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OBJECTIVES The primate talus is known to have a shape that varies according to differences in locomotion and substrate use. While the modern human talus is morphologically specialized for bipedal walking, relatively little is known on how its morphology varies in relation to cultural and environmental differences across time. Here we compare tali of modern human populations with different subsistence economies and lifestyles to explore how cultural practices and environmental factors influence external talar shape. MATERIALS AND METHODS The sample consists of digital models of 142 tali from 11 archaeological and post-industrial modern human groups. Talar morphology was investigated through 3D (semi)landmark based geometric morphometric methods. RESULTS Our results show distinct differences between highly mobile hunter-gatherers and more sedentary groups belonging to a mixed post-agricultural/industrial background. Hunter-gatherers exhibit a more "flexible" talar shape, everted posture, and a more robust and medially oriented talar neck/head, which we interpret as reflecting long-distance walking strictly performed barefoot, or wearing minimalistic footwear, along uneven ground. The talus of the post-industrial population exhibits a "stable" profile, neutral posture, and a less robust and orthogonally oriented talar neck/head, which we interpret as a consequence of sedentary lifestyle and use of stiff footwear. DISCUSSION We suggest that talar morphological variation is related to the adoption of constraining footwear in post-industrial society, which reduces ankle range of motion. This contrasts with hunter-gatherers, where talar shape shows a more flexible profile, likely resulting from a lack of footwear while traversing uneven terrain. We conclude that modern human tali vary with differences in locomotor and cultural behavior.

Objectives Palate morphology is constantly changing throughout an individual's lifespan, yet its asymmetry during growth is still little understood. In this research, we focus on the study of palate morphology by using 3D geometric morphometric approaches to observe changes at different stages of life, and to quantify the impact of directional and fluctuating asymmetry on different areas at different growth stages. Materials and Methods The sample consists of 183 individuals (1–72 years) from two identified human skeletal collections of 19th and early 20th Century Italian contexts. A 3D‐template of 41 (semi)landmarks was applied on digital palate models to observe morphological variation during growth. Results Asymmetrical components of the morphological structure appears multidirectional on the entire palate surface in individuals, Directional and fluctuating asymmetry of human palate.

An isolated human cranium, dated to the early Eneolithic period, was discovered in 2015 at the top of a vertical shaft in the natural Marcel Loubens gypsum Cave (Bologna area, northern Italy). No other anthropological or archaeological remains were found inside the cave. In other caves of the same area anthropic and funerary use are attested from prehistory to more recent periods. We focused on investigating the circumstances surrounding the death of this individual, since the cranium shows signs of some lesions that appear to be the results of a perimortem manipulation probably carried out to remove soft tissues. Anthropological analyses revealed that the cranium belonged to a young woman. We analysed the taphonomic features and geological context to understand how and why the cranium ended up (accidentally or intentionally) in the cave. The analyses of both the sediments accumulated inside the cranium and the incrustations and pigmentation covering its outer surface suggested that it fell into the cave, drawn by a flow of water and mud, likely from the edges of a doline. The accidental nature of the event is also seemingly confirmed by some post-mortem lesions on the cranium. The comparison with other Eneolithic archaeological sites in northern Italy made it possible to interpret the find as likely being from a funerary or ritual context, in which corpse dismemberment (in particular the displacement of crania) was practiced.

Recent work has disclosed the critical role played by enamel peptides in sex classification of old skeletal remains. In particular, protein AMELY (amelogenin isoform Y) is present in the enamel dental tissue of male individuals only, while AMELX (isoform X) can be found in both sexes. AMELY can be easily detected by LC-MS/MS in the ion extracted chromatograms of the SM(ox)IRPPY peptide (monoisotopic [M + 2 H]+2 mass = 440.2233 m/z). In this paper, we exploited the dimorphic features of the amelogenin protein to determine the sex of the so-called ‘Lovers of Modena’, two Late Antique individuals whose skeletons were intentionally buried hand-in-hand. Upon discovery, mass media had immediately assumed they were a male-female couple, even if bad preservation of the bones did not allow an effective sex classification. We were able to extract proteins from the dental enamel of both individuals (~1600 years old) and to confidently classify them as males. Results were compared to 14 modern and archaeological control samples, confirming the reliability of the ion chromatogram method for sex determination. Although we currently have no information on the actual relationship between the ‘Lovers of Modena’ (affective? Kin-based?), the discovery of two adult males intentionally buried hand-in-hand may have profound implications for our understanding of funerary practices in Late Antique Italy.

The adoption of bipedalism is a key benchmark in human evolution that has impacted talar morphology. Here, we investigate talar morphological variability in extinct and extant hominins using a 3D geometric morphometric approach. The evolutionary timing and appearance of modern human-like features and their contributions to bipedal locomotion were evaluated on the talus as a whole, each articular facet separately, and multiple combinations of facets. Distinctive suites of features are consistently present in all fossil hominins, despite the presence of substantial interspecific variation, suggesting a potential connection of these suites to bipedal gait. A modern human-like condition evolved in navicular and lateral malleolar facets early in the hominin lineage compared with other facets, which demonstrate more complex morphological variation within Homininae. Interestingly, navicular facet morphology of Australopithecus afarensis is derived in the direction of Homo, whereas more recent hominin species such as Australopithecus africanus and Australopithecus sediba retain more primitive states in this facet. Combining the navicular facet with the trochlea and the posterior calcaneal facet as a functional suite, however, distinguishes Australopithecus from Homo in that the medial longitudinal arch had not fully developed in the former. Our results suggest that a more everted foot and stiffer medial midtarsal region are adaptations that coincide with the emergence of bipedalism, whereas a high medial longitudinal arch emerges later in time, within Homo. This study provides novel insights into the emergence of talar morphological traits linked to bipedalism and its transition from a facultative to an obligate condition.

The 4th century BC marks the main entrance of Celtic populations in northern Italy. Their arrival has been suggested based on the presence of Celtic customs in Etruscan mortuary contexts, yet up to now few bioarchaeological data have been examined to support or reject the arrival of these newcomers. Here we use strontium isotopes, non-metric dental traits and funerary patterns to unravel the biocultural structure of the necropolis of Monterenzio Vecchio (Bologna, Italy). Subsamples of our total sample of 38 individuals were analyzed based on different criteria characterizing the following analyses: 1) strontium isotope analysis to investigate migratory patterns and provenance; 2) non-metric dental traits to establish biological relationships between Monterenzio Vecchio, 13 Italian Iron age necropolises and three continental and non-continental Celtic necropolises; 3) grave goods which were statistically explored to detect possible patterns of cultural variability. The strontium isotopes results indicate the presence of local and non-local individuals, with some revealing patterns of mobility. The dental morphology reveals an affinity between Monterenzio Vecchio and Iron Age Italian samples. However, when the Monterenzio Vecchio sample is separated by isotopic results into locals and non-locals, the latter share affinity with the sample of non- continental Celts from Yorkshire (UK). Moreover, systematic analyses demonstrate that ethnic background does not retain measurable impact on the distribution of funerary elements. Our results confirm the migration of Celtic populations in Monterenzio as archaeologically hypothesized on the basis of the grave goods, followed by a high degree of cultural admixture between exogenous and endogenous traits. This contribution shows that combining different methods offers a more comprehensive perspective for the exploration of biocultural processes in past and present populations. European Commission Horizon 2020

To evaluate OPN, MCM7, Ki-67, p53, Bcl-2 and 53BP1 presence, together with the abnormal adaptive CD4 and CD8 T-cell response markers expression in a series of oral lichen planus (OLP) affected patients and assess their combined contribution for a more objective disease classification.In this ex-vivo retrospective analysis, biopsy specimens from 28 adults with a clinical diagnosis of OLP at different progression degree (16 reticular, 2 plaque-like, 1 erosive and 9 mixed type) were collected. Sections were immunohistochemically investigated for the proinflammatory cytokine osteopontin (OPN), alpha-beta CD4 and CD8 positive T cells, DNA replication licensing factor (MCM7), proliferating cell marker (Ki-67), apoptotic and tumor antigen (p53), apoptosis modulator (Bcl-2) and cellular response regulator to double-strand breaks tumor suppressor p53-binding protein 1 expression. Statistical analysis revealed that 53BP1 is highly represented among the OLP study patients (p0.05). Moreover, on the basis of the quantification results of the highly expressed parameters, two illness categories with different severity were evidenced. The classification hypothesis was confirmed by i) OLP lesion persistence, ii) the development of oral severe lesions in the patients belonging to high grade activity OLP group (HGA-OLPs) and iii) the ascertainment of the same evidence both in the oral squamous cell tumor controls (OSCC) and in HGA-OLP cases.This study completes the scenario with respect to early detection, thanks to a more precise histological analysis, for rationalizing the clinical and histological findings toward a sharable international disease scoring system.

Entheses have rarely been systematically studied in the field of human evolution. However, the investigation of their morphological variability (e.g., robusticity) could provide new insight into their evolutionary significance in the European Neanderthal populations. The aim of this work is to study the entheses and joint features of the lower limbs of El Sidrón Neanderthals (Spain; 49 ka), using standardized scoring methods developed on modern samples. Paleobiology, growth, and development of both juveniles and adults from El Sidrón are studied and compared with those of Krapina Neanderthals (Croatia, 130 ka) and extant humans. The morphological patterns of the gluteus maximus and vastus intermedius entheses in El Sidrón, Krapina, and modern humans differ from one another. Both Neanderthal groups show a definite enthesis design for the gluteus maximus, with little intrapopulation variability with respect to modern humans, who are characterized by a wider range of morphological variability. The gluteus maximus enthesis in the El Sidrón sample shows the osseous features of fibrous entheses, as in modern humans, whereas the Krapina sample shows the aspects of fibrocartilaginous ones. The morphology and anatomical pattern of this enthesis has already been established during growth in all three human groups. One of two and three of five adult femurs from El Sidrón and from Krapina, respectively, show the imprint of the vastus intermedius, which is absent among juveniles from those Neanderthal samples and in modern samples. The scant intrapopulation and the high interpopulation variability in the two Neanderthal samples is likely due to a long-term history of small, isolated populations with high levels of inbreeding, who also lived in different ecological conditions. The comparison of different anatomical entheseal patterns (fibrous vs. fibrocartilaginous) in the Neanderthals and modern humans provides additional elements in the discussion of their functional and genetic origin., This work is funded by the Spanish Ministry of Economy and Competitiveness: CGL2016-75109-P.

Background Despite vaccination and screening measures, anogenital cancer, mainly promoted by HPV16 oncoproteins, still represents the fourth tumor and the second cause of death among women. Cell replication fidelity is the result of the host DNA damage response (DDR). Unlike many DNA viruses that promote their life cycle through the DDR inactivation, HR-HPVs encourage cells proliferation despite the DDR turned on. Why and how it occurs has been only partially elucidated. During HPV16 infection, E6 links and degrades p53 via the binding to the E6AP LXXLL sequence; unfortunately, E6 direct role in the DDR response has not clearly identified yet. Similarly, E7 increases DDR by competing with E2F1-pRb interaction, thus leading to the inactivation of pRb, and promotion, E2F1 mediated, of DDR genes translation, by binding to the pRb-like proteins CBP/p300 and p107, that also harbour LXXLL sequence, and via the interaction and activation of several DDR proteins. Methods To gain information regarding E6 and E7 contribution in DDR activation, we produced an in vitro 3D HPV16-E6E7 infected epithelium, already consolidated study model for HPVs, and validated it by assessing H&E staining and BrdU, HPV16 DNA, E6E7 proteins and γH2A.X/53BP1 double-strand break (DSBs) sensors expression; then we made an immuno-colocalization of E6 and E7 with cyclin E2 and B1. Since 53BP1, like E6 and E7, also binds p53 and pRb, we supposed their possible direct binding. To explore this hypothesis, we performed a double immunofluorescence of E6 and E7 with 53BP1, a sequence analysis of 53BP1 within its BRCT2 domain and then an in situ PLA within CaSki, E6E7HPV16 NHEKs and the 3D model. Results The in vitro epithelium resembled the histology and the events typical of in vivo infected tissues. E6E7HPV16 were both expressed in basal and differentiated strata and induced H2A.X phosphorylation and 53BP1 increment into nuclear foci. After highlighting E6 and E7 co-expression with 53BP1 and a LKVLL sequence within the 53BP1 BRCT2 domain, we demonstrated the bindings via the PLA technique. Conclusions Our results reinforce E6 and E7 role in cellular function control providing potentially new insights into the activity of this tumor virus.

Objectives Exact symmetry and perfect balance between opposite jaw halves, as well as between antagonistic teeth, is not frequently observed in natural masticatory systems. Research results show that asymmetry in our body, skull, and jaws is often related to genetic, epigenetic, environmental and individual ontogenetic factors. Our study aims to provide evidence for a significant link between masticatory asymmetry and occlusal contact between antagonist teeth by testing the hypothesis that tooth inclination is one of the mechanisms driving distribution of wear in masticatory phases in addition to dietary and cultural habits. Materials and Methods The present work investigates the relationship between dental macrowear patterns and tooth inclinations on a sample of complete maxillary and mandibular 3D models of dental arches from 19 young and adult Yuendumu Aboriginal individuals. The analysis was carried out on first molars (M1) from all quadrants. Occlusal Fingerprint Analysis was used for the quantification of macrowear patterns, and 2D cross‐sectional geometric analysis was carried out to investigate asymmetry in dental arches. Results The asymmetry is highly variable on both arches, and it is associated with differences in the inclination of upper M1 crowns. Each molar has variable inclination (buccal/lingual) which influence tooth to tooth contact, producing greater or lesser variation in wear pattern. Interindividual variability of morphological variation of the occlusal relationship has to be considered in macrowear analysis. Discussion Our results suggest that overall asymmetry in the masticatory apparatus in modern humans affects occlusal contact areas between antagonist teeth influencing macrowear and chewing efficiency during ontogeny.

Several studies have documented the ability of flavonoids to sensitize cancer cells to chemotherapeutics and reverse multidrug resistance by inhibition of efflux pumps (adenosine triphosphate-binding cassette transporters), apoptosis activation, and cell cycle arrest. In this study, the flavonoid rutin (quercetin 3-O-β-d-rutinoside) was investigated as chemosensitizer towards two different human epithelial breast cancer cell lines: (i) MB-MDA-231, selected as representative for triple-negative breast cancer and (ii) MCF-7 used as a well-characterized model of HER2-negative breast cancer. To assess the cytocompatibility of rutin against non-cancer cells, primary human mammary fibroblasts were used as control and non-target cells. In MDA-MB-231 cells, 20 μM rutin enhanced cytotoxicity related to cyclophosphamide and methotrexate. Rutin significantly (p 0.05) increased the anticancer activity of both chemotherapeutics, at 24-48-72 h, and decreased the activity of the adenosine triphosphate-binding cassette transporters, namely, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Flow cytometry analysis showed 20 μM and 50 μM rutin arrested cell cycle at G2/M and G0/G1 phases, respectively, significantly promoting cell apoptosis. Rutin, via non-selective inhibition of P-gp and BCRP pumps, efficiently reverses multidrug resistance and restores chemosensitivity to cyclophosphamide and cyclophosphamide of human chemoresistant, triple-negative breast cancer cells, successfully arresting cell cycle progression. Copyright © 2017 John WileySons, Ltd.

Randomized clinical trials have not shown long-term benefit of postmenopausal hormone replacement therapy (PHT) nor have they shown conclusively that the harmful consequences outweighs the benefits of the treatment. Rather, it is possible that an individualized hormone replacement therapy in questionably clinically healthy postmenopausal women may lead to different results than randomized trials. Design In this cross-sectional study we evaluated anthropometric parameters, body composition, serum lipids, blood pressure, heart rate variability (HRV) and neurocognitive functions in 39 healthy postmenopausal women PHT users or not users (n = 13, age 53.0 ± 3.3 and n = 26, age = 53.3 ± 5.0 SD, respectively) as well as in 27 younger controls (ages = 33.3 ± 7.1). Results Demographic parameters were similar in women PHT users and not users. Postmenopausal women showed a significantly increase of body mass index (BMI) as well as of waist circumference, compared to younger controls, but in PHT users the values of fat free mass were intermediate between the ones of not treated and younger women. The study of HRV showed a reduction in low frequency (LF) component (sympathetic modulation) during the day, and a reduction in high frequency (HF) component (parasympathetic modulation), particularly in postmenopausal women without PHT. PHT users were characterized by autonomic parameters intermediate between younger controls and age-matched women without PHT. Conclusions The impact of PHT on the age-dependent changes of anthropometric features and body composition seems to be modest but positive. Furthermore, PHT seems to play a positive role on the autonomic modulation of cardiac function, through a shift of LF / HF ratio values towards those of young controls.

Sex determination is a pivotal step in forensic and bioarchaeological fields. Generally, scholars focus on metric or qualitative morphological features, but in the last few years several contributions have applied geometric-morphometric (GM) techniques to overcome limitations of traditional approaches. In this study, we explore sexual dimorphism in modern human tali from three early 20th century populations (Sassari and Bologna, Italy; New York, USA) at intra- and interspecific population levels using geometric morphometric (GM) methods. Statistical analyses were performed using shape, form, and size variables. Our results do not show significant differences in shape between males and females, either considering the pooled sample or the individual populations. Differences in talar morphology due to sexual dimorphism are mainly related to allometry, i.e. size-related changes of morphological traits. Discriminant function analysis using form space Principal Components and centroid size correctly classify between 87.7% and 97.2% of the individuals. The result is similar using the pooled sample or the individual population, except for a diminished outcome for the New York group (from 73.9% to 78.2%). Finally, a talus from the Bologna sample (not included in the previous analysis) with known sex was selected to run a virtual resection, followed by two digital reconstructions based on the mean shape of both the pooled sample and the Bologna sample, respectively. The reconstructed talus was correctly classified with a Ppost between 99.9% and 100%, demonstrating that GM is a valuable tool to cope with fragmentary tali, which is a common occurrence in forensic and bioarchaeological contexts.