Publications by authors named "Ana C Pereira"

49 Publications

Neuronal Network Excitability in Alzheimer's Disease: The Puzzle of Similar versus Divergent Roles of Amyloid β and Tau.

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Apr 23.

Department of Neurology and Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder that commonly causes dementia in the elderly. Recent evidence indicates that network abnormalities, including hypersynchrony, altered oscillatory rhythmic activity, interneuron dysfunction, and synaptic depression, may be key mediators of cognitive decline in AD. In this review, we discuss characteristics of neuronal network excitability in AD, and the role of Aβ and tau in the induction of network hyperexcitability. Many patients harboring genetic mutations that lead to increased Aβ production suffer from seizures and epilepsy before the development of plaques. Similarly, pathologic accumulation of hyperphosphorylated tau has been associated with hyperexcitability in the hippocampus. We present common and divergent roles of tau and Aβ on neuronal hyperexcitability in AD, and hypotheses that could serve as a template for future experiments.
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http://dx.doi.org/10.1523/ENEURO.0418-20.2020DOI Listing
April 2021

Multi-target optimization of solid phase microextraction to analyse key flavour compounds in wort and beer.

Food Chem 2020 Jul 21;317:126466. Epub 2020 Feb 21.

Chemical Process Engineering and Forest Products Research Centre, Department of Chemical Engineering, University of Coimbra, Pólo II - Rua Sílvio Lima, 3030-790, Portugal.

Despite the literature comprises numerous studies dealing with the analysis of wort and beer flavour-related compounds by HS-SPME followed by GC-MS quantification, no generalized consensus exists regarding the optimal conditions for the extraction procedure. The complex chemistry nature of these matrices, the number of analytes, as well as the number and interactions among parameters affecting the extraction performance, requires the adoption of optimal experimental design protocols. This aspect is often overlooked and often not properly addressed in practice. Therefore, in the present work, the optimal conditions under which a range of wort and beer analytes can be extracted and quantified were analysed. The optimal extraction conditions were presented at two levels of aggregation: global (untargeted) and key-flavour analysis. Experimental data was generated by Definitive-Screening-Design, followed by model development and optimization. Both approaches were compared and critically analysed. For vicinal-diketones group, a complete validation study for the optimal conditions is presented.
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http://dx.doi.org/10.1016/j.foodchem.2020.126466DOI Listing
July 2020

The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.

Nat Commun 2020 01 16;11(1):319. Epub 2020 Jan 16.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
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http://dx.doi.org/10.1038/s41467-019-14082-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965647PMC
January 2020

Sex and age differentially affect GABAergic neurons in the mouse prefrontal cortex and hippocampus following chronic intermittent hypoxia.

Exp Neurol 2020 03 16;325:113075. Epub 2019 Dec 16.

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, United States of America; Department of Neurology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, United States of America; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America. Electronic address:

Obstructive sleep apnea (OSA), a chronic sleep disorder characterized by repetitive reduction or cessation of airflow during sleep, is widely prevalent and is associated with adverse neurocognitive sequelae including increased risk of Alzheimer's disease (AD). In humans, OSA is more common in elderly males. OSA is characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), and recent epidemiological studies point to CIH as the best predictor of neurocognitive sequelae associated with OSA. The sex- and age- specific effects of OSA-associated CIH on specific cell populations such as γ-aminobutyric acid (GABA)-ergic neurons in the hippocampus and the medial prefrontal cortex (mPFC), regions important for cognitive function, remain largely unknown. The present study examined the effect of 35 days of either moderate (10% oxygen) or severe (5% oxygen) CIH on GABAergic neurons in the mPFC and hippocampus of young and aged male and female mice as well as post-accelerated ovarian failure (AOF) female mice. In the mPFC and hippocampus, the number of GABA-labeled neurons increased in aged and young severe CIH males compared to controls but not in young moderate CIH males. This change was not representative of the individual GABAergic cell subpopulations, as the number of parvalbumin-labeled neurons decreased while the number of somatostatin-labeled neurons increased in the hippocampus of severe CIH young males only. In all female groups, the number of GABA-labeled cells was not different between CIH and controls. However, in the mPFC, CIH increased the number of parvalbumin-labeled neurons in young females and the number of somatostatin-labeled cells in AOF females but decreased the number of somatostatin-labeled cells in aged females. In the hippocampus, CIH decreased the number of somatostatin-labeled neurons in young females. CIH decreased the density of vesicular GABA transporter in the mPFC of AOF females only. These findings suggest sex-specific changes in GABAergic neurons in the hippocampus and mPFC with males showing an increase of this cell population as compared to their female counterparts following CIH. Age at exposure and severity of CIH also differentially affect the GABAergic cell population in mice.
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http://dx.doi.org/10.1016/j.expneurol.2019.113075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050962PMC
March 2020

Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures.

Proc Natl Acad Sci U S A 2019 10 7;116(43):21800-21811. Epub 2019 Oct 7.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer's disease (AD) patients' brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.
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http://dx.doi.org/10.1073/pnas.1903566116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815169PMC
October 2019

Correction: Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer's disease.

Transl Psychiatry 2019 02 4;9(1):61. Epub 2019 Feb 4.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahiro Okamoto" in the HTML and PDF of the article.
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http://dx.doi.org/10.1038/s41398-019-0408-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362026PMC
February 2019

Rapid Determination of Sotolon in Fortified Wines Using a Miniaturized Liquid-Liquid Extraction Followed by LC-MS/MS Analysis.

J Anal Methods Chem 2018 16;2018:4393040. Epub 2018 Dec 16.

Faculty of Exact Sciences and Engineering, University of Madeira, Campus da Penteada, 9020-105 Funchal, Portugal.

Sotolon (4,5-dimethyl-3-hydroxy-2,5-dihydrofuran-2-one) is a powerful odorant usually pointed out as being responsible not only for the characteristic curry notes of the finest fortified wines but also for the off-flavour notes in prematurely oxidized white wines. Most methods reported in literature for quantifying sotolon in wines are quite laborious and use large volumes of organic solvents. Thus, in the present study, the development of a simple, fast, and environment-friendly method for the quantification of sotolon in fortified wine is herein presented. The proposed method uses a single-step liquid-liquid extraction followed by RP-LC-MS/MS and was optimized using a full factorial design. The method showed good linearity ( = 0.9999), intra- and interday precision lower than 10% RSD, recovery of about 95%, and high sensitivity (LOQ of 0.04 g/L). The method was applied to analyse 44 fortified wines from different styles (from dry to sweet wines) and ages (3-115 years old), and it was found that it covers the concentration range usually found for this compound in this kind of alcoholic beverages, which was found to be within 6.3-810 g/L. Thus, it can be concluded that this method can be used as an accurate tool for the rapid analysis of sotolon, since the early stages of its formation up to long ageing periods.
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http://dx.doi.org/10.1155/2018/4393040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311786PMC
December 2018

Correlation between DNA/HSA-interactions and antimalarial activity of acridine derivatives: Proposing a possible mechanism of action.

J Photochem Photobiol B 2018 Dec 19;189:165-175. Epub 2018 Oct 19.

Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Campus A.C. Simões, 57072-900 Maceió, AL, Brazil. Electronic address:

Acridines are considered an important class of compounds due to their wide variety of biological activities. In this work, we synthesized four acridine derivatives (1-4) and evaluated their biological activity against the Plasmodium falciparum W2 line, as well as studied the interaction with ctDNA and HSA using spectroscopic techniques and molecular docking. The acridine derivative 2 (IC = 0.90 ± 0.08 μM) was more effective against P. falciparum than primaquine (IC = 1.70 ± 0.10 μM) and similar to amsacrine (IC = 0.80 ± 0.10 μM). In the fluorescence and UV-vis assays, it was verified that the acridine derivatives interact with ctDNA and HSA leading to a non-fluorescent supramolecular complex formation. The non-covalent binding constants ranged from 2.09 to 7.76 × 10 M, indicating moderate interaction with ctDNA. Through experiments with KI, fluorescence contact energy transfer and competition assays were possible to characterize the main non-covalent binding mode of the acridines evaluated with ctDNA as intercalation. The binding constants obtained showed a high linear correlation with the IC values against the antimalarial activity, suggesting that DNA may be the main biological target of these molecules. Finally, HSA interaction studies were performed and all evaluated compounds bind to the site II of the protein. The less active compounds (1 and 3) presented the highest affinity to HSA, indicating that the interaction with carrier protein can affect the (bio)availability of these compounds to the biological target.
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http://dx.doi.org/10.1016/j.jphotobiol.2018.10.016DOI Listing
December 2018

Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer's disease.

Transl Psychiatry 2018 08 14;8(1):153. Epub 2018 Aug 14.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Alzheimer's disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole's effect on amyloid beta (Aβ) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid β precursor protein (APP) and presenilin mutations and exhibit early Aβ accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced Aβ42, Aβ40, Aβ oligomers levels, and Aβ plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in NMDA receptor subunits gene expression, which are essential for learning and memory. These data demonstrate that riluzole exerts a disease modifying effect in an Aβ mouse model of early-onset familial AD.
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http://dx.doi.org/10.1038/s41398-018-0201-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092426PMC
August 2018

Nutritional and Phytochemical Composition of Vaccinium padifolium Sm Wild Berries and Radical Scavenging Activity.

J Food Sci 2017 Nov 29;82(11):2554-2561. Epub 2017 Sep 29.

Faculty of Exact Sciences and Engineering, Univ. of Madeira, Campus da Penteada, 9020-105 Funchal, Portugal.

Blueberries have a well-deserved reputation as a potential functional food, supported by studies which have identified and quantified various nutrients and bioactive phytochemicals with known benefits for human diet and health. Wild blueberries have attracted particular attention due to the levels and concentrations of those phytonutrients. This study aims to evaluate for the first time the chemical composition of Madeira Island's endemic Vaccinium padifolium Sm wild berry. Results show that this fruit contains high values of total soluble phenolic content (around 4 g GAE kg FW), as well as significant values of total monomeric anthocyanin content (around 3 g eq. cyanidin kg FW) and DPPH scavenging activity (around 86.72%). Additionally, results reveal that this fruit has water content of about 88% as well as low sugar content (17.98 and 29.73 g kg for glucose and fructose, respectively). Results also confirm that this wild blueberry is a good source of dietary fiber, fat and minerals. The high level of terpenoid compounds stands out in the aroma profile analysis.

Practical Application: This study is in line with the efforts of the scientific community to identify new sources of phytonutrients that are beneficial to human health, characterizing the wild Madeira blueberry in terms of phytonutrients that suggest there may be health benefits associated with its consumption. The findings of this research are very important for both the commercial and agricultural sectors that produce this fruit, and for consumers who seek phytonutrient-rich foods.
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http://dx.doi.org/10.1111/1750-3841.13928DOI Listing
November 2017

Dorsolateral prefrontal cortex GABA deficit in older adults with sleep-disordered breathing.

Proc Natl Acad Sci U S A 2017 09 5;114(38):10250-10255. Epub 2017 Sep 5.

Laboratory for Advanced MRS Research, Department of Radiology, Weill Cornell Medicine, New York, NY 10065;

Sleep-disordered breathing (SDB) is a common disorder in aging that is associated with cognitive decline, including significant executive dysfunction, for which the neurobiological underpinnings remain poorly understood. Using proton magnetic resonance spectroscopy (1H MRS), this study assessed whether dysregulation of the homeostatic balance of the major inhibitory and excitatory amino acid neurotransmitter systems of γ-aminobutyric acid (GABA) and glutamate, respectively, play a role in SDB. Levels of GABA and those of the combined resonances of glutamate and glutamine (Glx), were measured by 1H MRS in the left dorsolateral prefrontal cortex (l-DLPFC) and bilateral hippocampal regions of 19 older adults (age ± SD: 66.1 ± 1.9 years) with moderate to severe SDB, defined as having an Apnea-Hypopnea Index (AHI) greater than 15 as assessed by polysomnography, and in 14 older adults (age ± SD: 62.3 ± 1.3 years) without SDB (AHI < 5). In subjects with SDB, levels of l-DLPFC GABA, but not Glx, were significantly lower than in control subjects ( < 0.0002). Additionally, there was a negative correlation between l-DLPFC GABA levels, but not Glx, and SDB severity by AHI ( = -0.68, < 0.0001), and a positive correlation between l-DLPFC GABA levels, but not Glx, and minimal oxygen saturation during sleep ( = 0.62, = 0.0005). By contrast, no group differences or oxygenation associations were found for levels of GABA or Glx in right or left hippocampal region. These findings are interpreted in terms of a pathophysiological model of SDB in which hypoxia-mediated inhibitory neurotransmission deficit in DLPFC could lead to hyperexcitability and, potentially neuronal dysfunction and cognitive decline.
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http://dx.doi.org/10.1073/pnas.1700177114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617247PMC
September 2017

Advanced predictive methods for wine age prediction: Part II - A comparison study of multiblock regression approaches.

Talanta 2017 Aug 29;171:132-142. Epub 2017 Apr 29.

CIEPQPF, Department of Chemical Engineering, University of Coimbra, Rua Sílvio Lima, 3030-790 Coimbra, Portugal. Electronic address:

In this article, we extend the scope of the first paper of the sequel, which was dedicated to the analysis of advanced single-block regression methods (Rendall et al., 2016) [1], to the class of multiblock regression approaches. The datasets contemplated for developing the multiblock approaches are the same as in the former publication: volatile, polyphenols, organic acids composition and the UV-Vis spectra. The context is still the prediction of the ageing time of one of finest Portuguese fortified wines, the Madeira Wine, but now the data collected from the different analytical sources is explored simultaneously, in a more structured and informative way, through multiblock methodologies. The goal of this paper is to provide a critical assessment of a rich variety of multiblock regression methods, namely: Concatenated PLS, Multiblock PLS (MBPLS), Hierarchical PLS (HPLS), Network-Induced Supervised Learning (NI-SL) and Sequential Orthogonalised Partial Least Squares (SO-PLS). A comparison of block scaling methods was also undertaken for the Concatenated PLS algorithm, and new block scaling methods were proposed that led to better prediction performances. This study explores and reveals the potential advantages of applying multiblock methods for fusing datasets from different sources, from both the predictive and interpretability perspectives.
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http://dx.doi.org/10.1016/j.talanta.2017.04.064DOI Listing
August 2017

In vitro Activities of Pfaffia glomerata Root Extract, Its Hydrolyzed Fractions and Pfaffic Acid Against Trypanosoma cruzi Trypomastigotes.

Chem Biodivers 2017 Jan 3;14(1). Epub 2017 Jan 3.

School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

This article reports on the in vitro activity of the hydroalcoholic extract of Pfaffia glomerata roots, its hydrolyzed fractions, and pfaffic acid against Trypanosoma cruzi. The hydroalcoholic extract obtained from dried, milled P. glomerata roots was submitted to acid hydrolysis followed by partition with CHCl . The concentrated CHCl fraction was suspended in MeOH/H O and partitioned with hexane (F1), CHCl (F2), and AcOEt (F3), in this sequence. The trypanocidal activity of the hydrolyzed extract and its fractions was evaluated in vitro. The hydroalcoholic extract displayed low activity, but fraction F1 was active against trypomastigotes of the Y strain of T. cruzi, with IC = 47.89 μg/ml. The steroids campesterol (7.7%), stigmasterol (18.7%), β-sitosterol (16.8%), Δ -stigmastenol (4.6%), and Δ -spinasterol (7.5%) were the major constituents of F1, along with fatty acid esters (7.6%) and eight aliphatic hydrocarbons (30.1%). Fractions F2 and F3 exhibited moderate activity, and pfaffic acid, one of the main chemical constituents of these fractions, displayed IC = 44.78 μm (21.06 μg/ml). On the other hand, the hydroalcoholic extract of P. glomerata roots, which is rich in pfaffosides, was inactive. Therefore, the main aglycone of pfaffosides, pfaffic acid, is much more active against trypomastigotes of the Y strain of T. cruzi than its corresponding glycosides and should be further investigated.
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http://dx.doi.org/10.1002/cbdv.201600175DOI Listing
January 2017

Inactivation of plant-pathogenic fungus Colletotrichum acutatum with natural plant-produced photosensitizers under solar radiation.

J Photochem Photobiol B 2016 Sep 9;162:402-411. Epub 2016 Jul 9.

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil. Electronic address:

The increasing tolerance to currently used fungicides and the need for environmentally friendly antimicrobial approaches have stimulated the development of novel strategies to control plant-pathogenic fungi such as antimicrobial phototreatment (APT). We investigated the in vitro APT of the plant-pathogenic fungus Colletotrichum acutatum with furocoumarins and coumarins and solar radiation. The compounds used were: furocoumarins 8-methoxypsoralen (8-MOP) and 5,8-dimethoxypsoralen (isopimpinellin), coumarins 2H-chromen-2-one (coumarin), 7-hydroxycoumarin, 5,7-dimethoxycoumarin (citropten) and a mixture (3:1) of 7-methoxycoumarin and 5,7-dimethoxycoumarin. APT of conidia with crude extracts from 'Tahiti' acid lime, red and white grapefruit were also performed. Pure compounds were tested at 50μM concentration and mixtures and extracts at 12.5mgL(-1). The C. acutatum conidia suspension with or without the compounds was exposed to solar radiation for 1h. In addition, the effects of APT on the leaves of the plant host Citrus sinensis were determined. APT with 8-MOP was the most effective treatment, killing 100% of the conidia followed by the mixture of two coumarins and isopimpinellin that killed 99% and 64% of the conidia, respectively. APT with the extracts killed from 20% to 70% of the conidia, and the extract from 'Tahiti' lime was the most effective. No damage to sweet orange leaves was observed after APT with any of the compounds or extracts.
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http://dx.doi.org/10.1016/j.jphotobiol.2016.07.009DOI Listing
September 2016

Optimal design of experiments applied to headspace solid phase microextraction for the quantification of vicinal diketones in beer through gas chromatography-mass spectrometric detection.

Anal Chim Acta 2015 Aug 10;887:101-110. Epub 2015 Aug 10.

Centre of Exact Sciences and Engineering, University of Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.

Vicinal diketones, namely diacetyl (DC) and pentanedione (PN), are compounds naturally found in beer that play a key role in the definition of its aroma. In lager beer, they are responsible for off-flavors (buttery flavor) and therefore their presence and quantification is of paramount importance to beer producers. Aiming at developing an accurate quantitative monitoring scheme to follow these off-flavor compounds during beer production and in the final product, the head space solid-phase microextraction (HS-SPME) analytical procedure was tuned through experiments planned in an optimal way and the final settings were fully validated. Optimal design of experiments (O-DOE) is a computational, statistically-oriented approach for designing experiences that are most informative according to a well-defined criterion. This methodology was applied for HS-SPME optimization, leading to the following optimal extraction conditions for the quantification of VDK: use a CAR/PDMS fiber, 5 ml of samples in 20 ml vial, 5 min of pre-incubation time followed by 25 min of extraction at 30 °C, with agitation. The validation of the final analytical methodology was performed using a matrix-matched calibration, in order to minimize matrix effects. The following key features were obtained: linearity (R(2) > 0.999, both for diacetyl and 2,3-pentanedione), high sensitivity (LOD of 0.92 μg L(-1) and 2.80 μg L(-1), and LOQ of 3.30 μg L(-1) and 10.01 μg L(-1), for diacetyl and 2,3-pentanedione, respectively), recoveries of approximately 100% and suitable precision (repeatability and reproducibility lower than 3% and 7.5%, respectively). The applicability of the methodology was fully confirmed through an independent analysis of several beer samples, with analyte concentrations ranging from 4 to 200 g L(-1).
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http://dx.doi.org/10.1016/j.aca.2015.06.044DOI Listing
August 2015

In vitro and in vivo anthelmintic activity of (-)-6,6'-dinitrohinokinin against schistosomula and juvenile and adult worms of Schistosoma mansoni.

Acta Trop 2015 Sep 10;149:195-201. Epub 2015 Jun 10.

Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, CEP 14404-600 Franca, SP, Brazil. Electronic address:

The chemotherapy of schistosomiasis relies on the use of praziquantel. However, concerns over drug resistance have encouraged the search for new drug leads. This paper is the first report on the in vitro and in vivo activity of (-)-6,6'-dinitrohinokinin (DNK) against Schistosoma mansoni. In vitro, the lethal concentrations for 50% of parasites (LC50) of DNK against adult worms were 103.9±3.6 and 102.5±4.8μM at 24 and 72h, respectively. Scanning electron microscopy images showed extensive tegumental alterations such as peeling and smaller numbers of tubercles in the spine of adult worms. DNK also elicited high mortality of schistosomula, with LC50 values of 57.4±2.3, 32.5±0.9, and 20.4±1.2μM at 24, 48, and 72h, respectively. DNK displayed moderate activity against the juvenile liver parasite, with an LC50 value of 179.5±2.3 μM at 72h. This compound reduced the total number of eggs by over 83%, and it affected the development of eggs produced by adult worms. The selectivity index showed that at 24h, DNK was 8.5 and 15.4 times more toxic to the adult worms and schistosomula than to Chinese hamster lung fibroblast cells, respectively. Treatment of infected mice with DNK moderately decreased worm burden (33.8-52.3%), egg production (40.7-60.0%), and spleen and liver weights. Together, our results indicated that DNK presents moderate in vitro and in vivo activities against S. mansoni, and it might therefore be interesting to explore the structure-activity relationship of the antischistosomal activity of this compound.
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http://dx.doi.org/10.1016/j.actatropica.2015.06.005DOI Listing
September 2015

Microbial community dynamics associated with veterinary antibiotics removal in constructed wetlands microcosms.

Bioresour Technol 2015 Apr 31;182:26-33. Epub 2015 Jan 31.

Centro Interdisciplinar de Investigação Marinha e Ambiental, CIIMAR/CIMAR, Universidade do Porto, Rua dos Bragas, 289, 4050-123 Porto, Portugal. Electronic address:

This study aimed to evaluate the response of the microbial community from CWs microcosms tested for the removal of two veterinary antibiotics, enrofloxacin (ENR) and tetracycline (TET), from livestock industry wastewater. Three treatments were tested (control, ENR or TET (100 μg L(-1))) over 12 weeks in microcosms unplanted and planted with Phragmites australis. CWs removal efficiency was relatively stable along time, with removals higher than 98% for ENR and 94% for TET. In addition, CWs were able to reduce wastewater toxicity, independently of antibiotics presence. Despite no significant differences were observed in terms of microbial abundance, bacterial richness or diversity, analysis of similarities (two-way crossed ANOSIM) showed a significant effect of both time and treatments in bacterial community structure. This study points to CWs applicability for veterinary antibiotics removal from livestock wastewaters, showing that CWs microbial communities were able to adapt without significant changes in their diversity or depuration capacity.
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http://dx.doi.org/10.1016/j.biortech.2015.01.096DOI Listing
April 2015

Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering.

Proc Natl Acad Sci U S A 2014 Dec 15;111(52):18733-8. Epub 2014 Dec 15.

Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, The Friedman Brain Institute, and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029

The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age-related cognitive decline has been linked to synapse loss and/or alterations of synaptic proteins that impair function in regions such as the hippocampus and prefrontal cortex. These synaptic alterations are likely reversible, such that maintenance of synaptic health in the face of aging is a critically important therapeutic goal. Here, we show that riluzole can protect against some of the synaptic alterations in hippocampus that are linked to age-related memory loss in rats. Riluzole increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals. Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength. These findings further elucidate neuroplastic changes in glutamatergic circuits with aging and advance therapeutic development to prevent and treat age-related cognitive decline.
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http://dx.doi.org/10.1073/pnas.1421285111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284552PMC
December 2014

Chemical shift assignments and secondary structure determination of the ectodomain of Bacillus subtilis morphogenic protein RodZ.

Biomol NMR Assign 2015 Oct 11;9(2):285-8. Epub 2014 Dec 11.

Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal.

RodZ (also known as YfgA) is a component of the core bacterial morphogenic apparatus. RodZ is a key cell shape determinant in rod-shaped bacteria and it interacts with the actin-like cytoskeletal protein MreB. In Bacillus subtilis, this 304-residue transmembrane protein is composed of three distinct domains: a cytoplasmic domain (RodZn), a transmembrane domain, and an extra-cytoplasmic domain (RodZc). Here we report the (1)H, (13)C and (15)N backbone and side chain resonance assignments of the RodZc domain from B. subtilis by NMR spectroscopy, and the resulting secondary structure prediction.
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http://dx.doi.org/10.1007/s12104-014-9593-8DOI Listing
October 2015

Oxidative stress in pregnancy and fertility pathologies.

Cell Biol Toxicol 2014 Oct 17;30(5):301-12. Epub 2014 Jul 17.

Unit of Molecular Mechanisms of Disease (CISA) and Chemical and Biomolecular Sciences, School of Allied Health Sciences, Polytechnic Institute of Porto (ESTSP-IPP), Porto, Portugal.

Oxidative stress designates the state of imbalance between reactive oxygen species (ROS) production and antioxidant levels. In a healthy placenta, there is an increase in ROS production, due to formation of new tissues and inherent metabolism, but this is balanced by higher levels of antioxidants. However, this balance is lost in some situations, with a consequent increase in oxidative stress levels. Oxidative stress has been implicated in several placental disorders and pregnancy pathologies. The present review intends to summarize what is known about the relationship between oxidative stress and well-known pregnancy disorders.
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http://dx.doi.org/10.1007/s10565-014-9285-2DOI Listing
October 2014

Furocoumarins and coumarins photoinactivate Colletotrichum acutatum and Aspergillus nidulans fungi under solar radiation.

J Photochem Photobiol B 2014 Feb 22;131:74-83. Epub 2014 Jan 22.

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil; Research Support Center in Natural and Synthetic Products, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil. Electronic address:

The increasing tolerance to currently-used fungicides is a major problem both in clinical and agricultural areas leading to an urgent need for the development of novel antifungal strategies. This study investigated the in vitro antimicrobial photo treatment (APT) of conidia of the plant-pathogenic fungus Colletotrichum acutatum and the ascomycete Aspergillus nidulans with the furocoumarins 8-methoxypsoralen (8-MOP) and isopimpinellin, and a mixture of two coumarins (7-methoxy coumarin and citropten). Subcellular localization of the photosensitizer 8-MOP was also determined in C. acutatum conidia. Additionally, the effects of APT on the leaves of the plant host Citrus sinensis were determined. APT with 8-MOP (50μM) led to a reduction of approximately 4 logs in the survival of the conidia of both species, and the mixture of the two coumarins (12.5mgL(-1)) resulted in a reduction of approximately 4 logs for A. nidulans and 3 logs for C. acutatum. Isopimpinellin (50μM) displayed a reduction of 4 logs for A. nidulans but less than 2 logs for C. acutatum. Washing the conidia to remove unbound photosensitizers before light exposure reduced the photodynamic inactivation of C. acutatum both with 8-MOP and the mixture of the two coumarins. The reduction was smaller for A. nidulans. 8-MOP spread throughout the cytoplasm and accumulated in structures such as lipid bodies of C. acutatum conidia. No damage to orange tree leaves was observed after APT with any of the photosensitizers.
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http://dx.doi.org/10.1016/j.jphotobiol.2014.01.008DOI Listing
February 2014

Rapid and sensitive methodology for determination of ethyl carbamate in fortified wines using microextraction by packed sorbent and gas chromatography with mass spectrometric detection.

Anal Chim Acta 2014 Feb 21;811:29-35. Epub 2013 Dec 21.

Centre of Exact Sciences and Engineering, University of Madeira, Campus da Penteada, 9000-390 Funchal, Portugal; Institute of Nanostructures, Nanomodelling and Nanofabrication (I3N), University of Aveiro, Aveiro, Portugal.

This work presents a new methodology to quantify ethyl carbamate (EC) in fortified wines. The presented approach combines the microextraction by packed sorbent (MEPS), using a hand-held automated analytical syringe, with one-dimensional gas chromatography coupled with mass spectrometry detection (GC-MS). The performance of different MEPS sorbent materials was tested, namely SIL, C2, C8, C18, and M1. Also, several extraction solvents and the matrix effect were evaluated. Experimental data showed that C8 and dichloromethane were the best sorbent/solvent pair to extract EC. Concerning solvent and sample volumes optimization used in MEPS extraction an experimental design (DoE) was carried out. The best extraction yield was achieved passing 300 μL of sample and 100 μL of dichloromethane. The method validation was performed using a matrix-matched calibration using both sweet and dry fortified wines, to minimize the matrix effect. The proposed methodology presented good linearity (R(2)=0.9999) and high sensitivity, with quite low limits of detection (LOD) and quantification (LOQ), 1.5 μg L(-1) and 4.5 μg L(-1), respectively. The recoveries varied between 97% and 106%, while the method precision (repeatability and reproducibility) was lower than 7%. The applicability of the methodology was confirmed through the analysis of 16 fortified wines, with values ranging between 7.3 and 206 μg L(-1). All chromatograms showed good peak resolution, confirming its selectivity. The developed MEPS/GC-MS methodology arises as an important tool to quantify EC in fortified wines, combining efficiency and effectiveness, with simpler, faster and affordable analytical procedures that provide great sensitivity without using sophisticated and expensive equipment.
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http://dx.doi.org/10.1016/j.aca.2013.12.018DOI Listing
February 2014

Oxidative stress induced by tert-butylhydroperoxide interferes with the placental transport of glucose: in vitro studies with BeWo cells.

Eur J Pharmacol 2013 Nov;720(1-3):218-26

Increased oxidative stress is implicated in the onset and progression of prevalent pregnancy disorders (e.g. gestational diabetes and fetal growth restriction),and in programming the fetus to develop metabolic diseases later in life.Since the molecular mechanisms underlying these effects of oxidative stress are largely unexplored, we aimed to investigate if the placental transport of glucose – the main energetic substrate for the fetus and placenta – is altered by oxidative stress.In a human syncytiotrophoblast (STB)cell model, the BeWo cell line,oxidative stress was induced by treatment with 100 mM tert-butylhydroperoxide(tert-BOOH) for 24 h. Tert-BOOH decreased the steady-state intracellular accumulation (Amax) of[3H]2-deoxyglucose([3H]DG) mediated by both facilitative(GLUT) and non-facilitative(non-GLUT)glucose transporters.These effects were not associated with a change in the mRNA expression level of GLUT1, the major placental glucose transporter. Also,they seemed to be independent from phosphoinositide 3-kinase and protein kinase C signaling pathways and were unchanged either by inhibitors of free radical-generating enzymes or by free radical scavengers. In contrast, the dietary polyphenols quercetin, epigallocatechin-3-gallate and resveratrol completely reversed the inhibitory effect of tert-BOOH upon[3H]DG accumulation through a specific effect on GLUT-mediated transport. Finally, tert-BOOH induced an increase in the transepithelial permeability to [3H]DG in the apical-to-basal direction, apparently related to an increase in its paracellular transport. In conclusion, tert-BOOH-induced oxidative stress reduces STB accumulation of glucose associated with an increase in its transepithelial permeability. This effect may contribute to the deleterious consequences of pregnancy disorders associated with oxidative stress.
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November 2013

Anterior disconnection syndrome revisited using modern technologies.

Neurology 2012 Jul 3;79(3):290-1. Epub 2012 Jul 3.

Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.

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http://dx.doi.org/10.1212/WNL.0b013e31825fdf73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398430PMC
July 2012

Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling.

J Clin Immunol 2012 Oct 17;32(5):1059-70. Epub 2012 Apr 17.

King's College London, King's Health Partners Integrated Cancer Center, Department of Research Oncology, Guy's Hospital Campus, Great Maze Pond, London, SE1 9RT, UK.

Purpose: Chimeric antigen receptor (CAR) engineered T-cells occupy an increasing niche in cancer immunotherapy. In this context, CAR-mediated CD3ζ signaling is sufficient to elicit cytotoxicity and interferon-γ production while the additional provision of CD28-mediated signal 2 promotes T-cell proliferation and interleukin (IL)-2 production. This compartmentalisation of signaling opens the possibility that complementary CARs could be used to focus T-cell activation within the tumor microenvironment.

Methods: Here, we have tested this principle by co-expressing an ErbB2- and MUC1-specific CAR that signal using CD3ζ and CD28 respectively. Stoichiometric co-expression of transgenes was achieved using the SFG retroviral vector containing an intervening Thosea asigna peptide.

Results: We found that "dual-targeted" T-cells kill ErbB2(+) tumor cells efficiently and proliferate in a manner that requires co-expression of MUC1 and ErbB2 by target cells. Notably, however, IL-2 production was modest when compared to control CAR-engineered T-cells in which signaling is delivered by a fused CD28 + CD3ζ endodomain.

Conclusions: These findings demonstrate the principle that dual targeting may be achieved using genetically targeted T-cells and pave the way for testing of this strategy in vivo.
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http://dx.doi.org/10.1007/s10875-012-9689-9DOI Listing
October 2012

Development of a fast and reliable method for long- and short-term wine age prediction.

Talanta 2011 Oct 16;86:293-304. Epub 2011 Sep 16.

CIEPQPF, Department of Chemical Engineering, University of Coimbra, Pólo II - Rua Sílvio Lima, 3030-790 Coimbra, Portugal.

Wine age prediction based on its intrinsic characteristics can provide significant assistance to oenologists' quality evaluations, concerning wine ageing process control and wine quality assurance. Simpler, faster, cheaper and affordable analytical procedures would be greatly welcome to establish such a practice. In this study, we present a new and reliable strategy to predict wine age, in the long and short-term, centered on the use of wine UV-vis absorbance data, coupled with proper chemometric techniques. The strategy followed consists essentially in first pre-processing the UV-vis data, secondly to carry out variable selection over such pre-processed data sets, and finally to use the set of selected variables for developing a PLS model focused on wine age prediction. We tested different data pre-processing methodologies, namely first and second derivatives, multiplicative scatter correction, standard normal variate and orthogonal signal correction, as well as different variable selection approaches, specifically interval partial least squares, VIPS, genetic algorithms and the wavelet transformation combined with a genetic algorithm. In both case studies, regarding long and short-term ageing periods, we have found out that it is indeed possible to predict wine ages, in our case Madeira wine ages, with an accuracy of 1.4 years for longer ageing periods, and of 3 months for wines of an age comprised in the first two years of ageing. The genetic algorithm revealed to be very useful for proper wavelet coefficients selection, leading to the most parsimonious model among all those analyzed, which also presents the best predictive performance found.
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http://dx.doi.org/10.1016/j.talanta.2011.09.016DOI Listing
October 2011

Genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar affective disorder.

Am J Med Genet B Neuropsychiatr Genet 2011 Mar 13;156(2):177-87. Epub 2011 Jan 13.

Molecular Psychiatry Laboratory, Department of Mental Health Sciences, Windeyer Institute of Medical Sciences, University College London, 46 Cleveland Street, London, UK.

Insulin-like growth factor 1 (IGF1) has been shown to have an important role in brain development and function. Studies of IGF1 administration in rodents have shown that it has an anxiolytic and antidepressant effect. A genome-wide association study (GWAS) of the first University College London (UCL) cohort of 506 bipolar affective disorder subjects and 510 controls was carried out. The exons and flanking regions of IGF1 were resequenced, any new polymorphisms found were genotyped in an enlarged UCL sample of 937 cases and 941 controls. GWAS data gave good evidence of allelic and haplotypic association between multiple IGF1 SNP's and bipolar disorder (BD). New polymorphisms were found by resequencing IGF1 region. Data from GWAS and the new markers showed that twelve out of 43 SNPs showed association with BD with the four most significant SNPs having values of 3.7 × 10(-5) , 8.4 × 10(-4) , 2.6 × 10(-4) , and 2.5 × 10(-4) . A 5' promoter microsatellite polymorphism previously correlated with plasma lipoprotein concentration was also associated with BD (P = 0.013). Haplotypic association confirmed association with BD with significance values similar to the single marker SNP values. The marker rs12426318 has also been found to be associated with BD in a second sample. A test of gene wide significance with permutation testing for all markers genotyped at IGF1 was also significant. These data implicate IGF1 as a candidate gene to cause genetic susceptibility to BD.
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http://dx.doi.org/10.1002/ajmg.b.31153DOI Listing
March 2011

Improvement of recombinant protein production by an anti-apoptotic protein from hemolymph of Lonomia obliqua.

Cytotechnology 2010 Dec 10;62(6):547-55. Epub 2010 Oct 10.

Instituto de Biologia Experimental e Tecnologia/Instituto de Tecnologia Química e Biológica IBET/ITQB -UNL, Apartado 12, 2781-901, Oeiras, Portugal.

Apoptosis is a major problem in animal cell culture during production of biopharmaceuticals, such as recombinant proteins or viral particles. In the present work baculovirus-insect cell expression system (BEVS/IC) is used as model to produce rotavirus like-particles, composed by three layers of three different viral proteins (VP2, VP6 and VP7). In this model baculovirus infection also induces host cell death. Herein a new strategy to enhance cell life span and to increase recombinant rotavirus protein production of BEVS/IC system was developed. This strategy relies on hemolymph from Lonomia oblique (total extracts or a semi-purified fraction) medium supplementation. The total extract and a purified fraction from hemolymph of Lonomia obliqua were able to protect Sf-9 cell culture against apoptosis triggered by oxidative stress (using the pro-oxidant agents tert butylhydroperoxide and hydrogen peroxide) and by baculovirus infection. Furthermore, hemolymph enhance final recombinant protein production, as it was observed by the increased amounts of VP6 and VP7, which were measured by the semi-quantitative western blot method. In conclusion, hemolymph medium supplementation can be a promising strategy to improve cell viability and productivity of recombinant protein in BEVS/IC system.
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http://dx.doi.org/10.1007/s10616-010-9305-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995147PMC
December 2010

Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4.

J Biol Chem 2010 Aug 18;285(33):25538-44. Epub 2010 Jun 18.

Division of Cancer Studies, Research Oncology Section, Guy's Hospital Campus, King's College London School of Medicine, London, United Kingdom.

Polyclonal T-cells can be directed against cancer using transmembrane fusion molecules known as chimeric antigen receptors (CARs). Although preclinical studies have provided encouragement, pioneering clinical trials using CAR-based immunotherapy have been disappointing. Key obstacles are the need for robust expansion ex vivo followed by sustained survival of infused T-cells in patients. To address this, we have developed a system to achieve selective proliferation of CAR(+) T-cells using IL-4, a cytokine with several pathophysiologic and therapeutic links to cancer. A chimeric cytokine receptor (4alphabeta) was engineered by fusion of the IL-4 receptor alpha (IL-4Ralpha) ectodomain to the beta(c) subunit, used by IL-2 and IL-15. Addition of IL-4 to T-cells that express 4alphabeta resulted in STAT3/STAT5/ERK phosphorylation and exponential proliferation, mimicking the actions of IL-2. Using receptor-selective IL-4 muteins, partnering of 4alphabeta with gamma(c) was implicated in signal delivery. Next, human T-cells were engineered to co-express 4alphabeta with a CAR specific for tumor-associated MUC1. These T-cells exhibited an unprecedented capacity to elicit repeated destruction of MUC1-expressing tumor cultures and expanded through several logs in vitro. Despite prolonged culture in IL-4, T-cells retained specificity for target antigen, type 1 polarity, and cytokine dependence. Similar findings were observed using CARs directed against two additional tumor-associated targets, demonstrating generality of application. Furthermore, this system allows rapid ex vivo expansion and enrichment of engineered T-cells from small blood volumes, under GMP-compliant conditions. Together, these findings provide proof of principle for the development of IL-4-enhanced T-cell immunotherapy of cancer.
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http://dx.doi.org/10.1074/jbc.M110.127951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919118PMC
August 2010

Antimycobacterial activity of natural and semi-synthetic lignans.

Z Naturforsch C J Biosci 2009 Nov-Dec;64(11-12):779-84

Universidade de Franca, Av. Dr. Armando Salles de Oliveira, 201, CEP 14404-600--Franca, SP, Brazil.

The antimycobacterial activity of (-)-cubebin (1), hinokinin (2), and some of their semisynthetic derivatives, namely (-)-O-acetyl-cubebin (3), (-)-O-methyl-cubebin (4), (-)-O-(N,N-dimethylamine-ethyl)-cubebin (5) and (-)-6,6'-dinitrohinokinin (6), was evaluated against Mycobacterium tuberculosis (ATCC 27294), M. kansasii (ATCC 12478), and M. avium (ATCC 15769). The MIC values ranged from 31.25 to 2000 microg/mL. Among the evaluated compounds, 2 displayed a MIC value of 62.5 microg/mL against M. tuberculosis, while 3 and 4 displayed MIC values of 62.5 and 31.25 microg/mL, respectively, against M. avium. All compounds were inactive against M. kansasii. These are promising results concerning the search for biologically active natural products, highlighting that new approaches to the prevention, treatment, and cure of tuberculosis are extremely important.
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http://dx.doi.org/10.1515/znc-2009-11-1204DOI Listing
April 2010