Thomas Gross

The iron-sulphur protein RNase L inhibitor functions in translation termination

The iron–sulphur (Fe–S)‐containing RNase L inhibitor (Rli1) is involved in ribosomal subunit maturation, transport of both ribosomal subunits to the cytoplasm, and translation initiation through interaction with the eukaryotic initiation factor 3 (eIF3) complex. Here, we present a new function for Rli1 in translation termination. Through co‐immunoprecipitation experiments, we show that Rli1 interacts physically with the translation termination factors eukaryotic release factor 1 (eRF1)/Sup45 and eRF3/Sup35 in Saccharomyces cerevisiae. Genetic interactions were uncovered between a strain depleted for Rli1 and sup35‐21 or sup45‐2. Furthermore, we show that downregulation of RLI1 expression leads to defects in the recognition of a stop codon, as seen in mutants of other termination factors. By contrast, RLI1 overexpression partly suppresses the read‐through defects in sup45‐2. Interestingly, we find that although the Fe–S cluster is not required for the interaction of Rli1 with eRF1 or its other interacting partner, Hcr1, from the initiation complex eIF3, it is required for its activity in translation termination; an Fe–S cluster mutant of RLI1 cannot suppress the read‐through defects of sup45‐2.

Human-like hand use in Australopithecus africanus

Getting a grip The evolution of the hand—particularly the opposable thumb—was key to the success of early humans. Without a precise grip, involving forceful opposition of thumb with fingers, tool technology could not have emerged. Skinner et al. analyzed the internal bone structure of Pliocene Australopithecus hands, dated at 3.2 million years old. Internal bone structure reveals the patterns and directions of forces operating on the hand, providing clues to the kinds of activities performed. Modern human-like hand postures consistent with the habitual use of tools appeared about half a million years earlier than the first archaeological evidence of stone tools. Science, this issue p. 395 The internal bone structure of Pliocene australopiths suggests that precision grip evolved 3.2 million years ago. The distinctly human ability for forceful precision and power “squeeze” gripping is linked to two key evolutionary transitions in hand use: a reduction in arboreal climbing and the manufacture and use of tools. However, it is unclear when these locomotory and manipulative transitions occurred. Here we show that Australopithecus africanus (~3 to 2 million years ago) and several Pleistocene hominins, traditionally considered not to have engaged in habitual tool manufacture, have a human-like trabecular bone pattern in the metacarpals consistent with forceful opposition of the thumb and fingers typically adopted during tool use. These results support archaeological evidence for stone tool use in australopiths and provide morphological evidence that Pliocene hominins achieved human-like hand postures much earlier and more frequently than previously considered.

Human-like hand-use in the hand of Australopithecus africanus

Getting a grip The evolution of the hand—particularly the opposable thumb—was key to the success of early humans. Without a precise grip, involving forceful opposition of thumb with fingers, tool technology could not have emerged. Skinner et al. analyzed the internal bone structure of Pliocene Australopithecus hands, dated at 3.2 million years old. Internal bone structure reveals the patterns and directions of forces operating on the hand, providing clues to the kinds of activities performed. Modern human-like hand postures consistent with the habitual use of tools appeared about half a million years earlier than the first archaeological evidence of stone tools. Science, this issue p. 395 The internal bone structure of Pliocene australopiths suggests that precision grip evolved 3.2 million years ago. The distinctly human ability for forceful precision and power “squeeze” gripping is linked to two key evolutionary transitions in hand use: a reduction in arboreal climbing and the manufacture and use of tools. However, it is unclear when these locomotory and manipulative transitions occurred. Here we show that Australopithecus africanus (~3 to 2 million years ago) and several Pleistocene hominins, traditionally considered not to have engaged in habitual tool manufacture, have a human-like trabecular bone pattern in the metacarpals consistent with forceful opposition of the thumb and fingers typically adopted during tool use. These results support archaeological evidence for stone tool use in australopiths and provide morphological evidence that Pliocene hominins achieved human-like hand postures much earlier and more frequently than previously considered.

Bone Volume Fraction and Fabric Anisotropy Are Better Determinants of Trabecular Bone Stiffness than Other Morphological Variables

As our population ages, more individuals suffer from osteoporosis. This disease leads to impaired trabecular architecture and increased fracture risk. It is essential to understand how morphological and mechanical properties of the cancellous bone are related. Morphology‐elasticity relationships based on bone volume fraction (BV/TV) and fabric anisotropy explain up to 98% of the variation in elastic properties. Yet, other morphological variables such as individual trabeculae segmentation (ITS) and trabecular bone score (TBS) could improve the stiffness predictions. A total of 743 micro–computed tomography (μCT) reconstructions of cubic trabecular bone samples extracted from femur, radius, vertebrae, and iliac crest were analyzed. Their morphology was assessed via 25 variables and their stiffness tensor ( CFE ) was computed from six independent load cases using micro finite element (μFE) analyses. Variance inflation factors were calculated to evaluate collinearity between morphological variables and decide upon their inclusion in morphology‐elasticity relationships. The statistically admissible morphological variables were included in a multiple linear regression model of the dependent variable CFE . The contribution of each independent variable was evaluated (ANOVA). Our results show that BV/TV is the best determinant of CFE (r2adj = 0.889), especially in combination with fabric anisotropy (r2adj = 0.968). Including the other independent predictors hardly affected the amount of variance explained by the model (r2adj = 0.975). Across all anatomical sites, BV/TV explained 87% of the variance of the bone elastic properties. Fabric anisotropy further described 10% of the bone stiffness, but the improvement in variance explanation by adding other independent factors was marginal (<1%). These findings confirm that BV/TV and fabric anisotropy are the best determinants of trabecular bone stiffness and show, against common belief, that other morphological variables do not bring any further contribution. These overall conclusions remain to be confirmed for specific bone diseases and postelastic properties.

Trabecular bone structure correlates with hand posture and use in hominoids.

Bone is capable of adapting during life in response to stress. Therefore, variation in locomotor and manipulative behaviours across extant hominoids may be reflected in differences in trabecular bone structure. The hand is a promising region for trabecular analysis, as it is the direct contact between the individual and the environment and joint positions at peak loading vary amongst extant hominoids. Building upon traditional volume of interest-based analyses, we apply a whole-epiphysis analytical approach using high-resolution microtomographic scans of the hominoid third metacarpal to investigate whether trabecular structure reflects differences in hand posture and loading in knuckle-walking (Gorilla, Pan), suspensory (Pongo, Hylobates and Symphalangus) and manipulative (Homo) taxa. Additionally, a comparative phylogenetic method was used to analyse rates of evolutionary changes in trabecular parameters. Results demonstrate that trabecular bone volume distribution and regions of greatest stiffness (i.e., Youngs modulus) correspond with predicted loading of the hand in each behavioural category. In suspensory and manipulative taxa, regions of high bone volume and greatest stiffness are concentrated on the palmar or distopalmar regions of the metacarpal head, whereas knuckle-walking taxa show greater bone volume and stiffness throughout the head, and particularly in the dorsal region; patterns that correspond with the highest predicted joint reaction forces. Trabecular structure in knuckle-walking taxa is characterised by high bone volume fraction and a high degree of anisotropy in contrast to the suspensory brachiators. Humans, in which the hand is used primarily for manipulation, have a low bone volume fraction and a variable degree of anisotropy. Finally, when trabecular parameters are mapped onto a molecular-based phylogeny, we show that the rates of change in trabecular structure vary across the hominoid clade. Our results support a link between inferred behaviour and trabecular structure in extant hominoids that can be informative for reconstructing behaviour in fossil primates.

Fabric-based Tsai–Wu yield criteria for vertebral trabecular bone in stress and strain space

Osteoporosis related vertebral fractures are an increasing clinical problem in ageing societies. The prediction of vertebral fracture load from QCT-based anatomy-specific finite element simulations could be very useful in the management of patients with osteoporosis, especially with regard to a possible fracture prevention or treatment optimisation. A key property in finite element analysis is the yield surface for the trabecular bone material. This study is aimed at identifying continuum-level yield criteria for vertebral trabecular bone using micro-finite element models subjected to uni-axial, shear, and tri-axial loading. A fabric-dependent, orthotropic Tsai-Wu yield criterion is proposed in both stress and strain spaces. Nonlinear micro-finite element models of cubic vertebral trabecular bone samples with 5.62 mm edge length were generated from μCT-scans. Kinematic boundary conditions were imposed and the specimen was loaded force controlled beyond yield in 17 different load cases (six uni-axial, three shear and eight multi-axial). The proposed yield criteria were fitted to the resulting yield data. Yield strains on-axis were significantly lower (10% in tension and 6% in compression) than in the transverse directions. Average yield strains were 0.7% in tension, 1.1% in compression, 1.0% in shear and ranged from 0.6% to 1.1% under multi-axial loading. In axial direction, maximum yield stress was 2.6 MPa in tension and 4.7 MPa in compression. Lowest shear stress was found in the transverse plane with 1.3 MPa. Multi-axial yield stresses ranged between values for uni-axial tension and compression. Yield stresses depended significantly and substantially on both volume fraction and fabric. Yield strains depended also significantly on both bone volume fraction and fabric, but only weakly on the former. The standard error of the estimate and the concordance correlation coefficient of the yield surface were 5.47% and 0.93 in strain space and 13.58% and 0.96 in stress space. The results of this study are not only consistent with experimental data from the literature but also extend the current knowledge of yield to multi-axial load cases that can hardly be realised in a biomechanical experiment. The presented yield data and criteria will help improving the prediction of vertebral ultimate load using anatomy-specific finite element models.

Mineral heterogeneity has a minor influence on the apparent elastic properties of human cancellous bone: a SRμCT-based finite element study

At the tissue level, the local material properties of human cancellous bone are heterogeneous due to constant remodelling. Since standard high-resolution computed tomography scanning methods are unable to capture this heterogeneity in detail, local differences in mineralisation are normally not incorporated in computational models. To investigate the effects of heterogeneous mineral distribution on the apparent elastic properties, 40 cancellous bone samples from the human femoral neck were scanned by means of synchrotron radiation microcomputed tomography (SRμCT). SRμCT-based micromechanical finite element models that accounted for mineral heterogeneity were compared with homogeneous models. Evaluation of the apparent stiffness tensor of both model types revealed that homogeneous models led to a minor but significant (p < 0.05) overestimation of the elastic properties of heterogeneous models by 2.18 ± 1.89%. Variation of modelling parameters did not affect the overestimation to a great extent. It was concluded that the heterogeneous mineralisation has only a minor influence on the apparent elastic properties of human cancellous bone.

The mRNA export factor Npl3 mediates the nuclear export of large ribosomal subunits

The nuclear export of large ribonucleoparticles is complex and requires specific transport factors. Messenger RNAs are exported through the RNA‐binding protein Npl3 and the interacting export receptor Mex67. Export of large ribosomal subunits also requires Mex67; however, in this case, Mex67 binds directly to the 5S ribosomal RNA (rRNA) and does not require the Npl3 adaptor. Here, we have discovered a new function of Npl3 in mediating the export of pre‐60S ribosomal subunit independently of Mex67. Npl3 interacts with the 25S rRNA, ribosomal and ribosome‐associated proteins, as well as with the nuclear pore complex. Mutations in NPL3 lead to export defects of the large subunit and genetic interactions with other pre‐60S export factors.

Experimental validation of a nonlinear μFE model based on cohesive-frictional plasticity for trabecular bone

Trabecular bone is a porous mineralized tissue playing a major load bearing role in the human body. Prediction of age-related and disease-related fractures and the behavior of bone implant systems needs a thorough understanding of its structure-mechanical property relationships, which can be obtained using microcomputed tomography-based finite element modeling. In this study, a nonlinear model for trabecular bone as a cohesive-frictional material was implemented in a large-scale computational framework and validated by comparison of μFE simulations with experimental tests in uniaxial tension and compression. A good correspondence of stiffness and yield points between simulations and experiments was found for a wide range of bone volume fraction and degree of anisotropy in both tension and compression using a non-calibrated, average set of material parameters. These results demonstrate the ability of the model to capture the effects leading to failure of bone for three anatomical sites and several donors, which may be used to determine the apparent behavior of trabecular bone and its evolution with age, disease, and treatment in the future.

A CT-image-based framework for the holistic analysis of cortical and trabecular bone morphology

This study introduces a standardized framework for the holistic analysis of cortical and trabecular bone structure. This method, although applicable to all bones of the skeleton, is particularly useful for irregular-shaped or small bones for which the application of traditional methods has been especially challenging. Traditional analyses have quantified cortical or trabecular structure in only selected regions of a bone, such as single cross-sections of cortical bone or volumes of interest of trabecular structure in epiphyses. The proposed method improves on these traditional methods by visualizing and quantifying the internal bony structure throughout the entire bone and in user-defined anatomical subregions. Here, we describe and demonstrate the method using high-resolution microtomographic scans of a first metacarpal of an orangutan, gorilla, chimpanzee and human. Using automated morphological filters, the cortical bone is defined and extracted from the underlying trabecular structure to create two 3D models, one of the cortex and one of the trabecular bone that can be analysed separately. We test the sensitivity of the morphological parameters used to create these 3D models, demonstrating that the parameters defined here are robust and can provide accurate measures of cortical thickness, relative bone density, trabecular orientation, trabecular thickness and degree of anisotropy. This new, holistic method is able to reveal morphological and functional information about bone loading that is obscured or ignored using traditional methods, thus providing more informed interpretations of behaviour in extant and fossil taxa.