Classical Site Research Articles

S3080 Metastatic Renal Cell Carcinoma as a Cause of Solitary Gastric Polyp

Introduction: Renal Cell Carcinoma (RCC) is the most common cancer originating from the kidney, accounting for 80-85% of all primary renal neoplasms. Clear cell carcinoma represents the most common histopathological subtype. About 30% percent of RCC cases have metastasized at the time of initial presentation. The classical sites of metastasis include the lungs, bones, liver, and brain. RCC metastasis to the stomach is extremely rare, occurring in approximately 0.2% of RCC cases. We present a rare case of solitary gastric polyp due to metastatic RCC. Case Description/Methods: A 64-year-old female with a past medical history of hypertension and gastroesophageal reflux disease presented to the clinic with a 4-month history of post-prandial intermittent right-sided abdominal pain denied hematuria or melena. Vital signs were normal. On examination, she had right-sided fullness. Labs were significant for hemoglobin of 9 g/dL. Abdominal ultrasound revealed a 13-cm mass in the right upper quadrant arising from the pole of the right kidney. This was confirmed by MRI which showed significant parasitic vessels in and around the mass. The patient underwent esophagogastroduodenoscopy for evaluation of anemia that showed a solitary 5-mm sessile polyp in the gastric body with no evidence of active bleeding. The pathology of the polyp removed indicated clear cell carcinoma, consistent with metastatic RCC. Chest CT showed subcarinal lymphadenopathy with a conglomerate measuring 5.3 cm x 3.1 cm, evidence of multiple 4-7 mm lung nodules – two on the right and one on the left. The patient was referred to the medical oncologist and systemic immunotherapy was commenced. Discussion: This report highlights the rarity of stomach metastasis in RCC, which likely occurred by hematogenous spread due to an abundant renal blood supply. Other routes of metastasis include lymphangitic spread and contiguous spread via the renal capsule, renal pelvis, and ureter (3). The Stomach metastasis can present as solitary/multiple polyps or an ulcer. Lesions are usually asymptomatic and occur in the gastric fundus or body. When symptomatic, gastrointestinal bleeding and anemia are the most common presentation. Patients with RCC and gastric metastasis usually have metastatic lesions in other organ systems, as seen in our patient, and the prognosis for such patients is poor. Therefore, this rare entity should be considered in a patient with gastrointestinal symptoms in the setting of underlying Renal cell carcinoma.

Selective actions of benzodiazepines at the transmembrane anaesthetic binding sites of the GABAA receptor: In vitro and in vivo studies.

In addition to binding to the classical high-affinity extracellular benzodiazepine binding site of the GABAA receptor, some benzodiazepines occupy transmembrane inter-subunit anaesthetic sites that bind etomidate (β+ /α- sites) or the barbiturate derivative R-mTFD-MPAB (α+ /β- and γ+ /β- sites). We aimed to define the functional effects of these interactions on GABAA receptor activity and animal behaviour. With flumazenil blocking classical high-affinity extracellular benzodiazepine site effects, modulation of GABA-activated currents by diazepam, midazolam and flurazepam was measured electrophysiologically in wildtype and M2-15' mutant α1 β3 γ2L GABAA receptors. Zebrafish locomotive activity was also assessed in the presence of each benzodiazepine plus flumazenil. In the presence of flumazenil, micromolar concentrations of diazepam and midazolam both potentiated and inhibited wildtype GABAA receptor currents. β3 N265M (M2-15' in the β+ /α- sites) and α1 S270I (M2-15' in the α+ /β- site) mutations reduced or abolished potentiation by these drugs. In contrast, the γ2 S280W mutation (M2-15' in the γ+ /β- site) abolished inhibition. Flurazepam plus flumazenil only inhibited wildtype receptor currents, an effect unaltered by M2-15' mutations. In the presence of flumazenil, zebrafish locomotion was enhanced by diazepam at concentrations up to 30 μM and suppressed at 100 μM, suppressed by midazolam and enhanced by flurazepam. Benzodiazepine binding to transmembrane anaesthetic binding sites of the GABAA receptor can produce positive or negative modulation manifesting as decreases or increases in locomotion, respectively. Selectivity for these sites may contribute to the distinct GABAA receptor and behavioural actions of different benzodiazepines, particularly at high (i.e. anaesthetic) concentrations.

Degradation of ancient Maya carved tuff stone at Copan and its bacterial bioconservation

Much stone sculptural and architectural heritage is crumbling, especially in intense tropical environments. This is exemplified by significant losses on carvings made of tuff stone at the Classic Maya site of Copan. Here we demonstrate that Copan stone primarily decays due to stress generated by humidity-related clay swelling resulting in spalling and material loss, a damaging process that appears to be facilitated by the microbial bioweathering of the tuff stone minerals (particularly feldspars). Such a weathering process is not prevented by traditional polymer- and alkoxysilane-based consolidants applied in the past. As an alternative to such unsuccessful conservation treatments, we prove the effectiveness of a bioconservation treatment based on the application of a sterile nutritional solution that selectively activates the stone´s indigenous bacteria able to produce CaCO3 biocement. The treatment generates a bond with the original matrix to significantly strengthen areas of loss, while unexpectedly, bacterial exopolymeric substances (EPS) impart hydrophobicity and reduce clay swelling. This environmentally-friendly bioconservation treatment is able to effectively and safely preserve fragile stones in tropical conditions, opening the possibility for its widespread application in the Maya area, and elsewhere.

Rapid climate changes during the Lateglacial and the early Holocene as seen from plant community dynamics in the Polar Urals, Russia

ABSTRACTA detailed, well‐dated record of pollen and sedimentary ancient DNA (sedaDNA) for the period 15 000–9500 cal a bp describes changes at Lake Bolshoye Shchuchye in the Polar Ural Mountains, located far east of the classical Lateglacial sites in western Europe. Arctic tundra rapidly changed to lusher vegetation, possibly including both dwarf (Betula nana) and tree birch (B. pubescens), dated in our record to take place 14 565 cal a bp, coincident with the onset of the Bølling in western Europe; this was paralleled by increased summer temperatures. A striking feature is an early decline in Betula pollen and sedaDNA reads 300 years before the onset of the Younger Dryas (YD) in western Europe. Given the solid site chronology, this could indicate that the YD cooling started in Siberia and propagated westwards, or that the vegetation reacted to the inter‐Allerød cooling at 13 100 cal a bp and did not recover during the late Allerød. During the YD, increases in steppe taxa such as Artemisia and Chenopodiaceae suggest drier conditions. At the onset of the Holocene, the vegetation around the lake reacted fast to the warmer conditions, as seen in the increase of arboreal taxa, especially Betula, and a decrease in herbs such as Artemisia and Cyperaceae.

Mercury enrichment in anthrosols and adjacent coastal sediments at a Classic Maya site, Marco Gonzalez, Belize

AbstractElevated concentrations of total mercury (THg) are found in the surface soils and flanking wetland sediments at the Classic Maya coastal site of Marco Gonzalez, Belize. Significant concentrations (up to 1.3 µg·g−1dry mass) of THg occur in leaf litter‐rich soils, as well as in the artefact‐rich anthrosol spread over the vegetated mound site of structures and occupation debris. The abundance and spatial pattern of major and trace elements measured in the surface soils indicate both site‐scale controlling factors of topography, structures and vegetation on soil geochemistry as well as local highs in concentration compared with background, due to human activity. Geochemical stratigraphy of wetland sediment cores shows that a shift from carbonate‐reef sediments to mangrove peat in the 13th century AD was attended by an input of allogenic (mineral) elements, including mercury. A THg concentration peak (0.8 μg·g−1) in brackish pool sediment is210Pb‐dated to 1960–1970 AD, but the incorporation of mercury in multiple cores adjacent to the site shows increasing mercury inputs to have occurred before, during Classic‐period Maya occupation and following the sites abandonment. Analysis of element values from site‐scale soil sampling, combined with results from off‐site cores, provides a numerical framework upon which outlier values of THg and other element spatial patterns can be assessed, especially the spatial co‐association of elements related to differences in soil–sediment matrices. Geochemical results from active soils developing from occupation deposits (anthrosols) and sediment cores open up questions concerning contemporary and past mercury accumulation at coastal Mayan sites, and the wider interaction of human and natural biogeochemical processes that occur in human‐modified soils and coastal wetland sediments.

Smithian (Olenekian, Early Triassic) Conodonts from Ammonoid-Bearing Limestone Blocks at Crittenden Springs, Elko County, Nevada, USA

The ammonoid-bearing limestone blocks at the classic Crittenden Springs ammonoid site belong to the lower part of the Lower Triassic Thaynes Group. These 0.5–1.2 m thick blocks, consisting mainly of bioclastic floatstone and rudstone, contain abundant macro- and micro-fossils such as ammonoids, gastropods, bivalves and scaphopod shells, as well as conodont elements, fish and echinoid remains. Ammonoid and conodont assemblages obtained from three blocks are utilized for biostratigraphical analysis. Twelve informal Smithian ammonoid biostratigraphic intervals from a previous study are condensed into four ammonoid beds, based on the range of age-diagnostic taxa, in ascending order: Meekoceras millardense-M. aff. olivieri beds, Owenites koeneni beds, Anasibirites multiformis bed, and Condensoceras youngi bed. Conodonts recovered from the three blocks consist of 30 species distributed among 15 genera, including one newly described taxon, i.e., Guangxidella minuta Maekawa and Jenks sp. nov. The blocks are divided into two conodont interval zones, i.e., the Novispathodus ex gr. waageni Interval Zone and Nv. pingdingshanensis Interval Zone, based on the first occurrences of their eponymous taxa. Additionally, four conodont range zones, i.e., the Paullella meeki Range Zone, Guangxidella bransoni Range Zone, Scythogondolella milleri Range Zone, and Borinella buurensis Range Zone are recognized, based on the ranges of these four index species. Conodonts within these interval and range zones vary in age from middle Smithian to latest Smithian. The presence of key ammonoid and conodont taxa regarding the Smithian-Spathian boundary (SSB) such as the AW (Anasibirites and Wasatchites) and GXP (Glyptophiceras, Xenoceltites and Pseudosageceras) ammonoid assemblages and the conodonts B. buurensis, Nv. pingdingshanensis and S. milleri demonstrate that the study area is an important reference site for the SSB in the eastern Panthalassa area.

Identification of seven exonic variants in the SLC4A1, ATP6V1B1, and ATP6V0A4 genes that alter RNA splicing by minigene assay.

Primary distal renal tubular acidosis (dRTA) is a rare tubular disease associated with variants in SLC4A1, ATP6V0A4, ATP6V1B1, FOXⅠ1, or WDR72 genes. Currently, there is growing evidence that all types of exonic variants can alter splicing regulatory elements, affecting the precursor messenger RNA (pre-mRNA) splicing process. This study was to determine the consequences of variants associated with dRTA on pre-mRNA splicing combined with predictive bioinformatics tools and minigene assay. As a result, among the 15 candidate variants, 7 variants distributed in SLC4A1 (c.1765C>T, p.Arg589Cys), ATP6V1B1 (c.368G>T, p.Gly123Val; c.370C>T, p.Arg124Trp; c.484G>T, p.Glu162* and c.1102G>A, p.Glu368Lys) and ATP6V0A4 genes (c.322C>T, p.Gln108* and c.1572G>A, p.Pro524Pro) were identified to result in complete or incomplete exon skipping by either disruption of exonic splicing enhancers (ESEs) and generation of exonic splicing silencers, or interference with the recognition of the classic splicing site, or both. To our knowledge, this is the first study on pre-mRNA splicing of exonic variants in the dRTA-related genes. These results highlight the importance of assessing the effects of exonic variants at the mRNA level and suggest that minigene analysis is an effective tool for evaluating the effects of splicing on variants in vitro.

Structural basis for molecular recognition of G protein-coupled estrogen receptor by selected bisphenols

Complicated ligand-dependent signaling pathways of bisphenol A (BPA) and its analogues involve not only intranuclear estrogen receptor but also membrane receptor G protein-coupled estrogen receptor (GPER). However, the structural basis for molecular recognition of GPER by the environmental chemicals remains unknown. To reveal the structural dependence of GPER recognition by bisphenols, a systematic molecular dynamics simulation study was performed for selected bisphenols with different electron hybrid orbitals and substituents on their C atoms connecting two phenol rings. BPA was used as a control, bisphenol C(BPC) as an example for a connecting C with sp2 hybrid orbitals to provide more ligand rigidity, bisphenol E(BPE) and bisphenol F(BPF) for decreased steric hindrance and hydrophobicity around the connecting C, and bisphenol B(BPB) and bisphenol AF(BPAF) for increased hydrophobicity and steric hindrance. All the tested bisphenols can bind with GPER at its classic orthosteric site to obtain GPER-ligand complexes, while van der Waals interactions and direct inter-molecular electrostatic energies provide the driving forces for ligand binding. Bulky substituents and structural rigidity of the connecting C dramatically impair hydrogen bonding between GPER and the bisphenols, which results in decreased contribution of both favorable intermolecular hydrogen bonds and unfavorable polar solvation effect to complex stability of BPB and BPC since decreased number of key residues is expected. Increase in substituent lipophilicity enhances the van der Waals interactions and favorable non-polar solvation effect. The six bisphenols of high structural similarity shared two key recognition residues, Leu137TM3 and Trp272TM6, the latter of which was in the highly conserved CWxP motif of TM6 and has been reported as key residue for G protein-coupled receptor activation. Based on the obtained knowledge, GPER affinity and relevant toxicity of BPA alternatives can be easily predicted, and the calculated binding free energies are consistent with the available experimental observations.

Formation Processes of the Late Pleistocene Site Toca da Janela da Barra do Antonião – Piauí (Brazil)

ABSTRACT Archaeological research of late Pleistocene sites in northeastern Brazil has rarely analyzed site formation processes from a geoarchaeological perspective. This has contributed to the long-held debate over the reliability of Pleistocene ages and the anthropic origin of stone tools and combustion features. In this work, we combine high-resolution geoarchaeological methods to study the formation processes of the Toca da Janela da Barra do Antonião North site (TJBA-North), located in a surface karst about 12 km northeast of the classical site of Boqueirão da Pedra Furada (Serra da Capivara, Piauí). The site contains stone tools and megafauna remains in sedimentary levels that have been dated by optically stimulated luminescence (OSL) as more than 20,000 years ago up to the early Holocene. Using micromorphology, Fourier transform infrared spectrometry (FTIR), micro-FTIR on the micromorphology thin sections, and magnetic analyses, we carried out a comprehensive study of the climatic conditions during the late and terminal Pleistocene and investigated the depositional history of the site.

Generation of restriction endonucleases barcode map to trace SARS-CoV-2 origin and evolution

Since the first report of SARS-CoV-2 in China in 2019, there has been a huge debate about the origin. In this work, using a different method we aimed to strengthen the observation that no evidence of genetic manipulation has been found by (1) detecting classical restriction site (RS) sequence in human SARS-CoV-2 genomes and (2) comparing them with other recombinant SARS-CoV-like virus created for experimental purposes. Finally, we propose a novel approach consisting in the generation of a restriction endonucleases site map of SARS-CoV-2 and other related coronavirus genomes to be used as a fingerprint to trace the virus evolution.

Settlement Patterns and Urbanization in the Yautepec Valley of Central Mexico

Abstract We carried out a full-coverage survey of the Yautepec Valley in the 1990s to reconstruct demography and settlements and their changes through time. We investigated the extent to which well-documented developments in the adjacent Basin of Mexico were paralleled in Yautepec, as well as the impact of regional empires and economies on local society. Our analyses focused on Teotihuacan relations in the Classic period and relations with the Aztec empire and the Mesoamerican world system in the Middle and Late Postclassic periods. In addition to locating, mapping, and describing sites and taking grab-bag artifact collections, we also made a series of systematic intensive surface collections (5 × 5 m) and test excavations at samples of Classic and Postclassic sites. In this paper, we describe the survey and changing settlement patterns in the Yautepec Valley. We also present several analyses of changing patterns of urbanization through the Prehispanic era. We conclude with a synthesis of changing social and cultural dynamics in this region.

CD40L acts as an allosteric activator of integrins for signal transduction independent of inside-out signaling

Abstract CD40L plays a major role in immune response and is a target for inflammatory disease therapy. Besides CD40, CD40L binds to several integrins but their role in signaling is unclear. We showed that integrins αvβ3 and α5β1 bind to the CD40L trimeric interface through classical ligand binding site of integrins (site 1). Several CD40L mutants from HIGM1 (hyper-IgM syndrome type 1) patients were clustered in trimeric interface and defective in integrin binding, and in NF-κB and B cell activation, but still bound CD40 and acted as antagonists of CD40L signaling. Thus, integrins play a critical role in CD40L signaling. Previous studies showed that CX3CL1 and sPLA2-IIA can activate integrins by binding to a recently identified allosteric site (site 2) of integrins. Using cell-free assays, we found that soluble (s)-CD40L activated soluble integrins, α4β1, αvβ3 and α5β1, and induced their binding to known specific ligands independent of inside-out signaling. Also, sCD40L activated cell-surface integrins in CHO cells lacking CD40. Finally, sCD40L bound to a cyclic peptide derived from site 2. These findings indicate that CD40L acts as an allosteric activator of integrins by binding to site 2. Docking simulation predicted that the integrin site 2-binding site of CD40L is located outside of CD40L trimer. Importantly, four HIGM1 mutations are clustered in the predicted site 2-binding site of CD40L. The K143T and G144E mutants were the most defective in integrin activation, indicating that integrin binding occurs around these residues of the predicted site 2-binding site. We propose that allosteric integrin activation by CD40L plays a role in CD40L signaling and that defective integrin site 2-binding may be causal for defective CD40L signaling in HIGM1.

A Virtual Docking Screen at 23 SARS‐CoV‐2 Proteins Identifies Drug Repurposing Candidates at New Sites and Targets

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic requires treatments with rapid clinical translatability. As such, several studies have screened FDA‐approved drugs in silico at a limited number of classical antiviral sites for anti‐SARS‐CoV‐2 activity. We hypothesized that an extensive in‐silico drug repurposingscreen against a wide range of SARS‐COV‐2 proteins could identify novel antiviral drugs and help elucidate mechanisms of drug action of hits from in vitro screens. We selected 48 known or predicted drug sites across 23 SARS‐COV‐2 proteins using homology models and crystal structures based on known antiviral drug sites (i.e., polymerase or protease active sites), computational predictions, and protein‐protein interfaces. Then, using the software GOLD, we docked 1268 FDA‐approved small‐molecule drugs into each site. Virtual hits were prioritized based on their anti‐SARS‐COV‐2 activity found in a recent phenotypic drug‐repurposing screen using human huh‐7 epithelial cells. This resulted in the identification of a range of drugs acting at a variety of targets and sites. Several compelling drug/site pairs were identified, including sites on the Spike protein, which mediates viral entry. For example, we identified hits with anti‐SARS‐CoV2 activity in vitro, at a putative allosteric site that incorporates two functionalities required for viral entry, namely the Spike S2’ cleavage site – which a host protease must cleave for viral entry, and the critical ‘fusion peptide’ domain – which injects itself into the host membrane during viral entry. Moreover, these in silico results identify possible mechanisms for in vitro drug repurposing hits, potential additional targets for known drugs, and a starting point to test drug combinations that may have better activity by acting at different steps in the viral cycle activity in combination than on their own.8.5.5

It’s What’s Inside that Counts: Developing a paste group typology in Belize

The ceramic assemblage at the Classic Period Maya site of Alabama, Belize is poorly preserved and fragmentary. Most of the pottery cannot be classified using standard type-variety approaches, which privilege decoration and surface treatment. The nature of the Alabama ceramic assemblage requires a classification system organized by paste wares, as opposed to incorporating paste composition as a modal or analytical unit that crosscuts types and wares, as this is the only attribute that can be reliably evaluated across all contexts. We identified and systematically described paste groups as a first step toward a typology organized by ceramic paste wares. We analysed 100% of ceramics from settlement surface collection at the site, including non-diagnostic samples, using a scaffolded approach that integrates macroscopic observations, Dino-Lite USB microscopy, and thin section petrography. This approach facilitates the analysis of pottery from all contexts, regardless of the degree of preservation. Incorporating paste composition into classification schemes provides important data on pottery production traditions and the people responsible for their production, which cannot be determined from stylistic analyses alone. We established five new paste groups indicative of local and non-local pottery production. Our approach to ceramic classification provides a method that can be applied to any archaeological site, regardless of the prevailing classification system in place, and is especially relevant to sites with poorly preserved ceramic assemblages dominated by non-diagnostic sherds.

Evaluation and Monitoring of Urban Public Greenspace Planning Using Landscape Metrics in Kunming

Urban greenspace planning plays a crucial role in improving the quality of human settlements and the living standard of citizens. Urban public greenspace (UPGS) is an important part of urban greenspaces. Existing literature rarely includes a scientific evaluation of greenspace plans (including of UPGS) and plan implementation effects. To bridge this gap, this study evaluated and monitored the UPGS plan enacted in 2010 in Kunming, China. Object-based image classification and visual interpretation of satellite images and Google Earth imagery were used to quantify the different periods of UPGS implementation. Six indicators and monitoring at four classic sites were applied to explore the change at two scales (overall scale and district scale) for monitoring the UPGS plan execution. The results showed that UPGS structure greatly improved after plan implementation. However, UPGS provision per capita has not reached the level of greenspace planning and the connectivity was poor. Significant implementation inequalities existed in each district and implementation has lagged behind schedule. This study contributes to a better understanding of greenspace planning and urban planning in general, which can help improve future planning and planning decisions.

Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis.

Mitophagy is an essential cellular autophagic process that selectively removes superfluous and damaged mitochondria, and it is coordinated with mitochondrial biogenesis to fine tune the quantity and quality of mitochondria. Coordination between these two opposing processes to maintain the functional mitochondrial network is of paramount importance for normal cellular and organismal metabolism. However, the underlying mechanism is not completely understood. Here we report that PGC-1α and nuclear respiratory factor 1 (NRF1), master regulators of mitochondrial biogenesis and metabolic adaptation, also transcriptionally upregulate the gene encoding FUNDC1, a previously characterized mitophagy receptor, in response to cold stress in brown fat tissue. NRF1 binds to the classic consensus site in the promoter of Fundc1 to upregulate its expression and to enhance mitophagy through its interaction with LC3. Specific knockout of Fundc1 in BAT results in reduced mitochondrial turnover and accumulation of functionally compromised mitochondria, leading to impaired adaptive thermogenesis. Our results demonstrate that FUNDC1-dependent mitophagy is directly coupled with mitochondrial biogenesis through the PGC-1α/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis.

Impact of pore distribution characteristics on percolation threshold based on site percolation theory

In order to better simulate the porous media with different pore distribution characteristics, this paper introduced a pore distribution factor m (m represents the randomly generated pore volume in the site percolation model, which is expressed by the number of sites)into the classic site percolation model. On this basis, the influence of pore distribution characteristics of two-dimensional (2D) and three-dimensional (3D) porous media on the percolation threshold is studied using numerical simulations. The study found that, when the porosity is the same, larger the value of m, smaller the number of pores in both the simulated 2D and 3D porous media. The decrease in the number of pores leads to the changes in the pore volume distribution characteristics. The shape of each pore, generated using the simulation in this paper, is random, due to which, larger the value of m is, easier it is for pores to merge to form larger pore clusters, which result in a reduction in the percolation threshold. The percolation threshold of 2D (lattice type: square) and 3D (lattice type: simple cubic) site percolation models decreases with the increase in the value of m. When the value of m is unity, the percolation thresholds of 2D and 3D porous media are found to be 59.27% and 31.16%, respectively, which are in agreement with the existing research results. When the value of m increases to 40, the percolation thresholds of 2D and 3D porous media decrease to 38.38% and 8.65%, respectively. Therefore, the pore connectivity of porous media is determined by the porosity and the pore distribution characteristics, whereas the pore connectivity of porous media can be misjudged if only porosity is taken into account.

THE ARZAWA LANDS. THE HISTORICAL GEOGRAPHY OF IZMIR AND ITS ENVIRONS DURING LATE BRONZE AGE IN THE LIGHT OF NEW ARCHAEOLOGICAL RESEARCH

The core of Arzawa (Arzawa Minor) before Mursili II is defined as the maritime Ephesos/Apasa region extending from Mount Arinnanda (Mycale) to Lebedos (Hittite Lipa?), including the inland settlement Puranda (Bademgedigi Tepe). Cayster river basin and northern foothills of Mountain (Mt.) Tmolos from Karabel pass to the east seemed to constitute the land of Mira which had a legitimate vassal kingdom after Mursili II and incorporated into Arzawa Minor. Considering the northern foothills of Mt. Tmolos belonging to Mira we have then an important clue to locate the cities of Arsani, Sarawa, Impa and Hapanuwa which were fortified and garrisoned by Mursili II on his way from Seha River land back to Mira, following a route from west to east. This was plausibly the same geographic order for the cities of Mira i.e., Arsani - Sarawa - Impa - Hapanuwa written in the texts. If my proposal Sarawa > *Swar > Sfarλ > Sfarda > Sardis is correct we may localize these cities of Mira [1] with some certainity. Recently discovered Late Bronze Age (LBA) pottery at Sardis might also shed light. Arsani might be located in the west of Sarawa. LBA mound of Gavurtepe (Alasehir) in the east of Sardis (Sarawa), would be then presumably identified as Impa (Gavurtepe Alasehir). Hapanuwa is mentioned as the last city which might be related with Hypaipa located in the Cayster valley. New evidence for revising the boundaries of Kuwaliya provided the site for Elmacik near Usak. The classical site of Caualia/Cabalia located at Elmacik is related to Kuwaliya. A prehistoric mound with LBA pottery discovered at Elmacik is a hint that the area between Elmacik, Banaz and Akarcay (Astarpa) constituted the upper part of Kuwaliya adjacent partly to the Siyanta River land in the north. Finally we have new additions for “the web of interlocking locations [2] ” defining the historical geography of Central West Anatolia during LBA. Arzawa Minor: Arinnanda, Mycale, Apasa-Ephesos, Lipa?-Lebedos, Puranda-Bademgedigi Tepe. Mira: Karabel pass, Karakuyu stele, Arsani-?, Sarawa-Sardis, Impa-Gavurtepe (Alasehir), Hapanuwa-Hypaipa (Odemis). Kuwaliya: Caualia (Elmacik near Usak). [1] see supra n. ???. [2] Hawkins 2020: 342.

Het onzichtbare Olympia

Abstract Although ancient Olympia is usually viewed as a Classical Greek site, most buildings that are visible nowadays were not there yet when Pindar celebrated famous victors or Peisistratos and Alcibiades won their races. More generally, even though new research has substantially improved our knowledge, the early history of the site is often still neglected in introductory presentations of the site. In this article some important main issues are discussed. First, new excavations have revealed that Bronze Age occupation of the area cannot be connected to the later cult, as some scholars have argued in the past. The older remains were covered by flooding of the nearby rivers when the sanctuary was founded in the 11th century BCE. Up to the late 7th century the sanctuary remained an open area around a large ash altar. Its main structure was a large dam protecting it from floods. The temple now associated with Hera, built around 600 BCE, was the first monumental building of the sanctuary. Recent research suggests this may originally have been dedicated to Zeus, but this cannot be proven conclusively. The common idea that this temple was originally a wooden construction has now also been debunked.

Soluble CD40L activates soluble and cell-surface integrin αvβ3, α5β1, and α4β1 by binding to the allosteric ligand-binding site (site 2)

CD40L is a member of the TNF superfamily that participates in immune cell activation. It binds to and signals through several integrins, including αvβ3 and α5β1, which bind to the trimeric interface of CD40L. We previously showed that several integrin ligands can bind to the allosteric site (site 2), which is distinct from the classical ligand-binding site (site 1), raising the question of if CD40L activates integrins. In our explorations of this question, we determined that integrin α4β1, which is prevalently expressed on the same CD4+ T cells as CD40L, is another receptor for CD40L. Soluble (s)CD40L activated soluble integrins αvβ3, α5β1, and α4β1 in cell-free conditions, indicating that this activation does not require inside-out signaling. Moreover, sCD40L activated cell-surface integrins in CHO cells that do not express CD40. To learn more about the mechanism of binding, we determined that sCD40L bound to a cyclic peptide from site 2. Docking simulations predicted that the residues of CD40L that bind to site 2 are located outside of the CD40L trimer interface, at a site where four HIGM1 (hyper-IgM syndrome type 1) mutations are clustered. We tested the effect of these mutations, finding that the K143T and G144E mutants were the most defective in integrin activation, providing support that this region interacts with site 2. We propose that allosteric integrin activation by CD40L also plays a role in CD40L signaling, and defective site 2 binding may be related to the impaired CD40L signaling functions of these HIGM1 mutants.