Beneficiamento do sorgo em polidora de arroz para obtenção de farinhas de diferentes frações.

10º SLACA

Leaf development and demography explain photosynthetic seasonality in Amazon evergreen forests

In evergreen tropical forests, the extent, magnitude, and controls on photosynthetic seasonality are poorly resolved and inadequately represented in Earth system models. Combining camera observations with ecosystem carbon dioxide fluxes at forests across rainfall gradients in Amazônia, we show that aggregate canopy phenology, not seasonality of climate drivers, is the primary cause of photosynthetic seasonality in these forests. Specifically, synchronization of new leaf growth with dry season litterfall shifts canopy composition toward younger, more light-use efficient leaves, explaining large seasonal increases (~27%) in ecosystem photosynthesis. Coordinated leaf development and demography thus reconcile seemingly disparate observations at different scales and indicate that accounting for leaf-level phenology is critical for accurately simulating ecosystem-scale responses to climate change. © 2016 by the American Association for the Advancement of Science; all rights reserved

Configurazione di prodotto: nuove soluzioni per la gestione della variet\ue0 nel ciclo dell'ordine

Conciliare flessibilit\ue0 ed efficienza in contesti caratterizzati da elevata variet\ue0 di prodotto richiede l'impiego di varie tecniche: standardizzazione, modularizzazione, riduzione dei tempi di attrezzaggio, ecc. Tuttavia, avere una produzione flessibile non basta per offrire variet\ue0 al cliente senza compromettere la redditivit\ue0 dell'impresa. Altri processi, quali ad esempio il ciclo dell'ordine, devono essere opportunamente rivisti per effettuare un adeguato collegamento tra cliente, commerciale e produzione. Questo lavoro riporta alcuni dei risultati di una ricerca biennale su una classe di sistemi informativi che supporta il ciclo dell'ordine in contesti caratterizzati da un'elevata variet\ue0 di prodotto. Lo studio mostra che tali sistemi consentono una ristrutturazione di alcune attivit\ue0 del ciclo dell'ordine, aumentando l'efficienza e l'efficacia con cui un'azienda pu\uf2 tradurre i requisiti del cliente nella documentazione di prodotto che viene utilizzata per la produzione della variante desiderata

SISTEMI SOFTWARE PER LA CONFIGURAZIONE DI PRODOTTO

IL testo fornisce una descirizone generale del problema della configurazione di prodotto partendo da un caso esemplificativo. Presenta la configurazione di prodotto supportata da SW. Porta evidenza circa gli impatti sulle prestaazioni derivanti dall'introduzione di un sistema SW di configurazione di prodotto

Effects of testosterone on muscarinic acetylcholine receptors in the rat epididymis

The effect of testosterone on the expression of muscarinic acetylcholine receptor (mAChR) subtypes was studied in the rat epididymis, at mRNA and protein level. the rat androgen status was monitored by measuring plasma testosterone level and caput and cauda epididymis wet weight. Ribonuclease protection assay (RPA) and [(3)H]quinuclidinyl benzilate ([(3)H]QNB) binding assay were performed in the caput and cauda epididymis from control (50-day old), castrated, castrated and treated with testosterone and sexually immature (30-day old) rats. the expression of each mAChR transcript subtype differed depending on the epididymal region analyzed and rat testosterone and/or testicular factors status. in control rats, RPA showed the presence of mRNA for M(1), M(2) and M(3) mAChR in the caput and cauda epididymis. the abundance of m2 and m3 transcripts in the cauda was higher than that in the caput epididymis. Low amount of m1 transcript was observed in both regions. Orchidectomy increased m1 mRNA amount in the caput and cauda epididymis when compared to control rats, an effect slightly modified by testosterone replacement. Although orchidectomy down-regulated the level of m2 transcript in both epididymal regions, castration significantly increased m3 mRNA amount in the caput region. These effects on m2 and m3 transcripts were prevented by testosterone replacement to castrated rats. Similar abundance of m3 transcript, however, was detected in the cauda epididymis of all experimental group tested. [ (3)H]QNB binding studies revealed that orchidectomy down-regulated the number of mAChR detected in both epididymal regions, an effect also prevented by testosterone replacement. Thus, testosterone and/or testicular factors may play a role in the regulation of mAChR expression in the rat epididymis. (c) 2005 Elsevier Inc. All rights reserved.Universidade Federal de São Paulo, Escola Paulista Med, Dept Pharm, Sect Expt Endocrinol, BR-04044020 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Pharm, Sect Expt Endocrinol, BR-04044020 São Paulo, BrazilWeb of Scienc

Expression and localization of muscarinic acetylcholine receptor subtypes in rat efferent ductules and epididymis

The expression of muscarinic acetylcholine receptor (mAChR) subtypes (M-1-M-5) was studied in the rat efferent ductules and epididymis at the mRNA and protein levels. the relative abundance of each mAChR transcript subtype differed depending on the tissue and the epididymal region analyzed. the M-1 mAChR mRNA level was more abundant in the efferent ductules than in the caput and cauda of the epididymis. the M-2 mAChR mRNA level was similar between the efferent ductules and caput of the epididymis and higher in the cauda region. the M-3 mAChR mRNA level was low in the efferent ductules and caput of the epididymis, but high levels were detected in the cauda region. mRNAs for M-4 and M-5 mAChRs were not detected in these tissues. Our studies indicated a variable degree of immunostaining for each mAChR subtype in a cell-type and tissue-specific pattern. M-3 mAChR was detected over the efferent ductule epithelium. M-2 and M-3 mAChRs were observed in the apical region of the ciliated cells. Apical and narrow cells of the initial segment showed distinct staining by M-1 antibody, whereas a supranuclear reaction was noted in the principal cells of the caput of the epididymis. in addition, staining for M-1 and M-2 mAChRs was visible in the apical membrane of some epithelial cells of the cauda region. M-3 mAChR was detected in the peritubular smooth muscle of the efferent ductules and epididymis. Functional studies suggested the involvement of this subtype in epididymal tubule contraction. Thus, the cell-specific expression of the various mAChR subtypes in the efferent ductules and epididymis suggests that these receptors play a role in the modulation of luminal fluid composition and smooth muscle contraction.Universidade Federal de São Paulo, Escola Paulista Med, Dept Pharmacol, Sect Expt Endocrinol, BR-04044020 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Pharmacol, Sect Expt Endocrinol, BR-04044020 São Paulo, BrazilWeb of Scienc

Population state-space modelling of patient responses in antidepressant studies

Objectives: A major challenge posed by the analysis of the clinical scores used to assess the disease status in depression trials is the lack of "first principles" from which response models can be derived. The state-space framework, which is based on a set of differential (or difference) equations that describes the evolution of one or more variables characterizing the patient's health state [1], represents an appealing and more mechanistically driven approach to describe these data. In order to develop a comprehensive state-space approach, we address two main questions: (i) do state-space models give adequate descriptions of the clinical response? (ii) how should flexible dosing schedules be handled within a state-space framework? Methods: A double-blind, randomized, placebo controlled, flexible dose depression trial was used as a benchmark for alternative state-space approaches. Discrete- and continuous-time stochastic processes (i.e. integrated random walks and integrated Wiener processes [2, 3]) were used to describe the time-course of the HAMD score, within the framework of population modelling. In particular, each individual curve was expressed as the sum of an average curve and an individual shift, both described as random processes whose statistics were specified through hyperparameters. Dose changes were modelled as impulses on the second derivative of the patient's score. According to an empirical Bayes paradigm, hyperparameters were estimated through Maximum Likelihood. Estimation and post-processing were carried out with R 2.10.0 [4]. Results: Even low-order discrete- and continuous-time state-space models were able to fit very satisfactorily the whole range of shapes observed in individual responses. Moreover, the explicit description of dose changes improved the performances in terms of residuals. The continuous-time model appears to be marginally superior to the discrete-time one. Conclusions: The results demonstrate that state-space approaches not only provide adequate description of population responses but are also easily adapted to account for possible dose changes during the trial. Among the advantages, there is the possibility to model the presence of random perturbations that affect the patient's health state. A further step to explore is the development of an integrated response and dropout model within the state-space framework. References: [1] Russu A, Marostica E, De Nicolao G, Hooker AC, Poggesi I, Gomeni R, Zamuner S (2010), Integrated model for clinical response and dropout in depression trials: a state-space approach, Population Approach Group Europe (PAGE) 19th Meeting, Abstract 1852 [2] Magni P, Bellazzi R, De Nicolao G, Poggesi I, Rocchetti M (2002), Nonparametric AUC estimation in population studies with incomplete sampling: a Bayesian approach, Journal of Pharmacokinetics and Pharmacodynamics 29, pp. 445-471 [3] Neve M, De Nicolao G, Marchesi L (2007), Nonparametric identification of population models via Gaussian processes, Automatica 43, pp. 1134-1144 [4] R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria (2010)

Muscarinic acetylcholine receptor subtypes in the rat seminal vesicle

The aim of the present study was to identify the muscarinic acetylcholine receptor (mAChR) mRNA subtypes in the rat seminal vesicle. Furthermore, the mAChR subtypes involved in the contraction of the seminal vesicle were also explored. Reverse transcriptase-polymerase chain reaction (PCR) was performed and five PCR products corresponding to M-1-M-5 mAChR mRNA subtypes were detected in this tissue. Functional pharmacological studies indicated that the rank order of mAChR antagonists in blocking the contractile effects of carbachol was p-fluoro-hexahydro-sila-difenidol (pF-HHSiD) >> tropicamide > methoctramine = pirenzepine. This antagonist profile indicates that M-3 mAChR subtype is predominantly involved in the seminal vesicle contraction. Furthermore, immunohistochemical studies confirmed the presence of the M-3 mAChR subtype in the smooth muscle layers. M-2 mAChR subtype was also immunolocalized in smooth muscle cells and may be involved in the contraction of this tissue. the presence of M-2 and M-3 mAChR subtypes in the epithelial cells suggests that these receptors could be involved in the protein secretion. Taken together, the cholinergic neurotransmitter may be a factor controlling contractility and protein secretion in this tissue. (c) 2006 Elsevier Ireland Ltd. All rights reserved.Universidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, Escola Paulista Med,INFAR, BR-04044020 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, Escola Paulista Med,INFAR, BR-04044020 São Paulo, BrazilWeb of Scienc

Second-order indirect response modelling of complex biomarker dynamics

Objectives: Biomarker dynamics in response to drug action may not always be fully understood. Redundant pathways, tolerance, feedback and counter-regulation may be such that the response to a drug stimulus can show complex patterns [1-3]. This motivates the present work, where a new pharmacokinetic/pharmacodynamic (PK/PD) approach inspired by indirect response modelling (IRM) [4] and precursor-dependent IRM [5] is investigated. Methods: We propose a novel family of PK/PD models that feature a zero-order rate constant kin of precursor formation, and a first-order rate constant k of conversion from precursor to response. Drug concentration is assumed to modulate simultaneously kin and k (potentially by stimulation or inhibition) through specific SC50 or IC50 parameters. The rate of response dispersion can be assumed equal to k to reduce model complexity. The proposed models can structurally describe complex patterns, such as the combination of (i) inverse response (i.e. a drop of response levels immediately after dosing, followed by an increase above baseline level), (ii) fast achievement of peak response followed by slow return to baseline, after single dose, and (iii) average increase from baseline at steady-state, after repeated dosing. The mathematical properties of the proposed PK/PD models and the sensitivity of response profiles to parameter changes were investigated by simulation. Model identifiability was assessed using NONMEM version 7.1 [6] to perform parameter estimation. Results: In the sensitivity analysis, the new approach could describe a wide range of response profiles, following both single and repeated-dose administration. In particular, different real-life patterns of response could be reproduced. Simulations showed that, under a suitable study design, model parameters could be estimated with good precision. Moreover, the proposed approach was able to reconstruct both population and individual profiles. Conclusions: These results confirm the feasibility of a modeling approach for longitudinal data characterized by complex features. This approach extends and complements the well-known methodology of IRM [2,5], and is especially appealing when the mechanism of action of a drug is known (or assumed) to impact both the response itself and a precursor of response. Additionally, the proposed approach can be used effectively to describe inhibition of clearance for both a parent drug and its metabolite, in presence of a second drug that inhibits certain metabolic pathways (e.g. CYP3A4). References: [1] C. van Kesteren, A.S. Zandvliet, M.O. Karlsson et al. (2005). Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam. Invest. New Drugs 23:225-234. [2] A. Russu, E. Marostica, S. Zamuner et al. (2012). A new, second-order indirect model of depression time course. Population Approach Group in Europe 21st Meeting, Abstract 2516. [3] I. Ortega Azpitarte, A. Vermeulen, V. Piotrovsky (2006). Concentration-response analysis of antipsychotic drug effects using an indirect response model. Population Approach Group in Europe 15th Meeting, Abstract 995. [4] N.L. Dayneka, V. Garg, W.J. Jusko (1993). Comparison of four basic models of indirect pharmacodynamic responses. J. Pharmacokinet. Biopharm. 21:457-478. [5] D.E. Mager, E. Wyska, W.J. Jusko (2003). Diversity of mechanism-based pharmacodynamic models. Drug Metab. Dispos. 31:510-519. [6] Beal, S.L., Sheiner, L.B., Boeckmann, A.J. (Eds.), 1989-2006. NONMEM Users Guides. Icon Development Solutions, Ellicott City, Maryland, USA