Imperial and Local: Audience and Identity in the Idrimi Inscription

This article studies the Idrimi inscription from ancient Alalah, modern Tell Atchana, in order to explore how and to what effect manifestations of empire may have been socially consequential to local populations ruled by Mittani. Specifically, the article argues that Idrimi is presented as a Mittani hero, but the story of his life is told in a Northwest Semitic-Akkadian code; an imperial vision receives a local expression. From this conclusion, the article ends by trying to infer something about the inscription’s intended audience.

PHYSICAL-SPATIAL ASPECT IN LOCAL EXPRESSION OF TOWNSCAPE ON SAMIRONO YOGYAKARTA

- Cities change by time to time physically and non-physically. The city development produces a distinctive character even in the smallest urban creature. This distinctive character does not take quickly but is slowly and full of challenges. Townscape is a visual impression of buildings arrangement, roads, and spaces those are expressed organically to form urban spaces. Therefore, a townscape that exists in an urban area is created on delevlopment or grows by unintentionally. Apart from that, the character of a townscape from one place is different from the other. The townscapes had been created and specific in each place. The literatures for this research are: 'The Concise Townscape', 'The Aesthetic Townscape', and 'Road Form and Townscape'. The three literatures describe the existence of townscape in Europe and Japan. This is the basic knowledge in townscape and how it is applied in Indonesia, especially in the city of Yogyakarta. The urban space chosen in this research is Padukuhan Samirono. Padukuhan Samirono is located in the north of Yogyakarta City and is very close to Gadjah Mada University and Negri Yogyakarta University. Padukuhan Samirono is known as an area that provides student accomodation. The community still stand fot maintaining their cultural habit such as gathering, cultural performances, and parades. This study examines the Townscape in Padukuhan Samirono. The social and cultural activities expressed their locality as seen as in its townscape. The pictorial analysis method identify the elements of townscapes wich effects the urban space. By describing the elements of urban space with 7 factors: nature elements, space organization, mass, proportion, activity, carving, and streetscape, the local expression criteria of Padukuhan Samirono’s can be formulated. Based on observations, the local expression of townscape on Samirono changes into a modern form. This research attempts to enhance people’s aprrectiation about townscape, especially townscape in Indonesia. Key Words: townscape, pictorial analysis, Samirono, Javanese, locality

Glucocorticoid production in lymphoid organs: Acute effects of lipopolysaccharide in neonatal and adult mice

Glucocorticoids (GCs) are critical modulators of the immune system. The hypothalamic-pituitary-adrenal (HPA) axis regulates circulating GC levels and is stimulated by endotoxins. Lymphoid organs also produce GCs; however, it is not known how lymphoid GC levels are regulated in response to endotoxins. We assessed whether an acute challenge of lipopolysaccharide (LPS) increases lymphoid levels of GCs, steroidogenic enzymes expression, and components of the HPA axis (e.g., CRH) expression. We administered LPS (50µg/kg i.p.) or vehicle control to male and female C57BL/6J neonatal (post-natal day (PND) 5) and adult (PND90) mice and collected blood, bone marrow, thymus, and spleen 4 hr later. We measured progesterone, 11-deoxycorticosterone (DOC), corticosterone, and 11-dehydrocorticosterone (DHC) via liquid chromatography tandem mass spectrometry (LC-MS/MS). We measured gene expression of key steroidogenic enzymes (Cyp11b1, Hsd11b1, and Hsd11b2) and HPA axis components (Crh, Crhr1, Pomc, and Mc2r) via qPCR. At PND5, LPS induced greater increases in steroid levels in lymphoid organs than in blood. In contrast, at PND90, LPS induced greater increases in steroid levels in blood than in lymphoid organs. Steroidogenic enzyme transcripts were present in all lymphoid organs, and LPS altered steroidogenic enzyme expression predominately in the spleen. Lastly, we detected transcripts of key HPA axis components in all lymphoid organs, and there was an effect of LPS in the spleen. Taken together, these data suggest that LPS regulates GC production by lymphoid organs, similar to its effects on the adrenal glands, and the effects of LPS might be mediated by local expression of CRH and ACTH.

Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer

TGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-heavy tumors. Using B16 mouse melanoma and CT26 colon carcinoma as models of stroma-poor tumors, we demonstrate that myeloid/dendritic cells are the main sources of TGFβ1 and TGFβ3. Depending on local expression of TGFβ isoforms, isoform specific inhibition of either TGFβ1 or TGFβ3 may be effective. The TGFβ signature of CT26 colon carcinoma is defined by TGFβ1 and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. Using T cell functional assays, we show that the mechanism of tumor delay is through and dependent on enhanced CD8+ T cell function. To overcome the local immunosuppressive environment, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control. Our data suggest that TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor suppression.

Bone morphogenetic protein 2 controls steroid-induced osteonecrosis of the femoral head via directly inhibiting interleukin-34 expression

Increased inflammatory responses is one of the major characteristics of osteonecrosis of the femoral head (ONFH). We aimed to investigate the function of bone morphogenetic protein 2 (BMP-2)/interleukin (IL)-34 axis in the inflammatory responses of ONFH. The systemic and local expression of BMPs in ONFH patients were detected by qRT-PCR and ELISA. In vitro osteoclast differentiation and ONFH mouse models, induced by 20 mg/kg methylprednisolone through intramuscular injection, were established using wild type and BMP-2-/- mice to explore the regulatory role of BMP-2 in pro-inflammatory responses and bone defects of ONFH. IL-34 expression and function were examined in vitro and in vivo through qRT-PCR, TRAP staining, and gene knockout. The systemic and local expression of BMPs were elevated in ONFH patients. BMP-2 reduced the production of pro-inflammatory cytokines and inhibited the differentiation of osteoclasts. Mechanistically, BMP-2 inhibited osteoclasts formation through suppressing IL-34 expression, and then promoted bone repair and alleviated ONFH. In conclusion, our study reveals that BMP-2 inhibits inflammatory responses and osteoclast formation through down-regulating IL-34.

Pathways of IFN-alpha Activation in Patients with Cervical Intraepithelial Neoplasia (CIN)

Objective The aim of the present study was to compare the local and systemic expression of the factors linked to the interferon alpha (IFN-α) activation pathway in different degrees of cervical intraepithelial neoplasia (CIN) and cervical cancer. Methods A total of 128 patients with CIN I, CIN II, CIN III and cervical cancer was evaluated. The real-time polymerase chain reaction (RT-PCR) technique was used to evaluate the gene expression of IFNR1, IFNR2, IFN-α, oligoadenylate synthase (2'5′OAS), cytokine signal suppressor 1 (SOCS) 1, SOCS3, signal transducer and transcription activator 1 (STAT1), and IRF9 from 128 biopsies. A total of 46 out of 128 samples were evaluated by flow cytometry for IFNAR1, IFNAR2, STAT1, IRF7 and IFN-α in peripheral blood cells. Results Patients with CIN II and III (63 samples) had a low local expression of IFNR1, but not IFNR2. Patients with some degree of injury showed high expression of SOCS1 and SOCS3. Systemically, patients with CIN II and III (20 samples) had a significant increase in IFNR1, IFNR2, STAT1, IRF7, and IFN-α in helper, cytotoxic T lymphocytes, and in monocytes. Conclusion Patients with high-grade lesions have increased systemic expression of IFN-α and its activation pathways in helper and cytotoxic T lymphocytes, as well as in monocytes due to an exacerbation of the immune response in these patients. This phenomenon is not accompanied by resolution of the lesion due to a defect in the IFN-α activation pathway that revealed by low local IFNAR1 expression and high local expression of SOCS1 and SOCS3.

Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men

In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid hormones but also actively regulates testosterone signaling through putative plasma membrane receptors and by local expression of androgen-binding proteins apparently to reach local elevated testosterone concentrations in specific androgen target tissues. Circulating SHBG levels are influenced by metabolic and hormonal factors, and they are reduced in obesity and insulin resistance, suggesting that SHBG may have a broader clinical utility in assessing the risk for cardiovascular diseases. Importantly, plasma SHBG levels are strongly correlated with testosterone concentrations, and in men, low testosterone levels are associated with an adverse cardiometabolic profile. Although obesity and insulin resistance are associated with an increased incidence of cardiovascular disease, whether they lead to abnormal expression of circulating SHBG or its interaction with androgen signaling remains to be elucidated. SHBG is produced mainly in the liver, but it can also be expressed in several tissues including the brain, fat tissue, and myocardium. Expression of SHBG is controlled by peroxisome proliferator-activated receptor γ (PPARγ) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulate hepatocyte nuclear factor-4 (HNF4), a prerequisite for SHBG upregulation. In cardiomyocytes, testosterone activates AMPK and PPARs. Therefore, the description of local expression of cardiac SHBG and its circulating levels may shed new light to explain physiological and adverse cardiometabolic roles of androgens in different tissues. According to emerging clinical evidence, here, we will discuss the potential mechanisms with cardioprotective effects and SHBG levels to be used as an early metabolic and cardiovascular biomarker in men.

POS0578 CORRELATION BETWEEN EXPRESSION LEVELS OF MIR-155 AND MIR-223 IN SYNOVIAL FLUID AND ULTRASOUND SCORES FOR ACTIVE SYNOVITIS IN RHEUMATOID ARTHRITIS PATIENTS

Background:MicroRNAs (miRNAs) are a class of small, non-coding RNAs that negatively regulate gene expression at posttranscriptional level. In rheumatoid arthritis studies have shown that miRNA are differentially expressed systemically as well as locally in the inflamed joints [1,2]. The correlation between their systemic or local expression levels and scores for disease activity and progression in RA make them possible candidate for biomarkers in the clinical practice.Objectives:To analyze the expression levels of miR-155 and miR-223 in synovial fluid (SF) from RA patients in regard to the ultrasound scores for disease activity.Methods:A total number of 48 RA patients according to the 1987 ACR criteria were included in the study. Expression levels of miR-155 and miR-223 SF were determined by qPCR (SybrGreen technology) and compared to healthy controls (HCs). Relative changes of gene expression levels of the studied miRNAs were calculated by 2-ΔΔCt method. Musculoskeletal ultrasound (MSUS) examination was performed by two independent examiners on ESAOTE, MyLab60 using both grey scale and power Doppler technic. A semi-quantitative assessment of the peripheral joints was performed for detecting joint inflammation and determining the grade of synovial thickening and the degree of vascularization. Ultrasound features for active disease were correlated to the local expression of the studied miRNAs. SPSS was used for statistical analysis.Results:RA SF showed overexpression of miR-155 (in 79.17%, p=1.63x10-4) and of miR-223 (in 79.17%, p=1.64x10-3) when compared to HCs and both miRNAs could be used to differentiate RA patients from HCs (р=8.0х10-5 and р=2.8х10-4, respectively). When we analyzed the correlation between the diagnosis, the expression of miRNAs and the changes on the musculoskeletal ultrasound examination we found a statistically significant correlation between the presence of synovitis and the degree of the power Doppler signal on MSUS and the local expression of miR-223 (p=6.19 x 10-4 and p=0.003, respectively). SF levels of miR-223 correlated also with the degree of synovial hypertrophy on MSUS (p=0.013). The results for miRNA-155 were not statistically significant.Conclusion:The correlation between the local expression of miR-223 and the ultrasound features of active joint inflammation shows that this miRNA might be a better candidate for local disease biomarker than miR-155. Further analysis with larger sets is needed to confirm if altered local miRNA expression could be used in the clinical practice as biomarker for disease activity especially in cases with subclinical synovitis.References:[1]Filková M, Aradi B, Šenolt L, et al. Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis. ARD, 2014; 73: 1898-1904.[2]Kriegsmann, M., Randau, T.M., Gravius, S. et al. Expression of miR-146a, miR-155, and miR-223 in formalin-fixed paraffin-embedded synovial tissues of patients with rheumatoid arthritis and osteoarthritis. Virchows Arch, 2016; 469, 93–100.Acknowledgements:The study was supported by Grant 14-D/2012 and Grant 60/2013 funded by Medical University-Sofia.Disclosure of Interests:Russka Shumnalieva: None declared, Darina Kachakova: None declared, Radka Kaneva: None declared, Zlatimir Kolarov Speakers bureau: Amgen, Pfizer, Novartis, Abbvie, Roche, Astra-Zeneka, Simeon Monov Speakers bureau: Amgen, Pfizer, Novartis, Abbvie, Roche, Astra-Zeneka

mir124-dependent tagging of glutamatergic synapses by synaptopodin controls non-uniform and input-specific homeostatic synaptic plasticity

Homeostatic synaptic plasticity (HSP) is a process by which neurons adjust synaptic strengths to compensate for various perturbations and which allows to stabilize neuronal activity. Yet, whether the highly diverse synapses harboring a neuron respond uniformly to a same perturbation is unclear and the underlying molecular determinants remain to be identified. Here, using patch-clamp recordings, immunolabeling and imaging approaches, we report that the ability of individual synapses to undergo HSP in response to activity-deprivation paradigms depends on the local expression of the spine apparatus related protein synaptopodin (SP) acting as a synaptic tag to promote AMPA receptor synaptic accumulation and spine growth. Gain and loss-of-function experiments indicate that this process relies on the local de-repression of SP translation by miR124 which supports both non-uniform and synapse-autonomous HSP induced by global or input-specific activity deprivation, respectively. Our findings uncover an unexpected synaptic-tagging mechanism for HSP, whose molecular actors are intriguingly shared with Hebbian plasticity and linked to multiple neurological diseases.