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In the mammary gland, how alveolar progenitor cells are recruited to fuel tissue growth with each estrus cycle and pregnancy remains poorly understood. Here, we identify a regulatory pathway that controls alveolar progenitor differentiation and lactation by governing Notch activation in mouse. Loss of Robo1 in the mammary gland epithelium activates Notch signaling, which expands the alveolar progenitor cell population at the expense of alveolar differentiation, resulting in compromised lactation. ROBO1 is expressed in both luminal and basal cells, but loss of Robo1 in basal cells results in the luminal differentiation defect. In the basal compartment, ROBO1 inhibits the expression of Notch ligand Jag1 by regulating β-catenin (CTNNB1), which binds the Jag1 promoter. Together, our studies reveal how ROBO1/CTTNB1/JAG1 signaling in the basal compartment exerts paracrine control of Notch signaling in the luminal compartment to regulate alveolar differentiation during pregnancy., Summary: This study demonstrates that Robo1/β-catenin/JAG1 signaling in basal epithelial cells regulates luminal Notch activity and alveolar progenitor differentiation, offering a non-hormonal way to target milk production and mitigate lactation insufficiency.

This paper discusses a unique introduction of modular screens into the design of a deep water horizontal open hole injector completion offshore Nigeria and describes the complete quality assurance/quality control (QA/QC) and operational procedures of the first global deployment of modular screens with sliding sleeves. The Egina field, initially designed without a provision for mechanical or hydraulic isolation of panels, provided an opportunity to introduce a means of accomplishing isolation with modular screens and mechanical actuated sliding sleeves. This application provides the operator with the ability to (1) selectively inject into different intervals using mechanical intervention and (2) address erosion concerns on a high rate water injector without compromising the current upper completion (UC) and existing wellhead design. The paper details the successful installation, excellent completion equipment functionality, and well results. The operator's geosciences team targeted two separate reservoir panels in the Egina field for water injection. However, commingled injection into both panels would result in an early water breakthrough at one of the supported producers, causing a large loss in oil recovery. The current design for Egina does not provide a means of temporarily isolating the heel section while allowing communication into the toe during injection. Rather than drilling two separate water injectors at significantly higher costs, the completion team identified a solution combining the two targets into a single well while maintaining the ability to temporarily access, isolate, or isolate one interval. The team introduced a viable means to selectively inject by adding modular screens with integral sliding sleeves. The revised completion design used existing materials applied on earlier completions, which maintained complete compatibility with the UC and the existing wellhead configuration. Modular screens have long been used in cased hole gravel pack applications where multi-zone selectivity has been necessary. Applying this technology to a horizontal open hole scenario allowed the team to selectively inject into one interval and then return later to subsequently inject into the next interval using sliding sleeves. Injection rates vary based upon the number of sliding sleeves opened or closed. The subject well was run with a modified lower completion (LC) incorporating modular screens in the upper interval and standard wire-wrapped screens in the lower interval with a swell packer providing isolation of the two. This modified completion design allows for an adjustable rate for either individual or commingled injection through a mechanical intervention, and it provides a completion that can be deployed and installed in an efficient manner without any operational issues. Successful installation and injectivity testing have proven the completion concept, and have helped in providing a technical solution allowing the operator to recover the 3-Mbbl oil stake associated with water injection into the upper interval. The sliding sleeves incorporated into the system were manipulated opened and closed with no issues, and injectivity tests were performed with excellent results.

The unique introduction of production screens with mechanically shiftable flow isolation sleeves and inflow control devices for better injection flow distribution (ICD) fit with innovative dissolvable metal plugging rods that allow wash pipe free horizontal completion installation on a deep offshore project in Nigeria. This unique application provides the function of a mechanical selective completion with the incorporation of an ICD solution tailored to the reservoir with wash pipe-free execution. This would allow for selective injection from one zone to a comingled injection activated using mechanical intervention means while maintaining full compatibility with the already designed upper completion and the existing wellhead and topside equipment, as is. The completion was successfully installed following the standard field operations practices used on previous completions within the same field. The Egina development plan, operating with a standardized and simple design, does not provide for an intelligent completion that allows remotely activated zonal selectivity. Two separate reservoir zones, with two panels each, were targeted for water injection to achieve the sweep of by-passed oil in the shallower panels connected to two producer wells and pressure mainteneance in the deeper panels connected to one producer well. Commingled injection from start would result in early water breakthrough on one of the two producer wells connected to the shallower reservoir panels by virtue of both well drains being almost at same level depthwise, TVD/MSL. A solution was selected that would combine the two target reservoir zones on a single well. This would allow for selective injection using screens with mechanically shiftable integral sliding sleeves, maintaining temporary access or isolation on the shallower interval. This solution would allow for drilling one single water injection well instead of two. Incorporating ICDs in the deeper reservoir panels with "a dissolvable plug solution" allowed for a better injection flow distribution as well as the completion deployment, wash pipe free. Fluid compatibility testing was performed with dissolvable metals to establish dissolution rates under existing reservoir conditions with mud, brine, and filter cake breaker at field standard formulations. This provides an additional option for running wash pipe free when running lower completions in deepwater wells offshore West Africa. Drilling one well instead of two and deploying completions wash pipe free, allowed for CAPEX savings in the region of $60 Million. No modification to the existing completion processes was necessary with respect to the procedure for deploying completions, washing down or subsequently placing a filtercake breaker treatment. This paper describes the rationale behind the well design philosophy and the operational procedures that introduced a global first deployment of injection screens with mechanically shiftable integral sliding sleeves and ICDs with dissolvable plugs in deep water openhole horizontal completion. The successful installation, completion equipment functionality, and well injectivity test results are discussed.

The introductory use of existing inflow control devices (ICD’s) fitted with innovative dissolvable metal plugging rods to allow the operator to run washpipe free completions to reduce rig time is discussed. This work discusses an ICD washpipe-free application run in a long, deep water horizontal sandface completion in the Egina development. The completion was successfully installed following existing processes for tasks and sub-tasks applied in previous completions in the field. The washpipe-free solution was tailored to the reservoir, and is field-adjustable. The dissolvable plug solution was provided to be used with existing ICD’s available in country, without modification to the ICD housing. Fluid compatibility testing with dissolvable metals was performed establishing dissolution rates under existing reservoir conditions with mud, brine, and cake breaker at field formulations. Introduction of the dissolvable plug solution has provided the operator with an additional option to consider when seeking to further optimize times necessary to run lower completions in deep water wells offshore West Africa. No changes in existing completion procedures were necessary with respect to the procedure for washing down or subsequently placing cake breaker treatment. Running ICD’s with dissolvable plugs was identified as an opportunity to eliminate the need for running lower completion with washpipe. The subject well was run with ICD screens equipped with dissolvable plugs while maintaining full compatibility with the existing upper completion design. Once the well was completed and the tree installed, injectivity testing was successfully performed confirming ICD functionality was re-established. The ICD completion design saved the operator a minimum of 12 hours online rig time, further simplifying running the completion and associated handling times. Offline savings include (1) racking washpipe before running the lower completion, (2) subsequent racking back and laying washpipe upon completing the lower completion, (3) eliminating mobilization of washpipe to/from the rig, and (4) freeing up deck space typically used to accommodate the washpipe. During this saved offline time the auxiliary derrick could be used for other offline equipment preparation, helping provide further savings. Washpipe rental and maintenance costs were eliminated. An important reduction to safety risks related to extensive pipe handling was also achieved. This paper describes laboratory testing, full quality assurance/quality control (QA/QC) and operational procedures, leading to the first successful deployment and excellent functionality of ICD’s with dissolvable plugs in a long deep water horizontal completion eliminating the use of washpipe, while providing associated savings.

At the heart of your favorite games is the game loop. At the core of the game loop is control over the game clock. In each frame the game does some or all of the following: updates the game state, triggers timers, processes user inputs, renders graphics, and plays audio. Each of these operations must be synchronized using a virtual clock controlled by the game loop. This chapter explains how to implement a deterministic and efficient main loop for any type of game designed from the ground up to run in the browser.

Efficient use of system resources is essential to most game applications, to ensure that the game runs correctly and as smoothly as possible across a range of devices and browsers. Here, the term “resources” can refer to available memory, CPU execution time, or other processing or storage units in the system. Although JavaScript can be considered a rather high-level language, the data structures employed by JavaScript application code can significantly impact upon resource usage.

If you’re writing a 2D game in HTML5, chances are that you’ll want the user to have the ability to pick an object on the screen. More specifically, at some point, the user will need to select some item on the screen, or in your game, which may represent part of the world. We call this “picking” as the user is selecting what object they are interacting with. Consider, for instance, your standard social time-management game. The user is presented with a 2.5D play area where bitmaps (or “sprites”) are rendered with some perspective distortion on the screen. For the more advanced users, you can quickly saturate the play area with these sprites, often stacking many of them together, only leaving a few pixels visible between overlapping objects. In this environment, determining the picking result of a mouse click is quite difficult. The canvas API doesn’t provide any form of pixel-based selection and the large number of objects makes it difficult to brute-force the technique. This section will cover how to address performance and accuracy problems in canvas picking using a few old-school techniques that most of us have forgotten about.

Building an HTML5 game in the modern world is rife with difficulties. In addition to technical limitations and variations among browsers, you have the added burden of the current consumer world, which is predominantly driven by a boom in smartphones and tablet devices. What makes developing for this slew of heterogeneous devices difficult is the massive array of resolutions, physical sizes, and performance among them. For your web game to be successful, you’ll need to adapt it to take advantage of the many screen resolutions available so that users can experience it on as many devices as possible. To do this, you’ll need to adjust your game dynamically, depending on the current resolution, to achieve the desired game layout. This, at its core, is known as responsive design.

There is a great focus on making HTML5 games for mobile devices, which is good, of course, but core pro gamers are usually visualized as having a gamepad in their hands. So why not use it and deliver the full experience of a game using the Full Screen, Mouse Lock, and Gamepad APIs? The last API provides the ability to use a console's controller to play HTML5 games—how cool is that? With the W3C specification presently being written, we will have an API that is easy to implement, does not require any plug-ins to run in your browser, and is as simple as just plugging in your device and playing the game right away.

Designing an efficient method of loading game asset data for HTML5 games is essential in creating a good user experience for players. When games can be played immediately in the browser with no prior downloading there are different considerations to make, not only for the first time play experience but also for future plays of the game. The assets referred to by this chapter are not the usual HTML, CSS, JavaScript, and other media that make up a web site, but are the game assets required specifically for the game experience. The techniques mentioned in this chapter go beyond dealing with the standard image and sound data usually handled by the browser and aim at helping you consider assets such as models, animations, shaders, materials, UIs, and other structural data that is not represented in code. Whether this data is in text or binary form (the “Data Formats” section will discuss both) it somehow needs to be transferred to the player’s machine so that the JavaScript code running the game can turn it into something amazing that players can interact with.

TypeScript ( http://typescript.org ) is a typed superset of JavaScript that compiles to plain JavaScript. TypeScript is cross-platform, runs on any browser, and is open source. Microsoft created it, and it’s hands down one of the best languages for building HTML5 games. One of the great things about TypeScript, apart from adding typing to JavaScript, is that it allows you to start using some of the cool features of ECMAScript 6 (ES6) now, even though it may be years away from being finalized. This means that you can put to good use classes and other higher-level constructs that you find in languages such as C# and Java; moreover, TypeScript is incredibly similar to ActionScript 2 and 3. The final key advantage of TypeScript is that it outputs human readable JavaScript, plus you can use existing JavaScript libraries or inject the code directly into your TypeScript classes and start taking advantage of typing provided by the compiler.

It is a bit hard to imagine, but the Web wasn’t always as dynamic as it is today. Before I discuss WebSockets, let’s take a trip down memory lane.

In computer graphics, frames are processed and painted on the screen by what some people refer to as the “animation,” “main,” “game,” or “update” loop. Personally, I prefer to call it “main,” “game,” or “update loop” for the sole reason that it’s standard practice in the industry to use this routine to perform other tasks besides painting pixels on the screen.

As hardware evolved, games went from two-dimensional affairs into the third dimension. This evolution also happened in the browser. Although two-dimensional rendering could be done through the use of the Canvas application programming interface (API) it wasn’t until the Web Graphics Library (WebGL) debuted that the graphics hardware was actually exposed to a lower level within the context of the browser. This API has now been implemented by every major browser vendor, making it possible to create a fully three-dimensional game without relying on a plug-in.

HTML5 games are becoming more and more important in the mobile gaming industry. There are already many casual and social games available in HTML5. Compared to native games, HTML5 games support real-time updating, click-to-play without the need for installations, and efficient development cycles.

Many of the most popular games have a multiplayer component. All but one of the top ten most popular games on Steam, a digital distribution and communications platform for PCs, are either designed for a multiplayer experience or contain support for multiplayer (see Table 12-1). As you will discover in this chapter, adding multiplayer support to a game increases the range of experiences that a player can have by introducing the elements of human psychology and social interaction to the game agents. However, adding real-time multiplayer can be rather tricky to implement correctly. Although it may seem daunting, by following some principled methods, you can add a new, exciting dimension to your game.

Any two-dimensional game is going to, at some point, have a separation between semistatic background content and dynamically animated foreground content. The background content can become a burden to the rendering pipeline, as it can easily consume megabytes of data as well as a hefty chunk of your rendering pipeline. In this chapter, I’m going to discuss a few strategies for overcoming this burden, providing trade-offs where your game may need them.

If you had told me ten years ago that I'd someday compile real-time, 3D C++ games into JavaScript so I could run them in web browsers, I would have thought you were crazy. Since then, software has shifted from retail stores and optical discs to online app stores and web applications. Internet users have become increasingly security-conscious, and JavaScript engines have gotten faster by orders of magnitude.

When it comes to optimization, both real-time 3D applications and web pages happen to share a common target: images. Images, whether they take the form of textures or tags, often make up the majority of the visual information on your screen at any given time. The metrics for optimization differ based on the medium, however. 3D apps, such as games, need images that can be loaded quickly, drawn fast, and take up as little memory as possible by taking advantage of hardware-supported texture compression formats. Web pages, on the other hand, are primarily concerned with the bandwidth required to download the images to your device, skewing heavily towards small, lossy formats like JPG. In other words, 3D apps are concerned about the size of the image in video memory and web apps are concerned about the size of the file on the server.

Back in Chapter 3, we covered the common pitfalls that cause a game to perform poorly, as well as the techniques to address them. Now we will tackle techniques to make your game look and feel just like a native one on mobile.

As developers, we tend to do a lot of repetitive tasks. We are constantly compiling code, packaging it, and deploying it to different places. As the project scales, the complexity of these processes continues to grow. If there is one constant among humans, it’s that we are not great at doing repetitive tasks, especially complex ones. Sure, we can do one single task over and over again, but anything more complicated, and the system quickly breaks down. This isn’t anything new; Henry Ford realized it when he took advantage of the assembly line to lower the cost of making cars. We can do the same thing for our own code by taking advantage of automation.

Making games is exciting, exhilarating, and hugely fulfilling. Making good games isn’t easy. Making great games that work on multiple platforms is . . . what this chapter is about.

For a game to be enjoyable, smoothness is critical. A smooth game can feel lifelike and amazing; without smoothness, a game will be sluggish and annoying, even with the best art.

When we consider mobile HTML5 games, we usually compare them with native games. One might think that native games are always superior to browser games or that browser games can never touch native games in performance. But check out the top 10 games in the native app market. Often you will find that many of the top-selling games do not use 3D graphics, particle effects, and so on. It seems that we are able to create similar kinds of mobile games in the browser with HTML5.

This thesis studies the convergence of a singularly perturbed two-point boundary value problem of the convection-diffusion type. The problem is solved using a hp finite element method on a piecewise uniform fitted mesh. Results will show exponential convergenceof the solution independent of the singular perturbation parameter.