclear, in large part because we still know very little about the anatomy, phylogenetic relationships, and biology of the so-called 'archaic' eutherians that prospered during the ~10 million years after the extinction. We describe the first digital endocranial cast of a taeniodont, a bizarre group of eutherians that flourished in the early Paleogene, reconstructed from a computed tomography (CT) scan of a late Puercan (65.4 million year old) specimen of Onychodectes tisonensis that recovered most of the forebrain and midbrain and portions of the inner ear. Notable features of the endocast include long, broad olfactory bulbs, dorsally-positioned rhinal fissures, and a lissencephalic cerebrum. Comparison with other taxa shows that Onychodectes possessed some of the largest olfactory bulbs (relative to cerebral size) of any known mammal. Statistical analysis of modern mammals shows that relative olfactory bulb dimensions are not strongly correlated with body size or fossorial digging for shelter, but relative bulb width is significantly greater in taxa that habitually dig to forage for food. The anatomical description and statistical results allow us to present an ecological model for Onychodectes and similar taeniodonts, in which they are animals of simple behavior that rely on a strong sense of smell to locate buried food before extracting and processing it with their specialized skeletal anatomy.

The effect of nateglinide taken with food on gastric emptying rates in healthy subjects.

OBJECTIVES: The aim of this study was to determine the effect of the timing of food intake on the pharmacokinetics and pharmacodynamics of oral nateglinide 60 mg and the effect of nateglinide on the rate of gastric emptying. METHODS: A randomized, double-blind, placebo-controlled, single-dose, 6-period, crossover study conducted in healthy male volunteers aged 18 to 50 years. On 5 occasions, subjects received a single 60-mg tablet of nateglinide at -30, -10, -5, -1, or 40 minutes from the start of a standard metal. Treatment blind was maintained by administration of placebo tablets at all other time points. On the sixth occasion, subjects received placebo tablets at all dosing time points. Each subject received acetaminophen 1 g at the beginning of the standard breakfast on each treatment day as an indicator of the rate of gastric emptying. Plasma samples were collected over a 6-hour period to determine nateglinide, glucose, insulin, and acetaminophen concentrations. RESULTS: Twelve white men with a mean (SD) age of 30 (6.8) years (range, 21-47 years) and mean (SD) weight of 73.3 (11.0) kg completed all 6 periods of the study. Nateglinide absorption was faster when administered at -5 or -10 minutes relative to food, as characterized by higher nateglinide area under the concentration-time curve from 0 to 5 hours (AUC(0-5)) and maximum plasma concentration (C(max)) values, compared with those observed at other dosing time points. Mean time to C(max) (T(max)) was also shorter when nateglinide was given at -10 minutes versus other dosing time points. Mean nateglinide half-life was similar for all 5 treatments (range, 81.3-94.6 minutes). The overall treatment effect was statistically significant for nateglinide AUC(0-5) (P = 0.031), C(max) (P = 0.001), and T(max) (P < 0.001). Insulin T(max) was shorter after nateglinide administration at -30 or -10 minutes, which was associated with lower glucose C(max) values (-30 minutes, P < 0.05) and a tendency for lower glucose AUC(0-5) values (-10 minutes, P = NS). NS). No treatment effects were observed for any of the acetaminophen indices, as demonstrated by the absence of any change in acetaminophen T(max) or C(max) value. CONCLUSIONS: Nateglinide was well tolerated and no treatment-limiting adverse events were reported in the population studied. Nateglinide administration appeared to have no effect on the rate of gastric emptying as indicated by acetaminophen indices, regardless of the time of nateglinide administration. The findings imply that the time for nateglinide administration to obtain optimal pharmacodynamic effects is prior to food consumption.

No effect of the novel antidiabetic agent nateglinide on the pharmacokinetics and anticoagulant properties of warfarin in healthy volunteers.

The novel hypoglycemic agent nateglinide is pharmacologically distinct from oral hypoglycemic agents such as sulfonylureas and repaglinide. The present study investigated the effects in healthy volunteers of multiple doses of nateglinide on the pharmacokinetics and pharmacodynamics of warfarin. The study comprised a randomized two-group, two-way crossover, open-label design in 12 healthy male subjects. One group of 6 subjects initially received a single oral dose of warfarin 30 mg and then, after a 7- to 14-day washout, received both warfarin and nateglinide (120 mgnateglinide, 10 min before meals for 4 days and a single dose of 30 mg warfarin on the second day). The alternate group of 6 subjects received treatments in the opposite order. Pharmacokinetic profiles were derived from plasma warfarin and nateglinide concentrations. Prothrombin measurements were evaluated in both periods as a measure of warfarin activity. When administered alone or in combination, there were no statistically significant differences in mean warfarin (R- and S-enantiomers) or nateglinide pharmacokinetic parameters. The concurrent administration of nateglinide and warfarin did not affect the maximal change in prothrombin time that follows warfarin administration. In this study, there was no evidence of an effect of coadministration of nateglinide on the pharmacodynamic action of warfarin or any pharmacokinetic interaction between warfarin and nateglinide.