Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants.

Cys2-His2 zinc finger proteins (ZFPs) are the largest group of transcription factors in higher metazoans. A complete characterization of these ZFPs and their associated target sequences is pivotal to fully annotate transcriptional regulatory networks in metazoan genomes. As a first step in this process, we have characterized the DNA-binding specificities of 129 zinc finger sets from Drosophila using a bacterial one-hybrid system. This data set contains the DNA-binding specificities for at least one encoded ZFP from 70 unique genes and 23 alternate splice isoforms representing the largest set of characterized ZFPs from any organism described to date. These recognition motifs can be used to predict genomic binding sites for these factors within the fruit fly genome. Subsets of fingers from these ZFPs were characterized to define their orientation and register on their recognition sequences, thereby allowing us to define the recognition diversity within this finger set. We find that the characterized fingers can specify 47 of the 64 possible DNA triplets. To confirm the utility of our finger recognition models, we employed subsets of Drosophila fingers in combination with an existing archive of artificial zinc finger modules to create ZFPs with novel DNA-binding specificity. These hybrids of natural and artificial fingers can be used to create functional zinc finger nucleases for editing vertebrate genomes.

FlyFactorSurvey: a database of Drosophila transcription factor binding specificities determined using the bacterial one-hybrid system.

FlyFactorSurvey (http://pgfe.umassmed.edu/TFDBS/) is a database of DNA binding specificities for Drosophila transcription factors (TFs) primarily determined using the bacterial one-hybrid system. The database provides community access to over 400 recognition motifs and position weight matrices for over 200 TFs, including many unpublished motifs. Search tools and flat file downloads are provided to retrieve binding site information (as sequences, matrices and sequence logos) for individual TFs, groups of TFs or for all TFs with characterized binding specificities. Linked analysis tools allow users to identify motifs within our database that share similarity to a query matrix or to view the distribution of occurrences of an individual motif throughout the Drosophila genome. Together, this database and its associated tools provide computational and experimental biologists with resources to predict interactions between Drosophila TFs and target cis-regulatory sequences.

Antipsychotics and the Risk of Mortality or Cardiopulmonary Arrest in Hospitalized Adults.

OBJECTIVES: Prior studies in outpatient and long-term care settings demonstrated increased risk for sudden death with typical and atypical antipsychotics. To date, no studies have investigated this association in a general hospitalized population. We sought to evaluate the risk of death or nonfatal cardiopulmonary arrest in hospitalized adults exposed to antipsychotics. DESIGN: Retrospective cohort study. SETTING: Large academic medical center in Boston, Massachusetts. PARTICIPANTS: All hospitalizations between 2010 and 2016 were eligible for inclusion. We excluded those admitted directly to the intensive care unit (ICU), obstetric and gynecologic or psychiatric services, or with a diagnosis of a psychotic disorder. INTERVENTION: Typical and atypical antipsychotic administration, defined by pharmacy charges. MEASUREMENTS: The primary outcome was death or nonfatal cardiopulmonary arrest during hospitalization (composite). RESULTS: Of 150 948 hospitalizations in our cohort, there were 691 total events (515 deaths, 176 cardiopulmonary arrests). After controlling for comorbidities, ICU time, demographics, admission type, and other medication exposures, typical antipsychotics were associated with the primary outcome (hazard ratio [HR] = 1.6; 95% confidence interval [CI] = 1.1-2.4; P = .02), whereas atypical antipsychotics were not (HR = 1.1; 95% CI = .8-1.4; P = .5). When focusing on adults age 65 years and older, however, both typical and atypical antipsychotics were associated with increased risk of death or cardiopulmonary arrest (HR = 1.8; 95% CI = 1.1-2.9; and HR = 1.4; 95% CI = 1.1-2.0, respectively). Sensitivity analyses using a propensity score approach and a cohort of only patients with delirium both yielded similar results. CONCLUSION: In hospitalized adults, typical antipsychotics were associated with increased mortality or cardiopulmonary arrest, whereas atypical antipsychotics were only associated with increased risk among adults age 65 years and older. Providers should be thoughtful when prescribing antipsychotic medications, especially to older adults in settings where data regarding benefit are lacking. J Am Geriatr Soc 68:544-550, 2020.