Cranial remains of Ramsayia magna from the Late Pleistocene of Australia and the evolution of gigantism in wombats (Marsupialia, Vombatidae)

Giant wombats (defined here as ≥70 kg) are found in the genera Phascolonus, Ramsayia and perhaps Sedophascolomys. Ramsayia is currently the most poorly known, having been described from mandibular and cranial fragments. Here, we report the most complete cranial remains attributable to the genus, identified as R. magna. The specimen provides new insights into the anatomy of the species and evolutionary adaptations to gigantism in Vombatidae. We record parietal sinuses in a vombatid for the first time, an adaptation to increased skull size relative to the braincase. The presence of a prominent premaxillary spine may indicate that the species possessed a large, fleshy nose. Both features are convergent on other large‐bodied, non‐vombatid extinct megaherbivores of Australia such as Diprotodon optatum. We use the cranial remains to examine the phylogenetic relationships of giant wombats to other vombatids. Phylogenetic analysis using maximum parsimony and Bayesian inference indicates that Phascolomys, Ramsayia and Sedophascolomys form a clade, suggesting a single origin of gigantism within Vombatidae. This origin may be related to the exploitation of poor‐quality foods, and preceded extreme specializations observed in the cranial anatomy of the giant wombats. U‐series and combined U‐series and electron spin resonance (ESR) dating methods were applied to one fossil tooth. Age calculations systematically correlate the fossil remains to Marine Isotope Stage 5, and an age of c. 80 000 years can be proposed for this specimen. With only a single well‐dated occurrence for this taxon, it is currently impossible to determine when and why R. magna became extinct

Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection

Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage

New ages of the world's largest-ever marsupial: Diprotodon optatum from Pleistocene Australia

The extinction of large-bodied terrestrial ‘megafauna’ during earlier phases of the Quaternary had a significant impact on the transforming structure of ecosystems. However, the causes of such losses remains difficult to determine in part because of a paucity of reliable geochronological information about the taxa involved. This is especially true for continents such as Australia where the majority of extinct species have never been dated using radiometric and/or luminescence methods. Here we add new understanding about the geochronology of the world's largest-ever marsupial, the giant wombat-like Diprotodon optatum, an iconic member of the large herbivore guild of Pleistocene Australia. We present 28 new direct U-series ages (dentine) and 10 luminescence ages (sediments) for D. optatum fossils from three sites in tropical north and subtropical eastern Australia. The luminescence ages lie close to saturation for the tropical northern site of Floraville and therefore indicate minimum ages, and sediments from Gowrie Creek in the Darling Downs were mixed and can only be stated as a likely age range. Nevertheless the results assist in our broader understanding of the timing of persistence of the species. Our results demonstrate that the species roamed the northern tropics at least until the mid-Pleistocene (ca. 420 ka). They likely remained widespread during Marine Isotope Stage 5 (ca. 110 ka) and were abundant on the Darling Downs of eastern Australia. The youngest of the new ages that we report (ca. 60 ka) are from Neds Gully on the Darling Downs, a catchment previously considered by some to contain among the last survivors of the now-extinct megafauna. The new dated record demonstrates that deposits of varying ages occur within the catchment. Consequently, existing species lists that treat Neds Gully as a single faunal assemblage are likely significantly time-averaged and overinflated in terms of palaeo-diversity

Lack of efficacy of mTOR inhibitors and ACE pathway inhibitors as antifibrotic agents in evolving and established fibrosis in Mdr2-/- mice

Background & AimsMammalian target of rapamycin and angiotensin-converting enzyme inhibition has been shown to have antifibrotic activity in models of liver fibrosis. The aim of our study was to determine the efficacy of rapamycin, everolimus, irbesartan and captopril, alone and in combination, as antifibrotic agents in the Mdr2(-/-) model of cholestasis both in early injury and established disease