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We present a general framework for developing a machine learning (ML) tool that supports clinician assessment of patient risk using electronic health record-derived real-world data and apply the framework to a quality improvement use case in an oncology setting to identify patients at risk for a near-term (60 day) emergency department (ED) visit who could potentially be eligible for a home-based acute care program. Framework steps include defining clinical quality improvement goals, model development and validation, bias assessment, retrospective and prospective validation, and deployment in clinical workflow. In the retrospective analysis for the use case, 8% of patient encounters were associated with a high risk (pre-defined as predicted probability ≥20%) for a near-term ED visit by the patient. Positive predictive value (PPV) and negative predictive value (NPV) for future ED events was 26% and 91%, respectively. Odds ratio (OR) of ED visit (high- vs. low-risk) was 3.5 (95% CI: 3.4–3.5). The model appeared to be calibrated across racial, gender, and ethnic groups. In the prospective analysis, 10% of patients were classified as high risk, 76% of whom were confirmed by clinicians as eligible for home-based acute care. PPV and NPV for future ED events was 22% and 95%, respectively. OR of ED visit (high- vs. low-risk) was 5.4 (95% CI: 2.6–11.0). The proposed framework for an ML-based tool that supports clinician assessment of patient risk is a stepwise development approach; we successfully applied the framework to an ED visit risk prediction use case. [ABSTRACT FROM AUTHOR]

Online data collection has begun to revolutionize the behavioral sciences. However, conducting carefully controlled behavioral experiments online introduces a number of new of technical and scientific challenges. The project described in this paper, psiTurk, is an open-source platform which helps researchers develop experiment designs which can be conducted over the Internet. The tool primarily interfaces with Amazon's Mechanical Turk, a popular crowd-sourcing labor market. This paper describes the basic architecture of the system and introduces new users to the overall goals. psiTurk aims to reduce the technical hurdles for researchers developing online experiments while improving the transparency and collaborative nature of the behavioral sciences. [ABSTRACT FROM AUTHOR]

Left-handed Z-DNA is a higher-energy form of the double helix, stabilized by negative supercoiling generated by transcription or unwrapping nucleosomes. Regions near the transcription start site frequently contain sequence motifs favourable for forming Z-DNA, and formation of Z-DNA near the promoter region stimulates transcription. Z-DNA is also stabilized by specific protein binding; several proteins have been identified with low nanomolar binding constants. Z-DNA occurs in a dynamic state, forming as a result of physiological processes then relaxing to the right-handed B-DNA. Each time a DNA segment turns into Z-DNA, two B–Z junctions form. These have been examined extensively, but their structure was unknown. Here we describe the structure of a B–Z junction as revealed by X-ray crystallography at 2.6 Å resolution. A 15-base-pair segment of DNA is stabilized at one end in the Z conformation by Z-DNA binding proteins, while the other end remains B-DNA. Continuous stacking of bases between B-DNA and Z-DNA segments is found, with the breaking of one base pair at the junction and extrusion of the bases on each side (Fig. 1). These extruded bases may be sites for DNA modification. [ABSTRACT FROM AUTHOR]

Biologists were puzzled by the discovery of left-handed Z-DNA because it seemed unnecessary. Z-DNA was stabilized by the negative supercoiling generated by transcription, which indicated a transient localized conformational change. Few laboratories worked on the biology of Z-DNA. However, the discovery that certain classes of proteins bound to Z-DNA with high affinity and great specificity indicated a biological role. The most recent data show that some of these proteins participate in the pathology of poxviruses. [ABSTRACT FROM AUTHOR]

The first crystal structure of a protein, the Zα high affinity binding domain of the RNA editing enzyme ADAR1, bound to left-handed Z-DNA was recently described. The essential set of residues determined from this structure to be critical for Z-DNA recognition was used to search the database for other proteins with the potential for Z-DNA binding. We found that the tumor-associated protein DLM-1 contains a domain with remarkable sequence similarities to ZαADAR. Here we report the crystal structure of this DLM-1 domain bound to left-handed Z-DNA at 1.85 Å resolution. Comparison of Z-DNA binding by DLM-1 and ADAR1 reveals a common structure-specific recognition core within the binding domain. However, the domains differ in certain residues peripheral to the protein?DNA interface. These structures reveal a general mechanism of Z-DNA recognition, suggesting the existence of a family of winged-helix proteins sharing a common Z-DNA binding motif. [ABSTRACT FROM AUTHOR]

This study examined the reliability and construct validity of a modified version of the Colorado Symptom Index (MCSI), a brief, self-report measure of psychological symptomatology, in a study of interventions to prevent homelessness. Eight projects in a national, cooperative study collected new data at baseline, 6, and 12 months using a set of common measures as well as site-specific instruments. The pooled sample consisted of 1,381 persons in treatment for mental illness or substance abuse (or both), of which 84% had a history of homelessness. The analyses employed classical and Rasch methods to examine the MCSI's content validity, internal consistency and item quality, test/retest reliability, dimensionality, appropriateness for the sample, construct validity, and responsiveness to change. This 14-item scale was found to be a reliable and valid measure of psychological symptoms in this sample. Its content was consistent with other symptom measures, its high internal consistency and test-retest coefficients supported its reliability, its relationships to other measures indicated that it had good construct validity, and it was responsive to change. We conclude that the MCSI performed similarly to longer, more widely used measures of psychological symptomatology and could be useful in other studies targeting homeless adults with severe mental illness, substance use disorders, or both. [ABSTRACT FROM AUTHOR]

Human tRNA-specific adenosine deaminase (hADAT1) specifically converts A37 in the anticodon loop of human tRNAAla to inosine via a hydrolytic deamination mechanism. The enzyme is related to a family of RNA editing enzymes (ADARs) specific for pre-mRNA, and it has been cloned based on its sequence homology to the catalytic domain of ADARs. In the present study we have analyzed the 5′-flanking sequence of the murine ADAT1 gene, revealing that the first transcribed exon is located 1.1 kb downstream from the polyadenylation site of lysyl tRNA synthetase (KARS). The close proximity is conserved in the human genome with an intergenic distance of 5.5 kb. We determined the complete cDNA sequence as well as exon/intron organization of murine KARS. Significant sequence similarities between KARS and ADAT1 are apparent within their substrate interaction domains. Radiation hybrid panel analysis mapped human ADAT1 and human KARS to region q22.2–22.3 of Chromosome (Chr) 16 with alanyl tRNA synthetase (AARS) positioned centromeric to the KARS and ADAT1 genes. 16q22–24 has recently been recognized as a susceptibility candidate locus for several autoimmune inflammatory diseases. The clustering of three tRNA specific genes, of which two are specific for tRNAAla, may indicate their evolutionary relatedness or common factors involved in regulating their expression. [ABSTRACT FROM AUTHOR]

Z-DNA is a high energy conformer of B-DNA that forms in vivo during transcription as a result of torsional strain generated by a moving polymerase. An understanding of the biological role of Z-DNA has advanced with the discovery that the RNA editing enzyme double-stranded RNA adenosine deaminase type I (ADAR1) has motifs specific for the Z-DNA conformation. Editing by ADAR1 requires a double-stranded RNA substrate. In the cases known, the substrate is formed by folding an intron back onto the exon that is targeted for modification. The use of introns to direct processing of exons requires that editing occurs before splicing. Recognition of Z-DNA by ADAR1 may allow editing of nascent transcripts to be initiated immediately after transcription, ensuring that editing and splicing are performed in the correct sequence. Structural characterization of the Z-DNA binding domain indicates that it belongs to the winged helix-turn-helix class of proteins and is similar to the globular domain of histone-H5. [ABSTRACT FROM AUTHOR]

In eukaryotes, RNA processing events, including alternative splicing and RNA editing, can generate many different messages from a single gene. As a consequence, the RNA pool, which we refer to here as the 'ribotype', has a different information content from the genotype and can vary as circumstances change. The outcome of a single RNA processing event often regulates the outcome of another, giving rise to networks that affect the composition and expression of a particular ribotype. Successful ribotypes are determined by natural selection, and can be incorporated into the genome over time by reverse transcription. Eukaryotic evolution is therefore influenced by the alternate ways in which RNAs are processed and the continual interplay between RNA and DNA. [ABSTRACT FROM AUTHOR]

RNA editing alters pre-mRNA through site-selective adenosine deamination, which results in codon changes that lead to the production of novel proteins. An enzyme that catalyzes this reaction, double-stranded RNA adenosine deaminase (ADAR1), contains two N-terminal Z-DNA-binding motifs, Zα and Zβ, the function of which is as yet unknown. In this study, multidimensional NMR spectroscopy was used to show that the topology of Zα is α1β1α2α3β2β3. Long-range NOEs indicate that β1 and β3 interact with each other. Site-directed mutagenesis was used to identify residues in α3, β3 and the loop connecting β2 to β3 that affect Z-DNA binding. Also identified were 11 hydrophobic residues that are essential for protein stability. Comparison with known structures reveals some similarity between Zα and (α + β) helix—turn—helix proteins, such as histone 5 and the family of hepatocyte nuclear factor-3 winged-helix—turn—helix transcription factors. Taken together, the structural and functional data suggest that recognition of Z-DNA by Zα involves residues in both the α3 helix and the C-terminal β-sheet. [ABSTRACT FROM AUTHOR]

Many viruses regulate translation of polycistronic mRNA using a -1 ribosomal frameshift induced by an RNA pseudoknot. A pseudoknot has two stems that form a quasi-continuous helix and two connecting loops. A 1.6 Å crystal structure of the beet western yellow virus (BWYV) pseudoknot reveals rotation and a bend at the junction of the two stems. A loop base is inserted in the major groove of one stem with quadruple-base interactions. The second loop forms a new minor-groove triplex motif with the other stem, involving 2'-OH and triple-base interactions, as well as sodium ion coordination. Overall, the number of hydrogen bonds stabilizing the tertiary interactions exceeds the number involved in Watson?Crick base pairs. This structure will aid mechanistic analyses of ribosomal frameshifting. [ABSTRACT FROM AUTHOR]

At present we have some understanding about the mechanisms of prebiotic synthesis and polymerization. Experiments are also being carried out on the prebiotic replication of the nucleic acids. However, the greatest gap in our knowledge is the prebiotic mechanism for the polynucleotide directed synthesis of polypeptides. Some insight into potential mechanisms of this type is afforded by the recent determination of the three-dimensional structure of yeast phenylalanine rRNA. The poly-nucleotide chain id found to be highly folded and the molecule is found in an L shaped configuration. One end of the L shaped molecule contains the anticodon loop; that arm of the L is made of the double helical anticodon and dihydro U stems. The other end of the L shaped molecule contains the 3′OH adenosine to which the amino acid is added during aminoacylation. That arm of the L is built of the double helical CCA and TΨC stems. The corner of the L is formed by the close approximation of the TΨC loop and dihydro U loop. The distance between the anticodon and the 3′OH adenosine end of the molecule is 76 Å. Comments are made about the manner in which the tRNA molecule may have evolved and in addition, some suggestions are presented about the prebiotic interactions of primitive tRNA polynucleotides and messenger RNA strands. [ABSTRACT FROM AUTHOR]

Presents an obituary for biologist Francis Crick who died on July 28, 2004 at the age of 88.

Presents an obituary for Carl-Ivar Branden, an expert in biochemistry, who died on April 28, 2004.

Discusses the double helix structure of the DNA. Comparison of the structure of the DNA and the RNA; Information on the DNA-RNA hybrid helix; Details on the atomic resolution of the double helix structure of the DNA.

Reports on the death of chemist Linus Pauling on August 19, 1994. Contributions; Personal information; Published works.

Comments on the death of Robert W. Holley, a key figure in the establishment of the foundation for our understanding of how genetic information is expressed in living systems. Holley's isolation and determination of the nucleotide sequence of the first transfer RNA; Profile of Holley's work; Salk Institute; Holley's hobbies.