Background—Myocyte apoptosis plays an important role in pathological cardiac remodeling and the p... more Background—Myocyte apoptosis plays an important role in pathological cardiac remodeling and the progression of heart failure. cAMP signaling is crucial in the regulation of myocyte apoptosis and cardiac remodeling. Multiple cAMP-hydrolyzing phosphodiesterases (PDEs), such as PDE3 and PDE4, coexist in cardiomyocytes and elicit differential temporal/spatial regulation of cAMP signaling. However, the role of PDE3 and PDE4 in the regulation of
Stroke; a journal of cerebral circulation, Jan 9, 2015
Randomized trials have indicated a benefit for endovascular therapy in appropriately selected str... more Randomized trials have indicated a benefit for endovascular therapy in appropriately selected stroke patients at 3 months, but data regarding outcomes at 12 months are currently lacking. We compared functional and quality-of-life outcomes at 12 months overall and by stroke severity in stroke patients treated with intravenous tissue-type plasminogen activator followed by endovascular treatment as compared with intravenous tissue-type plasminogen activator alone in the Interventional Management of Stroke III Trial. The key outcome measures were a modified Rankin Scale score ≤2 (functional independence) and the Euro-QoL EQ-5D, a health-related quality-of-life measure. 656 subjects with moderate-to-severe stroke (National Institutes of Health Stroke Scale ≥8) were enrolled at 58 centers in the United States (41 sites), Canada (7), Australia (4), and Europe (6). There was an interaction between treatment group and stroke severity in the repeated measures analysis of modified Rankin Scale...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
Neurotransmitter-driven activation of transcription factors is important for control of neuronal ... more Neurotransmitter-driven activation of transcription factors is important for control of neuronal and neuroendocrine functions. We show with an in vivo approach that the norepinephrine cAMP-dependent rhythmic hormone production in rat pineal gland is accompanied by a temporally regulated switch in the ratio of a transcriptional activator, phosphorylated cAMP-responsive element-binding protein (pCREB), and a transcriptional inhibitor, inducible cAMP early repressor (ICER). pCREB accumulates endogenously at the beginning of the dark period and declines during the second half of the night. Concomitant with this decline, the amount of ICER rises. The changing ratio between pCREB and ICER shapes the in vivo dynamics in mRNA and, thus, protein levels of arylalkylamine-N-acetyltransferase, the rate-limiting enzyme of melatonin synthesis. Consequently, a silenced ICER expression in pinealocytes leads to a disinhibited arylalkylamine-N-acetyltransferase transcription and a primarily enhanced ...
European Society for Fuzzy Logic and Technology, 2007
In this paper we extend a previous deflnition of gradual dependence as a special kind of (crisp) ... more In this paper we extend a previous deflnition of gradual dependence as a special kind of (crisp) association rule, in order to measure not only the existence of a tendency, but its strength. The new proposal is based on the idea of fuzzy association rule and the defl- nition of variation strength in the degree of fulfllment of an
Core promoters are the gene regulatory regions most proximal to the transcription start site (TSS... more Core promoters are the gene regulatory regions most proximal to the transcription start site (TSS), central to the formation of pre-initiation complexes and for combinatorial gene regulation. The DNA elements required for core promoter function in plants are poorly understood. To establish the sequence motifs that characterize plant core promoters and to compare them to the corresponding sequences in animals, we took advantage of available full-length cDNAs (FL-cDNAs) and predicted upstream regulatory sequences to carry out the analysis of 12,749 Arabidopsis core promoters. Using a combination of expectation maximization and Gibbs sampling methods, we identified several motifs overrepresented in Arabidopsis core promoters. One of them corresponded to the TATA element, for which an in-depth analysis resulted in the generation of robust TATA Nucleotide Frequency Matrices (NFMs) capable of predicting Arabidopsis TATA elements with a high degree of confidence. We established that approx...
The purpose of the present study was to investigate the influence of the time course of inflammat... more The purpose of the present study was to investigate the influence of the time course of inflammation and the implication of spinal and supraspinal sites on the antihyperalgesic effects of the alpha(2)-adrenoceptor agonist medetomidine. Behavioral experiments showed a more intense antihyperalgesia in the phase of maintenance of inflammation than in the early or resolution stages. Maximum effect, without sedation, was observed with a dose of 40 microg/kg (66+/-12% and 76+/-15% reduction of mechanical and thermal hyperalgesia). No change was observed in the paw swelling, indicating that its effects were not secondary to a reduction of inflammation. In electrophysiological experiments, the effect was more pronounced in animals with an intact spinal cord than in spinalized animals (max. effects of 2+/-0.7% vs. 48+/-11% of control, noxious mechanical stimulation). We conclude that the antihyperalgesic effect of medetomidine depends on the time course of inflammation and that it is mainly ...
Intravenous thrombolysis is the only approved treatment for acute ischemic stroke when administer... more Intravenous thrombolysis is the only approved treatment for acute ischemic stroke when administered within the first 3 h of stroke onset. Response to systemic thrombolysis depends on several factors including the location of arterial occlusion, clot characteristics and, ultimately, the embolic source. In the last few years, tremendous progress has been made, resulting in the widespread implementation of noninvasive neurovascular techniques. These imaging modalities are being increasingly performed in the acute stroke setting, without substantial delay, in a large number of centers worldwide. Transcranial Doppler ultrasound provides a unique opportunity to assess several aspects of clot dissolution by means of continuous monitoring of recanalization during and after tissue plasminogen activator administration. This approach allows for the evaluation of patients at the bedside and in real time due to the commencement, timing, speed and degree of artery reopening in addition to allowin...
Numerous acute reperfusion therapies (RPT) are currently investigated as potential new therapeuti... more Numerous acute reperfusion therapies (RPT) are currently investigated as potential new therapeutic targets in acute ischemic stroke (AIS). We conducted a comprehensive benefit-risk analysis of available clinical studies assessing different acute RPT, and investigated the utility of each intervention in comparison to standard intravenous thrombolysis (IVT) and in relation to the onset-to-treatment time (OTT). A comprehensive literature search was conducted to identify all available published, peer-reviewed clinical studies that evaluated the efficacy of different RPT in AIS. Benefit-to-risk ratio (BRR), adjusted for baseline stroke severity, was estimated as the percentage of patients achieving favorable functional outcome (BRR1, mRS score: 0-1) or functional independence (BRR2, mRS score: 0-2) at 3 months divided by the percentage of patients who died during the same period. A total of 18 randomized (n = 13) and nonrandomized (n = 5) clinical studies fulfilled our inclusion criteria...
Early neurological deterioration (END) occurs in approximately one third of all ischemic stroke p... more Early neurological deterioration (END) occurs in approximately one third of all ischemic stroke patients and is associated with a poor outcome. Our study sought to assess the value of ultra-early MRI in the prediction of END in stroke patients. Between August 1999 and November 2001, 38 stroke patients with a proven middle cerebral artery (MCA) or intracranial internal carotid artery (ICA) occlusion on MR angiography underwent perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) within 6 hours after onset, and 30 fulfilled all inclusion criteria. Control DWI and MR angiography were performed between days 3 and 5. Cranial CT was performed to rule out hemorrhagic transformation. Vascular risk factors, temperature, blood pressure, glycemia, and blood count were assessed on admission. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and at 6, 12, 24, and 48 hours. At the same time points, transcranial Doppler (TCD) examinations were con...
The gene regulatory information is hardwired in the promoter regions formed by cis-regulatory ele... more The gene regulatory information is hardwired in the promoter regions formed by cis-regulatory elements that bind specific transcription factors (TFs). Hence, establishing the architecture of plant promoters is fundamental to understanding gene expression. The determination of the regulatory circuits controlled by each TF and the identification of the cis-regulatory sequences for all genes have been identified as two of the goals of the Multinational Coordinated Arabidopsis thaliana Functional Genomics Project by the Multinational Arabidopsis Steering Committee (June 2002). AGRIS is an information resource of Arabidopsis promoter sequences, transcription factors and their target genes. AGRIS currently contains two databases, AtTFDB (Arabidopsis thaliana transcription factor database) and AtcisDB (Arabidopsis thaliana cis-regulatory database). AtTFDB contains information on approximately 1,400 transcription factors identified through motif searches and grouped into 34 families. AtTFDB...
Symbiotic nitrogen fixation (SNF) in root nodules of grain legumes such as chickpea is a highly c... more Symbiotic nitrogen fixation (SNF) in root nodules of grain legumes such as chickpea is a highly complex process that drastically affects the gene expression patterns of both the prokaryotic as well as eukaryotic interacting cells. A successfully established symbiotic relationship requires mutual signaling mechanisms and a continuous adaptation of the metabolism of the involved cells to varying environmental conditions. Although some of these processes are well understood today many of the molecular mechanisms underlying SNF, especially in chickpea, remain unclear. Here, we reannotated our previously published transcriptome data generated by deepSuperSAGE (Serial Analysis of Gene Expression) to the recently published draft genome of chickpea to assess the root- and nodule-specific transcriptomes of the eukaryotic host cells. The identified gene expression patterns comprise up to 71 significantly differentially expressed genes and the expression of twenty of these was validated by quantitative real-time PCR with the tissues from five independent biological replicates. Many of the differentially expressed transcripts were found to encode proteins implicated in sugar metabolism, antioxidant defense as well as biotic and abiotic stress responses of the host cells, and some of them were already known to contribute to SNF in other legumes. The differentially expressed genes identified in this study represent candidates that can be used for further characterization of the complex molecular mechanisms underlying SNF in chickpea.
ABSTRACT This study focuses on the importance of quantifying the effect of prefetching on the int... more ABSTRACT This study focuses on the importance of quantifying the effect of prefetching on the interconnection network of a multiprocessor chip. This kind of microarchitectural effects are often quantified using simulators. However, if prefetching traffic in a CMP (Chip MultiProcessor) system is to be accurately evaluated, simulators should simulate not only the memory hierarchy module and the multicore system, but also the network-on-chip. Unfortunately, no open-source simulator is able to evaluate all these elements at the same time. This paper describes how to develop a prefetching module for the gem5 CMP simulator and how to integrate this into the Ruby memory system. Moreover, by using the infrastructure developed in this study, this paper shows the importance of taking the network effect in prefetching-related studies into account, in order for accurate results to be obtained: not doing so may lead to mistaken conclusions. For this purpose, we have carried out a detailed analysis of the behavior of three different prefetching engines, providing not only the typical statistics for instructions per cycle and the miss rate, but also specific network and prefetching statistics.
Background—Myocyte apoptosis plays an important role in pathological cardiac remodeling and the p... more Background—Myocyte apoptosis plays an important role in pathological cardiac remodeling and the progression of heart failure. cAMP signaling is crucial in the regulation of myocyte apoptosis and cardiac remodeling. Multiple cAMP-hydrolyzing phosphodiesterases (PDEs), such as PDE3 and PDE4, coexist in cardiomyocytes and elicit differential temporal/spatial regulation of cAMP signaling. However, the role of PDE3 and PDE4 in the regulation of
Stroke; a journal of cerebral circulation, Jan 9, 2015
Randomized trials have indicated a benefit for endovascular therapy in appropriately selected str... more Randomized trials have indicated a benefit for endovascular therapy in appropriately selected stroke patients at 3 months, but data regarding outcomes at 12 months are currently lacking. We compared functional and quality-of-life outcomes at 12 months overall and by stroke severity in stroke patients treated with intravenous tissue-type plasminogen activator followed by endovascular treatment as compared with intravenous tissue-type plasminogen activator alone in the Interventional Management of Stroke III Trial. The key outcome measures were a modified Rankin Scale score ≤2 (functional independence) and the Euro-QoL EQ-5D, a health-related quality-of-life measure. 656 subjects with moderate-to-severe stroke (National Institutes of Health Stroke Scale ≥8) were enrolled at 58 centers in the United States (41 sites), Canada (7), Australia (4), and Europe (6). There was an interaction between treatment group and stroke severity in the repeated measures analysis of modified Rankin Scale...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
Neurotransmitter-driven activation of transcription factors is important for control of neuronal ... more Neurotransmitter-driven activation of transcription factors is important for control of neuronal and neuroendocrine functions. We show with an in vivo approach that the norepinephrine cAMP-dependent rhythmic hormone production in rat pineal gland is accompanied by a temporally regulated switch in the ratio of a transcriptional activator, phosphorylated cAMP-responsive element-binding protein (pCREB), and a transcriptional inhibitor, inducible cAMP early repressor (ICER). pCREB accumulates endogenously at the beginning of the dark period and declines during the second half of the night. Concomitant with this decline, the amount of ICER rises. The changing ratio between pCREB and ICER shapes the in vivo dynamics in mRNA and, thus, protein levels of arylalkylamine-N-acetyltransferase, the rate-limiting enzyme of melatonin synthesis. Consequently, a silenced ICER expression in pinealocytes leads to a disinhibited arylalkylamine-N-acetyltransferase transcription and a primarily enhanced ...
European Society for Fuzzy Logic and Technology, 2007
In this paper we extend a previous deflnition of gradual dependence as a special kind of (crisp) ... more In this paper we extend a previous deflnition of gradual dependence as a special kind of (crisp) association rule, in order to measure not only the existence of a tendency, but its strength. The new proposal is based on the idea of fuzzy association rule and the defl- nition of variation strength in the degree of fulfllment of an
Core promoters are the gene regulatory regions most proximal to the transcription start site (TSS... more Core promoters are the gene regulatory regions most proximal to the transcription start site (TSS), central to the formation of pre-initiation complexes and for combinatorial gene regulation. The DNA elements required for core promoter function in plants are poorly understood. To establish the sequence motifs that characterize plant core promoters and to compare them to the corresponding sequences in animals, we took advantage of available full-length cDNAs (FL-cDNAs) and predicted upstream regulatory sequences to carry out the analysis of 12,749 Arabidopsis core promoters. Using a combination of expectation maximization and Gibbs sampling methods, we identified several motifs overrepresented in Arabidopsis core promoters. One of them corresponded to the TATA element, for which an in-depth analysis resulted in the generation of robust TATA Nucleotide Frequency Matrices (NFMs) capable of predicting Arabidopsis TATA elements with a high degree of confidence. We established that approx...
The purpose of the present study was to investigate the influence of the time course of inflammat... more The purpose of the present study was to investigate the influence of the time course of inflammation and the implication of spinal and supraspinal sites on the antihyperalgesic effects of the alpha(2)-adrenoceptor agonist medetomidine. Behavioral experiments showed a more intense antihyperalgesia in the phase of maintenance of inflammation than in the early or resolution stages. Maximum effect, without sedation, was observed with a dose of 40 microg/kg (66+/-12% and 76+/-15% reduction of mechanical and thermal hyperalgesia). No change was observed in the paw swelling, indicating that its effects were not secondary to a reduction of inflammation. In electrophysiological experiments, the effect was more pronounced in animals with an intact spinal cord than in spinalized animals (max. effects of 2+/-0.7% vs. 48+/-11% of control, noxious mechanical stimulation). We conclude that the antihyperalgesic effect of medetomidine depends on the time course of inflammation and that it is mainly ...
Intravenous thrombolysis is the only approved treatment for acute ischemic stroke when administer... more Intravenous thrombolysis is the only approved treatment for acute ischemic stroke when administered within the first 3 h of stroke onset. Response to systemic thrombolysis depends on several factors including the location of arterial occlusion, clot characteristics and, ultimately, the embolic source. In the last few years, tremendous progress has been made, resulting in the widespread implementation of noninvasive neurovascular techniques. These imaging modalities are being increasingly performed in the acute stroke setting, without substantial delay, in a large number of centers worldwide. Transcranial Doppler ultrasound provides a unique opportunity to assess several aspects of clot dissolution by means of continuous monitoring of recanalization during and after tissue plasminogen activator administration. This approach allows for the evaluation of patients at the bedside and in real time due to the commencement, timing, speed and degree of artery reopening in addition to allowin...
Numerous acute reperfusion therapies (RPT) are currently investigated as potential new therapeuti... more Numerous acute reperfusion therapies (RPT) are currently investigated as potential new therapeutic targets in acute ischemic stroke (AIS). We conducted a comprehensive benefit-risk analysis of available clinical studies assessing different acute RPT, and investigated the utility of each intervention in comparison to standard intravenous thrombolysis (IVT) and in relation to the onset-to-treatment time (OTT). A comprehensive literature search was conducted to identify all available published, peer-reviewed clinical studies that evaluated the efficacy of different RPT in AIS. Benefit-to-risk ratio (BRR), adjusted for baseline stroke severity, was estimated as the percentage of patients achieving favorable functional outcome (BRR1, mRS score: 0-1) or functional independence (BRR2, mRS score: 0-2) at 3 months divided by the percentage of patients who died during the same period. A total of 18 randomized (n = 13) and nonrandomized (n = 5) clinical studies fulfilled our inclusion criteria...
Early neurological deterioration (END) occurs in approximately one third of all ischemic stroke p... more Early neurological deterioration (END) occurs in approximately one third of all ischemic stroke patients and is associated with a poor outcome. Our study sought to assess the value of ultra-early MRI in the prediction of END in stroke patients. Between August 1999 and November 2001, 38 stroke patients with a proven middle cerebral artery (MCA) or intracranial internal carotid artery (ICA) occlusion on MR angiography underwent perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) within 6 hours after onset, and 30 fulfilled all inclusion criteria. Control DWI and MR angiography were performed between days 3 and 5. Cranial CT was performed to rule out hemorrhagic transformation. Vascular risk factors, temperature, blood pressure, glycemia, and blood count were assessed on admission. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and at 6, 12, 24, and 48 hours. At the same time points, transcranial Doppler (TCD) examinations were con...
The gene regulatory information is hardwired in the promoter regions formed by cis-regulatory ele... more The gene regulatory information is hardwired in the promoter regions formed by cis-regulatory elements that bind specific transcription factors (TFs). Hence, establishing the architecture of plant promoters is fundamental to understanding gene expression. The determination of the regulatory circuits controlled by each TF and the identification of the cis-regulatory sequences for all genes have been identified as two of the goals of the Multinational Coordinated Arabidopsis thaliana Functional Genomics Project by the Multinational Arabidopsis Steering Committee (June 2002). AGRIS is an information resource of Arabidopsis promoter sequences, transcription factors and their target genes. AGRIS currently contains two databases, AtTFDB (Arabidopsis thaliana transcription factor database) and AtcisDB (Arabidopsis thaliana cis-regulatory database). AtTFDB contains information on approximately 1,400 transcription factors identified through motif searches and grouped into 34 families. AtTFDB...
Symbiotic nitrogen fixation (SNF) in root nodules of grain legumes such as chickpea is a highly c... more Symbiotic nitrogen fixation (SNF) in root nodules of grain legumes such as chickpea is a highly complex process that drastically affects the gene expression patterns of both the prokaryotic as well as eukaryotic interacting cells. A successfully established symbiotic relationship requires mutual signaling mechanisms and a continuous adaptation of the metabolism of the involved cells to varying environmental conditions. Although some of these processes are well understood today many of the molecular mechanisms underlying SNF, especially in chickpea, remain unclear. Here, we reannotated our previously published transcriptome data generated by deepSuperSAGE (Serial Analysis of Gene Expression) to the recently published draft genome of chickpea to assess the root- and nodule-specific transcriptomes of the eukaryotic host cells. The identified gene expression patterns comprise up to 71 significantly differentially expressed genes and the expression of twenty of these was validated by quantitative real-time PCR with the tissues from five independent biological replicates. Many of the differentially expressed transcripts were found to encode proteins implicated in sugar metabolism, antioxidant defense as well as biotic and abiotic stress responses of the host cells, and some of them were already known to contribute to SNF in other legumes. The differentially expressed genes identified in this study represent candidates that can be used for further characterization of the complex molecular mechanisms underlying SNF in chickpea.
ABSTRACT This study focuses on the importance of quantifying the effect of prefetching on the int... more ABSTRACT This study focuses on the importance of quantifying the effect of prefetching on the interconnection network of a multiprocessor chip. This kind of microarchitectural effects are often quantified using simulators. However, if prefetching traffic in a CMP (Chip MultiProcessor) system is to be accurately evaluated, simulators should simulate not only the memory hierarchy module and the multicore system, but also the network-on-chip. Unfortunately, no open-source simulator is able to evaluate all these elements at the same time. This paper describes how to develop a prefetching module for the gem5 CMP simulator and how to integrate this into the Ruby memory system. Moreover, by using the infrastructure developed in this study, this paper shows the importance of taking the network effect in prefetching-related studies into account, in order for accurate results to be obtained: not doing so may lead to mistaken conclusions. For this purpose, we have carried out a detailed analysis of the behavior of three different prefetching engines, providing not only the typical statistics for instructions per cycle and the miss rate, but also specific network and prefetching statistics.
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Papers by Carlos Molina