Visual perceptual learning is traditionally thought to arise in visual cortex. However, typical perceptual learning tasks also involve systematic mapping of visual information onto motor actions. ...Because the motor system contains both effector-specific and effector-unspecific representations, the question arises whether visual perceptual learning is effector-specific itself, or not. Here, we study this question in an orientation discrimination task. Subjects learn to indicate their choices either with joystick movements or with manual reaches. After training, we challenge them to perform the same task with eye movements. We dissect the decision-making process using the drift diffusion model. We find that learning effects on the rate of evidence accumulation depend on effectors, albeit not fully. This suggests that during perceptual learning, visual information is mapped onto effector-specific integrators. Overlap of the populations of neurons encoding motor plans for these effectors may explain partial generalization. Taken together, visual perceptual learning is not limited to visual cortex, but also affects sensorimotor mapping at the interface of visual processing and decision making.
Idiopathic retroperitoneal fibrosis (IRF) is a rare disease often causing obstructive uropathy. We evaluated the clinicopathologic features of 24 patients with IRF to characterize the histopathology ...of the disease and to provide a framework for the differential diagnosis with other retroperitoneal fibrosing conditions. Retroperitoneal specimens were analyzed by light and electron microscopy and by immunohistochemistry. Most patients presented with abdominal/lumbar pain, constitutional symptoms, and high acute-phase reactants. Overall, 20 had ureteral involvement and 13 developed acute renal failure. The retroperitoneal tissue consisted of a fibrous component and a chronic inflammatory infiltrate with the former characterized by myofibroblasts within a type-I collagen matrix. The infiltrate displayed perivascular and diffuse patterns containing lymphocytes, macrophages, plasma cells, and eosinophils. The perivascular aggregates had a central core of CD20+ cells and a mantle of CD3+ cells in equal proportions. In the areas of diffuse infiltrate, CD3+ cells outnumbered the CD20+ cells. Most plasma cells were positive for the IgG4 isotype. Small vessel vasculitis was found in the specimens of 11 patients. Our study indicates that a sclerotic background with myofibroblasts associated with a diffuse and perivascular infiltrate mainly consisting of T and B lymphocytes may be a pathological hallmark of IRF.
Stimulus and location specificity are long considered hallmarks of visual perceptual learning. This renders visual perceptual learning distinct from other forms of learning, where generalization can ...be more easily attained, and therefore unsuitable for practical applications, where generalization is key. Based on the hypotheses derived from the structure of the visual system, we test here whether stimulus variability can unlock generalization in perceptual learning. We train subjects in orientation discrimination, while we vary the amount of variability in a task-irrelevant feature, spatial frequency. We find that, independently of task difficulty, this manipulation enables generalization of learning to new stimuli and locations, while not negatively affecting the overall amount of learning on the task. We then use deep neural networks to investigate how variability unlocks generalization. We find that networks develop invariance to the task-irrelevant feature when trained with variable inputs. The degree of learned invariance strongly predicts generalization. A reliance on invariant representations can explain variability-induced generalization in visual perceptual learning. This suggests new targets for understanding the neural basis of perceptual learning in the higher-order visual cortex and presents an easy-to-implement modification of common training paradigms that may benefit practical applications.
•Hallmark specificities of visual learning are overcome by variable training•Simulations allocate this effect to invariant neurons•Differential location and feature transfer suggest a flexible locus of plasticity
Manenti et al. find that training with variability overcomes the stimulus and location specificity of perceptual learning. Generalization also occurs in deep neural networks and relies on neurons invariant to task-irrelevant features. The data suggest that variability determines the involvement of invariant neurons and thus the locus of plasticity.
In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 ‘subtype’ can induce a complementary therapeutic effect through the induction of ...antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC.
We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies.
Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700mg) achieved a ‘pathological’ complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P<0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700mg, –34.6%; 1400mg, –41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response.
These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects.
NCT01046266 (ClinicalTrials.gov).
Ultra-low background mass spectrometry for rare-event searches Dobson, J.; Ghag, C.; Manenti, L.
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
01/2018, Volume:
879
Journal Article
Peer reviewed
Open access
Inductively Coupled Plasma Mass Spectrometry (ICP-MS) allows for rapid, high-sensitivity determination of trace impurities, notably the primordial radioisotopes 238U and 232Th, in candidate materials ...for low-background rare-event search experiments. We describe the setup and characterisation of a dedicated low-background screening facility at University College London where we operate an Agilent 7900 ICP-MS. The impact of reagent and carrier gas purity is evaluated and we show that twice-distilled ROMIL-SpATM-grade nitric acid and zero-grade Ar gas delivers similar sensitivity to ROMIL-UpATM-grade acid and research-grade gas. A straightforward procedure for sample digestion and analysis of materials with U/Th concentrations down to 10 ppt g/g is presented. This includes the use of 233U and 230Th spikes to correct for signal loss from a range of sources and verification of 238U and 232Th recovery through digestion and analysis of a certified reference material with a complex sample matrix. Finally, we demonstrate assays and present results from two sample preparation and assay methods: a high-sensitivity measurement of ultra-pure Ti using open digestion techniques, and a closed vessel microwave digestion of a nickel–chromium-alloy using a multi-acid mixture.
The antineoplastic compound aplidine, a new marine-derived depsipeptide, has shown preclinical activity in vitro on haematological and solid tumour cell lines. It is currently in early phase clinical ...trials. The exact mechanism of action of this anticancer agent still needs to be clarified. We have previously reported that aplidine blocks the secretion of the angiogenic factor vascular endothelial growth factor (VEGF) by the human leukaemia cells MOLT-4, suggesting a possible effect on tumour angiogenesis. This study was designed to investigate the antiangiogenic effect of aplidine. In vivo, in the chick embryo allantoic membrane (CAM) assay, aplidine inhibited spontaneous angiogenesis, angiogenesis elicited by exogenous VEGF and FGF-2, and induced by VEGF overexpressing 1A9 ovarian carcinoma cells. In vitro, at concentrations achievable in the plasma of patients, aplidine inhibited endothelial cell functions related to angiogenesis. It affected VEGF- and FGF-2-induced endothelial cell proliferation, inhibited cell migration and invasiveness assessed in the Boyden chamber and blocked the production of matrix metalloproteinases (MMP-2 and MMP-9) by endothelial cells. Finally, aplidine prevented the formation of capillary-like structures by endothelial cells on Matrigel. These findings indicate that aplidine has antiangiogenic activity in vivo and inhibits endothelial cell functional responses to angiogenic stimuli in vitro. This effect might contribute to the antineoplastic activity of aplidine.
We report results from searches for new physics with low-energy electronic recoil data recorded with the XENON1T detector. With an exposure of 0.65 tonne-years and an unprecedentedly low background ...rate of 76 ± 2stat events/(tonne × year × keVÞ between 1 and 30 keV, the data enable one of the most sensitive searches for solar axions, an enhanced neutrino magnetic moment using solar neutrinos, and bosonic dark matter. An excess over known backgrounds is observed at low energies and most prominent between 2 and 3 keV. The solar axion model has a 3.4σ significance, and a three-dimensional 90% confidence surface is reported for axion couplings to electrons, photons, and nucleons. This surface is inscribed in the cuboid defined by gae < 3.8 × 10−12, ..., and gaegaγ < 7.7 × 10−22 GeV−1, and excludes either gae = 0 or ... . The neutrino magnetic moment signal is similarly favored over background at 3.2σ, and a confidence interval of μν ∈ (1.4, 2.9) × 10−11 μB (90% C.L.) is reported. Both results are in strong tension with stellar constraints. The excess can also be explained by β decays of tritium at 3.2σ significance with a corresponding tritium concentration in xenon of (6.2 ± 2.0) × 10−25 mol/mol. Such a trace amount can neither be confirmed nor excluded with current knowledge of its production and reduction mechanisms. The significances of the solar axion and neutrino magnetic moment hypotheses are decreased to 2.0σ and 0.9σ, respectively, if an unconstrained tritium component is included in the fitting. With respect to bosonic dark matter, the excess favors a monoenergetic peak at (2.3 ± 0.2) keV (68% C.L.) with a 3.0σ global (4.0σ local) significance over background. This analysis sets the most restrictive direct constraints to date on pseudoscalar and vector bosonic dark matter for most masses between 1 and 210 keV/c2. We also consider the possibility that 37Ar may be present in the detector, yielding a 2.82 keV peak from electron capture. Contrary to tritium, the 37Ar concentration can be tightly constrained and is found to be negligible. (ProQuest: ... denotes formula omitted.)
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