Risk factors for early-onset colorectal cancer: A Canadian prospective cohort study.

PURPOSE: The incidence of early-onset (<50 years of age) colorectal cancer (eoCRC) has been steadily increasing in high-income countries including Canada. Despite this increase in incidence, the etiology of eoCRC remains unclear and prospective cohort studies of potential risk factors are limited. METHODS: We examined two prospective cohorts of healthy individuals (<50 years of age) who completed baseline questionnaires in the Ontario Health Study and Alberta's Tomorrow Project. We examined the associations between demographic characteristics, chronic health conditions, and lifestyle behaviours with the development of eoCRC using Cox proportional hazard models. Cohorts were analyzed separately and hazard ratios for each risk factor were pooled with random effects meta-analyses. RESULTS: During an average follow-up of 6.63 years, 98 eoCRC cases occurred among study participants (n=127,852). A family history of CRC alone or with a history of other cancer types was associated with an increased risk of developing eoCRC (HR: 2.76, 95% CI: 1.43-5.32), but a family history of a non-CRC cancer only was not (HR: 1.18, 95% CI: 0.61-2.30). Heavy smokers (≥ 10 pack-years) at baseline had a higher risk of eoCRC compared to non-smokers (HR: 1.87, 95% CI: 1.00-3.52). Sex, socioeconomic factors, diabetes, alcohol consumption, among other factors were not significantly associated with the risk of eoCRC. CONCLUSION: Our findings indicate that specific CRC risk factors are also associated with developing eoCRC. The data in the study offers valuable insights that could be integrated in future meta-analyses. Additional prospective cohort studies are required to understand the etiology of eoCRC.

Estimation of the forces exerted on the limb long bones of a white rhinoceros (Ceratotherium simum) using musculoskeletal modelling and simulation.

Heavy animals incur large forces on their limb bones, due to the transmission of body weight and ground reaction forces, and the contractions of the various muscles of the limbs. This is particularly true for rhinoceroses, the heaviest extant animals capable of galloping. Several studies have examined their musculoskeletal system and the forces their bones incur, but no detailed quantification has ever been attempted. Such quantification could help understand better the link between form and function in giant land animals. Here we constructed three-dimensional musculoskeletal models of the forelimb and hindlimb of Ceratotherium simum, the heaviest extant rhino species, and used static optimisation (inverse) simulations to estimate the forces applied on the bones when standing at rest, including magnitudes and directions. Overall, unsurprisingly, the most active muscles were antigravity muscles, which generate moments opposing body weight (thereby incurring the ground reaction force), and thus keep the joints extended, avoiding joint collapse via flexion. Some muscles have an antigravity action around several joints, and thus were found to be highly active, likely specialised in body weight support (ulnaris lateralis; digital flexors). The humerus was subjected to the greatest amount of forces in terms of total magnitude; forces on the humerus furthermore came from a great variety of directions. The radius was mainly subject to high-magnitude compressive joint reaction forces, but to little muscular tension, whereas the opposite pattern was observed for the ulna. The femur had a pattern similar to that of the humerus, and the tibia's pattern was intermediate, being subject to great compression in its caudal side but to great tension in its cranial side (i.e. bending). The fibula was subject to by far the lowest force magnitude. Overall, the forces estimated were consistent with the documented morphofunctional adaptations of C. simum's long bones, which have larger insertion areas for several muscles and a greater robusticity overall than those of lighter rhinos, likely reflecting the intense forces we estimated here. Our estimates of muscle and bone (joint) loading regimes for this giant tetrapod improve the understanding of the links between form and function in supportive tissues and could be extended to other aspects of bone morphology, such as microanatomy.

Static versus dynamic muscle modelling in extinct species: a biomechanical case study of the Australopithecus afarensis pelvis and lower extremity.

The force a muscle generates is dependent on muscle structure, in which fibre length, pennation angle and tendon slack length all influence force production. Muscles are not preserved in the fossil record and these parameters must be estimated when constructing a musculoskeletal model. Here, we test the capability of digitally reconstructed muscles of the Australopithecus afarensis model (specimen AL 288-1) to maintain an upright, single-support limb posture. Our aim was to ascertain the influence that different architectural estimation methods have on muscle specialisation and on the subsequent inferences that can be extrapolated about limb function. Parameters were estimated for 36 muscles in the pelvis and lower limb and seven different musculoskeletal models of AL 288-1 were produced. These parameters represented either a 'static' Hill-type muscle model (n = 4 variants) which only incorporated force, or instead a 'dynamic' Hill-type muscle model with an elastic tendon and fibres that could vary force-length-velocity properties (n = 3 variants). Each muscle's fibre length, pennation angle, tendon slack length and maximal isometric force were calculated based upon different input variables. Static (inverse) simulations were computed in which the vertical and mediolateral ground reaction forces (GRF) were incrementally increased until limb collapse (simulation failure). All AL 288-1 variants produced somewhat similar simulated muscle activation patterns, but the maximum vertical GRF that could be exerted on a single limb was not consistent between models. Three of the four static-muscle models were unable to support >1.8 times body weight and produced models that under-performed. The dynamic-muscle models were stronger. Comparative results with a human model imply that similar muscle group activations between species are needed to sustain single-limb support at maximally applied GRFs in terms of the simplified static simulations (e.g., same walking pose) used here. This approach demonstrated the range of outputs that can be generated for a model of an extinct individual. Despite mostly comparable outputs, the models diverged mostly in terms of strength.

The Association between Red Meat Consumption and Advanced Colorectal Adenomas in a Population Undergoing a Screening-Related Colonoscopy in Alberta, Canada.

The association between red meat consumption and colorectal cancer has been rigorously examined. However, a more comprehensive understanding of how the intake of unprocessed red meat contributes to the development of early precancerous colorectal lesions, such as advanced colorectal adenomas (ACRAs), requires further investigation. We examined the associations between different types of red meat intake and ACRAs in a sample population of 1083 individuals aged ≥ 50 years undergoing an initial screening colonoscopy in Calgary, Alberta, Canada. Associations between grams per day of total, processed, and unprocessed red meat from diet history questionnaires and ACRAs were evaluated with multivariable logistic regression models. We also applied cubic spline models fitted with three knots (10th, 50th, and 90th percentiles) to identify potential nonlinear associations. We did not observe a meaningful association between unprocessed red meat intake and the presence of ACRAs. In contrast, for every 10 g/d increase in total and processed meat intake, we observed an increase in the odds of ACRAs at the screening colonoscopy (adjusted odds ratio (OR) = 1.05, 95% [CI = 1.01-1.09], p = 0.04) and (adjusted OR = 1.11, 95% [CI = 1.02-1.20], p = 0.02), respectively. This study highlights the importance of differentiating between types of red meat consumption in the context of dietary risks associated with ACRAs.

Body weight-based iodinated contrast immersion timing for human fetal postmortem microfocus computed tomography.

Objectives: The aim of this study was to evaluate the length of time required to achieve full iodination using potassium tri-iodide as a contrast agent, prior to human fetal postmortem microfocus computed tomography (micro-CT) imaging. Methods: Prospective assessment of optimal contrast iodination was conducted across 157 human fetuses (postmortem weight range 2-298 g; gestational age range 12-37 weeks), following micro-CT imaging. Simple linear regression was conducted to analyse which fetal demographic factors could produce the most accurate estimate for optimal iodination time. Results: Postmortem body weight (r2 = 0.6435) was better correlated with iodination time than gestational age (r2 = 0.1384), producing a line of best fit, y = [0.0304 × body weight (g)] - 2.2103. This can be simplified for clinical use whereby immersion time (days) = [0.03 × body weight (g)] - 2.2. Using this formula, for example, a 100-g fetus would take 5.2 days to reach optimal contrast enhancement. Conclusions: The simplified equation can now be used to provide estimation times for fetal contrast preparation time prior to micro-CT imaging and can be used to manage service throughput and parental expectation for return of their fetus. Advances in knowledge: A simple equation from empirical data can now be used to estimate preparation time for human fetal postmortem micro-CT imaging.

Reconstruction of the pelvic girdle and hindlimb musculature of the early tetanurans Piatnitzkysauridae (Theropoda, Megalosauroidea).

Piatnitzkysauridae were Jurassic theropods that represented the earliest diverging branch of Megalosauroidea, being one of the earliest lineages to have evolved moderate body size. This clade's typical body size and some unusual anatomical features raise questions about locomotor function and specializations to aid in body support; and other palaeobiological issues. Biomechanical models and simulations can illuminate how extinct animals may have moved, but require anatomical data as inputs. With a phylogenetic context, osteological evidence, and neontological data on anatomy, it is possible to infer the musculature of extinct taxa. Here, we reconstructed the hindlimb musculature of Piatnitzkysauridae (Condorraptor, Marshosaurus, and Piatnitzkysaurus). We chose this clade for future usage in biomechanics, for comparisons with myological reconstructions of other theropods, and for the resulting evolutionary implications of our reconstructions; differential preservation affects these inferences, so we discuss these issues as well. We considered 32 muscles in total: for Piatnitzkysaurus, the attachments of 29 muscles could be inferred based on the osteological correlates; meanwhile, in Condorraptor and Marshosaurus, we respectively inferred 21 and 12 muscles. We found great anatomical similarity within Piatnitzkysauridae, but differences such as the origin of M. ambiens and size of M. caudofemoralis brevis are present. Similarities were evident with Aves, such as the division of the M. iliofemoralis externus and M. iliotrochantericus caudalis and a broad depression for the M. gastrocnemius pars medialis origin on the cnemial crest. Nevertheless, we infer plesiomorphic features such as the origins of M. puboischiofemoralis internus 1 around the "cuppedicus" fossa and M. ischiotrochantericus medially on the ischium. As the first attempt to reconstruct muscles in early tetanurans, our study allows a more complete understanding of myological evolution in theropod pelvic appendages.

DEVELOPMENT AND EVALUATION OF A STANDARDIZED SYSTEM FOR THE ASSESSMENT OF LOCOMOTOR HEALTH IN ELEPHANTS UNDER HUMAN CARE.

Although lameness is a common problem in elephants (Asian elephant [Elephas maximus] and African elephants Loxodonta africana and Loxodonta cyclotis) under human care, there has not been a standardized lameness assessment system to date. This study developed and evaluated a standardized system for the assessment of locomotion in elephants under human care regardless of husbandry system. In total, 72 elephants out of a possible 73 in the United Kingdom and Ireland were filmed from behind, from in front, and from both sides. Using a questionnaire and a select panel of elephant specialists, a zoo veterinarian, and a locomotion expert, a numerical rating scoring (NRS) system was proposed. Locomotion was scored on a 4-point scale with numerical values 0-4 corresponding to specific criteria as follows: 0 = clinically sound, 1 = stiffness, 2 = abnormal tracking, and 4 = reluctance to bear weight. The intra- and interobserver repeatability of five veterinary surgeons using this system was determined and compared with a visual analog scale (VAS) expressed as a 100-mm line. Overall intraobserver reliability was moderate (Cohen's kappa [κ] = 0.676) and interobserver reliability was fair (κ = 0.37) for the presence of lameness. Interobserver agreement improved from the first scoring to second scoring from slight agreement to fair agreement for stiffness and reluctance to bear weight. Abnormal tracking had moderate intraobserver agreement for both scoring sessions. There were wide widths of agreement for the VAS interobserver (67 mm); however, they were narrower for the intraobserver (33 mm). The developed NRS can be used on freely moving elephants to evaluate elephant locomotion, regardless of husbandry methods, and has been shown to be more reliable than a VAS.

Visual feedback influences the consistency of the locomotor pattern in Asian elephants (Elephas maximus).

Elephants are atypical of most quadrupeds in that they maintain the same lateral sequence footfall pattern across all locomotor speeds. It has been speculated that the preservation of the footfall patterns is necessary to maintain a statically stable support polygon. This should be a particularly important constraint in large, relatively slow animals. This suggests that elephants must rely on available sensory feedback mechanisms to actively control their massive pillar-like limbs for proper foot placement and sequencing. How the nervous system of elephants integrates the available sensory information for a stable gait is unknown. Here we explored the role that visual feedback plays in the control of the locomotor pattern in Asian elephants. Four Asian elephants (Elephas maximus) walked with and without a blindfold as we measured their stride time intervals. Coefficient of variation was used to assess changes in the overall variability of the stride time intervals, while approximate entropy was used to measure the stride-to-stride consistency of the time intervals. We show that visual feedback plays a role in the stride-to-stride consistency of the locomotor pattern in Asian elephants. These results suggest that elephants use visual feedback to correct and maintain proper sequencing of the limbs during locomotion.

Macroevolutionary patterns in the pelvis, stylopodium and zeugopodium of megalosauroid theropod dinosaurs and their importance for locomotor function.

During the Mesozoic, non-avian theropods represented one of the most successful clades globally distributed, with a wide diversity of forms. An example is the clade Megalosauroidea, which included medium- to large-bodied forms. Here, we analyse the macroevolution of the locomotor system in early Theropoda, emphasizing the Megalosauroidea. We scored the Spinosaurus neotype in a published taxon-character matrix and described the associated modifications in character states, mapping them onto a phylogeny and using these to study disparity. In the evolution of Megalosauroidea, there was the mosaic emergence of a low swollen ridge; enlargement of the posterior brevis fossa and emergence of a posterodorsal process on the ilium in some megalosauroids; emergence of a femoral head oriented anteromedially and medially angled, and appearance of posterolaterally oriented medial femoral condyles in spinosaurids. The greatest morphological disparity is in the ilium of megalosaurids; the ischium seems to have a high degree of homoplasy; there is a clear distinction in the femoral morphospace regarding megalosauroids and other theropods; piatnitzkysaurids show considerable disparity of zeugopodial characters. These reconstructions of osteological evolution form a stronger basis on which other studies could build, such as mapping of pelvic/appendicular musculature and/or correlating skeletal traits with changes in locomotor function.

Equilibration of precipitants in a counter-diffusion apparatus for protein crystallization.

A cost-effective capillary dialysis apparatus (Toledo Capillary Box, TCB) developed for biomacromolecule crystal growth in microgravity and unit gravity environments can provide slow equilibration between the precipitant reservoir and capillary solutions, nurturing growth of neutron-diffraction-quality crystals. Under microgravity conditions, mass transfer of precipitants and biomacro-mol-ecules occurs under diffusion-controlled conditions, promoting slow growth and suppressing defect formation. The equilibration of common precipitants (polyethyl-ene glycol and salts such as ammonium sulfate) between capillary and reservoir solutions was measured for capillaries oriented horizontally or vertically with respect to the gravitational field at unit gravity. Precipitants equilibrated less rapidly in the vertical orientation when capillary solution densities were lower than those of the reservoir solutions. A plug filled with agarose gel was introduced in the TCB apparatus for salt precipitants since salts often exhibit relatively high free diffusion. Equilibration of the capillaries with reservoir solutions was significantly delayed for many of the salt precipitants tested. Analytical and semi-analytical models allow the prediction of precipitant equilibration of capillary and reservoir solutions under diffusion-controlled transport and show good agreement with experimental results.

Skin-type-dependent development of murine mechanosensory neurons.

Mechanosensory neurons innervating the skin underlie our sense of touch. Fast-conducting, rapidly adapting mechanoreceptors innervating glabrous (non-hairy) skin form Meissner corpuscles, while in hairy skin, they associate with hair follicles, forming longitudinal lanceolate endings. How mechanoreceptors develop axonal endings appropriate for their skin targets is unknown. We report that mechanoreceptor morphologies across different skin regions are indistinguishable during early development but diverge post-natally, in parallel with skin maturation. Neurons terminating along the glabrous and hairy skin border exhibit hybrid morphologies, forming both Meissner corpuscles and lanceolate endings. Additionally, molecular profiles of neonatal glabrous and hairy skin-innervating neurons largely overlap. In mouse mutants with ectopic glabrous skin, mechanosensory neurons form end-organs appropriate for the altered skin type. Finally, BMP5 and BMP7 are enriched in glabrous skin, and signaling through type I bone morphogenetic protein (BMP) receptors in neurons is critical for Meissner corpuscle morphology. Thus, mechanoreceptor morphogenesis is flexibly instructed by target tissues.

Evolution of posture in amniotes-Diving into the trabecular architecture of the femoral head.

Extant amniotes show remarkable postural diversity. Broadly speaking, limbs with erect (strongly adducted, more vertically oriented) posture are found in mammals that are particularly heavy (graviportal) or show good running skills (cursorial), while crouched (highly flexed) limbs are found in taxa with more generalized locomotion. In Reptilia, crocodylians have a "semi-erect" (somewhat adducted) posture, birds have more crouched limbs and lepidosaurs have sprawling (well-abducted) limbs. Both synapsids and reptiles underwent a postural transition from sprawling to more erect limbs during the Mesozoic Era. In Reptilia, this postural change is prominent among archosauriforms in the Triassic Period. However, limb posture in many key Triassic taxa remains poorly known. In Synapsida, the chronology of this transition is less clear, and competing hypotheses exist. On land, the limb bones are subject to various stresses related to body support that partly shape their external and internal morphology. Indeed, bone trabeculae (lattice-like bony struts that form the spongy bone tissue) tend to orient themselves along lines of force. Here, we study the link between femoral posture and the femoral trabecular architecture using phylogenetic generalized least squares. We show that microanatomical parameters measured on bone cubes extracted from the femoral head of a sample of amniote femora depend strongly on body mass, but not on femoral posture or lifestyle. We reconstruct ancestral states of femoral posture and various microanatomical parameters to study the "sprawling-to-erect" transition in reptiles and synapsids, and obtain conflicting results. We tentatively infer femoral posture in several hypothetical ancestors using phylogenetic flexible discriminant analysis from maximum likelihood estimates of the microanatomical parameters. In general, the trabecular network of the femoral head is not a good indicator of femoral posture. However, ancestral state reconstruction methods hold great promise for advancing our understanding of the evolution of posture in amniotes.

Functional Annotation Routines Used by ABRF Bioinformatics Core Facilities - Observations, Comparisons, and Considerations.

The functional annotation of gene lists is a common analysis routine required for most genomics experiments, and bioinformatics core facilities must support these analyses. In contrast to methods such as the quantitation of RNA-Seq reads or differential expression analysis, our research group noted a lack of consensus in our preferred approaches to functional annotation. To investigate this observation, we selected 4 experiments that represent a range of experimental designs encountered by our cores and analyzed those data with 6 tools used by members of the Association of Biomolecular Resource Facilities (ABRF) Genomic Bioinformatics Research Group (GBIRG). To facilitate comparisons between tools, we focused on a single biological result for each experiment. These results were represented by a gene set, and we analyzed these gene sets with each tool considered in our study to map the result to the annotation categories presented by each tool. In most cases, each tool produces data that would facilitate identification of the selected biological result for each experiment. For the exceptions, Fisher's exact test parameters could be adjusted to detect the result. Because Fisher's exact test is used by many functional annotation tools, we investigated input parameters and demonstrate that, while background set size is unlikely to have a significant impact on the results, the numbers of differentially expressed genes in an annotation category and the total number of differentially expressed genes under consideration are both critical parameters that may need to be modified during analyses. In addition, we note that differences in the annotation categories tested by each tool, as well as the composition of those categories, can have a significant impact on results.

Decoupling body shape and mass distribution in birds and their dinosaurian ancestors.

It is accepted that non-avian theropod dinosaurs, with their long muscular tails and small forelimbs, had a centre-of-mass close to the hip, while extant birds, with their reduced tails and enlarged wings have their mass centred more cranially. Transition between these states is considered crucial to two key innovations in the avian locomotor system: crouched bipedalism and powered flight. Here we use image-based models to challenge this dichotomy. Rather than a phylogenetic distinction between 'dinosaurian' and 'avian' conditions, we find terrestrial versus volant taxa occupy distinct regions of centre-of-mass morphospace consistent with the disparate demands of terrestrial bipedalism and flight. We track this decoupled evolution of body shape and mass distribution through bird evolution, including the origin of centre-of-mass positions more advantageous for flight and major reversions coincident with terrestriality. We recover modularity in the evolution of limb proportions and centre-of-mass that suggests fully crouched bipedalism evolved after powered flight.

Modern three-dimensional digital methods for studying locomotor biomechanics in tetrapods.

Here, we review the modern interface of three-dimensional (3D) empirical (e.g. motion capture) and theoretical (e.g. modelling and simulation) approaches to the study of terrestrial locomotion using appendages in tetrapod vertebrates. These tools span a spectrum from more empirical approaches such as XROMM, to potentially more intermediate approaches such as finite element analysis, to more theoretical approaches such as dynamic musculoskeletal simulations or conceptual models. These methods have much in common beyond the importance of 3D digital technologies, and are powerfully synergistic when integrated, opening a wide range of hypotheses that can be tested. We discuss the pitfalls and challenges of these 3D methods, leading to consideration of the problems and potential in their current and future usage. The tools (hardware and software) and approaches (e.g. methods for using hardware and software) in the 3D analysis of tetrapod locomotion have matured to the point where now we can use this integration to answer questions we could never have tackled 20 years ago, and apply insights gleaned from them to other fields.

Locomotor and postural diversity among reptiles viewed through the prism of femoral microanatomy: Palaeobiological implications for some Permian and Mesozoic taxa.

The water-to-land transition by the first tetrapod vertebrates represents a key stage in their evolution. Selection pressures exerted by this new environment on animals led to the emergence of new locomotor and postural strategies that favoured access to different ecological niches and contributed to their evolutionary success. Today, amniotes show great locomotor and postural diversity, particularly among Reptilia, whose extant representatives include parasagittally locomoting erect and crouched bipeds (birds), sub-parasagittal 'semi-erect' quadrupeds (crocodylians) and sprawling quadrupeds (squamates and turtles). But the different steps leading to such diversity remain enigmatic and the type of locomotion adopted by many extinct species raises questions. This is notably the case of certain Triassic taxa such as Euparkeria and Marasuchus. The exploration of the bone microanatomy in reptiles could help to overcome these uncertainties. Indeed, this locomotor and postural diversity is accompanied by great microanatomical disparity. On land, the bones of the appendicular skeleton support the weight of the body and are subject to multiple constraints that partly shape their external and internal morphology. Here we show how microanatomical parameters measured in cross-section, such as bone compactness or the position of the medullocortical transition, can be related to locomotion. We hypothesised that this could be due to variations in cortical thickness. Using statistical methods that take phylogeny into account (phylogenetic flexible discriminant analyses), we develop different models of locomotion from a sample of femur cross-sections from 51 reptile species. We use these models to infer locomotion and posture in 7 extinct reptile taxa for which they remain debated or not fully clear. Our models produced reliable inferences for taxa that preceded and followed the quadruped/biped and sprawling/erect transitions, notably within the Captorhinidae and Dinosauria. For taxa contemporary with these transitions, such as Terrestrisuchus and Marasuchus, the inferences are more questionable. We use linear models to investigate the effect of body mass and functional ecology on our inference models. We show that body mass seems to significantly impact our model predictions in most cases, unlike the functional ecology. Finally, we illustrate how taphonomic processes can impact certain microanatomical parameters, especially the eccentricity of the section, while addressing some other potential limitations of our methods. Our study provides insight into the evolution of enigmatic locomotion in various early reptiles. Our models and methods could be used by palaeontologists to infer the locomotion and posture in other extinct reptile taxa, especially when considered in combination with other lines of evidence.

The Inverse Krogh Principle: All Organisms Are Worthy of Study.

AbstractKrogh's principle states, "For such a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied." The downside of picking a question first and then finding an ideal organism on which to study it is that it will inevitably leave many organisms neglected. Here, we promote the inverse Krogh principle: all organisms are worthy of study. The inverse Krogh principle and the Krogh principle are not opposites. Rather, the inverse Krogh principle emphasizes a different starting point for research: start with a biological unit, such as an organism, clade, or specific organism trait, then seek or create tractable research questions. Even the hardest-to-study species have research questions that can be asked of them: Where does it fall within the tree of life? What resources does it need to survive and reproduce? How does it differ from close relatives? Does it have unique adaptations? The Krogh and inverse Krogh approaches are complementary, and many research programs naturally include both. Other considerations for picking a study species include extreme species, species informative for phylogenetic analyses, and the creation of models when a suitable species does not exist. The inverse Krogh principle also has pitfalls. A scientist that picks the organism first might choose a research question not really suited to the organism, and funding agencies rarely fund organism-centered grant proposals. The inverse Krogh principle does not call for all organisms to receive the same amount of research attention. As knowledge continues to accumulate, some organisms-models-will inevitably have more known about them than others. Rather, it urges a broader search across organismal diversity to find sources of inspiration for research questions and the motivation needed to pursue them.

Quantitative biomechanical assessment of locomotor capabilities of the stem archosaur Euparkeria capensis.

Birds and crocodylians are the only remaining members of Archosauria (ruling reptiles) and they exhibit major differences in posture and gait, which are polar opposites in terms of locomotor strategies. Their broader lineages (Avemetatarsalia and Pseudosuchia) evolved a multitude of locomotor modes in the Triassic and Jurassic periods, including several occurrences of bipedalism. The exact timings and frequencies of bipedal origins within archosaurs, and thus their ancestral capabilities, are contentious. It is often suggested that archosaurs ancestrally exhibited some form of bipedalism. Euparkeria capensis is a central taxon for the investigation of locomotion in archosaurs due to its phylogenetic position and intermediate skeletal morphology, and is argued to be representative of facultative bipedalism in this group. However, no studies to date have biomechanically tested if bipedality was feasible in Eupakeria. Here, we use musculoskeletal models and static simulations in its hindlimb to test the influences of body posture and muscle parameter estimation methods on locomotor potential. Our analyses show that the resulting negative pitching moments around the centre of mass were prohibitive to sustainable bipedality. We conclude that it is unlikely that Euparkeria was facultatively bipedal, and was probably quadrupedal, rendering the inference of ancestral bipedal abilities in Archosauria unlikely.

Gut adaptation after gastric bypass in humans reveals metabolically significant shift in fuel metabolism.

OBJECTIVE: Roux-en-Y gastric bypass surgery (RYGB) is among the most effective therapies for obesity and type 2 diabetes, and intestinal adaptation is a proposed mechanism for these effects. It was hypothesized that intestinal adaptation precedes and relates to metabolic improvement in humans after RYGB. METHODS: This was a prospective, longitudinal, first-in-human study of gene expression (GE) in the "Roux limb" (RL) collected surgically/endoscopically from 19 patients with and without diabetes. GE was determined by microarray across six postoperative months, including at an early postoperative (1 month ± 15 days) time point. RESULTS: RL GE demonstrated tissue remodeling and metabolic reprogramming, including increased glucose and amino acid use. RL GE signatures were established early, before maximal clinical response, and persisted. Distinct GE fingerprints predicted concurrent and future improvements in HbA1c and in weight. Human RL exhibited GE changes characterized by anabolic growth and shift in metabolic substrate use. Paradoxically, anabolic growth in RL appeared to contribute to the catabolic state elicited by RYGB. CONCLUSIONS: These data support a role for a direct effect of intestinal energy metabolism to contribute to the beneficial clinical effects of RYGB, suggesting that related pathways might be potential targets of therapeutic interest for patients with obesity with or without type 2 diabetes.

Anatomically grounded estimation of hindlimb muscle sizes in Archosauria.

In vertebrates, active movement is driven by muscle forces acting on bones, either directly or through tendinous insertions. There has been much debate over how muscle size and force are reflected by the muscular attachment areas (AAs). Here we investigate the relationship between the physiological cross-sectional area (PCSA), a proxy for the force production of the muscle, and the AA of hindlimb muscles in Nile crocodiles and five bird species. The limbs were held in a fixed position whilst blunt dissection was carried out to isolate the individual muscles. AAs were digitised using a point digitiser, before the muscle was removed from the bone. Muscles were then further dissected and fibre architecture was measured, and PCSA calculated. The raw measures, as well as the ratio of PCSA to AA, were studied and compared for intra-observer error as well as intra- and interspecies differences. We found large variations in the ratio between AAs and PCSA both within and across species, but muscle fascicle lengths are conserved within individual species, whether this was Nile crocodiles or tinamou. Whilst a discriminant analysis was able to separate crocodylian and avian muscle data, the ratios for AA to cross-sectional area for all species and most muscles can be represented by a single equation. The remaining muscles have specific equations to represent their scaling, but equations often have a relatively high success at predicting the ratio of muscle AA to PCSA. We then digitised the muscle AAs of Coelophysis bauri, a dinosaur, to estimate the PCSAs and therefore maximal isometric muscle forces. The results are somewhat consistent with other methods for estimating force production, and suggest that, at least for some archosaurian muscles, that it is possible to use muscle AA to estimate muscle sizes. This method is complementary to other methods such as digital volumetric modelling.