Chewing Through the Miocene: An Examination of the Feeding Musculature in the Ground Sloth Hapalops from South America (Mammalia: Pilosa)

Hapalops, a smaller-sized and early sloth of the Megatheroidea, appeared in the middle Miocene Santa Cruz formation of Argentina. This genus is part of the group from which later, larger megatheroids arose, i.e., Nothrotheriops and Megatherium. Many cranial characters support this idea; however Hapalops is not merely a smaller antecedent of the later forms. Specifically, Hapalops retains short anterior caniniform teeth, and a temporomandibular joint elevated above the cheek tooth row; a combination distinct among sloths. An elevated temporomandibular joint occurs in Bradypus, a tree sloth with anterior chisel-shaped teeth instead of caniniforms, and the tree sloth Choloepus, which is aligned with the megalonychids, has anterior caniniforms. Hapalops has an elongated zygomatic ascending process that is reminiscent of that in Bradypus; however, the Bradypus skull is extremely foreshortened while that of Hapalops is elongated, as in nothrotheres, but not deepened as in megatheres. Previous work identified many sloth cranial character complexes, and functional limitations on skull feature combinations. The unique Hapalops character patterns indicate a selective feeder with a mediolaterally oriented grinding stroke during mastication

The Importance of Craniofacial Sutures in Biomechanical Finite Element Models of the Domestic Pig

Craniofacial sutures are a ubiquitous feature of the vertebrate skull. Previous experimental work has shown that bone strain magnitudes and orientations often vary when moving from one bone to another, across a craniofacial suture. This has led to the hypothesis that craniofacial sutures act to modify the strain environment of the skull, possibly as a mode of dissipating high stresses generated during feeding or impact. This study tests the hypothesis that the introduction of craniofacial sutures into finite element (FE) models of a modern domestic pig skull would improve model accuracy compared to a model without sutures. This allowed the mechanical effects of sutures to be assessed in isolation from other confounding variables. These models were also validated against strain gauge data collected from the same specimen ex vivo. The experimental strain data showed notable strain differences between adjacent bones, but this effect was generally not observed in either model. It was found that the inclusion of sutures in finite element models affected strain magnitudes, ratios, orientations and contour patterns, yet contrary to expectations, this did not improve the fit of the model to the experimental data, but resulted in a model that was less accurate. It is demonstrated that the presence or absence of sutures alone is not responsible for the inaccuracies in model strain, and is suggested that variations in local bone material properties, which were not accounted for by the FE models, could instead be responsible for the pattern of results

Success of Preoperative Radiotherapy in Inflammatory Breast Cancer with Inadequate Response to Taxane-Based Chemotherapies

Inflammatory breast cancer is a locally-aggressive and highly malignant cancer which often carries a poor prognosis for afflicted patients. Multi-modality treatment is often required, and taxane-based chemotherapy has shown improved outcomes and allowed for the pursuit of mastectomies, which are critical to disease control. Inadequate response to taxane-based chemotherapy indicates aggressive disease, and the role of preoperative radiotherapy for treatment in this patient group and its effects on patient outcomes and toxicity has not been studied. This study evaluates the effectiveness of preoperative radiotherapy on this patient group. Inflammatory breast cancer patients between 2012-2018 who were not deemed appropriate for resection following taxane-based chemotherapy leading to their referral for preoperative radiotherapy were identified. Patient, disease, and pre-surgical treatment characteristics were collected. A statistical analysis of surgical outcomes with regards to conversion to resectability, surgical margins, treatment response, complication rates, and locoregional recurrence was performed. 9 patients received neoadjuvant radiation following their inadequate response to taxane-based chemotherapy. 8 of 9 patients converted to resectable disease, 100% of which achieved R0 mastectomy. Median residual primary disease was 1cm, with a grade 1 toxicity being noted in 1 patient which resolved with conservative management. A single low cervical recurrence was observed 4 years after mastectomy. Based on the results of this study, preoperative radiation should be considered in inflammatory breast cancer patients who do not demonstrate adequate response to taxane-based chemotherapy. Use of preoperative radiotherapy in this patient group may lead to the improvement of patient outcomes and a decrease in treatment toxicity

Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis.

Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting

Cranial Ontogeny in Stegoceras validum (Dinosauria: Pachycephalosauria): A Quantitative Model of Pachycephalosaur Dome Growth and Variation

Historically, studies of pachycephalosaurs have recognized plesiomorphically flat-headed taxa and apomorphically domed taxa. More recently, it has been suggested that the expression of the frontoparietal dome is ontogenetic and derived from a flat-headed juvenile morphology. However, strong evidence to support this hypothesis has been lacking. Here we test this hypothesis in a large, stratigraphically constrained sample of specimens assigned to Stegoceras validum, the best known pachycephalosaur, using multiple independent lines of evidence including conserved morphology of ornamentation, landmark-based allometric analyses of frontoparietal shape, and cranial bone histology. New specimens show that the diagnostic ornamentation of the parietosquamosal bar is conserved throughout the size range of the sample, which links flat-headed specimens to domed S. validum. High-resolution CT scans of three frontoparietals reveal that vascularity decreases with size and document a pattern that is consistent with previously proposed histological changes during growth. Furthermore, aspects of dome shape and size are strongly correlated and indicative of ontogenetic growth. These results are complementary and strongly support the hypothesis that the sample represents a growth series of a single taxon. Cranial dome growth is positively allometric, proceeds from a flat-headed to a domed state, and confirms the synonymy of Ornatotholus browni as a juvenile Stegoceras. This dataset serves as the first detailed model of growth and variation in a pachycephalosaur. Flat-headed juveniles possess three characters (externally open cranial sutures, tuberculate dorsal surface texture, and open supratemporal fenestrae) that are reduced or eliminated during ontogeny. These characters also occur in putative flat-headed taxa, suggesting that they may also represent juveniles of domed taxa. However, open cranial sutures and supratemporal fenestrae are plesiomorphic within Ornithischia, and thus should be expected in the adult stage of a primitive pachycephalosaur. Additional lines of evidence will be needed to resolve the taxonomic validity of flat-headed pachycephalosaur taxa

Terrestrial-style feeding in a very early aquatic tetrapod is supported by evidence from experimental analysis of suture morphology

There is no consensus on when in the fish-tetrapod transition suction feeding, the primary method of prey capture in the aquatic realm, evolved into the direct biting on prey typical of terrestrial animals. Here, we show that differences in the morphology of selected cranial sutures between species that span the fish–tetrapod transition (the Devonian osteolepiform fish Eusthenopteron, the aquatic Devonian tetrapod Acanthostega, and the Permian terrestrial tetrapod Phonerpeton) can be used to infer when terrestrial feeding first appeared. Our approach consists of defining a sutural morphospace, assigning functional fields to that morphospace based on our previous measurements of suture function made during feeding in the living fish Polypterus, inferring the functions of the fossil sutures based on where they fall in the morphospace, and then using the correlation between feeding mode and the patterns of inferred suture function across the skull roof in taxa where feeding mode is unambiguous to infer the feeding mode practiced by Acanthostega. Using this procedure, we find that the suture morphologies of Acanthostega are inconsistent with the hypothesis that it captured prey primarily by means of suction, which suggests that it may have bitten directly on prey at or near the water's edge. Thus, our data strongly support the hypothesis that the terrestrial mode of feeding first emerged in aquatic taxa

Whispers from Vestigial Nubbins: Arrested Development Provokes Trait Loss in Toads

Despite the use of acoustic communication, many species of toads (family Bufonidae) have lost parts of the tympanic middle ear, representing at least 12 independent evolutionary occurrences of trait loss. The comparative development of the tympanic middle ear in toads is poorly understood. Here, we compared middle ear development among two pairs of closely related toad species in the genera Atelopus and Rhinella that have (eared) or lack (earless) middle ear structures. We bred toads in Peru and Ecuador, preserved developmental series from tadpoles to juveniles, and examined ontogenetic timing and volume of the otic capsule, oval window, operculum, opercularis muscle, columella (stapes), and extracolumella in three‐dimensional histological reconstructions. All species had similar ontogenesis of the otic capsule, oval window, operculum, and opercularis muscle. Moreover, cell clusters of primordial columella in the oval window appeared just before metamorphosis in both eared and earless lineages. However, in earless lineages, the cell clusters either remained as small nubbins or cell buds in the location of the columella footplate within the oval window or disappeared by juvenile and adult stages. Thus, columella growth began around metamorphosis in all species but was truncated and/or degenerated after metamorphosis in earless species, leaving earless adults with morphology typical of metamorphic anurans. Shifts in the timing or expression of biochemical pathways that regulate the extension or differentiation of the columella after metamorphosis may be the developmental mechanism underlying convergent trait loss among toad lineages