| file name: james.camerons.avatar.the.game.keygen.by.reloaded.rar |Disclaimer. Last Updated: May 8, 2020. Terms of Use Agreement 1. Acceptance of the Terms and Conditions. 1.1 RXR Realty LLC (herein referred to as the “Company ...In the following, we report on a study in which we combined functional and biophysical approaches to provide insights as to how TBT activates RXR–PPAR heterodimers. Figure 1. Chemical structures of some ligands used in this study. CD3254 and 9 cis -RA are RXR-α agonists, whereas BRL49653 is a PPAR-γ agonist.Nov 24, 2014 · The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. มาตรการภายในเพื่อส่งเสริมความโปร่งใสและป้องกันการทุจริต. รายงานการประเมิน ITA. การบริหารความเสี่ยงองค์กร. นโยบายและวัตถุ ...PHP is a server scripting language, and a powerful tool for making dynamic and interactive Web pages. PHP is a widely-used, free, and efficient alternative to competitors such as Microsoft's ASP. Start learning PHP now ». PHP: Hypertext Preprocessor. popular general-purpose scripting language that is especially suited to web development. Fast, flexible and pragmatic, PHP powers everything from your blog to the most popular websites in the world. What's new in 8.2 Download. 8.2.9 · Changelog · Upgrading. RXR agonists other than bexarotene, such as CD3254, also suppressed neuronal cell death accompanied by OGD/reoxygenation. The RXR antagonists HX531 and UVI3003 and the CYP19 inhibitor letrozole abolished the neuroprotection elicited by bexarotene, indicating that estradiol produced by RXR stimulation protects neurons from ischemic insult. Two others, RIP110 and RIP13, do not show significant similarities to previously reported proteins. RIP110 interacts with LexA-RXR only in yeast cells grown in the presence of the RXR ligand 9-cis-RA, while the interaction of the four receptor superfamily members and RIP13 is unaffected by the presence or absence of 9-cis-RA.জিপিএফে চাঁদার পরিমান/হার পরিবর্তনের সময়কাল . অর্থ বিভাগের সাম্প্রতিক পরিপত্র অনুযায়ী, প্রতি অর্থ বছরের শুরুতে মূল বেতনের সাথে বাৎসরিক ...PHP is a server-side scripting language designed specifically for web development. It is open-source which means it is free to download and use. It is very simple to learn and use. The files have the extension “.php”. Rasmus Lerdorf inspired the first version of PHP and participated in the later versions. It is an interpreted language and ...Mar 16, 2022 · Phoenix, AZ, March 16, 2022 (GLOBE NEWSWIRE) -- Korman Communities, in partnership with RXR, has completed the purchase of its first property in the Phoenix market. The brand new, 348-unit, seven ... The ability of a retinoid X receptor (RXR) to heterodimerize with many nuclear receptors, including LXR, PPAR, NGF1B and RAR, underscores its pivotal role within the nuclear receptor superfamily. Among these heterodimers, PPAR:RXR is considered an important signalling mediator of both PPAR ligands, such as fatty acids, and 9- cis retinoic acid ...Before starting RXR, Scott served as the Chair and CEO of Reckson Associates, which he helped take public in 1995. RXR was founded in 2007, on the day after Scott and his partners sold Reckson Associates for over $6 billion, generating a 700% return to Reckson’s investors.LG100268 and 9-cis-RA are RXR pan-agonists, whereas LG100754 is an agonist of PPAR/RXR and RAR/RXR heterodimers but an antagonist of RXR homodimers . Ccl6 and Ccl9 mRNA levels were maximally induced after 24 h stimulation with 9- cis -RA ( Fig. S2 A ), and the induction of Ccl6 and Ccl9 by LG100268 and 9- cis -RA was inhibited by LG100754 ( Fig ...PHP is a server scripting language, and a powerful tool for making dynamic and interactive Web pages. PHP is a widely-used, free, and efficient alternative to competitors such as Microsoft's ASP. Start learning PHP now ».RXR deficiency alters serous cavity macrophage populations. ChIP-seq and ATAC-seq of TRMs purified from six organs revealed pronounced enrichment of RXRα in TRMs from liver, spleen, lung and ...Webmail Login. The desired locale has been saved to your browser. To change the locale in this browser again, select another locale on this screen. Continue. Email Address. Senha. العربية. čeština. dansk.Nov 11, 2020 · The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due … The canonical pathways of LXR/RXR and ILK signaling are depicted in Figure S3. As shown in Table 2, 5 DEGs (ABCA1, APOD, CLU, LY96, and SERPINF1) significantly involved in the LXR/RXR pathway in the LV septum had an activation z‐score=−0.447, which suggested that these 5 genes mildly inhibited the LXR/RXR activation pathway. Four DEGs ...มาตรการภายในเพื่อส่งเสริมความโปร่งใสและป้องกันการทุจริต. รายงานการประเมิน ITA. การบริหารความเสี่ยงองค์กร. นโยบายและวัตถุ ...Number of Year*. Opening Balance (Up to June 30 of last fiscal year)*. Phone: +880 9609 000 555. +8802-41030290, +8802-41030296. Hishab Bhaban (3 rd Floor) Segunbagicha, Dhaka-1000.Drupalgeddon 2. Since early Friday (4/13), through its network security monitoring service, Volexity has observed thousands of scan and exploitation attempts for this latest Drupal vulnerability. If an unpatched server is found, the vulnerability allows for unauthenticated remote code execution under the privileges of the user which the web ...In the following, we report on a study in which we combined functional and biophysical approaches to provide insights as to how TBT activates RXR–PPAR heterodimers. Figure 1. Chemical structures of some ligands used in this study. CD3254 and 9 cis -RA are RXR-α agonists, whereas BRL49653 is a PPAR-γ agonist.Description of the Calculation Total (A) Opening Balance--(B) Interest on Opening Balance (A) x 0.13 (C) Total Monthly Subscription: Monthly Subscription x 12 | file name: james.camerons.avatar.the.game.keygen.by.reloaded.rar || file name: james.camerons.avatar.the.game.keygen.by.reloaded.rar | DISTRICT TREASURY OFFICE Class-IV GPF Annual Information(Old) Select District Name: Ultraspiracle protein/retinoid X receptor (USP/RXR) is a nuclear receptor and transcription factor which is an essential component of a heterodimeric receptor complex with the ecdysone receptor (EcR). In insects this complex binds ecdysteroids and plays an important role in the regulation of growth, development, metamorphosis and reproduction. phagocytes. Together, RXR modulates the cardiac immune response and impacts the outcome after ischemia-perfusion injury. 2. Materials and Methods 2.1. Mice Rxraflox/flox mice have been previously described [21]. In order to achieve a selective reduction of Rxra expression in mononuclear phagocytes, Rxraflox/flox mice were crossed with ...Apr 1, 2021 · In the present study, we explored the potential interplay between YAP and RAR-RXR signaling pathways on stemness maintenance in parental HT29 cells and 5-FU–resistant 5F31 counterparts. We established that a new YAP/RAR-RXR cross-talk initiated by ectopic YAP activation upregulates RA receptors and RARE-activated genes CYP26A1, ALDH1A3, and LGR5. We found that in vitro treatment with RXR ligands attenuates spreading and aggregation of platelets and increases proplatelet particle formation from megakaryocytes (MK). However, these effects are also observed in RXRβ-deficient platelets and MKs and are thus independent of RXRβ. Third, we investigated arterial thrombus formation in an iron ... Dec 15, 2022 · The cell protein retinoid X receptor (RXR) is a key factor in the maintenance of hematopoietic stem cells, the immature stem cells that give rise to all the blood cell lineages. RXR ensures that ... Number of Year*. Opening Balance (Up to June 30 of last fiscal year)*. Phone: +880 9609 000 555. +8802-41030290, +8802-41030296. Hishab Bhaban (3 rd Floor) Segunbagicha, Dhaka-1000.We also find that peritoneal LPMs infiltrate early ovarian tumours and that RXR deletion diminishes LPM accumulation in tumours and strongly reduces ovarian tumour progression in mice. Our study reveals that RXR signalling controls the maintenance of the serous macrophage pool and that targeting peritoneal LPMs may improve ovarian cancer outcomes.We built in to our chest protector our Air Shock Absorber Technology to protect riders in every situationBefore starting RXR, Scott served as the Chair and CEO of Reckson Associates, which he helped take public in 1995. RXR was founded in 2007, on the day after Scott and his partners sold Reckson Associates for over $6 billion, generating a 700% return to Reckson’s investors.Before starting RXR, Scott served as the Chair and CEO of Reckson Associates, which he helped take public in 1995. RXR was founded in 2007, on the day after Scott and his partners sold Reckson Associates for over $6 billion, generating a 700% return to Reckson’s investors.3.2.3 Retinoid X Receptor. Retinoid X Receptor (RXR) is an important member of the nuclear receptor superfamily and it functions via homodimerization with itself or several other nuclear receptors (Mangelsdorf, Ong, Dyck, & Evans, 1990 ). Altered expression and function of RXR has been reported as a contributing factor in the development of ...Mar 6, 2009 · In the following, we report on a study in which we combined functional and biophysical approaches to provide insights as to how TBT activates RXR–PPAR heterodimers. Figure 1. Chemical structures of some ligands used in this study. CD3254 and 9 cis -RA are RXR-α agonists, whereas BRL49653 is a PPAR-γ agonist. We found that in vitro treatment with RXR ligands attenuates spreading and aggregation of platelets and increases proplatelet particle formation from megakaryocytes (MK). However, these effects are also observed in RXRβ-deficient platelets and MKs and are thus independent of RXRβ. Third, we investigated arterial thrombus formation in an iron ...Enrichment analysis using Ingenuity Pathway Analysis and the activation z-score analysis method demonstrated that there were 5 DEG s ( ABCA 1, APOD , CLU , LY 96, and SERPINF 1) in the LV septum (z-score=-0.447) and 5 DEG s ( APOD , CLU , LY 96, MSR 1, and SERPINF 1) in the LV free wall (z-score=-1.000) inhibited the liver X receptor/retinoid X ...Description ¶. syslog () generates a log message that will be distributed by the system logger. For information on setting up a user defined log handler, see the syslog.conf (5) Unix manual page. More information on the syslog facilities and option can be found in the man pages for syslog (3) on Unix machines.Several dibenzodiazepine derivatives were identified as novel retinoid X receptor (RXR) antagonists on the basis of inhibitory activity on retinoid-induced cell differentiation of human promyelocytic leukemia cells HL-60 and transactivation assay using retinoic acid receptors (RARs) and RXRs in COS-1 cells. 4-(5H-2,3-(2,5-Dimethyl-2,5-hexano)-5 ... Mr. Frank serves as Senior Executive Vice President and General Counsel of RXR Realty LLC. Mr. Frank is responsible for legal matters related to the Company’s real estate transactions as well as real estate legal operational and leasing matters and plays a leadership role with respect to the formulating and implementing of the Company’s policies and objectives. Description of the Calculation Total (A) Opening Balance--(B) Interest on Opening Balance (A) x 0.13 (C) Total Monthly Subscription: Monthly Subscription x 12 About GPF Directorate. Provident Fund is said to be the backbone of every employee, employment of which has rules for provident fund. The small amount which keeps on trickling every month becomes sizeable and of immense for an employee to meet out various obligations and needs.The provision of Provident Fund rules keep on changing to meet the ...PHP is a server scripting language, and a powerful tool for making dynamic and interactive Web pages. PHP is a widely-used, free, and efficient alternative to competitors such as Microsoft's ASP. Start learning PHP now ».Aug 1, 2018 · Closed 4 years ago. While going through the root directory of my site I found this RxR__kyfet.php file. This is a wordpress site. I don't know php well enough to tell exactly what it does but it seems rather suspicious. I checked previous backups of the site and that file was not present. RXR Realty, a real estate owner, manager, and developer located in New York City. The Retinoid X receptor found in cells. Railroad crossing, railway crossing, or level crossing. Revco, American company, NYSE code RXR. Rosberg X Racing (Rosberg eXtreme Racing), an Extreme E electric offroad rally racing team founded by Nico Rosberg. PHP: Hypertext Preprocessor. popular general-purpose scripting language that is especially suited to web development. Fast, flexible and pragmatic, PHP powers everything from your blog to the most popular websites in the world. What's new in 8.2 Download. 8.2.9 · Changelog · Upgrading. We found that in vitro treatment with RXR ligands attenuates spreading and aggregation of platelets and increases proplatelet particle formation from megakaryocytes (MK). However, these effects are also observed in RXRβ-deficient platelets and MKs and are thus independent of RXRβ. Third, we investigated arterial thrombus formation in an iron ... PHP-GTK related documentation is hosted on the PHP-GTK website. Documentation of PEAR and the various packages can be found on a separate server. You can still read a copy of the original PHP/FI 2.0 Manual on our site, which we only host for historical purposes. The same applies to the PHP 3 Manual .bot.py. import requests, sys, os, re. from multiprocessing import Pool. from multiprocessing. dummy import Pool as ThreadPool. from time import time as timer. from platform import system. from colorama import Fore. from colorama import Style. Dec 15, 2022 · The cell protein retinoid X receptor (RXR) is a key factor in the maintenance of hematopoietic stem cells, the immature stem cells that give rise to all the blood cell lineages. RXR ensures that ... ANDHRA PRADESH. Home. GPF Annual Account Statement for year : Department Series. Select Department Series. GPF.A/C No. Enter GPF.A/C No. Mobile No (Enter 10 digit mobile no)Nov 11, 2020 · The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due … Ultraspiracle protein/retinoid X receptor (USP/RXR) is a nuclear receptor and transcription factor which is an essential component of a heterodimeric receptor complex with the ecdysone receptor (EcR). In insects this complex binds ecdysteroids and plays an important role in the regulation of growth, development, metamorphosis and reproduction. 3.2.3 Retinoid X Receptor. Retinoid X Receptor (RXR) is an important member of the nuclear receptor superfamily and it functions via homodimerization with itself or several other nuclear receptors (Mangelsdorf, Ong, Dyck, & Evans, 1990 ). Altered expression and function of RXR has been reported as a contributing factor in the development of ... Phone: +880 9609 000 555. +8802-41030290, +8802-41030296. Hishab Bhaban (3 rd Floor) Segunbagicha, Dhaka-1000. Open (09:00 AM to 05:00 PM)Before starting RXR, Scott served as the Chair and CEO of Reckson Associates, which he helped take public in 1995. RXR was founded in 2007, on the day after Scott and his partners sold Reckson Associates for over $6 billion, generating a 700% return to Reckson’s investors.UPDATED Feb. 3, 2023, 2:38 p.m. Scott Rechler’s RXR is confronting the impact of remote work and rising interest rates by parting ways with a slice of its office portfolio.PHP Operators. Operators are used to perform operations on variables and values. PHP divides the operators in the following groups: Arithmetic operators. Assignment operators. Comparison operators. Increment/Decrement operators. Logical operators. String operators. Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, p …After you installed the game install both patches (first 1.01, then 1.02) Open the directory with the game ( /James Cameron's AVATAR - THE GAME/bin/) and find Avatar.exe. Right click on Avatar.exe - Properties - Compatibility - Set "Run this app in compatibility mode with Windows XP, Vista or Windows 7" and "Run as administrator". Launch the game.PHP-GTK related documentation is hosted on the PHP-GTK website. Documentation of PEAR and the various packages can be found on a separate server. You can still read a copy of the original PHP/FI 2.0 Manual on our site, which we only host for historical purposes. The same applies to the PHP 3 Manual .Oct 10, 2010 · If you have the possibility to use a phpextension, php-zbarcode at https://github.com/mkoppanen/php-zbarcode can read qrcodes. It's a wrapper for ZBar from http://zbar.sourceforge.net , which in turn is a LGPL C library for decoding barcodes. Sep 1, 2023 · We built in to our chest protector our Air Shock Absorber Technology to protect riders in every situation The cell protein retinoid X receptor (RXR) is a key factor in the maintenance of hematopoietic stem cells, the immature stem cells that give rise to all the blood cell lineages. RXR ensures that ...RXR Realty, a real estate owner, manager, and developer located in New York City. The Retinoid X receptor found in cells. Railroad crossing, railway crossing, or level crossing. Revco, American company, NYSE code RXR. Rosberg X Racing (Rosberg eXtreme Racing), an Extreme E electric offroad rally racing team founded by Nico Rosberg.Peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor, plays an important role in the transcription of genes involved in fatty acid metabolism through heterodimerization with the retinoid x receptor (RXR). The consensus sequence of the PPAR response element (PPRE) is composed of two AGGTCA-like sequences directionally aligned with a single nucleotide spacer. PPARα and RXR ...Two others, RIP110 and RIP13, do not show significant similarities to previously reported proteins. RIP110 interacts with LexA-RXR only in yeast cells grown in the presence of the RXR ligand 9-cis-RA, while the interaction of the four receptor superfamily members and RIP13 is unaffected by the presence or absence of 9-cis-RA.Room-Across-Room (RxR) Dataset. Room-Across-Room (RxR) is a multilingual dataset for Vision-and-Language Navigation (VLN) for Matterport3D environments. In contrast to related datasets such as Room-to-Room (R2R), RxR is 10x larger, multilingual (English, Hindi and Telugu), with longer and more variable paths, and it includes and fine-grained visual groundings that relate each word to pixels ...PHP is a server scripting language, and a powerful tool for making dynamic and interactive Web pages. PHP is a widely-used, free, and efficient alternative to competitors such as Microsoft's ASP. Start learning PHP now ».Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively ...DISTRICT TREASURY OFFICE Class-IV GPF Annual Information(Old) Select District Name: Aug 2, 2023 · The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 to regulate transcription (PubMed:10195690, 11162439, 11915042, 17761950, 28167758). The high affinity ligand for retinoid X receptors (RXRs) is 9-cis retinoic acid (PubMed:1310260). This PHP tutorial, whether you’re a beginner or a professional, our tutorial is designed to provide you with in-depth knowledge of the PHP scripting language. With our PHP tutorial, you’ll learn all the important topics, including control statements, functions, arrays, strings, file handling, form handling, regular expressions, date and ...聯絡我們 (02) 2897-6307; [email protected]; 📍 台北市北投區中央北路二段165號 （營業時間：週二～六 13:00～19:00） （週一、日 ...Apr 26, 2022 · PPARγ binds PPAR response elements (PPREs) as the obligate heterodimer with retinoid X receptor (RXR) α, but exactly how PPARγ orchestrates the transcriptional response is unknown. This study ... RXR Realty, a real estate owner, manager, and developer located in New York City. The Retinoid X receptor found in cells. Railroad crossing, railway crossing, or level crossing. Revco, American company, NYSE code RXR. Rosberg X Racing (Rosberg eXtreme Racing), an Extreme E electric offroad rally racing team founded by Nico Rosberg. RXR agonists other than bexarotene, such as CD3254, also suppressed neuronal cell death accompanied by OGD/reoxygenation. The RXR antagonists HX531 and UVI3003 and the CYP19 inhibitor letrozole abolished the neuroprotection elicited by bexarotene, indicating that estradiol produced by RXR stimulation protects neurons from ischemic insult. We have examined the mechanism by which endogenous retinoid X receptor (RXR), vitamin D3 receptor (VDR), and cognate ligands regulate nuclear 1,25-dihydroxyvitamin D3 (D3) signaling in epidermal keratinocytes from skin, a physiologic D3 target. In vitro, RXR and VDR-specific antibodies identified en … ANDHRA PRADESH. Home. GPF Annual Account Statement for year : Department Series. Select Department Series. GPF.A/C No. Enter GPF.A/C No. Mobile No (Enter 10 digit mobile no) Swiss-model. Domains. InterPro. The retinoid X receptor ( RXR) [1] is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, [2] [3] and 9- cis -13,14-dihydroretinoic acid, which is likely to be the major endogenous mammalian RXR-selective agonist. [4]Drupalgeddon 2. Since early Friday (4/13), through its network security monitoring service, Volexity has observed thousands of scan and exploitation attempts for this latest Drupal vulnerability. If an unpatched server is found, the vulnerability allows for unauthenticated remote code execution under the privileges of the user which the web ...The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown.
Sep 1, 2023 · We built in to our chest protector our Air Shock Absorber Technology to protect riders in every situation . Netflix sleep timer mac
Retinoid X receptors (RXRs) control a wide variety of functions by virtue of their dimerization with other nuclear hormone receptors (NRs), contributing thereby to activities of different signaling pathways. We review known RXR ligands as transcriptional modulators of specific RXR-dimers and the ass …We found that in vitro treatment with RXR ligands attenuates spreading and aggregation of platelets and increases proplatelet particle formation from megakaryocytes (MK). However, these effects are also observed in RXRβ-deficient platelets and MKs and are thus independent of RXRβ. Third, we investigated arterial thrombus formation in an iron ... See full list on github.com See full list on github.com LG100268 and 9-cis-RA are RXR pan-agonists, whereas LG100754 is an agonist of PPAR/RXR and RAR/RXR heterodimers but an antagonist of RXR homodimers . Ccl6 and Ccl9 mRNA levels were maximally induced after 24 h stimulation with 9- cis -RA ( Fig. S2 A ), and the induction of Ccl6 and Ccl9 by LG100268 and 9- cis -RA was inhibited by LG100754 ( Fig ...RXR HO-Scale 4-6-2 Steam Locomotive Instructions. Download PDF. RXR HO-Scale AC-Series Locomotive Instructions. Download PDF. RXR HO-Scale Boxcar Rolling Stock Instructions. Download PDF. RXR HO-Scale Caboose Rolling Stock Instructions. Download PDF. RXR HO-Scale C-Series Locomotive Instructions.It appears that error_log () only logs the first line of multi-line log messages. To log a multi-line message, either log each line individually or write the message to another file. When error_log () unexpectedly uses stdout, you should check if the php.ini value for error_log is empty in your CLI environment.The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 to regulate transcription (PubMed:10195690, 11162439, 11915042, 17761950, 28167758). The high affinity ligand for retinoid X receptors (RXRs) is 9-cis retinoic acid (PubMed:1310260).UPDATED Feb. 3, 2023, 2:38 p.m. Scott Rechler’s RXR is confronting the impact of remote work and rising interest rates by parting ways with a slice of its office portfolio.We built in to our chest protector our Air Shock Absorber Technology to protect riders in every situationv2ray-step-by-step Public. Forked from v2fly/v2ray-step-by-step. This repo is a fork of ToutyRater/v2ray-guide, we aim to provide a new step-by-step guide of v2ray.Retinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the ...Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively ....