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1.  A cytotoxic dimeric furanoheliangolide from Piptocoma rufescens 
Tetrahedron letters  2013;54(40):5457-5460.
A new sesquiterpene lactone, rufescenolide C (1), the first furanoheliangolide dimer, was isolated from the leaves of Piptocoma rufescens, collected in the Dominican Republic. Its structure was determined by analysis of its spectroscopic data, with the absolute configuration being established by analysis of the CD spectrum. A plausible biogenesis of this dimer is proposed. This compound showed potent cytotoxicity with an IC50 value of 150 nM, when tested against HT-29 human colon cancer cells.
PMCID: PMC3804354  PMID: 24159245
Piptocoma rufescens; Furanoheliangolide dimer; Cytotoxicity
2.  From imitation to meaning: circuit plasticity and the acquisition of a conventionalized semantics 
The capacity for language is arguably the most remarkable innovation of the human brain. A relatively recent interpretation prescribes that part of the language-related circuits were co-opted from circuitry involved in hand control—the mirror neuron system (MNS), involved both in the perception and in the execution of voluntary grasping actions. A less radical view is that in early humans, communication was opportunistic and multimodal, using signs, vocalizations or whatever means available to transmit social information. However, one point that is not yet clear under either perspective is how learned communication acquired a semantic property thereby allowing us to name objects and eventually describe our surrounding environment. Here we suggest a scenario involving both manual gestures and learned vocalizations that led to the development of a primitive form of conventionalized reference. This proposal is based on comparative evidence gathered from other species and on neurolinguistic evidence in humans, which points to a crucial role for vocal learning in the early development of language. Firstly, the capacity to direct the attention of others to a common object may have been crucial for developing a consensual referential system. Pointing, which is a ritualized grasping gesture, may have been crucial to this end. Vocalizations also served to generate joint attention among conversants, especially when combined with gaze direction. Another contributing element was the development of pantomimic actions resembling events or animals. In conjunction with this mimicry, the development of plastic neural circuits that support complex, learned vocalizations was probably a significant factor in the evolution of conventionalized semantics in our species. Thus, vocal imitations of sounds, as in onomatopoeias (words whose sound resembles their meaning), are possibly supported by mirror system circuits, and may have been relevant in the acquisition of early meanings.
PMCID: PMC4126550  PMID: 25152726
imitation; language; circuit plasticity; onomatopoeia; pantomime; semantics
3.  GABAergic Alterations in Neocortex of Patients with Pharmacoresistant Temporal Lobe Epilepsy Can Explain the Comorbidity of Anxiety and Depression: The Potential Impact of Clinical Factors 
Temporal lobe epilepsy (TLE) is a chronic neurodegenerative disease with a high prevalence of psychiatric disorders. Temporal neocortex contributes to either seizure propagation or generation in TLE, a situation that has been associated with alterations of the γ-amino-butyric acid (GABA) system. On the other hand, an impaired neurotransmission mediated by GABA in temporal neocortex has also been involved with the pathophysiology of psychiatric disorders. In spite of these situations, the role of the necortical GABA system in the comorbidity of TLE and mood disorders has not been investigated. The present study was designed to identify alterations in the GABA system such as binding to GABAA and GABAB receptors and benzodiazepine site, the tissue content of GABA and the expression of the mRNA encoding the α1–6, β1–3, and γ GABAA subunits, in the temporal neocortex of surgically treated patients with TLE with and without anxiety, and/or depression. Neocortex of patients with TLE and comorbid anxiety and/or depression showed increased expression of the mRNA encoding the γ2-subunit, reduced GABAB-induced G-protein activation in spite of elevated GABAB binding, and lower tissue content of GABA when compared to autopsy controls. Some of these changes significantly correlated with seizure frequency and duration of epilepsy. The results obtained suggest a dysfunction of the GABAergic neurotransmission in temporal neocortex of patients with TLE and comorbid anxiety and/or depression that could be also influenced by clinical factors such as seizure frequency and duration of illness.
PMCID: PMC4283637  PMID: 25601827
GABA receptors; G-protein; temporal lobe epilepsy; temporal neocortex; anxiety; depression
4.  Cytotoxic and NF-κB inhibitory sesquiterpene lactones from Piptocoma rufescens 
Tetrahedron  2012;68(12):2671-2678.
Six new (1–6) and eight known germacranolide-type sesquiterpene lactones, along with several known phenylpropanol coumarates and methylated flavonoids, were isolated from the leaves of Piptocoma rufescens, collected in the Dominican Republic. The new compounds were identified by analysis of their spectroscopic data, with the molecular structure of 3 being established by single-crystal X-ray diffraction. The absolute configurations of the sesquiterpene lactones isolated were determined from their CD and NOESY NMR spectra, together with the analysis of Mosher ester reactions. Bioassay screening results showed the majority of the sesquiterpene lactones isolated (1–13) to be highly cytotoxic toward the HT-29 human colon cancer cell line, with the most potent compound being 15-deoxygoyazensolide (10, IC50, 0.26 µM). In addition, several of the sesquiterpene lactones exhibited NF-κB (p65) inhibitory activity.
PMCID: PMC3369275  PMID: 22685350
Piptocoma rufescens; Goyazensolide-type sesquiterpene lactones; Germacranolide-type sesquiterpene lactones; Cytotoxicity for HT-29 human colon cancer cells; NF-κB (p65) inhibition assay
5.  11β-Hydroxysteroid Dehydrogenase Type 1 Gene Knockout Attenuates Atherosclerosis and In Vivo Foam Cell Formation in Hyperlipidemic apoE−/− Mice 
PLoS ONE  2013;8(2):e53192.
Chronic glucocorticoid excess has been linked to increased atherosclerosis and general cardiovascular risk in humans. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) increases active glucocorticoid levels within tissues by catalyzing the conversion of cortisone to cortisol. Pharmacological inhibition of 11βHSD1 has been shown to reduce atherosclerosis in murine models. However, the cellular and molecular details for this effect have not been elucidated.
Methodology/Principal Findings
To examine the role of 11βHSD1 in atherogenesis, 11βHSD1 knockout mice were created on the pro-atherogenic apoE−/− background. Following 14 weeks of Western diet, aortic cholesterol levels were reduced 50% in 11βHSD1−/−/apoE−/− mice vs. 11βHSD1+/+/apoE−/− mice without changes in plasma cholesterol. Aortic 7-ketocholesterol content was reduced 40% in 11βHSD1−/−/apoE−/− mice vs. control. In the aortic root, plaque size, necrotic core area and macrophage content were reduced ∼30% in 11βHSD1−/−/apoE−/− mice. Bone marrow transplantation from 11βHSD1−/−/apoE−/− mice into apoE−/− recipients reduced plaque area 39–46% in the thoracic aorta. In vivo foam cell formation was evaluated in thioglycollate-elicited peritoneal macrophages from 11βHSD1+/+/apoE−/− and 11βHSD1−/−/apoE−/− mice fed a Western diet for ∼5 weeks. Foam cell cholesterol levels were reduced 48% in 11βHSD1−/−/apoE−/− mice vs. control. Microarray profiling of peritoneal macrophages revealed differential expression of genes involved in inflammation, stress response and energy metabolism. Several toll-like receptors (TLRs) were downregulated in 11βHSD1−/−/apoE−/− mice including TLR 1, 3 and 4. Cytokine release from 11βHSD1−/−/apoE−/−-derived peritoneal foam cells was attenuated following challenge with oxidized LDL.
These findings suggest that 11βHSD1 inhibition may have the potential to limit plaque development at the vessel wall and regulate foam cell formation independent of changes in plasma lipids. The diminished cytokine response to oxidized LDL stimulation is consistent with the reduction in TLR expression and suggests involvement of 11βHSD1 in modulating binding of pro-atherogenic TLR ligands.
PMCID: PMC3562192  PMID: 23383297
6.  Repulsive bimodal atomic force microscopy on polymers 
Bimodal atomic force microscopy can provide high-resolution images of polymers. In the bimodal operation mode, two eigenmodes of the cantilever are driven simultaneously. When examining polymers, an effective mechanical contact is often required between the tip and the sample to obtain compositional contrast, so particular emphasis was placed on the repulsive regime of dynamic force microscopy. We thus investigated bimodal imaging on a polystyrene-block-polybutadiene diblock copolymer surface and on polystyrene. The attractive operation regime was only stable when the amplitude of the second eigenmode was kept small compared to the amplitude of the fundamental mode. To clarify the influence of the higher eigenmode oscillation on the image quality, the amplitude ratio of both modes was systematically varied. Fourier analysis of the time series recorded during imaging showed frequency mixing. However, these spurious signals were at least two orders of magnitude smaller than the first two fundamental eigenmodes. Thus, repulsive bimodal imaging of polymer surfaces yields a good signal quality for amplitude ratios smaller than A 01 /A 02 = 10:1 without affecting the topography feedback.
PMCID: PMC3388370  PMID: 23016150
bimodal AFM imaging; diblock copolymer; polybutadiene; polystyrene
7.  Enzyme-assisted extraction of antioxidative phenolics from grape (Vitis vinifera L.) residues 
3 Biotech  2012;2(4):297-300.
Agro-industrial byproducts represent a serious environmental problem and the industries producing these residual materials have incurred expenses for their proper disposal and generally increase the pollution due to the high content of organic substances and might represent legal problems. However, the residues such as grape wastes are potential source of phenolic compounds which are widely known for their high antioxidant activity. Bioprocesses such as enzyme technology represent an alternative for production of those bioactive compounds from agro-industrial byproducts. In this study, different types of commercial enzymes such as Celluclast® 1.5 L, Pectinex® Ultra and Novoferm® were used to release phenolic compounds from grape wastes. The hydrolysates were analyzed in their total phenolic compounds and antioxidant activity with Folin–Ciocaletu test and DPPH· radical-scavenging assay, respectively. A good correlation was obtained between antioxidant activity and phenolics released. The highest antioxidant activities registered were 86.8 ± 0.81, 82.9 ± 0.31 and 90 ± 0.37 % at 12 h for Celluclast® 1.5 L, Pectinex® Ultra and Novoferm®, respectively. Novoferm® had the strongest effect on phenolic release from grape waste, followed by Pectinex® Ultra and Celluclast® 1.5 L. High performance liquid chromatography–electrospray–mass spectrometry clearly revealed that the increment of antioxidant activity is associated with the release of O-coumaric acid.
PMCID: PMC3482449
Grape waste; Enzyme technology; Polyphenolic compounds
8.  Comparison of Dysferlin Expression in Human Skeletal Muscle with That in Monocytes for the Diagnosis of Dysferlin Myopathy 
PLoS ONE  2011;6(12):e29061.
Dysferlinopathies are caused by mutations in the dysferlin gene (DYSF). Diagnosis is complex due to the high clinical variability of the disease and because dysferlin expression in the muscle biopsy may be secondarily reduced due to a primary defect in some other gene. Dysferlin is also expressed in peripheral blood monocytes (PBM). Studying dysferlin in monocytes is used for the diagnosis of dysferlin myopathies. The aim of the study was to determine whether dysferlin expression in PBM correlates with that in skeletal muscle.
Methodology/Principal Findings
Using western-blot (WB) we quantified dysferlin expression in PBM from 21 pathological controls with other myopathies in whom mutations in DYSF were excluded and from 17 patients who had dysferlinopathy and two mutations in DYSF. Results were compared with protein expression in muscle by WB and immunohistochemistry (IH). We found a good correlation between skeletal muscle and monocytes using WB. However, IH results were misleading because abnormal expression of dysferlin was also observed in 13/21 pathological controls.
The analysis of dysferlin protein expression in PBM is helpful when: 1) the skeletal muscle IH pattern is abnormal or 2) when muscle WB can not be performed either because muscle sample is lacking or insufficient or because the muscle biopsy is taken from a muscle at an end-stage and it mainly consists of fat and fibrotic tissue.
PMCID: PMC3241698  PMID: 22194990
9.  Prevalence of cognitive impairment in individuals aged over 65 in an urban area: DERIVA study 
BMC Neurology  2011;11:147.
Few data are available on the prevalence of cognitive impairment (CI) in Spain, and the existing information shows important variations depending on the geographical setting and the methodology employed. The aim of this study was to determine the prevalence of CI in individuals aged over 65 in an urban area, and to analyze its associated risk factors.
Design: A descriptive, cross-sectional, home questionnaire-based study; Setting: Populational, urban setting. Participants: The reference population comprised over-65s living in the city of Salamanca (Spain) in 2009. Randomized sampling stratified according to health district was carried out, and a total of 480 people were selected. In all, 327 patients were interviewed (68.10%), with a mean age of 76.35 years (SD: 7.33). Women accounted for 64.5% of the total. Measurements: A home health questionnaire was used to obtain the following data: age, sex, educational level, family structure, morbidity and functionality. All participants completed a neuropsychological test battery. The prevalence data were compared with those of the European population, with direct adjustment for age and sex. Diagnoses were divided into three general categories: normal cognitive function, cognitive impairment - no dementia (CIND), and dementia.
The prevalence of CI among these over-65s was 19% (14.7% CIND and 4.3% dementia). The age-and sex-adjusted global prevalence of CI was 14.9%. CI increased with age (p < 0.001) and decreased with increasing educational level (p < 0.001). Significant risk factors were found with the multivariate analyses: age (OR = 1.08, 95%CI: 1.03-1.12), anxiety-depression (OR = 3.47, 95%CI: 1.61-7.51) and diabetes (OR = 2.07, 95%CI: 1.02-4.18). In turn, years of education was found to be a protective factor (OR = 0.79, 95%CI: 0.70-0.90). Although CI was more frequent among women and in people living without a partner, these characteristics were not significantly associated with CI risk.
The observed raw prevalence of CI was 19% (14.9% after adjusting for age and sex). Older age and the presence of diabetes and anxiety-depression increased the risk of CI, while higher educational level reduced the risk.
PMCID: PMC3226440  PMID: 22093337
10.  Detection of mild cognitive impairment in people older than 65 years of age and its relationship to cardiovascular risk factors (DECRIVAM) 
BMC Public Health  2011;11:504.
Studies centered on the detection of cognitive impairment and its relationship to cardiovascular risk factors in elderly people have gained special relevance in recent years. Knowledge of the cardiovascular risk factors that may be associated to cognitive impairment could be very useful for introducing treatments in early stages - thereby possibly contributing to improve patient quality of life.
The present study explores cognitive performance in people over 65 years of age in Salamanca (Spain), with special emphasis on the identification of early symptoms of cognitive impairment, with the purpose of detecting mild cognitive impairment and of studying the relationships between this clinical situation and cardiovascular risk factors.
A longitudinal study is contemplated. The reference population will consist of 420 people over 65 years of age enrolled through randomized sampling stratified by healthcare area, and who previously participated in another study. Measurement: a) Sociodemographic variables; b) Cardiovascular risk factors; c) Comorbidity; d) Functional level for daily life activities; and e) Study of higher cognitive functions based on a neuropsychological battery especially adapted to the evaluation of elderly people.
We hope that this study will afford objective information on the representative prevalence of cognitive impairment in the population over 65 years of age in Salamanca. We also hope to obtain data on the relationship between cognitive impairment and cardiovascular risk factors in this specific population group. Based on the results obtained, we also will be able to establish the usefulness of some of the screening tests applied during the study, such as the Mini-Mental State Examination and the 7 Minute Screen test.
Trial registration NCT01327196
PMCID: PMC3141464  PMID: 21708036

Results 1-10 (10)