Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways

Migration and proliferation of smooth muscle cells are key to a number of physiological and pathological processes, including wound healing and the narrowing of the vessel wall.Previous work has shown links between inflammatory stimuli and vascular smooth muscle cell proliferation and migration through mitogen activated protein kinase (MAPK) activation, though the molecular mechanisms of this process are poorly understood. Here we report that tribbles-1, a recently described modulator of MAPK activation controls vascular smooth muscle cell proliferation and chemotaxis via the Jun Kinase pathway. Our findings demonstrate that this regulation takes place via direct interactions between tribbles-1 and MKK4/SEK1, a Jun activator kinase. The activity of this kinase is dependent on tribbles-1 levels, whilst the activation and the expression of MKK4/SEK1 is not. In addition, tribbles-1 expression is elevated in human atherosclerotic arteries compared to non-atherosclerotic controls, suggesting that this protein may pay a role in disease in vivo. In summary, the data presented here suggest an important regulatory role for trb-1 in vascular smooth muscle cell biology

An analysis of social interaction between novice older adults when learning gesture-based skills through simple digital games

This paper reports three exploratory empirical studies with older adults that had little or no prior experience with interactive technologies. The participants were introduced to interactive technology by playing games on touchscreens, playing in pairs with the assistance of a mentor. We focus on two principle aspects, the peer-to-peer interaction during these sessions, and the role of the mentor in progressing the sessions. In the case of peer-to-peer interaction we looked for ways in which players supported each other during interaction to assess the role of peer interaction in this context. In the case of mentoring, we examined the efficacy of a minimalist approach where verbal encouragement, suggestions or (in the last resort) intervention are used to provide support to learners. The sessions showed that learners typically could play and learn basic manipulations independently after initial help and guidance from mentors. We also found that peer interaction, both in verbal and non-verbal communication and cooperative action was broadly a positive influence within sessions, suggesting that there is significant value in building confidence as well as in learning

Faster adjustment of O-2 delivery does not affect Vo(2) on-kinetics in isolated in situ canine muscle

The mechanism(s) limiting muscle O2 uptake (V\u307O2) kinetics was investigated in isolated canine gastrocnemius muscles (n = 7) during transitions from rest to 3 min of electrically stimulated isometric tetanic contractions (200-ms trains, 50 Hz; 1 contraction/2 s; 60-70% of peak V\u307O2). Two conditions were mainly compared: 1) spontaneous adjustment of blood flow (Q\u307) [control, spontaneous Q\u307 (C Spont)]; and 2) pump-perfused Q\u307, adjusted ~15 s before contractions at a constant level corresponding to the steady-state value during contractions in C Spont [faster adjustment of O2 delivery (Fast O2 Delivery)]. During Fast O2 Delivery, 1-2 ml/min of 10-2 M adenosine were infused intra-arterially to prevent inordinate pressure increases with the elevated Q\u307. The purpose of the study was to determine whether a faster adjustment of O2 delivery would affect V\u307O2 kinetics. Q\u307 was measured continuously; arterial (Ca(O2)) and popliteal venous (CV(O2)) O2 contents were determined at rest and at 5- to 7-s intervals during contractions; O2 delivery was calculated as Q\u307 \ub7 Ca(O2), and V\u307O2 was calculated as Q\u307 \ub7 arteriovenous O2 content difference. Times to reach 63% of the difference between baseline and steady-state V\u307O2 during contractions were 23.8 \ub1 2.0 (SE) s in C Spont and 21.8 \ub1 0.9 s in Fast O2 Delivery (not significant). In the present experimental model, elimination of any delay in O2 delivery during the rest-to-contraction transition did not affect muscle V\u307O2 kinetics, which suggests that this kinetics was mainly set by an intrinsic inertia of oxidative metabolism

Bioenergetics of contracting skeletal muscle after partial reduction of blood flow

The purpose of this study was to examine the bioenergetics and regulation of O2 uptake (V\u307O2) and force production in contracting muscle when blood flow was moderately reduced during a steady-state contractile period. Canine gastrocnemius muscle (n = 5) was isolated, and 3-min stimulation periods of isometric, tetanic contractions were elicited sequentially at rates of 0.25, 0.33, and 0.5 contractions/s (Hz) immediately followed by a reduction of blood flow [ischemic (I) condition] to 46 \ub1 3% of the value obtained at 0.5 Hz with normal blood flow. The V\u307O2 of the contracting muscle was significantly (P < 0.05) reduced during the I condition [6.5 \ub1 0.8 (SE) ml \ub7 100 g-1 \ub7 min-1] compared with the same stimulation frequency with normal flow (11.2 \ub1 1.5 ml \ub7 100 g-1 \ub7 min- 1), as was the tension-time index (79 \ub1 12 vs. 123 \ub1 22 N \ub7 g-1 \ub7 min-1, respectively). The ratio of V\u307O2 to tension-time index remained constant throughout all contraction periods. Muscle phosphocreatine concentration, ATP concentration, and lactate efflux were not significantly different during the I condition compared with the 0.5-Hz condition with normal blood flow. However, at comparable rates of V\u307O2 and tension-time index, muscle phosphocreatine concentration and ATP concentration were significantly less during the I condition compared with normal-flow conditions. These results demonstrate that, in this highly oxidative muscle, the normal balance of O2 supply to force output was maintained during moderate ischemia by downregulation of force production. In addition, 1) the minimal disruption in intracellular homeostasis after the initiation of ischemia was likely a result of steady-state metabolic conditions having already been activated, and 2) the difference in intracellular conditions at comparable rates of V\u307O2 and tension-time index between the normal flow and I condition may have been due to altered intracellular O2 tension

Atherosclerosis in young Brazilians suffering violent deaths: a pathological study

<p>Abstract</p> <p>Background</p> <p>Atherosclerosis is the leading cause of coronary heart disease and ischemic stroke, which can cause sudden death in adulthood. In general, the clinical manifestations of cardiovascular diseases are caused by atherosclerosis, which is a process that starts during middle age. More recent studies indicate that the atherosclerotic process begins during childhood.</p> <p>Methods</p> <p>To evaluate the extent of atherosclerotic disease in young Brazilians, we conducted a study of the pathological alterations in the major arteries of victims of violent death. Samples of the right carotid artery, left coronary artery, and thoracic aorta of young victims of violent death were analyzed and graded in accordance with the histological atherosclerotic lesion types proposed by the American Heart Association. Samples were collected from 100 individuals who had died from external causes, aged from 12 to 33 years.</p> <p>Results</p> <p>The majority of cases (83%) were male, and 66% of deaths were homicides caused by firearms. The median age was 20.0 years and mean body mass index was 20.9 kg/m². Of the right carotid artery specimens, 3% were normal, 55% had type I, 40% had type II, 1% had type III, and 1% had type IV atherosclerotic lesions. Of the left coronary artery specimens, 5% were normal, 48% had type I, 41% had type II, 3% had type III, and 3% had type IV lesions. Of the thoracic aorta specimens, none were normal, 13% had type I, 64% had type II, 22% had type III, and 1% had type IV lesions. Overall, 97.34% of arteries examined had some degree of atherosclerosis. The most common histological type was type II (foam cells). No thoracic aorta specimens were normal, and the coronary artery specimens had the most atherosclerosis.</p> <p>Conclusions</p> <p>Our results show a high prevalence of atherosclerotic lesions among young people in Brazil. Intervention should be undertaken to decrease the rate of sudden cardiac death in the adult population.</p

Nuclear Data for Sustainable Nuclear Energy

Final report of a coordinated action on nuclear data for industrial development in Europe (CANDIDE). The successful development of advanced nuclear systems for sustainable energy production depends on high-level modelling capabilities for the reliable and cost-effective design and safety assessment of such systems, and for the interpretation of key benchmark experiments needed for performance and safety evaluations. High-quality nuclear data, in particular complete and accurate information about the nuclear reactions taking place in advanced reactors and the fuel cycle, are an essential component of such modelling capabilities. In the CANDIDE project, nuclear data needs for sustainable nuclear energy production and waste management have been analyzed and categorized, on the basis of preliminary design studies of innovative systems. Meeting those needs will require that the quality of nuclear data files be considerably improved. The CANDIDE project has produced a set of recommendations, or roadmap, for sustainable nuclear data development. In conclusion, a substantial long-term investment in an integrated European nuclear data development program is called for, complemented by some dedicated actions targeting specific issues.JRC.D.5-Neutron physic

Long-term clinical and experimental/surface analytical studies of carbon/carbon maxillofacial implants

BACKGROUND:Over the past 30-40years, various carbon implant materials have become more interesting, because they are well accepted by the biological environment. The traditional carbon-based polymers give rise to many complications. The polymer complication may be eliminated through carbon fibres bound by pyrocarbon (carbon/carbon). The aim of this study is to present the long-term clinical results of carbon/carbon implants, and the results of the scanning electron microscope and energy dispersive spectrometer investigation of an implant retrieved from the human body after 8years.METHODS:Mandibular reconstruction (8-10years ago) was performed with pure (99.99%) carbon implants in 16 patients (10 malignant tumours, 4 large cystic lesions and 2 augmentative processes). The long-term effect of the human body on the carbon/carbon implant was investigated by comparing the structure, the surface morphology and the composition of an implant retrieved after 8years to a sterilized, but not implanted one.RESULTS:Of the 16 patients, the implants had to be removed earlier in 5 patients because of the defect that arose on the oral mucosa above the carbon plates. During the long-term follow-up, plate fracture, loosening of the screws, infection or inflammations around the carbon/carbon implants were not observed. The thickness of the carbon fibres constituting the implants did not change during the 8-year period, the surface of the implant retrieved was covered with a thin surface layer not present on the unimplanted implant. The composition of this layer is identical to the composition of the underlying carbon fibres. Residual soft tissue penetrating the bulk material between the carbon fibre bunches was found on the retrieved implant indicating the importance of the surface morphology in tissue growth and adhering implants.CONCLUSIONS:The surface morphology and the structure were not changed after 8years. The two main components of the implant retrieved from the human body are still carbon and oxygen, but the amount of oxygen is 3-4 times higher than on the surface of the reference implant, which can be attributed to the oxidative effect of the human body, consequently in the integration and biocompatibility of the implant. The clinical conclusion is that if the soft part cover is appropriate, the carbon implants are cosmetically and functionally more suitable than titanium plates

Prenatal origin of childhood AML occurs less frequently than in childhood ALL

Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases