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Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants. Hundreds of mutations in the gene CFTR lead to cystic fibrosis and represent a challenge to developing therapeutics. Here, authors demonstrate the ability of airway cells derived from human iPSCs to model genotype-specific CFTR function as well as pharmacologic rescue of disease causing mutations.

Base editing (BE) can permanently correct over half of known human pathogenic genetic variants without requiring a repair template, thus serving as a promising therapeutic tool to treat a broad spectrum of genetic diseases. However, the broad activity windows of current base editors pose a major challenge to their therapeutic application. Here, we show that integrating a naturally occurring oligonucleotide binding module into the deaminase active center of TadA-8e, a highly active deoxyadenosine deaminase, enhances its editing specificity. When conjugated with a Cas9 nickase or alternative PAM Cas9 variants, the engineered TadA variant—TadA-NW1—consistently achieves robust A-to-G editing efficiencies within an editing window consisting of four nucleotides, substantially narrower than the 10-bp editing window of the TadA-8e-derived ABEs. Moreover, compared to ABE8e, ABE-NW1 shows significantly decreased Cas9-dependent and -independent off-target activity while maintaining similar on-target editing efficiency. Further, TadA-NW1 can be reprogrammed to perform desired cytidine deamination and adenine transversion within a restricted editing window. Finally, in a cystic fibrosis (CF) cell model, ABE-NW1 outperforms existing ABEs in accurately and efficiently correcting the CFTR W1282X variant, one of the most common CF-causing mutations. In all, we engineered a suite of base editors with refined activity windows, enabling more precise base editing. Importantly, this study presents a streamlined genome editor re-engineering strategy to accelerate the development of therapeutic base editing. The broad activity windows of current base editors pose a major challenge to their therapeutic application. Here, the authors established a generalizable re-engineering framework to narrow the activity windows of diverse base editors, streamlining the development of therapeutic base editing.

In a local area network (LAN) or intranet, there are many pieces of hardare trying to gain access to the network transmission media at the same time (i.e., phone lines, coax, wireless, etc.). However, a network cable or wireless transmission frequency can physically only allow one node to use it at a given time. Therefore, there must be some way to regulate which node has control of the medium (a media access control, or MAC, protocol). Ethernet is a MAC protocol; it is one way to regulate physical access to network tranmission media.Ethernet networking is used primarily by networks that are contained within a single physical location. If you need to design, install, and manage a network in such an envronment, i.e., home or small business office, then Ethernet Networking for the Small Office and Professional Home Office will give you an in-depth understanding of the technology involved in an Ethernet network.One of the major goals of this book is to demystify the jargon of networks so that the reader gains a working familiarity with common networking terminology and acronyms.In addition, this books explains not only how to choose and configure network hardware but also provides practical information about the types of network devices and software needed to make it all work. Tips and direction on how to manage an Ethernet network are also provided.This book therefore goes beyond the hardware aspects of Ethernet to look at the entire network from bottom to top, along with enough technical detail to enable the reader to make intelligent choices about what types of transmission media are used and the way in which the various parts of the network are interconnected.Explains how the Ethernet works, with emphasis on current technologies and emerging trends in gigabit and fast Ethernet, WiFi, routers, and security issuesTeaches how to design and select complementary components of Ethernet networks with a focus on home and small business applicationsDiscuses the various types of cables, software, and hardware involved in constructing, connecting, operating and monitoring Ethernet networks

Fully revised, updated, and expanded, Relational Database Design and Implementation, Third Edition is the most lucid and effective introduction to the subject available for IT/IS professionals interested in honing their skills in database design, implementation, and administration.

Fully revised, updated, and expanded, Relational Database Design and Implementation, Third Edition is the most lucid and effective introduction to the subject available for IT/IS professionals interested in honing their skills in database design, implementation, and administration. This book provides the conceptual and practical information necessary to develop a design and management scheme that ensures data accuracy and user satisfaction while optimizing performance, regardless of experience level or choice of DBMS.The book begins by reviewing basic concepts of databases and database design, then briefly reviews the SQL one would use to create databases. Topics such as the relational data model, normalization, data entities and Codd's Rules (and why they are important) are covered clearly and concisely but without resorting to \"Dummies\"-style talking down to the reader.Supporting the book's step-by-step instruction are three NEW case studies illustrating database planning, analysis, design, and management practices. In addition to these real-world examples, which include object-relational design techniques, an entirely NEW section consisting of three chapters is devoted to database implementation and management issues.Principles needed to understand the basis of good relational database design and implementation practicesExamples to illustrate core concepts for enhanced comprehension and to put the book's practical instruction to workMethods for tailoring DB design to the environment in which the database will run and the uses to which it will be putDesign approaches that ensure data accuracy and consistencyExamples of how design can inhibit or boost database application performanceObject-relational design techniques, benefits, and examplesInstructions on how to choose and use a normalization techniqueGuidelines for understanding and applying Codd's rulesTools to implement a relational design using SQLTechniques for using CASE tools for database design