Sex determination using proximal hand phalanges

Sex determination is among the most important biological data to be obtained from human skeletal remains. In anthropological sciences, the applied methodology involves the analysis of the quantitative and qualitative characteristics of skeletal parts. Measurements of proximal hand phalanges have been shown to exhibit prominent sexual dimorphism, in different populations examined. The aim of this study is to assess the utility of proximal hand phalanges for the sex diagnosis and develop a discriminant formula to be applied to Modern Greek populations. The material utilized consists of 661 proximal hand phalanges (left and right) from the Athens Collection, corresponding to 160 adult individuals (86 males and 74 females). Classification accuracies ranged between 94.6% and 100% for left and between 87.7% and 100% for right proximal phalanges. The results of this study indicate that proximal hand phalanges can be used for accurate sex diagnosis

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

The p53 tumor suppressor is a transcription factor with roles in cell development, apoptosis, oncogenesis, aging, and homeostasis in response to stresses and infections. p53 is tightly regulated by the MDM2 E3 ubiquitin ligase. The p53-MDM2 pathway has coevolved, with MDM2 remaining largely conserved, whereas the TP53 gene morphed into various isoforms. Studies on prevertebrate ancestral homologs revealed the transition from an environmentally induced mechanism activating p53 to a tightly regulated system involving cell signaling. The evolution of this mechanism depends on structural changes in the interacting protein motifs. Elephants such as Loxodonta africana constitute ideal models to investigate this coevolution as they are large and long-living as well as having 20 copies of TP53 isoformic sequences expressing a variety of BOX-I MDM2-binding motifs. Collectively, these isoforms would enhance sensitivity to cellular stresses, such as DNA damage, presumably accounting for strong cancer defenses and other adaptations favoring healthy aging. Here we investigate the molecular evolution of the p53-MDM2 system by combining in silico modeling and in vitro assays to explore structural and functional aspects of p53 isoforms retaining the MDM2 interaction, whereas forming distinct pools of cell signaling. The methodology used demonstrates, for the first time that in silico docking simulations can be used to explore functional aspects of elephant p53 isoforms. Our observations elucidate structural and mechanistic aspects of p53 regulation, facilitate understanding of complex cell signaling, and suggest testable hypotheses of p53 evolution referencing Peto's Paradox

New insights into the manual activities of individuals from the Phaleron cemetery (Archaic Athens, Greece)

Until the early 5th century BC, Phaleron Bay was the main port of ancient Athens (Greece). On its shore, archaeologists have discovered one of the largest known cemeteries in ancient Greece, including a range of burial forms, simple pits, cremations, larnaces (clay tubs), and series of burials of male individuals who appear to have died violent deaths, referred to here as “atypical burials”. Reconstructing the osteobiographies of these individuals will help create a deeper understanding of the socio-political conditions preceding the rise of Classical Athens. Here, we assess the habitual manual behavior of the people of Archaic Phaleron (ca. 7th – 6th cent. BC), relying on a new and precise three-dimensional method for reconstructing physical activity based on hand muscle attachment sites. This approach has been recently validated on laboratory animal samples as well as on recent human skeletons with a detailed level of long-term occupational documentation (i.e., the mid-19th century Basel Spitalfriedhof sample). Our Phaleron sample consists of 48 adequately preserved hand skeletons, of which 14 correspond to atypical burials. Our results identified consistent differences in habitual manual behaviors between atypical burials and the rest. The former present a distinctive power-grasping tendency in most skeletons, which was significantly less represented in the latter (p-values of <0.01 and 0.03). Based on a comparison with the uniquely documented Basel sample (45 individuals), this entheseal pattern of the atypical burials was exclusively found in long-term heavy manual laborers. These findings reveal an important activity difference between burials typical for the Phaleron cemetery and atypical burials, suggesting that the latter were likely involved in distinctive, strenuous manual activities. The results of this pilot study comprise an important first step towards reconstructing the identity of these human skeletal remains. Future research can further elucidate the occupational profiles of these individuals through the discovery of additional well-preserved hand skeletons and by extending our analyses to other anatomical regions

Technical note: Development of regression equations to reassociate upper limb bones from commingled contexts

The major upper limb skeletal elements (scapulae, humeri, ulnae and radii) are frequently utilized for sex determination and stature estimation. Consequently, in forensic cases that involve commingled remains, it is crucial to reassociate the aforementioned bones and attribute them to the right individual. The aim of the present study is to develop simple and multiple regression equations for sorting commingled human skeletal elements of the upper limb. In that context, ten common anthropological linear measurements of the articular surfaces of scapulae, humeri, ulnae, and radii were performed on 222 adult skeletons from the Athens Collection. The functions developed for sorting adjoining bones presented a strong positive linear relationship (r = 0.69–0.93, p < 0.05). The values of the determination coefficient statistics (r2 = 0.47–0.86) were found to be high and those of the standard errors of the estimate were found to be low (SEE = 0.88–1.61). Blind tests indicated that when metric and morphoscopic sorting techniques are combined, a reliable sorting of the skeletal elements of the upper limbs is possible

Revelen el paper crucial de l'ARNm en el control i resposta de tumors en la cèl·lula

Un estudi pioner de la UAB revela el paper fonamental de les estructures secundàries de l'ARNm codificant en la maquinària de detecció de danys a l'ADN, que dirigeix i estabilitza les proteïnes vitals en la resposta al dany genètic, com la p53. Les troballes suggereixen noves implicacions terapèutiques i diagnòstiques, obrint portes a la comprensió dels mecanismes moleculars subjacents a malalties com el càncer.Un estudio pionero de la UAB revela el papel fundamental de las estructuras secundarias del ARNm codificante en la maquinaria de detección de daños al ADN, que dirige y estabiliza las proteínas vitales en la respuesta al daño genético, como la p53. Los hallazgos sugieren nuevas implicaciones terapéuticas y diagnósticas, abriendo puertas a la comprensión de los mecanismos moleculares subyacentes a enfermedades como el cáncer.A pioneering UAB study reveals the fundamental role of secondary structures of encoding mRNA in the DNA damage detection machinery, which directs and stabilizes vital proteins in the response to genetic damage, such as p53. The findings suggest new therapeutic and diagnostic implications, opening doors to understanding the molecular mechanisms underlying diseases such as cancer

Shaping the regulation of the p53 mRNA tumour suppressor : the co-evolution of genetic signatures

Structured RNA regulatory motifs exist from the prebiotic stages of the RNA world to the more complex eukaryotic systems. In cases where a functional RNA structure is within the coding sequence a selective pressure drives a parallel co-evolution of the RNA structure and the encoded peptide domain. The p53-MDM2 axis, describing the interactions between the p53 tumor suppressor and the MDM2 E3 ubiquitin ligase, serves as particularly useful model revealing how secondary RNA structures have co-evolved along with corresponding interacting protein motifs, thus having an impact on protein - RNA and protein - protein interactions; and how such structures developed signal-dependent regulation in mammalian systems. The p53(BOX-I) RNA sequence binds the C-terminus of MDM2 and controls p53 synthesis while the encoded peptide domain binds MDM2 and controls p53 degradation. The BOX-I peptide domain is also located within p53 transcription activation domain. The folding of the p53 mRNA structure has evolved from temperature-regulated in pre-vertebrates to an ATM kinase signal-dependent pathway in mammalian cells. The protein - protein interaction evolved in vertebrates and became regulated by the same signaling pathway. At the same time the protein - RNA and protein - protein interactions evolved, the p53 trans-activation domain progressed to become integrated into a range of cellular pathways. We discuss how a single synonymous mutation in the BOX-1, the p53(L22 L), observed in a chronic lymphocyte leukaemia patient, prevents the activation of p53 following DNA damage. The concepts analysed and discussed in this review may serve as a conceptual mechanistic paradigm of the co-evolution and function of molecules having roles in cellular regulation, or the aetiology of genetic diseases and how synonymous mutations can affect the encoded protein

Accurate and semi-automated reassociation of intermixed human skeletal remains recovered from bioarchaeological and forensic contexts

Commingled remains describes the situation of intermixed skeletal elements, an extremely common occurrence in contemporary forensic cases, archaeological mass graves, as well as fossil hominin assemblages. Given that reliable identification is typically impossible for commingled contexts, a plethora of previous studies has focused on the development of refined methods for reassociating the bones of each individual skeleton. Here, a novel virtual approach for quantifying the degree of three-dimensional shape compatibility between two adjoining bone articular surfaces is put forth. Additionally, the integrability of this method with traditional osteometric techniques is evaluated. We focus on the paradigm of the hip joint, whose articulating bone elements (the femur and the innominate bone) are crucial for reconstructing the biological profile of unidentified human remains. The results demonstrate that this new semi-automated methodology is highly accurate both for large commingled assemblages (such as those resulting from mass disasters or burials) as well as smaller-scale contexts (such as those resulting from secondary burials)

The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway

Background: The ATM kinase constitutes a master regulatory hub of DNA damage and activates the p53 response pathway by phosphorylating the MDM2 protein, which develops an affinity for the p53 mRNA secondary structure. Disruption of this interaction prevents the activation of the nascent p53. The link of the MDM2 protein—p53 mRNA interaction with the upstream DNA damage sensor ATM kinase and the role of the p53 mRNA in the DNA damage sensing mechanism, are still highly anticipated. Methods: The proximity ligation assay (PLA) has been extensively used to reveal the sub-cellular localisation of the protein—mRNA and protein–protein interactions. ELISA and co-immunoprecipitation confirmed the interactions in vitro and in cells. Results: This study provides a novel mechanism whereby the p53 mRNA interacts with the ATM kinase enzyme and shows that the L22L synonymous mutant, known to alter the secondary structure of the p53 mRNA, prevents the interaction. The relevant mechanistic roles in the DNA Damage Sensing pathway, which is linked to downstream DNA damage response, are explored. Following DNA damage (double-stranded DNA breaks activating ATM), activated MDMX protein competes the ATM—p53 mRNA interaction and prevents the association of the p53 mRNA with NBS1 (MRN complex). These data also reveal the binding domains and the phosphorylation events on ATM that regulate the interaction and the trafficking of the complex to the cytoplasm. Conclusion: The presented model shows a novel interaction of ATM with the p53 mRNA and describes the link between DNA Damage Sensing with the downstream p53 activation pathways; supporting the rising functional implications of synonymous mutations altering secondary mRNA structures

Molecular and Biochemical Techniques for Deciphering p53-MDM2 Regulatory Mechanisms

The p53 and Mouse double minute 2 (MDM2) proteins are hubs in extensive networks of interactions with multiple partners and functions. Intrinsically disordered regions help to adopt function-specific structural conformations in response to ligand binding and post-translational modifications. Different techniques have been used to dissect interactions of the p53-MDM2 pathway, in vitro, in vivo, and in situ each having its own advantages and disadvantages. This review uses the p53-MDM2 to show how different techniques can be employed, illustrating how a combination of in vitro and in vivo techniques is highly recommended to study the spatio-temporal location and dynamics of interactions, and to address their regulation mechanisms and functions. By using well-established techniques in combination with more recent advances, it is possible to rapidly decipher complex mechanisms, such as the p53 regulatory pathway, and to demonstrate how protein and nucleotide ligands in combination with post-translational modifications, result in inter-allosteric and intra-allosteric interactions that govern the activity of the protein complexes and their specific roles in oncogenesis. This promotes elegant therapeutic strategies that exploit protein dynamics to target specific interactions

The p53 mRNA : an integral part of the cellular stress response

A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs