Trabecular architecture in the thumb of Pan and Homo: implications for investigating hand use, loading, and hand preference in the fossil record

Objectives: Humans display an 85–95% cross-cultural right-hand bias in skilled tasks, which is considered a derived behavior because such a high frequency is not reported in wild non-human primates. Handedness is generally considered to be an evolutionary byproduct of selection for manual dexterity and augmented visuo-cognitive capabilities within the context of complex stone tool manufacture/use. Testing this hypothesis requires an understanding of when appreciable levels of right dominant behavior entered the fossil record. Because bone remodels in vivo, skeletal asymmetries are thought to reflect greater mechanical loading on the dominant side, but incomplete preservation of external morphology and ambiguities about past loading environments complicate interpretations. We test if internal trabecular bone is capable of providing additional information by analyzing the thumb of Homo sapiens and Pan. Materials and methods: We assess trabecular structure at the distal head and proximal base of paired (left/right) first metacarpals using micro-CT scans of Homo sapiens (n?=?14) and Pan (n?=?9). Throughout each epiphysis we quantify average and local bone volume fraction (BV/TV), degree of anisotropy (DA), and elastic modulus (E) to address bone volume patterning and directional asymmetry. Results: We find a right directional asymmetry in H. sapiens consistent with population-level handedness, but also report a left directional asymmetry in Pan that may be the result of postural and/or locomotor loading. Conclusion: We conclude that trabecular bone is capable of detecting right/left directional asymmetry, but suggest coupling studies of internal structure with analyses of other skeletal elements and cortical bone prior to applications in the fossil record

Metacarpal trabecular architecture variation in the chimpanzee (Pan troglodytes): evidence for locomotion and tool-use

Trabecular architecture was assessed by 3D micro-computed tomography from spherical volumes of interest located within the head and base of metacarpals (MC) 1, 2, and 5 from n = 19 adult common chimpanzees. Two subspecies, West African Pan troglodytes verus from the Taï Forest, Côte d'Ivoire (n = 12) and Central African P. t. troglodytes from Cameroon (n = 7), were studied. For the combined sample, the metacarpal head is distinguished by greater bone volume fraction across all metacarpals, though the MC 1 is distinctive in having thicker, more plate-like trabeculae. The architecture in the MC 2 and MC 5 can be related to strains associated with terrestrial knuckle-walking. In particular, the relatively robust MC 5 head architecture may result from functional loading incurred during braking and use of a palm-in hand posture. Examining differences between samples, we found that the Cameroon chimpanzees possess a more robust architecture across all metacarpals in the form of greater bone volume fraction, higher connectivity, and somewhat more plate-like structure. These differences are not explicable in terms of population distinctions in body size or daily travel distance, but possibly reflect a combination of more terrestrial knuckle-walking in the Cameroon sample and more diverse hand postures and precision handling required of nut-cracking in West African chimpanzees

Scaling VOI size in 3D microCT studies of trabecular bone: a test of the over-sampling hypothesis

For comparative 3D ?CT studies of trabecular bone, the use of a volume of interest (VOI) scaled to body size may avoid over-sampling the trabecular mass in smaller versus larger-bodied taxa and comparison of regions that are not functionally homologous (Fajardo and Müller: Am J Phys Anthropol 115 (2001) 327–336), though the influence on quantitative analyses using scaled versus nonscaled VOIs remains poorly characterized. We compare trabecular architectural properties reflecting mass, organization, and orientation from three volumes of interest (large, scaled, and small) obtained from the distal first metacarpal in a sample of Homo (n = 10) and Pan (n = 12). We test the null hypotheses that neither absolute VOI size, nor scaling of the VOI to metacarpal size as a proxy for body size, biases intraspecific analyses nor impacts the detection of interspecific differences. These hypotheses were only partially supported. While certain properties (e.g., bone volume fraction or trabecular thickness) were not affected by varying VOI size within taxa, others were significantly impacted (e.g., intersection surface, connectivity, and structure). In comparing large versus scaled VOIs, we found that the large VOI inflated the number and/or magnitude of significant differences between Homo and Pan. In summary, our results support the use of scaled VOIs in studies of trabecular architecture

Quantitative Framework for Stochastic Nanopore Sensors Using Multiple Channels

Membrane protein channels employed as stochastic sensors offer large signal-to-noise ratios and high specificity in single molecule binding measurements. Stochastic events in a single ion channel system can be measured using current–time traces, which are straightforward to analyze. Signals arising from measurement using multiple ion channels are more complicated to interpret. We show that multiple independent ion channels offer improved detection sensitivity compared to single channel measurements and that increased signal complexity can be accounted for using binding event frequency. More specifically, the leading edge of binding events follows a Poisson point process, which means signals from multiple channels can be superimposed and the association times (between each binding event leading edge), allow for sensitive and quantitative measurements. We expand our calibration to high ligand concentrations and high numbers of ion channels to demonstrate that there is an upper limit of quantification, defined by the time resolution of the measurement. The upper limit is a combination of the instrumental time resolution and the dissociation time of a ligand and protein which limits the number of detectable events. This upper limit also allows us to predict, in general, the measurement requirements needed to observe any process as a Poisson point process. The nanopore-based sensing analysis has wide implications for stochastic sensing platforms that operate using multiple simultaneous superimposable signals

Graft-versus-host-like disease complicating thymoma: lack of AIRE expression as a cause of non-hereditary autoimmunity?

Three patients with graft-versus-host-like enterocolonopathy are reported. Their history was remarkable for thymoma and other autoimmune manifestations such as thrombocytopenia, red cell aplasia, interface dermatitis, Sjogren sialadenits, vanishing bile ducts and rheumatoid arthritis. In all patients, microsatellite analysis showed the autologous nature of the lymphocytes in the affected organs ruling out GVHD. In search for mechanisms that could mediate loss of tolerance to self-antigens we found in a panel of thymomas, including those of the three patients, a complete lack of autoimmune regulator (AIRE) and minimal expression of the transcription factor FOXP3 in the intra-tumoral T cells. AIRE is a recently discovered transcription factor which plays a key role in the maintenance of central tolerance and is mutated in the autosomal recessive autoimmune polyendocrinopathy syndrome APS-1. Our observations indicate that thymoma-related autoimmunity can potentially be elicited by an incomplete deletion of 'self'-specific T cells in concert with an insufficient formation of natural Treg

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis