Principal component and linear discriminant analyses for the classification of hominoid primate specimens based on bone shape data

In this study, we tested the hypothesis that machine learning methods can accurately classify extant primates based on triquetrum shape data. We then used this classification tool to observe the affinities between extant primates and fossil hominoids. We assessed the discrimination accuracy for an unsupervised and supervised learning pipeline, i.e. with principal component analysis (PCA) and linear discriminant analysis (LDA) feature extraction, when tasked with the classification of extant primates. The trained algorithm is used to classify a sample of known fossil hominoids. For the visualization, PCA and uniform manifold approximation and projection (UMAP) are used. The results show that the discriminant function correctly classified the extant specimens with an F1-score of 0.90 for both PCA and LDA. In addition, the classification of fossil hominoids reflects taxonomy and locomotor behaviour reported in literature. This classification based on shape data using PCA and LDA is a powerful tool that can discriminate between the triquetrum shape of extant primates with high accuracy and quantitatively compare fossil and extant morphology. It can be used to support taxonomic differentiation and aid the further interpretation of fossil remains. Further testing is necessary by including other bones and more species and specimens per species extinct primates

TNFAIP3 Maintains Intestinal Barrier Function and Supports Epithelial Cell Tight Junctions

Tight junctions between intestinal epithelial cells mediate the permeability of the intestinal barrier, and loss of intestinal barrier function mediated by TNF signaling is associated with the inflammatory pathophysiology observed in Crohn's disease and celiac disease. Thus, factors that modulate intestinal epithelial cell response to TNF may be critical for the maintenance of barrier function. TNF alpha-induced protein 3 (TNFAIP3) is a cytosolic protein that acts in a negative feedback loop to regulate cell signaling induced by Toll-like receptor ligands and TNF, suggesting that TNFAIP3 may play a role in regulating the intestinal barrier. To investigate the specific role of TNFAIP3 in intestinal barrier function we assessed barrier permeability in TNFAIP3−/− mice and LPS-treated villin-TNFAIP3 transgenic mice. TNFAIP3−/− mice had greater intestinal permeability compared to wild-type littermates, while villin-TNFAIP3 transgenic mice were protected from increases in permeability seen within LPS-treated wild-type littermates, indicating that barrier permeability is controlled by TNFAIP3. In cultured human intestinal epithelial cell lines, TNFAIP3 expression regulated both TNF-induced and myosin light chain kinase-regulated tight junction dynamics but did not affect myosin light chain kinase activity. Immunohistochemistry of mouse intestine revealed that TNFAIP3 expression inhibits LPS-induced loss of the tight junction protein occludin from the apical border of the intestinal epithelium. We also found that TNFAIP3 deubiquitinates polyubiquitinated occludin. These in vivo and in vitro studies support the role of TNFAIP3 in promoting intestinal epithelial barrier integrity and demonstrate its novel ability to maintain intestinal homeostasis through tight junction protein regulation

Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer

Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-Methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a β-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite

Locomotor versatility in the white-handed gibbon (Hylobates lar): A spatiotemporal analysis of the bipedal, tripedal, and quadrupedal gaits

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Functional signals and covariation in triquetrum and hamate shape of extant primates using 3D geometric morphometrics

In this study, we want to investigate the covariation in the shape of two carpal bones, the triquetrum and hamate, and the possible association with locomotor behavior in a broad range of primate taxa. We applied 3D Geometric Morphometrics on a large data set comprising 309 anthropoid primates of 12 different genera. Principal component analyses were performed on the covariance matrix of 18 (triquetrum) and 23 (hamate) Procrustes-aligned surface landmarks. A two-block partial least square analysis was done to test the covariance between triquetrum and hamate shape, without relying on the predictive models implicit in regression analyses. The results show that the carpal shape of quadrupedal anthropoids, which mainly use their wrist under compressive conditions, differs from that of suspensory primates as their wrist is possibly subjected to tensile and torsional forces. Within the hominids, differences in shape also distinguish more terrestrial from more arboreal species. Even within the great apes, we are able to capture shape differences between species of the same genus. In combination with behavioral and biomechanical studies, the results of this research can be used to establish form-function relationships of the primate hand which will aid the functional interpretation of primate fossil remains

A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis

A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-kappa B signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-kappa B activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies