The light responses of rod and cone photoreceptors have been studied electrophysiologically for decades, largely with ex vivo approaches that disrupt the photoreceptors' subretinal microenvironment. Here we report the use of optical coherence tomography (OCT) to measure light-driven signals of rod photoreceptors in vivo. Visible light stimulation over a 200-fold intensity range caused correlated rod outer segment (OS) elongation and increased light scattering in wildtype mice, but not in mice lacking the rod G-protein alpha subunit, transducin (Gα t ), revealing these responses to be triggered by phototransduction. For stimuli that photoactivated one rhodopsin per Gα t the rod OS swelling response reached a saturated elongation of 10.0 ± 2.1%, at a maximum rate of 0.11% s −1. Analyzing swelling as osmotically driven water influx, we find the H 2 O membrane permeability of the rod OS to be (2.6 ± 0.4) × 10 −5 cm·s, comparable to that of other cells lacking aquaporin expression. Application of Van't Hoff's law reveals that complete activation of phototransduction generates a potentially harmful 20% increase in OS osmotic pressure. The increased backscattering from the base of the OS is explained by a model combining cytoplasmic swelling, translocation of dissociated G-protein subunits from the disc membranes into the cytoplasm, and a relatively higher H 2 O permeability of nascent discs in the basal rod OS. Translocation of phototransduction components out of the OS may protect rods from osmotic stress, which could be especially harmful in disease conditions that affect rod OS structural integrity.osmotic stress | phototransduction | optical coherence tomography | intrinsic optical signals | photoreceptor waveguiding

Intravitreal administration of exosomes derived from hMSCs was well tolerated without immunosuppression and decreased the severity of retinal ischemia in this murine model. This appealing novel non-cellular therapeutic approach warrants further exploration.

Adaptive optics scanning laser ophthalmoscopy (AO-SLO) has recently been used to achieve exquisite subcellular resolution imaging of the mouse retina. Wavefront sensing-based AO typically restricts the field of view to a few degrees of visual angle. As a consequence the relationship between AO-SLO data and larger scale retinal structures and cellular patterns can be difficult to assess. The retinal vasculature affords a largescale 3D map on which cells and structures can be located during in vivo imaging. Phase-variance OCT (pv-OCT) can efficiently image the vasculature with near-infrared light in a label-free manner, allowing 3D vascular reconstruction with high precision. We combined widefield pv-OCT and SLO imaging with AO-SLO reflection and fluorescence imaging to localize two types of fluorescent cells within the retinal layers: GFPexpressing microglia, the resident macrophages of the retina, and GFPexpressing cone photoreceptor cells. We describe in detail a reflective afocal AO-SLO retinal imaging system designed for high resolution retinal imaging in mice. The optical performance of this instrument is compared to other state-of-the-art AO-based mouse retinal imaging systems. The spatial and temporal resolution of the new AO instrumentation was characterized with angiography of retinal capillaries, including blood-flow velocity analysis. Depth-resolved AO-SLO fluorescent images of microglia and cone photoreceptors are visualized in parallel with 469 nm and 663 nm reflectance images of the microvasculature and other structures. Additional applications of the new instrumentation are discussed.

The dynamic optimality conjecture is perhaps the most fundamental open question about binary search trees (BST). It postulates the existence of an asymptotically optimal online BST, i.e. one that is constant factor competitive with any BST on any input access sequence. The two main candidates for dynamic optimality in the literature are splay trees [Sleator and Tarjan, 1985], and Greedy [Lucas, 1988;Munro, 2000;Demaine et al. 2009]. Despite BSTs being among the simplest data structures in computer science, and despite extensive effort over the past three decades, the conjecture remains elusive. Dynamic optimality is trivial for almost all sequences: the optimum access cost of most length-n sequences is Θ(n log n), achievable by any balanced BST. Thus, the obvious missing step towards the conjecture is an understanding of the "easy" access sequences, and indeed the most fruitful research direction so far has been the study of specific sequences, whose "easiness" is captured by a parameter of interest. For instance, splay provably achieves the bound of O(nd) when d roughly measures the distances between consecutive accesses (dynamic finger), the average entropy (static optimality), or the delays between multiple accesses of an element (working set). The difficulty of proving dynamic optimality is witnessed by other highly restricted special cases that remain unresolved; one prominent example is the traversal conjecture [Sleator and Tarjan, 1985], which states that preorder sequences (whose optimum is linear) are linear-time accessed by splay trees; no online BST is known to satisfy this conjecture.In this paper, we prove two different relaxations of the traversal conjecture for Greedy: (i) Greedy is almost linear for preorder traversal, (ii) if a linear-time preprocessing 1 is allowed, Greedy is in fact linear. These statements are corollaries of our more general results that express the complexity of access sequences in terms of a pattern avoidance parameter k. Pattern avoidance is a well-established concept in combinatorics, and the classes of input sequences thus defined are rich, e.g. the k = 3 case includes preorder sequences. For any sequence X with parameter k, our most general result shows that Greedy achieves the cost n2 α(n) O(k) where α is the inverse Ackermann function. Furthermore, a broad subclass of parameter-k sequences has a natural combinatorial interpretation as k-decomposable sequences. For this class of inputs, we obtain an n2 O(k 2 ) bound for Greedy when preprocessing is allowed. For k = 3, these results imply (i) and (ii). To our knowledge, these are the first upper bounds for Greedy that are not known to hold for any other online BST. To obtain these results we identify an input-revealing property of Greedy. Informally, this means that the execution log partially reveals the structure of the access sequence. This property facilitates the use of rich technical tools from forbidden submatrix theory.Further studying the intrinsic complexity of k-decomposable sequences, we make several observ...

PurposeTo quantify bleaching-induced changes in fundus reflectance in the mouse retina.MethodsLight reflected from the fundus of albino (Balb/c) and pigmented (C57Bl/6J) mice was measured with a multichannel scanning laser ophthalmoscopy optical coherence tomography (SLO-OCT) optical system. Serial scanning of small retinal regions was used for bleaching rhodopsin and measuring reflectance changes.ResultsSerial scanning generated a saturating reflectance increase centered at 501 nm with a photosensitivity of 1.4 × 10−8 per molecule μm2 in both strains, 2-fold higher than expected were irradiance at the rod outer segment base equal to that at the retinal surface. The action spectrum of the reflectance increase corresponds to the absorption spectrum of mouse rhodopsin in situ. Spectra obtained before and after bleaching were fitted with a model of fundus reflectance, quantifying contributions from loss of rhodopsin absorption with bleaching, absorption by oxygenated hemoglobin (HbO2) in the choroid (Balb/c), and absorption by melanin (C57Bl/6J). Both mouse strains exhibited light-induced broadband reflectance changes explained as bleaching-induced reflectivity increases at photoreceptor inner segment/outer segment (IS/OS) junctions and OS tips.ConclusionsThe elevated photosensitivity of rhodopsin bleaching in vivo is explained by waveguide condensing of light in propagation from rod inner segment (RIS) to rod outer segment (ROS). The similar photosensitivity of rhodopsin in the two strains reveals that little light backscattered from the sclera can enter the ROS. The bleaching-induced increases in reflectance at the IS/OS junctions and OS tips resemble results previously reported in human cones, but are ascribed to rods due to their 30/1 predominance over cones in mice and to the relatively minor amount of cone M-opsin in the regions scanned.

An approximate membership query data structure (AMQ)-such as a Bloom, quotient, or cuckoo filter-maintains a compact, probabilistic representation of a set S of keys from a universe U. It supports lookups and inserts. Some AMQs also support deletes. A query for x ∈ S returns PRESENT. A query for x ∈ S returns PRESENT with a tunable false-positive probability ε, and otherwise returns ABSENT.AMQs are widely used to speed up dictionaries that are stored remotely (e.g., on disk or across a network). The AMQ is stored locally (e.g., in memory). The remote dictionary is only accessed when the AMQ returns PRESENT. Thus, the primary performance metric of an AMQ is how often it returns ABSENT for negative queries.Existing AMQs offer weak guarantees on the number of false positives in a sequence of queries. The false-positive probability ε holds only for a single query. It is easy for an adversary to drive an AMQ's false-positive rate towards 1 by simply repeating false positives.This paper shows what it takes to get strong guarantees on the number of false positives. We say that an AMQ is adaptive if it guarantees a false-positive probability of ε for every query, regardless of answers to previous queries.We establish upper and lower bounds for adaptive AMQs. Our lower bound shows that it is impossible to build a small adaptive AMQ, even when the AMQ is immediately told whenever a query is a false positive. On the other hand, we show that it is possible to maintain an AMQ that uses the same amount of local space as a non-adaptive AMQ (up to lower order terms), performs all queries and updates in constant time, and guarantees that each negative query to the dictionary accesses remote storage with probability ε, independent of the results of past queries. Thus, we show that adaptivity can be achieved effectively for free.

Abstract-In this paper we propose an algorithm to construct a "space filling" curve for a sensor network with holes. Mathematically, for a given multi-hole domain R, we generate a path P that is provably aperiodic (i.e., any point is covered at most a constant number of times) and dense (i.e., any point of R is arbitrarily close to P). In a discrete setting as in a sensor network, the path visits the nodes with progressive density, which can adapt to the budget of the path length. Given a higher budget, the path covers the network with higher density. With a lower budget the path becomes proportional sparser. We show how this density-adaptive space filling curve can be useful for applications such as serial data fusion, motion planning for data mules, sensor node indexing, and double ruling type in-network data storage and retrieval. We show by simulation results the superior performance of using our algorithm vs standard space filling curves and random walks.

BackgroundRetinal detachment (RD) can lead to proliferative vitreoretinopathy (PVR), a leading cause of intractable vision loss. PVR is associated with a cytokine storm involving common proinflammatory molecules like IL6, but little is known about the source and downstream signaling of IL6 and the consequences for the retina. Here, we investigated the early immune response and resultant cytokine signaling following RD in mice.MethodsRD was induced in C57BL/6 J and IL6 knockout mice, and the resulting inflammatory response was examined using immunohistochemistry and flow cytometry. Cytokines and signaling proteins of vitreous and retinas were quantified by multiple cytokine arrays and Western blotting. To attempt to block IL6 signaling, a neutralizing antibody of IL6 receptor α (IL6Rα) or IL6 receptor β (gp-130) was injected intravitreally immediately after RD.ResultsWithin one day of RD, bone marrow-derived Cd11b + monocytes had extravasated from the vasculature and lined the vitreal surface of the retina, while the microglia, the resident macrophages of the retina, were relatively unperturbed. Cytokine arrays and Western blot analysis revealed that this sterile inflammation did not cause activation of IL6 signaling in the neurosensory retina, but rather only in the vitreous and aqueous humor. Monocyte infiltration was inhibited by blocking gp130, but not by IL6 knockout or IL6Rα blockade.ConclusionsTogether, our results demonstrate that monocytes are the primary immune cell mediating the cytokine storm following RD, and that any resulting retinal damage is unlikely to be a direct result of retinal IL6 signaling, but rather gp130-mediated signaling in the monocytes themselves. These results suggest that RD should be treated immediately, and that gp130-directed therapies may prevent PVR and promote retinal healing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0886-6) contains supplementary material, which is available to authorized users.