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Abstract Variations in the cross-sectional properties of long bones are used to reconstruct the activity of human groups and differences in their respective habitual behaviors. Knowledge of what factors influence bone structure in Homo sapiens and Neandertals is still insufficient thus, this study investigated which biological and environmental variables influence variations in the femoral robusticity indicator of these two species. The sample consisted of 13 adult Neandertals from the Middle Paleolithic and 1959 adult individuals of H. sapiens ranging chronologically from the Upper Paleolithic to recent times. The femoral biomechanical properties were derived from the European data set, the subject literature, and new CT scans. The material was tested using a Mantel test and statistical models. In the models, the polar moment of area (J) was the dependent variable; sex, age, chronological period, type of lifestyle, percentage of the cortical area (%CA), the ratio of second moment areas of inertia about the X and Y axes (Ix/Iy), and maximum slope of the terrain were independent covariates. The Mantel tests revealed spatial autocorrelation of the femoral index in H. sapiens but not in Neandertals. A generalized additive mixed model showed that sex, %CA, Ix/Iy, chronological period, and terrain significantly influenced variation in the robusticity indicator of H. sapiens femora. A linear mixed model revealed that none of the analyzed variables correlated with the femoral robusticity indicator of Neandertals. We did not confirm that the gradual decline in the femoral robusticity indicator of H. sapiens from the Middle Paleolithic to recent times is related to the type of lifestyle; however, it may be associated with lower levels of mechanical loading during adolescence. The lack of correlation between the analysed variables and the indicator of femoral robusticity in Neandertals may suggest that they needed a different level of mechanical stimulus to produce a morphological response in the long bone than H. sapiens.

Background Tumor progression and resistance to therapy in children with neuroblastoma (NB), a common childhood cancer, are often associated with infiltration of monocytes and macrophages that produce inflammatory cytokines. However, the mechanism by which tumor-supportive inflammation is initiated and propagated remains unknown. Here, we describe a novel protumorigenic circuit between NB cells and monocytes that is triggered and sustained by tumor necrosis factor alpha (TNF-α).Methods We used NB knockouts (KOs) of TNF-α and TNFRSF1A mRNA (TNFR1)/TNFRSF1B mRNA (TNFR2) and TNF-α protease inbitor (TAPI), a drug that modulates TNF-α isoform expression, to assess the role of each component in monocyte-associated protumorigenic inflammation. Additionally, we employed NB-monocyte cocultures and treated these with clinical-grade etanercept, an Fc-TNFR2 fusion protein, to neutralize signaling by both membrane-bound (m) and soluble (s)TNF-α isoforms. Further, we treated NOD/SCID/IL2Rγ(null) mice carrying subcutaneous NB/human monocyte xenografts with etanercept and evaluated the impact on tumor growth and angiogenesis. Gene set enrichment analysis (GSEA) was used to determine whether TNF-α signaling correlates with clinical outcomes in patients with NB.Results We found that NB expression of TNFR2 and monocyte membrane-bound tumor necrosis factor alpha is required for monocyte activation and interleukin (IL)-6 production, while NB TNFR1 and monocyte soluble TNF-α are required for NB nuclear factor kappa B subunit 1 (NF-κB) activation. Treatment of NB-monocyte cocultures with clinical-grade etanercept completely abrogated release of IL-6, granulocyte colony-stimulating factor (G-CSF), IL-1α, and IL-1β and eliminated monocyte-induced enhancement of NB cell proliferation in vitro. Furthermore, etanercept treatment inhibited tumor growth, ablated tumor angiogenesis, and suppressed oncogenic signaling in mice with subcutaneous NB/human monocyte xenografts. Finally, GSEA revealed significant enrichment for TNF-α signaling in patients with NB that relapsed.Conclusions We have described a novel mechanism of tumor-promoting inflammation in NB that is strongly associated with patient outcome and could be targeted with therapy.

Abstract The origin of funerary practices has important implications for the emergence of so-called modern cognitive capacities and behaviour. We provide new multidisciplinary information on the archaeological context of the La Ferrassie 8 Neandertal skeleton (grand abri of La Ferrassie, Dordogne, France), including geochronological data -14C and OSL-, ZooMS and ancient DNA data, geological and stratigraphic information from the surrounding context, complete taphonomic study of the skeleton and associated remains, spatial information from the 1968–1973 excavations, and new (2014) fieldwork data. Our results show that a pit was dug in a sterile sediment layer and the corpse of a two-year-old child was laid there. A hominin bone from this context, identified through Zooarchaeology by Mass Spectrometry (ZooMS) and associated with Neandertal based on its mitochondrial DNA, yielded a direct 14C age of 41.7–40.8 ka cal BP (95%), younger than the 14C dates of the overlying archaeopaleontological layers and the OSL age of the surrounding sediment. This age makes the bone one of the most recent directly dated Neandertals. It is consistent with the age range for the Châtelperronian in the site and in this region and represents the third association of Neandertal taxa to Initial Upper Palaeolithic lithic technocomplex in Western Europe. A detailed multidisciplinary approach, as presented here, is essential to advance understanding of Neandertal behavior, including funerary practices.

Gigantism and acromegaly have been observed in past populations; however, analyses usually focus on the morphological features of the post-cranial skeleton. The aim of this study is to characterize the internal anatomical features of the skull (brain endocast anatomy and asymmetry, frontal pneumatization, cranial thickness, sella turcica size) of an adult individual from the 11-14th centuries with these two diseases, in comparison with non-pathological individuals from the same population. The material consisted of 33 adult skulls from a mediaeval population, one of them belonging to an adult female with endocrine disorders (OL-23/77). Based on the CT scans, the internal cranial anatomy was analysed. The sella turcica of OL-23/77 is much larger than in the comparative sample. The endocast of the individual OL-23/77 shows a left frontal/left occipital petalia, while the comparative population mostly had right frontal/left occipital petalias. The asymmetry in petalia location in OL-23/77 comes within the range of variation observed in the comparative population. The individual has high values for cranial thickness. The frontal sinuses of the specimen analysed are similar in size and shape to the comparative sample only for data scaled to the skull length. Enlarged sella turcica is typical for individuals with acromegaly/gigantism. The pattern of the left frontal/left occipital petalia in the specimen OL-23/77 is quite rare. The position of the endocranial petalias has not influenced the degree of asymmetry in the specimen. Despite the large bone thickness values, skull of OL-23/77 does not show any abnormal features. The skull/endocast relationship in this individual shows some peculiarities in relation to its large size, while other internal anatomical features are within the normal range of variation of the comparative sample.

Brain mapping studies often need to identify brain structures or functional circuits into a set of individual brains. To this end, multiple atlases have been published to represent such structures based on different modalities, subject sets, and techniques. The mainstream approach to exploit these atlases consists in spatially deforming each individual data onto a given atlas using dense deformation fields, which supposes the existence of a continuous mapping between atlases and individuals. However, this continuity is not always verified, and this “iconic” approach has limits. We present in this study an alternative, complementary, “structural” approach, which consists in extracting structures from the individual data, and comparing them without deformation. A “structural atlas” is thus a collection of annotated individual data with a common structure nomenclature. It may be used to characterize structure shape variability across individuals or species, or to train machine learning systems. This study exhibits Anatomist, a powerful structural 3D visualization software dedicated to building, exploring, and editing structural atlases involving a large number of subjects. It has been developed primarily to decipher the cortical folding variability; cortical sulci vary enormously in both size and shape, and some may be missing or have various topologies, which makes iconic approaches inefficient to study them. We, therefore, had to build structural atlases for cortical sulci, and use them to train sulci identification algorithms. Anatomist can display multiple subject data in multiple views, supports all kinds of neuroimaging data, including compound structural object graphs, handles arbitrary coordinate transformation chains between data, and has multiple display features. It is designed as a programming library in both C++ and Python languages, and may be extended or used to build dedicated custom applications. Its generic design makes all the display and structural aspects used to explore the variability of the cortical folding pattern work in other applications, for instance, to browse axonal fiber bundles, deep nuclei, functional activations, or other kinds of cortical parcellations. Multimodal, multi-individual, or inter-species display is supported, and adaptations to large scale screen walls have been developed. These very original features make it a unique viewer for structural atlas browsing.

Frontal pneumatisation is not present in all primates, and among extant species, ethmoidally-derived frontal sinuses are present only in the genera Pan, Gorilla and Homo. A simple and repeatable method is described here to quantify variation in the shape, size and bilateral variation of the frontal sinuses. This has allowed the first large study of these variables, including analyses of large samples of P. paniscus, P. troglodytes, G. gorilla and of several geographically diverse populations of H. sapiens. Frontal sinus shape and size are potential phylogenetic markers in primate systematics. We suggest that, in contrast to an allometric relationship between endocranial and frontal sinus form in Pan and Gorilla, H. sapiens is autapomorphic in having highly variable, supero-inferiorly large frontal sinuses, whose size is unrestricted by variation in cranial form. However, we also describe differences in frontal pneumatisation between those taxa. H. sapiens differs from the other taxa in having relatively smaller frontal sinuses that are more variable in shape and size. In P. troglodytes, P. paniscus and G. gorilla, the shape and size of frontal pneumatisation correlates positively with the overall size of the braincase. This suggests that the large space available in the bone structures of the non-human primates analysed allows the sinuses to develop under only slight constraint (if any) from surrounding structures. In H. sapiens, a significant correlation is observed between the asymmetry in the anterior extension of the frontal lobes of the brain and the shape and extension of the frontal sinuses. We suggest that the more vertical orientation of the H. sapiens frontal bone, its reduced thickness, the reduction of the supraorbital tori and the increased influence of the frontal lobes appear to have modified the integration between the skull, brain and sinuses in the frontal region in our species compared to our nearest extant relatives. Our results reduce the possibility of a strong functional origin for the variation in size and shape of the frontal sinuses in the primates analysed.

Our knowledge of human evolution has made particular progress over the last twenty years, thanks to the discovery of new fossils and the use of new methods and multidisciplinary approaches [...]

We are interested here in the central organ of our thoughts: the brain. Advances in neuroscience have made it possible to obtain increasing information on the anatomy of this organ, at ever-higher resolutions, with different imaging techniques, on ever-larger samples. At the same time, paleoanthropology has to deal with partial reflections on the shape of the brain, on fragmentary specimens and small samples in an attempt to approach the morphology of the brain of past human species. It undeniably emerges from the perspective we propose here that paleoanthropology has much to gain from interacting more with the field of neuroimaging. Improving our understanding of the morphology of the endocast necessarily involves studying the external surface of the brain and the link it maintains with the internal surface of the skull. The contribution of neuroimaging will allow us to better define the relationship between brain and endocast. Models of intra- and inter-species variability in brain morphology inferred from large neuroimaging databases will help make the most of the rare endocasts of extinct species. We also conclude that exchanges between these two disciplines will also be beneficial to our knowledge of the Homo sapiens brain. Documenting the anatomy among other human species and including the variation over time within our own species are approaches that offer us a new perspective through which to appreciate what really characterizes the brain of humanity today.

Background/Aims: We recently discovered that harmful variants in THSD1 (Thrombospondin type-1 domain-containing protein 1) likely cause intracranial aneurysm and subarachnoid hemorrhage in a subset of both familial and sporadic patients with supporting evidence from two vertebrate models. The current study seeks to elucidate how THSD1 and patient-identified variants function molecularly in focal adhesions. Methods: Co-immunostaining and co-immunoprecipitation were performed to define THSD1 subcellular localization and interacting partners. Transient expression of patient-identified THSD1 protein variants and siRNA-mediated loss-of-function THSD1 were used to interrogate gene function in focal adhesion and cell attachment to collagen I in comparison to controls. Results: THSD1 is a novel nascent adhesion protein that co-localizes with several known markers such as FAK, talin, and vinculin, but not with mature adhesion marker zyxin. Furthermore, THSD1 forms a multimeric protein complex with FAK/talin/vinculin, wherein THSD1 promotes talin binding to FAK but not to vinculin, a key step in nascent adhesion assembly. Accordingly, THSD1 promotes mature adhesion formation and cell attachment, while its rare variants identified in aneurysm patients show compromised ability. Interestingly, THSD1 also localizes at different stages of endosomes. Clathrin-mediated but not caveolae-mediated endocytosis pathway is involved in THSD1 intracellular trafficking, which positively regulates THSD1-induced focal adhesion assembly, in contrast to the traditional role of endosomes in termination of integrin signals. Conclusions: The data suggest that THSD1 functions at the interface between endosome dynamics and nascent focal adhesion assembly that is impaired by THSD1 rare variants identified from intracranial aneurysm patients.

Although recently the internal structure of the non-supranuchal fossa of Homo sapiens has been described and compared to that observed in the Neandertal suprainiac fossa, until now it has not been examined in any modern human children. In this study, the internal structure of this fossa in the occipital bones of three children (two aged 3‒4 years and one aged 5 years ± 16 months) and one adult individual representing recent Homo sapiens from Australia was analysed and compared to that of the Neandertal suprainiac fossa. In order to analyse the internal composition of the fossae of the examined specimens, initially, high-resolution micro-CT datasets were obtained for their occipital bones; next, 3D topographic maps of the variation in thickness of structural layers of the occipital bones were made and 2D virtual sections in the median region of these fossae were prepared. In the fossa of one immature individual, the thinning of the diploic layer characteristic of a Neandertal suprainiac fossa was firmly diagnosed. The other Neandertal-like trait, concerning the lack of substantial thinning of the external table of the bone in the region of the fossa, was established in two individuals (one child and one adult) due to the observation of an irregular pattern of the thickness of this table in the other specimens, suggesting the presence of an inflammatory process. Our study presents, for the first time, Neandertal-like traits (but not the whole set of features that justifies the autapomorphic status of the Neandertal supraniac fossa) in the internal structure of non-supranuchal fossae of some recent Homo sapiens. We discuss the phylogenetic implications of the results of our analysis and stress the reasons that use of the 3D topographic mapping method is important for the correct diagnosis of Neandertal traits of the internal structure of occipital fossae.

The anatomical asymmetries of the human brain are the subject of a great deal of scientific interest because of their links with handedness and lateralized cognitive functions. Information about lateralization in humans is also available from the post-cranial skeleton, particularly the arm bones, in which differences in size and shape are related to hand/arm preference. Our objective here is to characterize the possible correlations between the endocranial and post-cranial asymmetries of an archaeological sample. This, in turn, will allow us to try to identify and interpret prospective functional traits in the archaeological and fossil records. We observe that directional asymmetry (DA) is present both for some endocranial and humeral traits because of brain lateralization and lateralized behaviors, while patterns of fluctuating asymmetry (FA) vary. The combined study of these anatomical elements and of their asymmetries can shed light on the ways in which the body responds to dependent asymmetrical stimuli across biologically independent anatomical areas. Variations in FA are, in this context, indicators of differences in answers to lateralized factors. Humeri tend to show a much larger range of variation than the endocast. We show that important but complex information may be extracted from the combined study of the endocast and the arms in an archaeological sample of Homo sapiens.

Emerging evidence implicates a wide range of post-transcriptional RNA modifications that play crucial roles in fundamental biological processes including regulating gene expression. Collectively, they are known as epitranscriptomics. Recent studies implicate 3′ RNA uridylation, the non-templated addition of uridine(s) to the terminal end of RNA, as a key player in epitranscriptomics. In this review, we describe the functional roles and significance of 3′ terminal RNA uridylation that has diverse functions in regulating both mRNAs and non-coding RNAs. In mammals, three Terminal Uridylyl Transferases (TUTases) are primarily responsible for 3′ RNA uridylation. These enzymes are also referred to as polyU polymerases. TUTase 1 (TUT1) is implicated in U6 snRNA maturation via uridylation. The TUTases TUT4 and/or TUT7 are the predominant mediators of all other cellular uridylation. Terminal uridylation promotes turnover for many polyadenylated mRNAs, replication-dependent histone mRNAs that lack polyA-tails, and aberrant structured noncoding RNAs. In addition, uridylation regulates biogenesis of a subset of microRNAs and generates isomiRs, sequent variant microRNAs that have altered function in specific cases. For example, the RNA binding protein and proto-oncogene LIN28A and TUT4 work together to polyuridylate pre-let-7, thereby blocking biogenesis and function of the tumor suppressor let-7 microRNA family. In contrast, monouridylation of Group II pre-miRNAs creates an optimal 3′ overhang that promotes recognition and subsequent cleavage by the Dicer-TRBP complex that then yields the mature microRNA. Also, uridylation may play a role in non-canonical microRNA biogenesis. The overall significance of 3′ RNA uridylation is discussed with an emphasis on mammalian development, gene regulation, and disease, including cancer and Perlman syndrome. We also introduce recent changes to the HUGO-approved gene names for multiple terminal nucleotidyl transferases that affects in part TUTase nomenclature (TUT1/TENT1, TENT2/PAPD4/GLD2, TUT4/ZCCHC11/TENT3A, TUT7/ZCCHC6/TENT3B, TENT4A/PAPD7, TENT4B/PAPD5, TENT5A/FAM46A, TENT5B/FAM46B, TENT5C/FAM46C, TENT5D/FAM46D, MTPAP/TENT6/PAPD1).