Metabolism of a synthetic compared with a natural therapeutic pulmonary surfactant in adult mice

Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells, catabolism by alveolar macrophages, and loss up the bronchial tree. We compared the in vivo metabolism of animal-derived poractant alfa (Curosurf) and a synthetic surfactant (CHF5633) in adult male C57BL/6 mice. The mice were dosed intranasally with either surfactant (80 mg/kg body weight) containing universally 13C-labeled dipalmitoyl PC (DPPC) as a tracer. The loss of [U13C]DPPC from bronchoalveolar lavage and lung parenchyma, together with the incorporation of 13C-hydrolysis fragments into new PC molecular species, was monitored by electrospray ionization tandem mass spectrometry. The catabolism of CHF5633 was considerably delayed compared with poractant alfa, the hydrolysis products of which were cleared more rapidly. There was no selective resynthesis of DPPC and, strikingly, acyl remodeling resulted in preferential synthesis of polyunsaturated PC species. In conclusion, both surfactants were metabolized by similar pathways, but the slower catabolism of CHF5633 resulted in longer residence time in the airways and enhanced recycling of its hydrolysis products into new PC species

CBX7 and miR-9 are part of an autoregulatory loop controlling p16(INK) (4a).

Polycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR-9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR-9-1 and miR-9-2 as part of a regulatory negative feedback loop. The miR-9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin-dependent kinase inhibitor (CDKI) p16(INK4a) during senescence. The ability of the miR-9 family to regulate senescence could have implications for understanding the role of miR-9 in cancer and aging

Adjoint bulk scalars and supersymmetric unification in the presence of extra dimensions

There are several advantages of introducing adjoint superfields at intermediate energies around $M=10^{13}$ GeV. Such as (i) gauge couplings still unify (ii) neutrino masses and mixings are produced (iii) primordial lepton asymmetry can be produced. We point out that if adjoint scalars have bulk excitations along with gauge bosons whereas fermions and the doublet scalar live on boundary then N=2 supersymmetric beta functions $\tilde{b_i}$ vanish. Thus even if extra dimensions open up at an intermediate scale $\mu_0$ and all N=2 Yang-Mills fields as well as N=2 matter fields in the adjoint representation propagate in the bulk, still gauge couplings renormalize beyond $\mu_0$ just like they do in 4-dimensions with adjoint scalars. Consequently unification is achieved in the presence to extra dimensions, mass scales are determined uniquely via Renormalization Group Equations(RGE) and unification scale remains high enough to suppress proton decay. This scenario can be falsified if we get signatures of extra dimensions at low energy.Comment: New references added. This version will appear in Phys. Rev.

Surfactant proteins SP-B and SP-C and their precursors in bronchoalveolar lavages from children with acute and chronic inflammatory airway disease

<p>Abstract</p> <p>Background</p> <p>The surfactant proteins B (SP-B) and C (SP-C) are important for the stability and function of the alveolar surfactant film. Their involvement and down-regulation in inflammatory processes has recently been proposed, but their level during neutrophilic human airway diseases are not yet known.</p> <p>Methods</p> <p>We used 1D-electrophoresis and Western blotting to determine the concentrations and molecular forms of SP-B and SP-C in bronchoalveolar lavage (BAL) fluid of children with different inflammatory airway diseases. 21 children with cystic fibrosis, 15 with chronic bronchitis and 14 with pneumonia were included and compared to 14 healthy control children.</p> <p>Results</p> <p>SP-B was detected in BAL of all 64 patients, whereas SP-C was found in BAL of all but 3 children; those three BAL fluids had more than 80% neutrophils, and in two patients, who were re-lavaged later, SP-C was then present and the neutrophil count was lower. SP-B was mainly present as a dimer, SP-C as a monomer. For both qualitative and quantitative measures of SP-C and SP-B, no significant differences were observed between the four evaluated patient groups.</p> <p>Conclusion</p> <p>Concentration or molecular form of SP-B and SP-C is not altered in BAL of children with different acute and chronic inflammatory lung diseases. We conclude that there is no down-regulation of SP-B and SP-C at the protein level in inflammatory processes of neutrophilic airway disease.</p

Embodiment and Presence in Virtual Reality After Stroke. A Comparative Study With Healthy Subjects

[EN] The ability of virtual reality (VR) to recreate controlled, immersive, and interactive environments that provide intensive and customized exercises has motivated its therapeutic use after stroke. Interaction and bodily presence in VR-based interventions is usually mediated through virtual selves, which synchronously represent body movements or responses to events on external input devices. Embodied self-representations in the virtual world not only provide an anchor for visuomotor tasks, but their morphologies can have behavioral implications. While research has focused on the underlying subjective mechanisms of exposure to VR on healthy individuals, the transference of these findings to individuals with stroke is not evident and remains unexplored, which could affect the experience and, ultimately, the clinical effectiveness of neurorehabilitation interventions. This study determined and compared the sense of embodiment and presence elicited by a virtual environment under different perspectives and levels of immersion in healthy subjects and individuals with stroke. Forty-six healthy subjects and 32 individuals with stroke embodied a gender-matched neutral avatar in a virtual environment that was displayed in a first-person perspective with a head-mounted display and in a third-person perspective with a screen, and the participants were asked to interact in a virtual task for 10 min under each condition in counterbalanced order, and to complete two questionnaires about the sense of embodiment and presence experienced during the interaction. The sense of body-ownership, self-location, and presence were more vividly experienced in a first-person than in a third-person perspective by both healthy subjects (p < 0.001, eta(2)(p) = 0.212; p = 0.005, eta(2)(p) = 0.101; p = 0.001, eta(2)(p) = 0.401, respectively) and individuals with stroke (p = 0.019, eta(2)(p) = 0.070; p = 0.001, eta(2)(p) = 0.135; p = 0.014, eta(2)(p) = 0.077, respectively). In contrast, no agency perspective-related differences were found in any group. All measures were consistently higher for healthy controls than for individuals with stroke, but differences between groups only reached statistical significance in presence under the first-person condition (p < 0.010, eta(2)(p) = 0.084). In spite of these differences, the participants experienced a vivid sense of embodiment and presence in almost all conditions. These results provide first evidence that, although less intensively, embodiment and presence are similarly experienced by individuals who have suffered a stroke and by healthy individuals, which could support the vividness of their experience and, consequently, the effectiveness of VR-based interventions.This study was funded by Ministerio de Economía y Competitividad of Spain (Project RTC-2017-6051-7 and Grant BES-2014-068218), Fundació la Marató de la TV3 (Grant 201701-10), and Universitat Politècnica de València (Grant PAID-10-18). We acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research.Borrego, A.; Latorre, J.; Alcañiz Raya, ML.; Llorens Rodríguez, R. (2019). Embodiment and Presence in Virtual Reality After Stroke. A Comparative Study With Healthy Subjects. Frontiers in Neurology. 10:1-8. https://doi.org/10.3389/fneur.2019.01061S1810Berlucchi, G., & Aglioti, S. (1997). 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Consciousness and Cognition, 36, 277-288. doi:10.1016/j.concog.2015.07.008Kilteni, K., Maselli, A., Kording, K. P., & Slater, M. (2015). Over my fake body: body ownership illusions for studying the multisensory basis of own-body perception. Frontiers in Human Neuroscience, 9. doi:10.3389/fnhum.2015.00141Clark, A., Kiverstein, J., & Vierkant, T. (Eds.). (2013). Decomposing the Will. doi:10.1093/acprof:oso/9780199746996.001.0001Frith, C. D., Blakemore, S.-J., & Wolpert, D. M. (2000). Abnormalities in the awareness and control of action. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 355(1404), 1771-1788. doi:10.1098/rstb.2000.0734Bermúdez i Badia, S., Fluet, G. G., Llorens, R., & Deutsch, J. E. (2016). Virtual Reality for Sensorimotor Rehabilitation Post Stroke: Design Principles and Evidence. Neurorehabilitation Technology, 573-603. doi:10.1007/978-3-319-28603-7_28Perez-Marcos, D., Sanchez-Vives, M. V., & Slater, M. (2011). Is my hand connected to my body? The impact of body continuity and arm alignment on the virtual hand illusion. Cognitive Neurodynamics, 6(4), 295-305. doi:10.1007/s11571-011-9178-5IJsselsteijn, W. A., de Kort, Y. A. W., & Haans, A. (2006). Is This My Hand I See Before Me? The Rubber Hand Illusion in Reality, Virtual Reality, and Mixed Reality. Presence: Teleoperators and Virtual Environments, 15(4), 455-464. doi:10.1162/pres.15.4.455Banakou, D., Groten, R., & Slater, M. (2013). Illusory ownership of a virtual child body causes overestimation of object sizes and implicit attitude changes. Proceedings of the National Academy of Sciences, 110(31), 12846-12851. doi:10.1073/pnas.1306779110Yee, N., & Bailenson, J. (2007). The Proteus Effect: The Effect of Transformed Self-Representation on Behavior. Human Communication Research, 33(3), 271-290. doi:10.1111/j.1468-2958.2007.00299.xSteed, A., Frlston, S., Lopez, M. M., Drummond, J., Pan, Y., & Swapp, D. (2016). An ‘In the Wild’ Experiment on Presence and Embodiment using Consumer Virtual Reality Equipment. IEEE Transactions on Visualization and Computer Graphics, 22(4), 1406-1414. doi:10.1109/tvcg.2016.2518135Colomer, C., Llorens, R., Noé, E., & Alcañiz, M. (2016). Effect of a mixed reality-based intervention on arm, hand, and finger function on chronic stroke. Journal of NeuroEngineering and Rehabilitation, 13(1). doi:10.1186/s12984-016-0153-6Laver, K. E., Lange, B., George, S., Deutsch, J. E., Saposnik, G., & Crotty, M. (2017). Virtual reality for stroke rehabilitation. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd008349.pub4Llorens, R., Borrego, A., Palomo, P., Cebolla, A., Noé, E., i Badia, S. B., & Baños, R. (2017). Body schema plasticity after stroke: Subjective and neurophysiological correlates of the rubber hand illusion. Neuropsychologia, 96, 61-69. doi:10.1016/j.neuropsychologia.2017.01.007Zeller, D., Gross, C., Bartsch, A., Johansen-Berg, H., & Classen, J. (2011). Ventral Premotor Cortex May Be Required for Dynamic Changes in the Feeling of Limb Ownership: A Lesion Study. Journal of Neuroscience, 31(13), 4852-4857. doi:10.1523/jneurosci.5154-10.2011Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). «Mini-mental state». Journal of Psychiatric Research, 12(3), 189-198. doi:10.1016/0022-3956(75)90026-6Romero, M., Sánchez, A., Marín, C., Navarro, M. D., Ferri, J., & Noé, E. (2012). Clinical usefulness of the Spanish version of the Mississippi Aphasia Screening Test (MASTsp): validation in stroke patients. Neurología (English Edition), 27(4), 216-224. doi:10.1016/j.nrleng.2011.06.001Latorre, J., Llorens, R., Colomer, C., & Alcañiz, M. (2018). Reliability and comparison of Kinect-based methods for estimating spatiotemporal gait parameters of healthy and post-stroke individuals. Journal of Biomechanics, 72, 268-273. doi:10.1016/j.jbiomech.2018.03.008Lloréns, R., Noé, E., Naranjo, V., Borrego, A., Latorre, J., & Alcañiz, M. (2015). 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Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Extended-schedule dose-dense temozolomide in refractory gliomas

This multicenter phase II study conducted by the Spanish Neuro-Oncology Group evaluated the activity of an extended, dose-dense temozolomide regimen in patients with temozolomide-refractory malignant glioma. Adult patients (at least 18 years of age) with WHO grade III or IV glioma and a Karnofsky Performance Status of 60 or higher were treated with temozolomide (85 mg/m2/day) for 21 consecutive days every 28-day cycle until disease progression or unacceptable toxicity. All patients had developed progressive disease either during or less than 3 months after completing previous temozolomide treatment. Forty-seven patients were treated with a median of 2 (range, 1–13) cycles of temozolomide. Before study entry, patients had received a median of 6 cycles of temozolomide: 39 (83%) as part of initial therapy and 23 (49%) as second-line therapy. Three patients (6.4%) had a partial response with durations of 8.0, 3.5, and 3.2 months; 15 patients (31.9%) had stable disease with a median duration of 2.1 months, including 2 patients with stable disease (SD) for greater than 6 months (14 and 16 months). Median time to progression was 2 months, and median overall survival from study entry was 5.1 months. The 6-month progression-free survival rate was 16.7%. The most common hematologic toxicities were lymphopenia, thrombocytopenia, and leukopenia. Lymphopenia occurred in 83% of patients and was grade 3 in 28%, but no opportunistic infections occurred. In conclusion, this extended dose-dense schedule of temozolomide appears to have modest activity in patients refractory to previous treatment with temozolomide and is associated with manageable toxicity

Pharmacological Blockade of Serotonin 5-HT7 Receptor Reverses Working Memory Deficits in Rats by Normalizing Cortical Glutamate Neurotransmission

The role of 5-HT7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission

Genome-Wide Functional Divergence after the Symbiosis of Proteobacteria with Insects Unraveled through a Novel Computational Approach

Symbiosis has been among the most important evolutionary steps to generate biological complexity. The establishment of symbiosis required an intimate metabolic link between biological systems with different complexity levels. The strict endo-cellular symbiotic bacteria of insects are beautiful examples of the metabolic coupling between organisms belonging to different kingdoms, a eukaryote and a prokaryote. The host (eukaryote) provides the endosymbiont (prokaryote) with a stable cellular environment while the endosymbiont supplements the host's diet with essential metabolites. For such communication to take place, endosymbionts' genomes have suffered dramatic modifications and reconfigurations of proteins' functions. Two of the main modifications, loss of genes redundant for endosymbiotic bacteria or the host and bacterial genome streamlining, have been extensively studied. However, no studies have accounted for possible functional shifts in the endosymbiotic proteomes. Here, we develop a simple method to screen genomes for evidence of functional divergence between two species clusters, and we apply it to identify functional shifts in the endosymbiotic proteomes. Despite the strong effects of genetic drift in the endosymbiotic systems, we unexpectedly identified genes to be under stronger selective constraints in endosymbionts of aphids and ants than in their free-living bacterial relatives. These genes are directly involved in supplementing the host's diet with essential metabolites. A test of functional divergence supports a strong relationship between the endosymbiosis and the functional shifts of proteins involved in the metabolic communication with the insect host. The correlation between functional divergence in the endosymbiotic bacterium and the ecological requirements of the host uncovers their intimate biochemical and metabolic communication and provides insights on the role of symbiosis in generating species diversity