Animal hunts in late antiquity:Continuities and changes between the 4th and 6th century AD in the east of the Roman empire

Animal hunts (lat. venationes) were a popular form of mass entertainment in the Roman empire, from their origins in the republican period until Late Antiquity. Venationes continued to be presented even after gladiator fights, with which animal hunts were traditionally combined, disappeared from public life. They endured despite facing harsh and persistent opposition by Christian critics from the 2nd century AD onwards. The present thesis seeks to understand the reasons for the persistence and popularity of venationes in the late antique East from the beginning of the 4th century AD onward and for their eventual end in the mid-6th century AD. In previous scholarship, animal hunts have mostly been discussed in general works on Roman spectacles, in which they have often been sidelined next to gladiator fights and chariot racing. Additionally, evidence stemming from later periods and from outside Rome has received little attention. By centring animal hunts, this dissertation fills a lacuna in current research on Roman spectacles and highlights the unique circumstances and developments of venationes in Late Antiquity. The dissertation looks at a variety of sources to bring together local practices, inter-provincial networks, and imperial policies for a comprehensive understanding of the cultural and social significance of animal hunts for late antique society. By studying animal hunts as a historical instance of human-animal interaction, the dissertation acknowledges that animals are central to what venationes looked like, what venues were needed to accommodate them, what was necessary to organise them, and how the spectators and critics saw them

Fibroblast Growth Factor Receptor Splice Variants are Stable Markers of Oncogenic Transforming Growth Factor β1 Signaling in Metastatic Breast Cancers.

Introduction Epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) facilitate breast cancer (BC) metastasis; however, stable molecular changes that result as a consequence of these processes remain poorly defined. Therefore, with the hope of targeting unique aspects of metastatic tumor outgrowth, we sought to identify molecular markers that could identify tumor cells that had completed the EMT:MET cycle. Methods An in vivo reporter system for epithelial cadherin (E-cad) expression was used to quantify its regulation in metastatic BC cells during primary and metastatic tumor growth. Exogenous addition of transforming growth factor β1 (TGF-β1) was used to induce EMT in an in situ model of BC. Microarray analysis was employed to examine gene expression changes in cells chronically treated with and withdrawn from TGF-β1, thus completing one full EMT:MET cycle. Changes in fibroblast growth factor receptor type 1 (FGFR1) isoform expression were validated using PCR analyses of patient-derived tumor tissues versus matched normal tissues. FGFR1 gene expression was manipulated using short hairpin RNA depletion and cDNA rescue. Preclinical pharmacological inhibition of FGFR kinase was employed using the orally available compound BGJ-398. Results Metastatic BC cells undergo spontaneous downregulation of E-cad during primary tumor growth, and its expression subsequently returns following initiation of metastatic outgrowth. Exogenous exposure to TGF-β1 was sufficient to drive the metastasis of an otherwise in situ model of BC and was similarly associated with a depletion and return of E-cad expression during metastatic progression. BC cells treated and withdrawn from TGF-β stably upregulate a truncated FGFR1-β splice variant that lacks the outermost extracellular immunoglobulin domain. Identification of this FGFR1 splice variant was verified in metastatic human BC cell lines and patient-derived tumor samples. Expression of FGFR1-β was also dominant in a model of metastatic outgrowth where depletion of FGFR1 and pharmacologic inhibition of FGFR kinase activity both inhibited pulmonary tumor outgrowth. Highlighting the dichotomous nature of FGFR splice variants and recombinant expression of full-length FGFR1-α also blocked pulmonary tumor outgrowth. Conclusion The results of our study strongly suggest that FGFR1-β is required for the pulmonary outgrowth of metastatic BC. Moreover, FGFR1 isoform expression can be used as a predictive biomarker for therapeutic application of its kinase inhibitor

Response to combination therapy with interferon alfa-2a and ribavirin in chronic hepatitis C according to a TNF-alpha promoter polymorphism

Background. Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of chronic active hepatitis C. Polymorphisms in the promoter region of the TNF-alpha gene can alter the TNF-alpha expression and modify the host immune response. The present study aimed at the correlation of the G308A TNF-alpha polymorphism with the response to antiviral combination therapy in chronic hepatitis C. Patients and Methods: 62 patients with HCV and 119 healthy unrelated controls were genotyped for the G308A TNF-alpha promoter polymorphism. The patients received 3 x 3 million units of interferon alfa-2a and 1,0001,200 mg ribavirin daily according to their body weight. A response was defined as absence of HCV-RNA and normalization of S-ALT after 6 months of combination therapy. Results:With respect to the allele and genotype frequency, a significant difference was not observed between controls and patients with chronic hepatitis C. Furthermore, such a difference was also not observed if responders and non-responders to antiviral therapy were compared. Conclusions: The promoter polymorphism of the TNF-alpha gene investigated herein is equally distributed in healthy individuals and patients with hepatitis C and does not seem to predict the response to therapy with interferon alfa-2a and ribavirin. Copyright (C) 2003 S. Karger AG, Basel

The Antitumorigenic Function of EGFR in Metastatic Breast Cancer is Regulated by Expression of Mig6

Numerous studies by our lab and others demonstrate that epidermal growth factor receptor (EGFR) plays critical roles in primary breast cancer (BC) initiation, growth and dissemination. However, clinical trials targeting EGFR function in BC have lead to disappointing results. In the current study we sought to identify the mechanisms responsible for this disparity by investigating the function of EGFR across the continuum of the metastatic cascade. We previously established that overexpression of EGFR is sufficient for formation of in situ primary tumors by otherwise nontransformed murine mammary gland cells. Induction of epithelial-mesenchymal transition (EMT) is sufficient to drive the metastasis of these EGFR-transformed tumors. Examining growth factor receptor expression across this and other models revealed a potent downregulation of EGFR through metastatic progression. Consistent with diminution of EGFR following EMT and metastasis EGF stimulation changes from a proliferative to an apoptotic response in in situ versus metastatic tumor cells, respectively. Furthermore, overexpression of EGFR in metastatic MDA-MB-231 BC cells promoted their antitumorigenic response to EGF in three dimensional (3D) metastatic outgrowth assays. In line with the paradoxical function of EGFR through EMT and metastasis we demonstrate that the EGFR inhibitory molecule, Mitogen Induced Gene-6 (Mig6), is tumor suppressive in in situ tumor cells. However, Mig6 expression is absolutely required for prevention of apoptosis and ultimate metastasis of MDA-MB-231 cells. Further understanding of the paradoxical function of EGFR between primary and metastatic tumors will be essential for application of its targeted molecular therapies in BC

Different Asian monsoon rainfall responses to idealised orography sensitivity experiments in the HadGEM3-GA6 and FGOALS-FAMIL global climate models

Recent work has shown the dominance of the Himalayas in supporting the Indian summer monsoon (ISM), perhaps by surface sensible heating along its southern slope and by mechanical blocking acting to separate moist tropical flow from drier mid-latitude air. Previous studies have also shown that Indian summer rainfall is largely unaffected in sensitivity experiments that remove only the Tibetan Plateau. However, given the large biases in simulating the monsoon in CMIP5 models, such results may be model dependent. This study investigates the impact of orographic forcing from the Tibetan Plateau, Himalayas and Iranian Plateau on the ISM and East Asian summer monsoons (EASM) in the UK Met Office HadGEM3-GA6 and China’s Institute of Atmospheric Physics FGOALS-FAMIL GCMs. The models chosen feature opposite-signed biases in their simulation of the ISM rainfall and circulation climatology. The changes to ISM and EASM circulation across the sensitivity experiments are similar in both models and consistent with previous studies. However, considerable differences exist in the rainfall responses over India and China, and in the detailed aspects such as onset and retreat dates. In particular, the models show opposing changes in Indian monsoon rainfall when the Himalaya and Tibetan Plateau orography are removed. Our results show that a multi-model approach, as suggested in the forthcoming Global Monsoon Model Intercomparison Project (GMMIP) associated with CMIP6, is needed to clarify the impact of orographic forcing on the Asian monsoon and to fully understand the implications of model systematic error

Subtropical westerly jet influence on occurrence of western disturbances and Tibetan plateau vortices

Western disturbances (WDs) are mid-to-upper-tropospheric mesoscale vortices, which typically propagate along the subtropical westerly jet stream and bring heavy rainfall to Pakistan and northern India during boreal winter. They are dynamically similar to Tibetan Plateau vortices (TPVs), which affect southwest China during spring and summer and emanate from the Tibetan Plateau. Here, we propose that their similarity implies the existence of a more general group of upper-tropospheric vortices featuring interactions with the orography of the Hindu Kush-Himalaya-Tibetan Plateau region. Using existing track databases for WDs and TPVs derived from ERA-Interim reanalysis, we show that their respective occurrence frequencies are highly anticorrelated with each other through the seasonal cycle, yet both are strongly correlated with jet latitude. Our findings imply that the incidence of hazards due to WDs and TPVs is correlated on intra- and interannual timescales, particularly through upper-level baroclinicity

Two-Color Coherent Photodissociation of Nitrogen Oxide in Intense Laser Fields

A simple one-dimensional semi-classical model with a Morse potential is used to investigate the possibility of two-color infrared multi-photon dissociation of vibrationally excited nitrogen oxide. The amplitude ratio effects and adiabatic effects are investigated. Some initial states are found to have thresholds smaller than expected from single-mode considerations and multiple thresholds exist for initial states up to 32. PACS: 42.50.HzComment: 3 pages, old papers, add source files to replace original postscrip

In vivo Dual Substrate Bioluminescent Imaging

Our understanding of how and when breast cancer cells transit from established primary tumors to metastatic sites has increased at an exceptional rate since the advent of in vivo bioluminescent imaging technologies 1-3. Indeed, the ability to locate and quantify tumor growth longitudinally in a single cohort of animals to completion of the study as opposed to sacrificing individual groups of animals at specific assay times has revolutionized how researchers investigate breast cancer metastasis. Unfortunately, current methodologies preclude the real-time assessment of critical changes that transpire in cell signaling systems as breast cancer cells (i) evolve within primary tumors, (ii) disseminate throughout the body, and (iii) reinitiate proliferative programs at sites of a metastatic lesion. However, recent advancements in bioluminescent imaging now make it possible to simultaneously quantify specific spatiotemporal changes in gene expression as a function of tumor development and metastatic progression via the use of dual substrate luminescence reactions. To do so, researchers take advantage for two light-producing luciferase enzymes isolated from the firefly (Photinus pyralis) and sea pansy (Renilla reniformis), both of which react to mutually exclusive substrates that previously facilitated their wide-spread use in in vitro cell-based reporter gene assays 4. Here we demonstrate the in vivo utility of these two enzymes such that one luminescence reaction specifically marks the size and location of a developing tumor, while the second luminescent reaction serves as a means to visualize the activation status of specific signaling systems during distinct stages of tumor and metastasis development. Thus, the objectives of this study are two-fold. First, we will describe the steps necessary to construct dual bioluminescent reporter cell lines, as well as those needed to facilitate their use in visualizing the spatiotemporal regulation of gene expression during specific steps of the metastatic cascade. Using the 4T1 model of breast cancer metastasis, we show that the in vivo activity of a synthetic Smad Binding Element (SBE) promoter was decreased dramatically in pulmonary metastasis as compared to that measured in the primary tumor 4-6. Recently, breast cancer metastasis was shown to be regulated by changes within the primary tumor microenvironment and reactive stroma, including those occurring in fibroblasts and infiltrating immune cells 7-9. Thus, our second objective will be to demonstrate the utility of dual bioluminescent techniques in monitoring the growth and localization of two unique cell populations harbored within a single animal during breast cancer growth and metastasis

CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

Immunological memory is a hallmark of adaptive immunity, and understanding T cell memory will be central to the development of effective cell-mediated vaccines. The characteristics and functions of CD4 memory cells have not been well defined. Here we demonstrate that the increased size of the secondary response is solely a consequence of the increased antigen-specific precursor frequency within the memory pool. Memory cells proliferated less than primary responding cells, even within the same host. By analyzing the entry of primary and memory cells into the cell cycle, we found that the two populations proliferated similarly until day 5; after this time, fewer of the reactivated memory cells proliferated. At this time, fewer of the reactivated memory cells made IL-2 than primary responding cells, but more made IFNγ. Both these factors affected the low proliferation of the memory cells, because either exogenous IL-2 or inhibition of IFNγ increased the proliferation of the memory cells

How important are post-tropical cyclones for European windstorm risk?

Post-tropical cyclones (PTCs) extend many hazards associated with tropical cyclones (TCs) to the mid-latitudes. Despite recent high-impact cases affecting Europe such as Ophelia, little research has been done to characterize the risk of PTCs. Here we compare the climatologies and intensity distributions of mid-latitude cyclones (MLCs) and PTCs in the North Atlantic and Europe by tracking cyclones in the ERA5 reanalysis. Considering hurricane-season cyclones impacting Northern Europe, PTCs show a significantly higher mean maximum intensity than MLCs, but make only a small contribution to total windstorm risk. Our results show that a disproportionately large fraction of high-intensity cyclones impacting Europe during hurricane season are PTCs. The fraction of PTCs impacting N Europe with storm-force (>25ms-1) winds is approximately ten times higher than for MLCs. Less than 1% of cyclones impacting Northern Europe are identified to be PTCs. This rises to 8.8% when considering cyclones which impact with storm-force winds