High-latitude ocean habitats are a crucible of fish body shape diversification.

A decline in diversity from the equator to the poles is a common feature of Earth's biodiversity. Here, we examine body shape diversity in marine fishes across latitudes and explore the role of time and evolutionary rate in explaining the diversity gradient. Marine fishes' occupation of upper latitude environments has increased substantially over the last 80 million years. Fishes in the highest latitudes exhibit twice the rate of body shape evolution and one and a third times the disparity compared to equatorial latitudes. The faster evolution of body shape may be a response to increased ecological opportunity in polar and subpolar oceans due to (1) the evolution of antifreeze proteins allowing certain lineages to invade regions of cold water, (2) environmental disturbances driven by cyclical warming and cooling in high latitudes, and (3) rapid transitions across depth gradients. Our results add to growing evidence that evolutionary rates are often faster at temperate, not tropical, latitudes.

Impact of weight and creatinine adjustments on the accuracy of Cockcroft-gault equation in hematopoietic cell transplant patients.

BACKGROUND: Hematopoietic cell transplant (HCT) patients undergo pre- transplant renal function evaluation to confirm transplant eligibility and tailor pharmacotherapy. There is limited evidence regarding the most accurate method of estimating creatinine clearance (CrCl) within this patient population and no studies exist that evaluate the weight utilized within the Cockcroft-Gault (CG) equation in HCT patients. This study evaluates different weight and serum creatinine (SCr) adjustments utilized within the CG equation estimating for renal clearance in patients undergoing HCT. OBJECTIVE: This is a retrospective, single center analysis of adult HCT patients who underwent pre-transplant evaluation with a measured CrCl using a 24-h urine creatinine collection. The primary outcome was to evaluate the correlation of various weights used in estimation of CrCl compared to measured CrCl. Key secondary outcomes include evaluation of the impact of various weights on estimated CrCl in subpopulations, evaluation of adjusting SCr to pre-determined limits, and determination of an appropriate obesity threshold to utilize body weight adjustments. RESULTS: Seven-hundred and forty-two patients were included in the study. In the primary analysis, CG utilizing adjusted body weight (ADjBW0.4 ) had a greater correlation (r = .812) to measured CrCl when compared to total or ideal body weight (r = .801 and r = .790 respectively). The threshold of 120% of ideal body weight (IBW) produced less bias and greater accuracy in comparison to the threshold of 140% IBW. In patients 60 years or older, rounding low SCr values up .8 or 1 mg/dL resulted in decreased correlation and a greater mean difference in comparison to not rounding SCr. CONCLUSION: In HCT patients who are overweight or obese, ADjBW .4 is the most accurate weight for the CG equation. In HCT patients who have a total body weight < 120% IBW, total body weight is the most accurate weight to utilize. Rounding up low SCr to .8 or 1 mg/dL does not improve the accuracy or led to less bias of the CG equation.

What is a mammalian omnivore? Insights into terrestrial mammalian diet diversity, body mass and evolution.

Mammalian omnivores are a broad group of species that are often treated uniformly in ecological studies. Here, we incorporate omnivorous dietary differences to investigate previously found mammalian macroevolutionary and macroecological trends. We investigate the frequency with which vertebrate prey, invertebrate prey, fibrous plant material and non-fibrous plant material co-occur in the diets of terrestrial mammals. We quantify the body size distributions and phylogenetic signal of different omnivorous diets and use multistate reversible jump Markov chain Monte Carlo methods to assess the transition rates between diets on the mammalian phylogenetic tree. We find omnivores that consume all four food types are relatively rare, as most omnivores consume only invertebrate prey and non-fibrous plants. In addition, omnivores that only consume invertebrate prey, many of which are from Rodentia, are on average smaller than omnivores that incorporate vertebrate prey. Our transition models have high rates from invertivorous omnivory to herbivory, and from vertivory to prey mixing and ultimately invertivory. We suggest prey type is an important aspect of omnivore macroevolution and macroecology, as it is correlated with body mass, evolutionary history and diet-related evolutionary transition rates. Future work should avoid lumping omnivores into one category given the ecological variety of omnivore diets and their strong evolutionary influence.

Alternating regimes of shallow and deep-sea diversification explain a species-richness paradox in marine fishes.

The deep sea contains a surprising diversity of life, including iconic fish groups such as anglerfishes and lanternfishes. Still, >65% of marine teleost fish species are restricted to the photic zone <200 m, which comprises less than 10% of the ocean's total volume. From a macroevolutionary perspective, this paradox may be explained by three hypotheses: 1) shallow water lineages have had more time to diversify than deep-sea lineages, 2) shallow water lineages have faster rates of speciation than deep-sea lineages, or 3) shallow-to-deep sea transition rates limit deep-sea richness. Here we use phylogenetic comparative methods to test among these three non-mutually exclusive hypotheses. While we found support for all hypotheses, the disparity in species richness is better described as the uneven outcome of alternating phases that favored shallow or deep diversification over the past 200 million y. Shallow marine teleosts became incredibly diverse 100 million y ago during a period of warm temperatures and high sea level, suggesting the importance of reefs and epicontinental settings. Conversely, deep-sea colonization and speciation was favored during brief episodes when cooling temperatures increased the efficiency of the ocean's carbon pump. Finally, time-variable ecological filters limited shallow-to-deep colonization for much of teleost history, which helped maintain higher shallow richness. A pelagic lifestyle and large jaws were associated with early deep-sea colonists, while a demersal lifestyle and a tapered body plan were typical of later colonists. Therefore, we also suggest that some hallmark characteristics of deep-sea fishes evolved prior to colonizing the deep sea.

Biotic Interactions and the Future of Fishes on Coral Reefs: The Importance of Trait-Based Approaches.

Biotic interactions govern the structure and function of coral reef ecosystems. As environmental conditions change, reef-associated fish populations can persist by tracking their preferred niche or adapting to new conditions. Biotic interactions will affect how these responses proceed and whether they are successful. Yet, our understanding of these effects is currently limited. Ecological and evolutionary theories make explicit predictions about the effects of biotic interactions, but many remain untested. Here, we argue that large-scale functional trait datasets enable us to investigate how biotic interactions have shaped the assembly of contemporary reef fish communities and the evolution of species within them, thus improving our ability to predict future changes. Importantly, the effects of biotic interactions on these processes have occurred simultaneously within dynamic environments. Functional traits provide a means to integrate the effects of both ecological and evolutionary processes, as well as a way to overcome some of the challenges of studying biotic interactions. Moreover, functional trait data can enhance predictive modeling of future reef fish distributions and evolvability. We hope that our vision for an integrative approach, focused on quantifying functionally relevant traits and how they mediate biotic interactions in different environmental contexts, will catalyze new research on the future of reef fishes in a changing environment.

FishShapes v1: Functionally relevant measurements of teleost shape and size on three dimensions.

Teleost fishes account for 96% of all fish species and exhibit a spectacular variety of body forms. Teleost lineages range from deep bodied to elongate (e.g., eels, needlefish), laterally compressed (e.g., ribbonfish) to globular (e.g., pufferfish), and include uniquely shaped lineages such as seahorses, flatfishes, and ocean sunfishes. Adaptive body shape convergence within fishes has long been hypothesized but the nature of the relationships between fish form and ecological and environmental variables remain largely unknown at the macroevolutionary scale. To facilitate the investigation of the interacting factors influencing teleost body shape evolution we measured eight functionally relevant linear traits on adult-sized specimens along with specimen mass. Linear measurements of standard length, maximum body depth, maximum fish width, lower jaw length, mouth width, head depth, minimum caudal peduncle depth, and minimum caudal peduncle width were taken in millimeters with calipers, or tape measures for oversized specimens. We measured these traits on a total of 16,523 specimens (1-3 specimens per species) at the Smithsonian National Museum of Natural History and took approximately 7000 person hours of data collection to complete. The data went through a three-step error-checking process to clean and validate the data and then species averages were calculated. We present the complete specimen data set, which encompasses approximately one-fifth of extant teleost species diversity, spanning ~90% of teleost families and ~96% of orders. The species and family names are compatible with the taxonomy used by FishBase and the order information with the phylogenetically informed taxonomy of Betancur-R and colleagues published in 2014. This dataset is licensed under Creative Commons CC0 1.0 Universal (CC0 1.0) but please cite this paper when using the data or a subset of it.

The rise of biting during the Cenozoic fueled reef fish body shape diversification.

Diversity of feeding mechanisms is a hallmark of reef fishes, but the history of this variation is not fully understood. Here, we explore the emergence and proliferation of a biting mode of feeding, which enables fishes to feed on attached benthic prey. We find that feeding modes other than suction, including biting, ram biting, and an intermediate group that uses both biting and suction, were nearly absent among the lineages of teleost fishes inhabiting reefs prior to the end-Cretaceous mass extinction, but benthic biting has rapidly increased in frequency since then, accounting for about 40% of reef species today. Further, we measured the impact of feeding mode on body shape diversification in reef fishes. We fit a model of multivariate character evolution to a dataset comprising three-dimensional body shape of 1,530 species of teleost reef fishes across 111 families. Dedicated biters have accumulated over half of the body shape variation that suction feeders have in just 18% of the evolutionary time by evolving body shape ∼1.7 times faster than suction feeders. As a possible response to the ecological and functional diversity of attached prey, biters have dynamically evolved both into shapes that resemble suction feeders as well as novel body forms characterized by lateral compression and small jaws. The ascendance of species that use biting mechanisms to feed on attached prey reshaped modern reef fish assemblages and has been a major contributor to their ecological and phenotypic diversification.

Prolonged morphological expansion of spiny-rayed fishes following the end-Cretaceous.

Spiny-rayed fishes (Acanthomorpha) dominate modern marine habitats and account for more than a quarter of all living vertebrate species. Previous time-calibrated phylogenies and patterns from the fossil record explain this dominance by correlating the origin of major acanthomorph lineages with the Cretaceous-Palaeogene mass extinction. Here we infer a time-calibrated phylogeny using ultraconserved elements that samples 91.4% of all acanthomorph families and investigate patterns of body shape disparity. Our results show that acanthomorph lineages steadily accumulated throughout the Cenozoic and underwent a significant expansion of among-clade morphological disparity several million years after the end-Cretaceous. These acanthomorph lineages radiated into and diversified within distinct regions of morphospace that characterize iconic lineages, including fast-swimming open-ocean predators, laterally compressed reef fishes, bottom-dwelling flatfishes, seahorses and pufferfishes. The evolutionary success of spiny-rayed fishes is the culmination of multiple species-rich and phenotypically disparate lineages independently diversifying across the globe under a wide range of ecological conditions.

Modified Biering-Sorenson Protocol Changes Joint Contributions to Total Support in Individuals with a History of Anterior Cruciate Ligament Reconstruction During Drop Vertical Jump Landings.

BACKGROUND: There are persistent deficits of the proximal musculature in individuals with anterior cruciate ligament reconstruction. Previous research has shown that proximal musculature fatigue alters drop vertical jump performance in healthy individuals. It is unknown how proximal musculature fatigue will alter drop vertical jump performance in individuals who have undergone anterior cruciate ligament reconstruction. HYPOTHESIS/PURPOSE: The purpose of this study was to examine the effects of a proximal extensor musculature fatigue protocol on drop vertical jump landing biomechanics of individuals with a history of anterior cruciate ligament reconstruction using both single-joint parameters and total support moment analysis. STUDY DESIGN: Quasi-experimental pre-post laboratory experiment. METHODS: Nineteen participants with a history of unilateral anterior cruciate ligament reconstruction were recruited. Three-dimensional motion analysis was performed bilaterally during a drop vertical jump. Participants then completed a proximal extensor musculature fatigue protocol and immediately repeated the drop vertical jump task. Sagittal plane kinetics and kinematics were collected. Joint contributions to peak total support moment were calculated. A condition-by-limb repeated measures analysis of variance was performed to explore the effects of the fatigue protocol, using an alpha level of 0.05. RESULTS: There were no interactions observed for any parameters. However, the injured limb demonstrated less vertical ground reaction force (13%, p=0.013) and reduced peak dorsiflexion angle (2°, p=0.028) both before and after the protocol. After the fatigue protocol both limbs demonstrated reduced hip extensor contribution to peak total support moment (4%, p=0.035). CONCLUSIONS: Individuals with a history of anterior cruciate ligament reconstruction performed the drop vertical jump with an altered anti-gravity support strategy after the proximal extensor musculature fatigue protocol. The significant reduction in bilateral hip extensor contribution to peak total support moment suggests evidence of targeted fatigue. LEVEL OF EVIDENCE: III.

Three-dimensional joint kinematic and two-dimensional quality of movement comparison between lateral and forward step-downs.

OBJECTIVES: While lateral and forward step-down tasks are commonly used, they may have different kinematic and performance demands that could influence clinical assessment and rehabilitation. Therefore, the purpose of this study was to compare 3D lower extremity kinematics and 2D quality of movement between the tasks. DESIGN: Cross-sectional comparative study. SETTING: Research laboratory. PARTICIPANTS: Thirty healthy adults (18 females, age = 23.2 ± 1.4 years, BMI = 23.9 ± 2.2 kg/m2). MAIN OUTCOME MEASURES: Participants underwent 3D and 2D motion analysis. 3D variables were peak hip, knee, and ankle angles. Dichotomous clinical criteria were used for 2D assessment. An alpha level of 0.05 was used for statistical analyses. RESULTS: In the sagittal plane, the forward step-down averaged 7° more knee flexion (p < 0.001, d = 2.30) and 4° more ankle dorsiflexion (p < 0.001, d = 1.72), but 2° less hip flexion (p = 0.001, d = 0.64). In the frontal plane, forward step-downs averaged 1° more hip adduction (p = 0.006, d = 0.54) and 1° more ankle eversion (p < 0.001, d = 1.04). The forward step-down elicited 2D movement faults more often (p = 0.003). CONCLUSIONS: The increased knee flexion and ankle dorsiflexion demands of the forward step-down were accompanied by increases in frontal plane aberrations. The forward step-down may be more challenging for individuals with reduced tolerance to loaded knee flexion and/or limited ankle mobility.

The Effect of Locomotion Mode on Body Shape Evolution in Teleost Fishes.

Teleost fishes vary in their reliance on median and paired fins (MPF) or undulation of the body (BCF) to generate thrust during straight-line, steady swimming. Previous work indicates that swimming mode is associated with different body shapes, though this has never been empirically demonstrated across the diversity of fishes. As the body does not play as active a mechanical role in steady swimming by MPF swimmers, this may relax constraints and spur higher rates of body shape diversification. We test these predictions by measuring the impact of the dominant steady swimming mode on the evolution of body shape across 2295 marine teleost fishes. Aligning with historical expectations, BCF swimmers exhibit a more elongate, slender body shape, while MPF propulsion is associated with deeper and wider body shapes. However, in contrast to expectations, we find that BCF propulsion is associated with higher morphological diversity and greater variance around trait optima. This surprising result is consistent with the interpretation that stronger functional trade-offs stimulate phenotypic evolution, rather than constrain it.

The deep sea is a hot spot of fish body shape evolution.

Deep-sea fishes have long captured our imagination with striking adaptations to life in the mysterious abyss, raising the possibility that this cold, dark ocean region may be a key hub for physiological and functional diversification. We explore this idea through an analysis of body shape evolution across ocean depth zones in over 3000 species of marine teleost fishes. We find that the deep ocean contains twice the body shape disparity of shallow waters, driven by elevated rates of evolution in traits associated with locomotion. Deep-sea fishes display more frequent adoption of forms suited to slow and periodic swimming, whereas shallow living species are concentrated around shapes conferring strong, sustained swimming capacity and manoeuvrability. Our results support long-standing impressions of the deep sea as an evolutionary hotspot for fish body shape evolution and highlight that factors like habitat complexity and ecological interactions are potential drivers of this adaptive diversification.

Do key innovations unlock diversification? A case-study on the morphological and ecological impact of pharyngognathy in acanthomorph fishes.

Key innovations may allow lineages access to new resources and facilitate the invasion of new adaptive zones, potentially influencing diversification patterns. Many studies have focused on the impact of key innovations on speciation rates, but far less is known about how they influence phenotypic rates and patterns of ecomorphological diversification. We use the repeated evolution of pharyngognathy within acanthomorph fishes, a commonly cited key innovation, as a case study to explore the predictions of key innovation theory. Specifically, we investigate whether transitions to pharyngognathy led to shifts in the rate of phenotypic evolution, as well as shifts and/or expansion in the occupation of morphological and dietary space, using a dataset of 8 morphological traits measured across 3,853 species of Acanthomorpha. Analyzing the 6 evolutionarily independent pharyngognathous clades together, we found no evidence to support pharyngognathy as a key innovation; however, comparisons between individual pharyngognathous lineages and their sister clades did reveal some consistent patterns. In morphospace, most pharyngognathous clades cluster in areas that correspond to deeper-bodied morphologies relative to their sister clades, whereas occupying greater areas in dietary space that reflects a more diversified diet. Additionally, both Cichlidae and Labridae exhibited higher univariate rates of phenotypic evolution compared with their closest relatives. However, few of these results were exceptional relative to our null models. Our results suggest that transitions to pharyngognathy may only be advantageous when combined with additional ecological or intrinsic factors, illustrating the importance of accounting for lineage-specific effects when testing key innovation hypotheses. Moreover, the challenges we experienced formulating informative comparisons, despite the ideal evolutionary scenario of multiple independent evolutionary origins of pharyngognathous clades, illustrates the complexities involved in quantifying the impact of key innovations. Given the issues of lineage specific effects and rate heterogeneity at macroevolutionary scales we observed, we suggest a reassessment of the expected impacts of key innovations may be warranted.

The Future is Bright for Evolutionary Morphology and Biomechanics in the Era of Big Data.

In recent years, the fields of evolutionary biomechanics and morphology have developed into a deeply quantitative and integrative science, resulting in a much richer understanding of how structural relationships shape macroevolutionary patterns. This issue highlights new research at the conceptual and experimental cutting edge, with a special focus on applying big data approaches to classic questions in form-function evolution. As this issue illustrates, new technologies and analytical tools are facilitating the integration of biomechanics, functional morphology, and phylogenetic comparative methods to catalyze a new, more integrative discipline. Although we are at the cusp of the big data generation of organismal biology, the field is nonetheless still data-limited. This data bottleneck is primarily due to the rate-limiting steps of digitizing specimens, recording and tracking organismal movements, and extracting patterns from massive datasets. Automation and machine-learning approaches hold great promise to help data generation keep pace with ideas. As a final and important note, almost all the research presented in this issue relied on specimens-totaling the tens of thousands-provided by museum collections. Without collection, curation, and conservation of museum specimens, the future of the field is much less bright.

The influence of size on body shape diversification across Indo-Pacific shore fishes.

Understanding the causes of body shape variability across the tree of life is one of the central issues surrounding the origins of biodiversity. One potential mechanism driving observed patterns of shape disparity is a strongly conserved relationship between size and shape. Conserved allometry has been shown to account for as much as 80% of shape variation in some vertebrate groups. Here, we quantify the amount of body shape disparity attributable to changes in body size across nearly 800 species of Indo-Pacific shore fishes using a phylogenetic framework to analyze 17 geometric landmarks positioned to capture general body shape and functionally significant features. In marked contrast to other vertebrate lineages, we find that changes in body size only explain 2.9% of the body shape variation across fishes, ranging from 3% to 50% within our 11 sampled families. We also find a slight but significant trend of decreasing rates of shape evolution with increasing size. Our results suggest that the influence of size on fish shape has largely been overwhelmed by lineage-specific patterns of diversification that have produced the modern landscape of highly diverse forms that we currently observe in nature.

Ecology shapes the evolutionary trade-off between predator avoidance and defence in coral reef butterflyfishes.

Antipredator defensive traits are thought to trade-off evolutionarily with traits that facilitate predator avoidance. However, complexity and scale have precluded tests of this prediction in many groups, including fishes. Using a macroevolutionary approach, we test this prediction in butterflyfishes, an iconic group of coral reef inhabitants with diverse social behaviours, foraging strategies and antipredator adaptations. We find that several antipredator traits have evolved adaptively, dependent primarily on foraging strategy. We identify a previously unrecognised axis of diversity in butterflyfishes where species with robust morphological defences have riskier foraging strategies and lack sociality, while species with reduced morphological defences feed in familiar territories, have adaptations for quick escapes and benefit from the vigilance provided by sociality. Furthermore, we find evidence for the constrained evolution of fin spines among species that graze solely on corals, highlighting the importance of corals, as both prey and structural refuge, in shaping fish morphology.

Decoupled diversification dynamics of feeding morphology following a major functional innovation in marine butterflyfishes.

The diversity of fishes on coral reefs is influenced by the evolution of feeding innovations. For instance, the evolution of an intramandibular jaw joint has aided shifts to corallivory in Chaetodon butterflyfishes following their Miocene colonization of coral reefs. Today, over half of all Chaetodon species consume coral, easily the largest concentration of corallivores in any reef fish family. In contrast with Chaetodon, other chaetodontids, including the long-jawed bannerfishes, remain less intimately associated with coral and mainly consume other invertebrate prey. Here, we test (i) if intramandibular joint (IMJ) evolution in Chaetodon has accelerated feeding morphological diversification, and (ii) if cranial and post-cranial traits were affected similarly. We measured 19 cranial functional morphological traits, gut length and body elongation for 33 Indo-Pacific species. Comparisons of Brownian motion rate parameters revealed that cranial diversification was about four times slower in Chaetodon butterflyfishes with the IMJ than in other chaetodontids. However, the rate of gut length evolution was significantly faster in Chaetodon, with no group-differences for body elongation. The contrasting patterns of cranial and post-cranial morphological evolution stress the importance of comprehensive datasets in ecomorphology. The IMJ appears to enhance coral feeding ability in Chaetodon and represents a design breakthrough that facilitates this trophic strategy. Meanwhile, variation in gut anatomy probably reflects diversity in how coral tissues are procured and assimilated. Bannerfishes, by contrast, retain a relatively unspecialized gut for processing invertebrate prey, but have evolved some of the most extreme cranial mechanical innovations among bony fishes for procuring elusive prey.

Adult T-Cell Leukemia/Lymphoma: Rarely Encountered in the United States.

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is aggressive mature T-cell lymphoproliferative disorder with a poor outcome. METHODS: We present 10 patients with acute and lymphomatous subtypes of ATLL treated with distinct induction regimens, including CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], prednisone or prednisolone), interferon/zidovudine, and VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, prednisone; doxorubicin, ranimustine, prednisone; vindesine, etoposide, carboplatin, prednisone). RESULTS: The overall response rate was 50%, with 10% complete remission (CR). Two patients achieved CR with the second-line regimen. Three patients underwent consolidation with allogeneic stem cell transplantation (ASCT) in the first CR. The median overall survival was 51 months for the entire group and 84 months for the patients who had undergone ASCT versus 34 months for the non-ASCT patients.

The Impact of Organismal Innovation on Functional and Ecological Diversification.

Innovations in organismal functional morphology are thought to be a major force in shaping evolutionary patterns, with the potential to drive adaptive radiation and influence the evolutionary prospects for lineages. But the evolutionary consequences of innovation are diverse and usually do not result in adaptive radiation. What factors shape the macroevolutionary impact of innovations? We assert that little is known in general about the macroevolutionary outcomes associated with functional innovations and we discuss a framework for studying biological innovations in an evolutionary context. Innovations are novel functional mechanisms that enhance organismal performance. The ubiquity of trade-offs in functional systems means that enhanced performance on one axis often occurs at the expense of performance on another axis, such that many innovations result in an exchange of performance capabilities, rather than an expansion. Innovations may open up new resources for exploitation but their consequences for functional and ecological diversification depend heavily on the adaptive landscape around these novel resources. As an example of a broader program that we imagine, we survey five feeding innovations in labrid fishes, an exceptionally successful and ecologically diverse group of reef fishes, and explore their impact on the rate of evolution of jaw functional morphology. All of the innovations provide performance enhancements and result in changes in patterns of resource use, but most are not associated with subsequent functional diversification or substantial ecological diversification. Because selection acts on a specific performance enhancement and not on the evolutionary potential of an innovation, the enhancement of diversity may be highly serendipitous. The macroevolutionary potential of innovations depends critically on the interaction between the performance enhancement and the ecological opportunity that is exposed.

Increased food intake with oxyntomodulin analogues.

Oxyntomodulin analogues offer a novel treatment for obesity. However during analogue screening in a rat model increased food intake was consistently observed. To further investigate this finding, a series of representative analogues (OXM14 and OXM15) and their Glu-3 equivalents (OXM14E3 and OXM15E3) were administered to rats for 7 days and food intake and bodyweight measurements taken. To investigate the role of glucagon receptor activation glutamate (Glu/E) was substituted at amino acid position 3. GLP-1 and glucagon receptor efficacy of the oxyntomodulin analogues and their Glu-3 counterparts were measured at the rat receptors in vitro. Doses of 25 nmol/kg of OXM14 and OXM15 increased food intake by up to 20%. Bodyweight was not significantly increased. Food intake was not increased with the Glu-3 peptides, indicating that a glucagon receptor mechanism may be responsible for the increase in food intake.