Forging a New World Order? Interdisciplinary Perspectives on the Management of Metalworking and Ideological Change in the Late Bronze Age Carpathian Basin

The Carpathian Basin was a highly influential centre of metalworking in the 2nd mil. BC. Nevertheless, despite the abundance of metal objects from the Late Bronze Age, the scarcity of contextually associated metalworking remains representing distinct phases of the metalworking cycle from this region is striking. Here, we explore Late Bronze Age metalworking through the lens of a uniquely complete metalworking assemblage from the site of Șagu from contexts spanning the sixteenth to early thirteenth century BC. This material provides insights into changes in craft organisation following socio-political change after the collapse of Middle Bronze Age tell-centred communities. Our approach combines analytical and experimental data together with contextual analysis of technical ceramics (crucible, mould, and furnace fragments) to reconstruct the metalworking chaîne opératoire and place Șagu in its broader cultural context. Analyses demonstrate clear technological choices in ceramic paste recipes and strong interlinkages between metallurgy and other crafts practised on site, from domestic pottery production to building structures. Experimental replications reveal important intrinsic and experiential aspects of metallurgical activities at Șagu. Evidence on the spatial organisation of metallurgical workflows (routine sequence of actions and decisions) suggests they incorporated a high degree of visibility, which marks a distinct change in the use of craft space compared to the context of densely occupied Middle Bronze Age tells nearby. Combined, our archaeometric, experimental, and contextual results illustrate how changes in metalworking activities in the Late Bronze Age Carpathian Basin were deeply embedded in an ideological shift in the aftermath of the breakdown of Middle Bronze Age tells and the emergence of new social structures

Kinetics of maternal immunity against rabies in fox cubs (Vulpes vulpes)

BACKGROUND: In previous experiments, it was demonstrated that maternal antibodies (maAb) against rabies in foxes (Vulpes vulpes) were transferred from the vixen to her offspring. However, data was lacking from cubs during the first three weeks post partum. Therefore, this complementary study was initiated. METHODS: Blood samples (n = 281) were collected from 64 cubs (3 to 43 days old) whelped by 19 rabies-immune captive-bred vixens. Sera was collected up to six times from each cub. The samples were analysed by a fluorescence focus inhibition technique (RFFIT), and antibody titres (nAb) were expressed in IU/ml. The obtained data was pooled with previous data sets. Subsequently, a total of 499 serum samples from 249 cubs whelped by 54 rabies-immune vixens were fitted to a non-linear regression model. RESULTS: The disappearance rate of maAb was independent of the vixens' nAb-titre. The maAb-titre of the cubs decreased exponentially with age and the half-life of the maAb was estimated to be 9.34 days. However, maAb of offspring whelped by vixens with high nAb-titres can be detected for longer by RFFIT than that of offspring whelped by vixens with relatively low nAb-titres. At a mean critical age of about 23 days post partum, maAb could no longer be distinguished from unspecific reactions in RFFIT depending on the amount of maAb transferred by the mother. CONCLUSIONS: The amount of maAb cubs receive is directly proportional to the titre of the vixen and decreases exponentially with age below detectable levels in seroneutralisation tests at a relatively early age

Pigmentation and Vitamin D Metabolism in Caucasians: Low Vitamin D Serum Levels in Fair Skin Types in the UK

Background: Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated. Methodology/Principal Findings: We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18–79) and mean 25(OH)D levels were 77 nmol/L (6–289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p,0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p,0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001). Conclusions/Significance: Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in vie

Pigmentation and Vitamin D Metabolism in Caucasians: Low Vitamin D Serum Levels in Fair Skin Types in the UK

Background: Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated. Methodology/Principal Findings: We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18–79) and mean 25(OH)D levels were 77 nmol/L (6–289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p,0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p,0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001). Conclusions/Significance: Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in vie

Vitamin D and Foot and Ankle Trauma: An individual or societal problem?

Background Vitamin D deficiency is a worldwide health concern. Hypovitaminosis D may adversely affect recovery from bone injury. The authors aimed to perform an audit of the Vitamin D status of patients in three centres in the United Kingdom presenting with foot and ankle osseous damage. Methods Serum 25-hydroxyvitamin-D (vitamin D) levels were obtained in patients presenting with imaging confirmed foot and ankle osseous trauma. Variables including age, gender, ethnicity, location, season, month, anatomical location and type of bone injury were recorded. Results 308 patients were included from three different centres. 66.6% were female. The average age was 47.7 (range; 10–85). The mean hydroxyvitamin-D levels were 52.0 nmol/L (SD 28.5). 18.8% were grossly deficient, 23.7% deficient, 34.7% insufficient and 22.7% within normal range. 351 separate bone injuries were identified of which 104 were categorised as stress reactions, 134 as stress fractures, 105 as fractures and 8 non-unions. Age, gender, anatomical location and fracture type did not statistically affect vitamin D levels. Ethnicity did affect Vitamin D levels: non-Caucasians mean levels were 32.4 nmols/L compared to Caucasian levels of 53.2 nmol/L (p = 0.0026). Conclusion Only 18.8% of our trauma patients had a normal Vitamin D level and 22.7% were grossly deficient. Patient age, gender, anatomical location and injury type did not statistically affect vitamin D levels. No difference between trauma and elective patients were found. Hypovitaminosis D is a problem of society in general rather than specific to certain foot and ankle injury patterns or particular patient groups sustaining trauma. Level of evidence 2b

Lkb1 and Pten Synergise to Suppress mTOR-Mediated Tumorigenesis and Epithelial-Mesenchymal Transition in the Mouse Bladder

The AKT/PI3K/mTOR pathway is frequently altered in a range of human tumours, including bladder cancer. Here we report the phenotype of mice characterised by deletion of two key players in mTOR regulation, Pten and Lkb1, in a range of tissues including the mouse urothelium. Despite widespread recombination within the range of epithelial tissues, the primary phenotype we observe is the rapid onset of bladder tumorigenesis, with median onset of approximately 100 days. Single deletion of either Pten or Lkb1 had no effect on bladder cell proliferation or tumour formation. However, simultaneous deletion of Lkb1 and Pten led to an upregulation of the mTOR pathway and the hypoxia marker GLUT1, increased bladder epithelial cell proliferation and ultimately tumorigenesis. Bladder tissue also exhibited characteristic features of epithelial-mesenchymal transition, with loss of the epithelial markers E-cadherin and the tight junction protein ZO-1, and increases in the mesenchymal marker vimentin as well as nuclear localization of epithelial-mesenchymal transition (EMT) regulator Snail. We show that these effects were all dependent upon mTOR activity, as rapamycin treatment blocked both EMT and tumorigenesis. Our data therefore establish clear synergy between Lkb1 and Pten in controlling the mTOR pathway within bladder epithelium, and show that loss of this control leads to the disturbance of epithelial structure, EMT and ultimately tumorigenesis

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.

Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits