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Lysine (Lys) residues in proteins undergo a wide range of reversible post-translational modifications (PTMs), which can regulate enzyme activities, chromatin structure, protein-protein interactions, protein stability, and cellular localization. Here we discuss the "writers," "erasers," and "readers" of some of the common protein Lys PTMs and summarize examples of their major biological impacts. We also review chemical biology approaches, from small-molecule probes to protein chemistry technologies, that have helped to delineate Lys PTM functions and show promise for a diverse set of biomedical applications. Zhipeng Wang and Philip Cole review major types of chemical modifications of the amino acid lysine in proteins and how they are added and removed. They also discuss a number of chemical approaches and how they have been applied to clarify the roles of lysine modifications in biology and medicine. [ABSTRACT FROM AUTHOR]

Akt1-3 (Akt) are a subset of the AGC protein Ser/Thr kinase family and play important roles in cell growth, metabolic regulation, cancer, and other diseases. We describe some of the roles of Akt in cell signaling and the biochemical and structural mechanisms of the regulation of Akt catalysis by the phospholipid PIP3 and by phosphorylation. Recent findings highlight a diverse set of strategies to control Akt catalytic activity to ensure its normal biological functions. [ABSTRACT FROM AUTHOR]

Objectives: In this paper we report the evaluation of a proprietary recall system for promoting compliance with recommended follow-up in high-risk patients. Methods: We conducted a retrospective chart review for patients of an active private colon and rectal surgery practice having colonoscopy in 2006. Patients selected were <80 years of age and assessed to be high-risk by findings at exam or personal/family history of colorectal neoplasm with a recommendation for follow-up surveillance colonoscopy ranging from months to 5 years. Up to 6 months from recommendation was considered to be within compliance. Results: A total of 795 patients met the inclusion criteria, with average age of 63.2 years, 422 (53.1%) being men. Compliance with surveillance colonoscopy recommendations was 62.5%. The recall system impacted patient behavior with compliant patients being sent a median of one letter (average, 1.5) and late or no follow-up patients being sent a median of 4 letters (average, 3.9). Conclusions: Multiple contacts with patients are required to improve compliance with surveillance. Our findings support at least 4 to 5 efforts to remind patients of the importance to schedule a colonoscopy is necessary to optimize compliance. [ABSTRACT FROM AUTHOR]

Epigenetic enzymes including histone modifying enzymes are key regulators of gene expression in normal and disease processes. Many drug development strategies to target histone modifying enzymes have focused on ligands that bind to enzyme active sites, but allosteric pockets offer potentially attractive opportunities for therapeutic development. Recent biochemical studies have revealed roles for small molecule and peptide ligands binding outside of the active sites in modulating the catalytic activities of histone modifying enzymes. Here we highlight several examples of allosteric regulation of epigenetic enzymes and discuss the biological significance of these findings. [ABSTRACT FROM AUTHOR]

Lysine acetyltransferase (KAT) enzymes including the p300, MYST, and GCN5 families play major roles in modulating the structure of chromatin and regulating transcription. Because of their dysregulation in various disease states including cancer, efforts to develop inhibitors of KATs have steadily gained momentum. Here we provide an overview of recent progress on the development of high quality chemical probes of the p300 and MYST family of KATs and how they are emerging as useful tools for basic and translational investigation. [ABSTRACT FROM AUTHOR]

Reversible protein phosphorylation is critically important in biology and medicine. Hundreds of thousands of sites of protein phosphorylation have been discovered but our understanding of the functions of the vast majority of these post-translational modifications is lacking. This review describes several chemical and biochemical methods that are under development and in current use to install phospho-amino acids and their mimics site-specifically into proteins. The relative merits of total chemical synthesis, semisynthesis, and nonsense suppression strategies for studying protein phosphorylation are discussed in terms of technical simplicity, scope, and versatility. [ABSTRACT FROM AUTHOR]

In this paper we discuss our experimental work in photoproducing two medically-useful radioisotopes (Zn(γ,p) Cu and Ca(γ,n)Ca → Sc) using an electron linear accelerator. We further address the issues of production and separation of medical isotopes arising from photoneutron (γ,n) and photoproton (γ,p) reactions. While (γ,n) reactions typically result in greater yields, separating product nuclides from the target is challenging since the chemical properties of both nuclides are identical. Although the yields of (γ,p) reactions are typically lower than for (γ,n), these proton-rich isotopes have the advantage that target and product nuclides belong to different chemical species allowing for more straightforward chemical separation. We conclude the paper by touching upon the dire necessity of experimentally revisiting a broad swath of photonuclear reactions in the 10- to 50-MeV regime. The very paucity of empirical cross-sectional data makes it altogether impossible to realistically predict accelerator-based photoproduction of many promising radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

The article discusses the understanding of p300/CBP coactivator including the novel technologies with emphasis on lysine acetylation. Topics discussed include duplication of the DNA sequence, nonhistone proteins that have well-characterized acetylation sites and the role of sirtuin deacetylase enzymes in linking lysine acetylation to energy balance.

Transcriptionally silent genes can be marked by histone modifications and regulatory proteins that indicate the genes' potential to be activated. Such marks have been identified in pluripotent cells, but it is unknown how such marks occur in descendant, multipotent embryonic cells that have restricted cell fate choices. We isolated mouse embryonic endoderm cells and assessed histone modifications at regulatory elements of silent genes that are activated upon liver or pancreas fate choices. We found that the liver and pancreas elements have distinct chromatin patterns. Furthermore, the histone acetyltransferase P300, recruited via bone morphogenetic protein signaling, and the histone methyltransferase Ezh2 have modulatory roles in the fate choice. These studies reveal a functional "prepattern" of chromatin states within multipotent progenitors and potential targets to modulate cell fate induction. [ABSTRACT FROM AUTHOR]

Abstract: Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biological pathways. This study investigates the proposed Theorell–Chance or “hit-and-run” catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a negatively charged surface on the enzyme to interact with the histone tail. [ABSTRACT FROM AUTHOR]

Abstract: Objective: : This paper reviews and evaluates two recent epidemiologic studies of formaldehyde exposure and lymphohematopoietic cancers. One is an update of mortality in a retrospective cohort study of industrial workers and the other is a proportional mortality and case-control study among embalmers. Both studies included subjects with considerable exposure to formaldehyde and both are focused on the myeloid leukemias. Methods: The principal epidemiologic methods and analyses used in the studies are described and evaluated. Additional measures of risk are presented. Results: Neither study reports a significant excess of mortality from any form of lymphohematopoietic cancer. However, both studies are interpreted by their authors as positive for an association between formaldehyde and the myeloid leukemias. This is based on weak and transitory associations seen in exposure–response analyses of relative risks. Issues are raised relating to the interpretation of these findings. Conclusion: There is no statistically significant absolute excess mortality from any lymphohematopoietic cancer in either study. The study of industrial workers showed only a weak and transitory relationship between peak exposure to formaldehyde and the myeloid leukemias. Limited exposure–response relationships for the myeloid leukemias in the case-control study of embalmers apparently have not been analyzed for statistical significance. These limited exposure–response relationships do not provide clear evidence of a causal relationship between formaldehyde and the myeloid leukemias. [ABSTRACT FROM AUTHOR]

Introduction: It has been suggested that smokeless tobacco (ST) use by young people induces them to become smokers, but direct evidence is lacking. [ABSTRACT FROM PUBLISHER]

Background: Compared with smoking, there is much less information about smokeless tobacco (ST) use in the United States. The purpose of this study is to characterize and compare ST use among American men in 2000 and 2005. Methods: We used US National Health Interview Surveys from 2000 and 2005 to estimate the prevalence of ST use, describe the demographic and socioeconomic profile of ST users and evaluate ST use according to product type and with respect to smoking. Results: The prevalence of ST use among American men was 4.4% in 2000 and 4.3% in 2005. Almost all ST users were white, about half were 25–44 years old and 80% lived in the South or Midwest, commonly in small metropolitan and rural areas. Educational and income levels of ST users were lower than those of never users of tobacco. One-third of ST users also smoked; cigarette consumption was lower among dual users than among exclusive smokers. In 2005, 1.3 million current ST users were former smokers but 3.2 million smokers were former ST users. ST users were evenly distributed between snuff (43%) and chewing tobacco (44%) in 2000 and 13% used both products. By 2005 snuff use was clearly dominant. Conclusions: The prevalence of ST use among men is low but stable; dual use of cigarettes and ST is common, and snuff has become the dominant ST product. [ABSTRACT FROM AUTHOR]

The explosion of scientific interest in protein kinase-mediated signaling networks has led to the infusion of new chemical methods and their applications related to the analysis of phosphorylation pathways. We highlight some of these chemical biology approaches across three areas. First, we discuss the development of chemical tools to modulate the activity of protein kinases to explore kinase mechanisms and their contributions to phosphorylation events and cellular processes. Second, we describe chemical techniques developed in the past few years to dissect the structural and functional effects of phosphate modifications at specific sites in proteins. Third, we cover newly developed molecular imaging approaches to elucidate the spatiotemporal aspects of phosphorylation cascades in live cells. Exciting advances in our understanding of protein phosphorylation have been obtained with these chemical biology approaches, but continuing opportunities for technological innovation remain. [ABSTRACT FROM AUTHOR]

Aims: To describe how snus use has reduced smoking among men in Sweden, and to estimate how smoking-attributable lung cancer mortality would decline in other European Union countries if they had the smoking prevalence of Sweden. Methods: Lung cancer mortality rates (LCMRs) and numbers of deaths among men and women age 45+ years in 25 EU countries in 2002 were obtained from the World Health Organization mortality database, and the number of lung cancer deaths expected in each country at the LCMR of Sweden was calculated. LCMRs for EU countries were obtained during the period 1950-2004, and per capita consumption of nicotine from cigarettes and snus was estimated for men in Sweden from 1931 to 2004. Results: There were 172,000 lung cancer deaths among men in the EU in 2002. If all EU countries had the LCMR of men in Sweden, there would have been 92,000 (54%) fewer deaths. In contrast, the LCMR among Swedish women was the sixth highest in the EU; at the Swedish rate, deaths among EU women would have increased by 14,500 (26%). These LCMR patterns were in place for most of the last 50 years, and LCMRs among Swedish men can be correlated with snus and cigarette consumption. Conclusions: This study shows that snus use has had a profound effect on smoking prevalence and LCMRs among Swedish men. While it cannot be proven that snus would have the same effect in other EU countries, the potential reduction in smoking-attributable deaths is considerable. [ABSTRACT FROM AUTHOR]

Abstract: Several retrospective cohort epidemiology studies evaluated a number of health outcomes in workers exposed to acrylonitrile (AN). The epidemiology studies included in this review have been published since 1970 and were identified through Ovid and MEDLINE retrieval services using search words “acrylonitrile and cancer”. We identified 26 studies which examined mortality and/or incidence rates among persons with AN exposure. Where cohorts have been updated the most recent data were relied upon but descriptions of the earlier publications are provided for background and rationale. Results are provided for all causes of death and all cancers. Detailed results and discussions are provided for the cancers which have received the most attention and for which some positive results have been reported. These include lung, bladder, prostate, and central nervous system cancers. In this review the four most informative cohort studies are evaluated and it is apparent that the results do not support a causal relationship between AN and all cancers or any specific type of cancer. IARC actually downgraded acrylonitrile from “probably carcinogenic” to “possibly carcinogenic to humans” finding that “the earlier indications of an increased risk among workers exposed to acrylonitrile were not confirmed by the recent, more informative studies”. This was one of few downgrades of classification by IARC. Our review of the epidemiology data is consistent with the conclusions of the earlier IARC review which found no consistent findings of increased cancer risk across studies. [Copyright &y& Elsevier]

The histone-modifying enzymes that catalyze reversible lysine acetylation and methylation are central to the epigenetic regulation of chromatin remodeling. From the early discovery of histone deacetylase inhibitors to the more recent identification of histone demethylase blockers, chemical approaches offer increasingly sophisticated tools for the investigation of the structure and function of these lysine-modifying enzymes. This review summarizes progress to date on compounds identified from screens or by design that can modulate the activity of classical histone deacetylases, sirtuins, histone acetyltransferases, histone methyltransferases and histone demethylases. We highlight applications of compounds to mechanistic and functional studies involving these enzymes and discuss future challenges regarding target specificity and general utility. [ABSTRACT FROM AUTHOR]

The recent discovery that histone demethylation can be catalyzed by the flavin-dependent amine oxidase LSD1 has ushered in a new chapter in the chromatin-remodeling community. Herein, we discuss the rapid progress of the histone demethylase field including the recent identification of the non-heme iron-dependent histone demethylases (JmjC family), the basis for LSD1 substrate site specificity and the newly emerging potential for inhibition of these enzymes in structural and functional analysis. [Copyright &y& Elsevier]

The proportion of Americans who smoke cigarettes has declined 50% since 1965. The effect on mortality of this considerable reduction has received little attention and is described in this study. U.S. national data were used to enumerate current, former, and never-smokers aged 35 years or older in 1987 and 2002. Mortality rate ratios were used to estimate smoking-attributable deaths among these groups, and corresponding age-adjusted smoking-attributable mortality rates (SAMRs) were calculated. There were 402,000 deaths attributable to smoking in 1987 and 322,000 in 2002. The SAMR for men aged 35 years or more was 556 deaths per 100,000 person-years in 1987, accounting for 24% of all male deaths. By 2002 the SAMR declined 41% to 329 and accounted for only 17% of deaths. The SAMR for women in 1987 was 175, accounting for 12% of deaths. By 2002 the SAMR among women had declined 30% to 122, representing 9% of deaths. The U.S. mortality rate attributable to smoking declined about 35% between 1987 and 2002. The impact of smoking on American society will diminish even further in the foreseeable future as smoking prevalence continues its decline among men and women. [ABSTRACT FROM AUTHOR]

By contrast with the smoked drum and other mechanical systems, modern electronic rhinomanometers provide superior sensitivity and frequency response. They enable accurate measurement of nasal airflow resistance to be made and are commercially available. In addition to a rhinomanometer, nasal airflow measurements require a face mask fitted with a flow measuring device (a pneumotach connected to an electronic differential pressure transducer) or, as an alternative to a face mask, a head-out body plethysmograph. Concurrently with nasal respiratory airflow, transnasal pressures between the nostril and pharynx are measured via nasal or oral tubing by a second differential pressure transducer. The transduced electronic analogue signals are digitized, and nasal airflow resistances are computed from the ratio between transnasal pressure and air flow. At a single sitting, a series of measurements with modern rhinomanometry can determine (1) the response to topical decongestant of the mucovascular contribution to nasal airflow resistance at the time of examination and (2) in the decongested nose, the presence, side, site, and severity of structural obstruction. Rhinomanometry is not "medically necessary" in assessment of all cases of nasal obstructive symptoms, but, in many situations, it can provide valuable objective information in compliance with the requirements of evidence-based medicine. This article includes a table listing situations in which rhinomanometry is particularly useful. [ABSTRACT FROM AUTHOR]

The adaptation of native chemical ligation to protein semisynthesis has become a powerful way to address problems in the analysis of protein structure and function. In particular, the exploitation of nature''s inteins in expressed protein ligation is now a standard approach in the study of proteins. Site-specific incorporation of unnatural amino acids, biophysical probes and post-translational modifications in proteins have led to new insights into enzyme mechanisms, protein folding, ion channel function, translation and signaling. [Copyright &y& Elsevier]

Abstract: We used 49 epidemiologic studies based on 84 papers published since 1950 to develop an array of meta-analyses relating exposure to chrome-six compounds with 10 causes of death. Most exposures occurred in occupational settings. Studies were assessed for quality, and for control of smoking or economic status if they related to lung or stomach cancer. There was no excess mortality from all causes combined among chrome-exposed persons. A minimal excess of cancer (SMR=112), overall, was due primarily to an excess of lung cancer (SMR=141) but the SMR was 112 among the better-quality, smoking-controlled studies. The overall SMR for stomach cancer was 113 but it was 82 among the studies that were controlled for economic status. Findings were unremarkable for the six other cancers evaluated: prostate, kidney, and central nervous system cancer and leukemia, Hodgkin’s disease and other lymphatohematopoietic cancer. This series of meta-analyses indicates that chrome-six is a weak cause of lung cancer and is not a cause of any of the other seven forms of cancer evaluated. [Copyright &y& Elsevier]

Formaldehyde has been the subject of numerous toxicological and epidemiological investigations for almost 25 years. Though most toxicology studies have focused on the effects of the chemical on the nasal tract and respiratory system, epidemiology investigations have been more extensive evaluating the association between formaldehyde and cancers not only of the nasal cavities, nasopharynx, and lung, but also of the brain, prostate, pancreas, and hematopoietic system. Recenetly, three studies have been published which report on the possible association between exposure to formaldehyde and an increased incidence of leukemia, specifically myeloid leukemia. The article summarizes the results of these three studies, evaluates the evidence for causality based on recognized epidemiologic criteria, and provides an assessment that the association between formaldehyde and the increased incidence of leukemia reported in these studies is not plausible. [Copyright &y& Elsevier]

An ATP-peptide conjugate was synthesized as a bisubstrate analogue inhibitor of the serine/threonine kinase protein kinase A. The compound was found to be a linear, competitive inhibitor with respect to ATP substrate, exhibiting a Ki of 3.8 μM. The compound was noncompetitive with respect to peptide substrate. The inhibitor was shown to be selective for protein kinase A versus the closely related protein kinase C as well as tyrosine kinase Csk. This analysis provides new evidence for the dissociative transition state of protein serine/threonine kinases and illustrates a simple method to convert a low affinity peptide substrate to a selective and moderately potent inhibitor for these enzymes. [Copyright &y& Elsevier]

2,3,7,8-tetrachlordibenzo-p-doxin (TCDD) would not have been designated as a Group 1 carcinogen by IARC had there not been a change in the criteria used for inclusion in this category. Furthermore, there is no precedent for indicating, as did IARC, that a single chemical acts as a pluripotential carcinogen by modestly increasing human risk for all cancer while not increasing the risk for any single cancer at least moderately. IARC moved TCDD to Group 1 based on mechanistic considerations focusing on the Ah receptor. However, while occupancy of the Ah receptor by TCDD may be necessary for its toxicity, it is not sufficient for toxicity or for potential carcinogenicity. Animal evidence relating TCDD exposure to cancer is much stronger than that for humans. However, the large inter-species variation in the relevant dose–response slopes severely limits generalizations from animals to humans. The epidemiologic studies of occupational exposures, pesticide applicators, and community exposures following industrial accidents, notably Seveso, have generated overall relative risks of all cancer of about 1.0. Only case-control studies of soft-tissue sarcoma and non-Hodgkin’s lymphoma, all by the same investigator, reported elevated risk from TCDD exposure. However, these results have not been replicated. The representation that a chemical compound (TCDD) would be a late-stage carcinogen for all types of cancer has no precedent and lacks biological foundation. Virtually all late-stage or promoting carcinogens (e.g., hepatitis-C virus, asbestos, and estrogens) cause a very limited number of forms of cancer. The exposure–response meta-analysis of TCDD and cancer developed by the United States Environmental Protection Agency (USEPA) is seriously compromised by its failure to adequately fit the data. The studies used by the USEPA also likely underestimate TCDD body burdens and may be confounded by smoking and other occupational exposures. Furthermore, the use of a linear dose–response model by the USEPA is scientifically unjustified since the underlying model of TCDD as a human carcinogen is based primarily on its supposed receptor-mediated, non-genotoxic (or promotional) mode of action. There are few examples of an agent being suspected as a human carcinogen for decades and then eventually moving into the category of “known” human carcinogens. In contrast, there are hundreds of compounds that remain for decades on lists of “suspected” human carcinogens despite the lack of confirming evidence. The long-term accumulation of negative, weak, and inconsistent findings suggests that TCDD eventually will be recognized as not carcinogenic for humans. [Copyright &y& Elsevier]

Linker modified novel bisubstrate analog inhibitors 4–7 for serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) have been designed and synthesized. Examination of these inhibitors with AANAT in vitro suggested that: (i) linker hydrogen bonding makes only modest contributions to the affinity of bisubstrate analog inhibitors studied; (ii) greater than or equal to four methylene groups between the indole and the coenzyme A (CoASH) moieties are required for a bisubstrate analog inhibitor to achieve strong AANAT inhibition; (iii) the AANAT active site appears not to accommodate positively charged linkers as well as neutral ones; and (iv) substrate amine pKa depression may constitute one strategy for AANAT substrate recognition and catalysis. The results reported here have enhanced our understanding of AANAT substrate recognition/catalysis, and are important for novel inhibitor design. Since AANAT belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily, our experimental strategies should find applications for other acetyltransferases. [Copyright &y& Elsevier]

Csk and Src are two protein tyrosine kinases with similar amino acid sequences but very different structures and functions. Csk catalyzes a tail phosphorylation reaction on Src and thereby restrains Src’s activity and oncogenic potential. Comparative analysis of the domain interactions in these enzymes provides a lesson in signalling diversity and mechanisms of enzyme regulation. The molecular basis of the specificity of Csk targeting the Src tail appears to involve both local and long-range interactions and illustrates the complexity of selective targeting in post-translational modification. [Copyright &y& Elsevier]

Protein kinases play critical roles in signal transduction pathways by transmitting extracellular signals across the cell membrane to distant locations in the cytoplasm and the nucleus. The development of protein kinase inhibitors has been hindered by the broad overlapping substrate specificities exhibited by these enzymes. The design of bisubstrate analog inhibitors could provide for the enhancement of specificity and potency in protein kinase inhibition. Bisubstrate analog inhibitors form a special group of protein kinase inhibitors that mimic two natural substrates/ligands and that simultaneously associate with two regions of given kinases. Most bisubstrate analogs have been designed to mimic the phosphate donor (ATP) and the acceptor components (Ser-, Thr-, or Tyr-containing peptides). Recent studies have emphasized the importance of maintaining a specific distance between these two components to achieve potent inhibition. In this review, we present a discussion of the methods for designing protein kinase inhibitors by mechanism-based approaches. Emphasis is given to bivalent approaches, with an interpretation of what has been learned from more and less successful examples. Future challenges in this area are also highlighted. [Copyright &y& Elsevier]

Investigates the incorporation of five unnatural tyrosine kinase analogs into protein substrate Src using expressed protein litigation. Rates of Csk-catalyzed phosphorylation of tyrosine analogs; Evaluation of semisynthetic substrates; Effects of tyrosine phenol hydroxyl on Src ground state binding affinity for Csk.

Compares the upper airway pressures in snorers and non-snorers during sleep and wakefulness. Similarity in the differential nasal and pharyngeal pressures in seated snorers and non-snorers, independent of head position; Significant increase in pharyngeal pressures in non-snorers due to assumption of recumbency; Increased sleep differential pharyngeal pressures in snorers when compared to quiet sleep.

The article talks about an enzyme called Bruton's tyrosine kinase which are antibodies that mark the pathogens for destruction but mutations in this enzyme are known to cause immunodeficiency disease called X-linked agammaglobulinemia and Hyperactive Btk contributes to disease causing cancerous B cells to proliferate which has motivated the development of drugs that target Btk called ibrutinib.

This report summarizes the deliberations of an eight-member panel of scientists convened by Dow AgroSciences in cooperation with the U.S. Environmental Protection Agency (EPA). The panel was charged with evaluating the scientific literature on the health effects potentially associated with exposure to the insecticide chlorpyrifos. Specifically, the panel was asked to (1) evaluate human experience data available and address the adequacy of the available current literature; (2) develop a list of recommendations for epidemiology studies, including appropriate endpoints and study populations, and strengths and weaknesses of each approach; and (3) draft a report to summarize its recommendations. The panel assessed the quality of the existing epidemiologic literature on chlorpyrifos and specific outcomes such as neuropathy (including organophosphate induced delayed neurotoxicity), behavior (cognition and affect), immunologic, and multiple complaints (also referred to as multiple chemical sensitivities). The majority of panel members (five members) agreed that the literature reviewed provided little or no scientific evidence that chlorpyrifos exposure causes harm to human health other than its known cholinergic effects associated with acute poisoning. Those panel members voting in the minority (three members) agreed that the studies reviewed provided inadequate evidence to preclude the possibility of adverse effects to human health from chlorpyrifos exposure at levels associated with its manufacture or professional application. Those voting in the minority suggested further investigation of cohort(s) of workers engaged in either the manufacture or the professional application of chlorpyrifos, or both. Compared to the general population, these groups have relatively high levels of exposure to chlorpyrifos. The primary health outcomes recommended for study were cognitive and affective disorders, with consideration of the assessment of peripheral neuropathy also suggested for at least a subset of the cohort. [ABSTRACT FROM AUTHOR]

Examines the domain interactions in protein tyrosine kinase C-terminal Src kinase (Csk). Identification of the three principal domains of Csk; Function of noncatalytic domains in Csk; Probe on the impact of the noncatalytic domains on kinase analysis.

Discusses the estimates of the intake of several dietary trace elements obtained during a study of the relationship between dietary trace elements and esophageal cancer mortality rate among Chinese farmers. Zinc; Copper; Iron; Cadmium; Nickel Molybdenum; Silicon; Selenium.

Analyzes a series of fluorotyrosine-containing peptide substrates, to investigate the catalytic phosphoryl transfer transition state of a protein tryosine kinase reaction. How the reaction was catalyzed; Identification of the important enzymes in cell signal transduction; Information on the nature of the transition state in protein kinase reactions; Usefulness of linear free-energy relationships.

The descriptive and analytic epidemiology of breast cancer is reviewed. A strong new indicator, age at first birth, has emerged. Lactation is not protective against breast cancer, but multiparity is associated with low breast cancer risk in a noncausal way. The major causal hypotheses are discussed. The first, genetic, is based on the familial aggregation of breast cancer, but there is no recognizable pattern of inheritance. The viral hypothesis remains unevaluated. The endocrine hypotheses, relating to progesterone, prolactin, androgens, and estrogens, are reviewed in detail. [ABSTRACT FROM AUTHOR]

Abstract: This study evaluates the National Toxicology Program’s Report on Carcinogens program (RoCP) and compares it with the International Agency for Research on Cancer Monographs Program (IMP). We tracked agents classified in the RoCP since 1983 as known human carcinogens (A-List), or as reasonably anticipated to be human carcinogens (B-List). The first A-list included 24 agents, and twenty-four unique agents were added in the following 28years; twenty were listed by IMP as Group 1 (carcinogenic to humans) 7years before their A-list appearance. Group 1 also includes 30 or more agents eligible for, but not on, the A-list. The first B-list included 98 agents, and this increased to 185. Of these, 39 are in Group 2A (probably carcinogenic), and 122 are in Group 2B (possibly carcinogenic). Only 5% of the 204 agents ever on the B-list have been upgraded to the A-list. The RoCP is severely limited because it evaluates few agents and because its B-list does not distinguish between probable and possible human carcinogens. Further, it mislabels likely non-carcinogens as reasonably anticipated to be carcinogens. If the RoCP were terminated there would be no loss or delay of information available to scientific, public health and regulatory communities. [Copyright &y& Elsevier]

Deals with the use of protein kinase chips to evaluate the protein kinases encoded by the yeast genome. Examination of kinases ability to phosphorylate using the chips; Processes involved in the assays of protein kinase activity; Information on how the protein chip technology works; Discussion on other techniques to assess protein kinase function.

The propagation of electrical signals in excitable cells is orchestrated by a molecular family of voltage-dependent ion channel proteins. These K+, Na+, and Ca++ channels are all composed of four identical or similar units, each containing six transmembrane segments (S1?S6) in a roughly four-fold symmetric structure. The S5?S6 sequences fold into a central pore unit, which is surrounded by a voltage-gating module composed of S1?S4. The recent structure of KcsA, a two-transmembrane bacterial K+ channel, illuminates the physical character of the pore unit, but little is known about the arrangement of the surrounding S1?S4 sequences. To locate regions of this gating module in space, we synthesized a series of compounds of varying length that function as molecular ‘tape measures’: quaternary ammonium (QA) pore blockers that can be tethered to specific test residues. We show that in a Shaker K+ channel, the extracellular ends of S1 and S3 are ∼30 Å from the tetraethylammonium (TEA) blocking site at the external opening of the pore. A portion of the S3-S4 loop is, at 17?18 Å, considerably closer. [ABSTRACT FROM AUTHOR]

Sirtuin 2 (Sirt2) is a member of the sirtuin family of NADdependent lysine deacylases and plays important roles in regulation of the cell cycle and gene expression. As a nucleocytoplasmic deacetylase, Sirt2 has been shown to target both histone and nonhistone acetylated protein substrates. The central catalytic domain of Sirt2 is flanked by flexible N and C termini, which vary in length and composition with alternative splicing. These termini are further subject to posttranslational modifications including phosphorylation. Here, we investigate the function of the N and C termini on deacetylation of nuclear substrates by Sirt2. Remarkably, we find that the C terminus autoinhibits deacetylation, while the N terminus enhances deacetylation of proteins and peptides, but not nucleosomes—a chromatin model substrate. Using protein semisynthesis, we characterize the effect of cell cycle-linked N-terminal phosphorylation at two major phosphorylation sites (Ser23/Ser25) and find that these further enhance protein/peptide deacetylation, with no effect on nucleosome deacetylation. Additionally, we find that VRK1, an established binding partner of both Sirt2 and nucleosomes, can stimulate deacetylation of nucleosomes by Sirt2, likely through an electrostatic mechanism. Taken together, these findings reveal multiple mechanisms regulating the activity of Sirt2, which allow for a broad range of activities across its multiple biological roles. [ABSTRACT FROM AUTHOR]

This article discusses research on breast self-examination (BSE). It summarizes existing studies on BSE including, "The Value of Breast Self-Examination," by C. M. Huguley and R. L. Brown and "Breast Self-examination and Medical Examination Related to Breast Cancer Stage," by R. T. Rossen et al, and points out their limitations. It attempts to reconcile the findings of these studies and concludes that women should be encouraged to conduct BSE and undergo mammography.