Book Reviews

Reviews of the following books: Ordinary People and Everyday Life edited by James B. Gardner and George Rollie Adams; Those Who Stayed Behind: Rural Society in Nineteenth Century New England by Hal S. Barro

Specificity and Mechanism of Mandelamide Hydrolase Catalysis

The best-studied amidase signature (AS) enzyme is probably fatty acid amide hydrolase (FAAH). Closely related to FAAH is mandelamide hydrolase (MAH), whose substrate specificity and mechanism of catalysis are described in this paper. First, we developed a convenient chromogenic substrate, 4-nitrophenylacetamide, for MAH. The lack of reactivity of MAH with the corresponding ethyl ester confirmed the very limited size of the MAH leaving group site. The reactivity of MAH with 4-nitrophenyl acetate and methyl 4-nitrophenyl carbonate, therefore, suggested formation of an “inverse” acyl-enzyme where the small acyl-group occupies the normal leaving group site. We have interpreted the specificity of MAH for phenylacetamide substrates and small leaving groups in terms of its active site structure, using a homology model based on a FAAH crystal structure. The relevant structural elements were compared with those of FAAH. Phenylmethylboronic acid is a potent inhibitor of MAH (Ki = 27 nM), presumably because it forms a transition state analogue structure with the enzyme. O-Acyl hydroxamates were not irreversible inactivators of MAH but some were found to be transient inhibitors

Impact of Tumor Size on Probability of Pathologic Complete Response After Neoadjuvant Chemotherapy

BACKGROUND: The prospective Neoadjuvant Breast Symphony Trial (NBRST) study found that MammaPrint/BluePrint functional molecular subtype is superior to conventional immunohistochemistry/fluorescence in situ hybridization subtyping for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy. The purpose of this substudy was to determine if the rate of pCR is affected by tumor size. METHODS: The NBRST study includes breast cancer patients who received neoadjuvant chemotherapy. MammaPrint/BluePrint subtyping classified patients into four molecular subgroups: Luminal A, Luminal B, HER2 (human epidermal growth factor receptor 2), and Basal type. Probability of pCR (ypT0/isN0) as a function of tumor size and molecular subgroup was evaluated. RESULTS: A total of 608 patients were evaluable with overall pCR rates of 28.5 %. Luminal A and B patients had significantly lower rates of pCR (6.1 and 8.7 %, respectively) than either basal (37.1 %) or HER2 (55.0 %) patients (p < 0.001). The probability of pCR significantly decreased with tumor size >5 cm [p = 0.022, odds ratio (OR) 0.58, 95 % confidence interval (CI) 0.36, 0.93]. This relationship was statistically significant in the Basal (p = 0.026, OR 0.46, 95 % CI 0.23, 0.91) and HER2 (p = 0.039, OR 0.36, 95 % CI 0.14, 0.95) subgroups. In multivariate logistic regression analyses, the dichotomized tumor size variable was not significant in any of the molecular subgroups. DISCUSSION: Even though tumor size would intuitively be a clinical determinant of pCR, the current analysis showed that the adjusted OR for tumor size was not statistically significant in any of the molecular subgroups. Factors significantly associated with pCR were PR status, grade, lymph node status, and BluePrint molecular subtyping, which had the strongest correlation

Deploying aptameric sensing technology for rapid pandemic monitoring

The genome of virulent strains may possess the ability to mutate by means of antigenic shift and/or antigenic drift as well as being resistant to antibiotics with time. The outbreak and spread of these virulent diseases including avian influenza (H1N1), severe acute respiratory syndrome (SARS-Corona virus), cholera (Vibrio cholera), tuberculosis (Mycobacterium tuberculosis), Ebola hemorrhagic fever (Ebola Virus) and AIDS (HIV-1) necessitate urgent attention to develop diagnostic protocols and assays for rapid detection and screening. Rapid and accurate detection of first cases with certainty will contribute significantly in preventing disease transmission and escalation to pandemic levels. As a result, there is a need to develop technologies that can meet the heavy demand of an all-embedded, inexpensive, specific and fast biosensing for the detection and screening of pathogens in active or latent forms to offer quick diagnosis and early treatments in order to avoid disease aggravation and unnecessary late treatment costs. Nucleic acid aptamers are short, single-stranded RNA or DNA sequences that can selectively bind to specific cellular and biomolecular targets. Aptamers, as new-age bioaffinity probes, have the necessary biophysical characteristics for improved pathogen detection. This article seeks to review global pandemic situations in relation to advances in pathogen detection systems. It particularly discusses aptameric biosensing and establishes application opportunities for effective pandemic monitoring. Insights into the application of continuous polymeric supports as the synthetic base for aptamer coupling to provide the needed convective mass transport for rapid screening is also presented

Synthesis

Human activity in the last century has led to a substantial increase in nitrogen (N) emissions and deposition. This N deposition has reached a level that has caused or is likely to cause alterations to the structure and function of many ecosystems across the United States. One approach for quantifying the level of pollution that would be harmful to ecosystems is the critical loads approach. The critical load is dei ned as the level of a pollutant below which no detrimental ecological effect occurs over the long term according to present knowledge. The objective of this project was to synthesize current research relating atmospheric N deposition to effects on terrestrial and aquatic ecosystems in the United States and to identify empirical critical loads for atmospheric N deposition. The receptors that we evaluated included freshwater diatoms, mycorrhizal fungi and other soil microbes, lichens, herbaceous plants, shrubs, and trees. The main responses reported fell into two categories: (1) biogeochemical, and (2) individual species, population, and community responses. This report synthesizes current research relating atmospheric nitrogen (N) deposition to effects on terrestrial and aquatic ecosystems in the United States and to identify empirical critical loads for atmospheric N deposition. The report evaluates the following receptors: freshwater diatoms, mycorrhizal fungi and other soil microbes, lichens, herbaceous plants, shrubs, and trees. The main responses reported fell into two categories: (1) biogeochemical; and (2) individual species, population, and community responses. The range of critical loads for nutrient N reported for U.S. ecoregions, inland surface waters, and freshwater wetlands is 1 to 39 kg N ha-1 y-1. This range spans the range of N deposition observed over most of the country. The empirical critical loads for N tend to increase in the following sequence for different life forms: diatoms, lichens and bryophytes, mycorrhizal fungi, herbaceous plants and shrubs, trees

A Model State Act to Authorize and Regulate Physician-Assisted Suicide

Despite laws in many states prohibiting assisted suicide, an unknown but significant number of people each year commit suicide with the aid of a physician. In recent years, the phenomenon of physician-assisted suicide has attracted greater attention as physicians have openly risked prosecution to shed light on the subject, advocates have raised a series of legal challenges to laws banning assisted suicide, and a federal judge has struck down the nation\u27s first statute allowing physicians to assist patients in suicide. In this Article, nine authors from the fields of law, medicine, philosophy and economics propose a comprehensive statute to permit and regulate physician-assisted suicide for patients suffering from terminal illnesses or unbearable pain. The proposed statute provides a specific series of procedural requirements designed to prevent mistaken decisions and affords limited legal protection to physicians who follow its requirements

Synthesis

Human activity in the last century has led to a substantial increase in nitrogen (N) emissions and deposition. This N deposition has reached a level that has caused or is likely to cause alterations to the structure and function of many ecosystems across the United States. One approach for quantifying the level of pollution that would be harmful to ecosystems is the critical loads approach. The critical load is dei ned as the level of a pollutant below which no detrimental ecological effect occurs over the long term according to present knowledge. The objective of this project was to synthesize current research relating atmospheric N deposition to effects on terrestrial and aquatic ecosystems in the United States and to identify empirical critical loads for atmospheric N deposition. The receptors that we evaluated included freshwater diatoms, mycorrhizal fungi and other soil microbes, lichens, herbaceous plants, shrubs, and trees. The main responses reported fell into two categories: (1) biogeochemical, and (2) individual species, population, and community responses. This report synthesizes current research relating atmospheric nitrogen (N) deposition to effects on terrestrial and aquatic ecosystems in the United States and to identify empirical critical loads for atmospheric N deposition. The report evaluates the following receptors: freshwater diatoms, mycorrhizal fungi and other soil microbes, lichens, herbaceous plants, shrubs, and trees. The main responses reported fell into two categories: (1) biogeochemical; and (2) individual species, population, and community responses. The range of critical loads for nutrient N reported for U.S. ecoregions, inland surface waters, and freshwater wetlands is 1 to 39 kg N ha-1 y-1. This range spans the range of N deposition observed over most of the country. The empirical critical loads for N tend to increase in the following sequence for different life forms: diatoms, lichens and bryophytes, mycorrhizal fungi, herbaceous plants and shrubs, trees

Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling

Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS–PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination