Alteration of developmental and pathological retinal angiogenesis in angptl4-deficient mice

Proper vessel maturation, remodeling of endothelial junctions, and recruitment of perivascular cells is crucial for establishing and maintaining vessel functions. In proliferative retinopathies, hypoxia-induced angiogenesis is associated with disruption of the vascular barrier, edema, and vision loss. Therefore, identifying factors that regulate vascular maturation is critical to target pathological angiogenesis. Given the conflicting role of angiopoietin-like-4 (ANGPTL4) reported in the current literature using gain of function systems both in vitro and in vivo, the goal of this study was to characterize angiogenesis, focusing on perinatal retinal vascularization and pathological circumstances in angpl4-deficient mice. We report altered organization of endothelial junctions and pericyte coverage, both leading to impaired angiogenesis and increased vascular leakage that were eventually caught up, suggesting a delay in vessel maturation. In a model of oxygen-induced retinopathy, pathological neovascularization, which results from tissue hypoxia, was also strongly inhibited in angptl4-deficient mice. This study therefore shows that ANGPTL4 tunes endothelial cell junction organization and pericyte coverage and controls vascular permeability and angiogenesis, both during development and in pathological conditions.     

Neural Correlates of Illusory Line Motion

Illusory line motion (ILM) refers to a motion illusion in which a flash at one end of a bar prior to the bar''s instantaneous presentation or removal results in the percept of motion. While some theories attribute the origin of ILM to attention or early perceptual mechanisms, others have proposed that ILM results from impletion mechanisms that reinterpret the static bar as one in motion. The current functional magnetic resonance imaging study examined participants while they made decisions about the direction of motion in which a bar appeared to be removed. Preceding the instantaneous removal of the bar with a flash at one end resulted in a motion percept away from the flash. If this flash and the bar''s removal overlapped in time, it appeared that the bar was removed towards the flash (reverse ILM). Independent of the motion type, brain responses indicated activations in areas associated with motion (MT+), endogenous and exogenous attention (intraparietal sulcus, frontal eye fields, and ventral frontal cortex), and response selection (ACC). ILM was associated with lower percept scores and higher activations in ACC relative to real motion, but no differences in shape-selective areas emerged. This pattern of brain activation is consistent with the attentional gradient model or bottom-up accounts of ILM in preference to impletion.     

Crossing the Hands Increases Illusory Self-Touch

Manipulation of hand posture, such as crossing the hands, has been frequently used to study how the body and its immediately surrounding space are represented in the brain. Abundant data show that crossed arms posture impairs remapping of tactile stimuli from somatotopic to external space reference frame and deteriorates performance on several tactile processing tasks. Here we investigated how impaired tactile remapping affects the illusory self-touch, induced by the non-visual variant of the rubber hand illusion (RHI) paradigm. In this paradigm blindfolded participants (Experiment 1) had their hands either uncrossed or crossed over the body midline. The strength of illusory self-touch was measured with questionnaire ratings and proprioceptive drift. Our results showed that, during synchronous tactile stimulation, the strength of illusory self-touch increased when hands were crossed compared to the uncrossed posture. Follow-up experiments showed that the increase in illusion strength was not related to unfamiliar hand position (Experiment 2) and that it was equally strengthened regardless of where in the peripersonal space the hands were crossed (Experiment 3). However, while the boosting effect of crossing the hands was evident from subjective ratings, the proprioceptive drift was not modulated by crossed posture. Finally, in contrast to the illusion increase in the non-visual RHI, the crossed hand postures did not alter illusory ownership or proprioceptive drift in the classical, visuo-tactile version of RHI (Experiment 4). We argue that the increase in illusory self-touch is related to misalignment of somatotopic and external reference frames and consequently inadequate tactile-proprioceptive integration, leading to re-weighting of the tactile and proprioceptive signals.The present study not only shows that illusory self-touch can be induced by crossing the hands, but importantly, that this posture is associated with a stronger illusion.     

Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of omega-3- and omega-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy. We show that increasing omega-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive omega-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of omega-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-alpha. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of omega-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in omega-3-PUFA, and premature infants lack the important transfer from the mother to the infant of omega-3-PUFA that normally occurs in the third trimester of pregnancy. Supplementing omega-3-PUFA intake may be of benefit in preventing retinopathy.     

Illusory boundary interpolation from local association field

We previously showed that interpolation between vertically misaligned luminance edges of same polarity of contrast is preferred to that between co-linear edges of opposite polarity of contrast, although it results in illusory tilt (Roncato and Casco, 2003). We here analyze the spatial conditions that produce this illusory binding of vertically misaligned edges of light and dark tiles, alternated in a row, and in counterphase with those in the rows above and below. We find that, independently of scale and number of tiles in a row, the illusion is perceived when the vertical misalignment of more than three tiles is smaller than or equal to 9' and the horizontal separation between co-linear edges is smaller than or equal to 13'. These short distances suggest that the underlying mechanism is local. Both our phenomenological and psychophysical results support the notion of a local short-range association field, selective to contrast polarity, which produces a binding solution different from that of a phase-independent long-range mechanism. We suggest that the occurrence of the illusion at local-level is a result of the activation, within a local short-range association field, of units with orientation different from that stimulated by the physical edges. These units are not inhibited when they are close, iso-oriented and co-linear, and the misaligned edges from which they propagate have the same contrast polarity. We found that horizontal and vertical spatial limits for the interpolation covary but not such that their ratio is fixed, indicating that the two edges can be connected by projections having a relatively wide range of orientations.     

Bone marrow-derived cells are differentially involved in pathological and physiological retinal angiogenesis in mice

Purpose

Bone marrow-derived cells have been shown to play roles in angiogenesis. Although these cells have been shown to promote angiogenesis, it is not yet clear whether these cells affect all types of angiogenesis. This study investigated the involvement of bone marrow-derived cells in pathological and physiological angiogenesis in the murine retina.

Materials and methods

The oxygen-induced retinopathy (OIR) model was used as a retinal angiogenesis model in newborn mice. To block the influence of bone marrow-derived cells, the mice were irradiated with a 4-Gy dose of radiation from a ¹³⁷Cs source. Irradiation was performed in four different conditions with radio dense 2-cm thick lead disks; (1) H group, the head were covered with these discs to protect the eyes from radiation; (2) A group, all of the body was covered with these discs; (3) N group, mice were completely unshielded; (4) C group, mice were put in the irradiator but were not irradiated. On P17, the retinal areas showing pathological and physiological retinal angiogenesis were measured and compared to the retinas of nonirradiated mice.

Results

Although irradiation induced leukocyte depletion, it did not affect the number of other cell types or body weight. Retinal nonperfusion areas were significantly larger in irradiated mice than in control mice (P < 0.05), indicating that physiological angiogenesis was impaired. However, the formation of tuft-like angiogenesis processes was more prominent in the irradiated mice (P < 0.05), indicating that pathological angiogenesis was intact.

Conclusions

Bone marrow-derived cells seem to be differentially involved in the formation of physiological and pathological retinal vessels. Pathological angiogenesis in the murine retina does not require functional bone marrow-derived cells, but these cells are important for the formation of physiological vessels. Our results add a new insight into the pathology of retinal angiogenesis and bolster the hypothesis that bone marrow cells are involved in the pathology or severity of retinal angiogenic diseases.     

Line endings and subjective contours

Subjective forms depend exquisitely on the shapes of the termini of the bars acting as inducers. In particular, they follow small stretches of contour at the termini. Subjective brightness effects without precise boundaries are generated when the termini are pointed.     

Learning to link visual contours

In complex visual scenes, linking related contour elements is important for object recognition. This process, thought to be stimulus driven and hard wired, has substrates in primary visual cortex (V1). Here, however, we find contour integration in V1 to depend strongly on perceptual learning and top-down influences that are specific to contour detection. In naive monkeys, the information about contours embedded in complex backgrounds is absent in V1 neuronal responses and is independent of the locus of spatial attention. Training animals to find embedded contours induces strong contour-related responses specific to the trained retinotopic region. These responses are most robust when animals perform the contour detection task but disappear under anesthesia. Our findings suggest that top-down influences dynamically adapt neural circuits according to specific perceptual tasks. This may serve as a general neuronal mechanism of perceptual learning and reflect top-down mediated changes in cortical states.     

Signaling contours by neuromorphic wave propagation

We describe a neuromorphic retina that signals a luminance edge as a spike. In a fast process, the luminance profile of the receptor layer determines the membrane potential of the ganglion cells and their individual, adjustable spiking thresholds. In a slower process, a wave-propagation process, the charge of ganglion cells with high membrane potential will propagate toward neighboring cells with low membrane potential and low spiking threshold, thus signaling the edge as a spike. Following that, the signaled edge (or contour) actively propagates across the retinal map. The retinal signal can be used for a contour-integration or a contour-propagation approach.Acknowledgments. The study has been carried out in Miguel Ecksteins lab at UCSB, funded by NIH-RO1 53455, NASA NAG 9-1157, NSF 0135118. The author wishes to thank Miguel Eckstein for generous support, Giacomo Indiveri for comments on the circuit diagram, and the anonymous reviewers for helping to clarify quite a number of discussion points.     

On the detection of salient contours

When visual space is densely populated by elements of random orientation, elements which happen to be aligned may form a perceptually salient 'contour' (Field et al., 1993; Kovacs and Julesz, 1993). Here we further characterize human performance for detecting this type of Gestalt grouping. We find that detectability of salient contours reaches a plateau when they comprise at least 10 elements and are presented for at least 200 ms. It has been suggested that the detection of salient contours is mediated by the intrinsic connectivity of striate cortex and several computational models have been formulated on this basis. The present data provide a benchmark against which such models can be evaluated.     

Efficacy of New Generation Antidepressants: Differences Seem Illusory

Background

Recently, Cipriani and colleagues examined the relative efficacy of 12 new-generation antidepressants on major depression using network meta-analytic methods. They found that some of these medications outperformed others in patient response to treatment. However, several methodological criticisms have been raised about network meta-analysis and Cipriani''s analysis in particular which creates the concern that the stated superiority of some antidepressants relative to others may be unwarranted.

Materials and Methods

A Monte Carlo simulation was conducted which involved replicating Cipriani''s network meta-analysis under the null hypothesis (i.e., no true differences between antidepressants). The following simulation strategy was implemented: (1) 1000 simulations were generated under the null hypothesis (i.e., under the assumption that there were no differences among the 12 antidepressants), (2) each of the 1000 simulations were network meta-analyzed, and (3) the total number of false positive results from the network meta-analyses were calculated.

Findings

Greater than 7 times out of 10, the network meta-analysis resulted in one or more comparisons that indicated the superiority of at least one antidepressant when no such true differences among them existed.

Interpretation

Based on our simulation study, the results indicated that under identical conditions to those of the 117 RCTs with 236 treatment arms contained in Cipriani et al.''s meta-analysis, one or more false claims about the relative efficacy of antidepressants will be made over 70% of the time. As others have shown as well, there is little evidence in these trials that any antidepressant is more effective than another. The tendency of network meta-analyses to generate false positive results should be considered when conducting multiple comparison analyses.     

Perceptual rivalry between illusory and real contours

The interactions between illusory and real contours have been investigated under monocular, binocular and dichoptic conditions. Results show that under all three presentation conditions, periodic alternations, generally called rivalry, occur during the perception of cognitive (or illusory) triangles, while earlier research had failed to find such rivalry (Bradley and Dumais 1975). With line triangles, rivalry is experienced only under dichoptic conditions. A model is proposed to account for the observed phenomena.     

Perception of illusory contours enhanced in motion

Investigation on illusory contours is important for understanding the mechanisms underlying the object recognition of human visual system. Numerous researches have shown that illusory contours formed in motion and stereopsis are generated by the unmatched features. Here we conduct three psychophysical experiments to test if Kanizsa illusory contours are also caused by unmatched information. Different types of motion (including horizontal translation, radial expanding and shrinking) are utilized in the experiments. The results show that no matter under what kind of motion, when figures or background move separately illusory contours are perceived stronger, and there is no significant difference between the perceived strength in these two types of motion. However, no such enhancement of perceived strength is found when figures and background move together. It is found that the strengthened unmatched features generate the enhancement effect of illusory contour perception in motion. Thus the results suggest that the process of unmatched information in visual system is a critical step in the formation of illusory contours.     

错觉轮廓识别的视觉生理机制

错觉轮廓或主观边框是指人们知觉到的刺激图案中实际上并不存在的轮廓、线、边或面。在人们的视觉系统将视网膜平面上的二维图像还原成三维的过程中,错觉轮廓笑觉起着一定的作用。本文综述了近年来在生理学领域对视觉皮层ＩＣｓ反应细胞的研究和由此提出的ＩＣｓ知觉的可能神经机制,并简述了心理学上对ＩＣｓ相关研究。     

Perception of illusory contours enhanced in motion

Object perception is one of the most important components of visual perception of human beings and mammalian animals. It is a most confusing problem on object perception that how we separate object from background and obtain the picture of the whole object. In many cases one object partly occludes the other one in natural world. When the brightness of the occluding object is the same as or similar to that of the background, though there is no difference between visual stimuli, we can still ret…