scholarly journals Electronic "photoreceptors" enable prosthetic vision with acuity matching the natural resolution in rats

2021 ◽  
Author(s):  
Bing-Yi Wang ◽  
Zhijie Charles Chen ◽  
Mohajeet Bhuckory ◽  
Tiffany W Huang ◽  
Andrew Shin ◽  
...  
Keyword(s):  
Retinal Thickness ◽  
Ex Vivo ◽  
Forward Bias ◽  
Retinal Neurons ◽  
Photovoltaic Array ◽  
High Acuity ◽  
Grating Acuity ◽  
Novel Design ◽  
Stimulation Of

Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal cross-talk from neighboring electrodes. Local return electrodes within each pixel can limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 50 μm. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated computational modeling of the field confinement in such an optically-controlled circuit by ex-vivo and in-vivo measurements. Most importantly, we demonstrated that by using this strategy, the grating acuity of prosthetic vision with 20 μm pixels matches the 28 μm limit of the natural visual acuity in rats. This method will enable customized field shaping for each patient based on individual retinal thickness and distance from the implant, paving the way to prosthetic vision with acuity as high as 20/80 in atrophic macular degeneration.

Electrical stimulation of retinal neurons in epiretinal and subretinal configuration using a multicapacitor array

2012 ◽  
Vol 107 (10) ◽  
pp. 2742-2755 ◽  
Author(s):  
Max Eickenscheidt ◽  
Martin Jenkner ◽  
Roland Thewes ◽  
Peter Fromherz ◽  
Günther Zeck
Keyword(s):  
Electrical Stimulation ◽  
Ganglion Cells ◽  
Ex Vivo ◽  
Biophysical Model ◽  
Retinal Neurons ◽  
Direct Stimulation ◽  
Tungsten Electrode ◽  
Partial Restoration ◽  
Low Amplitude ◽  
Stimulation Of

Electrical stimulation of retinal neurons offers the possibility of partial restoration of visual function. Challenges in neuroprosthetic applications are the long-term stability of the metal-based devices and the physiological activation of retinal circuitry. In this study, we demonstrate electrical stimulation of different classes of retinal neurons with a multicapacitor array. The array—insulated by an inert oxide—allows for safe stimulation with monophasic anodal or cathodal current pulses of low amplitude. Ex vivo rabbit retinas were interfaced in either epiretinal or subretinal configuration to the multicapacitor array. The evoked activity was recorded from ganglion cells that respond to light increments by an extracellular tungsten electrode. First, a monophasic epiretinal cathodal or a subretinal anodal current pulse evokes a complex burst of action potentials in ganglion cells. The first action potential occurs within 1 ms and is attributed to direct stimulation. Within the next milliseconds additional spikes are evoked through bipolar cell or photoreceptor depolarization, as confirmed by pharmacological blockers. Second, monophasic epiretinal anodal or subretinal cathodal currents elicit spikes in ganglion cells by hyperpolarization of photoreceptor terminals. These stimuli mimic the photoreceptor response to light increments. Third, the stimulation symmetry between current polarities (anodal/cathodal) and retina-array configuration (epi/sub) is confirmed in an experiment in which stimuli presented at different positions reveal the center-surround organization of the ganglion cell. A simple biophysical model that relies on voltage changes of cell terminals in the transretinal electric field above the stimulation capacitor explains our results. This study provides a comprehensive guide for efficient stimulation of different retinal neuronal classes with low-amplitude capacitive currents.

scholarly journals Opposing Influence of Sensory and Motor Cortical Input on Striatal Circuitry and Choice Behavior

2018 ◽  
Author(s):  
Christian R. Lee ◽  
Alex J. Yonk ◽  
Joost Wiskerke ◽  
Kenneth G. Paradiso ◽  
James M. Tepper ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Dorsal Striatum ◽  
Behavioral Effect ◽  
Projection Neurons ◽  
Cortical Input ◽  
Optogenetic Stimulation ◽  
Main Input ◽  
Opposing Effects ◽  
Stimulation Of

SummaryThe striatum is the main input nucleus of the basal ganglia and is a key site of sensorimotor integration. While the striatum receives extensive excitatory afferents from the cerebral cortex, the influence of different cortical areas on striatal circuitry and behavior is unknown. Here we find that corticostriatal inputs from whisker-related primary somatosensory (S1) and motor (M1) cortex differentially innervate projection neurons and interneurons in the dorsal striatum, and exert opposing effects on sensory-guided behavior. Optogenetic stimulation of S1-corticostriatal afferents in ex vivo recordings produced larger postsynaptic potentials in striatal parvalbumin (PV)-expressing interneurons than D1- or D2-expressing spiny projection neurons (SPNs), an effect not observed for M1-corticostriatal afferents. Critically, in vivo optogenetic stimulation of S1-corticostriatal afferents produced task-specific behavioral inhibition, which was bidirectionally modulated by striatal PV interneurons. Optogenetic stimulation of M1 afferents produced the opposite behavioral effect. Thus, our results suggest opposing roles for sensory and motor cortex in behavioral choice via distinct influences on striatal circuitry.

Human papillomavirus type 16 (HPV16) E6/E7-specific cytotoxic T lymphocytes (CTL) for immunotherapy of HPV-associated cancer (Ca).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2558-2558
Author(s):  
Carlos Almeida Ramos ◽  
Neeharika Narala ◽  
Ann M. Leen ◽  
Ulrike Gerdemann ◽  
Erich M. Sturgis ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Effector Memory ◽  
Cellular Immunotherapy ◽  
Specific Lysis ◽  
Hpv16 E6 ◽  
Cd8 Cells ◽  
Tumor Recognition ◽  
E6 And E7 ◽  
Stimulation Of

2558 Background: Vaccines prevent HPV-associated Ca, but their benefits in established Ca are disappointing: although these tumors express viral E6 and E7 antigens (Ags) immune responses are limited even after vaccination, likely due to negative environmental cues that block tumor recognition and T cell (TC) activation in vivo. We postulated that ex vivo stimulation of TCs in an immunologically favorable milieu would allow us to reactivate tumor-directed CTLs from Ca patients and benefit the recipients on reinfusion. Methods: We studied 68 patients with HPV+ Ca. To detect HPV16 E6/E7-specific TCs (HPV-TCs) in blood, we measured the IFNγ ELISpot responses of TCs stimulated by monocyte-derived dendritic cells (DCs) loaded with pepmixes (peptide libraries of 15-mers overlapping by 11 aa) spanning E6/E7. Because HPV-TCs from these patients may be anergized by their tumors, potent Ag presenting strategies might be required for reactivation, and thus we stimulated these cells in the presence of IL-6, -7, -12 and -15, as we have shown that these can induce responses to poorly immunogenic Ags. Results: We successfully reactivated HPV-TCs from 8/16 cervical and 33/52 oropharyngeal Ca patients. We could expand these HPV-TCs to clinically useful numbers by using patient B-cell blasts (BBs) as APCs. Stimulation of DC-stimulated HPV-TCs by E6/E7 pepmix-loaded BBs further expanded (3.8 ± 1.5×/round) HPV-TC lines, which phenotypically are almost exclusively composed of TCs (98 ± 3% CD3+), with a variable proportion of mostly effector memory (CD45RA–, CD45RO+, CD62L– and CCR7–) CD4+ and CD8+ cells (37 ± 28% and 49 ± 27%, respectively). The viral/tumor associated epitopes recognized mapped to E6 aa 49-71, 77-91 and 125-143, and E7 aa 1-19 and 73-87. The expanded cells from patients killed E6/E7+ targets (specific lysis up to 45-61% vs. 0-8% in controls, 40:1 E:T ratio). Conclusions: We have developed a system that allows the robust generation of HPV-directed CTLs from patients with HPV16+ Ca, which recognize specific epitopes in tumor-associated Ags. Our lines have the potential to be used for adoptive cellular immunotherapy of HPV+ Ca.

scholarly journals All-optical recording and stimulation of retinal neurons in vivo in retinal degeneration mice

PLoS ONE ◽  
2018 ◽  
Vol 13 (3) ◽  
pp. e0194947 ◽  
Author(s):  
Soon Keen Cheong ◽  
Jennifer M. Strazzeri ◽  
David R. Williams ◽  
William H. Merigan
Keyword(s):  
Retinal Degeneration ◽  
Optical Recording ◽  
Retinal Neurons ◽  
All Optical ◽  
Stimulation Of

scholarly journals GPRC6A Mediates the Effects of l-Arginine on Insulin Secretion in Mouse Pancreatic Islets

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4608-4615 ◽  
Author(s):  
Min Pi ◽  
Yunpeng Wu ◽  
Nataliya I Lenchik ◽  
Ivan Gerling ◽  
L. Darryl Quarles
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Ex Vivo ◽  
Β Cells ◽  
Direct Role ◽  
Mouse Pancreatic Islets ◽  
Islet Size ◽  
G Protein Coupled ◽  
Stimulation Of

Abstract l-Arginine (l-Arg) is an insulin secretagogue, but the molecular mechanism whereby it stimulates insulin secretion from β-cells is not known. The possibility that l-Arg regulates insulin secretion through a G protein-coupled receptor (GPCR)-mediated mechanism is suggested by the high expression of the nutrient receptor GPCR family C group 6 member A (GPRC6A) in the pancreas and TC-6 β-cells and the finding that Gprc6a−/]minus] mice have abnormalities in glucose homeostasis. To test the direct role of GPRC6A in regulating insulin secretion, we evaluated the response of pancreatic islets derived from Gprc6a−/]minus] mice to l-Arg. We found that the islet size and insulin content were decreased in pancreatic islets from Gprac6a−/]minus] mice. These alterations were selective for β-cells, because there were no abnormalities in serum glucagon levels or glucagon content of islets derived from Gprac6a−/]minus] mice. Significant reduction was observed in both the pancreatic ERK response to l-Arg administration to Gprc6a−/]minus] mice in vivo and l-Arg-induced insulin secretion and production ex vivo in islets isolated from Gprc6a−/]minus] mice. l-Arg stimulation of cAMP accumulation in isolated islets isolated from Gprc6a−/]minus] mice was also diminished. These findings suggest that l-Arg stimulation of insulin secretion in β-cells is mediated, at least in part, through GPRC6A activation of cAMP pathways.

Lactobacillus gasseri LF221 and K7 — from isolation to application

Biologia ◽  
2006 ◽  
Vol 61 (6) ◽  
Author(s):  
Irena Rogelj ◽  
Bojana Bogovič Matijašić
Keyword(s):  
Immune Response ◽  
Cultured Cells ◽  
Ex Vivo ◽  
Probiotic Properties ◽  
Technological Parameters ◽  
Lactobacillus Gasseri ◽  
E Coli ◽  
Gnotobiotic Piglets ◽  
Stimulation Of

AbstractThe article presents research findings on two human strains with probiotic activity. On the basis of API 50 CHL fermentation pattern, PCR by species-specific primers and sequencing of the V2–V3 region of 16S rRNA both strains designated as LF221 and K7 were identified as members of the Lactobacillus gasseri species. Two LF221 bacteriocins, acidocin LF221 A and B were purified and sequenced. They were classified as members of the two-component class II bacteriocins. Among basic probiotic properties, the survival under conditions in gastro-intestinal tract, ability to adhere to cultured intestinal enterocytes and pig’s mucosa and stimulation of the immune response were demonstrated. In in vivo study of 24 weaned piglets, the survival rate of K7 Rifr and LF221 Rifr was quantified by selective enumeration on MRS agar with rifampicin. The survival of both strains was good (2.9 × 105 cfu of K7 Rifr /g faeces; 4.8 × 105 cfu of LF221 Rifr /g) and the LF221 Rifr /K7 Rifr viable cells were found either in the mucosa of duodenum, jejunum or in the ileum. The possible effect of K7 to inhibit adhesion of E. coli O8:K88 to enterocytes was studied on Caco-2 cultured cells, on tissue obtained from small intestines of pigs and in vivo on gnotobiotic piglets. Lactobacilli were found to be effective in reducing E. coli adhesion to enterocytes in Caco-2 model, but not on mucosa of pig’s jejunum under ex vivo conditions. Competitive exclusion, production of organic acids and stimulation of immune response, were involved in inhibition of E. coli by K7 strain in gnotobiotic piglets. Any inflammatory change in intestines of piglets treated with K7 was observed, which confirmed its safe use. Among the technological parameters the survival and activity of the strains during cheese-making are presented.

OR.93. Superagonistic Ex Vivo and In Vivo Stimulation of T Lymphocytes by Novel Human Cd28-specific Monoclonal Antibodies

2006 ◽  
Vol 119 ◽  
pp. S39
Author(s):  
Christine Guntermann ◽  
Martin Trischler ◽  
Niklas Beyersdorf ◽  
Peter Mueller ◽  
Thomas Kerkau ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Stimulation Of

ANTI-TUMOR IMMUNITY AND TUMOR ANTI-IMMUNITY IN A MATHEMATICAL MODEL OF TUMOR IMMUNOTHERAPY

2006 ◽  
Vol 14 (01) ◽  
pp. 13-30 ◽  
Author(s):  
URSZULA FORYŚ ◽  
JACEK WANIEWSKI ◽  
PETAR ZHIVKOV
Keyword(s):  
Immune System ◽  
Tumor Antigens ◽  
Ex Vivo ◽  
Equilibrium Points ◽  
Phase Portraits ◽  
Dimensional System ◽  
Immune Activity ◽  
The Impact ◽  
Stimulation Of

A two-dimensional system of ordinary differential equations is used to characterize the basic types of phase portraits of the immune system — tumor interactions model, and to study the impact of anti-immune activity by tumor on the outcome of immunotherapy. The focus is on specific (acquired) immunity and different forms of immunotherapy as active therapy with in vivo stimulation of the immunity and passive one with infusion of ex vivo produced specific immunity. The analysis is performed for two families of stimulation function, which describes the dynamics of the stimulation of the immune system by tumor antigens: (1) antigen dependent and (2) antigen per one immunity unit dependent functions, with Michaelis-Menten and sigmoid functions in each family. We show that there are no limit cycles in the system and that anti-immune activity by tumor changes all equilibrium points from global to local ones. In the latter case, the immune system has no control over the growth of large tumors. Furthermore, if the immunity is weak, the immune system cannot eradicate even small tumors. The weak immunity and stimulation strength result in unrestricted tumor growth. The patterns of asymptotic behavior of the system do not depend on the type of the stimulation function, but do depend on its parameters. Our results reflect the basic clinical and experimental knowledge about immunotherapy and its effectiveness and yield new suggestions for an efficient immunotherapy.

Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle

2021 ◽  
Author(s):  
Jonas Roland Knudsen ◽  
Kaspar W Persson ◽  
Jaroslawna Meister ◽  
Christian Strini Carl ◽  
Steffen H Raun ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Ex Vivo ◽  
Vastus Lateralis ◽  
Published Data ◽  
Vastus Lateralis Muscle ◽  
Mouse Muscle ◽  
Exercise Induced ◽  
Stimulation Of

In mice, exercise is suggested to activate the mechanistic target of rapamycin complex 2 (mTORC2) in skeletal muscle, and mTORC2 is required for normal muscle glucose uptake during exercise. Whether this translates to human skeletal muscle and what signaling pathways facilitate the exercise-induced mTORC2 activation is unknown but important to determine given the important role of mTORC2 in metabolism. We herein tested the hypothesis that exercise increases mTORC2 activity in human skeletal muscle and investigated if β2-adrenergic receptor (AR) activation mediates exercise-induced mTORC2 activation. We examined several mTORC2 activity readouts (p-NDRG1 Thr346, p-Akt Ser473, p-mTOR S2481, and p-Akt Thr450) in human skeletal muscle biopsies after uphill walking or cycling exercise. In mouse muscles, we assessed mTORC2 activity readouts following acute activation of muscle β2-adrenergic or Gs signaling and during in vivo and ex vivo muscle contractions. Exercise increased phosphorylation of NDRG1 Thr346 in human soleus, gastrocnemius, and vastus lateralis muscle, without changing p-Akt Ser473, p-Akt Thr450, and p-mTOR Ser2481. In mouse muscle, stimulation of β2-adrenergic or Gs signaling and ex vivo contractions failed to increase p-NDRG1 Thr346, while in vivo contractions were sufficient to induce p-NDRG1 Thr346. In conclusion, the mTORC2 activity readout p-NDRG1 Thr346 is a novel exercise-responsive signaling protein in human skeletal muscle. Notably, contraction-induced p-NDRG1 Thr346 appears to require a systemic factor. Unlike exercise, and in contrast to published data obtained in cultured muscles cells, stimulation of β2-adrenergic signaling is not sufficient to trigger NDRG1 phosphorylation in mature mouse skeletal muscle.

scholarly journals Proteomic exploration of pancreatic islets in mice null for the α2A adrenergic receptor

2005 ◽  
Vol 35 (1) ◽  
pp. 73-88 ◽  
Author(s):  
Xinran Hu ◽  
David Friedman ◽  
Salisha Hill ◽  
Richard Caprioli ◽  
Wendell Nicholson ◽  
...  
Keyword(s):  
Insulin Release ◽  
Adrenergic Receptor ◽  
Ex Vivo ◽  
Wild Type ◽  
Downstream Signaling ◽  
Glucose Levels ◽  
Endogenous Catecholamines ◽  
Stimulation Of

The present studies extend recent findings that mice null for the α2A adrenergic receptor (α2A AR KO mice) lack suppression of exogenous secretagogue-stimulated insulin secretion in response to α2 AR agonists by evaluating the endogenous secretagogue, glucose, ex vivo, and providing in vivo data that baseline insulin levels are elevated and baseline glucose levels are decreased in α2A AR KO mice. These latter findings reveal that the α2A AR subtype regulates glucose-stimulated insulin release in response to endogenous catecholamines in vivo. The changes in α2A AR responsiveness and resultant changes in insulin/glucose homeostasis encouraged us to utilize proteomics strategies to identify possible α2A AR downstream signaling molecules or other resultant changes due to perturbation of α2A AR expression. Although agonist stimulation of islets from wild type (WT) mice did not significantly alter islet protein profiles, several proteins were enriched in islets from α2A AR KO mice when compared with those from WT mice, including an enzyme participating in insulin protein processing. The present studies document the important role of the α2A AR subtype in tonic suppression of insulin release in response to endogenous catecholamines as well as exogenous α2 agonists and provide insights into pleiotropic changes that result from loss of α2A AR expression and tonic suppression of insulin release.

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