Africa's oldest dinosaurs reveal early suppression of dinosaur distribution.

The vertebrate lineages that would shape Mesozoic and Cenozoic terrestrial ecosystems originated across Triassic Pangaea1-11. By the Late Triassic (Carnian stage, ~235 million years ago), cosmopolitan 'disaster faunas' (refs. 12-14) had given way to highly endemic assemblages12,13 on the supercontinent. Testing the tempo and mode of the establishment of this endemism is challenging-there were few geographic barriers to dispersal across Pangaea during the Late Triassic. Instead, palaeolatitudinal climate belts, and not continental boundaries, are proposed to have controlled distribution15-18. During this time of high endemism, dinosaurs began to disperse and thus offer an opportunity to test the timing and drivers of this biogeographic pattern. Increased sampling can test this prediction: if dinosaurs initially dispersed under palaeolatitudinal-driven endemism, then an assemblage similar to those of South America4,19-21 and India19,22-including the earliest dinosaurs-should be present in Carnian deposits in south-central Africa. Here we report a new Carnian assemblage from Zimbabwe that includes Africa's oldest definitive dinosaurs, including a nearly complete skeleton of the sauropodomorph Mbiresaurus raathi gen. et sp. nov. This assemblage resembles other dinosaur-bearing Carnian assemblages, suggesting that a similar vertebrate fauna ranged high-latitude austral Pangaea. The distribution of the first dinosaurs is correlated with palaeolatitude-linked climatic barriers, and dinosaurian dispersal to the rest of the supercontinent was delayed until these barriers relaxed, suggesting that climatic controls influenced the initial composition of the terrestrial faunas that persist to this day.

The developing bird pelvis passes through ancestral dinosaurian conditions.

Living birds (Aves) have bodies substantially modified from the ancestral reptilian condition. The avian pelvis in particular experienced major changes during the transition from early archosaurs to living birds1,2. This stepwise transformation is well documented by an excellent fossil record2-4; however, the ontogenetic alterations that underly it are less well understood. We used embryological imaging techniques to examine the morphogenesis of avian pelvic tissues in three dimensions, allowing direct comparison with the fossil record. Many ancestral dinosaurian features2 (for example, a forward-facing pubis, short ilium and pubic 'boot') are transiently present in the early morphogenesis of birds and arrive at their typical 'avian' form after transitioning through a prenatal developmental sequence that mirrors the phylogenetic sequence of character acquisition. We demonstrate quantitatively that avian pelvic ontogeny parallels the non-avian dinosaur-to-bird transition and provide evidence for phenotypic covariance within the pelvis that is conserved across Archosauria. The presence of ancestral states in avian embryos may stem from this conserved covariant relationship. In sum, our data provide evidence that the avian pelvis, whose early development has been little studied5-7, evolved through terminal addition-a mechanism8-10 whereby new apomorphic states are added to the end of a developmental sequence, resulting in expression8,11 of ancestral character states earlier in that sequence. The phenotypic integration we detected suggests a previously unrecognized mechanism for terminal addition and hints that retention of ancestral states in development is common during evolutionary transitions.

Hypernetwork modeling and topology of high-order interactions for complex systems.

Interactions among the underlying agents of a complex system are not only limited to dyads but can also occur in larger groups. Currently, no generic model has been developed to capture high-order interactions (HOI), which, along with pairwise interactions, portray a detailed landscape of complex systems. Here, we integrate evolutionary game theory and behavioral ecology into a unified statistical mechanics framework, allowing all agents (modeled as nodes) and their bidirectional, signed, and weighted interactions at various orders (modeled as links or hyperlinks) to be coded into hypernetworks. Such hypernetworks can distinguish between how pairwise interactions modulate a third agent (active HOI) and how the altered state of each agent in turn governs interactions between other agents (passive HOI). The simultaneous occurrence of active and passive HOI can drive complex systems to evolve at multiple time and space scales. We apply the model to reconstruct a hypernetwork of hexa-species microbial communities, and by dissecting the topological architecture of the hypernetwork using GLMY homology theory, we find distinct roles of pairwise interactions and HOI in shaping community behavior and dynamics. The statistical relevance of the hypernetwork model is validated using a series of in vitro mono-, co-, and tricultural experiments based on three bacterial species.

The metabolomic physics of complex diseases.

Human diseases involve metabolic alterations. Metabolomic profiles have served as a vital biomarker for the early identification of high-risk individuals and disease prevention. However, current approaches can only characterize individual key metabolites, without taking into account the reality that complex diseases are multifactorial, dynamic, heterogeneous, and interdependent. Here, we leverage a statistical physics model to combine all metabolites into bidirectional, signed, and weighted interaction networks and trace how the flow of information from one metabolite to the next causes changes in health state. Viewing a disease outcome as the consequence of complex interactions among its interconnected components (metabolites), we integrate concepts from ecosystem theory and evolutionary game theory to model how the health state-dependent alteration of a metabolite is shaped by its intrinsic properties and through extrinsic influences from its conspecifics. We code intrinsic contributions as nodes and extrinsic contributions as edges into quantitative networks and implement GLMY homology theory to analyze and interpret the topological change of health state from symbiosis to dysbiosis and vice versa. The application of this model to real data allows us to identify several hub metabolites and their interaction webs, which play a part in the formation of inflammatory bowel diseases. The findings by our model could provide important information on drug design to treat these diseases and beyond.

The Unique Pt(II)-Induced Nucleolar Stress Response and its Deviation from DNA Damage Response Pathways.

The mechanisms of action for the platinum compounds cisplatin and oxaliplatin have yet to be fully elucidated, despite the worldwide use of these drugs. Recent studies suggest that the two compounds may be working through different mechanisms, with cisplatin inducing cell death via the DNA damage response (DDR) and oxaliplatin utilizing a nucleolar stress-based cell death pathway. While cisplatin-induced DDR has been subject to much research, the mechanisms for oxaliplatin's influence on the nucleolus are not well understood. Prior work has outlined structural parameters for Pt(II) derivatives capable of nucleolar stress induction. In this work, we gain insight into the nucleolar stress response induced by these Pt(II) derivatives by investigating potential correlations between this unique pathway and DDR. Key findings from this study indicate that Pt(II)-induced nucleolar stress occurs when DDR is inhibited and works independently of the ATM/ATR-dependent DDR pathway. We also determine that Pt(II)-induced stress may be linked to the G1 cell cycle phase, as cisplatin can induce nucleolar stress when cell cycle inhibition occurs at the G1/S checkpoint. Finally, we compare Pt(II)-induced nucleolar stress with other small-molecule nucleolar stress-inducing compounds Actinomycin D, BMH-21, and CX-5461, and find that only Pt(II) compounds cause irreversible nucleolar stress. Taken together, these findings contribute to a better understanding of Pt(II)-induced nucleolar stress, its deviation from ATM/ATR-dependent DDR, and the possible influence of cell cycle on the ability of Pt(II) compounds to cause nucleolar stress.

The dinosaurian femoral head experienced a morphogenetic shift from torsion to growth along the avian stem.

Significant evolutionary shifts in locomotor behaviour often involve comparatively subtle anatomical transitions. For dinosaurian and avian evolution, medial overhang of the proximal femur has been central to discussions. However, there is an apparent conflict with regard to the evolutionary origin of the dinosaurian femoral head, with neontological and palaeontological data suggesting seemingly incongruent hypotheses. To reconcile this, we reconstructed the evolutionary history of morphogenesis of the proximal end of the femur from early archosaurs to crown birds. Embryological comparison of living archosaurs (crocodylians and birds) suggests the acquisition of the greater overhang of the femoral head in dinosaurs results from additional growth of the proximal end in the medial-ward direction. On the other hand, the fossil record suggests that this overhang was acquired by torsion of the proximal end, which projected in a more rostral direction ancestrally. We reconcile this apparent conflict by inferring that the medial overhang of the dinosaur femoral head was initially acquired by torsion, which was then superseded by mediad growth. Details of anatomical shifts in fossil forms support this hypothesis, and their biomechanical implications are congruent with the general consensus regarding broader morpho-functional evolution on the avian stem.

Community formation in wealth-mediated thermodynamic strategy evolution.

We study a dynamical system defined by a repeated game on a 1D lattice, in which the players keep track of their gross payoffs over time in a bank. Strategy updates are governed by a Boltzmann distribution, which depends on the neighborhood bank values associated with each strategy, relative to a temperature scale, which defines the random fluctuations. Players with higher bank values are, thus, less likely to change strategy than players with a lower bank value. For a parameterized rock-paper-scissors game, we derive a condition under which communities of a given strategy form with either fixed or drifting boundaries. We show the effect of a temperature increase on the underlying system and identify surprising properties of this model through numerical simulations.

Genetic profiling of human bone marrow and adipose tissue-derived mesenchymal stem cells reveals differences in osteogenic signaling mediated by graphene.

BACKGROUND: In the last decade, graphene surfaces have consistently supported osteoblast development of stem cells, holding promise as a therapeutic implant for degenerative bone diseases. However, until now no study has specifically examined the genetic changes when stem cells undergo osteogenic differentiation on graphene. RESULTS: In this study, we provide a detailed overview of gene expressions when human mesenchymal stem cells (MSCs) derived from either adipose tissue (AD-MSCs) or bone marrow (BM-MSCs), are cultured on graphene. Genetic expressions were measured using osteogenic RT2 profiler PCR arrays and compared either over time (7 or 21 days) or between each cell source at each time point. Genes were categorized as either transcriptional regulation, osteoblast-related, extracellular matrix, cellular adhesion, BMP and SMAD signaling, growth factors, or angiogenic factors. Results showed that both MSC sources cultured on low oxygen graphene surfaces achieved osteogenesis by 21 days and expressed specific osteoblast markers. However, each MSC source cultured on graphene did have genetically different responses. When compared between each other, we found that genes of BM-MSCs were robustly expressed, and more noticeable after 7 days of culturing, suggesting BM-MSCs initiate osteogenesis at an earlier time point than AD-MSCs on graphene. Additionally, we found upregulated angiogenic markers in both MSCs sources, suggesting graphene could simultaneously attract the ingrowth of blood vessels in vivo. Finally, we identified several novel targets, including distal-less homeobox 5 (DLX5) and phosphate-regulating endopeptidase homolog, X-linked (PHEX). CONCLUSIONS: Overall, this study shows that graphene genetically supports differentiation of both AD-MSCs and BM-MSCs but may involve different signaling mechanisms to achieve osteogenesis. Data further demonstrates the lack of aberrant signaling due to cell-graphene interaction, strengthening the application of specific form and concentration of graphene nanoparticles in bone tissue engineering.

Dendritic cell biocompatibility of ether-based urethane films.

The use of synthetic materials for biomedical applications is ever expanding. One of the major requirements for these materials is biocompatibility, which includes prevention of immune system responses. Due to the inherent complexity of their structural composition, the polyurethane (PU) family of polymers is being used in a variety of medical applications, from soft and hard tissue scaffolds to intricate coatings on implantable devices. Herein, we investigated whether two polymer materials, D3 and D7, induced an immune response, measured by their effects on a dendritic cell (DC) line, JAWS II. Using a lactate dehydrogenase cytotoxicity assay and Annexin V/PI staining, we found that the PU materials did not induce cytotoxicity in DC cells. Using confocal microscopy, we also showed that the materials did not induce activation or maturation, as compared to positive controls. This was confirmed by looking at various markers, CD80, CD86, MHC class I, and MHC class II, via flow cytometry. Overall, the results indicated that the investigated PU films are biocompatible in terms of immunotoxicology and immunogenicity and show great promise for use in regenerative medicine.

Anomalously high variation in postnatal development is ancestral for dinosaurs but lost in birds.

Compared with all other living reptiles, birds grow extremely fast and possess unusually low levels of intraspecific variation during postnatal development. It is now clear that birds inherited their high rates of growth from their dinosaurian ancestors, but the origin of the avian condition of low variation during development is poorly constrained. The most well-understood growth trajectories of later Mesozoic theropods (e.g., Tyrannosaurus, Allosaurus) show similarly low variation to birds, contrasting with higher variation in extant crocodylians. Here, we show that deep within Dinosauria, among the earliest-diverging dinosaurs, anomalously high intraspecific variation is widespread but then is lost in more derived theropods. This style of development is ancestral for dinosaurs and their closest relatives, and, surprisingly, this level of variation is far higher than in living crocodylians. Among early dinosaurs, this variation is widespread across Pangaea in the Triassic and Early Jurassic, and among early-diverging theropods (ceratosaurs), this variation is maintained for 165 million years to the end of the Cretaceous. Because the Late Triassic environment across Pangaea was volatile and heterogeneous, this variation may have contributed to the rise of dinosaurian dominance through the end of the Triassic Period.

Sacral anatomy of the phytosaur Smilosuchus adamanensis, with implications for pelvic girdle evolution among Archosauriformes.

The sacrum - consisting of those vertebrae that articulate with the ilia - is the exclusive skeletal connection between the hindlimbs and axial skeleton in tetrapods. Therefore, the morphology of this portion of the vertebral column plays a major role in the evolution of terrestrial locomotion. Whereas most extant reptiles only possess the two plesiomorphic sacral vertebrae, additional vertebrae have been incorporated into the sacrum multiple times independently among early-diverging archosaurian (crocodylians + birds) clades. Phytosauria was a diverse, abundant, and cosmopolitan clade of archosauriforms throughout the Late Triassic, but postcrania of this clade are rarely described and few species-level taxonomic placements of phytosaurian postcranial material are available, potentially hampering knowledge of morphological disparity in the postcranial skeleton among phytosaurs. Here, we describe the sacrum of Smilosuchus adamanensis, a phytosaur recovered from the Upper Triassic Chinle Formation of Arizona. This sacrum consists of the two primordial sacral vertebrae, but has a vertebra incorporated from the trunk into the sacrum (= a dorsosacral) and is therefore the first Late Triassic phytosaur and one of the first non-archosaurian archosauromorphs to be described with more than two sacral vertebrae. Our interpretation of this element as a dorsosacral is justified by the lateral extent of the dorsosacral ribs, clear surfaces of articulation between the distal ends of the dorsosacral ribs and the first primordial sacral ribs, and the scar on the medial surface of each ilium for articulation with each dorsosacral rib. Additionally, we provide the first detailed description of the vertebral junction formed by two anteriorly projecting flanges on the first primordial sacral ribs and their corresponding facets on the centrum of the dorsosacral. Computed tomographic (CT) imaging reveals that the two primordial sacrals are not co-ossified and that the dorsosacral morphology of this specimen is not the result of obvious pathology. We place this incorporation of a trunk vertebra into the phytosaurian sacrum in a broader evolutionary context, with this shift in vertebral identity occurring at least seven times independently among Triassic archosauriforms, including at least three times in early crocodylian-line archosaurs and at least four times among bird-line archosaurs. Additionally, anteriorly projecting flanges of sacral ribs which articulate with the anterior-adjacent centrum have evolved several times in archosauriforms, and we interpret 'shared' sacral ribs (= a sacral rib that articulates with two adjacent sacral centra more or less equally) present in some archosaurian clades as a more extreme example of this morphology. In extant taxa the highly conserved Hox gene family plays a central role in the patterning of the axial skeleton, especially vertebral identity; therefore, the independent incorporation of a trunk vertebra into the sacrum across multiple archosauriform lineages may suggest a homologous underlying developmental mechanism for this evolutionary trend.

Impact of the new IADPSG gestational diabetes diagnostic criteria on pregnancy outcomes in Western Australia.

BACKGROUND: There is debate as to the most appropriate diagnostic criteria to diagnose gestational diabetes mellitus (GDM). The proposed International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria have recently been endorsed by various bodies, but there remains no national consensus. AIM: To assess the perinatal outcomes of women with GDM classified according to the 1998 Australasian Diabetes in Pregnancy Society (ADIPS) criteria compared to those with GDM by the IADPSG criteria. MATERIALS AND METHODS: Results of glucose tolerance tests performed between January 2011 and January 2014 were linked with the perinatal data of those who delivered singleton fetuses after 24 weeks' gestation. Analysed data included birthweight, gestational age at birth, macrosomia, mode of delivery, perinatal mortality, nursery admission, maternal body mass index, and gestational weight gain. RESULTS: Of 3571 women, 466 (13%) and 559 (16%) met the criteria for the 1998 ADIPS and IADPSG criteria for GDM, respectively. Those with GDM according to the IADPSG criteria only (6%) were more obese (95% CI 2.3-4.8 kg/m(2) ), delivered neonates on average 106 g heavier (95% CI 19-193 g) and had more fetal macrosomia (18% vs 11%, P = 0.002) than those with normal glucose tolerance. CONCLUSIONS: The IADPSG criteria for GDM identified a group of women at previously unrecognised increased risk of adverse perinatal outcomes. Adopting the IADPSG criteria would increase the number of women diagnosed with GDM by 20%; however, the improvements in perinatal morbidity, in addition to potential long-term benefits, may justify the increase in healthcare workload.

Patient attitudes towards outpatient cervical ripening prior to induction of labour at an Australian tertiary hospital.

A prospective patient questionnaire was conducted to assess attitudes and opinions towards outpatient cervical ripening in women attending an Australian tertiary hospital's labour and birth suite for a booked induction of labour. Questionnaires were distributed over a three-month period and information collected included demographic data, pregnancy and obstetric history, attitudes towards cervical ripening and willingness to undergo cervical ripening in the outpatient setting. Responses to 57 completed questionnaires were analysed. Forty-one patients (72%) underwent cervical ripening with Foley Catheter Balloon (FCB) only, eight (14%) with FCB and vaginal prostaglandins (VP), two (3.5%) with VP only and six patients (10.5%) did not require cervical ripening. One-third (33%) of patients stated, both before the commencement of cervical ripening and after delivery, that they would feel happy to undergo outpatient cervical ripening. Patient acceptance of outpatient cervical ripening has potential economic and psychosocial benefits for the healthcare system and patient respectively.

Changes in Caesarean Delivery Rates in Western Australia from 1995 to 2010 by Gestational Age at Birth.

BACKGROUND: The caesarean delivery rate in the developed world has been increasing. It is not well understood how caesarean delivery rates have changed by gestational age at birth in Western Australia, particularly in relation to the introduction of the early-term delivery guidelines in Australia in 2006. METHODS: Data from the Western Australian Midwives Notification System were used to identify 193,136 singletons born to primiparous women at 34-42 weeks' gestation during 1995-2010. Caesarean delivery rates were calculated by gestational age group (34-36 weeks, 37-38 weeks, and 39-42 weeks) and stratified into pre-labour and in-labour caesarean delivery. The average annual percent change (AAPC) for the caesarean delivery rates was calculated using joinpoint regression. Log-binomial regression was used to estimate the risk of having a caesarean delivery while adjusting for maternal and antenatal factors. RESULTS: Caesarean delivery rates rose steadily from 1995 to 2005 (AAPC = 5.9%, [95% confidence interval (CI) 4.9, 6.9]), but stabilised since then (AAPC = 0.9%, [95% CI -1.9, 3.8]). The rate of in-labour caesarean deliveries rose consistently from 1995 to 2010 across all gestational age groups. The pre-labour caesarean delivery rate rise was most dominant at 37-38 weeks' gestation from 1995 to 2005 (AAPC = 6.8%, [95% CI 5.4, 8.2]), but declined during 2006-10 (AAPC = -4.5, [95% CI -6.7, -2.3]), while at the same time the rate at 39-42 weeks rose slightly. CONCLUSIONS: The rise in pre-labour caesarean deliveries during 1995-2005 occurred predominantly at 37-38 weeks' gestation, but declined again from 2006 to 2010. This suggests that the recently developed Australian early-term delivery guidelines may have had some success in reducing early-term deliveries in Western Australia.

Probiotics in obstetrics and gynaecology.

Despite the great advances in modern medicine, our understanding of the most basic function of our complete genetic makeup is extremely poor. Our complete genetic make up is complemented by 100 trillion cells living within or on our body and is called the microbiome. Manipulation of the microbiome is in the embryological stages of investigation but promises great hope in targeting both pregnancy specific and general medical / gynaecological conditions. This review presents an undertanding of the microbiome manipulation with probiotics in women's health in 2015.

Topological learning in multiclass data sets.

We specialize techniques from topological data analysis to the problem of characterizing the topological complexity (as defined in the body of the paper) of a multiclass data set. As a by-product, a topological classifier is defined that uses an open subcovering of the data set. This subcovering can be used to construct a simplicial complex whose topological features (e.g., Betti numbers) provide information about the classification problem. We use these topological constructs to study the impact of topological complexity on learning in feedforward deep neural networks (DNNs). We hypothesize that topological complexity is negatively correlated with the ability of a fully connected feedforward deep neural network to learn to classify data correctly. We evaluate our topological classification algorithm on multiple constructed and open-source data sets. We also validate our hypothesis regarding the relationship between topological complexity and learning in DNN's on multiple data sets.