WHAT THE BRICKS TELL US FROM A TEMPLE AT BURKHAN KHALDUN MOUNTAINS: CHRONOLOGICAL INSIGHTS FROM pIRIR LUMINESCENCE

The Burkhan Khaldun Mountains (Mongolia) and its surrounding sacred landscape are associated with Genghis Khan’s birth and burial place as described in “The Secret History of the Mongols”. It was listed as a UNESCO World Heritage Site on 4 July 2015 under the title «Great Burkhan Khaldun Mountain and its surrounding sacred landscape.”This study offered a great opportunity to apply the recently developed post-IR infrared luminescence (pIRIR) approach to feldspar using coarse and polymineral fine grain techniques and determine the manufacturing date of a brick sample associated with the ruins of the Buddhist temple at the Burkhan Khaldun Mountains. Furthermore, the mineralogical composition of different blue-grey colored bricks from various temple buildings such as the Buddhist temples in Karakorum, Dugan in Erdene Zuu and Avargyn Balgas were studied. The original place and date of manufacturing of the bricks was revealed using the pIRIR180 and pIRIR240 from coarse and fine grains from a heated feldspar sample and were 1280±40 AD and 1230±50 AD, correspondingly, which falls into the time period of extensive constructions in Karakorum

LUMINESCENCE DATING OF AN ANCIENT WALLED SETTLEMENT IN ORKHON VALLEY, MONGOLIA

We investigated the potential of the optically stimulated luminescence (OSL) method to date young (<1000 years) samples collected in the Orkhon Valley Cultural Landscape, Mongolia. Quartz showed an infrared signal; therefore the post-IR OSL method was applied to small aliquots which are considered proxies for single grain measurements. Statistical analysis of the dose distribution produced CAM De of 5.14±0.10 Gy and over dispersion of 47.5%, and MAM De of 3.7±0.6 Gy. Since no partial bleaching was suspected, the analysis of signal composition was done and the fast quartz post-IR OSL lead to De of 4.9±0.2 Gy. Based on the quartz fast component and CAM De we propose the new chronology of ancient construction at 785±80 AD, rather than 906-1125 AD as suggested by archaeological evidence. However, the MAM age is in good agreement with independent age control for construction of the ramparts suggesting the date of reconstruction, collapse or reuse for the square walled enclosure MOR3 during 1090±80AD

Regulation of ENaC-Mediated Sodium Reabsorption by Peroxisome Proliferator-Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are members of a steroid hormone receptor superfamily that responds to changes in lipid and glucose homeostasis. Peroxisomal proliferator-activated receptor subtype γ (PPARγ) has received much attention as the target for antidiabetic drugs, as well as its role in responding to endogenous compounds such as prostaglandin J2. However, thiazolidinediones (TZDs), the synthetic agonists of the PPARγ are tightly associated with fluid retention and edema, as potentially serious side effects. The epithelial sodium channel (ENaC) represents the rate limiting step for sodium absorption in the renal collecting duct. Consequently, ENaC is a central effector impacting systemic blood volume and pressure. The role of PPARγ agonists on ENaC activity remains controversial. While PPARγ agonists were shown to stimulate ENaC-mediated renal salt absorption, probably via Serum- and Glucocorticoid-Regulated Kinase 1 (SGK1), other studies reported that PPARγ agonist-induced fluid retention is independent of ENaC activity. The current paper provides new insights into the control and function of ENaC and ENaC-mediated sodium transport as well as several other epithelial channels/transporters by PPARs and particularly PPARγ. The potential contribution of arachidonic acid (AA) metabolites in PPAR-dependent mechanisms is also discussed

Intact Cytoskeleton Is Required for Small G Protein Dependent Activation of the Epithelial Na+ Channel

BACKGROUND: The Epithelial Na(+) Channel (ENaC) plays a central role in control of epithelial surface hydration and vascular volume. Similar to other ion channels, ENaC activity is regulated, in part, by cortical cytoskeleton. Besides, the cytoskeleton is an established target for small G proteins signaling. Here we studied whether ENaC activity is modulated by changes in the state of the cytoskeleton and whether cytoskeletal elements are involved in small G protein mediated increase of ENaC activity. METHODS AND FINDINGS: First, the functional importance of the cytoskeleton was established with whole-cell patch clamp experiments recording ENaC reconstituted in CHO cells. Pretreatment with Cytochalasin D (CytD; 10 microg/ml; 1-2 h) or colchicine (500 microM; 1-3 h) to disassembly F-actin and destroy microtubules, respectively, significantly decreased amiloride sensitive current. However, acute application of CytD induced rapid increase in macroscopic current. Single channel measurements under cell-attached conditions revealed similar observations. CytD rapidly increased ENaC activity in freshly isolated rat collecting duct, polarized epithelial mouse mpkCCD(c14) cells and HEK293 cells transiently transfected with ENaC subunits. In contrast, colchicine did not have an acute effect on ENaC activity. Small G proteins RhoA, Rac1 and Rab11a markedly increase ENaC activity. 1-2 h treatment with colchicine or CytD abolished effects of these GTPases. Interestingly, when cells were coexpressed with ENaC and RhoA, short-term treatment with CytD decreased ENaC activity. CONCLUSIONS: We conclude that cytoskeleton is involved in regulation of ENaC and is necessary for small G protein mediated increase of ENaC activity

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease

Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst-lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1(RC/RC) mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin-1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin-1 function with probenecid can be used to attenuate ADPKD development. Renal function in male and female Pkd1(RC/RC) and control mice was monitored between 9 and 20 months of age. To test the therapeutic effects of probenecid (a uricosuric agent and a pannexin-1 blocker), osmotic minipumps were implanted in male and female Pkd1(RC/RC) mice, and probenecid or vehicle was administered for 42 days until 1 year of age. Probenecid treatment improved glomerular filtration rates and slowed renal cyst formation in male mice (as shown in histopathology). The mechanistic effects of probenecid on sodium reabsorption and fluid transport were tested on polarized mpkCCD(cl4) cells subjected to short-circuit current measurements, and in 3D cysts grown in Matrigel. In the mpkCCD(cl4) epithelial cell line, probenecid elicited higher ENaC currents and attenuated in vitro cyst formation, indicating lower sodium and less fluid retention in the cysts. Our studies open new avenues of research into targeting pannexin-1 in ADPKD pathology

ATP release into ADPKD cysts via pannexin-1/P2X7 channels decreases ENaC activity

Genetic predisposition is necessary for polycystic kidney disease (PKD) initiation, although there are other, incompletely identified downstream processes that are required for cyst growth. Their characterization may provide a unique opportunity for clinical interventions. One of the poorly studied phenomena in PKD is high ATP content in cysts. Unfortunately, neither origins of uncontrolled ATP release, nor consequences of abnormal purinergic signaling in relation to epithelial transport are well explored in the polycystic kidney. We tested the distribution of pannexin-1 (Panx1) and P2X7, two proteins potentially involved in ATP release, in the kidneys of the Pkd1(RC/RC) mice, a model of autosomal dominant PKD (ADPKD). Abundances of both proteins were abnormally increased in the cyst lining cells compared to non-dilated collecting ducts. To establish if pannexin-1 contributes to ATP release in the collecting ducts (CD), we measured luminal accumulation of ATP in M1 cell renal CD monolayers, and found that treatment with probenecid, a Panx1 blocker, prevents ATP release. Single channel patch clamp analysis of polarized M1 cells revealed that apical stimulation of P2X receptors with alphabeta-MeATP acutely reduces ENaC activity. We conclude that in ADPKD progression, an abnormal hyperexpression of both PANX1 and P2RX7 occurs in the cyst lining epithelial cells. High abundance of both proteins is not typical for non-dilated CDs but, when it happens in cysts, pannexin1/P2X7 cooperation elevates ATP release into the luminal space. High ATP level is a pathogenic factor facilitating cystogenesis by reducing ENaC-mediated reabsorption from the lumen

Involvement of ENaC in the development of salt-sensitive hypertension

Salt-sensitive hypertension is associated with renal and vascular dysfunctions, which lead to impaired fluid excretion, increased cardiac output, and total peripheral resistance. It is commonly accepted that increased renal sodium handling and plasma volume expansion are necessary factors for the development of salt-induced hypertension. The epithelial sodium channel (ENaC) is a trimeric ion channel expressed in the distal nephron that plays a critical role in the regulation of sodium reabsorption in both normal and pathological conditions. In this mini-review, we summarize recent studies investigating the role of ENaC in the development of salt-sensitive hypertension. On the basis of experimental data obtained from the Dahl salt-sensitive rats, we and others have demonstrated that abnormal ENaC activation in response to a dietary NaCl load contributes to the development of high blood pressure in this model. The role of different humoral factors, such as the components of the renin-angiotensin-aldosterone system, members of the epidermal growth factors family, arginine vasopressin, and oxidative stress mediating the effects of dietary salt on ENaC are discussed in this review to highlight future research directions and to determine potential molecular targets for drug development

Testing the pIRIR on pottery and SG-OSL on clay sediment from the known age Xiongnu “Royal” tomb at Noin-Ula, Mongolia

Understanding the timing of the world's first nomadic empire Xiongnu is critical to understanding nomadic politics of the Eurasian past. This study presents a geochronological study conducted on a selection of archeological materials including clay sediment and three potteries from elite Xiongnu tomb at the Noin-Ula Mountains, Mongolia. In order to obtain an accurate OSL chronology, at least two different luminescence methods were applied for clay sediment (e.g., quartz single-grain OSL and pIRIR on the feldspar component of the polymineral fine grains) and for pottery samples (pIRIR to sand-sized K-feldspar and to polymineral fine grains). For the clay sediment, the quartz FMM age of 2160þinspace±þinspace160 a is consistent with independent age control for the site, revealing the time of mixing of clay sediment for construction, while the pIRIR on polymineral fine grains failed to date the timing of construction of the tomb. In contrast, for fired potteries, the pIRIR ages (for preheats between 180 to 270 °C) show a consistency with the existing chronology for the site. The study shows that the advantage of luminescence dating human activities in archeological contexts, e.g., construction of the tomb and firing the pottery, is achieved by the combination of luminescence results from different materials