|Exam Name||:||Application Development with IBM Rational Application Developer For Web Sphere Software V6.0|
|Questions and Answers||:||107 Q & A|
|Updated On||:||March 21, 2018|
|PDF Download Mirror||:||000-256 Dump|
|Get Full Version||:||Pass4sure 000-256 Full Version|
IBM is collaborating with Pivotal to make its utility less demanding to access within Spring, Pivotal's open-supply framework, in addition to on Pivotal Cloud Foundry cloud platforms.
The conception is to assist builders immediately and simply construct cloud-native applications and microservices using their very best framework and equipment, Andrew Hoyt, director of development for IBM Cloud Integration, noted in a blog post. Spring is likely one of the most accepted frameworks for setting up Java functions, and the collaboration changed into announced at Pivotal's annual developer convention.
specially, IBM and Pivotal announced:
IBM has taken a series of recent steps to guide open innovation. The business is a founding member of the Eclipse MicroProfile venture, which is defining general APIs and infrastructure for growing microservices applications without seller lock in. IBM also helped launch Itsio, an open supply provider that gives builders a dealer-neutral approach to control networks of distinctive microservices on cloud systems.
SAN DIEGO, Dec. 06, 2017 (GLOBE NEWSWIRE) -- ImageWare methods, Inc. (ImageWare or IWS) (OTCQB:IWSY), a frontrunner in mobile and cloud-primarily based, multi-modal biometric identification management options, nowadays introduced that GoVerifyID for IBM safety access manager (ISAM) is now purchasable on the IBM security App change.
GoVerifyID seamlessly integrates with IBM identity and entry administration technology to give a flexible, conclusion-to-conclusion, multi-modal, biometric protection answer for all ISAM authentication techniques. ImageWare’s GoVerifyID, combined with ISAM, allows users to swipe a fingerprint, take a selfie, communicate a passphrase, show their palm, or enter a PIN on their cellular instruments to authenticate for any ISAM managed useful resource. The commercial enterprise-competent integration equipment deploys automatically into latest ISAM environments and has been validated via IBM security.
This new integration is freely available to the security community via IBM security App change, a market where developers throughout the business can share applications in response to IBM safety applied sciences. As id-connected attacks persist as a leading reason behind most important security breaches, collaborative construction amongst the safety neighborhood will help businesses adapt right now and velocity innovation within the combat against cybercrime.
GoVerifyID integrates with IBM safety access supervisor, which helps companies supply secure and simplified access to web, cellular, and cloud applied sciences via a single integrated platform. This new integration permits ImageWare and IBM shoppers to change or increase passwords with biometrics to give an superior user event, increased person identification trust, and improved protection. by getting rid of passwords or featuring biometric multi-ingredient authentication (MFA), the possibility of a data breach is decreased.
“The important information breaches within the headlines over the last few months remind us of the severe business penalties of such incidents. The ImageWare GoVerifyID product mitigates the chance of those devastating thefts that may bankrupt a corporation and trigger untold pain for their companions and purchasers,” noted Jim Miller, Chairman and CEO of ImageWare. “we're excited to have positioned our GoVerifyID for ISAM answer on the IBM protection App alternate to make it with no trouble attainable to present IBM shoppers. We look ahead to assisting corporations straight away and easily deploy this integration to provide the foremost in security and ease of use for their ISAM environments.”
About IBM SecurityIBM’s security platform provides the protection intelligence to aid corporations holistically give protection to their americans, records, purposes and infrastructure. IBM offers options for identification and access administration, protection information and adventure administration, database safety, utility building, possibility administration, endpoint administration, next-technology intrusion insurance policy and more. IBM operates one of the most world’s broadest security research and construction, and delivery agencies. For greater suggestions, please talk over with www.IBM.com/security, follow @IBMSecurity on Twitter or talk over with the IBM safety Intelligence weblog.
About ImageWare techniques, Inc.ImageWare programs, Inc. is a number one developer of cell and cloud-primarily based id administration options, presenting patented biometric authentication options for the enterprise. The enterprise provides next-technology biometrics as an interactive and scalable cloud-primarily based answer. ImageWare brings together cloud and cell expertise to offer multi-factor authentication for smartphone clients, for the enterprise, and across industries.
ImageWare’s items help multi-modal biometric authentication including, however now not limited to, face, voice, fingerprint, iris, palm, and more. the entire biometrics may also be combined with or used as replacements for authentication and access handle tools, together with tokens, digital certificates, passwords, and PINS, to deliver the most efficient level of assurance, accountability, and ease of use for corporate networks, internet purposes, cellular instruments, and workstation computing device environments.
ImageWare is headquartered in San Diego, California, with offices in Portland, Oregon, Ottawa, Ontario, and Mexico metropolis, Mexico. To study extra about ImageWare, talk over with https://iwsinc.com; comply with us on Twitter, LinkedIn, YouTube, and facebook.
Investor relations: enterprise identify: LioliosContact identify: Cody SlachPhone number: 949.574.3860
IBM-date-time IBM-textcolor-gray-40">December 6, 2017 | Written via: Andrew Hoyt
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It’s a thrilling time to be a developer, isn’t it? There has in no way been so many choices in programming fashions, cloud capabilities and frameworks. providing option to developers in an open group is core to what we do at IBM – and were doing for quite some time. We recently open-sourced types of our WebSphere Liberty Java app server, Open Liberty, and Java digital computer, OpenJ9. IBM has been a strong supporter of the Eclipse MicroProfile group to advertise microservices in Java.
That’s why i'm excited to share that IBM and Pivotal software Inc. introduced this week at the SpringOne Platform, Pivotal’s annual developer convention, a collaboration to provide the neighborhood of Spring builders with more equipment for developing new applications and lengthening present functions to new areas. The collaboration will provide builders less demanding entry within the open-supply Spring framework to IBM’s potent, market main software, together with WebSphere, Db2 and MQ, standard with the aid of agencies to support their core applications.Simplifying App development with Spring and IBM application
The Spring framework is a popular alternative within the Java development community, in part because of its emphasis on streamlining software construction. IBM’s collaboration with Pivotal has as its aim to lower cumbersome steps inside your construction approaches to use Spring and IBM software collectively. It’s designed so so you might spend much less time navigating complicated IT methods and have more time to truly write code. readily put, the aim is so that you can be able to create cloud-native applications and microservices simpler and quicker using IBM’s software and your favorite framework and equipment, including Spring.
The collaboration additionally offers legit support for containerized types of IBM software operating on Pivotal Container capabilities (PKS). IBM made available containerized types of this IBM application earlier this 12 months on the new IBM Cloud inner most platform. These efforts are designed to make it easier for builders to connect enterprise-vital apps to services and facts throughout distinctive clouds and provide greater flexibility to install functions in diverse cloud environments, both public and private.here’s a closer look at what we introduced to the Spring neighborhood:
additionally, Spring Starters and Spring Cloud flow binders that simplify the procedure of connecting applications to IBM databases and utility, together with MQ, Db2, Cloudant and greater, are expected to be purchasable in early 2018.
I look forward to listening to from the neighborhood and welcome your feedback. Please put up feedback or inquiries to this blog or discuss with probably the most websites beneath to continue the discussion. in the meantime, right here’s to freedom of alternative!
For advice on OpenLiberty/Spring Boot, talk over with the Open Liberty weblog
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000-256 Certification Brain Dumps Source : Application Development with IBM Rational Application Developer For Web Sphere Software V6.0
Test Code : 000-256
Test Name : Application Development with IBM Rational Application Developer For Web Sphere Software V6.0
Vendor Name : IBM
Q&A : 107 Real Test Questions/Answers
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TORONTO, ONTARIO -- (Marketwired) -- 11/29/17 -- BWR Exploration Inc. (TSX venture: BWR) ("BWR" or the "business") declares that it has initiated non-brokered non circulation-through and circulate-via deepest placement unit offerings for combination proceeds of as much as $1,350,000 (the "offering"), such as up to 5 million ("instruments") at Cdn $0.07 per Unit for proceeds of up to Cdn $350,000 together with 10 million circulate-through devices ("toes gadgets") at Cdn $0.10 per share for gross proceeds of $1,000,000. every non circulate-via Unit incorporates 1 commonplace share (a "standard Share") of the enterprise plus one half average share purchase warrant (a "Warrant") of the enterprise. each and every Warrant will expire 24 months from the date of issue (the "Warrant Expiry Date") and should entitle the holder thereof to buy one ordinary Share (a "Warrant Share") at a price of $0.15 per Warrant Share.
while the choices are being effected by way of the business on a non-brokered foundation, the company might also pay finder's prices to arm's-size third events such as: (i) cash fee of up to 8% of the gross proceeds of the offering; and (ii) broking service warrants ("broker Warrants") in an quantity up to 8% of the full variety of contraptions issued below the offering.
The proceeds from the non flow-via element of the providing might be used for typical corporate purposes. The move-through portion of the providing should be used for certified exploration expenses in Canada, with a focus on the Little Stull Lake Gold venture discovered in Northeastern Manitoba. The enterprise might also decide on to close this financing in various tranches.
BWR Exploration Inc. is a public business focused on exploring for base and valuable metals, with its flagship Little Stull Lake Gold venture in NE Manitoba together with other exploration projects in Northern Ontario, and northern Quebec, Canada. administration of BWR includes an completed group of exploration/mining consultants with many decades of operational event in the junior aid sector. There are at present fifty five,727,461 shares issued in BWR.
Neither the Toronto mission trade nor its regulation capabilities provider (as that time period is described within the policies of the TSX mission exchange) accepts responsibility for the adequacy or accuracy of this unencumber.
Contacts:BWR Exploration Inc.Neil Novak, P.Geo.President, CEO & Director416email@example.com
For tips regarding this financing please contact:Paradox Investor functions Inc.Carl DesjardinsCell: firstname.lastname@example.org
The iPhone 8’s 4.7-inch monitor and the iPhone 8 Plus’ 5.5-inch screen are of the equal measurement and determination as earlier than, however have been tweaked for more suitable brightness and richer colours.
The iPhone eight (Rs64,000 (64 GB); Rs77,000 (256 GB)) and iPhone eight Plus (Rs73,000 (64 GB); Rs86,000 (256 GB)) have retained a lot of the design language from the predecessors, the iPhone 7 and iPhone 7 Plus. for example, there is the domestic button beneath the monitor, they are dust-and-water-resistant too and the twin camera geometry is still the equal. This means your iPhone 7 and iPhone 7 Plus case covers may work with the brand new phones too. youngsters, this is the place the similarities conclusion.
The series 7000 aluminum chassis is more desirable. The returned panel has a pitcher layer, which looks wonderful when gentle reflects off it, and the oleophobic coating prevents smudges and fingerprints from ruining the pristine seem. Many Android phones, such because the Sony Xperia flagship phones, have glass returned panels, however these get smudged inside seconds of unpacking from the container.
Apple has tweaked the shades. The space grey alternative continues to be because it is, however the Silver and Gold colorations have been significantly improved. The Silver iPhone gives off a classy light blue hue in certain ambient lights, whereas the new Gold is accentuated via the glass layer.
as it seems, the glass lower back isn’t just for design proposal. These are the primary iPhones with instant charging capabilities embedded, in keeping with the Qi normal. What this ability is that you should buy a instant charger accent (Belkin and Mophie are making them for the time being; Apple’s AirPower Mat arrives subsequent year) and place the cell flat on its lower back on the charger to juice up the battery. sure, some costly Android phones (Samsung Galaxy S7 launched in 2016, for instance) have had this for a long time, but whereas they're limited to five watts of power, Apple will upgrade the charging capabilities of the new iPhones to 7.5-watts with a future application replace.
The iPhone eight’s four.7-inch screen and the iPhone eight Plus’ 5.5-inch screen are of the equal size and backbone as before, however had been tweaked for more advantageous brightness and richer colours. the brand new iPhones also get the skills of the true Tone feature (the iPad professional already had this), which tweaks the reveal’s color warmness according to the ambient lighting fixtures to reduce the stress on eyes. Sheer numbers apart (there are people who decide on 2K and 4K decision smartphone displays), iPhone displays have pretty much set the benchmark when it comes to usability all this while, and now they have been additional more desirable. We seen that the computerized brightness algorithm, when doubtful, errs on the facet of caution and maintains the brightness on a a little bit higher side.
The A11 Bionic processor turns out to be as an awful lot as 75% faster than the predecessor counting on the variety of cores used by way of an app or online game you may well be the use of. the brand new iPhones center of attention tremendously on augmented fact (AR) and laptop learning, and the brand new A11 Bionic neural engine can manner up to 600 billion operations per 2d. Add the brand new iOS 11 application in the combine, with its personal set of efficiency improvements, and also you get battery life that isn't any lesser than the iPhone 7 line-up, regardless of much more energy on tap.
The cameras within the new iPhones reap the merits of better shade filters, deeper pixels and an stronger graphic sign processor, wider coloration capture, sooner auto center of attention in low gentle and richer HDR photographs. while the camera specs continue to be generally the identical on paper, the optical hardware has been drastically upgraded. The iPhone eight now gets optical graphic stabilization. The twin camera within the iPhone 8 Plus gets the new Portrait lights filters for photographs captured in Portrait mode.
because it seems, Apple has performed away with the 128 GB storage variant and not introduced the in any other case anticipated 512 GB alternative within the new iPhones. What you get is a call between 64 GB and 256 GB storage for each iPhones.
From what we've experienced, the new iPhones if truth be told take the next start when it comes to outright performance and the cameras are certainly enhanced. but for all the excellence of the two new iPhones, the iPhone X looms significant. There should be inevitable query of even if to buy the iPhone 8 or iPhone eight Plus, or look forward to the iPhone X (that arrives on three November). The answer is basically somewhat basic—if you can spend Rs1,02,000, then obviously look forward to the X (256 GB version). in any other case, evaluating the rate difference between the 256 GB variant of the iPhone 8 and the iPhone eight Plus with the sixty four GB entry-spec variant (Rs89,000) of the iPhone X isn’t thoroughly a logical evaluation when it comes to the space for storing you’ll get.First posted: Tue, Sep 19 2017. 07 30 PM IST
Apple's iPhone X has launched on November 3 within the markets around the world. India is also involved in these international locations. In India, the iPhone X has begun. users can buy iPhone X from the online store of Airtel too. Airtel is among the selected digital platforms which are selling iPhone X in India.
The price of this iPhone is Rs 89,000 (64 GB) and Rs 1,02,000 (256 GB). The enterprise says that handiest its postpaid consumers should be able to buy this mobile and some presents like cashback are additionally being offered. Let's let you know that on October 27, the pre-reserving of the iPhone X on e-commerce web sites Amazon, Flipkart, Apple Reseller and so forth. changed into made. at present these e-commerce sites had also given tons cashback offers to the shoppers.
iPhone X has a 5.eight-inch bezel-much less display with a decision of 1125x2436 pixels. The business has named it a super retina screen. Swipe down from the bottom of the screen in it and go home. This mobile has been launched in two color versions, house grey, and silver color. Its monitor comes with OLED technology which comprises 3D contact. Apple is additionally featuring add-ons related to the iPhone X during which leather-based and silicon case are blanketed so we can cost round 3,500 rupees.
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Laboratory Investigation (2013) ninety three, 733–743; doi:10.1038/labinvest.2013.fifty two; posted on-line 15 April 2013
James H Tabibian1,2, Slobodan I Macura3, Steven P O'Hara1,2, Jeff L Fidler4, James F Glockner4, Naoki Takahashi4, Val J Lowe5, Bradley J Kemp5, Prasanna okay Mishra3, Pamela S Tietz1,2, Patrick L Splinter1,2, Christy E Trussoni1,2 and Nicholas F LaRusso1,2
The cholangiopathies are an etiopathogenically distinctive neighborhood of problems affecting the epithelial cells that line the three dimensional (3D) tubular network of bile ducts.1, 2, 3, 4, 5 because of their occurrence, development to liver cirrhosis and melanoma, and generally obscure pathogenesis, cholangiopathies account for a considerable share of the morbidity and mortality of all liver diseases.1, 6, 7 seriously important to unraveling the primary underpinnings of these complicated disorders is the construction of animal models and novel equipment to more desirable study 000-256 and symbolize them.eight, 9
fundamental sclerosing cholangitis (PSC) is an instance of a persistent, idiopathic cholangiopathy, which lacks valuable medical remedy, and in which animal fashions have begun to display mechanistic insights.5, 10, eleven in the united states on my own, the incidence of PSC is estimated at 25 000 teenagers and adults, and estimated median survival from time of prognosis to demise or liver transplantation is 12 years.6, 7 PSC is characterised microscopically with the aid of biliary inflammation and fibrosis, and cholangiographically by biliary strictures alternating with dilatations and, hence, an irregular, ‘ragged’-performing biliary tree.10, 12, 13, 14 presently, probably the most favourite model of PSC is the mdr2 (abcb4) knockout (mdr2KO) mouse.eight, 9 Biliary disease during this model is as a result of increased hydrophobicity of bile (because of lowered phospholipid content), and includes ldl cholesterol gallstones, multifocal biliary strictures and dilations, cholestasis, and biliary fibrosis.8, 12, 15 aside from serum biochemical records, assessment of biliary sickness within the mdr2KO mouse, as well as choice murine models of PSC and different cholangiopathies, relies heavily on liver histology; this, besides the fact that children, requires killing the animal and limits longitudinal monitoring and is useful resource ingesting.
Noninvasive imaging continues to benefit value and use in both clinical administration and animal fashions of the cholangiopathies and different diseases. on account that its preliminary description over twenty years ago,sixteen noninvasive hepatobiliary imaging with magnetic resonance (MR) cholangiopancreatography (MRCP) has evolved into a vital modality for the diagnosis and longitudinal surveillance of PSC and different cholangiopathies.13, 17, 18 MRCP offers effective, global anatomic records involving hepatobiliary sickness. however, it has some inherent barriers; eg, motion artifacts can lead to suboptimal picture first-class and cause false-advantageous interpretations or poor visualization of the bile ducts. moreover, the spatial resolution of MR can also not allow visualization of small intrahepatic bile ducts. as a result of these obstacles, some investigators have evaluated computed tomography (CT) cholangiography. CT cholangiography offers a considerable number of theoretical merits that may permit more advantageous visualization of smaller ducts however requires the administration of a contrast agent that's excreted into the biliary device.19, 20, 21 These contrast brokers, despite the fact, raise the risks linked to the exam and may not be excreted smartly in livers with impaired characteristic, consequently resulting in poor visualization of the bile ducts. In mouse fashions of cholangiopathy, a noninvasive hepatobiliary imaging components is required however is at the moment lacking.
There are a few predominant challenges associated with live-mouse stomach imaging, in particular cholangiography. These include the simultaneous need for prime resolution (because of the diminutive dimension of murine bile ducts), high speed (to eliminate movement artifact from the lungs, coronary heart, bowel, and biliary easy muscle), high distinction (to differentiate bile ducts from surrounding liver tissue and adjacent blood vessels), and brief period of scans (to not cause undue morbidity). thus, the purpose of this examine became to investigate the methodological feasibility of micro-computed tomography (microCT) and MR imaging for noninvasive, live-mouse cholangiography and evaluate their advantage utility in assessing mouse models of cholangiopathy in vivo.top of web page materials and strategies Experimental Animals
All animal processes have been reviewed and permitted by, and performed in accordance with, the Mayo health center Institutional Animal Care and Use Committee. a total of 15 mdr2KO (9 feminine, 6 male) mice, 7 wild-category (WT) mice (4 female, 3 male), and two bile duct-ligated (BDL) mice (1 feminine, 1 male) were protected in this examine. WT mice had been used as poor controls. BDL mice were used as tremendous controls to determine the ability of imaging to differentiate between acute biliary obstruction and sclerosing cholangitis (ie, mdr2KO mice); one BDL mouse underwent usual bile duct (CBD) ligation, while the different underwent selective appropriate hepatic duct ligation. All mice have been between 4 and eight months of age and weighed a median of twenty-two g (range 19–29).
Mdr2KO mice had been killed and dissected instantly after imaging to correlate imaging effects with intraoperative findings. For mdr2KO mice that didn't have grossly distinguishable (ie, uniquely characteristic) biliary tract facets, livers had been perfused with 10% neutral buffered formalin, and liver histopathology turned into assessed with Masson’s Trichrome-stained paraffin-embedded serial sections as previously described22 to corroborate imaging findings. in a similar way, one BDL mouse become killed and dissected immediately after imaging and turned into examined grossly and histopathologically.
Mice have been bred and maintained at the animal facility at Mayo hospital, with a 12 h light/dark cycle and free access to average mouse chow and water.Mouse instruction and Imaging
Mice had been fasted for up to six h earlier than imaging. Anesthesia turned into precipitated in an animal chamber with a gasoline blend of oxygen (1 l/min) and 2% isoflurane (Abbott Laboratories, North Chicago, IL, united states). Following anesthesia, mice were transferred to a small rodent cradle or mouse coil for microCT and MR imaging, respectively. Anesthesia became maintained with 1.5–2.5% inhalational isoflurane.Micro-computed tomography
MicroCT turned into performed the usage of a Siemens Inveon PET/CT scanner (Siemens clinical solutions, Knoxville, TN, country). Parameters have been as follows: 360° rotation, 360 projections, 500 ms exposure time, eighty kV voltage, 500 μA present, and positive pixel dimension 28.09 μm. Acquisitions were reconstructed with a filtered backprojection algorithm, matrix dimension 512 × 512 × 256, the usage of manufacturer-provided application.
To permit visualization of the biliary tree, three mice were injected intraperitoneally (IP) and two mice were injected intravenously (IV) with iodipamide meglumine (Cholografin) biliary contrast (Bracco Diagnostics, Princeton, NJ, u . s . a .). Escalating doses from 0.9 to 3 ml/kg had been used in response to physique floor enviornment normalization and results of preliminary scans.23 IP injection became carried out in the left decrease quadrant of the stomach put up-induction of anesthesia. IV injection changed into performed within the tail vein with mice in a custom cylindrical restrainer and under a heat lamp pre-induction of anesthesia. Mice have been scanned at distinctive time points after distinction injection.
each mouse become scanned for up to a total of 2 h per day to evaluate diverse scans (eg, with and without contrast at distinctive time features post-distinction administration). Scans lasted ~11 min. After scanning, mice were observed for 1 h to ensure sufficient reheating and anesthetic recovery.Magnetic resonance
MR imaging turned into carried out the use of a Bruker Avance seven-hundred MHz, 16.four T vertical bore MR spectrometer equipped with mini-imaging accessories (Bruker BioSpin, Billerica, MA, country). A 16.four T spectrometer turned into used to maximize sensitivity (ie, sign-to-noise ratio, SNR). on account of shortening of the T2 (and T2*) and lengthening of the T1 tissue water relaxation instances at such excessive container strengths, repetition time (TR) must be longer and echo time (TE) shorter at sixteen.4 T than at 7 T as a way to keep the same detectable magnetization. the most remarkable effect of the T2 shortening is that the infrequent element should be lessen. thus, despite the fact imaging at sixteen.four T consequences in SNR advancements, these are in part offset by way of the alterations in leisure time alternate, the end outcomes of which is improved photos at larger fields, albeit less so than expected.
besides the aforementioned challenges linked to mouse cholangiography, there are a couple of others which might be often not a controversy in clinical MRCP; eg, the mouse heart is discovered an awful lot closer to the liver, beats practically an order of magnitude sooner, and causes oscillatory action it's on the magnitude of mouse bile duct size. for this reason, we evaluated a number of diverse measuring (ie, imaging) methods, each and every with a various latitude of acquisition parameters, to check which would give the most effective visualization of the biliary tree, chiefly the intrahepatic bile ducts (table 1). The three methods that we ultimately pursued in line with promising preliminary outcomes have been faster quick Acquisition with rest Enhancement (TurboRARE), Half-Fourier Acquisition Single-shot faster Spin Echo (HASTE), and IntraGate quickly Low angle Shot (IntraGateFLASH). As described under, every of these three strategies has certain homes (or is appropriate with extra manipulations) that mitigate motional artifacts or present other benefits.
TurboRARE, a spin echo method, changed into the simple 3D method investigated. TurboRARE imaging was performed together with respiratory triggering or gating to dispose of respiratory motion artifact; this is critical as pictures are acquired by way of Fourier transformation of the proper 3D raw information from ok-area, and action anywhere within the field of view (FOV) throughout a scan produces artifact along section and slice domains. To in the reduction of the fraction of blanking time with respiratory gating, the respiratory cost turned into invariably monitored (SA instruments, big apple, the big apple, united states of america) and managed via adjusting the heating air temperature (34–37 °C) and isoflurane attention (1.5–2.5%). normally, in 3D methods the FOV have to cover the complete visible object to keep away from aliasing. As regular intrahepatic bile ducts have a diameter on the order of one hundred μm, in-plane resolution of about the equal measurement is required. With FOV 51.2 mm × 25.6 mm × 25.6 mm, a matrix of 512 × 256 × 256 is imperative, which means that sixty five 000 (2562) k-space vectors should be received for a 3D records set with 100 μm/voxel isotropic decision. therefore, for prime-decision photographs (where 10 000–65 000 ok-area vectors should be accrued), 3D methods are intrinsically time-intensive, and much more so when combined with respiratory triggering (and to a lesser extent gating) techniques. Contributing to this long scanning time is the aforementioned precept of tissue water T2 (and T2*) rest time fitting shorter and T1 becoming longer at greater fields, on account of which rare element is restricted to ≤16 and TR to >1000 ms. hence, despite the strengths of TurboRARE methodology, there's an linked time penalty.
IntraGateFLASH, a gradient echo method, eliminates periodic motional artifacts with the aid of recording the scout scan earlier than each and every ok-area vector and by way of reconstructing images from the k-space vectors with similar scout scans (a sort of retrospective gating). thus, acquisition need to be repeated repeatedly (10–100) to create a vector library gigantic sufficient to have a few k-area vectors with the equal scout phase to generate pretty much artifact-free pictures. Performing more repetitions helps dispose of respiratory and cardiac artifact, but additionally leads to longer scan time. The number of repetitions necessary is basically based on and raises with the volume of movement (eg, respiratory) and may range from 10–15 repetitions (yielding an approximate scan time of 5–10 min) to 50–one hundred repetitions (yielding an approximate scan time of 20–30 min). Of note, although clinically used FLASH (ie, for MRCP) is T1 weighted, we lengthened the echo time to consist of T2* weighting.
HASTE, an ultrafast spin echo technique, eliminates motional artifacts by means of unexpectedly accumulating records from a single slice. youngsters respiratory movement artifact is not tricky to eliminate, cardiac action artifact is difficult. counting on the body temperature and degree of anesthesia, the mouse heart cost ranges between 250–500 beats/min, with a motional length between 150–240 ms. therefore, acquisition instances should still ideally be shorter than 100 ms. With an estimated echo time of four ms (in line with anticipated resolution and spectral width), this one hundred ms threshold is reached with rare ingredient 20–30. To maintain resolution on the order of 200 μm/pixel, a single slice is generated in two to four segments; with repetition instances on the order of seconds, this will also be bought within a couple of seconds. The biliary tree can then be reconstructed from multislice data; accordingly, 20 to 200 skinny slices are gathered, leading to a total acquisition time of 3–20 min. moreover acquisition being faster than the heartbeat, the leading abilities of HASTE in comparison with TurboRARE is that it's inherently a 2nd system; for that reason, motional artifacts (if any) don't propagate between the slices. therefore, in spite of the fact that some slices are corrupted, a valuable photo of the biliary tree can nonetheless be received.
besides the above suggestions, we additionally evaluated the utility of IP gadoxetate disodium (Eovist, Bayer, Berkeley, CA, us of a), a gadolinium-containing paramagnetic distinction agent it is excreted during the biliary system, for making improvements to duct visualization. The dose used become in accordance with the body surface enviornment normalization formulation.23 We additionally assessed the utility of using IP glucagon (Sigma-Aldrich, St Louis, MO, country) at a dose of 0.15 mg/kg to assist decrease intestine motion artifact.24 each gadoxetate disodium and glucagon had been injected in the left reduce quadrant of the abdomen immediately earlier than scanning.
MR scan instances ranged from ~2–70 min, reckoning on the system and parameters used. Mice have been imaged for as much as a total of four h per day and accompanied for 1 h later on to ensure anesthetic restoration.graphic Processing and analysis
PMOD Biomedical picture Quantification and Kinetic Modeling application version 2.eighty five (PMOD applied sciences, Zurich, Switzerland) and Paravision 5.0/5.1 application (Bruker BioSpin) were used to manner and check out microCT and MR images, respectively. MR images have been additionally post-processed through the use of a highest-intensity projection (MIP) algorithm to create a projection cholangiogram that may be turned around and viewed from consumer-described angles.
Visualization of here biliary constructions in mdr2KO mice, BDL mice, and handle mice become assessed by means of as a minimum three coinvestigators experienced in hepatobiliary imaging: gallbladder, extrahepatic (including hilar) bile ducts, and intrahepatic bile ducts. furthermore, detection of (1) cholelithiasis, ductal dilation, strictures, and irregularity changed into assessed in mdr2KO mice, and (2) gallbladder and ductal dilation changed into assessed in BDL mice.
Ductal dilation changed into described as any duct with a diameter >300 μm or any intrahepatic duct with a diameter >a hundred and fifty μm or beyond third order (ie, branching).25 Ductal stricture became defined as a focal (circumferential) luminal narrowing or tapering with upstream dilation.26 Ductal irregularity turned into described as either strictures alternating with typical or dilated-acting ducts or as ‘ragged’-appearing intrahepatic ducts, as seen in PSC.13, 27, 28correct of web page consequences Micro-computed Tomography
MicroCT scans have been performed in three mdr2KO mice (two feminine, one male). Preliminary scans without biliary contrast injection resulted in nonvisualization of biliary buildings because of insufficient hepatic smooth tissue distinction. hence, mice have been rescanned after IP injection of iodipamide meglumine biliary contrast. This amendment yielded visualization of the gallbladder, extrahepatic ducts, and intrahepatic ducts in three, two, and none of the three mdr2KO mice, respectively (figure 1a). It become referred to that hyperdense intragastric chow perceived to imprecise photos by causing streaking artifact, and for that reason fasting periods of 4 h had been made standard. This change resulted in decreased artifact, but once again, intrahepatic ducts couldn't be recognized.figure 1.
distinction-more advantageous micro-computed tomography (microCT) photograph of mdr2 knockout (mdr2KO) mouse. (a) Intraperitoneal distinction-more suitable axial graphic demonstrating a normal-appearing gallbladder and common bile duct; intrahepatic ducts are not visualized. Hyperdense gastric contents are present and trigger streak artifact. (b) Intravenous contrast-improved coronal photo demonstrating normal-performing gallbladder and dilated hilar ducts; intrahepatic ducts are again no longer visualized regardless of addition of 6 h fasting.Full determine and legend (112K)
hence, subsequent microCT imaging turned into performed with IV biliary distinction administration moreover 6 h fasting. This yielded marginally stronger visualization of hilar ducts, but intrahepatic ducts (or any aspects of sclerosing cholangitis) once more could not be definitively identified (determine 1b), in spite of the time interval between contrast administration and imaging. Of word, height biliary excretion following intravenous distinction passed off after ~15 min. regardless of better concentrations of IV distinction, the most effective appreciable alternate became the stronger amount of contrast within the proximal small bowel (unintentionally yielding enterographic photographs). moreover, one mouse that obtained a dose of three ml/kg of IV distinction in a single session died within a day. The other two mdr2KO mice survived IP and IV contrast injection, microCT scanning, and anesthesia.
on account of the want for invasive contrast injection, the mortality associated with larger doses of contrast, and the nonvisualization of intrahepatic ducts despite these maneuvers, additional investigation with microCT was not pursued. These consequences, and those from MR imaging, are summarized in desk 2.Magnetic Resonance mdr2KO mice
Preliminary MR imaging turned into performed with the identical three mdr2KO mice used for microCT. the use of a lot of mainly T2-weighted strategies, there turned into respectable contrast between the biliary tree and surrounding liver tissue; this was carried out without administration of contrast and facilitated by the lengthy T2 rest time of bile. The gallbladder and extrahepatic ducts have been with no trouble visualized in all three mdr2KO mice, and intrahepatic ducts have been visualized in two of the three mice. Cholelithiasis became stated in these equal two mice as round, hypointense filling defects (determine 2a). One of these mice also had a markedly dilated CBD (1 mm in diameter) with choledocholithiasis, which was proven by anatomic dissection automatically after imaging (figure 2b).determine 2.
Cholelithiasis and dilated commonplace bile duct in mdr2 knockout (mdr2KO) mouse seen with magnetic resonance (MR) imaging and confirmed by way of anatomic dissection. (a) Gallstones are seen as 0.35 mm, circular hypointensities. standard bile duct is dilated to over 1 mm, whereas the cystic duct appears to be of average or a little bit enlarged caliber (IntraGateFLASH (IntraGate fast Low perspective Shot), echo time three ms, repetition time eighty two ms, 30 repetitions, picture matrix 256 × 256 pixels, acquisition matrix dimension 128 × 128 pixels, decision one hundred twenty five × one hundred twenty five μm, slice thickness 250 μm, acquisition time 5.3 min). (b) Dissection of the equal mouse immediately after imaging demonstrates extensive cholelithiasis and a severely dilated typical bile duct with choledocholithiasis, according to MR findings.Full determine and legend (352K)
certainly, it became apparent that scans longer than 20–25 min frequently resulted in compromised image nice. This time penalty was seemingly related to spontaneous biliary clean muscle contraction, various respiratory and heart quotes, periodic respiratory ‘sighs’ (ie, excessive-amplitude breaths), and intestinal motion. youngsters nonrespiratory-gated, rapid imaging might alter for some of these elements with photo oversampling and retrospective gating (ie, IntraGateFLASH formulation), it became not appropriate with 3D imaging (but became useful for high decision (eg, 100 μm) in-airplane photographs). Glucagon administration to reduce intestinal action had no apparent impact on graphic exceptional (statistics now not proven).
five further mdr2KO mice had been scanned in an try to adjust methodology and enrich visualization of intrahepatic ducts. the usage of 3D respiratory-triggered TurboRARE, intrahepatic ducts had been extra evidently visualized, and MIP post-processing algorithms yielded visualization of the intrahepatic biliary tree in its totality, revealing irregular, strictured, dilated intrahepatic ducts per sclerosing cholangitis (figure 3a). further morphological particulars could be seen via rotating the 3D MIP video info, together with ‘beading’ of the intrahepatic ducts in some mice, a function attribute of PSC (figure 3b and Supplementary Video S1). Liver histology in these mice validated sclerosing cholangitis (determine 3c), as a result accounting for and corroborating the cholangiographic appearance. mainly, ductal abnormalities on MR imaging regarded more renowned in feminine mice; this discrepancy is according to the prior observation that hepatic biochemical parameters are more deranged in female as compared with male mdr2KO mice.29 All mdr2KO mice survived anesthesia and MR imaging.figure three.
Magnetic resonance (MR) imaging with optimum depth projection (MIP) submit-processing demonstrates intrahepatic changes according to sclerosing cholangitis in mdr2 knockout (mdr2KO) mouse, as corroborated by using liver histology. (a) Coronal view of mdr2KO mouse biliary tree the use of MIP algorithm demonstrates dilated, diffusely irregular intrahepatic ducts (arrows) (TurboRARE (faster speedy Acquisition with leisure Enhancement) with respiratory triggering, echo time 8 ms, advantageous echo time 24, infrequent ingredient 8, photo and acquisition matrix 256 × 128 × 128 pixels, resolution 200 μm isotropic, acquisition time 39 min with respiratory rate of ~70 breath/min). (b) On sagittal view, the same MIP demonstrates extra aspects, including beading (arrow) and a sclerotic left ductal equipment, hallmarks of basic sclerosing cholangitis. (c) Trichrome-stained section of mdr2KO mouse liver ( × 10) demonstrates attribute aspects of sclerosing cholangitis, in line with MR findings.Full figure and legend (358K) WT (poor handle) mice
Seven WT mice were imaged with the same strategies as above. despite the fact the gallbladder and (at least a portion of) extrahepatic ducts were always visualized, visualization of the intrahepatic ducts was commonly marginal regardless of adequate contrast and suppression of vascular structures, corresponding to portal veins (figure four), albeit stronger with 2nd respiration-triggered HASTE imaging. When visualized, ducts were diminutive (none >300 μm), fewer in number in comparison with mdr2KO mice, and easy, ie, devoid of considerable abnormalities. Glucagon administration pre-imaging did not greatly enrich image quality or visualization of ducts. All WT mice survived anesthesia and MR imaging.figure four.
Coronal magnetic resonance (MR) photo of untamed-type mouse demonstrating regular-performing gallbladder and a faint linear hyperintensity (white arrows) suggestive of the cystic duct. Black streaks in the liver signify attenuated vascular structures (IntraGateFLASH (IntraGate speedy Low attitude Shot), echo time four ms, repetition time 200 ms, 80 repetitions, picture matrix 512 × 256 pixels, acquisition matrix measurement 256 × 128 pixels, decision a hundred × 100 μm, slice thickness 1 mm, acquisition time 34 min).Full figure and legend (81K) BDL mice
BDL mice have been used to interrogate the capacity of MR imaging to distinguish between acute biliary obstruction and the sclerosing biliary disorder considered in mdr2KO mice. BDL mice have been imaged 1 and a pair of days post-BDL, all over which time progressive biliary tree dilation changed into visualized. via the 2d day, the mouse with CBD ligation changed into found to have a markedly dilated gallbladder with a distinct, circular morphology (figure 5a). The mouse with selective appropriate hepatic duct ligation verified expanding ductal dilation and hyperintensity of the right side of the liver (figure 5b). This mouse became dissected after the second day, and corresponding findings of a correct liver lobe infarction were observed grossly (determine 5c) and on histopathology (Supplementary determine S1).determine 5.
photographs of bile duct-ligated mice demonstrating dilated biliary tree (with out sclerotic changes) and bile infarct. (a) Coronal magnetic resonance (MR) photograph of regular bile duct (CBD)-ligated wild-category mouse in which gallbladder (GB) is dilated to 5 mm in largest dimension, and distinctive intrahepatic ducts (arrows) are considered on account of biliary obstruction (HASTE (Half-Fourier Acquisition Single-shot rapid Spin Echo), echo time three.9 ms, positive echo time 19.5 ms, repetition time 3000 ms, four repetitions, infrequent element 36, graphic matrix 256 × 128 pixels, acquisition matrix size 256 × seventy two pixels, resolution 250 × 250 μm, slice thickness 0.5 mm, acquisition time 24 s per slice). (b) Coronal MR photo of correct hepatic duct-ligated mouse demonstrating dilated appropriate ductal gadget and right liver lobe hyperintensity, suggesting infarction (HASTE, echo time four.18 ms, helpful echo time 20.9 ms, repetition time 3000 ms, 4 repetitions, rare ingredient 36, picture matrix 256 × 128 pixels, acquisition matrix size 256 × 72 pixels, resolution 250 × 250 μm, slice thickness 0.5 mm, acquisition time 24 s per slice). (c) Dissection instantly after MR imaging on day 2 publish-appropriate hepatic duct ligation revealing gross findings of right liver lobe infarction ex vivo, corroborating in vivo MR findings. (d) Sagittal view of CBD-ligated mouse biliary tree using highest intensity projection publish-processing algorithm demonstrating vastly dilated GB, extra-, and intrahepatic ducts (arrows) (TurboRARE (faster speedy Acquisition with leisure Enhancement) with respiratory gating, echo time eight.45 ms, helpful echo time 42.2, infrequent element 16, picture matrix 512 × 256 × 200 pixels, acquisition matrix 364 × 176 × 142 pixels, decision one hundred μm isotropic, acquisition time fifty nine min with respiratory cost of ≈25 breath/min).Full figure and legend (251K)
The basic condition of each BDL mice changed into tenuous, and protecting strong a must-have signals changed into intricate. thankfully, youngsters, it became obvious that after ~1 h of anesthesia and acclimation of the mouse inner the MR spectrometer, respiratory (and heart) fee became greater general and could be stably suppressed and maintained at 20–30 breaths/min. throughout this ‘deep’ anesthesia, for explanations which are discussed later, longer imaging times (as much as 60 min) have been viable and yielded superior 3D imaging consequences (figure 5d and Supplementary Video S2). As may also be viewed, youngsters the gallbladder and bile ducts have been diffusely dilated within the BDL mice, there turned into no facts of ductal strictures or irregularity, for this reason permitting correct big difference between BDL and mdr2KO mice.
both BDL mice survived anesthesia and MR imaging, but have been killed after day 2 of imaging.Gadoxetate disodium distinction-stronger imaging of mdr2KO mice
although the biliary tree become frequently neatly-visualized with MR in diseased mice devoid of contrast administration, we explored the incremental utility of IP contrast enhancement in seven further mdr2KO mice. We found that at parameters optimized for contrast-improved imaging, use of gadoxetate disodium allowed for greater visualization of the biliary tree, mainly the intrahepatic ducts (determine 6a). exceptionally, it increased SNR and mitigated the time penalty mandatory for top-resolution scanning. here is further validated in figure 6b (and Supplementary Video S3), wherein 100 μm isotropic decision 3D cholangiography may be acquired in only 25 min (as in comparison with 45–60 min without distinction). Of be aware, one mouse died following distinction administration.determine 6.
highest depth projection (MIP) magnetic resonance (MR) images of mdr2 knockout (mdr2KO) mice with and devoid of distinction. (a) With acquisition parameters optimized for contrast use (together with shorter scan instances, which would not be plausible devoid of contrast), use of gadoxetate disodium (right) allows improved visualization of the biliary tree, principally the intrahepatic ducts (TurboRARE (faster quick Acquisition with leisure Enhancement) with respiratory gating (TR 500) and partial Fourier radically change acceleration component 1.3, echo time eight ms, advantageous echo time 16, rare factor 4, picture matrix 256 × 128 × 128 pixels, acquisition matrix 197 × 84 × a hundred pixels, resolution 200 μm isotropic, acquisition time 19 min for each scan with respiratory price of ≈25 breath/min). (b) Accelerated, excessive-resolution in vivo cholangiography facilitated by using gadoxetate disodium-enhancement demonstrating irregular, focally dilated intrahepatic ducts because of multifocal strictures (arrows), consistent with sclerosing cholangitis (TurboRARE with respiratory gating (TR a hundred and fifty) and partial Fourier seriously change acceleration element 1.3, echo time eight ms, helpful echo time 16, infrequent component four, graphic matrix 512 × 256 × 256 pixels, acquisition matrix 394 × 168 × 198 pixels, decision one hundred μm isotropic, acquisition time 25 min with respiratory price of ~25 breaths/min).Full figure and legend (120K) properly of page dialogue
during this look at, we investigated the feasibility and utility of using noninvasive imaging to function reside-mouse cholangiography. Our work demonstrates that: (1) microCT yields suboptimal bile duct visualization regardless of escalating doses of IP and IV contrast; (2) MR is secure and allows for visualization of the gallbladder, further-, and intrahepatic bile ducts in just about all mdr2KO mice with out requiring distinction administration; (3) the cholangiographic appearance of mdr2KO mice is akin to human PSC; (four) MR cholangiography can differentiate between mdr2KO, BDL, and WT mice; and (5) use of gadoxetate disodium MR distinction can enrich duct visualization and shorten scan instances. To our potential, this is the first look at of noninvasive, live-mouse cholangiography; the findings herein suggest that MR cholangiography is a promising novel modality to noninvasively and longitudinally investigate mouse (and sure other small rodent) fashions of PSC and other cholangiopathies, together with polycystic kidney and liver sickness,30C. parvum-brought on cholangitis,31 and hepatic graft versus host disorder.32 As such, it holds expertise as a brand new tool to greater look at disorder pathogenesis and therapeutic response in existing fashions of cholangiopathy and facilitate construction of novel and greater clinically relevant models. in addition, MR cholangiography may also accelerate translation of animal model findings to the scientific enviornment, in which MRCP has now not handiest enhanced patient care, but is also rising as an endpoint in clinical trials.
Drawing on our event with MRCP and in accordance with outcomes obtained herein from our mouse imaging experiments, a number of important observations have been made during this analyze. Fasting of mice become mentioned to be a vital prerequisite as with hepatobiliary imaging in humans; the mechanism involved is not totally clear, but is probably going a mixture of expanded bile-duct filling and diminished smooth muscle pastime in bile ducts and viscera. Glucagon administration had no obvious effect on picture fine; opioid agonists akin to morphine could be more useful in this regard and can merit future exploration, besides the fact that children with warning to now not cause undue mouse morbidity. Respiratory triggering or gating was imperative in definite methods (ie, 3D TurboRARE), however become much less critical with quicker imaging (ie, HASTE) and graphic oversampling (ie, IntraGateFLASH) methods. additionally, the utility of respiratory triggering or gating became compromised when mouse respiratory rate changed into irregular or quick; this referred to, as outlined previously, we followed that deep anesthesia (ie, after 1 h of mouse acclimation to being inner the spectrometer and below anesthesia) accepted mouse stabilization and longer scans devoid of SNR diminution as a result of artifact, consequently yielding advanced photo great (determine 5d and Supplementary Video S2). finally, as with clinical MRCP, there are certain strengths and weaknesses to each and every imaging formula; eg, we found that second HASTE and IntraGateFLASH yielded swift scans with amazing in-aircraft decision, whereas 3D TurboRARE with submit-processing the usage of a MIP algorithm provided a simplified, enormously useful world view of the biliary tree in a single photograph (or video). an additional skills of HASTE is that motion artifact is localized within the affected slice (ie, it doesn't propagate through the whole photo).
however mouse stomach imaging with microCT and MR is smartly based, the software of those suggestions to performing committed are living-mouse cholangiography has now not been described before. it can be cited, even though, that other strategies of researching the murine biliary tree had been mentioned. as an instance, close-infrared fluorescent cholangiography has been these days applied to murine biliary imaging; despite the fact preliminary consequences seem favorable, this is an intraoperative method that requires laparotomy and intravenous injection of a fluorochrome probe.33 in addition, even within the setting of comprehensive biliary obstruction, it has now not been proven to enable visualization of intrahepatic ducts, whereas this changed into carried out with our strategies (Figures 5a and d, and Supplementary Video S2). We and others have proven that biliary casting gives wonderful counsel regarding biliary architecture, however this is a labor-intensive technique that requires killing the animal and ex vivo retrograde biliary injection of liquid resin, hence precluding longitudinal studies.34, 35 Diffraction-more desirable radiography has been previously stated, but this too is performed ex vivo and doesn't differentiate smartly between bile ducts and veins, especially in non-BDL mice.36 for this reason, despite the fact a number of alternative strategies exist, they're substantially greater invasive, labor-intensive, and/or much less delicate than people who we have described herein.
several limitations advantage acknowledgment in our study 000-256. For microCT, we didn't employ nanoparticulate contrast, continual infusion of contrast through an IV catheter, respiratory triggering or gating, or deep anesthesia (ie, for ≥1 h earlier than imaging); besides the fact that children these maneuvers would greater entirely interrogate the knowledge of microCT, we agree with they might result in only modest improvements. furthermore, they might no longer alter the proven fact that microCT mandates contrast administration to imagine the biliary tree and would likely lead to improved labor and/or expenses. With respect to MR, our preliminary experiments on 7-T spectrometers imply that longer echo times may be used, but this benefit doesn't entirely catch up on the advanced sensitivity of the 16.four T gadget; imaging with three T medical scanners does not supply adequate resolution to visualize the murine biliary tree (information not proven). Slice thickness changed into now not a focus of this examine, youngsters in usual, increasing slice thickness resulted in bigger SNRs, albeit sacrificing anatomic details. We did not systematically get rid of nonhepatobiliary structures, akin to spine or belly, from MIP photographs and videos; in future stories, we hope to crop these structures pre-projection to be able to maximize distinction and picture clarity and facilitate quantitative measurements. lastly, the number of animals investigated turned into constrained, but ample to finished the objectives of this preliminary analyze.
The experiences herein have led to positive insights for additional development and protocol development, together with right here counsel: (a) fasting mice for ~6 h before imaging; (b) pre-anesthetizing for at least 1 h earlier than imaging; (c) preserving respirations at 20–30 breaths/min, principally for respiratory-gated TurboRARE scans; (d) respiratory gating or varied repetitions (ie, oversampling) to alter for respiratory motion; and (e) when you consider that use of gadoxetate disodium MR contrast to increase duct visualization and shorten scanning times (depending on the aims of the specific test, and weighing the knowledge physiologic affect and dangers of repeated distinction injection for longitudinal experiences). We consider that as with the scientific MRCP journey, construction of a murine MR cholangiography protocol will require further work guided in part by way of the above, as well because the adventure of other investigators. until then, a mixture of numerous methods is likely to deliver essentially the most complete counsel, however fewer methods can also be used counting on the query of hobby.
In conclusion, noninvasive mouse MR cholangiography is a feasible and promising formula for evaluation and longitudinal monitoring of hepatobiliary disease in vivo. Our findings up to now motivate further development and optimization of this components, in addition to adaptation to a broader latitude of mouse and other small rodent fashions of cholangiopathy.precise of web page conflict of pastime
The authors declare no conflict of pastime.desirable of web page References