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A second K/Pg boundary interval in the northern sector of the Antarctic Peninsula on Vega Island has been proposed, yet current temporal resolution of these strata prohibits direct testing of this hypothesis. To not only test for the existence of a K/Pg boundary on Vega Island but also provide increased age resolution for the associated vertebrate fauna (e.g., marine reptiles, non-avian dinosaurs, and avian dinosaurs), the Vega Island succession was intensively re-sampled. Stratigraphic investigation of the Cape Lamb Member of the Snow Hill Island Formation, and in particular, the overlying Sandwich Bluff Member of the López de Bertodano Formation, was conducted using biostratigraphy, strontium isotope stratigraphy, magnetostratigraphy, and detrital zircon geochronology. These data indicate a Late Campanian–early Maastrichtian age for the Cape Lamb Member and present three possible correlations to the global polarity time scale (GPTS) for the overlying Sandwich Bluff Member. The most plausible correlation, which is consistent with biostratigraphy, detrital zircon geochronology, sequence stratigraphy, and all but one of the Sr-isotope ages, correlates the base of the section to C31N and the top of the section with C29N, which indicates that the K/Pg boundary passes through the top of the unit. A second, less plausible option conflicts with the biostratigraphy and depends on a series of poorly defined magnetic reversals in the upper part of the stratigraphy that also correlates the section between C31N and C29R and again indicates an inclusive K/Pg boundary interval. The least likely correlation, which depends on favoring only a single Srisotope age at the top of the section over biostratigraphy, correlates the section between C31N and C30N and is inconsistent with an included K/Pg boundary interval. Although our preferred correlation is well supported, we failed to identify an Ir-anomaly, spherules/impact ejecta, or other direct evidence typically used to define the precise position of a K/Pg boundary on Vega Island. This study does, however, confirm that Vegavis, from the base of the Sandwich Bluff Member, is the oldest (69.2–68.4 Ma) phylogenetically placed representative of the avian crown clade, and that marine vertebrates and non-avian dinosaurs persisted in Antarctica up to the terminal Cretaceous.

Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12-weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared with wildtype mice, with a reduction of white and brown adipose tissues. Partitioning of dietary [3H]triolein showed a marked increase in intestinal uptake and secretion, whereas hepatic production and clearance of triglyceride-rich lipoproteins did not differ from wildtype controls. Uptake of dietary triolein was also elevated in brown adipose tissue (BAT), and notable increases in beige adipose tissue occurred, resulting in hyperthermia, hyperphagia, hyperdipsia, and increased energy expenditure. Furthermore, fasted MPS IIIa mice remained hyperthermic when subjected to low temperature but became cachexic and profoundly hypothermic when treated with a lipolytic inhibitor. We demonstrated that the reliance on increased lipid fueling of BAT was driven by a reduced ability to generate energy from stored lipids within the depot. These alterations arose from impaired autophagosome-lysosome fusion, resulting in increased mitochondria content in beige and BAT. Finally, we show that increased mitochondria content in BAT and postprandial dyslipidemia was partially reversed upon 5-week treatment with recombinant sulfamidase. We hypothesize that increased BAT activity and persistent increases in energy demand in MPS IIIa mice contribute to the negative energy balance observed in patients with MPS IIIa.

Myhrvold et al.1 suggest that our inference of subaqueous foraging among spinosaurids2 is undermined by selective bone sampling, inadequate statistical procedures, and use of inaccurate ecological categorizations. Myhrvold et al.1 ignore major details of our analyses and results, and instead choose to portray our inferences as if they were based on qualitative interpretations of our plots, without providing additional analyses to support their claims. In this manuscript, we thoroughly discuss all the concerns exposed by Myhrvold et al.1. Additional analyses based on our original datasets2 and novel data presented by Myhrvold et al.1 do not change our original interpretations: while the spinosaurid dinosaurs Spinosaurus and Baryonyx are recovered as subaqueous foragers, Suchomimus is inferred as a non-diving animal.

The brain, unlike other organs, is normally completely dependent on glucose, but is capable of using ketones as an alternate energy source, as occurs with prolonged starvation or chronic feeding of a ketogenic diet (high fat, low carbohydrate). Over the past decade, research has consistently shown that ketosis is neuroprotective against ischemic insults in rodents. This chapter focuses on investigation of the mechanistic links to neuroprotection by ketosis in the aged. Recovery from stroke and other pathophysiologic conditions in the aged is challenging. Cerebral metabolic rate for glucose (CMRglu), cerebral blood flow (CBF), and/or the defenses against oxidative stress are known to decline with age, suggesting dysfunction of the neurovascular unit. One mechanism of neuroprotection by ketosis involves succinate-induced stabilization of hypoxia-inducible factor 1α (HIF-1α) and its downstream effects on intermediary metabolism. It is possible that ketone bodies play a role in the restoration of energy balance (stabilization of ATP supply), as well as act as signaling molecules, through the upregulation of anti-inflammatory and prosurvival pathways targeted by HIF-1α.

Osteological correlates preserve more readily than their soft tissue counterparts in the fossil record; therefore, they can more often provide insight into the soft tissue anatomy of the organism. These insights can in turn elucidate the biology of these extinct organisms. In this study, we reconstruct the pelvic girdle and hind limb musculature of the giant titanosaurian sauropod Dreadnoughtus schrani based on observations of osteological correlates and Extant Phylogenetic Bracket comparisons. Recovered fossils of Dreadnoughtus exhibit remarkably well-preserved, well-developed, and extensive muscle scars. Furthermore, this taxon is significantly larger bodied than any titanosaurian for which a myological reconstruction has previously been performed, rendering this contribution highly informative for the group. All 20 of the muscles investigated in this study are sufficiently well supported to enable reconstruction of at least one division, including reconstruction of the M. ischiocaudalis for the first time in a sauropod dinosaur. In total, 34 osteological correlates were identified on the pelvic girdle and hind limb remains of Dreadnoughtus, allowing the reconstruction of 14 muscles on the basis of Level I or Level II inferences (i.e., not Level I' or Level II' inferences). Comparisons among titanosaurians suggest widespread myological variation, yet potential phylogenetic and other paleobiologic patterns are often obscured by fragmentary preservation, infrequent myological studies, and lack of consensus on the phylogenetic placement of many taxa. However, a ventrolateral accessory process is present on the preacetabular lobe of the ilium in all of the largest titanosauriforms that preserve this skeletal element, suggesting that the presence of this process (representing the origin of the M. puboischiofemoralis internus part II) may be associated with extreme body size. By identifying such myological patterns among titanosauriforms, we can begin to address specific evolutionary and biomechanical questions related to their skeletal anatomy, how they were capable of leaving wide-gauge trackways, and resulting locomotor attributes unique to this clade.

Secondary aquatic adaptations evolved independently more than 30 times from terrestrial vertebrate ancestors1,2. For decades, non-avian dinosaurs were believed to be an exception to this pattern. Only a few species have been hypothesized to be partly or predominantly aquatic3,4,5,6,7,8,9,10,11. However, these hypotheses remain controversial12,13, largely owing to the difficulty of identifying unambiguous anatomical adaptations for aquatic habits in extinct animals. Here we demonstrate that the relationship between bone density and aquatic ecologies across extant amniotes provides a reliable inference of aquatic habits in extinct species. We use this approach to evaluate the distribution of aquatic adaptations among non-avian dinosaurs. We find strong support for aquatic habits in spinosaurids, associated with a marked increase in bone density, which precedes the evolution of more conspicuous anatomical modifications, a pattern also observed in other aquatic reptiles and mammals14,15,16. Spinosaurids are revealed to be aquatic specialists with surprising ecological disparity, including subaqueous foraging behaviour in Spinosaurus and Baryonyx, and non-diving habits in Suchomimus. Adaptation to aquatic environments appeared in spinosaurids during the Early Cretaceous, following their divergence from other tetanuran theropods during the Early Jurassic17.

Group work can engage students in active learning, yet students often resist working with peers in class. We investigated the impact of five minimally structured, easily implemented group work strategies used during weekly problem-based discussion sections in two introductory chemistry courses through student surveys and quiz score analyses. Students reported increased interaction with their classmates as a result of group work but did not feel more prepared for the weekly quiz. Interestingly, students’ performance on the weekly quizzes was anticorrelated with the strategy they felt prepared them best for the quiz. Students at the introductory level appeared unable to “self-assess” what helps them learn. However, group work strategies with greater interaction between students were associated with higher quiz scores. Furthermore, we found that implementing specific strategies over time resulted in more collaboration than simply instructing students to work together. These results are consistent with previous work that highlights the importance of student interaction in learning and suggest that positive interdependence can be created among students even in a less structured collaborative environment.

The mammalian brain modulates its microvascular network to accommodate tissue energy demand in a process referred to as angioplasticity. There is an aging effect on cognitive function and adaptive responses to hypoxia. Hypoxia-induced angiogenesis is delayed in the aging mouse brain. Additionally, it has been shown that environmental enrichment provides an environment that fosters increased physical activity and sensory stimulation for mice as compared to standard housing; this stimulation increases neuronal activity and consequently brain oxygen demand. In this study, we investigated the effect of environmental enrichment and chronic hypoxia on cognitive performance in the young (2-4 months old) and the aged mice (17-21 months old). Mice were placed in a non-enriched or an enriched environment for 4 weeks under normoxia followed by 3 weeks of hypobaric hypoxia (~0.4 atm, equivalent to 8% normobaric oxygen at sea level). Cognitive function was evaluated using the Y-maze and the novel object recognition tests in the enriched or non-enriched mice under normoxic or hypoxic conditions. In Y-maze, a high alternation rate is indicative of sustained cognition as the animals must remember which arm was entered last, so as not to re-enter it. Novel object recognition is based on the natural tendency of rodents to investigate a novel object instead of a familiar one; a higher novel object exploration rate is indicative of better cognitive function. The young mice showed a significantly higher alternation rate (%, 63 ± 7 vs. 48 ± 10, n = 8 and 10, respectively) in the Y-Maze test as compared to the aged mice. Under normoxia, the enriched mice showed an improved alternation rate (%, 63 ± 10, n = 10) in Y-Maze test and a higher novel object exploration rate (%, 68 ± 10 vs. 52 ± 10) compared to the non-enriched controls. Similar results were observed for both young and aged mice following hypoxic exposure. Our data suggests that environmental enrichment improved the cognitive performance in the young and aged mice under normoxic and hypoxic conditions.

We have previously reported that in a rat model of chronic hypoxia, HIF-1α and its target genes have significantly accumulated by 3 days of exposure, whereas no significant increase in capillary density has occurred; there is a significant increase in capillary density at 21 days of chronic hypoxic exposure. In this study we hypothesize that by utilizing 3 days and 21 days of hypoxic preconditioning, we would distinguish between the relative neuroprotective contributions of the accumulation of HIF-1α and its target genes and angiogenic adaptation in a rat middle cerebral artery occlusion (MCAO) model. Rats were randomly assigned to either hypoxic precondition groups (3-day and 21-day hypoxia) or normoxic control group. Hypoxic animals were kept in a hypobaric chamber at a constant pressure of 0.5 atmosphere (380 mmHg, equivalent to 10% normobaric oxygen at sea level) for either 3 or 21 days. Normoxic controls were housed in the same room next to the hypobaric chamber. Erythropoietin (EPO) was measured at 3 and 21 days of hypoxia using Western blotting analysis. Infarct volumes were measured following 24 hours of permanent MCAO. We found that EPO is upregulated at 3 days of hypoxia and returns to baseline by 21 days of hypoxia. The infarct volumes following 24-hour MCAO were significantly reduced with 3-day hypoxic preconditioning when compared to normoxic controls (%, 31.8 ± 5, n = 9 vs. 50.1 ± 10.9, n = 7). No significant differences in infarct volume were seen between the normoxic controls and 21-day hypoxic preconditioned rats. We have shown that a 3-day hypoxic preconditioning, but not 21-day hypoxic preconditioning, provides significant neuroprotection against focal ischemia in rats, supporting a larger role for the accumulations of HIF-1α and upregulation of its target genes in the neuroprotection against focal ischemia.

Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate in mice for HIF-1 and HIF-2. The objective of this study was to investigate the effect of neuronal deletion of HIF-1 and HIF-2 in hypoxic adaptation by using the neuron-specific knockout (KO) mice. The floxed control and KO mice were used. Hypoxic mice were kept in a hypobaric chamber at a pressure of 300 torr (0.4 ATM, which was equivalent to 8% oxygen under normobaric condition) for 3 weeks. The littermate, normoxic control mice were housed in the same room next to the chamber to match ambient conditions. Body weights were monitored throughout the 3-week course. Cognitive function was measured using a Y-maze test; motor functions were measured using the rotarod test and the grip strength test. The hematocrit increased significantly at the end of 3-week hypoxic exposure in both control and KO mice. In the Y-maze test, the alternation rate (indicative of sustained cognition) trended lower in the KO mice compared to the controls following hypoxia (%, 51.3 ± 13.1, n = 6 vs. 63.2 ± 12.0, n = 8). In the rotarod test, the latency (seconds) in the KO mice was significantly lower compared to the controls (50.4 ± 5.7 vs. 77.1 ± 5.0, n = 3 each before hypoxia and 66.4 ± 3.4, n = 6 vs. 98.1 ± 15.4 after hypoxia, n = 3). The grip strength in the KO mice was similar compared to the control mice before hypoxia, but the strength of KO mice trended higher after hypoxic exposure. Our data suggest that deficiency of neuronal HIF-1 and HIF-2 may result in changes in behavioral performance and other adaptative responses to hypoxia.

The mammalian brain modulates its microvascular network to accommodate tissue energy demand in a process referred to as angioplasticity. There is an aging effect on cognitive function and adaptive responses to hypoxia. Hypoxia-induced angiogenesis is delayed in the aging mouse brain. Additionally, it has been shown that environmental enrichment provides an environment that fosters increased physical activity and sensory stimulation for mice as compared to standard housing; this stimulation increases neuronal activity and consequently brain oxygen demand. In this study, we investigated the effect of environmental enrichment and chronic hypoxia on cognitive performance in the young (2–4 months old) and the aged mice (17–21 months old). Mice were placed in a non-enriched or an enriched environment for 4 weeks under normoxia followed by 3 weeks of hypobaric hypoxia (~0.4 atm, equivalent to 8% normobaric oxygen at sea level). Cognitive function was evaluated using the Y-maze and the novel object recognition tests in the enriched or non-enriched mice under normoxic or hypoxic conditions. In Y-maze, a high alternation rate is indicative of sustained cognition as the animals must remember which arm was entered last, so as not to re-enter it. Novel object recognition is based on the natural tendency of rodents to investigate a novel object instead of a familiar one; a higher novel object exploration rate is indicative of better cognitive function. The young mice showed a significantly higher alternation rate (%, 63 ± 7 vs. 48 ± 10, n = 8 and 10, respectively) in the Y-Maze test as compared to the aged mice. Under normoxia, the enriched mice showed an improved alternation rate (%, 63 ± 10, n = 10) in Y-Maze test and a higher novel object exploration rate (%, 68 ± 10 vs. 52 ± 10) compared to the non-enriched controls. Similar results were observed for both young and aged mice following hypoxic exposure. Our data suggests that environmental enrichment improved the cognitive performance in the young and aged mice under normoxic and hypoxic conditions.

Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate in mice for HIF-1 and HIF-2. The objective of this study was to investigate the effect of neuronal deletion of HIF-1 and HIF-2 in hypoxic adaptation by using the neuron-specific knockout (KO) mice. The floxed control and KO mice were used. Hypoxic mice were kept in a hypobaric chamber at a pressure of 300 torr (0.4 ATM, which was equivalent to 8% oxygen under normobaric condition) for 3 weeks. The littermate, normoxic control mice were housed in the same room next to the chamber to match ambient conditions. Body weights were monitored throughout the 3-week course. Cognitive function was measured using a Y-maze test; motor functions were measured using the rotarod test and the grip strength test. The hematocrit increased significantly at the end of 3-week hypoxic exposure in both control and KO mice. In the Y-maze test, the alternation rate (indicative of sustained cognition) trended lower in the KO mice compared to the controls following hypoxia (%, 51.3 ± 13.1, n = 6 vs. 63.2 ± 12.0, n = 8). In the rotarod test, the latency (seconds) in the KO mice was significantly lower compared to the controls (50.4 ± 5.7 vs. 77.1 ± 5.0, n = 3 each before hypoxia and 66.4 ± 3.4, n = 6 vs. 98.1 ± 15.4 after hypoxia, n = 3). The grip strength in the KO mice was similar compared to the control mice before hypoxia, but the strength of KO mice trended higher after hypoxic exposure. Our data suggest that deficiency of neuronal HIF-1 and HIF-2 may result in changes in behavioral performance and other adaptative responses to hypoxia.

Hypoxia inducible factor alpha (HIF1α) is associated with neuroprotection conferred by diet-induced ketosis, but the underlying mechanism remains unclear. In this study, we use a ketogenic diet in rodents to induce a metabolic state of chronic ketosis, as measured by elevated blood ketone bodies. Chronic ketosis correlates with neuroprotection in both aged and following focal cerebral ischemia and reperfusion (via middle cerebral artery occlusion, MCAO) in mouse and rat models. Ketone bodies are known to be used efficiently by the brain, and metabolism of ketone bodies is associated with increased cytosolic succinate levels that inhibits prolyl hydroxylases allowing HIF1α to accumulate. Ketosis also regulates inflammatory pathways, and HIF1α is reported to be essential for gene expression of interleukin 10 (IL10). Therefore, we hypothesized that ketosis-stabilized HIF1α modulates the expression of inflammatory cytokines orchestrating neuroprotection. To test changes in cytokine levels in rodent brain, 8-week-rats were fed either the standard chow diet (SD) or the KG diet for 4 weeks before ischemia experiments (MCAO) were performed and the brain tissues were collected. Consistent with our hypothesis, immunoblotting analysis shows IL10 levels were significantly higher in KG diet rat brain compared to SD, whereas the TNFα and IL6 levels were significantly lower in the brains of KG diet-fed group.

We have previously reported that in a rat model of chronic hypoxia, HIF-1α and its target genes have significantly accumulated by 3 days of exposure, whereas no significant increase in capillary density has occurred; there is a significant increase in capillary density at 21 days of chronic hypoxic exposure. In this study we hypothesize that by utilizing 3 days and 21 days of hypoxic preconditioning, we would distinguish between the relative neuroprotective contributions of the accumulation of HIF-1α and its target genes and angiogenic adaptation in a rat middle cerebral artery occlusion (MCAO) model. Rats were randomly assigned to either hypoxic precondition groups (3-day and 21-day hypoxia) or normoxic control group. Hypoxic animals were kept in a hypobaric chamber at a constant pressure of 0.5 atmosphere (380 mmHg, equivalent to 10% normobaric oxygen at sea level) for either 3 or 21 days. Normoxic controls were housed in the same room next to the hypobaric chamber. Erythropoietin (EPO) was measured at 3 and 21 days of hypoxia using Western blotting analysis. Infarct volumes were measured following 24 hours of permanent MCAO. We found that EPO is upregulated at 3 days of hypoxia and returns to baseline by 21 days of hypoxia. The infarct volumes following 24-hour MCAO were significantly reduced with 3-day hypoxic preconditioning when compared to normoxic controls (%, 31.8 ± 5, n = 9 vs. 50.1 ± 10.9, n = 7). No significant differences in infarct volume were seen between the normoxic controls and 21-day hypoxic preconditioned rats. We have shown that a 3-day hypoxic preconditioning, but not 21-day hypoxic preconditioning, provides significant neuroprotection against focal ischemia in rats, supporting a larger role for the accumulations of HIF-1α and upregulation of its target genes in the neuroprotection against focal ischemia.

Fil: Lamanna, Matthew C.. Carnegie Museum of Natural History. Section of Vertebrate Paleontology; Estados Unidos

The middle–late Eocene of Antarctica was characterized by dramatic change as the continent became isolated from the other southern landmasses and the Antarctic Circumpolar Current formed. These events were crucial to the formation of the permanent Antarctic ice cap, affecting both regional and global climate change. Our best insight into how life in the high latitudes responded to this climatic shift is provided by the fossil record from Seymour Island, near the eastern coast of the Antarctic Peninsula. While extensive collections have been made from the La Meseta and Submeseta formations of this island, few avian taxa other than penguins have been described and mammalian postcranial remains have been scarce. Here, we report new fossils from Seymour Island collected by the Antarctic Peninsula Paleontology Project. These include a mammalian metapodial referred to Xenarthra and avian material including a partial tarsometatarsus referred to Gruiformes (cranes, rails, and allies). Penguin fossils (Sphenisciformes) continue to be most abundant in new collections from these deposits. We report several penguin remains including a large spear-like mandible preserving the symphysis, a nearly complete tarsometatarsus with similarities to the large penguin clade Palaeeudyptes but possibly representing a new species, and two small partial tarsometatarsi belonging to the genus Delphinornis. These findings expand our view of Eocene vertebrate faunas on Antarctica. Specifically, the new remains referred to Gruiformes and Xenarthra provide support for previously proposed, but contentious, earliest occurrence records of these clades on the continent.

We describe Tratayenia rosalesi gen. et sp. nov., a new megaraptoran theropod dinosaur from the Upper Cretaceous of Patagonia, Argentina. The holotype consists of a well-preserved, mostly articulated series of dorsal and sacral vertebrae, two partial dorsal ribs, much of the right ilium, and pubis and ischium fragments. It was found in a horizon of the Upper Cretaceous (Santonian) Bajo de la Carpa Formation of the Neuquen Group in the Neuquen Basin exposed near the town of Anelo in Neuquen Province of northwestern Patagonia. Phylogenetic analysis recovers Tratayenia within the Gondwanan megaraptoran subclade Megaraptoridae. The new taxon exhibits similarities to other megaraptorids such as Aerosteon riocoloradensis, Megaraptor namunhuaiquii, and Murusraptor barrosaensis, but also presents differences in the architecture of the dorsal and sacral vertebrae and the morphology of the ilium. Tratayenia is the first megaraptoran that unequivocally preserves the complete sequence of sacral vertebrae, thereby increasing knowledge of the osteology of the clade. Moreover, depending on the chronostratigraphic ages of the stratigraphically controversial megaraptorids Aerosteon and Orkoraptor burkei, as well as the phylogenetic affinities of several fragmentary specimens, the new theropod may be the geologically youngest megaraptorid or megaraptoran yet discovered. Tratayenia is also the largest-bodied carnivorous tetrapod named from the Bajo de la Carpa Formation, reinforcing the hypothesis that megaraptorids were apex predators in southern South America from the Turonian through the Santonian or early Campanian, following the extinction of carcharodontosaurids.

Introduction: Biopharmaceuticals are large protein based drugs which are heterogeneous by nature due to post translational modifications resulting from cellular production, processing and storage. Changes in the abundance of different variants over time are inherent to biopharmaceuticals due to their sensitivity to subtle process differences and the necessity for regular manufacturing changes. Product variability must thus be carefully controlled to ensure that it does not result in changes in safety or efficacy. Areas covered: The focus of this manuscript is to provide improved understanding of the science and strategies used to maintain the quality and clinical performance of biopharmaceuticals, including biosimilars, throughout their lifecycle. This review summarizes rare historical instances where clinically relevant changes have occurred, defined here as clinical drift, and discusses modern tools used to prevent such changes, including improved analytics, quality systems and regulatory frameworks. Expert opinion: Despite their size complexity and heterogeneity, modern analytics, manufacturing quality systems and comparability requirements for the evaluation of manufacturing changes cumulatively help to ensure the consistent quality and clinical performance of biopharmaceuticals throughout their product lifecycle. Physicians and patients can expect the same safety and efficacy from biopharmaceuticals and their respective biosimilars irrespective of batch or production history.

We describe and incorporate fragmentary new cranial and postcranial materials of hadrosaurid ornithopods into the non-avian dinosaur assemblage of the Upper Cretaceous (Coniacian–Maastrichtian) Lago Colhue Huapi Formation of central Patagonia, south-central Chubut Province, Argentina. The fossils come from the upper part of the formation, probably from a stratigraphic interval close to the Cretaceous/Paleogene boundary. The materials belong to at least two ontogenetically distinct individuals that are assigned to Hadrosauridae due to their possession of anatomical features that characterize this derived ornithopod group. Sedimentological inferences reveal that the paleoenvironment of these hadrosaurids was characterized by high-sinuosity, meandering-type fluvial channels, whereas palynological data suggest the existence of low-energy freshwater bodies in the floodplains of these rivers and a warm and humid paleoclimate. The deposition of the upper part of the Lago Colhue Huapi Formation was probably influenced by the Patagonian Atlantic marine transgression, which may have played an important role in the distribution of this sedimentary unit. The new Lago Colhue Huapi Formation hadrosaurid specimens constitute the most stratigraphically recent records of this clade from Argentina. The materials contribute to the interpretation of Upper Cretaceous hadrosaurid paleobiogeography in Patagonian basins; moreover, sedimentological and palynological data suggest that paleoenvironmental conditions may have exerted an important influence on South American hadrosaur distribution, supporting hypotheses of ornithopod faunal turnover during the Late Cretaceous of central Patagonia. Finally, the new remains add to the generally depauperate record of Late Cretaceous ornithopods in the Southern Hemisphere.

Xenotarsosaurus bonapartei was the third abelisaurid theropod dinosaur to be named from Argentina. The holotype comprises two partial anterior dorsal vertebrae and a nearly complete right hind limb from the Upper Cretaceous (lower Cenomanian–upper Turonian) Bajo Barreal Formation, central Patagonia, Argentina. The materials display morphological features that undoubtedly position Xenotarsosaurus within Abelisauroidea. Moreover, detailed comparisons with members of that theropod group confirm the close relationship of this taxon to abelisaurids. Here we provide an emended diagnosis of Xenotarsosaurus bonapartei that includes five newly recognized autapomorphies: (1) anterior dorsal vertebrae with large, strongly dorsoventrally developed parapophyses; (2) anterior dorsal vertebrae with well-developed centroprezygapophyseal fossae that are taller dorsoventrally than wide mediolaterally; (3) fibular condyle of femur triangular in shape and projecting posteriorly; (4) well-marked groove on anterolateral corner of proximal fibula; and (5) iliofibularis tubercle of fibula distally interrupted by hook-like concavity. To determine its systematic position within Abelisauroidea, we incorporated Xenotarsosaurus into a phylogenetic analysis, recovering this theropod as a non-carnotaurine abelisaurid more derived than Eoabelisaurus mefi. Xenotarsosaurus displays several plesiomorphic traits when compared with penecontemporaneous abelisaurids from the Neuquen Group. Similarly, other non-avian dinosaur taxa from the Bajo Barreal Formation are frequently postulated as more phylogenetically basal than coeval forms from northern Patagonia. This scenario suggests the potential existence of provincialism in early Late Cretaceous continental vertebrate faunas of southern South America. The present study increases knowledge of abelisaurid systematics, evolution, and paleobiogeography and augments our understanding of the Upper Cretaceous dinosaur assemblage of central Patagonia.

Purpose The purpose of this study was to evaluate the in-use physicochemical and biological stability of the Sandoz rituximab biosimilar, marketed under the trade names Rixathon® and Riximyo® in the European Union, upon preparation for intravenous infusion. Methods Three batches of Rixathon®/Riximyo® in the final month of their 36 month shelf life were exposed to room temperature and light for 14 days to recapitulate a major temperature excursion. Samples were diluted to the lowest allowable concentration of 1 mg/mL in 0.9% NaCl solution in either polypropylene or polyethylene infusion bags and stored for 14 or 30 days at 5 ± 3℃ followed by an additional 24 h at room temperature to simulate product handling. Samples stored in infusion bags were analyzed using SEC, CEX, non-reducing CE-SDS, peptide mapping and CDC to assess physicochemical and biological stability. Results Analysis of Rixathon®/Riximyo® diluted to the lowest allowable concentration in 0.9% sodium chloride in either polypropylene or polyethylene infusion bags revealed no change in molecular weight variants, charge variants, deamidation, oxidation, overall composition or potency over a 31-day period. Conclusion Physicochemical and biological analyses demonstrate that Rixathon®/Riximyo® stability is not impacted by dilution and formulation conditions required for intravenous infusion, even under worst case conditions with regard to product shelf life, temperature excursion, light exposure, dilution factor and infusion bag storage time over a 31-day period.

We describe five partial middle and posterior dorsal vertebrae from an upper Kimmeridgian exposure of the Upper Jurassic Morrison Formation at the Carnegie Quarry of Dinosaur National Monument (Utah, USA), and refer these vertebrae to the poorly known diplodocid sauropod dinosaur genus Barosaurus Marsh, 1890. The small size and unfused neurocentral junctions of these vertebrae indicate that they belonged to a subadult individual and the osteologically youngest specimen yet described for the genus. We also provide corroborating evidence for the pneumatic hiatus previously hypothesized for Barosaurus and identify a previously unrecognized autapomorphy of the genus, the presence of an anterodorsallyoriented accessory lamina arising from the spinodiapophyseal lamina on dorsal vertebrae. Furthermore, we document a temporal uncoupling of neural spine lamination and pneumatization of the centrum, such that full development of the laminae preceded development of sharp-lipped pleurocoels in dorsal vertebrae.

Key points Extreme aviation is accompanied by ever-present risks of hypobaric hypoxia and decompression sickness. Neuroprotection against those hazards is conferred through fractional inspired oxygen ( F I , O 2 ) concentrations of 60-100% (hyperoxia). Hyperoxia reduces global cerebral perfusion (gCBF), increases reactive oxygen species within the brain and leads to cell death within the hippocampus. However, an understanding of hyperoxia's effect on cortical activity and concomitant levels of cognitive performance is lacking. This limits our understanding of whether hyperoxia could lower the brain's threshold of tolerance to physiological stressors inherent to extreme aviation, such as high gravitational forces. This study aimed to quantify the impact of hyperoxia upon global cerebral perfusion (gCBF), cognitive performance and cortical electroencephalography (EEG). Hyperoxia evoked a rapid reduction in gCBF, yet cognitive performance and vigilance were enhanced. EEG measurements revealed enhanced alpha power, suggesting less desynchrony, within the cortical temporal regions. Collectively, this work suggests hyperoxia-induced brain hypoperfusion is accompanied by enhanced cognitive processing and cortical arousal. Abstract Extreme aviators continually inspire hyperoxic gas to mitigate risk of hypoxia and decompression injury. This neuroprotection carries a physiological cost: reduced cerebral perfusion (CBF). As reduced CBF may increase vulnerability to ever-present physiological challenges during extreme aviation, we defined the magnitude and duration of hyperoxia-induced changes in CBF, cortical electrical activity and cognition in 30 healthy males and females. Magnetic resonance imaging with pulsed arterial spin labelling provided serial measurements of global CBF (gCBF), first during exposure to 21% inspired oxygen ( F I , O 2 ) followed by a 30-min exposure to 100% F I , O 2 . High-density EEG facilitated characterization of cortical activity during assessment of cognitive performance, also measured during exposure to 21% and 100% F I , O 2 . Acid-base physiology was measured with arterial blood gases. We found that exposure to 100% F I , O 2 reduced gCBF to 63% of baseline values across all participants. Cognitive performance testing at 21% F I , O 2 was accompanied by increased theta and beta power with decreased alpha power across multiple cortical areas. During cognitive testing at 100% F I , O 2 , alpha activity was less desynchronized within the temporal regions than at 21% F I , O 2 . The collective hyperoxia-induced changes in gCBF, cognitive performance and EEG were similar across observed partial pressures of arterial oxygen ( P a O 2 ), which ranged between 276-548 mmHg, and partial pressures of arterial carbon dioxide ( P aC O 2 ), which ranged between 34-50 mmHg. Sex did not influence gCBF response to 100% F I , O 2 . Our findings suggest hyperoxia-induced reductions in gCBF evoke enhanced levels of cortical arousal and cognitive processing, similar to those occurring during a perceived threat.

In 2006, a partial avian femur (South Dakota School of Mines and Technology (SDSM) 78247) from the Upper Cretaceous (Maastrichtian) Sandwich Bluff Member of the López de Bertodano Formation of Sandwich Bluff on Vega Island of the northern Antarctic Peninsula was briefly reported as that of a cariamiform—a clade that includes extant and volant South American species and many extinct flightless and cursorial species. Although other authors have since rejected this taxonomic assignment, SDSM 78247 had never been the subject of a detailed description, hindering a definitive assessment of its affinities. Here we provide the first comprehensive description, illustration, and comparative study of this specimen. Comparison of characters that may be assessed in this femur with those of avian taxa scored in published character matrices refutes the inclusion of SDSM 78247 within Cariamiformes, instead supporting its assignment to a new, as-yet unnamed large-bodied species within the genus Vegavis, and therefore its referral to a clade of semiaquatic anseriforms. Important character states diagnostic of Vegavis + Polarornis include strong craniocaudal bowing of the femoral shaft, the presence of a distinct fossa just proximal to the fibular trochlea, and the broad and flat shape of the patellar sulcus. Referral to Vegavis is based on the presence of a distinctive proximocaudal fossa and distolateral scar. This genus was previously known only from Vegavis iaai, a smaller-bodied taxon from the same locality and stratigraphic unit. Our reassignment of SDSM 78247 to Vegavis sp. removes the record of cariamiform landbirds from the Antarctic Cretaceous.

Understanding non-crown dinosaur reproduction is hindered by a paucity of directly associated adults with reproductive traces. Here we describe a new enantiornithine, Avimaia schweitzerae gen. et sp. nov., from the Lower Cretaceous Xiagou Formation with an unlaid egg two-dimensionally preserved within the abdominothoracic cavity. Ground-sections reveal abnormal eggshell proportions, and multiple eggshell layers best interpreted as a multi-layered egg resulting from prolonged oviductal retention. Fragments of the shell membrane and cuticle are both preserved. SEM reveals that the cuticle consists of nanostructures resembling those found in neornithine eggs adapted for infection-prone environments, which are hypothesized to represent the ancestral avian condition. The femur preserves small amounts of probable medullary bone, a tissue found today only in reproductively active female birds. To our knowledge, no other occurrence of Mesozoic medullary bone is associated with indications of reproductive activity, such as a preserved egg, making our identification unique, and strongly supported., The fossil record of the reproductive traits of early birds is limited. Here, Bailleul and colleagues describe the Cretaceous enantiornithine bird Avimaia schweitzerae, which preserves an unlaid egg in the abdominal cavity and putative medullary bone.

Aquaporin-4 (AQP4) plays an important role in regulating water exchange across the blood-brain barrier (BBB) and brain-cerebrospinal fluid interface. Studies on AQP-4 knockout mice (AQP4-KO) have reported considerable protection from brain edema induced by acute water intoxication and ischemic stroke, identifying AQP4 as a potential target for therapeutic interventions. However, the long-term effects of chronic AQP4 suppression are yet to be elucidated. In the current study, we evaluated the physiological and structural changes in adult AQP4-KO mice using magnetic resonance imaging (MRI) and immunohistochemical analysis. Water exchange across BBB was assessed by tracking an intravenous bolus injection of oxygen-17 (17O) water (H217O) using 17O-MRI. Cerebral blood flow (CBF) was quantified using arterial spin-labeling (ASL) MRI. Capillary density was determined by immunohistochemical staining for glucose transporter-1 (GLUT1). Compared to wildtype control mice, AQP4-KO mice showed a significant reduction in peak and steady-state H217O uptake despite unaltered CBF. Interestingly, a 22% increase in cortical capillary density was observed in AQP4-KO mice. These results suggest that increased cerebral vascularization may be an adaptive response to chronic reduction in water exchange across BBB in AQP4-KO mice.