There is a growing demand for data regarding the environmental and economic performance of additi... more There is a growing demand for data regarding the environmental and economic performance of additive manufacturing to establish the role of this technology in the future circular industrial economy. This paper provides a comparative analysis of direct energy deposition technology with conventional manufacturing, specifically iron casting, in the context of the repairing capabilities of the direct energy deposition system in a damaged glass bottle mold. Making use of already established methodologies for environmental and economic assessment, a life cycle assessment and a life cycle costing study was conducted on each scenario to provide a holistic perspective on the advantages and limitations of each system. With the gathered life cycle inventory, the main environmental impacts and life cycle costs were determined. The hybrid repairing scenario results show a reduction of the environmental impacts and life cycle costs by avoiding resource consumption in the production of a new mold, ...
Background Genomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National... more Background Genomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National Institute of Health in the early stages of the COVID-19 epidemic, in collaboration with more than 50 laboratories distributed nationwide. Methods By applying recent phylodynamic models that allow integration of individual-based travel history, we reconstructed and characterized the spatio-temporal dynamics of SARS-CoV-2 introductions and early dissemination in Portugal. Results We detected at least 277 independent SARS-CoV-2 introductions, mostly from European countries (namely the United Kingdom, Spain, France, Italy, and Switzerland), which were consistent with the countries with the highest connectivity with Portugal. Although most introductions were estimated to have occurred during early March 2020, it is likely that SARS-CoV-2 was silently circulating in Portugal throughout February, before the first cases were confirmed. Conclusions Here we conclude that the earlier implementatio...
Recent production demand for more flexibility has driven new technologies to arise. From the earl... more Recent production demand for more flexibility has driven new technologies to arise. From the early days of rapid prototyping, additive manufacturing has grown to a maturity level that allows it to be competitive with conventional manufacturing methods under certain circumstances. Always as a hybrid approach, firstly additive, and subsequently subtractive, parts produced with high-performance materials can sometimes offset their metal counterparts in a strength-to-weight ratio perspective. System design in these cases needs to take into account the process potential, through design capabilities, and the consequent execution of the parts, highly optimized. In this chapter, an introduction to design for AM is showcased, as well as system architectures to exploit design methodologies.
Structured abstractIMPORTANCEAdults are being vaccinated against SARS-CoV-2 worldwide, but the lo... more Structured abstractIMPORTANCEAdults are being vaccinated against SARS-CoV-2 worldwide, but the longitudinal protection of these vaccines is uncertain, given the ongoing appearance of SARS-CoV-2 variants. Children are susceptible to infection, and some studies reported that they actively transmit the virus even when asymptomatic, thus affecting the community. Methods to easily test infected children and track the virus they carry are in demand.OBJECTIVETo determine if saliva is an effective sample for detecting SARS-CoV-2 RNA and antibodies in children aged 10 years and under, and associate viral RNA levels to infectivity.DESIGN, SETTING, AND PARTICIPANTSIn this cross-sectional study, saliva SARS-CoV-2 RT-qPCR tests, with and without RNA extraction, were validated in 49 hospitalized adults. The test was then applied to 85 children, aged 10 years and under, admitted to the hospital regardless of COVID-19 symptomatology. Amongst 85 children, 29 (63.0%) presented at least one COVID-19 s...
Subarachnoid hemorrhage (SAH) is a life-threatening event that most frequently leads to severe di... more Subarachnoid hemorrhage (SAH) is a life-threatening event that most frequently leads to severe disability and death. Its most frequent cause is the rupture of a saccular intracranial aneurysm (IA), which is a blood vessel dilation caused by disease or weakening of the vessel wall. Although the genetic contribution to IA is well established, to date no single gene has been unequivocally identified as responsible for IA formation or rupture. We aimed to identify IA susceptibility genes in the Portuguese population through a pool-based multistage genome-wide association study. Replicate pools were allelotyped in triplicate in a discovery dataset (100 IA cases and 92 gender-matched controls) using the Affymetrix Human SNP Array 6.0. Top SNPs (absolute value of the relative allele score difference between cases and controls |RAS diff |13.0%) were selected for technical validation by individual genotyping in the discovery dataset. From the 101 SNPs successfully genotyped, 99 SNPs were nominally associated with IA. Replication of technically validated SNPs was conducted in an independent replication dataset (100 Portuguese IA cases and 407 controls). rs4667622 (between UBR3 and MYO3B), rs6599001 (between SCN11A and WDR48), rs3932338 (214 kilobases downstream of PRDM9), and rs10943471 (96 kilobases upstream of HTR1B) were associated with IA (unadjusted allelic chi-square tests) in the datasets tested (discovery: 6.84E-04P1.92E-02, replication: 2.66E-04P2.28E-02, and combined datasets: 6.05E-05P5.50E-04). Additionally, we confirmed the known association with IA of rs1333040 at the 9p21.3 genomic region, thus validating our dataset. These novel findings in the Portuguese population warrant further replication in additional independent studies, and provide additional candidates to more comprehensively understand IA etiopathogenesis.
Introduction. This study aims to compare the molecular gene expression during ischemia reperfusio... more Introduction. This study aims to compare the molecular gene expression during ischemia reperfusion injury. Several surgical times were considered: in the beginning of the harvesting (T0), at the end of the cold ischemia period (T1), and after reperfusion (T2) and compared with graft dysfunction after liver transplant (OLT). Methods. We studied 54 patients undergoing OLT. Clinical, laboratory data, and histologic data (Suzuki classification) as well as the Survival Outcomes Following Liver Transplantation (SOFT) score were used and compared with the molecular gene expression of the following genes: Interleukin (IL)-1b, IL-6, tumor necrosis factor-a, perforin, E-selectin (SELE), Fas-ligand, granzyme B, heme oxygenase-1, and nitric oxide synthetase. Results. Fifteen patients presented with graft dysfunction according to SOFT criteria. No relevant data were obtained by comparing the variables graft dysfunction and histologic variables. We observed a statistically significant relation between SELE at T0 (P ¼ .013) and IL-1b at T0 (P ¼ .028) and early graft dysfunction. Conclusions. We conclude that several genetically determined proinflammatory expressions may play a critical role in the development of graft dysfunction after OLT.
This study aimed to compare the histologic and molecular gene expression at several surgical time... more This study aimed to compare the histologic and molecular gene expression at several surgical times (beginning of harvesting, T0; end of cold ischemia period, T1; and after reperfusion, T2) to characterize the ischemia-reperfusion injury (IRI) in deceased-donor liver grafts harvested from patients with familial amyloidotic polyneuropathy (FAP). For this purpose, 54 patients undergoing liver transplantation were studied and divided into 3 groups: deceased donor to cirrhotic recipient (group 1; n ¼ 27), deceased donor to FAP recipient (group 2; n ¼ 15), and FAP donor to cirrhotic recipient (group 3; n ¼ 12). The main comparison was performed between a histologic score (Suzuki score, adding steatosis and neutrophil infiltration), and molecular gene expression of the following genes: interleukin (IL) 1b, IL-6, E-selectin, Fas-ligand, granzyme B, heme oxygenase 1 (HO1), and nitric oxide synthetase (iNOS2A). We observed less neutrophil infiltration levels in group 3 in sample T0 (P ¼ .0082), which was associated with gene expression of HO1 in the biopsies at T2 (P ¼ .022). In group 3, the molecular expression of genes related to attenuated proinflammatory reaction during IRI, iNOS2A at T0 and HO1 at T2, was detected. We conclude that FAP liver grafts express differently the genes associated with an attenuated proinflammatory reaction, presenting less neutrophil infiltration at harvesting. These findings add more knowledge about the better short-term outcomes in patients receiving this type of liver graft.
Journal of Cerebral Blood Flow & Metabolism, 2012
We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility g... more We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Sever...
Journal of Cerebral Blood Flow & Metabolism, 2011
There is substantial evidence that inflammation within the central nervous system contributes to ... more There is substantial evidence that inflammation within the central nervous system contributes to stroke risk and recovery. Inflammatory conditions increase stroke risk, and the inflammatory response is of major importance in recovery and healing processes after stroke. We investigated the role of inflammatory genes IL1B, IL6, MPO, and TNF in stroke susceptibility and recovery in a population sample of 672 patients and 530 controls, adjusting for demographic, clinical and lifestyle risk factors, and stroke severity parameters. We also considered the likely complexity of inflammatory mechanisms in stroke, by assessing the combined effects of multiple genes. Two interleukin 6 ( IL6) and one myeloperoxidase ( MPO) single-nucleotide polymorphisms were significantly associated with stroke risk (0.022corrected P < 0.042), highlighting gene variants of low to moderate effect in stroke risk. An epistatic interaction between the IL6 and MPO genes was also identified in association with str...
Background and purpose: Growth factors are thought to modulate neurological function in stroke re... more Background and purpose: Growth factors are thought to modulate neurological function in stroke recovery through effects in angiogenesis, neurogenesis, and neuroprotection. Methods: We tested the association of variants in the brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) genes, and epistatic interactions between them, with functional outcome in a sample of 546 stroke patients. Results: While none of the tested genes was independently associated with stroke outcome, two significant gene-gene interaction models were identified. One model combined one BDNF and three FGF2 markers, with a global odds ratio (OR) (95% confidence interval [CI]) of 4.15 [2.86-6.04]. The second model included one FGF2 and two VEGFA markers with a global OR [95% CI] = 2.54 [1.76-3.67]. Conclusions: The results provide evidence for gene interactions in stroke outcome, highlighting the complexity of the recovery mechanisms after a stroke event.
Background Multiple lines of evidence suggest that genetic factors contribute to stroke recovery.... more Background Multiple lines of evidence suggest that genetic factors contribute to stroke recovery. The matrix metalloproteinases -2 (MMP-2) and -9 (MMP-9) are modulators of extracellular matrix components, with important regulatory functions in the Central Nervous System (CNS). Shortly after stroke, MMP-2 and MMP-9 have mainly damaging effects for brain tissue. However, MMPs also have a beneficial activity in angiogenesis and neurovascular remodelling during the delayed neuroinflammatory response phase, thus possibly contributing to stroke functional recovery. Methods In the present study, the role of MMP-2 and MMP-9 genetic variants in stroke recovery was investigated in 546 stroke patients. Functional outcome was assessed three months after a stroke episode using the modified Rankin Scale (mRS), and patients were classified in two groups: good recovery (mRS ≤ 1) or poor recovery (mRS>1). Haplotype tagging single nucleotide polymorphisms (SNPs) in the MMP-2 (N = 21) and MMP-9 (N ...
Objectives: Replication of GWAS association findings remains the gold standard for results valida... more Objectives: Replication of GWAS association findings remains the gold standard for results validation. Our aim was to test the association of four polymorphisms (rs1671021 in LLGL2, rs753307 in RUVBL2, rs6007897 and rs4044210 in CELSR1) previously identified as ischemic stroke (IS) risk factors in a phased GWAS performed on 6341 Japanese individuals [1]. Methods: These polymorphisms were genotyped in a Portuguese sample of 566 IS cases and 525 controls, and their allele, genotype and haplotype associations were assessed. Results: rs6007897 and rs4044210 in CELSR1 were associated with stroke risk individually (OR[95%CI] = 1.43[1.13-1.81], p = 0.003 and 1.38[1.09-1.74], p = 0.007, respectively), and in combination as a haplotype. These associations remain after correction for multiple testing and in a meta-analysis with the original findings. The other polymorphisms were not associated. Conclusions: Our study independently confirmed for the first time the association between IS and CELSR1. This finding and the mechanisms by which these genetic variants exert their effects on stroke pathogenesis warrant further replication and investigation.
Objective: Animal studies have allowed important insights into the role of the nitric oxide synth... more Objective: Animal studies have allowed important insights into the role of the nitric oxide synthase (NOS) enzymes in atherosclerosis and hypertension, as well as in stroke. In this study we tested the hypothesis that the NOS1 and NOS3 genes, respectively encoding neuronal NOS (nNOS) and endothelial NOS (eNOS), influence stroke susceptibility and outcome after a stroke event. Methods: We conducted a case-control association study in 551 ischemic stroke patients and 530 controls to assess the role of NOS1 and NOS3 variants in stroke susceptibility. The same genes were tested for association with stroke outcome in a subset of 431 patients. Results: Four NOS1 single nucleotide polymorphisms (SNPs) (rs2293050, rs2139733, rs7308402 and rs1483757) and four haplotypes were significantly associated with stroke susceptibility after adjusting for demographic, clinical and lifestyle risk factors, and correcting for multiple testing using the false discovery rate (FDR) method (SNPs: 0.004 < uncorrected P < 0.007 and 0.036 < FDR q < 0.048; haplotypes: 0.001 < uncorrected P < 0.010 and 0.018 < FDR q < 0.032). NOS1 variants were not associated with stroke outcome. We did not find any evidence for a role of the NOS3 gene in stroke susceptibility or outcome. Conclusion: Our results highlight NOS1 as a susceptibility factor for stroke, but do not corroborate previous NOS3 association findings with stroke risk. nNOS is known to play a major role in atherosclerosis development and in blood flow regulation, and it is plausible that its influence in stroke may be mediated through these two main clinical risk factors.
The transition from fertilized oocyte to totipotent embryo relies on maternal factors that are sy... more The transition from fertilized oocyte to totipotent embryo relies on maternal factors that are synthetized and accumulated during oocyte development. Yet, it is unclear how oocytes regulate the expression of maternal genes within the transcriptional program of oogenesis. Here, we report that the Trithorax group protein dMLL3/4 (also known as Trr) is essential for the transition to embryo fate at fertilization. In the absence of dMLL3/4, oocytes develop normally but fail to initiate the embryo mitotic divisions after fertilization. This incapability results from defects in paternal genome reprogramming and maternal meiotic completion. The methyltransferase activity of dMLL3/4 is dispensable for both these processes. We further show that dMLL3/4 promotes the expression of a functionally coherent gene subset that is required for the initiation of post-fertilization development. Accordingly, we identify the evolutionarily conserved IDGF4 glycoprotein (known as oviductin in mammals) as a...
There is a growing demand for data regarding the environmental and economic performance of additi... more There is a growing demand for data regarding the environmental and economic performance of additive manufacturing to establish the role of this technology in the future circular industrial economy. This paper provides a comparative analysis of direct energy deposition technology with conventional manufacturing, specifically iron casting, in the context of the repairing capabilities of the direct energy deposition system in a damaged glass bottle mold. Making use of already established methodologies for environmental and economic assessment, a life cycle assessment and a life cycle costing study was conducted on each scenario to provide a holistic perspective on the advantages and limitations of each system. With the gathered life cycle inventory, the main environmental impacts and life cycle costs were determined. The hybrid repairing scenario results show a reduction of the environmental impacts and life cycle costs by avoiding resource consumption in the production of a new mold, ...
Background Genomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National... more Background Genomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National Institute of Health in the early stages of the COVID-19 epidemic, in collaboration with more than 50 laboratories distributed nationwide. Methods By applying recent phylodynamic models that allow integration of individual-based travel history, we reconstructed and characterized the spatio-temporal dynamics of SARS-CoV-2 introductions and early dissemination in Portugal. Results We detected at least 277 independent SARS-CoV-2 introductions, mostly from European countries (namely the United Kingdom, Spain, France, Italy, and Switzerland), which were consistent with the countries with the highest connectivity with Portugal. Although most introductions were estimated to have occurred during early March 2020, it is likely that SARS-CoV-2 was silently circulating in Portugal throughout February, before the first cases were confirmed. Conclusions Here we conclude that the earlier implementatio...
Recent production demand for more flexibility has driven new technologies to arise. From the earl... more Recent production demand for more flexibility has driven new technologies to arise. From the early days of rapid prototyping, additive manufacturing has grown to a maturity level that allows it to be competitive with conventional manufacturing methods under certain circumstances. Always as a hybrid approach, firstly additive, and subsequently subtractive, parts produced with high-performance materials can sometimes offset their metal counterparts in a strength-to-weight ratio perspective. System design in these cases needs to take into account the process potential, through design capabilities, and the consequent execution of the parts, highly optimized. In this chapter, an introduction to design for AM is showcased, as well as system architectures to exploit design methodologies.
Structured abstractIMPORTANCEAdults are being vaccinated against SARS-CoV-2 worldwide, but the lo... more Structured abstractIMPORTANCEAdults are being vaccinated against SARS-CoV-2 worldwide, but the longitudinal protection of these vaccines is uncertain, given the ongoing appearance of SARS-CoV-2 variants. Children are susceptible to infection, and some studies reported that they actively transmit the virus even when asymptomatic, thus affecting the community. Methods to easily test infected children and track the virus they carry are in demand.OBJECTIVETo determine if saliva is an effective sample for detecting SARS-CoV-2 RNA and antibodies in children aged 10 years and under, and associate viral RNA levels to infectivity.DESIGN, SETTING, AND PARTICIPANTSIn this cross-sectional study, saliva SARS-CoV-2 RT-qPCR tests, with and without RNA extraction, were validated in 49 hospitalized adults. The test was then applied to 85 children, aged 10 years and under, admitted to the hospital regardless of COVID-19 symptomatology. Amongst 85 children, 29 (63.0%) presented at least one COVID-19 s...
Subarachnoid hemorrhage (SAH) is a life-threatening event that most frequently leads to severe di... more Subarachnoid hemorrhage (SAH) is a life-threatening event that most frequently leads to severe disability and death. Its most frequent cause is the rupture of a saccular intracranial aneurysm (IA), which is a blood vessel dilation caused by disease or weakening of the vessel wall. Although the genetic contribution to IA is well established, to date no single gene has been unequivocally identified as responsible for IA formation or rupture. We aimed to identify IA susceptibility genes in the Portuguese population through a pool-based multistage genome-wide association study. Replicate pools were allelotyped in triplicate in a discovery dataset (100 IA cases and 92 gender-matched controls) using the Affymetrix Human SNP Array 6.0. Top SNPs (absolute value of the relative allele score difference between cases and controls |RAS diff |13.0%) were selected for technical validation by individual genotyping in the discovery dataset. From the 101 SNPs successfully genotyped, 99 SNPs were nominally associated with IA. Replication of technically validated SNPs was conducted in an independent replication dataset (100 Portuguese IA cases and 407 controls). rs4667622 (between UBR3 and MYO3B), rs6599001 (between SCN11A and WDR48), rs3932338 (214 kilobases downstream of PRDM9), and rs10943471 (96 kilobases upstream of HTR1B) were associated with IA (unadjusted allelic chi-square tests) in the datasets tested (discovery: 6.84E-04P1.92E-02, replication: 2.66E-04P2.28E-02, and combined datasets: 6.05E-05P5.50E-04). Additionally, we confirmed the known association with IA of rs1333040 at the 9p21.3 genomic region, thus validating our dataset. These novel findings in the Portuguese population warrant further replication in additional independent studies, and provide additional candidates to more comprehensively understand IA etiopathogenesis.
Introduction. This study aims to compare the molecular gene expression during ischemia reperfusio... more Introduction. This study aims to compare the molecular gene expression during ischemia reperfusion injury. Several surgical times were considered: in the beginning of the harvesting (T0), at the end of the cold ischemia period (T1), and after reperfusion (T2) and compared with graft dysfunction after liver transplant (OLT). Methods. We studied 54 patients undergoing OLT. Clinical, laboratory data, and histologic data (Suzuki classification) as well as the Survival Outcomes Following Liver Transplantation (SOFT) score were used and compared with the molecular gene expression of the following genes: Interleukin (IL)-1b, IL-6, tumor necrosis factor-a, perforin, E-selectin (SELE), Fas-ligand, granzyme B, heme oxygenase-1, and nitric oxide synthetase. Results. Fifteen patients presented with graft dysfunction according to SOFT criteria. No relevant data were obtained by comparing the variables graft dysfunction and histologic variables. We observed a statistically significant relation between SELE at T0 (P ¼ .013) and IL-1b at T0 (P ¼ .028) and early graft dysfunction. Conclusions. We conclude that several genetically determined proinflammatory expressions may play a critical role in the development of graft dysfunction after OLT.
This study aimed to compare the histologic and molecular gene expression at several surgical time... more This study aimed to compare the histologic and molecular gene expression at several surgical times (beginning of harvesting, T0; end of cold ischemia period, T1; and after reperfusion, T2) to characterize the ischemia-reperfusion injury (IRI) in deceased-donor liver grafts harvested from patients with familial amyloidotic polyneuropathy (FAP). For this purpose, 54 patients undergoing liver transplantation were studied and divided into 3 groups: deceased donor to cirrhotic recipient (group 1; n ¼ 27), deceased donor to FAP recipient (group 2; n ¼ 15), and FAP donor to cirrhotic recipient (group 3; n ¼ 12). The main comparison was performed between a histologic score (Suzuki score, adding steatosis and neutrophil infiltration), and molecular gene expression of the following genes: interleukin (IL) 1b, IL-6, E-selectin, Fas-ligand, granzyme B, heme oxygenase 1 (HO1), and nitric oxide synthetase (iNOS2A). We observed less neutrophil infiltration levels in group 3 in sample T0 (P ¼ .0082), which was associated with gene expression of HO1 in the biopsies at T2 (P ¼ .022). In group 3, the molecular expression of genes related to attenuated proinflammatory reaction during IRI, iNOS2A at T0 and HO1 at T2, was detected. We conclude that FAP liver grafts express differently the genes associated with an attenuated proinflammatory reaction, presenting less neutrophil infiltration at harvesting. These findings add more knowledge about the better short-term outcomes in patients receiving this type of liver graft.
Journal of Cerebral Blood Flow & Metabolism, 2012
We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility g... more We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Sever...
Journal of Cerebral Blood Flow & Metabolism, 2011
There is substantial evidence that inflammation within the central nervous system contributes to ... more There is substantial evidence that inflammation within the central nervous system contributes to stroke risk and recovery. Inflammatory conditions increase stroke risk, and the inflammatory response is of major importance in recovery and healing processes after stroke. We investigated the role of inflammatory genes IL1B, IL6, MPO, and TNF in stroke susceptibility and recovery in a population sample of 672 patients and 530 controls, adjusting for demographic, clinical and lifestyle risk factors, and stroke severity parameters. We also considered the likely complexity of inflammatory mechanisms in stroke, by assessing the combined effects of multiple genes. Two interleukin 6 ( IL6) and one myeloperoxidase ( MPO) single-nucleotide polymorphisms were significantly associated with stroke risk (0.022corrected P < 0.042), highlighting gene variants of low to moderate effect in stroke risk. An epistatic interaction between the IL6 and MPO genes was also identified in association with str...
Background and purpose: Growth factors are thought to modulate neurological function in stroke re... more Background and purpose: Growth factors are thought to modulate neurological function in stroke recovery through effects in angiogenesis, neurogenesis, and neuroprotection. Methods: We tested the association of variants in the brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) genes, and epistatic interactions between them, with functional outcome in a sample of 546 stroke patients. Results: While none of the tested genes was independently associated with stroke outcome, two significant gene-gene interaction models were identified. One model combined one BDNF and three FGF2 markers, with a global odds ratio (OR) (95% confidence interval [CI]) of 4.15 [2.86-6.04]. The second model included one FGF2 and two VEGFA markers with a global OR [95% CI] = 2.54 [1.76-3.67]. Conclusions: The results provide evidence for gene interactions in stroke outcome, highlighting the complexity of the recovery mechanisms after a stroke event.
Background Multiple lines of evidence suggest that genetic factors contribute to stroke recovery.... more Background Multiple lines of evidence suggest that genetic factors contribute to stroke recovery. The matrix metalloproteinases -2 (MMP-2) and -9 (MMP-9) are modulators of extracellular matrix components, with important regulatory functions in the Central Nervous System (CNS). Shortly after stroke, MMP-2 and MMP-9 have mainly damaging effects for brain tissue. However, MMPs also have a beneficial activity in angiogenesis and neurovascular remodelling during the delayed neuroinflammatory response phase, thus possibly contributing to stroke functional recovery. Methods In the present study, the role of MMP-2 and MMP-9 genetic variants in stroke recovery was investigated in 546 stroke patients. Functional outcome was assessed three months after a stroke episode using the modified Rankin Scale (mRS), and patients were classified in two groups: good recovery (mRS ≤ 1) or poor recovery (mRS>1). Haplotype tagging single nucleotide polymorphisms (SNPs) in the MMP-2 (N = 21) and MMP-9 (N ...
Objectives: Replication of GWAS association findings remains the gold standard for results valida... more Objectives: Replication of GWAS association findings remains the gold standard for results validation. Our aim was to test the association of four polymorphisms (rs1671021 in LLGL2, rs753307 in RUVBL2, rs6007897 and rs4044210 in CELSR1) previously identified as ischemic stroke (IS) risk factors in a phased GWAS performed on 6341 Japanese individuals [1]. Methods: These polymorphisms were genotyped in a Portuguese sample of 566 IS cases and 525 controls, and their allele, genotype and haplotype associations were assessed. Results: rs6007897 and rs4044210 in CELSR1 were associated with stroke risk individually (OR[95%CI] = 1.43[1.13-1.81], p = 0.003 and 1.38[1.09-1.74], p = 0.007, respectively), and in combination as a haplotype. These associations remain after correction for multiple testing and in a meta-analysis with the original findings. The other polymorphisms were not associated. Conclusions: Our study independently confirmed for the first time the association between IS and CELSR1. This finding and the mechanisms by which these genetic variants exert their effects on stroke pathogenesis warrant further replication and investigation.
Objective: Animal studies have allowed important insights into the role of the nitric oxide synth... more Objective: Animal studies have allowed important insights into the role of the nitric oxide synthase (NOS) enzymes in atherosclerosis and hypertension, as well as in stroke. In this study we tested the hypothesis that the NOS1 and NOS3 genes, respectively encoding neuronal NOS (nNOS) and endothelial NOS (eNOS), influence stroke susceptibility and outcome after a stroke event. Methods: We conducted a case-control association study in 551 ischemic stroke patients and 530 controls to assess the role of NOS1 and NOS3 variants in stroke susceptibility. The same genes were tested for association with stroke outcome in a subset of 431 patients. Results: Four NOS1 single nucleotide polymorphisms (SNPs) (rs2293050, rs2139733, rs7308402 and rs1483757) and four haplotypes were significantly associated with stroke susceptibility after adjusting for demographic, clinical and lifestyle risk factors, and correcting for multiple testing using the false discovery rate (FDR) method (SNPs: 0.004 < uncorrected P < 0.007 and 0.036 < FDR q < 0.048; haplotypes: 0.001 < uncorrected P < 0.010 and 0.018 < FDR q < 0.032). NOS1 variants were not associated with stroke outcome. We did not find any evidence for a role of the NOS3 gene in stroke susceptibility or outcome. Conclusion: Our results highlight NOS1 as a susceptibility factor for stroke, but do not corroborate previous NOS3 association findings with stroke risk. nNOS is known to play a major role in atherosclerosis development and in blood flow regulation, and it is plausible that its influence in stroke may be mediated through these two main clinical risk factors.
The transition from fertilized oocyte to totipotent embryo relies on maternal factors that are sy... more The transition from fertilized oocyte to totipotent embryo relies on maternal factors that are synthetized and accumulated during oocyte development. Yet, it is unclear how oocytes regulate the expression of maternal genes within the transcriptional program of oogenesis. Here, we report that the Trithorax group protein dMLL3/4 (also known as Trr) is essential for the transition to embryo fate at fertilization. In the absence of dMLL3/4, oocytes develop normally but fail to initiate the embryo mitotic divisions after fertilization. This incapability results from defects in paternal genome reprogramming and maternal meiotic completion. The methyltransferase activity of dMLL3/4 is dispensable for both these processes. We further show that dMLL3/4 promotes the expression of a functionally coherent gene subset that is required for the initiation of post-fertilization development. Accordingly, we identify the evolutionarily conserved IDGF4 glycoprotein (known as oviductin in mammals) as a...
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