An Integrated Developmental Approach to Personality Disorders in Adolescence: Expanding Kernberg's Object Relations Theory.

This article is a tribute to Dr. Otto F. Kernberg and his contribution to the theoretical understanding of personality pathology in adolescence.

Transference-Focused Psychotherapy for Adolescents With Personality Disorders.

This article presents a conceptualization of personality disorders in adolescence and the adaptation of transference-focused psychotherapy (TFP) for personality disordered adolescents (TFP-A). The model of assessment and treatment presented is based on contemporary psychoanalytic object relations theory developed by Otto F. Kernberg and supported by findings from current evidence-based outcome research.

Psychotherapy for Borderline Personality Disorder in Adolescents.

Research on borderline personality disorder (BPD) in adolescence has helped to clarify the characteristics of BPD in young people. The considerable emotional and economic cost associated with adolescent BPD supports calls for early intervention and requires that the assessment of personality functioning be an essential component in the psychological evaluation of adolescents. Adult treatment models with demonstrated efficacy have been adapted for adolescents.

TFOS DEWS II iatrogenic report.

Dry eye can be caused by a variety of iatrogenic interventions. The increasing number of patients looking for eye care or cosmetic procedures involving the eyes, together with a better understanding of the pathophysiological mechanisms of dry eye disease (DED), have led to the need for a specific report about iatrogenic dry eye within the TFOS DEWS II. Topical medications can cause DED due to their allergic, toxic and immuno-inflammatory effects on the ocular surface.

PGBD5: a neural-specific intron-containing piggyBac transposase domesticated over 500 million years ago and conserved from cephalochordates to humans.

Background: piggyBac domain (PGBD) transposons are found in organisms ranging from fungi to humans. Three domesticated piggyBac elements have been described. In the ciliates Paramecium tetraurelia and Tetrahymena thermophila, homologs known as piggyMacs excise internal eliminated sequences from germline micronuclear DNA during regeneration of the new somatic macronucleus.

What role (if any) does the highly conserved CSB-PGBD3 fusion protein play in Cockayne syndrome?

The PGBD3 piggyBac transposon inserted into CSB intron 5 early in the primate lineage. As a result of alternative splicing, the human CSB gene now encodes three proteins: CSB, a CSB-PGBD3 fusion protein that joins the N-terminal CSB domain to the C-terminal PGBD3 transposase domain, and PGBD3 transposase. The fusion protein is as highly conserved as CSB, suggesting that it is advantageous in health; however, expression of the fusion protein in CSB-null cells induces a constitutive interferon (IFN) response.

Tethering of the conserved piggyBac transposase fusion protein CSB-PGBD3 to chromosomal AP-1 proteins regulates expression of nearby genes in humans.

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.

The conserved Cockayne syndrome B-piggyBac fusion protein (CSB-PGBD3) affects DNA repair and induces both interferon-like and innate antiviral responses in CSB-null cells.

Cockayne syndrome is a segmental progeria most often caused by mutations in the CSB gene encoding a SWI/SNF-like ATPase required for transcription-coupled DNA repair (TCR). Over 43Mya before marmosets diverged from humans, a piggyBac3 (PGBD3) transposable element integrated into intron 5 of the CSB gene. As a result, primate CSB genes now generate both CSB protein and a conserved CSB-PGBD3 fusion protein in which the first 5 exons of CSB are alternatively spliced to the PGBD3 transposase.

Advancements in ocular drug delivery.

This review covers both noninvasive and invasive ophthalmic drug delivery systems that can have application to therapy of veterinary ophthalmic diseases. Noninvasive approaches include gel technologies, permeation enhancement via pro-drug development, solubilization agents and nanoparticle technologies, iontophoresis, microneedles, drug-eluting contact lenses and eye misters, and microdroplets. More invasive systems include both eroding implants and noneroding technologies that encompass diffusion based systems, active pumps, intraocular lenses, suprachoroidal drug delivery, and episcleral reservoirs.

Ubiquitin recognition by the Cockayne syndrome group B protein: binding will set you free.

Transcription-coupled nucleotide excision repair (TC-NER) requires the coordinated efforts of many proteins. In this issue of Molecular Cell, Anindya et al. (2010) show that the proteins assemble at the site of DNA damage but cannot begin repair until the Cockayne syndrome group B protein (CSB) binds ubiquitin.

On the role of a conserved, potentially helix-breaking residue in the tRNA-binding alpha-helix of archaeal CCA-adding enzymes.

Archaeal class I CCA-adding enzymes use a ribonucleoprotein template to build and repair the universally conserved 3'-terminal CCA sequence of the acceptor stem of all tRNAs. A wealth of structural and biochemical data indicate that the Archaeoglobus fulgidus CCA-adding enzyme binds primarily to the tRNA acceptor stem through a long, highly conserved alpha-helix that lies nearly parallel to the acceptor stem and makes many contacts with its sugar-phosphate backbone. Although the geometry of this alpha-helix is nearly ideal in all available cocrystal structures, the helix contains a highly conserved, potentially helix-breaking proline or glycine near the N terminus.

Controlled flow-through dissolution methodology: a high-performance system.

Measuring release rates using compendial systems, especially for sparingly soluble compounds, often produces complex results with less than desired precision and lacks relevance to key formulation or biological parameters. A flow-through approach was used by focusing on convective diffusion and controlling certain key physical-chemical factors. Results are presented for an automated multisample flow-through system that displays significant advantages over compendial (1) stirred and (2) flow-through systems.

Human U2 snRNA genes exhibit a persistently open transcriptional state and promoter disassembly at metaphase.

In mammals, small multigene families generate spliceosomal U snRNAs that are nearly as abundant as rRNA. Using the tandemly repeated human U2 genes as a model, we show by footprinting with DNase I and permanganate that nearly all sequences between the enhancer-like distal sequence element and the initiation site are protected during interphase whereas the upstream half of the U2 snRNA coding region is exposed. We also show by chromatin immunoprecipitation that the SNAPc complex, which binds the TATA-like proximal sequence element, is removed at metaphase but remains bound under conditions that induce locus-specific metaphase fragility of the U2 genes, such as loss of CSB, BRCA1, or BRCA2 function, treatment with actinomycin D, or overexpression of the tetrameric p53 C terminus.

An abundant evolutionarily conserved CSB-PiggyBac fusion protein expressed in Cockayne syndrome.

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.

Reengineering CCA-adding enzymes to function as (U,G)- or dCdCdA-adding enzymes or poly(C,A) and poly(U,G) polymerases.

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.

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling.

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.

A model for C74 addition by CCA-adding enzymes: C74 addition, like C75 and A76 addition, does not involve tRNA translocation.

The CCA-adding enzyme adds CCA to the 3'-end of tRNA one nucleotide at a time, using CTP and ATP as substrates. We found previously that tRNA does not rotate or translocate on the enzyme during the addition of C75 and A76. We therefore predicted that the growing 3'-end of tRNA must, upon addition of each nucleotide, refold to reposition the new 3'-hydroxyl equivalently relative to the solitary nucleotidyltransferase motif.

E Pluribus Unum: 3' end formation of polyadenylated mRNAs, histone mRNAs, and U snRNAs.

The 3' ends of almost all eukaryotic RNAs are generated by nucleolytic cleavage. Remarkably, three groups now demonstrate that similar or identical endonucleases of the metallo-beta-lactamase family generate the 3' ends of polyadenylated mRNAs, nonpolyadenylated histone mRNAs, and U snRNAs.

L2L: a simple tool for discovering the hidden significance in microarray expression data.

L2L is a database consisting of lists of differentially expressed genes compiled from published mammalian microarray studies, along with an easy-to-use application for mining the database with the user's own microarray data. As illustrated by re-analysis of a recent study of diabetic nephropathy, L2L identifies novel biological patterns in microarray data, providing insights into the underlying nature of biological processes and disease. L2L is available online at the authors' website [http://depts.

Archaeal CCA-adding enzymes: central role of a highly conserved beta-turn motif in RNA polymerization without translocation.

The CCA-adding enzyme (tRNA nucleotidyltransferase) builds and repairs the 3' end of tRNA. A single active site adds both CTP and ATP, but the enzyme has no nucleic acid template, and tRNA does not translocate or rotate during C75 and A76 addition. We modeled the structure of the class I archaeal Sulfolobus shibatae CCA-adding enzyme on eukaryotic poly(A) polymerase and mutated residues in the vicinity of the active site.

tRNA maturation: RNA polymerization without a nucleic acid template.

The CCA-adding enzyme, which builds and repairs the 3' terminal CCA sequence of tRNA, is the only RNA polymerase that can synthesize a defined nucleotide sequence without using a nucleic acid template. New cocrystal structures tell us how this remarkable enzyme works.

A single catalytically active subunit in the multimeric Sulfolobus shibatae CCA-adding enzyme can carry out all three steps of CCA addition.

The CCA-adding enzyme ATP(CTP):tRNA nucleotidyltransferase builds and repairs the 3'-terminal CCA sequence of tRNA. Although this unusual RNA polymerase has no nucleic acid template, it can construct the CCA sequence one nucleotide at a time using CTP and ATP as substrates. We found previously that tRNA does not translocate along the enzyme during CCA addition (Yue, D.

Comparison of the diurnal ocular hypotensive efficacy of travoprost and latanoprost over a 44-hour period in patients with elevated intraocular pressure.

Background: Prostaglandin analogues are effective ocular hypotensive agents and are being used increasingly in the treatment of elevated intraocular pressure (IOP). These agents are typically dosed once daily.

Objectives: A pilot study was conducted to evaluate the duration of travoprost's IOP-lowering efficacy up to 84 hours after the final dose in patients with open-angle glaucoma.