DNA-Compatible Copper/TEMPO Oxidation for DNA-Encoded Libraries.

Aldehydes are important synthons for DNA-encoded library (DEL) construction, but the development of a DNA-compatible method for the oxidation of alcohols to aldehydes remains a significant challenge in the field of DEL chemistry. We report that a copper/TEMPO catalyst system enables the solution-phase DNA-compatible oxidation of DNA-linked primary activated alcohols to aldehydes. The semiaqueous, room-temperature reaction conditions afford oxidation of benzylic, heterobenzylic, and allylic alcohols in high yield, with DNA compatibility verified by mass spectrometry, qPCR, Sanger sequencing, and ligation assays. Subsequent transformations of the resulting aldehydes demonstrate the potential of this method for robust library diversification.

Inattentiveness and Language Abilities in Preschoolers: A Latent Profile Analysis.

Growing evidence suggests that early symptoms of inattentiveness may affect the language development and academic success of young children. In the present study, we examined the extent to which profiles of inattentiveness and language could be discerned within a heterogeneous group of preschoolers attending early childhood special education programs (n = 461). Based on parent-reported observations of children's symptoms of inattentiveness and direct assessments of children's language skills (grammar, vocabulary, and narrative ability), three distinct profiles were identified. The three groups, representing levels of severity (at risk, almost average, above average), differed not only by their end of year performance, but also with respect to which their abilities changed over the course of the academic year. Children in the poorest performing profile had poorer mean scores in the spring of their preschool year on all measures, but exhibited patterns of gain that exceeded or equaled their peers in higher-performing groups, in the domains of vocabulary and grammar. Examination of subsequent kindergarten reading skills suggested that profile differences remained consistent. Findings underscore the associations between early symptoms of inattentiveness and language difficulties, and further indicate that these relations extend to the acquisition of early reading skills. Future research is needed to corroborate these findings with more robust measures of attention, and to understand the long-term associations between inattentiveness, language and literacy, and potential effects on these associations from early intervention.

Left main dissection and thrombosis in a young athlete.

Spontaneous coronary artery dissection is a rare but morbid event. We present the case of a previously healthy 38-year-old man who experienced severe chest discomfort while vigorously exercising. An acute anterolateral myocardial infarction was diagnosed. The patient underwent coronary angiography, demonstrating acute thrombosis of the left main coronary artery. The patient was referred for immediate bypass surgery. Examination of the left main coronary artery in the operating room revealed a dissection flap with thrombosis. With successful surgical intervention, the patient made an uneventful recovery. This case is discussed and the literature reviewed.

Parkinson's disease: focus on management alternatives.

AUDIENCE: This activity is designed for physicians, pharmacists, nurses, health planners, directors of managed care organizations, and payers of health services. GOAL: To understand the impact that Parkinson's disease has on patients and to identify areas of drug therapy that can be optimized to improve a patient's quality of life. OBJECTIVES: 1. Discuss the epidemiology and pathophysiology of idiopathic Parkinson's disease (IPD). 2. Identify causes of secondary parkinsonism and medications associated with drug-induced parkinsonism. 3. Discuss the cardinal and secondary manifestations of IPD. 4. Outline the 6 stages of IPD. 5. Identify therapeutic alternatives for various levodopa treatment failures. 6. Identify the 3 newer antiparkinson agents and state their mechanisms of action, common adverse effects, drug interactions, and appropriate use. 7. Identify the appropriate use, common adverse effects, and drug interactions of dopamine agonists, anticholinergic agents, monoamine oxidase inhibitors, and catechol-O-methyltransferase inhibitors in Parkinson's disease therapy.

An inhibitor of CD28-CD80 interactions impairs CD28-mediated costimulation of human CD4 T cells.

We have identified and characterized a microbial extract-derived inhibitor of T cell CD28-dependent costimulation, NP1835-2, utilizing an in vitro system in which anti-human CD3 antibody and a human CD80-Ig fusion protein are immobilized on protein A-coated microspheres. This system is CD28-CD80-dependent, as judged by the specific ability of anti-CD80 antibody or cytotoxic T lymphocyte antigen-4-Ig to block human CD4 T cell responses. Activation of CD4 T cells in this system in presence of NP1835-2 resulted in a concentration-dependent inhibition of T cell proliferation (IC50 of 1-4 microg/ml), surface activation marker expression, and the production of many T cell cytokines, with the exception of TGFbeta. Impairment of T cell activation correlated with a blockade of cell cycle progression at G0/G1 and was only partly restored by addition of 100 U/ml IL-2. No inhibition by NP1835-2 of T cell proliferation stimulated by plate-bound anti-CD3 antibody, phorbol 12-myristate 13-acetate + A23187, or P815 cells expressing the costimulatory molecule CD58 was observed. NP1835-2 was unable to modulate anti-IgM-stimulated B cell proliferation or LPS-induced monocyte activation. Suboptimal concentrations of NP1835-2 and cyclosporin together were able to impair T cell activation in an additive fashion. NP1835-2 was also able to inhibit the primary human MLR. These data indicate that NP1835-2 may belong to a class of molecules capable of selectively impairing CD28-mediated T cell costimulation and suggest its potential usefulness in the treatment of a variety of T cell-dependent diseases. Moreover, NP1835-2 may serve as a useful probe for investigating the mechanisms involved in T cell nonresponsiveness.

Regulation of granulocyte colony-stimulating factor gene expression by interleukin-17.

Interleukin-17 (IL-17) has been previously reported to induce stromal cells to produce a number of hematopoietic and proinflammatory cytokines, including granulocyte colony-stimulating factor (G-CSF). Here, we have evaluated the mechanisms responsible for the augmentation of G-CSF gene expression by IL-17, using the murine 3T3 fibroblast cell line. Treatment of 3T3 cells, but not primary bone marrow-derived macrophages or murine monocyte/macrophage cell lines, resulted in increased steady-state G-CSF mRNA levels within 2-4 h and augmented G-CSF protein production. The combination of IL-17 and LPS enhanced G-CSF expression in an additive fashion. Stability studies revealed that IL-17 stabilized G-CSF mRNA levels, with a t1/2 of 4 h, compared to a t1/2 of less than 2 h in medium or LPS-treated cells. Induction of G-CSF expression in 3T3 cells by IL-17 did not appear to require tyrosine kinase activation or de novo protein synthesis. These studies indicate that post-transcriptional mechanisms play an important role in IL-17-induced G-CSF expression in fibroblasts and suggest that IL-17 may be useful for further delineating mechanisms of G-CSF gene regulation.

A specific stimulator of granulocyte colony-stimulating factor accelerates recovery from cyclophosphamide-induced neutropenia in the mouse.

We have identified a small molecular weight compound, SCH 14988, which specifically stimulates in vitro granulocyte-colony stimulating factor (G-CSF) production from activated human peripheral blood mononuclear cells and monocytes but not other cytokines or CSFs with hematoregulatory activity. In vivo administration of SCH 14988 to mice rendered neutropenic by cyclophosphamide treatment resulted in the accelerated recovery of the peripheral neutrophil compartment. This activity correlated with increased in vivo G-CSF levels and stimulation of marrow granulopoiesis, and was comparable to that of exogenously administered recombinant human G-CSF. No alterations to other leukocyte populations in peripheral blood, spleen, or the peritoneal cavity were observed. These findings suggest that SCH 14988 may be clinically useful to enhance neutrophil granulopoiesis, as well as to study the mechanisms involved in G-CSF gene regulation.

Effect of vocal disguise on estimations of speakers' ages.

To determine the effect of speakers' attempts to disguise their voices on listeners' accuracy in age judgments, 26 speakers, 13 females and 13 males, recorded six sentences under three conditions: (a) in a normal manner, actually were, and (c) in a manner in which they attempted to sound much older than they actually were. Three master tapes were constructed, one for each of the three conditions. A total of 20 judges, 10 females and 10 males, participated in three sessions, one for each of the three master tapes. In each session they were asked to judge the age of the speaker of each sentence and, using a seven-point confidence rating scale, to indicate the over-all confidence in their judgments at the end of each session. Although a majority of speakers yielded age estimates consistent with the conditions of intended disguise, the differences in listeners' estimates among all three conditions were relatively small. Moreover, differences between speakers' actual ages and listeners' age estimates in the control condition were also small. Implications of the findings and suggestions for research are discussed.