Genetico-demographic patterns of the prevalence of various forms of endogenous psychoses

Prevalence rates (PRs) for EFP (schizophrenic, schizoaffective and affective psychoses), with allowance for proband sex and age-of-onset data were studied in a subdivided population from the North-East of the European Region of the USSR. The population includes three subpopulations: a small old religious semi-isolate of Russians ("Rs"), aboriginal Komi people ("Ks")--an ethnic community of Ugro-Finnish lineage, and a mixed group of migrants ("Ms") from various regions of the USSR. The latter is mainly an urban population, while the "Rs" and "Ks" are, on the whole, rural populations. The total PR for EFP was found to be 0.97% for the "Rs", 0.63% for the "Ks" and 0.35% for the "Ms", whereas PRs-0.85-1.15% in other parts of the USSR, mainly for "panmixed" populations in large towns. The lower PRs for EFP in the "Ms" is caused by a backmigration flow involving certain groups of patients; consequently, the mean liability for "Ms" offsprings (as a whole) should also be lower. On the other hand, the lower PRs for EFP in the "Ks" is caused by underpresentation of clinically mild cases of the mental disease (mainly, pseudoneurotic schizophrenia), especially among female patients, probably due to that the so affected persons are sufficiently adapted to the cultural traditions of this rural population. It was shown that in the "Rs" the total PR for "nuclear" and paranoid schizophrenia is 0.68% versus 0.25% in a "panmixed" population. The increase is most likely caused by the high inbreeding level in the "Rs" semi-isolate, and if this is correct, we may suppose that at least one or two recessive genes are involved in the liability to the most heavy forms of schizophrenia. On the other hand, in the "Ms" (as in other "panmixed" populations) positive assortative mating among hereditary-predisposed persons is a more significant factor influencing family transmission of EFP, since the correlation between probands and their spouses is rpp = 0.31 (p less than 0.001) in the "Ms", as compared to rpp = 0.19 (p less than 0.1) in the "Rs". Thus, our general conclusion is that neither the place of inhabitance nor the life mode are the causal factors for EFP, but rather some genetic factors, more accurately, certain sets of specific genes.     

Source-sink landscape theory and its ecological significance

Exploring the relatiouships between landscape pattern and ecological processes is the key topic of landscape ecology,for which,a large number of indices as well as landscape pattern analysis model were developed.However,one problem faced by landscape ecologists is that it is hard to link the landscape indices with a specific ecological process.Linking landscape pattern and ecological processes has become a challenge for landscape ecologists."Source" and "sink" are common concepts used in air pollution research,by which the movement direction and pattern of different pollutants in air can be clearly identified.In fact,for any ecological process,the research can be considered as a balance between the source and the sink in space.Thus,the concepts of "source" and "sink" could be implemented to the research of landscape pattern and ecological processes.In this paper,a theory of sourcesink landscape was proposed,which include:(1) In the research of landscape pattern and ecological process,all landscape types can be divided into two groups,"source"landscape and "sink" landscape."Source" landscape contributes positively to the ecological process,while "sink" landscape is unhelpful to the ecological process.(2) Both landscapes are recognized with regard to the specific ecological process."Source" landscape in a target ecological process may change into a "sink"landscape as in another ecological process.Therefore,the ecological process should be determined before "source"or "sink" landscape were defined.(3) The key point to distinguish "source" landscape from "sink" landscape is to quantify the effect of landscape on ecological process.The positive effect is made by "source" landscape,and the negative effect by "sink" landscape.(4) For the same ecological process,the contribution of "source" landscapes may vary,and it is the same to the "sink"landscapes.It is required to determine the weight of each landscape type on ecological processes.(5) The sourcesink principle can be applied to non-point source pollution control,biologic diversity protection,urban heat island effect mitigation,etc.However,the landscape evaluation models need to be calibrated respectively,because different ecological processes correspond with different source-sink landscapes and evaluation models for the different study areas.This theory is helpful to further study landscape pattern and ecological process,and offers a basis for new landscape index design.     

Regulatory affairs and biotechnology in Europe II.

This paper describes the EEC regulatory requirements for the preparation and execution of a community concertation "High Tech" procedure and compares this "High Tech" procedure with the Multi-State procedure. According to a decision of the European Commission enforced in July 1987, medicinal products, derived from high technology methods have been grouped in two categories: A. and B. Category A. concerns biotechnology products made by R-DNA techniques and by manipulation of mammalian cells. Category B. comprises all other products made by high technology. Before applying for an EEC marketing licence (e.g. submission for registration) one must ascertain whether a product is most appropriate in Category A. or B. and one should contact a licencing authority at an early stage to discuss the planned submission. Various procedures for submission have to be followed: 1. for the so-called "High Tech" products and especially products derived from biotechnology with therapeutic applications (Category A.), it is mandatory that one of the Member States accepts the submission. 2. The "High Tech" procedure is derived from the so-called "2-country" (Multi-State) procedure, in which for the latter procedure a marketing licence in one of the Member States (except Portugal) is required before application in other Member States. The Multi-State and "High Tech" (other products: Category B.) procedures are optional. When the procedures are started, all Member States concerned are involved in evaluation of full or abbreviated dossiers through mediation of the European Commission represented by the CPMP (Committee for Proprietary Medicinal Products), Brussels, Belgium. No application for a marketing licence of Category A. products is allowed without mediation of the CPMP. For Category B. products the applicant may opt for a national submission in one or more of the Member States without using the "High Tech" procedure. However, after consultation with the competent authority in one of the Member States, a "High Tech" procedure for Category B. products might still be advisable, but the applicant is not required to follow this procedure. Both the "High Tech" and the Multi-State procedure are currently executed by the mediation of a rapporteur, who liaises with the applicant from the start of the "High Tech" procedure. Ideally, the applicant should contact a licencing authority some 6 to 9 months before an application is planned: to ensure that the near future submission is acceptable. The institution of a rapporteur (appointed by the licencing authority in the country from where the procedure has recently been established) is introduced for the Multi-State procedure.(ABSTRACT TRUNCATED AT 400 WORDS)     

基于“肝肾失调”探讨阿片类物质心瘾形成的中医病理基础

阿片类物质滥用是目前社会及医学领域的一大难题,其戒断复杂而艰难,关键问题在于阿片类物质心瘾难以戒除。阿片类物质心瘾是指物质滥用者对阿片类物质强烈持久的渴求和难以抑制的用药欲望,其形成的核心机制在于成瘾者对于阿片类物质的异常动机。异常动机的形成在于两个方面,即"产生动机不良"以及"控制不良动机能力下降",本研究即从异常动机形成的两个方面切入,通过类比法、引证法及演绎法进行理论研究,分析认为阿片类物质心瘾的形成与肝肾功能的失调相关相关性,研究认为不良动机形成的关键在于阿片类物质引起的肝失疏泄功能的异常,而控制不良动机能力下降则与肝胆主谋略司决断以及肾所藏之志功能的异常相关。     

Again on language of biology]

Some time ago I proposed in an Editorial in this journal some considerations on the language of biology. I concluded that, to realize an autonomy of such a language (and therefore of biology), we have to develop a valid language for biology. In such a context, it seemed to me that the term "metaphors" referred to the concepts concerning the information carried by genetic code, was a reasonable one. However, Barbieri's article in this issue of Rivista di Biologia / Biology Forum calls for a reply. Of course, we do not know very much in this field, even if we have some evidence that a sequence of bases on a DNA is not determined only by chance. In any case we can exclude that nature in this occasion has "invented" a code. Nature doesn't "invent" anything: it only follows its rules, that we name "laws of nature". Barbieri quotes the Morse code, but forgets to say that such a code is "conventional" in the sense that it is valid only because it is the result of an "agreement" between Morse and the users of that code. There is nothing more unnatural than a "code": with whom nature should actually have to "reach an agreement"? As a matter of fact, we interpret as "information" what happens by law of nature. Also Barbieri's thesis that genes and proteins are molecular artifacts, assembled by external agents, whereas generally molecules are determined by their bonds, i.e. by internal factors, is a disputable one. It is examined how much an external structure plays a role in ordinary chemical reactions. The "information" of physics is not a semantic information. For such information we can refer to history of literature, telegraphic offices, genetics or biochemistry.     

Defining,Comparing, and Improving iTRAQ Quantification in Mass Spectrometry Proteomics Data

The purpose of this study was to generate a basis for the decision of what protein quantities are reliable and find a way for accurate and precise protein quantification. To investigate this we have used thousands of peptide measurements to estimate variance and bias for quantification by iTRAQ (isobaric tags for relative and absolute quantification) mass spectrometry in complex human samples. A549 cell lysate was mixed in the proportions 2:2:1:1:2:2:1:1, fractionated by high resolution isoelectric focusing and liquid chromatography and analyzed by three mass spectrometry platforms; LTQ Orbitrap Velos, 4800 MALDI-TOF/TOF and 6530 Q-TOF. We have investigated how variance and bias in the iTRAQ reporter ions data are affected by common experimental variables such as sample amount, sample fractionation, fragmentation energy, and instrument platform. Based on this, we have suggested a concept for experimental design and a methodology for protein quantification. By using duplicate samples in each run, each experiment is validated based on its internal experimental variation. The duplicates are used for calculating peptide weights, unique to the experiment, which is used in the protein quantification. By weighting the peptides depending on reporter ion intensity, we can decrease the relative error in quantification at the protein level and assign a total weight to each protein that reflects the protein quantitation confidence. We also demonstrate the usability of this methodology in a cancer cell line experiment as well as in a clinical data set of lung cancer tissue samples. In conclusion, we have in this study developed a methodology for improved protein quantification in shotgun proteomics and introduced a way to assess quantification for proteins with few peptides. The experimental design and developed algorithms decreased the relative protein quantification error in the analysis of complex biological samples.Recent developments in methods and instruments for mass spectrometry enable quantitative proteomics analysis of complex samples with good coverage (1–4). Several techniques for quantification by mass spectrometry exist, both using isotopic labeling and label free methods (5, 6). Quantification by isotopic labeling can be done on precursor ion level or by quantifying isobaric label fragments in fragment spectra. Isotope-coded affinity tag (7), isobaric tags for relative and absolute quantification (iTRAQ)¹ (8), and stable isotope labeling by amino acids in cell culture (SILAC) (9) are among the most commonly used labeling methods based on stable isotopes. iTRAQ allows for simultaneous relative quantification of up to eight samples within a single run. Quantification by mass spectrometry is however a challenge, and several factors contribute to the uncertainty in the quantitative estimate; differences in labeling efficiency, protein digestion, precursor mixing, ion suppression, peak detection, data preprocessing, and data analysis (10). The quality of quantitation methods can be measured in terms of precision and accuracy. Precision is affected by random errors, that is, random fluctuations around the true value (variance). Lack of accuracy is caused by systematic errors, that is, differences between true and observed values (bias).Several studies have shown that iTRAQ labeling is associated with bias; fold changes are compressed toward one (11–14). It has been suggested that this underestimation of fold change is caused by co-eluting peptides with similar m/z values that are isolated together, creating mixed iTRAQ intensities in complex samples (14). Concerning precision, iTRAQ data has been reported to exhibit variance heterogeneity. The coefficient of variance (CV) of the signal depends on the intensity, with larger CV for low intensity peaks (11, 12, 15, 16). Measurements of iTRAQ intensities for quantification are made in the MS/MS spectra of the peptides, and thereafter combined to calculate a summarized relative protein quantity. There are several different approaches for combining the iTRAQ peptide data to compute a reliable protein ratio. Methods to improve the protein quantification by addressing the variance heterogeneity have been based on excluding low intensity peptide data (17, 18), weighting the peptide data according to intensity (18–21) or stabilizing the variance (12).Quantitative studies of complex human samples are subject to even more challenges related to large biological variation, large and unknown complexity of the human proteome and a large concentration range of proteins. This in turn results in many peptides and a large variety of peptides that can cause interference and related problems in the mass spectrometry analysis. In, for example, biomarker discovery research the goal is to measure quantitative changes or differences in protein levels between two or more clinical conditions. It is therefore crucial to achieve as accurate and precise quantitative information from the data as possible as well as to correctly estimate the limitations of the quantification. Setting adequate standards for quantitative proteomics analysis is hence essential for being able to detect relevant changes in protein abundance, select important proteins, and further use those proteins to interpret the biological and clinical meaning (10, 22). Selecting a protein as significant and taking it to further validation in other clinical material using complementary techniques is time consuming and costly (23). For successful use of iTRAQ labeling in biomarker discovery, and to avoid false discoveries, it is hence essential to assess the accuracy and precision of the methodology.A common approach to study variance and bias in mass spectrometry based protein quantification is to spike a set of standard proteins into a sample and then measure the CV and bias of the intensities of those peptides. Spike-in of proteins has the benefit of looking at a small controlled set of peptides and how they behave in the studied system. This strategy has been used in several of the previously mentioned papers that address iTRAQ quantification (11–14). However, the number of data points studied may be unlikely to represent the complexity of a real biological sample, which often contains thousands of proteins (24). In the current study, all peptides detected in a complex human cell line sample (A549) are used to get an estimate of the quantitative accuracy and precision. This experimental setup is hence more similar to a real biomarker discovery study with high complex human proteome samples. The quality of the protein quantifications is compared among several different mass spectrometers in this work; also the influence of different loaded peptide amounts and the use of different methods for sample separation are examined. Factors such as variance and bias of peptide quantification by iTRAQ are systematically evaluated in those high complex samples. Further, methods for improving the protein quantification are investigated; by filtering on the peptide level to remove low quality intensities and by weighting the peptide values to account for the higher risk of errors at low intensities (20).We have described the factors contributing to bias and variance in protein quantification by iTRAQ labeling. This has generated guidelines for how to estimate the accuracy of protein quantities, which will be an essential tool in both biomarker discovery and studies of biological systems. Based on the results, we suggest an experimental design where each labeling set (e.g., iTRAQ) includes duplicate samples, and we describe how these duplicates are used for calculating peptide weights that can be used in addressing the accuracy of protein quantities. This novel approach is shown to improve protein quantification by iTRAQ in six data sets of A431 cell line samples treated with drug and a clinical data set of lung cancer tissue samples.     

Clinical ethics and nursing: "yes" to caring, but "no" to a female ethics of care

According to a contemporary school of thought there is a specific female approach to ethics which is based not on abstract "male" ethical principles or rules, but on "care". Nurses have taken a keen interest in these female approaches to ethics. Drawing on the views expounded by Carol Gilligan and Nel Noddings, nurses claim that a female "ethics of care" better captures their moral experiences than a traditional male "ethics of justice". This paper argues that "care" is best understood in a dispositional sense, that is, as sensitivity and responsiveness to the particularities of a situation and the needs of "concrete" others. While "care", in this sense, is necessary for ethics, it is not sufficient. Ethics needs "justice" as well as "care". If women and nurses excessively devalue principles and norms, they will be left without the theoretical tools to condemn some actions or practices, and to defend others. They will, like generations of nurses before them, be condemned to silence.     

Generation of Single-Copy Transposon Insertions in Clostridium perfringens by Electroporation of Phage Mu DNA Transposition Complexes

Transposon mutagenesis is a tool that is widely used for the identification of genes involved in the virulence of bacteria. Until now, transposon mutagenesis in Clostridium perfringens has been restricted to the use of Tn916-based methods with laboratory reference strains. This system yields primarily multiple transposon insertions in a single genome, thus compromising its use for the identification of virulence genes. The current study describes a new protocol for transposon mutagenesis in C. perfringens, which is based on the bacteriophage Mu transposition system. The protocol was successfully used to generate a single-insertion mutant library both for a laboratory strain and for a field isolate. Thus, it can be used as a tool in large-scale screening to identify virulence genes of C. perfringens.Clostridium perfringens is a gram-positive, anaerobic bacterium that forms heat-resistant spores. It is widespread in the soil and commonly found in the gastrointestinal tract of mammals. It has been implicated in several medical conditions in humans, ranging from mild food poisoning to necrotic enteritis and gas gangrene. C. perfringens strains also cause a variety of important diseases in domestic animals, including several enteric syndromes, such as enterotoxemia in cattle, sheep, and pigs, necrotic enteritis in poultry, and typhocolitis in equines (17, 40).Understanding the pathogenesis of these infections is of crucial importance for the development of new tools for the prevention and control of C. perfringens-related diseases. Genetic modification is a valuable approach to identify new virulence factors and to study their role in the pathogenesis of C. perfringens.Since the 1980s, several tools for manipulation of C. perfringens at the molecular level have been developed (1, 5, 28, 35, 38). Among these tools, transposon mutagenesis is a method that is widely used for identification of virulence genes. Until now, the only reproducible method for transposon mutagenesis in C. perfringens was based on Tn916, a tetracycline resistance-encoding conjugative transposon originally isolated from Enterococcus faecalis (10, 11, 13). Tn916 has been used extensively for transposon mutagenesis due to its broad host range and has been proven to be valuable for the identification of genes in C. perfringens (3, 7, 22). Nevertheless, this method has major disadvantages; multiple Tn916 insertion events occur with an incidence of 65% to 75%, severely complicating identification of genes responsible for phenotype changes (3, 7, 19). Furthermore, Tn916 is still active after insertion, resulting in unstable mutants (6, 39, 42). To our knowledge, generation of Tn916-derived transposon mutants in C. perfringens field strains has never been described.Although a variety of transposon mutagenesis methods are available for gram-positive bacteria (4, 37, 41, 43), the inherent species nonspecificity, as well as the lack of mobility of the integrated transposon, makes the bacteriophage Mu-based transposon delivery system a system of choice for a variety of species (16, 26, 46). The Mu transposition approach includes in vitro assembly of a complex between the transposon DNA and the transposase enzyme, the transpososome, followed by delivery of the transpososome into the recipient cells. Once inside a cell, the Mu transpososome becomes activated in the presence of divalent cations, resulting in genomic integration of the delivered transposon. The bacteriophage Mu transposition system is also functional in vitro (15, 32, 33), in contrast to the Tn916 mutagenesis strategy, which is restricted to transposon mobilization in vivo following conjugation or electroporation. Under the optimal in vitro conditions, the Mu transposition reaction requires only the MuA transposase, a mini-Mu transposon, and target DNA as macromolecular components (15).In this study, a novel protocol is described for transposon mutagenesis in C. perfringens that exploits the bacteriophage Mu transposition system. To our knowledge, this report is the first report describing a mutagenesis method generating single-insertion transposon mutants in laboratory and field isolates of C. perfringens. This method is important for the identification of C. perfringens virulence factors involved in the numerous diseases caused by this bacterium.     

The buckling of spherical liposomes

In the classical "first approximation" theory of thin-shell structures, the constitutive relations for a generic shell element--i.e. the elastic relations between the bending moments and membrane stresses and the corresponding changes in curvature and strain, respectively-are written as if an element of the shell is flat, although in reality it is curved. In this theory it is believed that discrepancies on account of the use of "flat" constitutive relations will be negligible provided the ratio shell-radius/thickness is of sufficiently large order. In the study of drawing of narrow, cylindrical "tethers" from liposomes it has been known for many years that it is necessary to use instead a constitutive law which explicitly describes a curved element in order to make sense of the mechanics; and indeed such tethers are generally of "thick-walled" proportions. In this paper we show that the proper constitutive relations for a curved element must also be used in the study, by means of shell equations, of the buckling of initially spherical thin-walled giant liposomes under exterior pressure: these involve the inclusion of what we call the "Mkappa" terms, which are not present in the standard "first-approximation" theory. We obtain analytical expressions for both the bifurcation buckling pressure and the slope of the post-buckling path, in terms of the dimensions and elastic constants of the lipid bi-layer, and also the initial state of bending moment in the vesicle. We explain physically how the initial bending moment can affect the bifurcation pressure, whereas it cannot in "first-approximation" theory. We use these results to map the conditions under which the vesicle buckles into an oblate, as distinct from a prolate ("rugby-ball") shape. Some of our results were obtained long ago by the use of energy methods; but our aim here has been to identify precisely what is lacking in "first-approximation" theory in relation to liposomes, and so to put the "shell equations" approach onto a firm footing in mechanics.     

An updated nomenclature for keratin-associated proteins (KAPs)

Most protein in hair and wool is of two broad types: keratin intermediate filament-forming proteins (commonly known as keratins) and keratin-associated proteins (KAPs). Keratin nomenclature was reviewed in 2006, but the KAP nomenclature has not been revised since 1993. Recently there has been an increase in the number of KAP genes (KRTAPs) identified in humans and other species, and increasingly reports of variation in these genes. We therefore propose that an updated naming system is needed to accommodate the complexity of the KAPs. It is proposed that the system is founded in the previous nomenclature, but with the abbreviation sp-KAPm-nL*x for KAP proteins and sp-KRTAPm-n(p/L)*x for KAP genes. In this system "sp" is a unique letter-based code for different species as described by the protein knowledge-based UniProt. "m" is a number identifying the gene or protein family, "n" is a constituent member of that family, "p" signifies a pseudogene if present, "L" if present signifies "like" and refers to a temporary "place-holder" until the family is confirmed and "x" signifies a genetic variant or allele. We support the use of non-italicised text for the proteins and italicised text for the genes. This nomenclature is not that different to the existing system, but it includes species information and also describes genetic variation if identified, and hence is more informative. For example, GenBank sequence JN091630 would historically have been named KRTAP7-1 for the gene and KAP7-1 for the protein, but with the proposed nomenclature would be SHEEP-KRTAP7-1*A and SHEEP-KAP7-1*A for the gene and protein respectively. This nomenclature will facilitate more efficient storage and retrieval of data and define a common language for the KAP proteins and genes from all mammalian species.     

Evaluation of the evolution rate in Eigen's and Kuhn's models

The stage evolution of a "population" consisting of informational sequences having fixed length N is investigated. It is assumed that at each stage sequences of a "population" are selected, reproduced, mutated and diluted. Character of an evolution is revealed and the evolution rate is estimated for different values of N, "population" size n, and a number of different symbols lambda in sequences. According to the obtained estimations it is possible to find sequences in an evolution process which are close to the "optimum" one using far less number of sequences (approximately lambda N4) than for a random search (approximately lambda N).     

Development of a microscale cell culture analog to probe naphthalene toxicity

Prediction of human response to drugs or chemicals is difficult as a result of the complexity of living organisms. We describe an in vitro model that can realistically and inexpensively study the adsorption, distribution, metabolism, elimination, and potential toxicity (ADMET) of chemicals. A microscale cell culture analog (microCCA) is a physical replica of the physiologically based pharmacokinetics (PBPK) model. Such a microfabricated device consists of a fluidic network of channels to mimic the circulatory system and chambers containing cultured mammalian cells representing key functions of animal "organ" systems. This paper describes the application of a two-cell system, four-chamber microCCA ("lung"-"liver"-"other tissue"-"fat") device for proof-of-concept study using naphthalene as a model toxicant. Naphthalene is converted into reactive metabolites (i.e., 1,2-naphthalenediol and 1,2-naphthoquinone) in the "liver" compartment, which then circulate to the "lung" depleting glutathione (GSH) in lung cells. Such microfabricated in vitro devices are potential human surrogates for testing chemicals and pharmaceutics for toxicity and efficacy.     

THE POWER OF THE " A" -" NOT A" METHOD

The " A" - " Not A" method is a rating method with two categories. It is often treated as a discrimination method. Unlike forced choice procedures, the Thurstonian model for this method involves a choice criterion. In statistical tests, it is treated as a comparison of two proportions. In this paper, the power for hypothesis tests involving the monadic and replicated monadic " A" - " Not A" method is discussed. The power functions and the sample sizes needed for 80% power are given based on Thurstone's δ. Designs with equal and unequal allocations for A and A (Not A) samples are considered. The power of the method is also compared with that of four forced choice methods under the assumption that the perceptual variance is identical among methods. The comparison shows that, in general, the power for the five methods ranks from high to low: the 3-AFC, 2-AFC, " A" - " Not A", triangular and duo-trio. The comparison also shows that, based on the same number of panelists and/or the same sample size for the A and A⁻ samples for the methods, if the panelists are not too discrepant and the choice criterion in the " A" - " Not A" method is not too strict or too lax, the power of the " A" - " Not A" method is very close to that of the 2-AFC method.     

Deubiquitination of Tip60 by USP7 Determines the Activity of the p53-Dependent Apoptotic Pathway

Tip60 is an essential acetyltransferase required for acetylation of nucleosomal histones and other nonhistone proteins. Tip60 acetylates the p53 tumor suppressor at lysine 120 (K120), a modification essential for p53-dependent induction of PUMA and apoptosis. It is known that Tip60 is turned over in cells by the ubiquitin-proteasome system. However, the deubiquitinase activity for stabilizing Tip60 is unknown. Here we show that USP7 interacts with and deubiquitinates Tip60 both in vitro and in vivo. USP7 deubiquitinase activity is required for the stabilization of Tip60 in order to operate an effective p53-dependent apoptotic pathway in response to genotoxic stress. Inhibiting USP7 with the small-molecule inhibitor {"type":"entrez-protein","attrs":{"text":"P22077","term_id":"134707","term_text":"P22077"}}P22077 attenuates the p53-dependent apoptotic pathway by destabilizing Tip60. {"type":"entrez-protein","attrs":{"text":"P22077","term_id":"134707","term_text":"P22077"}}P22077, however, is still cytotoxic, and this is partly due to destabilization of Tip60.     

Isolation of two forms of rat alpha-fetoprotein and comparison of their binding parameters with estradiol-17beta.

In polyacrylamide gels, highly purified rat alpha1-fetoprotein shows a molecular heterogeneity, i.e. a "slow" and a "fast" moving fraction. We have isolated by electrophoretic fractionation and subsequent elution these two forms of alpha1-fetoprotein, and we have studied comparatively the binding parameters for estradiol-17beta of whole alpha1-fetoprotein preparations and of the isolated forms. We have shown that the number of binding sites per molecule of whole alpha1-fetoprotein is always, in our experimental conditions, a fractional number, inferior to unity (0.3). Furthermore, the analysis of the binding parameters of the "two forms" of alpha1-fetoprotein allows discrimination between different classes of binding sites. For the "slow" fraction, the number of predominant binding sites per molecule of protein is close to unity (0.7-0.9), whereas for the "fast" fraction, a very low fractional value is found (0.1). The corresponding association constants are reproducibly different for the two fractions: Ka = 0.1.10(8) M-1 for the "slow" alpha1-fetoprotein, and Ka = 0.7.10(8) M-1 for the "fast" alpha1-fetoprotein. Traces of a very high affinity (10(9) M-1) minor class of binding sites are demonstrated in the "slow" fraction. These results point to the existence of a molecular population of alpha1-fetoprotein, some forms of which have a strong or very strong affinity, and some a negligible affinity, for estrogens.     

Preferred orientations of His64 in human carbonic anhydrase II

Histidine at position 64 (His64) in human carbonic anhydrase II (HCA II) is believed to be the proton acceptor in the hydration direction and the proton donor in the dehydration direction for the rate-limiting proton transfer (PT) event. Although the biochemical effect of histidine at position 64 has been thoroughly investigated, the role of its orientation in the PT event is a topic of considerable debate. X-ray data of HCA II suggests that His64 can adopt either an "in" or "out" orientation. The "in" orientation is believed to be favored for the hydration direction PT event because the Ndelta of His64 is closer to the catalytic zinc. This orientation allows for smaller water bridges, which are postulated to be more conducive to PT. In the present work, classical molecular dynamics simulations have been conducted to elucidate the role that the His64 orientation may play in its ability to act as a proton donor/acceptor in HCA II. The free energy profile for the orientation of His64 suggests that the histidine will adopt an "in" orientation in the hydration direction, which brings Ndelta in close proximity to the catalytic zinc. When the histidine becomes protonated, it then rotates to an "out" orientation, creating a more favorable solvation environment for the protonated His64. In this "out" orientation, the imidazole ring releases the delta nitrogen's excess proton into the bulk environment. After the second PT event and when the zinc-bound water is regenerated, the His64 is again favored to reorient to the "in" orientation, completing the catalytic cycle.     

CLINICAL ETHICS AND NURSING: "YES" TO CARING, BUT "NO" TO A FEMALE ETHICS OF CARE

According to a contemporary school of thought there is a specific female approach to ethics which is based not on abstract "male" ethical principles or rules, but on "care". Nurses have taken a keen interest in these female approaches to ethics. Drawing on the views expounded by Carol Gilligan and Nel Noddings, nurses claim that a female "ethics of care" better captures their moral experiences than a traditional male "ethics of justice". This paper argues that "care" is best understood in a dispositional sense, that is, as sensitivity and responsiveness to the particularities of a situation and the needs of "concrete" others. While "care", in this sense, is necessary for ethics, it is not sufficient. Ethics needs "justice" as well as "care". If women and nurses excessively devalue principles and norms, they will be left without the theoretical tools to condemn some actions or practices, and to defend others. They will, like generations of nurses before them, be condemned to silence.     

Quantification of the Impact of Feature Selection on the Variance of Cross-Validation Error Estimation

Given the relatively small number of microarrays typically used in gene-expression-based classification, all of the data must be used to train a classifier and therefore the same training data is used for error estimation. The key issue regarding the quality of an error estimator in the context of small samples is its accuracy, and this is most directly analyzed via the deviation distribution of the estimator, this being the distribution of the difference between the estimated and true errors. Past studies indicate that given a prior set of features, cross-validation does not perform as well in this regard as some other training-data-based error estimators. The purpose of this study is to quantify the degree to which feature selection increases the variation of the deviation distribution in addition to the variation in the absence of feature selection. To this end, we propose the coefficient of relative increase in deviation dispersion (CRIDD), which gives the relative increase in the deviation-distribution variance using feature selection as opposed to using an optimal feature set without feature selection. The contribution of feature selection to the variance of the deviation distribution can be significant, contributing to over half of the variance in many of the cases studied. We consider linear-discriminant analysis, 3-nearest-neighbor, and linear support vector machines for classification; sequential forward selection, sequential forward floating selection, and the -test for feature selection; and -fold and leave-one-out cross-validation for error estimation. We apply these to three feature-label models and patient data from a breast cancer study. In sum, the cross-validation deviation distribution is significantly flatter when there is feature selection, compared with the case when cross-validation is performed on a given feature set. This is reflected by the observed positive values of the CRIDD, which is defined to quantify the contribution of feature selection towards the deviation variance.[1,2,3,4,5,6,7,8,9,10,11,12,13]