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\"In Flour Water Salt Yeast, author Ken Forkish demonstrates that high-quality artisan bread and pizza is within the reach of any home baker. Whether it's a basic straight dough, dough made with a pre-ferment, or complex levain, each of Forkish's impeccable recipes yields exceptional results. But in addition to the recipes, Flour Water Salt Yeast offers readers a complete baking education, with a thorough yet accessible explanation of the tools and techniques that set artisan bread apart. With a tutorial on baker's percentages, advice for manipulating ingredients ratios to create custom doughs, and tips for creating and adapting bread baking schedules that fit in readers' day-to-day lives (enabling them to bake the breads they love in the time they have available), Flour Water Salt Yeast is an indispensable resource for bakers, be they novices or serious enthusiasts\"-- Provided by publisher.

Transference-Focused Psychotherapy for Adolescents With Severe Personality Disorders offers clinicians a comprehensive, compassionate presentation of this specialized psychodynamic psychotherapy. Like the transference-focused psychotherapy model developed for borderline personality disorder (BPD) in adults, the version for adolescents is based on contemporary psychoanalytic object relations theory as developed by the leading thinker in the field, Otto Kernberg, one of the authors of this insightful manual. The book fills an acute need: Currently, there is relatively little research on promising treatments for adolescents with PDs, in part because clinicians hesitate to diagnose PD in patients so young (because of stigma and other factors), although it is evident that a constellation of symptoms can be observed in children and adolescents. However, these personality issues are unlikely to resolve without interventions developed explicitly to treat adolescents. In TFP-A, the psychotherapist provides patients with a safe space to examine emotions, relationships, and past trauma, with the focus on helping them gain better behavioral control; increase affect regulation; develop more intimate and gratifying relationships with family, peers, or close friends; and engage in a productive life aimed at realizing current and future goals. Noteworthy themes and features of the text include: • Emphasis on the therapist as \"third voice, \" acting as interpreter and mediator between the adolescent, the parental couple, and conventional society and its values, with the ultimate goal of fostering ego integration sufficient to allow the adolescent to proceed under his own agency.• Detailed coverage of the techniques of TFP-A, including creating a holding environment, assuming an active stance, engaging in the interpretive process, analyzing transference and countertransference, achieving technical neutrality, and ensuring interventions are developmentally informed.• Practical and accessible review of TFP-A \"tactics, \" including establishing the treatment frame, collaborating with parents, and other interventions that maintain the conditions necessary for working effectively with the adolescent and for protecting treatment integrity.• Thoughtful review of the attributes that make a clinician a good \"fit\" for transference-focused psychotherapy. For example, therapists must have their own lives \"together, \" because they will have to use countertransference reactions to identity and understand what is projected onto them.• A rich and useful repository of assessment scales and forms in the Appendices, as well as extended and illustrative patient interviews. Navigating adolescence is fraught under the best of circumstances, but patients with PDs are hampered in their quest for individuation. Transference-Focused Psychotherapy for Adolescents With Severe Personality Disorders fills a critical gap in the treatment literature and is an eminently useful guide for clinicians serving this vulnerable population.

The CSB-PGBD3 fusion protein arose more than 43 million years ago when a 2.5-kb piggyBac 3 (PGBD3) transposon inserted into intron 5 of the Cockayne syndrome Group B (CSB) gene in the common ancestor of all higher primates. As a result, full-length CSB is now coexpressed with an abundant CSB-PGBD3 fusion protein by alternative splicing of CSB exons 1-5 to the PGBD3 transposase. An internal deletion of the piggyBac transposase ORF also gave rise to 889 dispersed, 140-bp MER85 elements that were mobilized in trans by PGBD3 transposase. The CSB-PGBD3 fusion protein binds MER85s in vitro and induces a strong interferon-like innate antiviral immune response when expressed in CSB-null UVSS1KO cells. To explore the connection between DNA binding and gene expression changes induced by CSB-PGBD3, we investigated the genome-wide DNA binding profile of the fusion protein. CSB-PGBD3 binds to 363 MER85 elements in vivo, but these sites do not correlate with gene expression changes induced by the fusion protein. Instead, CSB-PGBD3 is enriched at AP-1, TEAD1, and CTCF motifs, presumably through protein-protein interactions with the cognate transcription factors; moreover, recruitment of CSB-PGBD3 to AP-1 and TEAD1 motifs correlates with nearby genes regulated by CSB-PGBD3 expression in UVSS1KO cells and downregulated by CSB rescue of mutant CS1AN cells. Consistent with these data, the N-terminal CSB domain of the CSB-PGBD3 fusion protein interacts with the AP-1 transcription factor c-Jun and with RNA polymerase II, and a chimeric CSB-LacI construct containing only the N-terminus of CSB upregulates many of the genes induced by CSB-PGBD3. We conclude that the CSB-PGBD3 fusion protein substantially reshapes the transcriptome in CS patient CS1AN and that continued expression of the CSB-PGBD3 fusion protein in the absence of functional CSB may affect the clinical presentation of CS patients by directly altering the transcriptional program.

Cockayne syndrome (CS) is a devastating progeria most often caused by mutations in the CSB gene encoding a SWI/SNF family chromatin remodeling protein. Although all CSB mutations that cause CS are recessive, the complete absence of CSB protein does not cause CS. In addition, most CSB mutations are located beyond exon 5 and are thought to generate only C-terminally truncated protein fragments. We now show that a domesticated PiggyBac-like transposon PGBD3, residing within intron 5 of the CSB gene, functions as an alternative 3' terminal exon. The alternatively spliced mRNA encodes a novel chimeric protein in which CSB exons 1-5 are joined in frame to the PiggyBac transposase. The resulting CSB-transposase fusion protein is as abundant as CSB protein itself in a variety of human cell lines, and continues to be expressed by primary CS cells in which functional CSB is lost due to mutations beyond exon 5. The CSB-transposase fusion protein has been highly conserved for at least 43 Myr since the divergence of humans and marmoset, and appears to be subject to selective pressure. The human genome contains over 600 nonautonomous PGBD3-related MER85 elements that were dispersed when the PGBD3 transposase was last active at least 37 Mya. Many of these MER85 elements are associated with genes which are involved in neuronal development, and are known to be regulated by CSB. We speculate that the CSB-transposase fusion protein has been conserved for host antitransposon defense, or to modulate gene regulation by MER85 elements, but may cause CS in the absence of functional CSB protein.

Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. Using expression microarrays and a unique method for comparative expression analysis called L2L, we sought to define this defect in cells lacking a functional CS group B (CSB) protein, the SWI/SNF-like ATPase responsible for most cases of CS. Remarkably, many of the genes regulated by CSB are also affected by inhibitors of histone deacetylase and DNA methylation, as well as by defects in poly(ADP-ribose)-polymerase function and RNA polymerase II elongation. Moreover, consistent with these microarray expression data, CSB-null cells are sensitive to inhibitors of histone deacetylase or poly(ADP-ribose)-polymerase. Our data indicate a general role for CSB protein in maintenance and remodeling of chromatin structure and suggest that CS is a disease of transcriptional deregulation caused by misexpression of growth-suppressive, inflammatory, and proapoptotic pathways.

CCA-adding enzymes build and repair the 3'-terminal CCA sequence of tRNA. These unusual RNA polymerases use either a ribonucleoprotein template (class I) or pure protein template (class II) to form mock base pairs with the Watson-Crick edges of incoming CTP and ATP. Guided by the class II Bacillus stearothermophilus CCA-adding enzyme structure, we introduced mutations designed to reverse the polarity of hydrogen bonds between the nucleobases and protein template. We were able to transform the CCA-adding enzyme into a (U,G)-adding enzyme that incorporates UTP and GTP instead of CTP and ATP; we transformed the related Aquifex aeolicus CC- and A-adding enzymes into UU- and G-adding enzymes and Escherichia coli poly(A) polymerase into a poly(G) polymerase; and we transformed the B. stearothermophilus CCA-adding enzyme into a poly(C,A) polymerase by mutations in helix J that appear, based on the apoenzyme structure, to sterically limit addition to CCA. We also transformed the B. stearothermophilus CCA-adding enzyme into a dCdCdA-adding enzyme by mutating an arginine that interacts with the incoming ribose 2' hydroxyl. Most importantly, we found that mutations in helix J can affect the specificity of the nucleotide binding site some 20 Å away, suggesting that the specificity of both class I and II enzymes may be dictated by an intricate network of hydrogen bonds involving the protein, incoming nucleotide, and 3' end of the tRNA. Collaboration between RNA and protein in the form of a ribonucleoprotein template may help to explain the evolutionary diversity of the nucleotidyltransferase family.

The universal 3′-terminal CCA sequence of all transfer RNAs (tRNAs) is repaired, and sometimes constructed de novo, by the CCA-adding enzyme [ATP(CTP):tRNA nucleotidyltransferase]. This RNA polymerase has no nucleic acid template, yet faithfully builds the CCA sequence one nucleotide at a time using cytidine triphosphate (CTP) and adenosine triphosphate (ATP) as substrates. All previously characterized CCA-adding enzymes from all three kingdoms are single polypeptides with CCA-adding activity. Here, we demonstrate through biochemical and genetic approaches that CCA addition in Aquifex aeolicus requires collaboration between two related polypeptides, one that adds CC and another that adds A.

We propose a phylogeny for the evolution of tRNA that is based on the ubiquity and conservation of tRNA-like structures in the replication of contemporary genomes. This phylogeny is unique in suggesting that the function of tRNA in replication dates back to the very beginnings of life on earth, before the advent of templated protein synthesis. The origin we propose for tRNA has distinct implications for the order in which other components of the modern translational apparatus evolved. We further suggest that the \"top half\" of modern tRNA-a coaxial stack of the acceptor stem on the TΨ C arm-is the ancient structural and functional domain and that the \"bottom half\" of tRNA-a coaxial stack of the dihydrouracil arm on the anticodon arm-arose later to provide additional specificity.

More than 30% of the human genome consists of retroposed sequences—including retroposons and processed genes—but retroposition events are rare. New experimental methods that accelerate retroposition are now clarifying the mechanisms that shape the genome.