An integrated clinical approach to children at genetic risk for neurodevelopmental and psychiatric conditions: interdisciplinary collaboration and research infrastructure.

Background: A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary 'genetic-diagnosis-first' clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians.

Predictors of valproic acid steady-state serum levels in adult and pediatric psychiatric inpatients: a comparative analysis.

Rationale: Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined.

Objectives: To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients.

Support to caregivers who have received genetic information about neurodevelopmental and psychiatric vulnerability in their young children: A narrative review.

Diagnosis of pathogenic genetic variants associated with neurodevelopmental and psychiatric disorders (NPDs) is increasingly made early in life. This narrative review focuses on the need for, and provision of, psychological supports following genetic diagnosis. We conducted a literature search of publications on how caregivers are informed about the NPD vulnerability associated with genetic variants, challenges and unmet needs when receiving this information, and whether psychological supports are provided.

Endometrial Cancer Surgery for Elderly Women--The Early Postoperative Period.

Objective: The aim of this study was to examine the early postoperative period and assess whether elderly patients recuperate differently than do their younger counterparts after surgery for endometrial cancer.

Methods: This retrospective chart review comprised all women older than 75 years who underwent laparotomy for endometrial cancer staging at our center from January 2005 through December 2010 and a consecutive control group of women younger than 74 years. Parameters included demographic variables, surgical procedure/findings, postoperative morbidity, and pathology.

A structural analysis of the group II intron active site and implications for the spliceosome.

Group II introns are self-splicing, mobile genetic elements that have fundamentally influenced the organization of terrestrial genomes. These large ribozymes remain important for gene expression in almost all forms of bacteria and eukaryotes and they are believed to share a common ancestry with the eukaryotic spliceosome that is required for processing all nuclear pre-mRNAs. The three-dimensional structure of a group IIC intron was recently determined by X-ray crystallography, making it possible to visualize the active site and the elaborate network of tertiary interactions that stabilize the molecule.

A DEAD-box protein alone promotes group II intron splicing and reverse splicing by acting as an RNA chaperone.

Group II intron RNAs self-splice in vitro but only at high salt and/or Mg2+ concentrations and have been thought to require proteins to stabilize their active structure for efficient splicing in vivo. Here, we show that a DEAD-box protein, CYT-19, can by itself promote the splicing and reverse splicing of the yeast aI5gamma and bI1 group II introns under near-physiological conditions by acting as an ATP-dependent RNA chaperone, whose continued presence is not required after RNA folding. Our results suggest that the folding of some group II introns may be limited by kinetic traps and that their active structures, once formed, do not require proteins or high Mg2+ concentrations for structural stabilization.

The splicing of yeast mitochondrial group I and group II introns requires a DEAD-box protein with RNA chaperone function.

Group I and II introns self-splice in vitro, but require proteins for efficient splicing in vivo, to stabilize the catalytically active RNA structure. Recent studies showed that the splicing of some Neurospora crassa mitochondrial group I introns additionally requires a DEAD-box protein, CYT-19, which acts as an RNA chaperone to resolve nonnative structures formed during RNA folding. Here we show that, in Saccharomyces cerevisiae mitochondria, a related DEAD-box protein, Mss116p, is required for the efficient splicing of all group I and II introns, some RNA end-processing reactions, and translation of a subset of mRNAs, and that all these defects can be partially or completely suppressed by the expression of CYT-19.

Abortive transposition by a group II intron in yeast mitochondria.

Group II intron homing in yeast mitochondria is initiated at active target sites by activities of intron-encoded ribonucleoprotein (RNP) particles, but is completed by competing recombination and repair mechanisms. Intron aI1 transposes in haploid cells at low frequency to target sites in mtDNA that resemble the exon 1-exon 2 (E1/E2) homing site. This study investigates a system in which aI1 can transpose in crosses (i.

The risk of aspiration of pureed food as determined by flexible endoscopic evaluation of swallowing with sensory testing.

Objective: This study evaluates the risk of aspiration of pureed foods in patients with dysphagia with increasing sensory deficits of the hypopharynx with intact versus impaired pharyngeal muscular tone (pharyngeal squeeze).

Study Design: Two hundred four dysphagic patients underwent flexible endoscopic evaluation of swallowing with sensory testing and were prospectively divided into 3 groups, with normal, moderate, and severe sensory deficits. Each group was divided into those with normal and those with impaired pharyngeal squeeze.

The DIVa maturase binding site in the yeast group II intron aI2 is essential for intron homing but not for in vivo splicing.

Splicing of the Saccharomyces cerevisiae mitochondrial DNA group II intron aI2 depends on the intron-encoded 62-kDa reverse transcriptase-maturase protein (p62). In wild-type strains, p62 remains associated with the excised intron lariat RNA in ribonucleoprotein (RNP) particles that are essential for intron homing. Studies of a bacterial group II intron showed that the DIVa substructure of intron domain IV is a high-affinity binding site for its maturase.

A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae.

The yeast mitochondrial chaperonin Hsp60 has previously been implicated in mitochondrial DNA (mtDNA) transactions: it is found in mtDNA nucleoids associated with single-stranded DNA; it binds preferentially to the template strand of active mtDNA ori sequences in vitro; and wild-type (rho+) mtDNA is unstable in hsp60 temperature-sensitive (ts) mutants grown at the permissive temperature. Here we show that the mtDNA instability is caused by a defect in mtDNA transmission to daughter cells. Using high resolution, fluorescence deconvolution microscopy, we observe a striking alteration in the morphology of mtDNA nucleoids in rho+ cells of an hsp60-ts mutant that suggests a defect in nucleoid division.

Reverse transcriptase and reverse splicing activities encoded by the mobile group II intron cobI1 of fission yeast mitochondrial DNA.

Mobile group II introns encode multidomain proteins with maturase activity involved in splicing and reverse transcriptase (RT) and (often) endonuclease activities involved in intron mobility. These activities are present in a ribonucleoprotein complex that contains the excised intron RNA and the intron-encoded protein. Here, we report biochemical studies of the protein encoded by the group IIA1 intron in the cob gene of fission yeast Schizosaccharomyces pombe mitochondria (cobI1).

The association between laryngopharyngeal sensory deficits, pharyngeal motor function, and the prevalence of aspiration with thin liquids.

Objective: The study goal was to evaluate the association among laryngopharyngeal sensory deficits, pharyngeal motor function, and the prevalence of aspiration with thin liquids.

Study Design And Setting: We conducted a prospective study of 204 consecutive patients undergoing flexible endoscopic evaluation of swallowing with sensory testing and an assessment of pharyngeal motor function (pharyngeal squeeze). Patients were divided into 6 groups depending on the results of sensory and motor testing in the laryngopharynx.

The safety of flexible endoscopic evaluation of swallowing with sensory testing in an outpatient otolaryngology setting.

Objective: To study the safety of flexible endoscopic evaluation of swallowing with sensory testing in a private otolaryngology office setting.

Study Design: Five parameters were prospectively evaluated. These included airway compromise, epistaxis, change in heart rate, level of discomfort, and patient's willingness to repeat the examination in the future.

Bacterial group II introns in a deep-sea hydrothermal vent environment.

Group II introns are catalytic RNAs and mobile retrotransposable elements known to be present in the genomes of some nonmarine bacteria and eukaryotic organelles. Here we report the discovery of group II introns in a bacterial mat sample collected from a deep-sea hydrothermal vent near 9 degrees N on the East Pacific Rise. One of the introns was shown to self-splice in vitro.

Mitochondrial DNA instability mutants of the bifunctional protein Ilv5p have altered organization in mitochondria and are targeted for degradation by Hsp78 and the Pim1p protease.

Ilv5p is a bifunctional mitochondrial protein in Saccharomyces cerevisiae required for branched-chain amino acid biosynthesis and for the stability of wild-type (rho(+)) mitochondrial DNA (mtDNA). Mutant forms of Ilv5p defective in mtDNA stability (a(+)D(-)) are present as 5-10 punctate structures in mitochondria, whereas mutants lacking enzymatic function (a(-)D(+)) show a reticular distribution, as does wild-type Ilv5p. a(+)D(-) ilv5 mutations are recessive, and the mutant protein is redistributed to a reticular form when co-expressed with wild-type Ilv5p.

Mutational bisection of the mitochondrial DNA stability and amino acid biosynthetic functions of ilv5p of budding yeast.

Ilv5p is a bifunctional yeast mitochondrial enzyme required for branched chain amino acid biosynthesis and for the stability of mitochondrial DNA (mtDNA) and its parsing into nucleoids. The latter occurs when the general amino acid control (GAC) pathway is activated. We have isolated ilv5 mutants that lack either the enzymatic (a(-)D(+)) or the mtDNA stability function (a(+)D(-)) of the protein.

Control of branch-site choice by a group II intron.

The branch site of group II introns is typically a bulged adenosine near the 3'-end of intron domain 6. The branch site is chosen with extraordinarily high fidelity, even when the adenosine is mutated to other bases or if the typically bulged adenosine is paired. Given these facts, it has been difficult to discern the mechanism by which the proper branch site is chosen.

Retrotransposition of a yeast group II intron occurs by reverse splicing directly into ectopic DNA sites.

Group II introns, the presumed ancestors of nuclear pre-mRNA introns, are site-specific retroelements. In addition to "homing" to unoccupied sites in intronless alleles, group II introns transpose at low frequency to ectopic sites that resemble the normal homing site. Two general mechanisms have been proposed for group II intron transposition, one involving reverse splicing of the intron RNA directly into an ectopic DNA site, and the other involving reverse splicing into a site in RNA followed by reverse transcription and integration of the resulting cDNA by homologous recombination.

Laryngopharyngeal sensory deficits as a predictor of aspiration.

Objective: This study evaluates whether patients with severe sensory deficits in the hypopharynx are at increased risk for aspiration and determines the relationship between pharyngeal muscular weakness and hypopharyngeal sensory deficits.

Study Design And Setting: Forty patients with dysphagia who underwent flexible endoscopic evaluation of swallowing with sensory testing were prospectively divided into 2 groups. One group included patients with severe sensory deficits determined by an absent laryngeal adductor reflex and the other with normal sensitivity.

Replication and preferential inheritance of hypersuppressive petite mitochondrial DNA.

Wild-type yeast mitochondrial DNA (mtDNA) is inherited biparentally, whereas mtDNA of hypersuppressive petite mutants is inherited uniparentally in crosses to strains with wild-type mtDNA. Genomes of hypersuppressive petites contain a conserved ori sequence that includes a promoter, but it is unclear whether the ori confers a segregation or replication advantage. Fluorescent in situ hybridization analysis of wild-type and petite mtDNAs in crosses reveals no preferential segregation of hypersuppressive petite mtDNA to first zygotic buds.