Hepatitis C virus (HCV) is classified into seven major genotypes and 67 subtypes. Recent studies have shown that in HCV genotype 1-infected patients, response rates to regimens containing direct acting antivirals (DAAs) are subtype-dependent. Currently available genotyping methods have limited subtyping accuracy.
Lithium has a narrow therapeutic index with a subtle balance between effectiveness and adverse effects. Current guidelines recommend the use of lithium as a treatment for acute bipolar depression; however, the therapeutic range for the treatment has not been fully defined. Recently, the adjunctive lower lithium dose in bipolar depression has revealed potential efficacy; however, no study has investigated it predominantly in monotherapy. In this open-label, proof-of-concept study, 31 individuals with bipolar disorder during a depressive episode were randomized and 29 were followed up for six weeks with flexible lithium dosing. All subjects had a 21-item Hamilton Rating Scale for Depression (HAM-D) score of ?18 at baseline. Subjects were divided into two groups, with higher (Li ?0.5 mEq/l) or lower (Li <0.5 mEq/l) blood lithium levels. Response and remission rates were evaluated using the HAM-D scores. Following 6 weeks of lithium treatment, the remission rate for all patients was 62.0%. The plasma lithium levels did not impact the clinical response. However, subjects with higher blood lithium levels had an increased prevalence of nausea, restlessness, headaches and cognitive complaints. The results indicate that the lithium dose for the treatment of bipolar depression in an individual should be based on the clinical efficacy and side-effects. In the context of personalized psychiatric treatments, it is necessary to evaluate the therapeutic action of lithium with individual regimens in order to develop more tolerable and effective treatment approaches.
Extracellular metolloproteases have been implied in different process such as cell death, differentiation and migration. Membrane-bound metalloproteases of the ADAM family shed the extracellular domain of many cytokines and receptor controlling auto and para/juxtacrine cell signaling in different tissues. ADAM17 and ADAM10 are two members of this family surface metalloproteases involved in germ cell apoptosis during the first wave of spermatogenesis in the rat, but they have other signaling functions in somatic tissues.
The cholesterol content of the sperm membrane is regulated during both maturation in the epididymis and capacitation in the female tract, two processes required for the spermatozoa to acquire their fertilising ability. Because Niemann-Pick disease, type C2 (NPC2) protein is one of the most abundant components of the epididymal fluid and contains a functional cholesterol-binding site that can transfer cholesterol between membranes, it has been suggested for years that NPC2 could be involved in the regulation of cholesterol levels in spermatozoa during epididymal maturation. In the present study, western blot and immunohistochemistry analyses demonstrated significant levels of NPC2 in the mouse epididymal epithelium. Epididymal spermatozoa obtained from NPC2(-/-) mice were morphologically normal and had normal motility parameters, but had a reduced cholesterol content compared with that of wild-type (WT) spermatozoa, as determined by both biochemical and by flow cytometry analyses. These results suggest that NPC2 could be involved in regulating cholesterol levels in spermatozoa during epididymal maturation. To understand the relevance of epididymal NPC2 for sperm function, the ability of spermatozoa to undergo events influenced by epididymal maturation, such as capacitation and fertilisation, were compared between WT and NPC2(-/-) mice. Capacitated NPC2(-/-) spermatozoa exhibited defective tyrosine phosphorylation patterns and a reduced ability to fertilise cumulus-oocyte complexes compared with WT spermatozoa, supporting the relevance of mouse epididymal NPC2 for male fertility.
The purpose of this study was to examine the association between sarcopenia and sarcopenic obesity (SO) with cardiometabolic risk factors in postmenopausal women. 149 volunteers (67.17±6.12 years) underwent body composition assessment using dual energy X-ray absorptiometry (DXA) and had analyzed blood samples collected for lipid profile, glucose metabolism and C-reactive protein (CRP). Sarcopenia was defined as an appendicular fat-free mass (AFFM) divided by height squared ?5.45 kg/m(2) while SO was classified based on the residuals of a regression. Waist circumference (WC) and arterial blood pressure were also measured. Student's t-tests and correlations were used for analyses. Prevalence of sarcopenia and SO were respectively 16.8 and 21.5%. WC was significantly correlated with all the examined risk factors. AFFM relative to height squared was positively correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP), CRP, insulinaemia, HOMA score, and those classified as sarcopenic presented lower HOMA score when compared to nonsarcopenic. Regarding SO, although volunteers classified presented significantly higher fat mass (FM) and lower AFFM, it was not observed association with the examined risk factors. These findings support the association between WC and cardiometabolic risk factors in older women. In contrast, the approaches used to define sarcopenia and SO are not associated with cardiometabolic impairments.
Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. Recently, shorten telomeres length has been reported in bipolar disorder (BD) and depression. The enzyme telomerase regulates telomeres? length, which has been associated with cellular viability; however it is not clear how telomerase may be involved in the pathophysiology and therapeutics of BD. In the present study, leukocyte telomerase activity was assessed in 28 medication-free BD depressed individuals (DSM-IV-TR criteria) at baseline and after 6 weeks of lithium therapy (n=21) also matching with 23 healthy controls. There was no difference between telomerase activity in subjects with BD depression (before or after lithium) and controls. Improvement of depressive symptoms was negatively associated with telomerase activity after 6 weeks of lithium therapy. This is the first study describing telomerase activity in BD research. Overall, telomerase activity seems not directly involved in the pathophysiology of short-term BD. Lithium?s antidepressant effects may involve regulation at telomerase activity. Further studies with larger samples and long-term illness are also warranted.
People with lower-limb amputation have reduced mobility due to loss of sensory information, which may be restored by artificial sensory feedback systems built into prostheses. For an effective system, it is important to understand how humans sense, interpret, and respond to the feedback that would be provided. The goal of this study was to examine sensorimotor responses to mobility-relevant stimuli. Three experiments were performed to examine the effects of location of stimuli, frequency of stimuli, and means for providing the response. Stimuli, given as vibrations, were applied to the thigh region, and responses involved leg movements. Sensorimotor reaction time (RT) was measured as the duration between application of the stimulus and initiation of the response. Accuracy of response was also measured. Overall average RTs for one response option were 0.808 +/- 0.142 s, and response accuracies were >90%. Higher frequencies (220 vs 140 Hz) of vibration stimulus provided in anterior regions of the thigh produced the fastest RTs. When participants were presented with more than one stimulus and response option, RTs increased. Findings suggest that long sensorimotor responses may be a limiting factor in the development of an artificial feedback system for mobility rehabilitation applications; however, feed-forward techniques could potentially help to address these limitations.
Emergence and re-emergence of arboviral disease in new areas of southern Europe is becoming a public health problem. Since Aedes albopictus was first detected in 2004 in Catalonia, it has spread along the Spanish Mediterranean coast. Results of an entomological surveillance carried out by the Spanish Ministry of Health to monitor the expansion of Ae. albopictus along the Spanish Mediterranean coast between 2009 and 2012 are presented. Besides the new locations in Valencia and Murcia regional communities, it was identified in five municipalities in the Balearic Islands in 2012. A comprehensive plan aiming the control of invasive vector-borne diseases including entomological surveillance should be considered.
Periostin (PN), a novel fasciclin-related matricellular protein, has been implicated in cardiac development and postnatal remodeling, but the mechanism remains unknown. We examined the role of PN in mediating intracellular kinase activation for atrioventricular valve morphogenesis using well defined explant cultures, gene transfection systems, and Western blotting. The results show that valve progenitor (cushion) cells secrete PN into the extracellular matrix, where it can bind to INTEGRINs and activate INTEGRIN/focal adhesion kinase signaling pathways and downstream kinases, PI3K/AKT and ERK. Functional assays with prevalvular progenitor cells showed that activating these signaling pathways promoted adhesion, migration, and anti-apoptosis. Through activation of PI3K/ERK, PN directly enhanced collagen expression. Comparing PN-null to WT mice also revealed that expression of hyaluronan (HA) and activation of hyaluronan synthase-2 (Has2) are also enhanced upon PN/INTEGRIN/focal adhesion kinase-mediated activation of PI3K and/or ERK, an effect confirmed by the reduction of HA synthase-2 in PN-null mice. We also identified in valve progenitor cells a potential autocrine signaling feedback loop between PN and HA through PI3K and/or ERK. Finally, in a three-dimensional assay to simulate normal valve maturation in vitro, PN promoted collagen compaction in a kinase-dependent fashion. In summary, this study provides the first direct evidence that PN can act to stimulate a valvulogenic signaling pathway.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease (CLD) and is frequently linked to intrahepatic microvascular disorders. Activation of hepatic stellate cells (HSC) is a central event in liver damage, due to their contribution to hepatic renewal and to the development of fibrosis and hepatocarcinoma. During the progression of CLDs, HSC attempt to restore injured tissue by stimulating repair processes, such as fibrosis and angiogenesis. Because HSC express the key vascular receptor Tie2, among other angiogenic receptors and mediators, we analyzed its involvement in the development of CLD.
Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of alterations that go from simple steatosis to steatohepatitis and cirrhosis. Type 2 diabetes mellitus (DM-2) and obesity are the principle factors associated to NAFLD. A 20-30 % prevalence in general population has been described. The survival of this type of patient is lower than the general population´s, showing a higher incidence of hepatic and cardiovascular complications. The aetiopathogenesis is still unclear, but we know the intervention of different factors that produce fatty-acid accumulation in hepatic parenchyma, causing oxidative stress, oxygen-free radicals and the synthesis of an inflammatory cascade, that determine the progression of this disease from steatosis up to advanced fibrosis.The diagnostic gold-standard is still the liver biopsy, even though the development of newer non-invasive techniques, like serological and imaging (radiology), have opened a new field for research that allows bloodless testing of these patients and better study of the natural history of this disease. Nowadays, there is still no specific treatment for NAFLD. The development of healthy life habits and moderate exercise continue to be the pillars of treatment. Different pharmacological approaches have been studied and applied, such as the control of insulin resistance, lowering cholesterol levels, antioxidants, and other alternatives in experimental trials.
The ability to recognize facial emotions is altered in patients with Bipolar Disorder (BD) during mood episodes and even in euthymia, while cognitive functioning is similarly impaired. This recognition is considered a fundamental skill for successful social interaction. However, it is unclear whether the ability to recognize facial emotions is correlated with the cognitive deficits observed in BD.
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of unknown etiology, presenting a dense mucosal infiltration of eosinophils that is not reversible with proton pump inhibitor therapy. Endoscopy has reported EoE commonly polymorphous disease with subtle mucosal changes, accompanied by variations in the caliber of the esophagus. The suggestion of EoE as an allergic disease is still short of evidence and recently, it has only been confirmed that the esophagus mucosal layer infiltrated by eosinophils may determine an association with allergy after exposure to allergens. A comprehensive review of symptoms, risk factors, diagnoses and mechanisms involved in the pathogenesis of EoE was carried out, with an analysis of the different treatment options available for this disease firmly maximizing in incidence and prevalence. The management of EoE is multidisciplinary and can involve gastroenterologists, pathologists, allergists and dietitians, particularly in pediatric patients, because dietary food restrictions appear to be more beneficial in children versus adults. EoE can successfully be treated with topical corticosteroids, which eliminate the clinical manifestations and histological lesions in most cases. Prolonged treatment is advised for EoE because it recurs frequently, particularly on discontinuation of therapy. Experimental treatments using immunotherapy are being investigated, but their safety and efficacy are yet to be defined.
The aim of this study was to assess structural and biochemical differences in the extracellular matrix of the fetal and adult porcine mitral heart valves in relation to their mechanical characteristics. Using tensile tests it was demonstrated that the material properties of porcine mitral heart valves progressively change with age. The collagen content of the adult heart valve, as estimated by hydroxyproline assay, increases three times as compared with fetal heart valves. Transmission electron microscopy demonstrated that the diameter of collagen fibrils increased in adult heart valves compared with fetal heart valves. The level of collagen cross-linking is lower in the fetal heart valve than the adult heart valve. The reported age differences in the material properties of fetal and adult porcine heart valves were associated with increases in collagen content, the diameter of collagen fibrils and the level of collagen cross-linking. These data lay a foundation for systematic elucidation of the structural determinants of material properties of heart valves during embryonic and postnatal valvulogenesis. They are also essential to define the desirable level of tissue maturation in heart valve tissue engineering.
We have measured the single-molecule conductance of a family of bithiophene derivatives terminated with methyl sulfide gold-binding linkers using a scanning tunneling microscope based break-junction technique. We find a broad distribution in the single-molecule conductance of bithiophene compared with that of a methyl sulfide terminated biphenyl. Using a combination of experiments and calculations, we show that this increased breadth in the conductance distribution is explained by the difference in 5-fold symmetry of thiophene rings as compared to the 6-fold symmetry of benzene rings. The reduced symmetry of thiophene rings results in a restriction on the torsion angle space available to these molecules when bound between two metal electrodes in a junction, causing each molecular junction to sample a different set of conformers in the conductance measurements. In contrast, the rotations of biphenyl are essentially unimpeded by junction binding, allowing each molecular junction to sample similar conformers. This work demonstrates that the conductance of bithiophene displays a strong dependence on the conformational fluctuations accessible within a given junction configuration, and that the symmetry of such small molecules can significantly influence their conductance behaviors.
Helicobacter pylori infects more than half of the worlds population, making it the most widespread infection of bacteria. It has high genetic diversity and has been considered as one of the most variable bacterial species. In the present study, a PCR-based method was used to detect the presence and the relative frequency of homologous recombination between repeat sequences (>500 bp) in H. pylori 26695. All the recombinant structures have been confirmed by sequencing. The inversion generated between inverted repeats showed distinct features from the recombination for duplication or deletion between direct repeats. Meanwhile, we gave the mathematic reasoning of a general formula for the calculation of relative recombination frequency and indicated the conditions for its application. This formula could be extensively applied to detect the frequency of homologous recombination, site-specific recombination, and other types of predictable recombination. Our results should be helpful for better understanding the genome evolution and adaptation of bacteria.
The aim of this study was to compare impulsivity among patients with bipolar disorder, their siblings, and healthy controls in order to examine whether impulsivity in bipolar disorder is related to genetic liability for the illness.
The purpose of this study was to investigate the association between the GHR exon 3 fl/d3 polymorphism and body composition traits in Brazilian cohorts of normal post-menarche adolescent girls and in post-menopausal women with and without osteoporosis. First, multiplex PCR and quantitative PCR (TaqMan) were used with 105 DNA samples from the general Brazilian population to validate the SNP rs6873545 as a surrogate marker for the GHR polymorphism. Subsequently, genotyping was carried out to evaluate associations for this polymorphism in 136 post-menarche adolescents and 175 post-menopausal women, who were evaluated for body composition traits such as bone mineral density and fat-free mass. Statistical analysis used an independent sample t test, one-way ANOVA test and post hoc Tukey HSD test. Significant values were assumed by p < 0.05. Genotyping indicated complete linkage disequilibrium between the GHR polymorphism and the SNP alleles (r (2) = 1.0). Adolescents and healthy post-menopausal women showed no genotype associations for body composition traits or osteoporosis. However, a lower total body bone mineral density was observed in fl/fl post-menopausal women with osteoporosis (p = 0.0004). These results suggest that the SNP rs6873545 can be used as a surrogate for the GHR fl/d3 polymorphism due to linkage disequilibrium in the Brazilian population and that the fl/fl genotype is a severity-related risk factor for osteoporosis, but did not appear to be associated with disease status.
Reproductive success stems from a finely regulated balance between follicular maturation and atresia, in which the role of carbohydrate structure is poorly understood. Here, we describe for the first time a fraction of purified recombinant human FSH that is capable of bringing about the cell death of granulosa cells and preventing follicular maturation in a rat model. Further analysis by mass spectrometry revealed the presence of the lectin Concanavalin-A (Con-A) within this fraction of recombinant FSH. Using both the fractionated FSH and Con-A, the observed cell death was predominantly located to the granulosa cells. Ex vivo culture of rat follicles demonstrated that follicle degeneration occurred and resulted in the release of a denuded and deteriorated oocyte. Moreover, in vivo experiments confirmed an increase in atresia and a corresponding reduction confined to follicle in early antral stage. As a mechanism of action, Con-A reduces ovarian proliferation, Von Willebrand staining, and angiogenesis. Based on the observation that Con-A may induce granulosa cell death followed by follicle death, our results further demonstrate that follicular carbohydrate moiety is changing under the influence of FSH, which may allow a carbohydrate-binding lectin to increase granulosa cell death. The physiological consequences of circulating lectin-like molecules remain to be determined. However, our results suggest a potential exploitation of carbohydrate binding in fertility and ovarian cancer treatment. This work may shed light on a key role of carbohydrates in the still obscure physiological process of follicular selection and atresia.
Bipolar disorder (BD) is a major public health problem characterized by progressive functional impairment. A number of clinical variables have been associated with progression of the disease, most notably number of affective episodes and presence of psychotic symptoms, both of which correlate with greater cognitive impairment, lower response rates for lithium, and possibly lower levels of neurotrophic factors. Oxidative damage to cytosine and guanosine (8-OHdG) has been described as a modulator of DNA methylation, but the extent of DNA oxidative damage involvement in BD remains unclear. The aim of this study was to evaluate the extent of DNA oxidative damage to 8-OHdG and 5-methylcytosine (5-HMec), as well as global methylation (5-Mec), in BD patients and healthy controls. Potential association with clinical variables was also investigated. DNA levels of 8-OHdG, 5-HMec and 5-Mec were measured in 50 BD type I patients and 50 healthy controls. DNA 8-OHdG levels were higher in BD patients compared to healthy controls and found to be positively influenced by number of previous manic episodes. BD subjects had lower levels of 5-HMec compared to controls, whereas this measure was not influenced by the clinical features of BD. Number of manic episodes was correlated with higher levels of 8-OHdG, but not of 5-Mec or 5-HMec. Lower demethylation activity (5-HMec) but no difference in global 5-Mec levels was observed in BD. This finding suggests that oxidative damage to 8-OHdG might be a potential marker of disease progression, although further prospective cross-sectional studies to confirm neuroprogression in BD are warranted.
The purpose of the present study was to compare dynamic muscle strength, functional performance, fatigue, and quality of life in premenopausal systemic lupus erythematosus (SLE) patients with low disease activity versus matched-healthy controls and to determine the association of dynamic muscle strength with fatigue, functional performance, and quality of life in SLE patients.
Dopamine (DA) is considered to be an important neurotransmitter in the control of impulsive behavior, however, its underlying mechanisms have not been fully elucidated. Catechol-O-methyltransferase (COMT) is a key enzyme in the catabolism of DA within the prefrontal cortex (PFC) and has been suggested to play a role in the mediation of impulsive behavior. The COMT single nucleotide polymorphism (SNP) rs4680 (Val158Met) Met allele has been shown to decrease COMT enzyme activity and is associated with improved PFC cognitive function (intelligence and executive functions). Studies have associated the rs4680 genotype with impulsivity as a symptom in attention deficit hyperactivity disorder and substance abuse. However, only a few studies have assessed the effects of rs4680 on impulsiveness in healthy subjects, the results of which remain controversial. The Barratt Impulsiveness Scale (BIS-11) was applied to 82 healthy volunteers (including 42 females) who were genotyped for COMT rs4680. Subjects carrying the Met/Met genotype scored higher for the BIS-11 second-order factor Non-planning than carriers of the Val/Val genotype. No interaction between gender genotype was detected. Age, gender and education had no effect on the results. The COMT rs4680 Met/Met genotype was associated with higher impulsivity on the BIS-11 second-order factor Non-planning. These results suggest that COMT enzyme activity may be important in the regulation of impulsiveness among young adults. Further studies involving larger samples should be conducted to confirm the results of the present study.
The treatment of bipolar disorder (BD) remains a challenge due to the complexity of the disease. Current guidelines represent an effort to assist clinicians in routine practice but have several limitations, particularly concerning long-term treatment. The ARIQUELI (efficacy and tolerability of the combination of lithium or aripiprazole in young bipolar non or partial responders to quetiapine monotherapy) study aims to evaluate two different augmentation strategies for quetiapine nonresponders or partial responders in acute and maintenance phases of BD treatment.
Cognitive performance in healthy individuals is associated with gender differences in specific tests; a female advantage has been demonstrated in language tests, whereas a male advantage has been demonstrated in spatial relation examinations. The prefrontal cortex (PFC) mediates important cognitive domains and is influenced by dopamine (DA) activity. The single nucleotide polymorphism (SNP) rs4680 in the catechol?O?methyltransferase (COMT) gene results in an amino acid substitution from valine (Val) to methionine (Met). The Met allele has been demonstrated to decrease COMT enzyme activity and improve PFC cognitive function. COMT regulates DA activity in the PFC and exhibits gender effects. The aim of the present study was to investigate the gender?specific effects of the COMT genotype on cognition in healthy young adults. Seventy?six healthy subjects were genotyped for COMT rs4680 and submitted to an extensive range of neuropsychological tests assessing aspects of PFC function. The COMT Met allele influenced the performance of executive function. The results revealed gender effects of the COMT rs4680 Met allele on verbal fluency, with positive effects in males and negative effects in females. This suggested that DA activity affects cognitive function in different ways, according to gender.
Severe combined immunodeficiency includes a group of diseases characterized by different inherited immunological defects. A 4-month-old girl diagnosed with Omenn syndrome, a subtype of severe combined immunodeficiency presenting with generalized erythroderma, was referred to our hospital for an allogeneic stem cell transplantation. Days before transplantation, she developed hyperpigmented macules that increased in number in the following months. As the erythroderma resolved after transplantation, diffuse hypopigmentation was simultaneously noted together with the expansion of hyperpigmented lesions. Cutaneous biopsy samples were taken at different moments, showing features of Omenn syndrome at first, and 2 months later changes consistent with hypopigmentation and repigmentation were observed. Although pigmentary disorders are rarely described in this context, these must be taken into account as a possible alternative diagnosis to graft-versus-host disease and toxicoderma in immunosuppressed patients.
The aim of the present study was to investigate the prevalence of sarcopenic obesity and its association with obesity and sarcopenia in elderly Brazilian women. Two hundred and seventy-two sedentary women with a mean age of 66.75 ± 5.38 years were recruited for participation in this study. Obesity was determined by both body mass index and dual-energy X-ray absorptiometry (DXA) evaluations. Sarcopenic obesity diagnosis was established from the ratio between fat-free mass and body surface area as obtained by DXA. There was no association of obesity with sarcopenic obesity (P = 0.424). In contrast, sarcopenia was significantly related to sarcopenic obesity (P < 0.001), although most of the elderly women with sarcopenia (n = 171) did not exhibit sarcopenic obesity. These results highlight the importance of diagnosing sarcopenic obesity as elderly women exhibiting sarcopenia could be either eutrophic or obese.
BACKGROUND: Several studies seek biological markers that give diagnostic and degree of tumor development. The aim of this study was to validate the determination of plasma DNA using nanotechnology (Nanovue™-NV) in samples of 80 patients with prostate cancer. METHODS: Blood samples of 80 patients of the Urology Ambulatory of Faculdade de Medicina do ABC with prostate cancer confirmed by anatomical-pathology criteria were analyzed. DNA extraction was performed using a GFX TM kit (Amersham Pharmacia Biotech, Inc, USA) following the adapted protocol. Plasma was subjected to centrifugation. RESULTS: There was a big difference between the first and the second value obtained by NanoVue Only two samples had no differences between duplicates. Maximum difference between duplicates was 38??g/mL. Average variation between 51 samples was 10.29??g/mL, although 21 samples had differences above this average. No correlation was observed between pDNA obtained by traditional spectrophotometry and by nanotechnology. CONCLUSION: Determination of plasma DNA by nanotechnology was not reproducible.
Serum baseline tryptase (sBT) is a minor diagnostic criterion for systemic mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome.
Accurate liver fibrosis staging is crucial for the management of chronic hepatitis C (CHC). The invasiveness and cost burden of liver biopsy have driven the search for new noninvasive biomarkers of fibrosis. Based on the link between serum angiopoietin-1 and 2 levels and CHC progression, we aimed to determine the value of these angiogenic factors as noninvasive biomarkers of liver fibrosis.
Impairments in facial emotion recognition (FER) have been reported in bipolar disorder (BD) subjects during all mood states. This study aims to investigate the impact of limbic system morphology on FER scores in BD subjects and healthy controls.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) like superoxide and nitric oxide are produced by testis and spermatogenic cells in response to heat stress. However, the magnitude and mechanisms of this production in spermatogenic cells have not been described. In this work, we evaluated ROS/RNS production, its pharmacology, mitochondrial oxidative metabolism, membrane potential and antioxidant capacity at different temperatures in isolated rat pachytene spermatocytes and round spermatids. Our results showed an increment in ROS/RNS production by pachytene spermatocytes when increasing the temperature to 40?°C. Instead, ROS/RNS production by round spermatids did not change at temperatures higher than 33?°C. ROS/RNS production was sensitive to NADPH oxidase inhibitor diphenylene iodonium or the mitochondrial complex I inhibitor rotenone. No additive effects were observed for these two compounds. Our results suggest an important mitochondrial ROS/RNS production in spermatogenic cells. Oligomycin-insensitive oxygen consumption (uncoupled oxygen consumption) increased with temperature and was significantly larger in round spermatids than pachytene spermatocytes, indicating a likely round spermatid mitochondrial uncoupling at high temperatures. A similar conclusion can be reached by measuring the mitochondrial membrane potential using rhodamine 123 fluorescence in permeabilized cells or JC-1 fluorescence in intact cells. The antioxidant capacity was higher in round spermatids than pachytene spermatocytes at 40?°C. Our results strongly suggest that at high temperatures (40?°C) pachytene spermatocytes are more susceptible to oxidative stress, but round spermatids are more protected because of a temperature-induced mitochondrial uncoupling together with a larger antioxidant capacity.
The aim of this study was to compare temperament and character traits among patients with bipolar disorder (BD), their siblings, and healthy controls (HCs) in order to examine whether personality traits are related to the genetic vulnerability to develop BD.
One hundred and ninety three odor detection thresholds, ODTs, obtained by Nagata using the Japanese triangular bag method can be correlated as log (1/ODT) by a linear equation with R(2) = 0.748 and a standard deviation, SD, of 0.830 log units; the latter may be compared with our estimate of 0.66 log units for the self-consistency of Nagatas data. Aldehydes, acids, unsaturated esters, and mercaptans were included in the equation through indicator variables that took into account the higher potency of these compounds. The ODTs obtained by Cometto-Muñiz and Cain, by Cometto-Muñiz and Abraham, and by Hellman and Small could be put on the same scale as those of Nagata to yield a linear equation for 353 ODTs with R(2) = 0.759 and SD = 0.819 log units. The compound descriptors are available for several thousand compounds, and can be calculated from structure, so that further ODT values on the Nagata scale can be predicted for a host of volatile or semivolatile compounds.
Mammalian germ cell apoptosis plays a key role in controlling the correct number of germ cells supported by Sertoli cells during the first wave of spermatogenesis in mammalian puberty. However, little is known about hormonal factors that could influence the rate of germ cell apoptosis during puberty or adulthood. In this work we evaluate germ cell apoptosis under hypothyroidism induced by goitrogen propylthiouracil (PTU) during the first wave of spermatogenesis. Neonatally administered PTU promoted a delay in the differentiation of Sertoli cells as evaluated by the expression of clusterin using immunohistochemistry and RT-PCR. Clusterin had different expression levels in control and PTU-treated animals, but under both conditions the highest levels were found in 35-day-old rats. In addition, clusterin displayed a cytoplasmic localization in control testes, but appeared located in the nucleus in PTU-treated animals. The wave of apoptosis (determined by caspase activity and quantification of apoptotic cells) characteristic of the first round of spermatogenesis was delayed by at least 10 days in these animals. The expression levels of proapoptotic genes like BAX or BAD were different between control and PTU-treated rats; although in both groups the highest level was found at the same age (days). Thus our results indicate that the characteristic pubertal apoptotic wave during rat spermatogenesis is delayed in neonatal hypothyroid rats.
The interaction between acrosome-reacted sperm and zona pellucida proteins is not yet fully understood. Serine protease acrosin and its zymogen proacrosin have been proposed to fulfill this function due to their capacity to bind zona pellucida glycoproteins. However, the molecular mechanism underlying this interaction has been merely speculative. Here we show that fucoidan (a sulfated polysaccharide) and solubilized zona pellucida glycoproteins, but not soybean trypsin inhibitor, are able to detach bound spermatozoa, which suggests that live sperm binds to the zona pellucida in a non-enzymatical way. Interestingly, mild proteolytic digestion with acrosin or trypsin does not modify the structure of the zona pellucida, but rather results in fewer spermatozoa binding to the zona. These results agree with a model where the active site of acrosin digests the zona pellucida and binds through the polysulfate-binding domain through a three-dimensional zona structure rather than a single ligand.
Constitutive germ cell apoptosis during mammalian spermatogenesis is a key process for controlling sperm output and to eliminate damaged or unwanted cells. An increase or decrease in the apoptosis rate has deleterious consequences and leads to low sperm production. Apoptosis in spermatogenesis has been widely studied, but the mechanism by which it is induced under physiological or pathological conditions has not been clarified. We have recently identified the metalloprotease ADAM17 (TACE) as a putative physiological inducer of germ cell apoptosis. The mechanisms involved in regulating the shedding of the ADAM17 extracellular domain are still far from being understood, although they are important in order to understand cell-cell communications. Here, we review the available data regarding apoptosis during mammalian spermatogenesis and the localization of ADAM proteins in the male reproductive tract. We propose an integrative working model where ADAM17, p38 MAPK, protein kinase C (PKC) and the tyrosine kinase c-Abl participate in the physiological signalling cascade inducing apoptosis in germ cells. In our model, we also propose a role for the Sertoli cell in regulating the Fas/FasL system in order to induce the extrinsic pathway of apoptosis in germ cells. This working model could be applied to further understand constitutive apoptosis in spermatogenesis and in pathological conditions (e.g., varicocele) or following environmental toxicants exposure (e.g., genotoxicity or xenoestrogens).
Hepatitis C virus (HCV) infects more than three million new individuals worldwide each year. In a high percentage of patients, acute infections become chronic, eventually progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Given the lack of effective prophylactic or therapeutic vaccines, and the limited sustained virological response rates to current therapies, new approaches are needed to prevent, control, and clear HCV infection. Entry into the host cell, being the first step of the viral cycle, is a potential target for the design of new antiviral compounds. Despite the recent discovery of the tight junction-associated proteins claudin-1 and occludin as HCV co-receptors, which is an important step towards the understanding of HCV entry, the precise mechanisms are still largely unknown. In addition, increasing evidence indicates that tools that are broadly employed to study HCV infection do not accurately reflect the real process in terms of viral particle composition and host cell phenotype. Thus, systems that more closely mimic natural infection are urgently required to elucidate the mechanisms of HCV entry, which will in turn help to design antiviral strategies against this part of the infection process.
Methotrexate (MTX) safety is questioned by the risk of inducing liver fibrosis (LF). As transient elastography (FibroScan®) is an effective non-invasive technique to evaluate LF, our aims were to assess LF in MTX-treated patients, to evaluate LF regarding treatment duration and cumulative dose, and to determine differences depending on the underlying disease.
Creativity is a complex construct involving affective and cognitive components. Bipolar Disorder (BD) has been associated with creativity and is characterized by a wide range of affective and cognitive symptoms. Although studies of creativity in BD have tended to focus on creativity as a trait variable in medicated euthymic patients, it probably fluctuates during symptomatic states of BD. Since creativity is known to involve key affective and cognitive components, it is plausible to speculate that cognitive deficits and symptoms present in symptomatic BD could interfere with creativity.
The purpose of our study is to determine whether body mass index (BMI = weight in kg/height in meters(2)) was related to the rate of negative appendectomy in patients who underwent preoperative CT. A surgical database search performed using the procedure code for appendectomy identified 925 patients at least 18 years of age who underwent urgent appendectomy between January 1998 and September 2007. BMI was computed for the 703 of these 925 patients for whom height and weight information was available. Patients were stratified based on body mass index (BMI 15-18.49 = underweight; 18.5-24.9 = normal weight; 25-29.9 = overweight; 30-39.9 = obese; ? 40 = morbidly obese). Negative appendectomy rates were computed. Negative appendectomy rates for patients who did and did not undergo preoperative CT were 27 per cent and 50 per cent for underweight patients, 10 per cent and 15 per cent for normal weight patients, 12 per cent and 17 per cent for overweight patients, 7 per cent and 30 per cent for obese patients, and 10 per cent and 100 per cent for morbidly obese patients. The difference in negative appendectomy rates for overweight patients, obese patients, and morbidly obese patients who underwent preoperative CT as compared with patients in the same BMI category who did not undergo preoperative CT was statistically significant (P ? 0.001). The negative appendectomy rates for overweight patients, obese patients, and morbidly obese patients who underwent preoperative CT were significantly lower than for patients in these same BMI categories who did not undergo preoperative CT.
Viral factors are considered the best predictors of response to treatment for chronic hepatitis C (CHC), but genetic factors are known to have an important role in this respect. This paper investigates the relationships among the host genetic factors HLA and IL28B, viral factors, and the outcome of combination therapy.
Esophageal motility abnormalities, as measured by conventional manometry (CM), are non-specific in the majority of patients with eosinophilic esophagitis (EoE). Moreover, the study of CM is limited by poor interobserver agreement. The aims of the present study were: (i) to assess the esophageal patterns in EoE by a topographic analysis of high-resolution manometry (HRM) data; and (ii) to establish a relationship between motility abnormalities and symptoms of EoE, such as dysphagia and bolus impaction.
The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments. Among amniotes, genome sequences are available for mammals and birds, but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes. Also, A. carolinensis mobile elements are very young and diverse-more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds. We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.
Population stratification is the main source of spurious results and poor reproducibility in genetic association findings. Population heterogeneity can be controlled for by grouping individuals in ethnic clusters; however, in admixed populations, there is evidence that such proxies do not provide efficient stratification control. The aim of this study was to evaluate the relation of self-reported with genetic ancestry and the statistical risk of grouping an admixed sample based on self-reported ancestry.
Bipolar Disorder (BD) is a chronic, recurrent and highly prevalent illness. Despite the need for correct diagnosis to allow proper treatment, studies have shown that reaching a diagnosis can take up to ten years due to the lack of recognition of the broader presentations of BD. Frequent comorbidities with other psychiatric disorders are a major cause of misdiagnosis and warrant thorough evaluation.
To evaluate the capacity to perceive bitter taste in a sample of the elderly population of the Brazilian Federal District, and to investigate its association with the consumption profile of distinct food groups. A total of 255 female outpatients aged 60 years or older took part in this cross-sectional study. The following data were determined for all the volunteers: alimentary frequency by clinical dieticians; genotyping of the G145C polymorphism in the TAS2r38 gene; cognitive status; sensorial (visual and hearing) acuity and drugs related to ageusia or dysgeusia. Sensitivity to bitter taste was assessed using phenylthiocarbamide (PTC) in a subset. Non-parametric tests confirmed the remarkable effect of the C allele in determining sensitivity to PTC (p<0.001). C allele carriers displayed diminished consumption of type B vegetables as well as of some vegetables generally recognized as bitter: arugula (p=0.044) and chard (p=0.006). No associations were observed for the remaining food classes. The present findings suggest that the G145C genetic variation in the TAS2r38 gene modestly influenced food consumption habits of Brazilian older women. Nonetheless, the results do not rule out possible effects of past experiences on choices of elderly individuals.
To assess the clinical, biochemical and virological long-term outcome in chronic hepatitis C (CHC) patients with a sustained virological response (SVR) after peginterferon (PEG-IFN) plus ribavirin combination therapy.
Methotrexate (MTX) therapy may be effective in patients with rheumatoid arthritis (RA) or psoriasis due to its anti-inflammatory and immunosuppressive properties. Potential liver toxicity of MTX exists, but the incidence of MTX-specific lesions in liver biopsy of patients with RA and elevated serum transaminase levels is rare; however, severe hepatic damage may occurs unexpectedly in these patients. We describe the first documented case of an adult patient with RA who developed an acute flare of severe hepatitis after long-term therapy with MTX. Autoantibodies positivity, elevated serum IgG levels and compatible liver biopsy findings prompted us to diagnose autoimmune hepatitis, most probably triggered by a breakdown of immune tolerance induced by MTX. A complete remission was achieved in this patient with corticosteroids therapy.
The porphyries are a group of metabolic disorders characterized by deficiencies in the activity of enzymes involved in the biosynthesis of heme. In erythropoietic protoporphyria (EPP), in the majority of cases an autosomal dominant disease, there is a mutation of the gene that encodes ferrochelatase (FECH). FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes, plasma, skin and liver. The prevalence of this inherited disorder oscillates between 1:75 000 and 1:200 000. Clinical manifestations of EPP appear in early infancy upon first exposure to the sun. Nevertheless, approximately 5%-20% of patients with EPP develop liver manifestations. Retention of protoporphyrin in the liver is associated with cholestatic phenomena and oxidative stress that predisposes to hepatobiliary disease of varying degrees of severity, such as cholelithiasis, mild parenchymal liver disease, progressive hepatocellular disease with end-stage liver disease and acute liver failure. Liver damage is the major risk in EPP patients, so surveillance and frequent clinical and biochemical liver follow-up is mandatory. The diagnostic approach consists in detecting increased levels of protoporphyrin, decreased activity of FECH and genetic analysis of the FECH gene. A variety of non-surgical therapeutic approaches have been adopted for the management of EPP associated with liver disease, but none of these has been shown to be unequivocally efficacious. Nevertheless, some may have a place in preparing patients for liver transplantation. Liver transplantation does not correct the constitutional deficiency of FECH. Consequently, there is a risk of recurrence of liver disease after liver transplantation as a result of continuing overproduction of protoporphyrin. Some authors recommend that bone marrow transplantation should be considered in liver allograft recipients to prevent recurrence of hepatic disease.
International research projects sponsored by the pharmaceutical industry are a recent modality of biomedical research, which is driven by interests that are not only scientific, but also commercial. This combination of interests is one of the natural consequences of globalization, which has brought unquestionable benefits for the world, but has also created a wider gap between the wealthy and the poor. Given that globalization has been led by the the worlds leading economies, the level of injustice in the world has increased, often to the favor of the already wealthy. Globalization has a well-established dynamics, whose main characteristic is domain over the following: technological innovation, the organization of the production of goods and services, human needs, and consumption. International biomedical research fits well in this dynamics, and the result is often a poor distribution of benefits, added to a loss of scientific integrity for the sake of commercial interests. This phenomenon raises many ethical questions and it demands a reflection from different bioethical points of view, particularly an economic ethics and a global justice.
Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response.
The challenge of Bipolar Disorder (BD) treatment is due to the complexity of the disease. Current guidelines represent an effort to help clinicians in their everyday practice but still have limitations, specially concerning to long term treatment. LICAVAL (efficacy and tolerability of the combination of LIthium and CArbamazepine compared to lithium and VALproic acid in the treatment of young bipolar patients) study aim to evaluate acute and maintenance phase of BD treatment with two combined drugs.
Bipolar disorders are often not recognized and undertreated. The diagnosis of current or past episodes of hypomania is of importance in order to increase diagnostic certainty. The Hypomania Checklist-32 is a self-applied questionnaire aimed at recognizing these episodes. As part of the international collaborative effort to develop multi-lingual versions of the Hypomania Checklist-32, we aimed to validate the Brazilian version and to compare its psychometric properties with those of the Mood Disorder Questionnaire.
Etoposide is a commonly used drug in testicular cancer chemotherapy. However, the molecular pathways that activate germ cell apoptosis in response to etoposide are poorly understood. The aim of this study was to evaluate the participation of p73, a member of the p53 family, in apoptosis induced by etoposide in male germ cells. First, we used GC2-spc cells-a male germ cell model-to evaluate apoptotic signaling after treatment of etoposide. We found an important increase in p73 protein levels, along with the c-Abl kinase, its physiological activator, in response to etoposide. This increase was accompanied by a decrease in cell viability and activation of caspase-3. Pifithrin (PFT) treatment prevented p73 increase and apoptosis induced by etoposide. Also, the in vitro knockdown of p73 or p53 by shRNA, significantly prevented the decrease in cell viability after etoposide treatment. In an in vivo model-21-day-old rat testes-we observed an up-regulation of the protein levels of p73 and phosphorylated p73-at c-Abl site Tyr99-in response to the etoposide injection. STI571 (a pharmacological inhibitor of c-Abl) or PFT co-injection prevented etoposide-induced up-regulation of phospho-p73 and pro-apoptotic TAp73 isoform levels. Moreover, caspases-3, -8, -9 activation and germ cell death induced by etoposide were significantly decreased by these drugs. These results support the notion that the c-Abl/p73 pathway is activated in germ cells after etoposide treatment, triggering apoptosis, possibly assisting p53.
The pathways leading to male germ cell apoptosis in vivo are poorly understood, but are highly relevant for the comprehension of sperm production regulation by the testis. In this work, we show the evidence of a mechanism where germ cell apoptosis is induced through the inactivation and shedding of the extracellular domain of KIT (c-kit) by the protease TACE/a disintegrin and metalloprotease 17 (ADAM17) during the first wave of spermatogenesis in the rat. We show that germ cells undergoing apoptosis lacked the extracellular domain of the KIT receptor. TACE/ADAM17, a membrane-bound metalloprotease, was highly expressed in germ cells undergoing apoptosis as well. On the contrary, cell surface presence of ADAM10, a closely related metalloprotease isoform, was not associated with apoptotic germ cells. Pharmacological inhibition of TACE/ADAM17, but not ADAM10, significantly prevented germ cell apoptosis in the male pubertal rat. Induction of TACE/ADAM17 by the phorbol-ester phorbol 12-myristate 13-acetate (PMA) induced germ cell apoptosis, which was prevented when an inhibitor of TACE/ADAM17 was present in the assay. Ex-vivo rat testis culture showed that PMA induced the cleavage of the KIT extracellular domain. Isolation of apoptotic germ cells showed that even though protein levels of TACE/ADAM17 were higher in apoptotic germ cells than in nonapoptotic cells, the contrary was observed for ADAM10. These results suggest that TACE/ADAM17 is one of the elements triggering physiological germ cell apoptosis during the first wave of spermatogenesis.
Apolipoprotein E (APOE) has been extensively studied as a risk factor for sporadic and late onset Alzheimers Disease (AD). APOE allele (?)3, the most frequent variant, is not associated to cognitive dysfunction (CD) or to increased AD risk. Differently, the (?)4 allele is a well-established risk factor for CD, while the (?)2 allele is associated with survival and longevity. CD is an important feature of Bipolar Disorder (BD) and recent data suggest that CD may be one of its endophenotypes, although controversial results exist. The aim of this research is to study the association of APOE genotype (APOE) and neurocognitive function in a sample of drug free young BD-type I patients. Sample consisted of 25 symptomatic BD (type I) patients (age 18-35 years old). They were submitted to an extensive neuropsychological evaluation and genotyped for APOE. Subjects with allele (?)2 presented better cognitive performance. The presence of allele (?)4 was associated with worse performance in a few executive tasks. APOE (?)3(?)3 was associated with overall severe dysfunction on cognitive performance. In young individuals with nontreated BD-type I, APOE may predict cognitive performance. Further and larger studies on APOE and cognition in BD are required to clarify whether APOE is a BD cognitive endophenotype.
Etoposide is a widely used anticancer drug in the treatment of different tumors. Etoposide is known to activate a wide range of intracellular signals, which may in turn induce cellular responses other than apoptosis. ADAM10 and TACE/ADAM17 belong to a family of transmembrane extracellular metalloproteinases involved in paracrine/juxtacrine regulation of many signaling pathways. The aim of this work was to evaluate if etoposide induces upregulation of ADAM10 or TACE/ADAM17 in two cell lines (GC-1 and GC-2) derived from male germ cells. Results showed that etoposide induced apoptosis in a dose-response manner in both GC-1 and GC-2 cells. Apoptosis started to increase 6h after etoposide addition in GC-2 cells, whereas the same was observed 18h after addition to the GC-1 cells. Protein and mRNA levels of ADAM10 and TACE/ADAM17 increased 18h after etoposide was removed from the GC-1 cells. In GC-2 cells, the protein levels of both proteins increased 12h after etoposide was removed. ADAM10 mRNA increased after 3h and then steadily decreased up to 12h after removal, whereas TACE/ADAM17 mRNA decreased after etoposide removal. Finally, apoptosis was prevented in GC-1 and GC-2 cells by the addition of pharmacological inhibitors of ADAM10 and TACE/ADAM17 to the culture medium of etoposide-treated cells. Our results show for the first time that etoposide upregulates ADAM10 and TACE/ADAM17 mRNA and protein levels. In addition, we also show that ADAM10 and TACE/ADAM17 have a role in etoposide-induced apoptosis.
We have read with interest the paper published in issue 2, volume 16 of World Journal of Gastroenterology 2010 by Nakamura et al, demonstrating that the antioxidant resveratrol (RVT) enhances hepatitis C virus (HCV) replication, consequently, they conclude that RVT is not a suitable antioxidant therapy for HCV chronic infection. The data raise some concern regarding the use of complementary and alternative medicine since the most frequent supplements taken by these patients are antioxidants or agents that may be beneficial for different chronic liver diseases. A recent study by Vidali et al on oxidative stress and steatosis in the progression of chronic hepatitis C concludes that oxidative stress and insulin resistance contribute to steatosis, thus accelerating the progression of fibrosis. We are particularly interested in investigating how the oxidative and nitrosative stress mechanisms are involved in the pathogenesis of different chronic liver diseases.
The purpose of this study was to determine if carcinoid tumors of the appendix were identified prospectively on preoperative CT at our institution during the last decade. A surgical database search performed using the Current Procedural Terminology codes for appendectomy and colectomy yielded 2108 patients who underwent appendectomy or colectomy with removal of the appendix from January 1998 through September 2007. Pathology reports were reviewed to identify patients in whom an appendiceal carcinoid tumor was identified. Preoperative CT reports and images were reviewed. Twenty-three carcinoid tumors (1.1%; 15 women [65.2%], eight men [34.8%]; average age 54 years [range, 23 to 86 years]) were identified. Ten patients underwent preoperative CT. No tumors were identified prospectively on CT. Images were available for rereview for eight patients. Studies were acquired with 16- (n = 7) and four- (n = 1) slice CT scanners. Average reported tumor size was 6.1 mm (range, 1.5 to 15 mm; n = 18). A tip or distal location was reported for all tumors for which a location was given (n = 15). Carcinoid tumors occurred in 1.1 per cent of appendix specimens. These tumors were all less than or 1.5 cm in size. Likely as a result of their small size, none of these tumors was identified prospectively on preoperative CT.
EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients.
Caspases, cystein proteases traditionally related to programmed cell death, have recently been found to be involved in vital processes such as cell proliferation, adhesion and differentiation. Although caspases are expressed in mouse embryos before the blastocyst stage, their role is unclear, since apoptosis does not occur significantly before implantation. In this work, we have used mouse preimplantation development as a model to evaluate the existence of non-lethal caspase activities. The use of specific caspase inhibitors during in vitro embryo culture showed that caspase 8 activity, but not caspase 2 or 9, was relevant for development. The inhibition of caspase 8 affected the compaction of morulae and the progression to the blastocyst stage. In agreement with these results, caspase 8 was expressed in mouse embryos, as shown by indirect immunofluorescence and RT-PCR. An in silico approach was used to find putative caspase targets expressed in mouse preimplantation embryos. Large-scale management of sequence data from mouse embryos was used to predict caspase substrates by tools matrix-based on known cleavage sites. A total of 510 potential caspase targets expressed in mouse embryos were identified by this procedure. The functional characterization of these proteins by Gene Onthology associations showed that many of these putative caspase targets were previously related to non-apoptotic functions and only 63 had been previously reported to be actually cleaved by caspases. Interestingly, eleven knockout mice models for caspase substrates identified in our work, i.e. catenin alpha and beta, geminin, pescadillo, calpain-2, have preimplantation lethal phenotypes. This work supports the involvement of caspases in vital functions during mouse preimplantation development and proposes a model in which the regulated cleavage of caspase substrates could account for this role.
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