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The Institute of Medicine provides references of daily nutrient intake stratified by age and gender groups, considering that the basal metabolic rate varies according to these aspects. In this context, this study aimed to evaluate the recommendation of zinc in healthy adults according to the energy expenditure. The study database "Influence of Gender and SNPs in GPX1 Gene on Biomarkers of Selenium Status in Healthy Brazilians" was used, which collected information from 116 apparently healthy adults recruited in São Paulo. The mean age of the sample was 28.7 ± 7.2 years and the mean for zinc intake was 7.63 ± 3.32 mg, with a statistically significant correlation observed between energy expenditure and zinc intake (R = 0.321; p = 0.004). No linear correlation was found between age and energy expenditure and the difference between sex was not statistically significant. Conclusion: The metabolic rate can be considered as a reference variable for the recommendation of the daily intake of the nutrient, aiming to avoid deficiencies and food poisoning because of its poor intake.

The intake of dietary fibers has been associated with a reduction in the risk of colorectal cancer. Pectins - a class of dietary fibers - are polysaccharides that have a complex structure with a wide range of direct and indirect biological beneficial effects on humans. Direct effects include dilution of carcinogens, reduction in cholesterol levels, and interaction with immune cells. Indirect effects include the fermentation and production of short-chain fatty acids. All these biological effects have implications for colon cancer development; however, the exact mechanisms are not fully understood. In this review, we explore the clinical trials regarding dietary fibers and colorectal cancer, thus indicating the potential anti-cancer effects of pectins and modified pectins. We focused on the emerging biological effects of pectins through targeting colorectal cancer hallmark effects and the enabling characteristics. We provide an overview of the mechanisms for each hallmark capability and how the different pectins might exert that anti-cancer effect, such as induction of apoptosis, reduction in cancer cell proliferation and metastasis. The data compilation described herein can guide future clinical trials to investigate how to target specific pectin structures to act as an adjuvant in colon cancer treatment.

Selenium (Se) is an essential micronutrient for human biology that executes its functions as the amino acid selenocysteine via selenoproteins, which have important functions in, for example, antioxidation, immunomodulation, thyroid metabolism, and human fertility. Se nutritional status is assessed using the quantification of blood Se biomarkers, which are influenced by several factors, including diet, age, gender, smoking status, alcohol consumption, health condition, and the genetic characteristics of individuals. Nutrigenetic studies have identified single nucleotide polymorphisms in selenoproteins that might clarify the high variability in values reported for biomarkers of Se nutritional status in different populations, and the response of these biomarkers to Se supplementation with either organic or inorganic forms of Se. This review aims to (1) define the basic aspects of Se biology, (2) describe the current most commonly used biomarkers of Se nutritional status, and (3) provide a summary of associations between functional single nucleotide polymorphisms in selenoproteins and biomarkers of Se status in healthy populations.

International audience; PURPOSE:The consumption of Brazil nuts has been associated with benefits to lipid metabolism and reductions in total cholesterol and LDL concentrations. They are the richest natural source of selenium which has essential functions in human physiology. Genetic polymorphisms in Selenoprotein P could impair lipid and glucose metabolisms. The aim of this work was to verify the influence of polymorphisms in genes for selenoproteins on blood lipid levels after dietary supplementation with Brazil nuts in healthy adults.METHODS:The study included 130 healthy volunteers selected at the University of São Paulo, Brazil. They were supplemented with one nut a day for 8 weeks, followed by 8 weeks without intervention. The following analyses were performed: anthropometric measurements, serum fasting glucose, lipid profile, C-reactive protein and plasma MDA levels. The volunteers were genotyped for SNPs rs1050450, rs3811699, rs1800699, rs713041, rs3877899, rs7579, rs34713741, and rs5845 in genes for selenoproteins.RESULTS:The concentrations of total cholesterol and fasting glucose levels decreased after 8 weeks of supplementation (p < 0.05). Glucose levels were modulated by rs3877899 in SEPP1, with significantly lower levels observed for individuals with the GA + AA genotype (p = 0.025). In addition, rs7579 was associated with cholesterol concentrations, which were significantly lower for individuals with the GG genotype (p = 0.053).CONCLUSIONS:Supplementation with one Brazil nut a day for 8 weeks reduced total cholesterol and glucose levels. Furthermore, our results suggest that rs3877899 might be associated with glucose concentrations and rs7579 with cholesterol concentrations. Therefore, the effect of genetic variations should be considered in future nutritional interventions evaluating the response to Brazil nut supplementation.

Selenium (Se) is an essential micronutrient for human biology that exerts its functions as the amino acid selenocysteine, which is inserted into selenoproteins with a wide range of important functions for the human organism, such as antioxidant, immune-modulatory, thyroid metabolism and male fertility functions. There is accumulating epidemiological evidence linking Se supplementation of non-Se deficient subjects and reduced cancer risk. The doses used in these trials are above those recommended for maximal selenoprotein expression, and thus, alternative mechanisms of action that are independent of selenoprotein activities have been proposed. Several factors might explain the different results obtained from human clinical trials, such as the baseline Se status and the genetic variation of the study population. In this chapter, we discuss selenium’s cancer prevention potential, focusing on human evidence and potential cellular and molecular mechanisms, as well as emerging topics such as the importance of epigenetics and genetic polymorphisms that modify breast, prostate and colorectal cancer risk.

Background: NKX3.1 is a tumor suppressor frequently lost in prostate cancer. Previous studies by others indicated that the risks associated with reduced NKX3.1 levels can be enhanced by anti-oxidant supplementation. Selenium is an essential component of several proteins with anti-oxidant functions and lower levels of selenium have been associated with greater risk of prostate cancer. In contrast, participants of the select prostate cancer prevention trial were at increased risk of prostate cancer when supplemented with selenium when their baseline selenium levels were high. Methods: In order to investigate whether there was an interaction between a functional polymorphism in NKX3.1 that results in less protein and selenium status with prostate cancer grade or outcome, plasma selenium levels and the genotypes of NKX3.1 and the selenium carrier protein SELENOP were determined from a cohort of men who underwent radical protatectomy. Results: NKX3.1 and SELENOP genotypes were associated with a more aggressive prostate tumor grade at the time of prostatectomy, but there were no significant interactions of NKX3.1 genotype with either selenium status or SELENOP genotype. There was also a significant association between NKX3.1 genotype and prostate cancer recurrence, however this association was modified by SELENOP genotype, but not with plasma selenium levels. Conclusions: These data indicate that the impact of selenium status on prostate cancer may be influenced by factors other than the amount of selenium in circulation. Please note that the title of this document, 'Deinteraction of NKX3.1 and SELENOP genotype with prostate cancer recurrence', differs slightly from the published version.

Summary Background The beneficial effects of selenium (Se) to human health are exerted by selenoproteins, which can be quantified in blood and used as biomarkers of Se status. Different responses of Se biomarkers after supplementation with selenomethionine and sodium selenite have been observed and some of them could be due to genetic polymorphisms, mainly single nucleotide polymorphisms (SNPs). Brazil nuts are known to be the richest natural source of Se. Objective Investigate how genetic variations in selenoprotein genes modulate biomarkers of Se status in response to Brazil nut supplementation. Methods The SU.BRA.NUT study was a four month interventional trial which involved healthy volunteers of both genders, selected in University of Sao Paulo. The supplementation was done with one Brazil nut a day for 8 weeks, followed by 8 weeks of washout. Blood samples were collected at 5 time points: baseline, 4 and 8 weeks of supplementation and 4 and 8 weeks of washout for analysis of five biomarkers of Se status – erythrocyte GPx1 (Glutathione Peroxidase 1) activity, plasma GPx3 activity, plasma Se, erythrocyte Se, and plasma selenoprotein P. The gene expression of GPX1, SELENOP, SELENOF and SELENOS was done before and after 8 weeks of supplementation. The volunteers were genotyped for SNPs in GPX1 (rs1050450, rs3811699 and rs1800699), GPX4 (rs713041), SELENOP (rs3877899 and rs7579), SELENOF (rs5845) and SELENOS (rs34713741). Results A total of 130 volunteers finished the protocol. The concentrations of four biomarkers of Se status increased significantly after 4 and 8 weeks of supplementation, being modulated by gender. In addition, erythrocyte GPx1 activity was associated with rs1050450, rs713041 and rs5845. Plasma Se was associated with rs7579 and selenoprotein P with plasma Se at baseline. Nut supplementation significantly increased GPX1 mRNA expression only in subjects with CC genotype at rs1050450. SELENOP mRNA expression was significantly lower in subjects with GG genotype at rs7579 before and after supplementation. Conclusion Genetic variations in GPX1 and SELENOP genes are associated with different responses of molecular and biochemical biomarkers of Se status after Brazil nut supplementation in healthy Brazilians. The SU.BRA.NUT study was registred at www.clinicaltrials.gov as NCT 03111355.

Selenium (Se) is an essential micronutrient for human health. Its beneficial effects are exerted by selenoproteins, which can be quantified in blood and used as molecular biomarkers of Se status. We hypothesize that the presence of genetic polymorphisms in selenoprotein genes may: (1) influence the gene expression of specific selenoproteins and (2) influence the pattern of global gene expression after Brazil nut supplementation. The study was conducted with 130 healthy volunteers in Sao Paulo, Brazil, who consumed one Brazil nut (300 μg/Se) a day for eight weeks. Gene expression of GPX1 and SELENOP and genotyping were measured by real-time PCR using TaqMan Assays. Global gene expression was assessed by microarray using Illumina HumanHT-12 v4 BeadChips. Brazil nut supplementation significantly increased GPX1 mRNA expression only in subjects with CC genotype at rs1050450 (p < 0.05). SELENOP mRNA expression was significantly higher in A-carriers at rs7579 either before or after supplementation (p < 0.05). Genotype for rs713041 in GPX4 affected the pattern of blood cell global gene expression. Genetic variations in selenoprotein genes modulated both GPX1 and SELENOP selenoprotein gene expression and global gene expression in response to Brazil nut supplementation.

The clustering of agents in the market is a typical problem discussed by the new approaches to macroeconomic modelling, that describe macroscopic variables in terms of the behavior of a large collection of microeconomic entities. Clustering is often described by Ewens Sampling Formula (ESF), that admits a very nice interpretation in terms of rational vs herding behavior. Focusing on the evergreen problem of the size of firms, we discuss the incompatibility between empirical data and ESF. An alternative model is suggested, inspired to Simon's approaches to the firm size problem. It differs from the Ewens model both in destruction and in creation. In particular the probability of herding is independent on the size of the herd. This very simple assumption destroys the exchangeability of the random partitions, and forbids an analytical solution. Simple computational simulations look to confirm that actually the mean number of clusters of size i (the equilibrium distribution) follows the corresponding Yule distribution. Finally we introduce a Markov chain, that resembles the marginal dynamics of a cluster, which drives the cluster to the right-censored Yule distribution.

Clustering has often described by Ewens Sampling Formula (ESF). Focusing the attention on the evergreen problem of the size of firms, we discuss the compatibility of empirical data and ESF. In order to obtain a power law for all sizes in the present paper we shall explore the route inspired by Yule, Zipf and Simon. It differs from the Ewens model both for destruction and creation. In particular the probability of herding is independent on the size of the herd. Computer simulations seem to confirm that actually the mean number of clusters of size i (the equilibrium distribution) follows the corresponding Yule distribution. Finally we introduce a finite Markov chain, that resembles the marginal dynamics of a cluster, which drives the cluster to a censored Yule distribution.

Statistical methods play a significant role throughout the life-cycle of physics experiments, being an essential component of physics analysis. The present project in progress aims to develop an object-oriented software Toolkit for statistical data analysis. The Toolkit contains a variety of Goodness-of-Fit (GoF) tests, from Chi-squared to Kolmogorov-Smirnov, to less known, but generally much more powerful tests such as Anderson-Darling, Goodman, Fisz-Cramer-von Mises, Kuiper. Thanks to the component-based design and the usage of the standard abstract interfaces for data analysis, this tool can be used by other data analysis systems or integrated in experimental software frameworks. In this paper we describe the statistical details of the algorithms and the computational features of the Toolkit. With the aim of showing the consistency between the code and the mathematical features of the algorithms, we describe the results we obtained reproducing by means of the Toolkit a couple of Goodness-of-Fit testing examples of relevance in statistics literature.

Summary Diagnostic of thyroid dysfunction is largely based on TSH measurement in blood. Defining the upper reference limit of TSH values is of paramount importance to establish normal level of TSH. Ideally, accurate TSH measurement around the normal reference range should permit to determine which of the patients will undergo additional investigation and/or hormonal therapy. At present, there is a common agreement on the 0.4–4.0 mIU/L values but the upper limit range of TSH remains controversial. Work from the past 10 years has rather denied the proposal of lowering the threshold. TSH is a glycoprotein hormone for which the nature and circulating level may widely change depending on environmental (iodine intake and photoperiod) and physiological (age, sex, weight and ethnic origin) factors as well as on patient habits (smoking). In addition, the hormone is composed of multiple glycoforms, which display variable immunological behavior and thereby lead to altered TSH measurement. Therefore, this review aims at reinvestigating the biological significance of blood TSH values and at proposing how to reach improved accuracy in TSH testing.

Selenium (Se) status varies worldwide as a result of natural variation of Se content in soils, dietary pattern, and the presence of SNPs. Further, Se status in Brazilians and its relationship between genetic variation and Se biomarkers is unknown. This work investigated the association between SNPs in glutathione peroxidase genes and biomarkers of Se status in healthy Brazilians. The study was conducted in 116 healthy adults in São Paulo, Brazil. Plasma and erythrocyte Se were measured by HGFAAS. Erythrocyte GPx (eGPx) activity was measured spectrometrically in a biochemical analyzer. Genotypes were determined by real-time PCR using Taqman(®) Assays. eGPx activity was higher in females compared with males. Lower erythrocyte Se concentrations were found in heterozygous GC carriers for GPX1 rs8179169. eGPx activity was higher in females with the common genotypes, except for rs8179169. GC carriers for rs8179169 had lower erythrocyte Se in both genders, and only male carriers of the variant alleles of both rs1050450 and rs1800668 had higher eGPx activity. In conclusion, the genotype for SNPs in GPX1 and gender affected biomarkers of Se status in this pilot study with healthy Brazilians.

Propagation of the scrapie isoform of the prion protein (PrP(Sc)) depends on the expression of endogenous cellular prion (PrP(C)). During oral infection, PrP(Sc) propagates, by conversion of the PrP(C) to PrP(Sc), from the gastrointestinal tract to the nervous system. Intestinal epithelium could serve as the primary site for PrP(C) conversion. To investigate PrP(C) sorting in epithelia cells, we have generated both a green fluorescent protein (EGFP) or hemagglutinin (HA) tagged human PrP(C) (hPrP(C)). Combined molecular, biochemical, and single living polarized cell imaging characterizations suggest that hPrP(C) is selectively targeted to the apical side of Madin-Darby canine kidney (MDCKII) and of intestinal epithelia (Caco2) cells.

Atrophy and other brain changes, which are typical of aging, generate wide inter-individual variability of morphology in the medial temporal lobe (MTL), including the hippocampal formation. Starting from a sample population of 133 MR images we developed a procedure that extracts from each MR two sub images, containing the hippocampal formations plus a portion of the adjacent tissues and cavities. Then, a small number of templates is selected among the previously obtained sub images, able to describe the morphological variability present in the whole population. Finally an automatic procedure is prepared which, on the basis of the given set of templates, is able to find both hippocampal formations in any new MR image. MR images ranging from normalcy to extreme atrophy can be successfully processed. The proposed approach, besides being a preliminary step towards the unsupervised segmentation of the hippocampus, extracts from the MR image information useful for diagnostic purposes and, in particular, could give the possibility of performing morphometric studies on the medial temporal lobe in an automated way. The automated analysis of MTL atrophy in the segmented volume is readily applied to the early assessment of Alzheimer Disease (AD), leading to discriminating converters from Mild Cognitive Impairment (MCI) to AD with an average three years follow-up. This procedure can quickly and reliably provide additional information in early diagnosis of AD.

A computer-aided detection (CAD) system for the identification of lung internal nodules in low-dose multi-detector helical Computed Tomography (CT) images was developed in the framework of the MAGIC-5 project. The three modules of our lung CAD system, a segmentation algorithm for lung internal region identification, a multi-scale dot-enhancement filter for nodule candidate selection and a multi-scale neural technique for false positive finding reduction, are described. The results obtained on a dataset of low-dose and thin-slice CT scans are shown in terms of free response receiver operating characteristic (FROC) curves and discussed.

The present project aims to develop an open-source and object-oriented software Toolkit for statistical data analysis. Its statistical testing component contains a variety of Goodness-of-Fit tests, from Chi-squared to Kolmogorov-Smirnov, to less known, but generally much more powerful tests such as Anderson-Darling, Goodman, Fisz-Cramer-von Mises, Kuiper, Tiku. Thanks to the component-based design and the usage of the standard abstract interfaces for data analysis, this tool can be used by other data analysis systems or integrated in experimental software frameworks. This Toolkit has been released and is downloadable from the web. In this paper we describe the statistical details of the algorithms, the computational features of the Toolkit and describe the code validation.

Lo scopo di questo lavoro è fornire uno strumento di software sofisticato per la validazione statistica delle distribuzioni isodosi calcolate da un toolkit adottato per la simulazione del passaggio delle particelle nella materia (Geant4). Tale validazione si basa sul confronto dei risultati delle simulazioni con set di misure sperimentali, con dati di riferimento disponibili in letteratura o con dati ottenuti da calcoli teorici o da fit.

Statistical methods play a significant role throughout the life-cycle of HEP experiments, being an essential component of physics analysis. Only a few basic tools for statistical analysis were available in the public domain FORTRAN libraries for HEP. Nowadays the situation is hardly unchanged even among the libraries of the new generation. The present project in progress aims to develop an object-oriented software toolkit for statistical data analysis. More in particular, the Statistical Comparison component of the toolkit provides algorithms for the comparison of data distributions in a variety of use cases typical of HEP experiments, as regression testing (in various phases of the software life-cycle), validation of simulation through comparison to experimental data, comparison of expected versus reconstructed distributions, comparison of data from different sources - such as different sets of experimental data, or experimental with respect to theoretical distributions. The toolkit contains a variety of goodness-of-fit tests, from chi-squared to Kolmogorov-Smirnov, to less known, but generally much more powerful tests such as Anderson-Darling, Lilliefors, Cramer-von Mises, Kuiper. Thanks to the component-based design and the usage of the standard AIDA interfaces, this tool can be used by other data analysis systems or integrated in experimental software frameworks. We present the architecture of the system, the statistics methods implemented and the results of its first applications to the validation of the Geant4 Simulation Toolkit and to experimental data analysis.

In this note we discuss in general how to test the implementation code of statistical tests, and then we treat in detail the case of the Kolmogorov-Smirnov test. It will be shown that some 'obvious' expected properties, like the flatness distributions of p-values from repeating drawings from the same parent distribution, are not indeed reproduced even in absence of bugs in the code, due to either asymptotic approximations in the formulas used to compute the p-value, or to the discreteness of the distance distribution in the case of direct Monte Carlo evaluation of the p-value. This makes the code-testing more complicated. Some practical advice is presented anyhow.

Our aim was to evaluate the factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease (AD). Five hundred and twenty-four consecutive outpatients at their first diagnostic work-up (age 78.02+/-6.07 years, education 6.62+/-3.48 years, mean MMSE score 20.23+/-4.89) (+/-S.D.) with probable AD (based on DSM-IV and NINCDS-ADRDA criteria) were enrolled in a multicenter, cross-sectional, regional-based study. For the purpose of the present study, the 11 subtests composing the MMSE and the global MMSE score (ranging from 10 to 29, included) were considered. Factor analysis with Varimax rotation method identified two factors that explained about the 85% of total variance. The first factor explained the 65% of variance and mainly included temporal orientation, delayed recall, attention/concentration, and constructional praxia. The second factor explained the 20% of variance and included reading a sentence, writing a sentence, naming, verbal repetition and immediate memory. The first factor was a reliable index of cognitive deterioration along the MMSE score interval between 29 and 10, whereas the second factor was not a suitable marker in this range. The two-factor structure of the MMSE in AD is shown in a large series of patients. The first factor expresses the ability to use new information and is related with working memory. The second factor is related with a more consolidated knowledge, namely verbal abilities, and is essentially useless in mild to moderate AD.

A 3,373-base-pair DNA segment from a clone fortuitously isolated from Saccharopolyspora erythraea by hybridization to an oligodeoxynucleotide probe was sequenced. Computer-assisted analysis of the nucleotide sequence reveals three closely linked Streptomyces open reading frames plus a fourth converging on the others. The deduced product of one of them, ORF2, shows considerable similarity to bovine liver rhodanese. orf2, and the closely linked orf3 located just downstream of it, were disrupted by insertion of an apramycin resistance cassette into the orf2 coding sequence along with inversion of the fragment carrying most of orf2 and orf3 via two successive recombinational events in the wild-type strain. The mutant strain thus created contains wild-type levels of rhodanese activity but cannot grow on minimal medium. It is a cysteine auxotroph, capable of utilizing efficiently only thiosulfate among the inorganic sulfur sources tested. orf2 has been designated cysA. The possible role of the rhodaneselike cysA gene product in thiosulfate formation is discussed.

International audience; Copper is an essential trace element for successful pregnancy. However, the mechanisms by which copper is transported from maternal circulation to the fetus have not been clearly elucidated. Two proteins, cellular prion (PrP(C)) and COMMD1, are known to be responsible for prion diseases and canine copper toxicosis, respectively, and are thought to play a role in copper homeostasis. However, their placental expression and localization throughout human gestation are still unknown. In this study, we used quantitative RT-PCR, western blotting and immunohistochemistry to investigate in detail the expression and localization of PrP(C) and COMMD1 proteins in human placenta throughout pregnancy. Our results show that both proteins are expressed in human placenta. PrP(C) showed the highest mRNA and protein expression levels during the first trimester of pregnancy. PrP(C) and COMMD1 proteins are similarly localized within the placental villi. Both proteins are present in the syncytiotrophoblast, the cytotrophoblast, vascular endothelial cells and Hofbauer cells. These data offer some insights into possible roles for PrP(C) and COMMD1 within the placenta.

Study Objective: We present a mathematical model of sleep-EEG structure applied to the analysis of sleep patterns in narcoleptics by combining the 2-process model of sleep regulation and the reciprocal interaction model of REM regulation suggested by McCarley and Hobson. The aim was the individuation of parameters characterizing narcoleptic sleep in comparison to controls. Design: Polysomnographic data were drawn from a previous study about sleep in narcolepsy. The mathematical model was fitted to quantitative EEG data by an optimization procedure. Setting: Polysomnographic data were recorded in single and sound attenuated hospital rooms, for one night following an adaptation night. Participants: 9 narcoleptic subjects (7 males, 2 females, mean age 39.6±4.3 years) and 9 age- and sex- matched controls. Measurements: Slow Wave Activity (SWA) time series were evaluated by spectral analysis. The sleep model was fitted to SWA profile for each recording and to the averaged SWA profile for each group. Bartlett and Kolmogorov-Smirnov test were used to evaluate the goodness of fit and the accuracy of model predictions. Results: In both controls and narcoleptics the optimization procedure produced a good fit of SWA raw data. The only significant difference between the groups were the RemOn /RemOff coupling parameters, reflecting an enhanced strength of the REM oscillator in narcoleptics. Conclusions: The mathematical model of sleep provides a substantial description of empirical patterns for both controls and narcoleptics. The variation of values in the parameters describing the strength of RemOn /RemOff interaction is the major feature characterizing narcoleptics; it can explain sleep onset REM periods (SOREMPs) and variations of REMNREM sleep cycle duration.

Simple stochastic exchange games are based on random allocation of finite resources. These games are Markov chains that can be studied either analytically or by Monte Carlo simulations. In particular, the equilibrium distribution can be derived either by direct diagonalization of the transition matrix, or using the detailed balance equation, or by Monte Carlo estimates. In this paper, these methods are introduced and applied to the Bennati-Dragulescu-Yakovenko (BDY) game. The exact analysis shows that the statistical-mechanical analogies used in the previous literature have to be revised., Comment: 11 pages, 3 figures, submitted to EPJB

Simple stochastic exchange games are based on random allocation of finite resources. These games are Markov chains that can be studied either analytically or by Monte Carlo simulations. In particular, the equilibrium distribution can be derived either by direct diagonalization of the transition matrix, or using the detailed balance equation, or by Monte Carlo estimates. In this paper, these methods are introduced and applied to the Bennati-Dragulescu-Yakovenko (BDY) game. The exact analysis shows that the statistical-mechanical analogies used in the previous literature have to be revised.

There is growing evidence that cyclic alternating pattern (CAP) and arousals are woven into the basic mechanisms of sleep regulation. In the present study, the overnight sleep cycles (SC) of 20 normal subjects were analyzed according to their stage composition, CAP rate, phase A subtypes and arousals. Individual SC were then divided into 10 normalized temporal epochs. CAP parameters and arousals were measured in each epoch and averaged in relation to the SC order. Subtypes A2 and A3 of CAP in non-rapid eye movement (NREM) sleep, and arousals, both in REM and NREM sleep when not coincident with a A2 or A3 phases, were lumped together as fast electroencephalographic (EEG) activities (FA). Subtypes A1 of CAP, characterized by slow EEG activities (SA), were analyzed separately. The time distribution of SA and FA was compared to the mathematical model of normal sleep structure including functions representing the homeostatic process S, the circadian process C, the ultradian process generating NREM/REM cycles and the slow wave activity (SWA) resulting from the interaction between homeostatic and ultradian processes. The relationship between SA and FA and the sleep-model components was evaluated by multiple regression analysis in which SA and FA were considered as dependent variables while the covariates were the process S, process C, SWA, REM-on and REM-off activities and their squared values. Regression was highly significant (P < 0.0001) for both SA and FA. SA were prevalent in the first three SC, and exhibited single or multiple peaks immediately before and in the final part of deep sleep (stages 3 + 4). The peaks of FA were delayed and prevailed during the pre-REM periods of light sleep (stages 1 + 2) and during REM sleep. SA showed an exponential decline across the successive SC, according to the homeostatic process. In contrast, the distribution of FA was not influenced by the order of SC, with periodic peaks of FA occurring before the onset of REM sleep, in accordance with the REM-on switch. The dynamics of CAP and arousals during sleep can be viewed as an intermediate level between cellular activities and macroscale EEG phenomena as they reflect the decay of the homeostatic process and the interaction between REM-off and REM-on mechanisms while are slightly influenced by circadian rhythm.

The genetic determinants for the biosynthesis of the glycopeptide antibiotic teicoplanin were identified. In order to isolate the corresponding gene cluster, oligonucleotides derived from highly conserved motifs in peptide synthetases were used. These synthetic probes, and gene fragments derived from the balhimycin gene cluster of Amycolatopsis mediterranei, led to the identification of the likely teicoplanin gene cluster centered on a region of ca. 110 kb from the genome of Actinoplanes teichomyceticus, the teicoplanin producer. Partial nucleotide sequences identified partial ORFs likely to encode two glycosyltransferases, three P-450 monooxygenases and one ABC transporter. The corresponding genes have been found in other glycopeptide gene clusters. Furthermore, upstream to the peptide synthetase region a segment was identified with a remarkable similarity to the vanHAX operon, conferring resistance to glycopeptides in enterococci. Thus, in contrast to the other glycopeptide producers thus far analyzed, in A. teichomyceticus the genes for teicoplanin biosynthesis are closely linked to homologs of glycopeptide resistance commonly found in vancomycin-resistant enterococci.

Metastasis to the breast from extramammary malignancies are rare especially from ovarian carcinoma. We report a case of a 72-year-old woman with a mass in the right ovary and a lump in the left breast together with axillary lymph node enlargement. Both the ovarian and mammary neoplasms were found to be papillary carcinoma with similar immunohistochemical pattern (anti-CA-125: positive; anti-GCDFP-15: negative); some of the axillary lymph nodes showed metastasis with papillary features. On the basis of clinical, morphological and immunohistochemical data we proposed the diagnosis of papillary cystoadenocarcinoma of the ovary with simultaneous metastasis to the breast and axillary lymph nodes.

Publisher Summary This chapter provides an overview on macrolides. Macrolides are a class of antibiotics that contain a macrocylic lactone ring composed of a polyketide-derived backbone to which one or two sugars are commonly attached. They are produced as secondary metabolites by mycelium-forming soil bacteria from the order Actinomycetales; the majorities are from members of the genera Streptomyces, Micromonospora, and Saccharopolyspora. Most of the enzyme functions required for macrolide biosynthesis have been proposed from examination of the pathways, attempts to characterize the enzymes in the producing organisms have encountered limited success. Macrolides differ from each other in the size, composition, and modification of the lactone ring. The lactone ring in macrolides is enzymatically modified after assembly. Common to all biosynthetic pathways is mono-, di-, or tri-glycosylation. All macrolide antibiotics contain one, two, or three sugars attached directly to the macrolactone ring and some have an additional sugar linked by a glycosidic bond to a lactone-bound sugar. All 14-membered macrolides except lankamycin and kujimycin contain an amino sugar at the C-5 hydroxyl and a deoxysugar at the C-3 hydroxyl.

Three bacteriophages infecting Streptomyces erythreus, called G3, G4 and G5, were isolated and characterized. They contain double-stranded linear DNA molecules with cohesive ends. The restriction map of G3 DNA (48 kilobases long) for four restriction endonucleases and that of G4 DNA (43 kilobases long) for seven restriction endonucleases are reported. Restriction analysis and hybridization experiments showed that G3 and G4 share little DNA homology, while G4 and G5 are apparently identical except for an additional EcoRI site present in G5. The region containing this EcoRI site has been mapped on G4 DNA. Microbiological and serological data showed that G5 is very similar to G4. G3- and G4-resistant mutants of S. erythreus PS1 were isolated. The screening of phage-resistant mutants showed a high frequency of strains with increased erythromycin production. The mechanism of phage resistance of strain PS3 (G3 resistant) and of strain PS16 (G4 resistant) was examined. The DNA of the resistant strains contains no phage DNA, ruling out lysogeny as a cause of phage resistance. Transfection of strains PS1, PS3, and PS16 with DNA of the three phages showed the same efficiency, indicating that resistance is at the level of the bacterial wall.

Active-site-directed N-nitrosamides inhibit alpha-chymotrypsin through an enzyme-activated-substrate mechanism. In this work, the activation results in the release--in the active site--of benzyl carbonium ions, which alkylate and inhibit the enzyme. The final ratio of benzyl groups to enzyme molecules is 1.0, but the alkyl groups are scattered over a number of sites. Reduction and alkylation of the inhibited enzyme generate peptides insoluble in most media. Guanidine hydrochloride at 6 M proved a good solvent, and its use as an eluant on G-75 Sephadex permitted separation of the peptides. In the case of 14C-labeled enzyme, such an approach has shown that all of the alkylation occurs on the C chain of the enzyme, the chain of which the active site is constructed. Chemical modification of the peptides with ethylenediamine and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide rendered them soluble in dilute acid, permitting high-performance liquid chromatographic separation. Model studies have shown that the benzyl carbonium ions are highly reactive, alkylating amide linkages at both oxygen and nitrogen. Alkylation at oxygen produces imidate esters, which are labile centers. Hydrolysis of protein imidates results in a cleavage of the chain at that point, and separation of the peptides formed (followed by analysis) permits their identification. In our inhibition of alpha-chymotrypsin, a major site of O-alkylation has been identified as the carbonyl oxygen of Ser-214. Alkylation at the nitrogen atom of amide linkages generates stable labels; full hydrolysis with 6 N HC1 then leads to N-benzyl amino acids characteristic of those sites. Chromatography of this mixture and also 13C NMR spectroscopy of the intact inhibited enzyme have shown that three major N-alkylations have occurred. Tryptic digestion of the C chain of chymotrypsin, which contains all of the alkylation sites, provides evidence that the stable N sites are principally located between residue 216 and residue 230. These locations are consistent with predictions of alkylation sites based on inspection of a molecular model of chymotrypsin, with special reference to the aromatic binding pocket.

The Geant4 toolkit provides an ample set of physics models for electromagnetic interactions. Results from a series of detailed tests with respect to well established reference data sources and experiments are presented, focusing on the precision validation of cross sections and angular distributions of various alternative physics models available in Geant4. Such precision tests are especially relevant for critical applications of simulation models, such as tracking detectors, calorimetry, neutrino and other astroparticle experiments, medical physics.

Le biotecnologie possono essere definite come sistemi mediante i quali trasformare materie prime in prodotti a maggior valore attraverso l'uso razionale di organismi viventi. Le biotecnologie microbiche si basano sulla valorizzazione di microrganismi o delle loro molecole biologiche (proteine e metaboliti). Il capitolo mira ad approfondire gli aspetti economico aziendali collegati al settore delle biotecnologie, nel quale le imprese sviluppano innovazioni applicando in ambito economico gli avanzamenti nella scienza e nelle tecnologie biomolecolari al fine di realizzare un prodotto o un servizio da lanciare sul mercato.

Spinal cord stimulation (SCS) restores motor control after spinal cord injury (SCI) and stroke. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Instead, here we show that SCS does not facilitate residual supraspinal inputs but directly triggers motoneurons action potentials. However, supraspinal inputs can shape SCS-mediated activity, mimicking volitional control of motoneuron firing. Specifically, by combining simulations, intraspinal electrophysiology in monkeys and single motor unit recordings in humans with motor paralysis, we found that residual supraspinal inputs transform subthreshold SCS-induced excitatory postsynaptic potentials into suprathreshold events. We then demonstrated that only a restricted set of stimulation parameters enables volitional control of motoneuron firing and that lesion severity further restricts the set of effective parameters. Our results explain the facilitation of voluntary motor control during SCS while predicting the limitations of this neurotechnology in cases of severe loss of supraspinal axons., Competing Interests: COMPETING INTERESTS MC and DW hold patents in relation to spinal cord stimulation. MC and DW are the founders of Reach Neuro, a company developing spinal cord stimulation technologies for stroke. All other authors declare they have no competing interests.

Spinal cord stimulation (SCS) restores motor control after spinal cord injury (SCI) and stroke. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Instead, here we show that SCS does not facilitate residual supraspinal inputs but directly triggers motoneurons action potentials. However, supraspinal inputs can shape SCS-mediated activity, mimicking volitional control of motoneuron firing. Specifically, by combining simulations, intraspinal electrophysiology in monkeys and single motor unit recordings in humans with motor paralysis, we found that residual supraspinal inputs transform subthreshold SCS-induced excitatory postsynaptic potentials into suprathreshold events. We then demonstrated that only a restricted set of stimulation parameters enables volitional control of motoneuron firing and that lesion severity further restricts the set of effective parameters. Our results explain the facilitation of voluntary motor control during SCS while predicting the limitations of this neurotechnology in cases of severe loss of supraspinal axons.