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Evolutionary analyses of joint kinematics and muscle mechanics suggest that, during cyclic behaviors, tetrapod feeding systems are optimized for precise application of forces over small displacements during chewing, whereas locomotor systems are more optimized for large and rapid joint excursions during walking and running. If this hypothesis is correct, then it stands to reason that other biomechanical variables in the feeding and locomotor systems should also reflect these divergent functions. We compared rhythmicity of cyclic jaw and limb movements in feeding and locomotor systems in 261 tetrapod species in a phylogenetic context. Accounting for potential confounding variables, our analyses reveal higher rhythmicity of cyclic movements of the limbs than of the jaw. Higher rhythmicity in the locomotor system corroborates a hypothesis of stronger optimization for energetic efficiency: deviation from the limbs' natural frequency results in greater variability of center of mass movements and limb inertial changes, and therefore more work by limb muscles. Relatively lower rhythmicity in the feeding system may be a consequence of the necessity to prevent tooth breakage and wear, the greater complexity of coordination with tongue movements, and/or a greater emphasis on energy storage in elastic elements rather than the kinetics of limb movement.

No vertebrate, living or extinct, is known to have possessed an odd number of limbs. Despite this ‘forbidden phenotype’, gaits that use odd numbers of limbs (e.g. tripedalism or pentapedalism) have evolved in both avian and mammalian lineages. Tripedal locomotion is commonly employed by parrots during climbing, who use their beaks as an additional support. However, it is unclear whether the beak functions simply as a stabilizing hook, or as a propulsive limb. Here, we present data on kinetics of tripedal climbing in six rosy-faced lovebirds ( Agapornis roseicollis ). Our findings demonstrate that parrots use cyclical tripedal gaits when climbing and the beak and hindlimbs generate comparable propulsive and tangential substrate reaction forces and power. Propulsive and tangential forces generated by the beak are of magnitudes equal to or greater than those forces generated by the forelimbs of humans and non-human primates during vertical climbing. We conclude that the feeding apparatus and neck flexors of parrots have been co-opted to function biomechanically as a propulsive third limb during vertical climbing. We hypothesize that this exaptation required substantive alterations to the neuromuscular system including enhanced force-generating capabilities of the neck flexors and modifications to locomotor central pattern generators.

Birds encompass vast ecomorphological diversity and practise numerous distinct locomotor modes. One oft-cited feature seen in climbing birds is an increase in tail ‘stiffness’, yet it remains unclear to what extent these feathers are altered, and the specific mechanism by which differences in functional performance are attained. We collected a broad taxonomic sample of tail feathers (6525 total, from 774 species representing 21 avian orders and ranging in size from approximately 3 g to greater than 11 kg) and present data on their material properties, cross-sectional geometry and morphometrics. Ordinary and phylogenetic least-squares regressions of each variable versus body mass were conducted to assess scaling relationships and demonstrate that tail-supported climbers exhibit longer tail feathers with a wider rachis base and tip, and a greater second moment of area and maximum bending moment. However, no differences were observed in the material properties of the keratin itself. This suggests that tail-supported arboreal climbing birds of multiple orders have independently adopted similar morphologies. Moreover, these geometric relationships follow the same allometric scaling relationships as seen in the long bones of mammalian limbs, suggesting that the morphology of these developmentally and evolutionarily distinct structures are governed by similar functional constraints of weight support.

Modern tree sloths are one of few mammalian taxa for which quadrupedal suspension is obligatory. Sloth limb musculature is specialized for slow velocity, large force contractions that stabilize their body below branches and conserve energy during locomotion. However, it is unknown whether two- and three-toed sloths converge in their use of limb kinetics and if these patterns are comparable to how primates perform arboreal suspensory locomotion. This study addressed this need by collecting limb loading data in three-toed sloths (Bradypus variegatus; N=5) during suspensory walking. Sloths performed locomotor trials at their preferred speed on an instrumented beam apparatus with a force platform as the central supporting segment. Peak forces and impulses of the forelimb and hindlimb were recorded and analyzed in three dimensions. The hindlimbs of B. variegatus apply large braking forces greater in magnitude than peak forces generated by the forelimbs in propulsion, a pattern consistent with that observed in two-toed sloths. However, B. variegatus exhibits hindlimb-biased body weight support in vertical peak forces and impulse, with appreciable laterally directed forces in each limb pair, both of which vary from limb loading distributions in two-toed sloths. Moreover, body weight distribution between limb pairs is opposite to that employed by primates during quadrupedal suspension. Thus, there appear to be multiple strategies for achieving suspensory locomotion in arboreal mammals. These differences may be attributable to anatomical variation or phylogenetic position, but as of yet an explanation remains unknown. Future EMG analyses are expected to provide insight into how specific hindlimb muscle groups contribute to braking forces and stabilizing the center of mass of sloths during suspension.

Despite the high mechanical demands associated with climbing, the ability to ascend vertically has evolved independently in most major animal lineages. However, little is known about the kinetics, mechanical energy profiles or spatiotemporal gait characteristics of this locomotor mode. In this study, we explored the dynamics of horizontal locomotion and vertical climbing on both flat substrates and narrow poles in five Australian green tree frogs (Ranoidea caerulea). Vertical climbing is associated with slow, deliberate movements (i.e. reduced speed and stride frequency and increased duty factors) and propulsive fore–aft impulses in both the forelimb and hindlimb. By comparison, horizontal walking was characterized by a braking forelimb and a propulsive hindlimb. In the normal plane, tree frogs mirrored other taxa in exhibiting a net pulling forelimb and a net pushing hindlimb during vertical climbing. In terms of mechanical energy, tree frogs matched theoretical predictions of climbing dynamics (i.e. the total mechanical energetic cost of vertical climbing was predominantly driven by potential energy, with negligible kinetic contributions). Utilizing power as a means of estimating efficiency, we also demonstrate that Australian green tree frogs show total mechanical power costs only slightly above the minimum mechanical power necessary to climb, highlighting their highly effective locomotor mechanics. This study provides new data on climbing dynamics in a slow-moving arboreal tetrapod and raises new testable hypotheses about how natural selection can act upon a locomotor behavior that is notably constrained by external physical forces.

The ability to securely grasp substrates of variable diameter is critical to arboreal animals. Arboreal specialists have emerged across several vertebrate lineages – including mammals, lizards and amphibians – and several attempts have been made to quantify their grasping performance, by measuring either gripping (i.e. forces generated about an object or substrate enclosed within the digits) or pulling (i.e. the ability to resist being removed from a substrate) forces. In this study, we present data on both pulling and gripping performance across a range of substrate diameters (0.5–17.5 mm) within a model parrot species (Agapornis roseicollis). Parrots represent an ancient arboreal lineage, allowing us to compare their abilities with those of arboreal specialists within other tetrapod groups. Data were collected using 3D-printed perches of variable diameter, and forces were registered using either an AMTI low-load force plate (grip force) or a Harvard Apparatus portable strength tester (pull force). Gripping forces peaked at a 5 mm diameter perch, while pulling forces were greatest at a 2.5 mm diameter. All forces strongly diminished above 10 mm size, suggesting grip force is optimized when utilizing small perches, a finding which corresponds to observational studies of preferential perching habits among free-ranging parrots. Relative grasping performance (adjusted for body size) in parrots is roughly equivalent to that of other arboreal specialists from other tetrapod lineages, but low when compared with that of raptorial birds that utilize their feet during aerial prey capture. Further taxonomic sampling is encouraged to contextualize how grasping performance varies in an adaptive evolutionary context.

The biomechanical demands of arboreal locomotion are generally thought to necessitate specialized kinetic and kinematic gait characteristics. While such data have been widely collected across arboreal quadrupeds, no study has yet explored how arboreal substrates influence the locomotor behavior of birds. Parrots – an ancient arboreal lineage that exhibit numerous anatomical specializations towards life in the trees – represent an ideal model group within which to examine this relationship. Here, we quantifiy limb loading patterns within the rosy-faced lovebird (Agapornis roseicollis) across a range of experimental conditions to define the circumstances under which arboreal gaits are triggered, and how, during arboreal walking, gait patterns change across substrates of varying diameter. In so doing, we address longstanding questions as to how the challenges associated with arboreality affect gait parameters. Arboreal locomotion was associated with the adoption of a sidling gait, which was employed exclusively on the small and medium diameter poles but not terrestrially. When sidling, the hindlimbs are decoupled into a distinct leading limb (which imparts exclusively braking forces) and trailing limb (which generates only propulsive forces). Sidling was also associated with relatively low pitching forces, even on the smallest substrate. Indeed, these forces were significantly lower than mediolateral forces experienced during striding on terrestrial and large diameter substrates. We propose that the adoption of sidling gaits is a consequence of avian foot morphology and represents a novel form of arboreal locomotion where inversion/eversion is impossible. Such movement mechanics is likely widespread among avian taxa and may also typify patterns of arboreal locomotion in humans.

A key characteristic of primate above-branch arboreal locomotion is hindlimb-biased weight support, subverting the typical mammalian condition in which the majority of the body weight is supported by the forelimb. This shift is thought to reflect an adaptation toward the arboreal niches exploited by early primates. However, above-branch quadrupedalism represents only one locomotor mode employed by primates in arboreal contexts. Inverted quadrupedal gaits, in which primates are suspended beneath branches by their hands and feet, have been documented in more than 50 primate taxa. This gait is characterized by a return to forelimb-biased weight distributions and a transition from peak vertical forces being greatest in the hindlimb to being greatest in the forelimb, which may occur to protect the hindlimb from high magnitudes of tensile loading when inverted. In this study, we compare kinetic and kinematic data during upright and inverted quadrupedalism in Lemur catta, Varecia variegata, Cebus capucinus, and Saimiri sciureus. These data are referenced against a classical inverted quadrupedal model: the two-toed sloth (Choloepus didactylus). Our findings show that inverted quadrupedalism in primates is differentiated from above-branch quadrupedalism by increases in forelimb weight support, forelimb contact times, and both forelimb and hindlimb joint excursions. Previously postulated biomechanical models outlining mechanisms relating to the control of weight support during upright walking do not translate well to inverted quadrupedal walking. We suggest that inverted primates may simply be adopting basal neuromuscular gait characteristics and applying them facultatively to this infrequent locomotor behavior.

The locomotor behaviors of treeshrews are often reported as scurrying "squirrel-like" movements. As such, treeshrews have received little attention beyond passing remarks in regard to primate locomotor evolution. However, scandentians vary considerably in habitat and substrate use, thus categorizing all treeshrew locomotion based on data collected from a single species is inappropriate. This study presents data on gait characteristics, positional, and grasping behavior of the northern treeshrew (Tupaia belangeri) and compares these findings to the fat-tailed dwarf lemur (Cheirogaleus medius) to assess the role of treeshrews as a model for understanding the origins of primate locomotor and grasping evolution. We found that northern treeshrews were primarily arboreal and shared their activities between quadrupedalism, climbing and leaping in rates similar to fat-tailed dwarf lemurs. During quadrupedal locomotion, they exhibited a mixture of gait characteristics consistent with primates and other small-bodied non-primate mammals and demonstrated a hallucal grasping mode consistent with primates. These data reveal that northern treeshrews show a mosaic of primitive mammalian locomotor characteristics paired with derived primate features. Further, this study raises the possibility that many of the locomotor and grasping characteristics considered to be "uniquely" primate may ultimately be features consistent with Euarchonta.

No vertebrate, living or extinct, is known to have possessed an odd number of limbs. Despite this “forbidden phenotype", gaits that utilize odd numbers of limbs (e.g., tripedalism or pentapedalism) have evolved in both avian and mammalian lineages. Tripedal locomotion is commonly employed by parrots during climbing, who utilize their beaks as an additional support. However, it is unclear whether the beak functions simply as a stabilizing hook, or as a propulsive limb. Here, we present data on kinetics of tripedal climbing in six rosy-faced lovebirds (Agapornis rosiecollis). Our findings demonstrate that parrots utilize cyclical tripedal gaits when climbing and the beak and hindlimbs generate comparable propulsive and tangential substrate reaction forces and power. Propulsive and tangential forces generated by the beak are of equal or greater magnitudes to those forces generated by the forelimbs of humans and non-human primates during vertical climbing. We conclude that the feeding apparatus and neck musculature of parrots has been co-opted to function biomechanically as a third limb during vertical climbing. We hypothesize that this exaptation required substantive alterations to the neuromuscular system including enhanced force-generating capabilities of the neck musculature and modifications to limb central pattern generators.

Simple Summary Since it was first described over two decades ago, the Alternative Lengthening of Telomeres (ALT) pathway has been well accepted to hold clinical significance in cancer development, cancer diagnosis, and cancer treatment. In this review, first, we discuss how the activation of this pathway is determined. Then, we provide up-to-date statistics on the cancers ALT activity is detected in. We discuss the relationships between ALT positivity and prognosis as well as the pathogenetics of ALT positive cancers. Finally, we evaluate pre-clinical and clinical investigations of potential therapies targeting ALT. Abstract Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism of this unique telomere maintenance pathway, many studies have also evaluated ALT activity in various cancer subtypes. We first briefly review and assess a variety of commonly used ALT biomarkers. Then, we provide both an update on ALT-positive (ALT+) tumor prevalence as well as a systematic clinical assessment of the presently studied ALT+ malignancies. Additionally, we discuss the pathogenetic alterations in ALT+ cancers, for example, the mutation status of ATRX and DAXX, and their correlations with the activation of the ALT pathway. Finally, we highlight important ALT+ clinical associations within each cancer subtype and subdivisions within, as well as their prognoses. We hope this alternative perspective will allow scientists, clinicians, and drug developers to have greater insight into the ALT cancers so that together, we may develop more efficacious treatments and improved management strategies to meet the urgent needs of cancer patients.

Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers. BRCA1-associated RING domain 1 (BARD1) gene has also been identified as an important tumor suppressor gene in breast, ovarian, and uterine cancers. Underscoring the functional significance of the BRCA1 and BARD1 interactions, prevalent mutations in the BRCA1 gene are found in its RING domain, through which it binds the RING domain of BARD1. BARD1-BRCA1 heterodimer plays a crucial role in a variety of DNA damage response (DDR) pathways, including DNA damage checkpoint and homologous recombination (HR). However, many mutations in both BARD1 and BRCA1 also exist in other domains that significantly affect their biological functions. Intriguingly, recent genome-wide studies have identified various single nucleotide polymorphisms (SNPs), genetic alterations, and epigenetic modifications in or near the BARD1 gene that manifested profound effects on tumorigenesis in a variety of non-breast and non-gynecological cancers. In this review, we will briefly discuss the molecular functions of BARD1, including its BRCA1-dependent as well as BRCA1-independent functions. We will then focus on evaluating the common BARD1 related SNPs as well as genetic and epigenetic changes that occur in the non-BRCA1-dominant cancers, including neuroblastoma, lung, and gastrointestinal cancers. Furthermore, the pro- and anti-tumorigenic functions of different SNPs and BARD1 variants will also be discussed.