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[Purpose] To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum., [Methods] Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker’s Initiative using mixed linear model analysis., [Results] Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker’s Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = −2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time., [Conclusion] Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

Hyperhomocysteinemia is considered an independent risk factor for cognitive impairment.To study the correlation between homocysteine levels and cognitive impairment in patients with PD.We conducted a case-control study that included 246 patients with PD, of whom 32 were cognitively impaired. The levels of homocysteine, folate, and vitamin B12 were measured in peripheral blood. Multivariate logistic regression analysis was applied to determine differences in homocysteine levels between PD patients with and without cognitive impairment. A meta-analysis was performed to clarify the role of Hcy levels in PD with cognitive decline. Five polymorphisms in genes involved in Hcy metabolism, including MTHFR rs1801133 and rs1801131, COMT rs4680, MTRR rs1801394, and TCN2 rs1801198, were genotyped.Our case-control study showed that homocysteine levels were associated with cognitive impairment in PD after adjusting for possible confounding factors such as levodopa equivalent daily dose. The results of our meta-analysis further supported the positive association between homocysteine levels and cognition in PD. We found that the MTHFR rs1801133 TT genotype led to higher homocysteine levels in PD patients, whereas the MTHFR rs1801131 CC genotype resulted in higher folate levels. However, the polymorphisms studied were not associated with cognitive impairment in PD.Increased homocysteine levels were a risk factor for cognitive decline in PD. However, no association was found between polymorphisms in genes involved in homocysteine metabolism and cognitive impairment in PD. Large-scale studies of ethnically diverse populations are required to definitively assess the relationship between MTHFR and cognitive impairment in PD.

Parkinson's disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age- and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress., This work was supported by the Horizon 2020 Framework Programme (grant number 634821, PROPAG-AGEING).

Bacteria, filamentous fungi, and plants synthesize thousands of secondary metabolites with important biological and pharmacological activities. The biosynthesis of these metabolites is performed by networks of complex enzymes such as non-ribosomal peptide synthetases, polyketide synthases, and terpenoid biosynthetic enzymes. The efficient production of these metabolites is dependent upon the supply of precursors that arise from primary metabolism. In the last decades, an impressive array of biosynthetic enzymes that provide specific precursors and intermediates leading to secondary metabolites biosynthesis has been reported. Suitable knowledge of the elaborated pathways that synthesize these precursors or intermediates is essential for advancing chemical biology and the production of natural or semisynthetic biological products. Two of the more prolific routes that provide key precursors in the biosynthesis of antitumor, immunosuppressant, antifungal, or antibacterial compounds are the lysine and ornithine pathways, which are involved in the biosynthesis of β-lactams and other non-ribosomal peptides, and bacterial and fungal siderophores. Detailed analysis of the molecular genetics and biochemistry of the enzyme system shows that they are formed by closely related components. Particularly the focus of this study is on molecular genetics and the enzymatic steps that lead to the formation of intermediates of the lysine pathway, such as α-aminoadipic acid, saccharopine, pipecolic acid, and related compounds, and of ornithine-derived molecules, such as N5-Acetyl-N5-Hydroxyornithine and N5-anhydromevalonyl-N5-hydroxyornithine, which are precursors of siderophores. We provide evidence that shows interesting functional relationships between the genes encoding the enzymes that synthesize these products. This information will contribute to a better understanding of the possibilities of advancing the industrial applications of synthetic biology.

A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had

This article examines some aspects related to perceptions of agricultural cooperative members. Most arguments employed are based on agency and property rights theories. The sample consists of 196 satisfaction surveys completed by agricultural cooperative members and accounting information from Spanish cooperatives. The results show that when members do not perceive any serious agency problems, the performance of the firm is higher. We also find that members are not discouraged from investing by awareness of the free-rider problem, and the less risk averse members are, the higher is the long-term debt ratio. Finally, members’ perceptions of the time horizon problem have no impact on the time frame for investment.

The purpose of this paper is to examine the relationship between women on the board of directors and firm performance in a comparative analysis between Italy and Spain.,The generalized method of moment is employed to examine this relationship in a sample of 1,393 firm-year observations.,The results show that the presence of women on the board has a positive impact on the performance of Italian and Spanish firms. However, when the whole sample is divided into Italy and Spain, some results are remarkable. For Spain, the presence of women on the board has a positive influence on firm performance, whereas for Italy the authors find a negative and significant effect on firm performance. This study also finds that the “masculinity” dimension has a negative impact on firm performance.,The results of this study have several practical implications. First, masculinity differences within the countries can have a large impact on firm performance and can explain some differences between similar countries. Second, the legal system of countries might not explain adequately some differences in the decision-making process. Third, cultural values and thinking styles, in terms of masculinity, might better explain why the results on the relationship between female directors and firm performance are mixed. Fourth, the findings suggest that it is very important to promote gender equality, not only by passing laws but also taking action about the educational system.,To the best of the authors’ knowledge, this is the first study that investigates the relationship between female directors and firm performance between Italy and Spain considering the cultural differences in term of “masculinity.”,el objetivo de este trabajo es examinar la relacion entre la presencia de mujeres en el Consejo de Administracion y el rendimiento de la empresa, realizando un analisis comparativo entre Italia y Espana.,Se emplea el metodo generalizado de los Momentos (GMM), utilizando una muestra de 1.393 observaciones.,los resultados muestran que la presencia de mujeres en el consejo tiene un impacto positivo en el rendimiento de las empresas italianas y espanolas. Sin embargo, cuando se analizan por separado ambas submuestras se obtienen algunos resultados destacables. Para Espana, la presencia de mujeres en el consejo tiene un efecto positivo, mientras que para Italia la influencia resulta negativa. Este estudio tambien muestra que la dimension “masculinidad” tiene un efecto negativo en la rentabilidad de la empresa.,Los resultados de este estudio tienen varias implicaciones practicas. En primer lugar, la diferencia en la masculinidad entre paises puede tener un gran impacto en el rendimiento de las empresas y explicar algunas diferencias entre paises de caracteristicas similares. En segundo lugar, el sistema legal de los paises podria no explicar adecuadamente algunas diferencias en el proceso de toma de decisiones. En tercer lugar, los valores culturales y el modo de pensar, en terminos de “masculinidad” podria explicar mejor el hecho de que los resultados de la relacion entre consejeras y rendimiento de la empresa no sea concluyente. En cuarto lugar, nuestros hallazgos sugieren que es muy importante promover la igualdad de genero no solo a traves de la aprobacion de leyes, sino tambien actuando sobre el sistema educativo.,Que tengamos conocimiento, este es el primer estudio que investiga la relacion entre la presencia de consejeras y rendimiento de la empresa para Italia y Espana considerando las diferencias culturales en terminos de “masculinidad.”

This paper focuses on gender diversity on the boards of Spanish agricultural cooperatives. Specifically, it examines the effect that gender diversity on the board exerts on returns, debt level, and economic risk. Cooperatives differ significantly from investor‐owned firms because cooperative members are producers, agents, and customers of the cooperatives. In Spain, there is an ongoing debate about the importance of women in business management. Spain is also a pioneer in terms of enacting specific legislation for the social economy. The sample examined includes 672 agricultural cooperatives. The results show that firms with greater female representation on their boards have higher returns and operational risk and lower levels of debt. [EconLit Classifications: J16, J54, Q13].

Purpose The construction industry has traditionally been a male-dominated economic sector. Barely 10% of managers are women. On the other hand, this sector is considered an engine of the economy. For these reasons, it is important to examine the influence of women CEOs on financial variables of firms in the construction industry. Design/methodology/approach The empirical study is carried out using a sample from the Iberian Balance Sheet Analysis System record (“Sistema de Análisis de Balances Ibérico”, SABI). The sample includes 8,492 Spanish companies from the construction sector. The methodology employed is a three-stage least squares (3SLS) analysis. This methodology controls for the endogeneity of explanatory variables. It is employed in accordance with the peculiar characteristics of the sample, which includes data for only one year. Findings The results show that firms with a woman CEO have a lower level of debt, whatever the terms of the maturity of the debt are. In contrast to most previous evidence, firms managed by women are found to be less profitable. Originality/value The paper gives evidence of the influence of the CEO's gender on the performance (return and risk) of a firm. It provides original empirical evidence for the male-dominated construction sector. An extensive search identified no literature in which the researchers had focused on the construction industry.

[Background] Surgical resection of diffuse low-grade gliomas (DLGGs) involving cortical eloquent areas and subcortical functional pathways represents a challenge in neurosurgery. Patient-specific, 3-dimensional (3D)-printed models of head and brain structures have emerged in recent years as an educational and clinical tool for patients, doctors, and surgical residents., [Methods] Using multimodal high-definition magnetic resonance imaging data, which incorporates information from specific task-based functional neuroimaging and diffusion tensor imaging tractography and rapid prototyping technologies with specialized software and “in-house” 3D printing, we were able to generate 3D-printed head models that were used for preoperative patient education and consultation, surgical planning, and resident training in 2 complicated DLGG surgeries., [Results] This 3D-printed model is rapid prototyped and shows a means to model individualized, diffuse, low-level glioma in 3D space with respect to cortical eloquent areas and subcortical pathways. Survey results from 8 surgeons with different levels of expertise strongly support the use of this model for surgical planning, intraoperative surgical guidance, doctor-patient communication, and surgical training (>95% acceptance)., [Conclusions] Spatial proximity of DLGG to cortical eloquent areas and subcortical tracts can be readily assessed in patient-specific 3D printed models with high fidelity. 3D-printed multimodal models could be helpful in preoperative patient consultation, surgical planning, and resident training., Funding for this technical paper was received from the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (PI14/01823, PI16/01575, PI18/01898, PI19/01576), Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI-02526, CTS-7685), Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0471–2013, PE-0210–2018, PI-0459–2018, PE-0186–2019), the Fundación Alicia Koplowitz and the Spanish Ministry of Science and Innovation “Retos Colaboración” 2019 program (TC2019–007150–1). Jose Gomez-Feria Ferreiro is supported by the Spanish Ministry of Education, Culture and Sports (FPU16/03550). The Hospital Virgen del Rocío Fabrication Laboratory is partially funded by (PIN-0213–2018) 3D printing Laboratory for Andalusian Public Health Service. Juan F Martín-Rodríguez is supported by the VI-PPIT-US from the University of Seville (USE-18817-A).

This study examines the influence of CEO gender on returns and risk for a sample of 2,157 Spanish publishing firms in 2013. The publishing sector is relevant in Spain, in terms of output, because of its positive contribution to the cultural sector's trade balance and also because it plays a key strategic role in a knowledge-based society. Previous evidence suggests that women in senior management position affect the performance of firms and also the level of risk that the firm is exposed to. Our results show that publishing companies whose CEO is female have greater returns. This result is observed when both the return on assets and the return on equity are considered as the dependent variable. When we focus on risk, we find a lower debt level and lower financial leverage when the CEO is a woman.

This paper analyzes the relationship between the gender of mayors in Spanish local government and different budget items. It uses a sample of local budgets for 8,112 town councils between 2002 and ...

Introduction Vascular parkinsonism is a syndrome that develops as a result of cerebrovascular disease. Although several studies on clinical features and neuroimaging have been published, little is known about its pathophysiology. Our aim was to study sensorimotor integration using transcranial magnetic stimulation in this condition and to correlate the potential abnormalities in this technique with the cognitive profile of these patients. Methods We studied 11 vascular parkinsonism patients and 13 controls. We applied transcranial magnetic stimulation to investigate sensorimotor inhibition and sensorimotor plasticity and we performed extensive neuropsychological examinations. Results Vascular parkinsonism patients showed reduced short latency afferent inhibition and lack of long term potentiation-like plasticity after paired associative stimulation protocol. Correlations were found in these patients between short latency afferent inhibition and sensorimotor plasticity with verbal memory tests. Conclusions Our neurophysiological findings suggest deficiencies of a variety of receptors and signalling systems in vascular parkinsonism, including cortical glutamatergic and cholinergic synapses, which may be a consequence of the disruption of subcortical-cortical connections caused by vascular lesions. The correlations found suggest that these neurotransmitter systems may be involved in the processes of cognitive decline in these patients.

Transport of penicillin intermediates and penicillin secretion are still poorly characterized in Penicillium chrysogenum (re-identified as Penicillium rubens ). Calcium (Ca 2 + ) plays an important role in the metabolism of filamentous fungi, and casein phosphopeptides (CPP) are involved in Ca 2 + internalization. In this study we observe that the effect of CaCl 2 and CPP is additive and promotes an increase in penicillin production of up to 10–12 fold. Combination of CaCl 2 and CPP greatly promotes expression of the three penicillin biosynthetic genes. Comparative proteomic analysis by 2D-DIGE, identified 39 proteins differentially represented in P. chrysogenum Wisconsin 54-1255 after CPP/CaCl 2 addition. The most interesting group of overrepresented proteins were a peroxisomal catalase, three proteins of the methylcitrate cycle, two aminotransferases and cystationine β-synthase, which are directly or indirectly related to the formation of penicillin amino acid precursors. Importantly, two of the enzymes of the penicillin pathway (isopenicillin N synthase and isopenicillin N acyltransferase) are clearly induced after CPP/CaCl 2 addition. Most of these overrepresented proteins are either authentic peroxisomal proteins or microbody-associated proteins. This evidence suggests that addition of CPP/CaCl 2 promotes the formation of penicillin precursors and the penicillin biosynthetic enzymes in peroxisomes and vesicles, which may be involved in transport and secretion of penicillin. Significance Penicillin biosynthesis in Penicillium chrysogenum is one of the best characterized secondary metabolism processes. However, the mechanism by which penicillin is secreted still remains to be elucidated. Taking into account the role played by Ca 2 + and CPP in the secretory pathway and considering the positive effect that Ca 2 + exerts on penicillin production, the analysis of global protein changes produced after CPP/CaCl 2 addition is very helpful to decipher the processes related to the biosynthesis and secretion of penicillin.

Maladaptive cortical plasticity has been described in individuals with heroin and methamphetamine addiction and may mediate other substance abuse disorders. It is unknown whether cannabis dependence in humans alters the capacity for induction of cortical plasticity. The aim of this study was to non‐invasively investigate cortical plasticity with transcranial magnetic stimulation in young adults who meet DSM‐5 criteria for cannabis use disorder (CUD). Thirty men (ages 20– 30) who used cannabis daily over the previous 6 months (15 diagnosed of CUD) and 15 demographically matched non‐users were enrolled in this study. All participants underwent two sessions of theta burst stimulation (TBS) in which either continuous TBS (cTBS; 600 pulses, 80% active motor threshold) or intermittent TBS (iTBS; 2‐s train of cTBS repeated every 10 s for a total of 190 s, 600 pulses) was applied over the primary motor cortex. The effects of these protocols were assessed by analysing the contralateral motor evoked potentials (MEPs). The relationships between cortical plasticity and problematic cannabis use, degree of dependence, and nicotine addiction were also investigated. Significant MEP inhibition after cTBS was observed in both cannabis users without CUD and non‐users, while this inhibition was not seen in cannabis users with CUD. Strikingly, less motor cortical plasticity was observed in subjects with severe problematic cannabis use. No significant differences between users and non‐users were found in the iTBS‐induced cortical plasticity measures. Our study provides the first evidence of maladaptive cortical plasticity associated with cannabis use disorder and problematic cannabis use in humans., This work was supported by the Instituto de Salud Carlos III‐Fondo Europeo de Desarrollo Regional (ISCIII‐FEDER) (PI14/01823, PI16/01575), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI‐02526, CTS‐7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI‐0437‐2012, PI‐0471/2013), the Fundación Progreso y Salud (FPS 2014 PI‐0055‐2014), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz and the Fundación Mutua Madrileña. J.F.M.‐R. was supported by the “Sara Borrell” Programme from the Instituto de Salud Carlos III and the VI PPIT‐US from the University of Seville; P.A.d.T. was supported by the FPU programme of the Ministry of Education, Culture and Sport of Spain; and M.R.‐V. was supported by Grant BAE 09/90088.

Ripening of blue-veined cheeses, such as the French Bleu and Roquefort, the Italian Gorgonzola, the English Stilton, the Danish Danablu or the Spanish Cabrales, Picón Bejes-Tresviso, and Valdeón, requires the growth and enzymatic activity of the mold Penicillium roqueforti, which is responsible for the characteristic texture, blue-green spots, and aroma of these types of cheeses. This filamentous fungus is able to synthesize different secondary metabolites, including andrastins, mycophenolic acid, and several mycotoxins, such as roquefortines C and D, PR-toxin and eremofortins, isofumigaclavines A and B, and festuclavine. This review provides a detailed description of the main secondary metabolites produced by P. roqueforti in blue cheese, giving a special emphasis to roquefortine, PR-toxin and mycophenolic acid, and their biosynthetic gene clusters and pathways. The knowledge of these clusters and secondary metabolism pathways, together with the ability of P. roqueforti to produce beneficial secondary metabolites, is of interest for commercial purposes.

En el presente trabajo se aborda la reclamación por el mercado de una nueva gestión empresarial que asegure la presencia de la mujer en la toma de decisiones para dar respuesta a las nuevas necesidades sociales. Así, este trabajo analiza la influencia de la diversidad de género de los consejeros sobre la rentabilidad y el nivel de endeudamiento para una muestra de 5.199 cooperativas españolas. A diferencia de las sociedades capitalistas, estas organizaciones presentan una serie de peculiaridades en su gobierno, ya que los socios son a su vez principales, agentes y clientes. El estudio se centra en el contexto español, donde existe un debate abierto sobre la importancia de la gestión empresarial femenina impulsado, como en otros países, por la proliferación de legislación sobre la igualdad de género, siendo, además, España el país pionero en contar con una legislación específica sobre Economía Social. Los resultados muestran que las cooperativas con mayor representación femenina en su Consejo Rector presentan una mayor rentabilidad. Por otro lado, en aquellos consejos con un mayor porcentaje de mujeres muestran un menor nivel de endeudamiento.

There is increasing evidence that supports the role of the cerebellum in the pathophysiology of dystonia. We used transcranial magnetic stimulation to test the hypothesis that patients with cervical dystonia may have a disrupted cerebellar cortical connectivity at rest, and that cerebellar plasticity is altered too. We enrolled 12 patients with isolated cervical dystonia and 13 controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right cerebellum and the left primary motor area. Changes in the amplitude of motor evoked potentials were analysed. Continuous and intermittent Theta Burst Stimulation over the cerebellum was also applied. The effects of these repetitive protocols on cortical excitability, on intra-cortical circuits and on cerebellar cortical inhibition were analysed. In healthy subjects, but not in dystonic patients, a conditioning stimulus over the cerebellum was able to inhibit the amplitude of the motor evoked potentials from primary motor cortex. In healthy subjects continuous and intermittent cerebellar Theta Burst Stimulation were able to decrease and increase respectively motor cortex excitability. Continuous Theta Burst Stimulation was able to abolish the cerebellar cortical inhibition observed in basal condition. These effects were not observed in patients with cervical dystonia. Cerebellar cortical connectivity and cerebellar plasticity is altered at rest in patients with cervical dystonia., This research was supported by grants from the Ministerio de Economía y Competitividad de España (SAF2007-60700), the Instituto de Salud Carlos III (CP08/00174, PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0377/2007, PI-0741/2010, PI-0437-2012, PI-0471/2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña and the Jaques and Gloria Gossweiler Foundation.

Biosynthesis of benzylpenicillin in filamentous fungi (e.g. Penicillium chrysogenum - renamed as Penicillium rubens- and Aspergillus nidulans) depends on the addition of CoA-activated forms of phenylacetic acid to isopenicillin N. Phenylacetic acid is also detoxified by means of the homogentisate pathway, which begins with the hydroxylation of phenylacetic acid to 2-hydroxyphenylacetate in a reaction catalysed by the pahA-encoded phenylacetate hydroxylase. This catabolic step has been tested in three different penicillin-producing strains of P. rubens (P. notatum, P. chrysogenum NRRL 1951 and P. chrysogenum Wisconsin 54–1255) in the presence of sucrose and lactose as non-repressing carbon sources. P. chrysogenum Wisconsin 54–1255 was able to accumulate 2-hydroxyphenylacetate at late culture times. Analysis of the P. rubens genome showed the presence of several PahA homologs, but only Pc16g01770 was transcribed under penicillin production conditions. Gene knock-down experiments indicated that the protein encoded by Pc16g01770 seems to have residual activity in phenylacetic acid degradation, this catabolic activity having no effect on benzylpenicillin biosynthesis. Proteome-wide analysis of the Wisconsin 54–1255 strain in response to phenylacetic acid revealed that this molecule has a positive effect on some proteins directly related to the benzylpenicillin biosynthetic pathway, the synthesis of amino acid precursors and other important metabolic processes. Significance The adaptive response of Penicillium rubens to benzylpenicillin production conditions remains to be fully elucidated. This article provides important information about the molecular mechanisms interconnected with phenylacetate (benzylpenicillin side chain precursor) utilization and penicillin biosynthesis, and will contribute to the understanding of the complex physiology and adaptation mechanisms triggered by P. rubens (P. chrysogenum Wisconsin 54–1255) under benzylpenicillin production conditions.

Working memory (WM) has been defined as a cerebral function which allows us to maintain and manipulate information "online". One of the most widely used paradigms to assess WM is the n-back test. Despite its extensive application, some authors have questioned its capacity to assess the manipulation of WM load. The present study introduces a new version of the n-back test to carry out this assessment. We use functional near-infrared spectroscopy (fNIRS) to evaluate prefrontal cortex (PFC) activation. The modified n-back requires monitoring of sequentially presented stimuli (in this case the days of the week). The target response relates to a stimulus which appears previously, from 0 to 2 items back, on the computer screen. Our data reveals that while modified and unmodified n-back activate the same regions of the left PFC, our modified 2-back version shows significantly higher activation in the left dorsolateral PFC (DLPFC) and the left frontal opercula. These results suggest that increased complexity in verbal WM tasks entail greater executive control, which would lead to an increase in cerebral blood flow to the areas associated with verbal WM. Therefore, an increase in the manipulation of WM load in verbal tasks reflects greater physiological activity in the left DLPFC and the left frontal opercula. The modified n-back test may also be incorporated into the armamentarium of valid instruments for the neuropsychological assessment of the maintenance and manipulation of verbal information in tasks requiring working memory.

Background Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. Methods We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). Results The polymorphism rs3096140 in glial cell line–derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. Conclusions As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. © 2015 International Parkinson and Movement Disorder Society

Parkinson’s disease (PD) patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA), a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT) availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36), intermediate (I, n = 22), and tremor-dominant (TD, n = 17) subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P, This work was supported by grants from the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) [PI14/01823, PI16/01575], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0437-2012, PI-0471/2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz and the FundaciónMutuaMadrileña. Ismael Huertas was supported by the "PFIS" programme [FI14/00497], Silvia Jesús by the Rio Hortega programme, Juan Francisco Martin Rodríguez by the Sara Borrell programme, and Pilar Gómez-Garre by the Miguel Servet programme, all from the ISCIII-FEDER.

Traditionally, Parkinson's disease (PD) has been considered a single neurotransmitter (dopaminergic) disease. However, research over the past 20 years has shed light on the involvement of multiple neurotransmission systems, in particular, the cholinergic system. Research has mainly focused on the role of this system in the pathophysiology of PD and its implications in the development of motor and non-motor disorders. Short-latency sensory afferent inhibition (SAI), investigates sensori-motor integration, and has emerged as a putative neurophysiological marker of cholinergic function in the human brain. In this quantitative review, a moderate-to-severe reduction in SAI was observed in PD patients. Furthermore, through moderator analysis, the impairment of SAI was shown to be associated with disease duration and therapeutic state. Patients under dopaminergic agents ("on" state) displayed worse SAI than those after dopaminergic agent withdrawal ("off"). We further assess the potential value of SAI as a marker of cognitive impairment in PD, and its association with four specific cognitive domains. This analysis revealed that patients with cognitive impairment displayed significantly lower levels of SAI than those without cognitive impairment. To conclude, a set of challenges to be addressed before SAI can be validated as a useful clinical tool in PD are presented.

Background The clinical profile in vascular parkinsonism (VP) patients is well described in the literature, but little is known about the neuropsychological features of this disease. The aim of our study was to evaluate the clinical characteristics and the profile of cognitive impairment in patients with VP. Methods We prospectively evaluated 12 patients with VP, 15 with Parkinson's disease (PD) and 13 healthy controls (HC) with similar age and sex distribution. Different clinical and demographic details were collected. All subjects underwent detailed neurological and neuropsychological examinations. The neuropsychological tests included analysis of global efficiency, executive function, verbal memory, language and visuospatial function. Results VP patients exhibited lower disease duration, older age at onset and higher frequency of cardiovascular risk factors. Non-motor symptoms were found to be more frequent in PD. We found that VP patients developed cognitive impairment with a significantly higher frequency than HC of a similar age. Additionally, we found that these patients had a global pattern of cognitive impairment, including executive function, verbal memory and language. Only visuospatial function was more impaired in PD than in HC. Conclusions Our data contribute to clarify the pattern of neuropsychological impairment in VP. Therefore, in the clinical evaluation, besides assessing the motor status of the patient, given that these symptoms are frequently found not to be self-reported complaints, the neurologist should evaluate them routinely as a comprehensive assessment of this disease.

This study examines gender diversity on boards of directors in a sample of nonfinancial Spanish small and medium-sized enterprises (SMEs) for 2003–8, finding that the probability of women on the board increases with firm performance, defined as return on assets, and family ownership, but diminishes with corporate ownership and firm risk. It also finds, when examining the full sample, a positive effect of the presence of women board members on firm performance. The study also obtains a similar positive effect in most subsamples, including in firms with corporate ownership, where family connections play less role in the election of board members, and in firms in the secondary and tertiary sectors, which are characterized by having greater proximity to final consumers than those in the primary sector.

The current literature shows great interest in the issue of gender diversity on boards of directors. Some studies have hypothesized a direct relationship between diversity and the value of the firm, but not many examine the intermediate mechanisms that may exert an influence on such relationships. We employ two stages of GMM estimation methodology to exhibit evidences of the relationship between gender diversity and compensation of top managers in the Spanish context. Results show that gender diversity positively affects the effectiveness of boards—in terms of composition, structure, size and functioning—influencing a proper design of top managers compensation linked to company performance. Evidences suggest that legislative actions aimed at increasing the presence of women on boards of directors are justified not only for ethical reasons, but also for reasons of economic efficiency.

Los centros educativos constituyen espacios de encuentro donde las relaciones interpersonales juegan un papel central. Favorecer la convivencia entre sus miembros se convierte en una necesidad que es preciso abordar si queremos promover el bienestar personal y social de todos los implicados en el proceso de enseñanza-aprendizaje.En este sentido, trabajar la competencia emocional en los docentes de educación secundaria se convierte en una estrategia de prevención y desarrollo. Como estrategia de prevención, nuestra pretensión es dotar al profesorado de las habilidades necesarias para hacer frente a los desafíos de su práctica diaria, y prevenir el malestar, estrés y sentimientos de frustración que pueden aparecer ante las demandas y conflictos por parte de padres, alumnos, otros compañeros y equipo directivo. Como estrategia de desarrollo, entendemos que los profesores han de ser capaces de trasmitir y desarrollar la competencia emocional de aquellos alumnos con los que tienen ocasión de trabajar, favoreciendo así una educación integral y de calidad.

Objective To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case. Material and methods Laboratory tests included morning and midnight serum cortisol levels, 24 h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques. Results A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results. Conclusions Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis.

et al., The PR-toxin is a potent mycotoxin produced by Penicillium roqueforti in moulded grains and grass silages and may contaminate blue-veined cheese. The PR-toxin derives from the 15 carbon atoms sesquiterpene aristolochene formed by the aristolochene synthase (encoded by ari1). We have cloned and sequenced a four gene cluster that includes the ari1 gene from P. roqueforti. Gene silencing of each of the four genes (named prx1 to prx4) resulted in a reduction of 65-75% in the production of PR-toxin indicating that the four genes encode enzymes involved in PR-toxin biosynthesis. Interestingly the four silenced mutants overproduce large amounts of mycophenolic acid, an antitumor compound formed by an unrelated pathway suggesting a cross-talk of PR-toxin and mycophenolic acid production. An eleven gene cluster that includes the above mentioned four prx genes and a 14-TMS drug/H+ antiporter was found in the genome of Penicillium chrysogenum. This eleven gene cluster has been reported to be very poorly expressed in a transcriptomic study of P. chrysogenum genes under conditions of penicillin production (strongly aerated cultures). We found that this apparently silent gene cluster is able to produce PR-toxin in P. chrysogenum under static culture conditions on hydrated rice medium. Noteworthily, the production of PR-toxin was 2.6-fold higher in P. chrysogenum npe10, a strain deleted in the 56.8kb amplifiable region containing the pen gene cluster, than in the parental strain Wisconsin 54-1255 providing another example of cross-talk between secondary metabolite pathways in this fungus. A detailed PR-toxin biosynthesis pathway is proposed based on all available evidence. © 2013 Elsevier Inc., This work was supported by a Grant of the European Union (EUROFUNGBASE, LSSG-CT-2005-018964). Pedro Hidalgo received a fellowship from the AECID (Agencia Española de Cooperación Internacional para el Desarrollo).

In this article we studied the differential protein abundance of Penicillium chrysogenum in response to either 1,3-diaminopropane (1,3-DAP) or spermidine, which behave as inducers of the penicillin production process. Proteins were resolved in 2-DE gels and identified by tandem MS spectrometry. Both inducers produced largely identical changes in the proteome, suggesting that they may be interconverted and act by the same mechanism. The addition of either 1,3-DAP or spermidine led to the overrepresentation of the last enzyme of the penicillin pathway, isopenicillin N acyltransferase (IAT). A modified form of the IAT protein was newly detected in the polyamine-supplemented cultures. Both inducers produced a rearrangement of the proteome resulting in an overrepresentation of enzymes involved in the biosynthesis of valine and other precursors (e.g. coenzyme A) of penicillin. Interestingly, two enzymes of the homogentisate pathway involved in the degradation of phenylacetic acid (a well-known precursor of benzylpenicillin) were reduced following the addition of either of these two inducers, allowing an increase of the phenylacetic acid availability. Both inducers produced also an increase in the intracellular content of vesicles that derived to vacuoles in late stages and promoted sporulation of P. chrysogenum in solid medium. Biological significance The analysis of global protein changes produced in response to polyamines 1,3-DAP and spermidine provides a valuable information for the understanding of the molecular mechanisms underlying the production of penicillin. This represents useful information to improve the production of this antibiotic and many other bioactive secondary metabolites not only in P. chrysogenum , but in other filamentous fungi as well.

Transport of penicillin intermediates and penicillin secretion are still poorly characterized in Penicillium chrysogenum (re-identified as Penicillium rubens). Calcium (CaPenicillin biosynthesis in Penicillium chrysogenum is one of the best characterized secondary metabolism processes. However, the mechanism by which penicillin is secreted still remains to be elucidated. Taking into account the role played by Ca

La formación del profesorado en contextos de marginación era una realidad sobre la que indagar. El objetivo de nuestro estudio era conocer la problemática, las expectativas y las necesidades que los docentes que trabajan en contextos de marginación identifican sobre su formación. A través del método descriptivo, diseñamos un cuestionario, llamado “Cuestionario sobre la Formación del Profesorado en Contextos de Marginación (CFPCM)” del que obtuvimos un alfa de Cronbach de .838 y en su análisis de componentes principales una KMO de .080 y esferidad de Barlett significativa. Se pasó a una muestra de 385 docentes que trabajan en contextos de marginación y aplicamos el análisis de contingencias. Podemos concluir que los docentes más experimentados se mostraron más desconfiados y realistas con la problemática que rodea la enseñanza en contextos de marginación y dudaron de la capacidad de abordaje de los problemas por parte del sistema educativo. El profesorado con experiencia manifestó expectativas más negativas sobre su formación a la hora de trabajar en contextos de marginación, frente al profesorado con menos años de docencia, que sí confiaba en alcanzar determinados presupuestos que mejorarían su formación. El tipo de necesidades sobre la formación en contextos de marginación que se expusieron también variaron en función del grado de experiencia, aunque la que logró el acuerdo de todos ha sido la relacionada con la Administración, de manera que esta tenga en cuenta al profesorado y refuerce la colaboración entre el centro y las instituciones, Teacher training in the context of those working in areas of exclusion was a reality which had to be investigated. The aim of our study was to identify the problems, the expectations and the needs which teachers working in areas of exclusion identified in their training. Through the descriptive method, we designed a questionnaire, which we called "Questionnaire on the Training of Teachers working in the Context of Marginalization (CFPCM)" that obtained a Cronbach's alpha of .838, a KMO of .080 in its PCA and was significant on the Bartlett test. We used a sample of 385 teachers working in areas of exclusion and applied a contingency analysis. We concluded that the most experienced teachers were more wary and realistic about the problems surrounding education in areas of exclusion and had doubts regarding the ability of the education system to address these. Experienced teachers expressed more negative expectations regarding their training when working in areas of exclusion, compared to teachers with fewer years of experience of teaching who had confidence in, that by reaching certain budgets their training would be improved. The expressed training needs in areas of exclusion also varied depending on the degree of experience, although what obtained the agreement of all was related to the Administration, in that this should take teachers into account and reinforce the collaboration between the centers and institutions

Peroxisomes are eukaryotic organelles surrounded by a single bilayer membrane, containing a variety of proteins depending on the organism; they mainly perform degradation reactions of toxic metabolites (detoxification), catabolism of linear and branched-chain fatty acids, and removal of H2O2 (formed in some oxidative processes) by catalase. Proteins named peroxins are involved in recruiting, transporting, and introducing the peroxisomal matrix proteins into the peroxisomes. The matrix proteins contain the peroxisomal targeting signals PTS1 and/or PTS2 that are recognized by the peroxins Pex5 and Pex7, respectively. Initial evidence indicated that the penicillin biosynthetic enzyme isopenicillin N acyltransferase (IAT) of Penicillium chrysogenum is located inside peroxisomes. There is now solid evidence (based on electron microscopy and/or biochemical data) confirming that IAT and the phenylacetic acid- and fatty acid-activating enzymes are also located in peroxisomes. Similarly, the Acremonium chrysogenum CefD1 and CefD2 proteins that perform the central reactions (activation and epimerization of isopenicillin N) of the cephalosporin pathway are targeted to peroxisomes. Growing evidence supports the conclusion that some enzymes involved in the biosynthesis of mycotoxins (e.g., AK-toxin), and the biosynthesis of signaling molecules in plants (e.g., jasmonic acid or auxins) occur in peroxisomes. The high concentration of substrates (in many cases toxic to the cytoplasm) and enzymes inside the peroxisomes allows efficient synthesis of metabolites with interesting biological or pharmacological activities. This compartmentalization poses additional challenges to the cell due to the need to import the substrates into the peroxisomes and to export the final products; the transporters involved in these processes are still very poorly known. This article focuses on new aspects of the metabolic processes occurring in peroxisomes, namely the degradation and detoxification processes that lead to the biosynthesis and secretion of secondary metabolites.

The first step in the penicillin biosynthetic pathway is the non-ribosomal condensation of L-α-aminoadipic acid, L-cysteine and L-valine into the tripeptide δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV). This reaction is catalysed by the multienzyme ACV synthetase (ACVS), which is encoded in the filamentous fungus Penicillium chrysogenum by the pcbAB gene. This enzyme contains at least ten catalytic domains. The precise role of the C-terminal domain of this multidomain NRPS still remains obscure. The C-terminal region of ACVS bears the epimerase and the thioesterase domains and may be involved in the epimerization of LLL-ACV to LLD-ACV and in the hydrolysis of the thioester bond. In this work, the conserved motifs (3371)EGHGRE(3376) (located in the putative epimerase domain) and (3629)GWSFG(3633) (located in the thioesterase domain) were changed by site-directed-mutagenesis to LGFGLL and GWAFG, respectively. In addition, the whole thioesterase domain (230 amino acids) and the different parts of this domain were deleted. The activity of these mutant enzymes was assessed in vivo by two different procedures: i) through the quantification of bisACV produced by the fungus and ii) by quantifying the benzylpenicillin production using tailored strains of P. chrysogenum, which lack the pcbAB gene, as host strains. All indicated mutant enzymes showed lower or null activity than the control strain confirming that E3371, H3373, R3375 and E3376 belong to the epimerase active centre. Different fragments included in the C-terminal region of ACVS control thioester hydrolysis. Overexpression of the sequence encoding the ACVS integrated thioesterase domain as a separate (stand-alone) transcriptional unit complemented mutants lacking the integrated thioesterase domain, although with low ACV releasing activity, suggesting that the stand-alone thioesterease interacts with the other ACVS domains.