Lucy's Flat Feet: The Relationship between the Ankle and Rearfoot Arching in Early Hominins

BACKGROUND. In the Plio-Pleistocene, the hominin foot evolved from a grasping appendage to a stiff, propulsive lever. Central to this transition was the development of the longitudinal arch, a structure that helps store elastic energy and stiffen the foot during bipedal locomotion. Direct evidence for arch evolution, however, has been somewhat elusive given the failure of soft-tissue to fossilize. Paleoanthropologists have relied on footprints and bony correlates of arch development, though little consensus has emerged as to when the arch evolved. METHODOLOGY/PRINCIPAL FINDINGS. Here, we present evidence from radiographs of modern humans (n=261) that the set of the distal tibia in the sagittal plane, henceforth referred to as the tibial arch angle, is related to rearfoot arching. Non-human primates have a posteriorly directed tibial arch angle, while most humans have an anteriorly directed tibial arch angle. Those humans with a posteriorly directed tibial arch angle (8%) have significantly lower talocalcaneal and talar declination angles, both measures of an asymptomatic flatfoot. Application of these results to the hominin fossil record reveals that a well developed rearfoot arch had evolved in Australopithecus afarensis. However, as in humans today, Australopithecus populations exhibited individual variation in foot morphology and arch development, and "Lucy" (A.L. 288-1), a 3.18 Myr-old female Australopithecus, likely possessed asymptomatic flat feet. Additional distal tibiae from the Plio-Pleistocene show variation in tibial arch angles, including two early Homo tibiae that also have slightly posteriorly directed tibial arch angles. CONCLUSIONS/SIGNIFICANCE. This study finds that the rearfoot arch was present in the genus Australopithecus. However, the female Australopithecus afarensis "Lucy" has an ankle morphology consistent with non-pathological flat-footedness. This study suggests that, as in humans today, there was variation in arch development in Plio-Pleistocene hominins.Leakey Foundatio

The relationship between foot arch measurements and walking parameters in children

BACKGROUND: Walking mechanics are influenced by body morphology. Foot arch height is one aspect of body morphology central to walking. However, generalizations about the relationship between arch height and walking are limited due to previous methodologies used for measuring the arch and the populations that have been studied. To gain the knowledge needed to support healthy gait in children and adults, we need to understand this relationship in unimpaired, typically developing children and adults using dynamic measures. The purpose of the current study was to examine the relationship between arch height and gait in a sample of healthy children and adults using dynamic measures. METHODS: Data were collected from 638 participants (n = 254 children and n = 384 adults) at the Museum of Science, Boston (MOS) and from 18 4- to 8-year-olds at the Motor Development and Motor Control Laboratories. Digital footprints were used to calculate two arch indices: the Chippaux-Smirak (CSI) and the Keimig Indices (KI). The height of the navicular bone was measured. Gait parameters were captured with a mechanized gait carpet at the MOS and three-dimensional motion analyses and in-ground force plates in the Motor Development and Motor Control Laboratories. RESULTS: Linear regression analyses on data from the MOS confirmed that as age increases, step length increases. With a linear mixed effect regression model, we found that individuals who took longer steps had higher arches as measured by the KI. However, this relationship was no longer significant when only adults were included in the model. A model restricted to children found that amongst this sample, those with higher CSI and higher KI values take longer relative step lengths. Data from the Motor Development and Motor Control Laboratories showed that both CSI and KI added to the prediction; children with lower anterior ground reaction forces had higher CSI and higher KI values. Arch height indices were correlated with navicular height. CONCLUSIONS: These results suggest that more than one measure of the arch may be needed elucidate the relationship between arch height and gait.K12 HD055931 - NICHD NIH HHS; K12HD055931 - NICHD NIH HH

Metacarpal trabecular bone varies with distinct hand-positions used in hominid locomotion

Trabecular bone remodels during life in response to loading and thus should, at least in part, reflect potential variation in the magnitude, frequency and direction of joint loading across different hominid species. Here we analyse the trabecular structure across all non-pollical metacarpal distal heads (Mc2-5) in extant great apes, expanding on previous volume of interest and whole-epiphysis analyses that have largely focussed on only the first or third metacarpal. Specifically, we employ both a univariate statistical mapping and a multivariate approach to test for both inter-ray and interspecific differences in relative trabecular bone volume fraction (RBV/TV) and degree of anisotropy (DA) in Mc2-5 subchondral trabecular bone. Results demonstrate that while DA values only separate Pongo from African apes (Pan troglodytes, Pan paniscus, Gorilla gorilla), RBV/TV distribution varies with the predicted loading of the metacarpophalangeal (McP) joints during locomotor behaviours in each species. Gorilla exhibits a relatively dorsal distribution of RBV/TV consistent with habitual hyper-extension of the McP joints during knuckle-walking, whereas Pongo has a palmar distribution consistent with flexed McP joints used to grasp arboreal substrates. Both Pan species possess a disto-dorsal distribution of RBV/TV, compatible with multiple hand postures associated with a more varied locomotor regime. Further inter-ray comparisons reveal RBV/TV patterns consistent with varied knuckle-walking postures in Pan species in contrast to higher RBV/TV values toward the midline of the hand in Mc2 and Mc5 of Gorilla, consistent with habitual palm-back knuckle-walking. These patterns of trabecular bone distribution and structure reflect different behavioural signals that could be useful for determining the behaviours of fossil hominins

Human-Specific Evolution and Adaptation Led to Major Qualitative Differences in the Variable Receptors of Human and Chimpanzee Natural Killer Cells

Natural killer (NK) cells serve essential functions in immunity and reproduction. Diversifying these functions within individuals and populations are rapidly-evolving interactions between highly polymorphic major histocompatibility complex (MHC) class I ligands and variable NK cell receptors. Specific to simian primates is the family of Killer cell Immunoglobulin-like Receptors (KIR), which recognize MHC class I and associate with a range of human diseases. Because KIR have considerable species-specificity and are lacking from common animal models, we performed extensive comparison of the systems of KIR and MHC class I interaction in humans and chimpanzees. Although of similar complexity, they differ in genomic organization, gene content, and diversification mechanisms, mainly because of human-specific specialization in the KIR that recognizes the C1 and C2 epitopes of MHC-B and -C. Humans uniquely focused KIR recognition on MHC-C, while losing C1-bearing MHC-B. Reversing this trend, C1-bearing HLA-B46 was recently driven to unprecedented high frequency in Southeast Asia. Chimpanzees have a variety of ancient, avid, and predominantly inhibitory receptors, whereas human receptors are fewer, recently evolved, and combine avid inhibitory receptors with attenuated activating receptors. These differences accompany human-specific evolution of the A and B haplotypes that are under balancing selection and differentially function in defense and reproduction. Our study shows how the qualitative differences that distinguish the human and chimpanzee systems of KIR and MHC class I predominantly derive from adaptations on the human line in response to selective pressures placed on human NK cells by the competing needs of defense and reproduction

Stiffness of the human foot and evolution of the transverse arch

The stiff human foot enables an efficient push-off when walking or running, and was critical for the evolution of bipedalism(1-6). The uniquely arched morphology of the human midfoot is thought to stiffen it(5-9), whereas other primates have flat feet that bend severely in the midfoot(7,10,11). However, the relationship between midfoot geometry and stiffness remains debated in foot biomechanics(12,13), podiatry(14,15) and palaeontology(4-6). These debates centre on the medial longitudinal arch(5,6) and have not considered whether stiffness is affected by the second, transverse tarsal arch of the human foot(16). Here we show that the transverse tarsal arch, acting through the inter-metatarsal tissues, is responsible for more than 40% of the longitudinal stiffness of the foot. The underlying principle resembles a floppy currency note that stiffens considerably when it curls transversally. We derive a dimensionless curvature parameter that governs the stiffness contribution of the transverse tarsal arch, demonstrate its predictive power using mechanical models of the foot and find its skeletal correlate in hominin feet. In the foot, the material properties of the inter-metatarsal tissues and the mobility of the metatarsals may additionally influence the longitudinal stiffness of the foot and thus the curvature-stiffness relationship of the transverse tarsal arch. By analysing fossils, we track the evolution of the curvature parameter among extinct hominins and show that a human-like transverse arch was a key step in the evolution of human bipedalism that predates the genus Homo by at least 1.5 million years. This renewed understanding of the foot may improve the clinical treatment of flatfoot disorders, the design of robotic feet and the study of foot function in locomotion

Nanostructural Diversity of Synapses in the Mammalian Spinal Cord

This work for funded by the Biotechnology and Biological Sciences Research Council (BBSRC; BB/M021793/1), RS MacDonald Charitable Trust, Motor Neurone Disease (MND) Association UK (Miles/Apr18/863-791), the Engineering and Physical Sciences Research Council (EPSRC; EP/P030017/1), Welcome Trust (202932/Z/16/Z), European Research Council (ERC; 695568) and the Simons Initiative for the Developing Brain.Functionally distinct synapses exhibit diverse and complex organisation at molecular and nanoscale levels. Synaptic diversity may be dependent on developmental stage, anatomical locus and the neural circuit within which synapses reside. Furthermore, astrocytes, which align with pre and post-synaptic structures to form “tripartite synapses”, can modulate neural circuits and impact on synaptic organisation. In this study, we aimed to determine which factors impact the diversity of excitatory synapses throughout the lumbar spinal cord. We used PSD95-eGFP mice, to visualise excitatory postsynaptic densities (PSDs) using high-resolution and super-resolution microscopy. We reveal a detailed and quantitative map of the features of excitatory synapses in the lumbar spinal cord, detailing synaptic diversity that is dependent on developmental stage, anatomical region and whether associated with VGLUT1 or VGLUT2 terminals. We report that PSDs are nanostructurally distinct between spinal laminae and across age groups. PSDs receiving VGLUT1 inputs also show enhanced nanostructural complexity compared with those receiving VGLUT2 inputs, suggesting pathway-specific diversity. Finally, we show that PSDs exhibit greater nanostructural complexity when part of tripartite synapses, and we provide evidence that astrocytic activation enhances PSD95 expression. Taken together, these results provide novel insights into the regulation and diversification of synapses across functionally distinct spinal regions and advance our general understanding of the ‘rules’ governing synaptic nanostructural organisation.Publisher PDFPeer reviewe

The position of Australopithecus sediba within fossil hominin hand use diversity

The human lineage is marked by a transition in hand use, from locomotion towards increasingly dexterous manipulation, concomitant with bipedalism. The forceful precision grips used by modern humans probably evolved in the context of tool manufacture and use, but when and how many times hominin hands became principally manipulative remains unresolved. We analyse metacarpal trabecular and cortical bone, which provide insight into behaviour during an individual’s life, to demonstrate previously unrecognized diversity in hominin hand use. The metacarpals of the palm in Australopithecus sediba have trabecular morphology most like orangutans and consistent with locomotor power-grasping with the fingers, while that of the thumb is consistent with human-like manipulation. This internal morphology is the first record of behaviour consistent with a hominin that used its hand for both arboreal locomotion and human-like manipulation. This hand use is distinct from other fossil hominins in this study, including A. afarensis and A. africanus

Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior

Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene

Assessment of Incurred Sample Reanalysis for Macromolecules to Evaluate Bioanalytical Method Robustness: Effects from Imprecision

Incurred sample reanalysis (ISR) is recommended by regulatory agencies to demonstrate reproducibility of validated methods and provide confidence that methods used in pharmacokinetic and toxicokinetic assessments give reproducible results. For macromolecules to pass ISR, regulatory recommendations require that two thirds of ISR samples be within 30% of the average of original and reanalyzed values. A modified Bland–Altman (mBA) analysis was used to evaluate whether total error (TE), the sum of precision and accuracy, was predictive of a method’s passing ISR and to identify potential contributing parameters for ISR success. Simulated studies determined minimum precision requirements for methods to have successful ISR and evaluated the relationship between precision and the probability of a method’s passing ISR acceptance criteria. The present analysis evaluated ISRs conducted for 37 studies involving ligand-binding assays (LBAs), with TEs ranging from 15% to 30%. An mBA approach was used to assess accuracy and precision of ISR, each with a threshold of 30%. All ISR studies met current regulatory criteria; using mBA, all studies met the accuracy threshold of 30% or less, but two studies (5%) failed to meet the 30% precision threshold. Simulation results showed that when an LBA has ≤15% imprecision, the ISR criteria for both the regulatory recommendation and mBA would be met in 99.9% of studies. Approximately 71% of samples are expected to be within 1.5 times the method imprecision. Therefore, precision appears to be a critical parameter in LBA reproducibility and may also be useful in identifying methods that have difficulty passing ISR