Background
Spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) are thought to reduce pain by activating a sufficient number of large myelinated (Aβ) fibres, which in turn initiate ...spinal segmental mechanisms of analgesia. However, the volume of neuronal activity and how this activity is associated with different treatment targets is unclear under neuropathic pain conditions.
Methods
We sought to delineate the intensity‐dependent mechanisms of SCS and PNS analgesia by in vivo extracellular recordings from spinal wide‐dynamic range neurons in nerve‐injured rats. To mimic therapeutic SCS and PNS, we used bipolar needle electrodes and platinum hook electrodes to stimulate the dorsal column and the tibial nerve, respectively. Compound action potentials were recorded to calibrate the amplitude of conditioning stimulation required to activate A‐fibres and thus titrate the volume of activation.
Results
Dorsal column stimulation (50 Hz, five intensities) inhibited the windup (a short form of neuronal sensitization) and the C‐component response of wide‐dynamic range neurons to graded intracutaneous electrical stimuli in an intensity‐dependent manner. Tibial nerve stimulation (50 Hz, three intensities) also suppressed the windup in an intensity‐dependent fashion but did not affect the acute C‐component response.
Conclusions
SCS and PNS may offer similar inhibition of short‐term neuronal sensitization. However, only SCS attenuates spinal transmission of acute noxious inputs under neuropathic pain conditions. Our findings begin to differentiate peripheral from spinal‐targeted neuromodulation therapies and may help to select the best stimulation target and optimum therapeutic intensity for pain treatment.
Context. Debris disks are observed around 10 to 20% of FGK main-sequence stars as infrared excess emission. They are important signposts for the presence of colliding planetesimals and therefore ...provide important information about the evolution of planetary systems. Direct imaging of such disks reveals their geometric structure and constrains their dust-particle properties. Aims. We present observations of the known edge-on debris disk around HIP 79977 (HD 146897) taken with the ZIMPOL differential polarimeter of the SPHERE instrument. We measure the observed polarization signal and investigate the diagnostic potential of such data with model simulations. Methods. SPHERE-ZIMPOL polarimetric data of the 15 Myr-old F star HIP 79977 (Upper Sco, 123 pc) were taken in the Very Broad Band (VBB) filter (λc = 735 nm, Δλ = 290 nm) with a spatial resolution of about 25 mas. Imaging polarimetry efficiently suppresses the residual speckle noise from the AO system and provides a differential signal with relatively small systematic measuring uncertainties. We measure the polarization flux along and perpendicular to the disk spine of the highly inclined disk for projected separations between 0.2′′ (25 AU) and 1.6′′ (200 AU). We perform model calculations for the polarized flux of an optically thin debris disk which are used to determine or constrain the disk parameters of HIP 79977. Results. We measure a polarized flux contrast ratio for the disk of (Fpol)disk/F∗ = (5.5 ± 0.9) × 10-4 in the VBB filter. The surface brightness of the polarized flux reaches a maximum of SBmax = 16.2 mag arcsec-2 at a separation of 0.2′′–0.5′′ along the disk spine with a maximum surface brightness contrast of 7.64 mag arcsec-2. The polarized flux has a minimum near the star <0.2′′ because no or only little polarization is produced by forward or backward scattering in the disk section lying in front of or behind the star. The width of the disk perpendicular to the spine shows a systematic increase in FWHM from 0.1′′ (12 AU) to 0.3′′−0.5′′, when going from a separation of 0.2′′ to >1′′. This can be explained by a radial blow-out of small grains. The data are modelled as a circular dust belt with a well defined disk inclination i = 85( ± 1.5)° and a radius between r0 = 60 and 90 AU. The radial density dependence is described by (r/r0)α with a steep (positive) power law index α = 5 inside r0 and a more shallow (negative) index α = −2.5 outside r0. The scattering asymmetry factor lies between g = 0.2 and 0.6 (forward scattering) adopting a scattering-angle dependence for the fractional polarization such as that for Rayleigh scattering. Conclusions. Polarimetric imaging with SPHERE-ZIMPOL of the edge-on debris disk around HIP 79977 provides accurate profiles for the polarized flux. Our data are qualitatively very similar to the case of AU Mic and they confirm that edge-on debris disks have a polarization minimum at a position near the star and a maximum near the projected separation of the main debris belt. The comparison of the polarized flux contrast ratio (Fpol)disk/F∗ with the fractional infrared excess provides strong constraints on the scattering albedo of the dust.
The transmembrane glycoprotein, CUB (complement C1r/C1s, Uegf, Bmp1) domain-containing protein 1 (CDCP1) is overexpressed in several cancer types and is a predictor of poor prognosis for patients on ...standard of care therapies. Phosphorylation of CDCP1 tyrosine sites is induced upon loss of cell adhesion and is thought to be linked to metastatic potential of tumor cells. Using a tyrosine-phosphoproteomics screening approach, we characterized the phosphorylation state of CDCP1 across a panel of breast cancer cell lines. We focused on two phospho-tyrosine pTyr peptides of CDCP1, containing Tyr707 and Tyr806, which were identified in all six lines, with the human epidermal growth factor 2-positive HCC1954 cells showing a particularly high phosphorylation level. Pharmacological modulation of tyrosine phosphorylation indicated that, the Src family kinases (SFKs) were found to phosphorylate CDCP1 at Tyr707 and Tyr806 and play a critical role in CDCP1 activity. We demonstrated that CDCP1 overexpression in HEK293 cells increases global phosphotyrosine content, promotes anchorage-independent cell growth and activates several SFK members. Conversely, CDCP1 downregulation in multiple solid cancer cell lines decreased both cell growth and SFK activation. Analysis of primary human tumor samples demonstrated a correlation between CDCP1 expression, SFK and protein kinase C (PKC) activity. Taken together, our results suggest that CDCP1 overexpression could be an interesting therapeutic target in multiple solid cancers and a good biomarker to stratify patients who could benefit from an anti-SFK-targeted therapy. Our data also show that multiple tyrosine phosphorylation sites of CDCP1 are important for the functional regulation of SFKs in several tumor types.
In non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Oxytocin reduces anxiety and ...impacts on fear conditioning and extinction. Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals. However, no human data on the effects of this peptide on brain function were available. Here, we show that human amygdala function is strongly modulated by oxytocin. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo, oxytocin potently reduced activation of the amygdala and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.
CD8
T cells drive anti-cancer immunity in response to antigen-presenting cells such as dendritic cells and subpopulations of monocytes and macrophages. While CD14
classical monocytes modulate CD8
T ...cell responses, the contributions of CD16
nonclassical monocytes to this process remain unclear. Herein we explored the role of nonclassical monocytes in CD8
T cell activation by utilizing E2-deficient (E2
) mice that lack nonclassical monocytes. During early metastatic seeding, modeled by B16F10-OVA cancer cells injected into E2
mice, we noted lower CD8
effector memory and effector T cell frequencies within the lungs as well as in lung-draining mediastinal lymph nodes in the E2
mice. Analysis of the myeloid compartment revealed that these changes were associated with depletion of MHC-II
Ly6C
nonclassical monocytes within these tissues, with little change in other monocyte or macrophage populations. Additionally, nonclassical monocytes preferentially trafficked to primary tumor sites in the lungs, rather than to the lung-draining lymph nodes, and did not cross-present antigen to CD8
T cells. Examination of the lung microenvironment in E2
mice revealed reduced CCL21 expression in endothelial cells, which is chemokine involved in T cell trafficking. Our results highlight the previously unappreciated importance of nonclassical monocytes in shaping the tumor microenvironment via CCL21 production and CD8
T cell recruitment.
Photic memory for executive brain responses Chellappa, Sarah Laxhmi; Ly, Julien Q. M.; Meyer, Christelle ...
Proceedings of the National Academy of Sciences - PNAS,
04/2014, Letnik:
111, Številka:
16
Journal Article, Web Resource
Recenzirano
Odprti dostop
Light is a powerful stimulant for human alertness and cognition, presumably acting through a photoreception system that heavily relies on the photopigment melanopsin. In human, evidence for ...melanopsin involvement in light-driven cognitive stimulation remains indirect, due to the difficulty to selectively isolate its contribution. Therefore, a role for melanopsin in human cognitive regulation remains to be established. Here, sixteen participants underwent consecutive and identical functional MRI recordings, during which they performed a simple auditory detection task and a more difficult auditory working memory task, while continuously exposed to the same test light (515 nm). We show that the impact of test light on executive brain responses depends on the wavelength of the light to which individuals were exposed prior to each recording. Test-light impact on executive responses in widespread prefrontal areas and in the pulvinar increased when the participants had been exposed to longer (589 nm), but not shorter (461 nm), wavelength light, more than 1 h before. This wavelength-dependent impact of prior light exposure is consistent with recent theories of the light-driven melanopsin dual states. Our results emphasize the critical role of light for cognitive brain responses and are, to date, the strongest evidence in favor of a cognitive role for melanopsin, which may confer a form of "photic memory" to human cognitive brain function.
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