2,360 research outputs found

    miR-542 promotes mitochondrial dysfunction and SMAD activity and is raised in ICU Acquired Weakness

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    Rationale: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases but the mechanisms by which this occurs are unclear. Objectives: We aimed to identify miRNAs that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. Methods: miR-542-3p/-5p were quantified in the quadriceps of patients with COPD and intensive care unit acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and TGF-β signaling in vitro and in vivo. Measurements and main results: miR-542-3p/5p were elevated in patients with COPD but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10, and reduced 12S rRNA expression suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1 and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation suggesting that miR-542-5p increased TGF-β signaling. In mice, miR-542 over-expression caused muscle wasting, reduced mitochondrial function, 12S rRNA expression and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased TGF-β signaling. In patients undergoing aortic surgery, pre-operative levels of miR-542-3p/5p were positively correlated with muscle loss following surgery. Conclusion; Elevated miR-542-3p/5p may cause muscle atrophy in ICU patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation

    Training pediatric health care providers in prevention of dental decay: results from a randomized controlled trial

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    Background: Physicians report willingness to provide preventive dental care, but optimal methods for their training and support in such procedures are not known. This study aimed to evaluate the effect of three forms of continuing medical education (CME) on provision of preventive dental services to Medicaid-enrolled children by medical personnel in primary care physician offices. Methods: Practice-based, randomized controlled trial. Setting: 1,400 pediatric and family physician practices in North Carolina providing care to an estimated 240,000 Medicaid-eligible children aged 0–3 years. Interventions: Group A practices (n = 39) received didactic training and course materials in oral health screening, referral, counseling and application of fluoride varnish. Group B practices (n = 41) received the same as Group A and were offered weekly conference calls providing advice and support. Group C practices (n = 41) received the same as Group B and were offered in-office visit providing hands-on advice and support. In all groups, physicians were reimbursed 38–38–43 per preventive dental visit. Outcome measures were computed from reimbursement claims submitted to NC Division of Medical Assistance. Primary outcome measure: rate of preventive dental services provision per 100 well-child visits. Secondary outcome measure: % of practices providing 20 or more preventive dental visits. Results: 121 practices were randomized, and 107 provided data for analysis. Only one half of Group B and C practices took part in conference calls or in-office visits. Using intention-to-treat analysis, rates of preventive dental visits did not differ significantly among CME groups: GroupA = 9.4, GroupB = 12.9 and GroupC = 8.5 (P = 0.32). Twenty or more preventive dental visits were provided by 38–49% of practices in the three study groups (P = 0.64). Conclusion: A relatively high proportion of medical practices appear capable of adopting these preventive dental services within a one year period regardless of the methods used to train primary health care providers.Gary D Slade, R Gary Rozier, Leslie P Zeldin, and Peter A Margoli

    The role of the right temporoparietal junction in perceptual conflict: detection or resolution?

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    The right temporoparietal junction (rTPJ) is a polysensory cortical area that plays a key role in perception and awareness. Neuroimaging evidence shows activation of rTPJ in intersensory and sensorimotor conflict situations, but it remains unclear whether this activity reflects detection or resolution of such conflicts. To address this question, we manipulated the relationship between touch and vision using the so-called mirror-box illusion. Participants' hands lay on either side of a mirror, which occluded their left hand and reflected their right hand, but created the illusion that they were looking directly at their left hand. The experimenter simultaneously touched either the middle (D3) or the ring finger (D4) of each hand. Participants judged, which finger was touched on their occluded left hand. The visual stimulus corresponding to the touch on the right hand was therefore either congruent (same finger as touch) or incongruent (different finger from touch) with the task-relevant touch on the left hand. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the rTPJ immediately after touch. Accuracy in localizing the left touch was worse for D4 than for D3, particularly when visual stimulation was incongruent. However, following TMS, accuracy improved selectively for D4 in incongruent trials, suggesting that the effects of the conflicting visual information were reduced. These findings suggest a role of rTPJ in detecting, rather than resolving, intersensory conflict

    Robotic milking technologies and renegotiating situated ethical relationships on UK dairy farms

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    Robotic or automatic milking systems (AMS) are novel technologies that take over the labor of dairy farming and reduce the need for human-animal interactions. Because robotic milking involves the replacement of 'conventional' twice-a-day milking managed by people with a system that supposedly allows cows the freedom to be milked automatically whenever they choose, some claim robotic milking has health and welfare benefits for cows, increases productivity, and has lifestyle advantages for dairy farmers. This paper examines how established ethical relations on dairy farms are unsettled by the intervention of a radically different technology such as AMS. The renegotiation of ethical relationships is thus an important dimension of how the actors involved are re-assembled around a new technology. The paper draws on in-depth research on UK dairy farms comparing those using conventional milking technologies with those using AMS. We explore the situated ethical relations that are negotiated in practice, focusing on the contingent and complex nature of human-animal-technology interactions. We show that ethical relations are situated and emergent, and that as the identities, roles, and subjectivities of humans and animals are unsettled through the intervention of a new technology, the ethical relations also shift. © 2013 Springer Science+Business Media Dordrecht

    Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.

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    Angiogenesis and the development of a vascular network are required for tumour progression, and they involve the release of angiogenic factors, including vascular endothelial growth factor (VEGF-A), from both malignant and stromal cell types. Infiltration by cells of the myeloid lineage is a hallmark of many tumours, and in many cases the macrophages in these infiltrates express VEGF-A. Here we show that the deletion of inflammatory-cell-derived VEGF-A attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumours in mice. Vasculature in tumours lacking myeloid-cell-derived VEGF-A was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF-A decreases the phosphorylation of VEGF receptor 2 (VEGFR2) in tumours, even though overall VEGF-A levels in the tumours are unaffected. However, deletion of myeloid-cell VEGF-A resulted in an accelerated tumour progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumour cell death and decreased tumour hypoxia. Furthermore, loss of myeloid-cell VEGF-A increased the susceptibility of tumours to chemotherapeutic cytotoxicity. This shows that myeloid-derived VEGF-A is essential for the tumorigenic alteration of vasculature and signalling to VEGFR2, and that these changes act to retard, not promote, tumour progression

    Nitrogen transfer from forage legumes to nine neighbouring plants in a multi-species grassland

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    Legumes play a crucial role in nitrogen supply to grass-legume mixtures for ruminant fodder. To quantify N transfer from legumes to neighbouring plants in multi-species grasslands we established a grass-legume-herb mixture on a loamy-sandy site in Denmark. White clover (Trifolium repens L.), red clover (Trifolium pratense L.) and lucerne (Medicago sativa L.) were leaf-labelled with 15N enriched urea during one growing season. N transfer to grasses (Lolium perenne L. and xfestulolium), white clover, red clover, lucerne, birdsfoot trefoil (Lotus corniculatus L.), chicory (Cichorium intybus L.), plantain (Plantago lanceolata L.), salad burnet (Sanguisorba minor L.)and caraway (Carum carvi L.) was assessed. Neighbouring plants contained greater amounts of N derived from white clover (4.8 gm-2) compared with red clover (2.2 gm-2) and lucerne (1.1 gm-2). Grasses having fibrous roots received greater amounts of N from legumes than dicotyledonous plants which generally have taproots. Slurry application mainly increased N transfer from legumes to grasses. During the growing season the three legumes transferred approximately 40 kg N ha-1 to neighbouring plants. Below-ground N transfer from legumes to neighbouring plants differed among nitrogen donors and nitrogen receivers and may depend on root characteristics and regrowth strategies of plant species in the multi-species grassland

    Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

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    Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis

    ExprTarget: An Integrative Approach to Predicting Human MicroRNA Targets

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    Variation in gene expression has been observed in natural populations and associated with complex traits or phenotypes such as disease susceptibility and drug response. Gene expression itself is controlled by various genetic and non-genetic factors. The binding of a class of small RNA molecules, microRNAs (miRNAs), to mRNA transcript targets has recently been demonstrated to be an important mechanism of gene regulation. Because individual miRNAs may regulate the expression of multiple gene targets, a comprehensive and reliable catalogue of miRNA-regulated targets is critical to understanding gene regulatory networks. Though experimental approaches have been used to identify many miRNA targets, due to cost and efficiency, current miRNA target identification still relies largely on computational algorithms that aim to take advantage of different biochemical/thermodynamic properties of the sequences of miRNAs and their gene targets. A novel approach, ExprTarget, therefore, is proposed here to integrate some of the most frequently invoked methods (miRanda, PicTar, TargetScan) as well as the genome-wide HapMap miRNA and mRNA expression datasets generated in our laboratory. To our knowledge, this dataset constitutes the first miRNA expression profiling in the HapMap lymphoblastoid cell lines. We conducted diagnostic tests of the existing computational solutions using the experimentally supported targets in TarBase as gold standard. To gain insight into the biases that arise from such an analysis, we investigated the effect of the choice of gold standard on the evaluation of the various computational tools. We analyzed the performance of ExprTarget using both ROC curve analysis and cross-validation. We show that ExprTarget greatly improves miRNA target prediction relative to the individual prediction algorithms in terms of sensitivity and specificity. We also developed an online database, ExprTargetDB, of human miRNA targets predicted by our approach that integrates gene expression profiling into a broader framework involving important features of miRNA target site predictions
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