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Relating neuromuscular control to functional anatomy of limb muscles in extant archosaurs

Cuff, Andrew R. ; Daley, Monica A. ; Michel, Krijn B. ; [et al.]

Wiley ; 2019

In: Journal of Morphology Vol. 280, No. 5 ( 2019-05), p. 666-680

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In: Journal of Morphology, Wiley, Vol. 280, No. 5 ( 2019-05), p. 666-680

Abstract: Electromyography (EMG) is used to understand muscle activity patterns in animals. Understanding how much variation exists in muscle activity patterns in homologous muscles across animal clades during similar behaviours is important for evaluating the evolution of muscle functions and neuromuscular control. We compared muscle activity across a range of archosaurian species and appendicular muscles, including how these EMG patterns varied across ontogeny and phylogeny, to reconstruct the evolutionary history of archosaurian muscle activation during locomotion. EMG electrodes were implanted into the muscles of turkeys, pheasants, quail, guineafowl, emus (three age classes), tinamous and juvenile Nile crocodiles across 13 different appendicular muscles. Subjects walked and ran at a range of speeds both overground and on treadmills during EMG recordings. Anatomically similar muscles such as the lateral gastrocnemius exhibited similar EMG patterns at similar relative speeds across all birds. In the crocodiles, the EMG signals closely matched previously published data for alligators. The timing of lateral gastrocnemius activation was relatively later within a stride cycle for crocodiles compared to birds. This difference may relate to the coordinated knee extension and ankle plantarflexion timing across the swing‐stance transition in Crocodylia, unlike in birds where there is knee flexion and ankle dorsiflexion across swing‐stance. No significant effects were found across the species for ontogeny, or between treadmill and overground locomotion. Our findings strengthen the inference that some muscle EMG patterns remained conservative throughout Archosauria: for example, digital flexors retained similar stance phase activity and M. pectoralis remained an ‘anti‐gravity’ muscle. However, some avian hindlimb muscles evolved divergent activations in tandem with functional changes such as bipedalism and more crouched postures, especially M. iliotrochantericus caudalis switching from swing to stance phase activity and M. iliofibularis adding a novel stance phase burst of activity.

Type of Medium: Online Resource

ISSN: 0362-2525 , 1097-4687

URL: Issue

URL: Article

DOI: 10.1002/jmor.v280.5

DOI: 10.1002/jmor.20973

Language: English

Publisher: Wiley

Publication Date: 2019

detail.hit.zdb_id: 1479991-1

SSG: 12

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Computational modelling of muscle fibre operating ranges in the hindlimb of a small ground bird (Eudromia elegans), with implications for modelling locomotion in extinct species

Bishop, Peter J. ; Michel, Krijn B. ; Falisse, Antoine ; [et al.]

Public Library of Science (PLoS) ; 2021

In: PLOS Computational Biology Vol. 17, No. 4 ( 2021-4-1), p. e1008843-

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In: PLOS Computational Biology, Public Library of Science (PLoS), Vol. 17, No. 4 ( 2021-4-1), p. e1008843-

Abstract: The arrangement and physiology of muscle fibres can strongly influence musculoskeletal function and whole-organismal performance. However, experimental investigation of muscle function during in vivo activity is typically limited to relatively few muscles in a given system. Computational models and simulations of the musculoskeletal system can partly overcome these limitations, by exploring the dynamics of muscles, tendons and other tissues in a robust and quantitative fashion. Here, a high-fidelity, 26-degree-of-freedom musculoskeletal model was developed of the hindlimb of a small ground bird, the elegant-crested tinamou ( Eudromia elegans , ~550 g), including all the major muscles of the limb (36 actuators per leg). The model was integrated with biplanar fluoroscopy (XROMM) and forceplate data for walking and running, where dynamic optimization was used to estimate muscle excitations and fibre length changes throughout both gaits. Following this, a series of static simulations over the total range of physiological limb postures were performed, to circumscribe the bounds of possible variation in fibre length. During gait, fibre lengths for all muscles remained between 0.5 to 1.21 times optimal fibre length, but operated mostly on the ascending limb and plateau of the active force-length curve, a result that parallels previous experimental findings for birds, humans and other species. However, the ranges of fibre length varied considerably among individual muscles, especially when considered across the total possible range of joint excursion. Net length change of muscle–tendon units was mostly less than optimal fibre length, sometimes markedly so, suggesting that approaches that use muscle–tendon length change to estimate optimal fibre length in extinct species are likely underestimating this important parameter for many muscles. The results of this study clarify and broaden understanding of muscle function in extant animals, and can help refine approaches used to study extinct species.

Type of Medium: Online Resource

ISSN: 1553-7358

URL: Article

DOI: 10.1371/journal.pcbi.1008843

DOI: 10.1371/journal.pcbi.1008843.g001

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DOI: 10.1371/journal.pcbi.1008843.r007

DOI: 10.1371/journal.pcbi.1008843.r008

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2021

detail.hit.zdb_id: 2193340-6

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Relationships of mass properties and body proportions to locomotor habit in terrestrial Archosauria

Bishop, Peter J. ; Bates, Karl T. ; Allen, Vivian R. ; [et al.]

Cambridge University Press (CUP) ; 2020

In: Paleobiology Vol. 46, No. 4 ( 2020-11), p. 550-568

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In: Paleobiology, Cambridge University Press (CUP), Vol. 46, No. 4 ( 2020-11), p. 550-568

Abstract: Throughout their 250 Myr history, archosaurian reptiles have exhibited a wide array of body sizes, shapes, and locomotor habits, especially in regard to terrestriality. These features make Archosauria a useful clade with which to study the interplay between body size, shape, and locomotor behavior, and how this interplay may have influenced locomotor evolution. Here, digital volumetric models of 80 taxa are used to explore how mass properties and body proportions relate to each other and locomotor posture in archosaurs. One-way, nonparametric, multivariate analysis of variance, based on the results of principal components analysis, shows that bipedal and quadrupedal archosaurs are largely distinguished from each other on the basis of just four anatomical parameters ( p 〈 0.001): mass, center of mass position, and relative forelimb and hindlimb lengths. This facilitates the development of a quantitative predictive framework that can help assess gross locomotor posture in understudied or controversial taxa, such as the crocodile-line Batrachotomus (predicted quadruped) and Postosuchus (predicted biped). Compared with quadrupedal archosaurs, bipedal species tend to have relatively longer hindlimbs and a more caudally positioned whole-body center of mass, and collectively exhibit greater variance in forelimb lengths. These patterns are interpreted to reflect differing biomechanical constraints acting on the archosaurian Bauplan in bipedal versus quadrupedal groups, which may have shaped the evolutionary histories of their respective members.

Type of Medium: Online Resource

ISSN: 0094-8373 , 1938-5331

URL: Article

DOI: 10.1017/pab.2020.47

Language: English

Publisher: Cambridge University Press (CUP)

Publication Date: 2020

detail.hit.zdb_id: 2052186-8

SSG: 12

SSG: 13

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ONC201 Induces p53-Independent Apoptosis and Cell Cycle Arrest in Hematological Malignancies and Leukemic Stem/Progenitor Cells By Inducing ER Stress and mTOR Inhibition

Ishizawa, Jo ; Kojima, Kensuke ; Chachad, Dhruv ; [et al.]

American Society of Hematology ; 2014

In: Blood Vol. 124, No. 21 ( 2014-12-06), p. 3122-3122

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In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3122-3122

Abstract: ONC201 is a novel agent with profound anti-tumor effects, reported to induce p53-independent apoptosis in diverse types of cancers while sparing normal cells (Allen JE et al., Sci Transl Med, 2013). We further investigated its activity and mechanism(s) of action (MOA) in hematological malignancies. We studied mantle cell lymphoma (MCL) cell lines Z-138 and JVM-2 with wild-type (WT) p53, MINO and Jeko-1 with mutant (mut) p53, and Z-138 and JVM-2 cells with knockdown of p53 by lentiviral shRNA, as well as acute myeloid leukemia (AML) cell lines OCI-AML and MOLM-13 with WT p53, and HL-60 with null p53. We also studied primary cells of MCL (n = 8, 2 with mut p53) and AML (n = 11, 2 with mut p53). In vitro treatment with ONC201, ranging from 2.5 to 10 μM, confirmed that ONC201 induces apoptosis independent of p53 status, and has consistent efficacy against primary AML stem/progenitor cells (CD45 dim+/ CD34+/ CD38-) (Figure 1A). In addition to cytotoxic effects, cell cycle analysis using PI/EdU demonstrated induction of p53-independent cell cycle arrest with S phase delay (diminished incorporation of EdU into S phase cells). The IC50 in most samples was 〈 5 μM, well within the therapeutic window of ONC201 according to previous pharmacokinetic studies with mice, rats and dogs. Consistent with this, ONC201 showed little toxicity in vitro in normal bone marrow and stem/progenitor cells, suggesting a very favorable therapeutic window (Figure 1B). In contrast to previous reports of its MOA, ONC201 did not induce TRAIL in AML and MCL cell lines, although DR5 mRNA was induced 2-fold. As further evidence of a TRAIL-independent MOA of ONC201, its toxicity was not diminished by FOXO3a knockdown in OCI-AML3 and Z-138 cells, or by mutation of caspase 8 (i.e., the Jurkat clone I9.2 was as sensitive as Jurkat cells with WT caspase 8). Gene Set Enrichment Analysis (GSEA) of gene expression profiling (GEP) data of Jeko-1 and Z-138 cells treated with ONC201 implicated upregulated Endoplasmic Reticulum (ER) stress-related genes, such as targets of the ER stress-induced transcription factor CHOP (DDIT3; FDR q = 0.016), and ER component proteins (FDR q = 0.039). Direct investigation of ER stress-induced changes found that XBP-1 splicing begins 6 hr after ONC201 exposure (Figure 2A), followed by transcriptional induction of DDIT3 and its targets (GADD34, TRIB3 and DR5) at 12-24 hr (Figure 2B). In addition, GEP of Jeko-1 cells treated with the ER stress inducer tunicamycin showed high overlap with the changes (both up and down) caused by ONC201. GSEA also implicated mTOR inhibition, such as modulation of the Molecular Signatures Database gene set "mTOR UP.N4.V1 UP" (FDR q = 0.000), and we found dephosphorylation of p70S6K and S6 12 hr after ONC201 exposure (Figure 3). Therefore, we hypothesized that post-translational inhibition of p70S6K/S6 could be another activity of ONC201. In support of this, the combination of tunicamycin and mTORC1 inhibitor rapamycin revealed synergistic effects in Jeko-1 cells. Although the correlation between ER stress and mTOR pathway inhibition has been reported previously, the mechanisms underlying this correlation are not known. However, we found that the oxidative stress gene DDIT4, known as a negative regulator of the TSC1/2 complex (thus inhibiting the mTORC1 pathway) and HIF-1-alpha, is upregulated much more in Jeko-1 cells by ONC201 than by tunicamycin, possibly explaining mTOR pathway inhibition by ONC201. In conclusion, we confirmed that ONC201 induces p53-independent cell death, with little toxicity to normal cells. We identified a novel MOA in leukemias and lymphomas for ONC201 that involves induction of ER stress and inhibition of mTOR pathway signaling. ONC201 is the first clinical candidate known to both induce ER stress and inhibit mTOR signaling, and will soon enter Phase I trials in hematological malignancies. This finding could provide important biomarkers to predict and monitor the efficacy of ONC201. Disclosures Allen: Oncoceutics, Inc.: Employment. Andreeff:Oncoceutics, Inc.: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3122.3122

RVK:

XA 33000

RVK:

XA 10000

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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Reverse-engineering the locomotion of a stem amniote

Nyakatura, John A. ; Melo, Kamilo ; Horvat, Tomislav ; [et al.]

Springer Science and Business Media LLC ; 2019

In: Nature Vol. 565, No. 7739 ( 2019-1), p. 351-355

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In: Nature, Springer Science and Business Media LLC, Vol. 565, No. 7739 ( 2019-1), p. 351-355

Type of Medium: Online Resource

ISSN: 0028-0836 , 1476-4687

URL: Article

DOI: 10.1038/s41586-018-0851-2

RVK:

TA 1000

RVK:

UA 1000

RVK:

WA 15000

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2019

detail.hit.zdb_id: 120714-3

detail.hit.zdb_id: 1413423-8

SSG: 11

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Appendicular Muscle Physiology and Biomechanics in Crocodylus niloticus

Michel, Krijn B ; West, Tim G ; Daley, Monica A ; [et al.]

Oxford University Press (OUP) ; 2020

In: Integrative Organismal Biology Vol. 2, No. 1 ( 2020-01-01)

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In: Integrative Organismal Biology, Oxford University Press (OUP), Vol. 2, No. 1 ( 2020-01-01)

Abstract: Archosaurian reptiles (including living crocodiles and birds) had an explosive diversification of locomotor form and function since the Triassic approximately 250 million years ago. Their limb muscle physiology and biomechanics are pivotal to our understanding of how their diversity and evolution relate to locomotor function. Muscle contraction velocity, force, and power in extinct archosaurs such as early crocodiles, pterosaurs, or non-avian dinosaurs are not available from fossil material, but are needed for biomechanical modeling and simulation. However, an approximation or range of potential parameter values can be obtained by studying extant representatives of the archosaur lineage. Here, we study the physiological performance of three appendicular muscles in Nile crocodiles (Crocodylus niloticus). Nile crocodile musculature showed high power and velocity values—the flexor tibialis internus 4 muscle, a small “hamstring” hip extensor, and knee flexor actively used for terrestrial locomotion, performed particularly well. Our findings demonstrate some physiological differences between muscles, potentially relating to differences in locomotor function, and muscle fiber type composition. By considering these new data from a previously unstudied archosaurian species in light of existing data (e.g., from birds), we can now better bracket estimates of muscle parameters for extinct species and related extant species. Nonetheless, it will be important to consider the potential specialization and physiological variation among muscles, because some archosaurian muscles (such as those with terrestrial locomotor function) may well have close to double the muscle power and contraction velocity capacities of others.

Type of Medium: Online Resource

ISSN: 2517-4843

URL: Article

DOI: 10.1093/iob/obaa038

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2020

detail.hit.zdb_id: 2947578-8

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Analysis of the moment arms and kinematics of ostrich ( Struthio camelus ) double patellar sesamoids

Regnault, Sophie ; Allen, Vivian R. ; Chadwick, Kyle P. ; [et al.]

Wiley ; 2017

In: Journal of Experimental Zoology Part A: Ecological and Integrative Physiology Vol. 327, No. 4 ( 2017-04), p. 163-171

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In: Journal of Experimental Zoology Part A: Ecological and Integrative Physiology, Wiley, Vol. 327, No. 4 ( 2017-04), p. 163-171

Abstract: The patella (“kneecap”) is a biomechanically important feature of the tendinous insertion of the knee extensor muscles, able to alter the moment arm lengths between its input and output tendons, and so modify the mechanical advantage of the knee extensor muscle. However, patellar gearing function is little‐explored outside of humans, and the patella is often simplified or ignored in biomechanical models. Here, we investigate patellar gearing and kinematics in the ostrich—frequently used as an animal analogue to human bipedal locomotion and unusual in its possession of two patellae at the knee joint. We use x‐ray reconstruction of moving morphology (XROMM) techniques to capture the kinematics of the patellae in an adult ostrich cadaver, passively manipulated in flexion‐extension. Moment arm ratios between the input and output tendons of each patella are calculated from kinematically determined centers of patellofemoral joint rotation. Both patellae are found to decrease the mechanical advantage of the extensor muscle–tendon complex, decreasing the tendon output force for a given muscle input force, but potentially increasing the relative speed of knee extension. Mechanically and kinematically, the proximal patella behaves similarly to the single patella of most other species, whereas the distal patella has properties of both a fixed retroarticular process and a moving sesamoid. It is still not clear why ostriches possess two patellae, but we suggest that the configuration in ostriches benefits their rapid locomotion and provides tendon protection.

Type of Medium: Online Resource

ISSN: 2471-5638 , 2471-5646

URL: Issue

URL: Article

DOI: 10.1002/jez.v327.4

DOI: 10.1002/jez.2082

Language: English

Publisher: Wiley

Publication Date: 2017

detail.hit.zdb_id: 1474896-4

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Engaging with communities, engaging with patients: amendment to the NAPCRG 1998 Policy Statement on Responsible Research With Communities: Table 1.

Allen, Michele L ; Salsberg, Jon ; Knot, Michaela ; [et al.]

Oxford University Press (OUP) ; 2016

In: Family Practice

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In: Family Practice, Oxford University Press (OUP)

Type of Medium: Online Resource

ISSN: 0263-2136 , 1460-2229

URL: Article

DOI: 10.1093/fampra/cmw074

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2016

detail.hit.zdb_id: 1484852-1

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ONC201 Exerts p53-Independent Cytotoxicity Through TRAIL and DR5 Induction In Mantle Cell Lymphomas

Ishizawa, Jo ; Kojima, Kensuke ; Dilip, Archana ; [et al.]

American Society of Hematology ; 2013

In: Blood Vol. 122, No. 21 ( 2013-11-15), p. 3822-3822

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In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3822-3822

Abstract: ONC201 (TIC10) is a novel small molecule that induces TRAIL-dependent apoptosis in various cancer cell types and is under development to enter a first-in-man study in advanced cancer patients .It was identified in a screen for small molecules capable of up-regulating endogenous TRAIL gene transcription in a p53-independent manner (Allen JE et al, Sci Transl Med., 2013). ONC201 triggers FOXO3a activation through dual inhibition of ERK and AKT, which transcriptionally upregulates TRAIL and TNFRSF10B (TRAIL-R2/DR5) in solid tumors. Because PI3K/AKT and MEK/ERK activation have been shown to be major contributors to drug resistance, ONC201 is potentially promising since it not only promotes TRAIL activation, but also upregulates its pro-apoptotic receptor DR5. Here we report the anti-lymphoma effects of ONC201 in MCL, a presently incurable disease. We treated three human MCL cell lines with wild-type p53 (Z-138, JVM-2, and Granta-519) and two similar lines with mutant p53 (MINO and Jeko-1) with ONC201. A 72-hour ONC201 treatment induced apoptosis in all MCL cell lines. Surprisingly, the p53 mutant MINO and Jeko-1 cells were more susceptible in apoptosis assays to ONC201 than cells with wild-type p53 (Fig.1) The effective concentrations inducing cell killing (as measured by annexin V positivity) in 50%/75% of the cells in the Z-138, JVM-2, MINO, Jeko-1, and Granta-519 cells were 9.9/ 〉 10, 〉 10/ 〉 10, 2.6/5.2, 2.7/4.6 and 〉 10/ 〉 10 micromolar, respectively. We also treated five primary human MCL samples (three with wild-type p53 and two with mutant p53), and found that one of the two mutant p53 samples was highly sensitive to ONC201 as were the three samples with wild-type p53. One mutant p53 sample that was less sensitive to ONC201, was also resistant to Nutlin-3a and Ibrutinib suggesting an extremely drug-resistant phenotype. Real-time PCR analysis revealed that both DR5 and TRAIL mRNAs were transcriptionally upregulated in the primary MCL samples (a relative ratio of 7.25 compared to 3.13 in controls) after 72-hour treatment with ONC201. To determine the significance of p53 functional status in ONC201-induced apoptosis, p53 wild-type Z-138 and JVM-2 cells were stably transduced with lentivirus encoding either negative control shRNA or p53-specific shRNA and were exposed to ONC201 and results demonstrated complete p53-independence. Normal human bone marrow cells and mesenchymal stem cells were completely resistant to the cytotoxic effects of ONC201, which illustrated this agent's low toxicity against normal tissues. In order to examine the role of p53 activation in ONC201-induced apoptosis in MCL cells, we combined ONC201 with the MDM2 inhibitor Nutlin-3a. The combination cytotoxic effects of this combination were synergistic in p53 wild-type Z-138 and JVM-2 cells (combination index 0.87 and 0.63, respectively). Similar synergistic effects of ONC201 combined with the BTK inhibitor Ibrutinib were observed in Z-138 and MINO cells (combination index 0.63 and 0.61, respectively). This combination also triggered synergistic apoptotic effects in two primary MCL samples with combination indexes of 0.0011 and 0.073, respectively. Conclusion ONC201 induces p53-independent apoptosis in MCL cells, and may have significant clinical impact by targeting both p53 wild type and p53 mutant drug-resistant MCL cells. ONC201 exerts synergistic effects with MDM2 and BTK inhibitors that may be explored clinically. Disclosures: Allen: Drug Company: Employment. Andreeff:Oncoceutics: SAB Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.3822.3822

RVK:

XA 33000

RVK:

XA 10000

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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Variation in limb loading magnitude and timing in tetrapods

Granatosky, Michael C. ; McElroy, Eric J. ; Lemelin, Pierre ; [et al.]

The Company of Biologists ; 2019

In: Journal of Experimental Biology

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In: Journal of Experimental Biology, The Company of Biologists

Abstract: Comparative analyses of locomotion in tetrapods reveal two patterns of stride cycle variability. Tachymetabolic tetrapods (birds and mammals) have lower inter-cycle variation in stride duration than bradymetabolic tetrapods (amphibians, lizards, turtles, and crocodilians). This pattern has been linked to the fact that birds and mammals share enlarged cerebella, relatively enlarged and heavily myelinated Ia afferents, and γ-motoneurons to their muscle spindles. Tachymetabolic tetrapod lineages also both possess an encapsulated Golgi tendon morphology, thought to provide more spatially precise information on muscle tension. The functional consequence of this derived Golgi tendon morphology has never been tested. We hypothesized that one advantage of precise information on muscle tension would be lower and more predictable limb bone stresses, achieved in tachymetabolic tetrapods by having less variable substrate reaction forces than bradymetabolic tetrapods. To test this hypothesis, we analyzed hindlimb substrate reaction forces during locomotion of 55 tetrapod species in a phylogenetic comparative framework. Variation in species-means of limb loading magnitude and timing confirm that, for most of the variables analyzed, variance in hindlimb loading and timing is significantly lower in species with encapsulated versus unencapsulated Golgi tendon organs. These findings suggest that maintaining predictable limb loading provides a selective advantage for birds and mammals by allowing for energy-savings during locomotion, lower limb bone safety factors, and quicker recovery from perturbations. The importance of variation in other biomechanical variables in explaining these patterns, such as posture, effective mechanical advantage, and center-of-mass mechanics, remains to be clarified.

Type of Medium: Online Resource

ISSN: 1477-9145 , 0022-0949

URL: Article

DOI: 10.1242/jeb.201525

Language: English

Publisher: The Company of Biologists

Publication Date: 2019

detail.hit.zdb_id: 1482461-9

SSG: 12

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