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1.
IEEE Comput Graph Appl ; 41(4): 29-39, 2021.
Article in English | MEDLINE | ID: mdl-34010127

ABSTRACT

Most of the real-world virtual reality (VR) content available today is captured and rendered from a fixed vantage point. The visual-vestibular conflict arising from the lack of head-motion parallax degrades the feeling of presence in the virtual environment and has been shown to induce nausea and visual discomfort. We present an end-to-end framework for VR with head-motion parallax for real-world scenes. To capture both horizontally and vertically separated perspectives, we use a camera rig with two vertically stacked rings of outward-facing cameras. The data from the rig are processed offline and stored into a compact intermediate representation, which is used to render novel views for a head-mounted display, in accordance with the viewer's head movements. We compare two promising intermediate representations-Stacked OmniStereo and Layered Depth Panoramas-and evaluate them in terms of objective image quality metrics and the occurrence of disocclusion holes in synthesized novel views.


Subject(s)
Smart Glasses , Virtual Reality , Head Movements , Motion
2.
Neuroimage ; 237: 118139, 2021 08 15.
Article in English | MEDLINE | ID: mdl-33964460

ABSTRACT

Horizontal disparities between the two eyes' retinal images are the primary cue for depth. Commonly used random ot tereograms (RDS) intentionally camouflage the disparity cue, breaking the correlations between monocular image structure and the depth map that are present in natural images. Because of the nonlinear nature of visual processing, it is unlikely that simple computational rules derived from RDS will be sufficient to explain binocular vision in natural environments. In order to understand the interplay between natural scene structure and disparity encoding, we used a depth-image-based-rendering technique and a library of natural 3D stereo pairs to synthesize two novel stereogram types in which monocular scene content was manipulated independent of scene depth information. The half-images of the novel stereograms comprised either random-dots or scrambled natural scenes, each with the same depth maps as the corresponding natural scene stereograms. Using these stereograms in a simultaneous Event-Related Potential and behavioral discrimination task, we identified multiple disparity-contingent encoding stages between 100 ~ 500 msec. The first disparity sensitive evoked potential was observed at ~100 msec after an earlier evoked potential (between ~50-100 msec) that was sensitive to the structure of the monocular half-images but blind to disparity. Starting at ~150 msec, disparity responses were stereogram-specific and predictive of perceptual depth. Complex features associated with natural scene content are thus at least partially coded prior to disparity information, but these features and possibly others associated with natural scene content interact with disparity information only after an intermediate, 2D scene-independent disparity processing stage.


Subject(s)
Depth Perception/physiology , Electroencephalography/methods , Evoked Potentials, Visual/physiology , Functional Neuroimaging/methods , Vision Disparity/physiology , Vision, Monocular/physiology , Visual Cortex/physiology , Adolescent , Adult , Female , Humans , Male , Young Adult
3.
ACS Med Chem Lett ; 8(12): 1309-1313, 2017 Dec 14.
Article in English | MEDLINE | ID: mdl-29259753

ABSTRACT

The discovery of a novel, selective and fully efficacious CB2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB2 receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, 6 (APD371) was selected for further development for the treatment of pain.

4.
Bioorg Med Chem Lett ; 25(3): 659-63, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25532755

ABSTRACT

Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.


Subject(s)
Drug Design , Indoles/chemistry , Receptors, Lysosphingolipid/agonists , Animals , Dogs , Half-Life , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Mice , Protein Binding , Protein Isoforms/agonists , Protein Isoforms/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Lysosphingolipid/metabolism , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 25(2): 322-6, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-25488844

ABSTRACT

The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.


Subject(s)
Analgesics, Non-Narcotic/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Inflammation/drug therapy , Microsomes, Liver/drug effects , Osteoarthritis/drug therapy , Pain/drug therapy , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB2/agonists , Administration, Oral , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/chemistry , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inflammation/metabolism , Male , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Osteoarthritis/metabolism , Pain/metabolism , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/agonists , Stereoisomerism , Structure-Activity Relationship
6.
ACS Med Chem Lett ; 5(12): 1313-7, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25516790

ABSTRACT

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

7.
ACS Med Chem Lett ; 5(12): 1334-9, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25516794

ABSTRACT

S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.

8.
J Med Chem ; 56(21): 8224-56, 2013 Nov 14.
Article in English | MEDLINE | ID: mdl-23865723

ABSTRACT

The cannabinoid receptor type 2 (CB2) is a class A GPCR that was cloned in 1993 while looking for an alternative receptor that could explain the pharmacological properties of Δ(9)-tetrahydrocannabinol. CB2 was identified among cDNAs based on its similarity in amino acid sequence to the CB1 receptor and helped provide an explanation for the established effects of cannabinoids on the immune system. In addition to the immune system, CB2 has widespread tissue expression and has been found in brain, peripheral nervous system, and gastrointestinal tract. Several "mixed" cannabinoid agonists are currently in clinical use primarily for controlling pain, and it is believed that selective CB2 agonism may afford a superior analgesic agent devoid of the centrally mediated CB1 effects. Thus, selective CB2 receptor agonists represent high value putative therapeutics for treating pain and other disease states. In this Perspective, we seek to provide a concise update of progress in the field.


Subject(s)
Drug Design , Receptor, Cannabinoid, CB2/agonists , Animals , Humans , Ligands , Models, Molecular , Molecular Conformation , Receptor, Cannabinoid, CB2/chemistry , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Substrate Specificity
9.
Bioorg Med Chem Lett ; 22(13): 4404-9, 2012 Jul 01.
Article in English | MEDLINE | ID: mdl-22633692

ABSTRACT

Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.


Subject(s)
Immunologic Factors/chemistry , Indoles/chemistry , Receptors, Lysosphingolipid/agonists , Animals , Autoimmune Diseases/drug therapy , Disease Models, Animal , Female , Humans , Immunologic Factors/pharmacokinetics , Immunologic Factors/therapeutic use , Indoles/pharmacokinetics , Indoles/therapeutic use , Lymphocytes/immunology , Male , Mice , Mice, Inbred C57BL , Microsomes/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Lysosphingolipid/metabolism , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 21(19): 6013-8, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21852130
11.
J Clin Invest ; 115(12): 3473-83, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16308575

ABSTRACT

The respiratory tract is a primary site of infection and exposure to environmental antigens and an important site of memory T cell localization. We analyzed the migration and retention of naive and activated CD8+ T cells within the noninflamed lungs and quantitated the partitioning of adoptively transferred T cells between the pulmonary vascular and interstitial compartments. Activated but not naive T cells were retained within the lungs for a prolonged period. Effector CD8+ T cells preferentially egressed from the pulmonary vascular compartment into the noninflamed pulmonary interstitium. T cell retention within the lung vasculature was leukocyte function antigen-1 dependent, while the egress of effector T cells from the vascular to the interstitium functions through a pertussis toxin-sensitive (PTX-sensitive) mechanism driven in part by constitutive CC chemokine ligand 5 expression in the lungs. These results document a novel mechanism of adhesion receptor- and pulmonary chemokine-dependent regulation of the migration of activated CD8+ T cells into an important nonlymphoid peripheral site (i.e., the normal/noninflamed lung).


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cell Movement , Lung/cytology , Lung/pathology , T-Lymphocytes/immunology , Animals , CD8-Positive T-Lymphocytes/metabolism , Cell Adhesion Molecules/metabolism , Cell Separation , Chemokine CCL5/metabolism , Chemokines/metabolism , Flow Cytometry , Immunologic Memory , Inflammation , Lymphocyte Activation , Lymphocyte Function-Associated Antigen-1/metabolism , Mice , Mice, Inbred BALB C , Mice, Transgenic , Pertussis Toxin/pharmacology , Respiratory System/pathology , T-Lymphocytes/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Time Factors
12.
J Vasc Res ; 41(3): 252-60, 2004.
Article in English | MEDLINE | ID: mdl-15153775

ABSTRACT

BACKGROUND: The alpha(4)beta(1) integrin (VLA-4) supports rolling and firm adhesion of leukocytes to inflamed tissues via ligation of VCAM-1 or fibronectin expressed on the activated endothelium. We tested the hypothesis that VLA-4 mediates leukocyte recruitment and neointimal growth after arterial injury in the atherosclerosis-prone apolipoprotein E (ApoE)-deficient mouse. METHODS: ApoE (-/-) mice fed a Western diet underwent air desiccation injury, and the expression patterns of VLA-4 and VCAM-1 were determined by immunohistochemistry (IHC). To determine the effect of targeted VLA-4 blockade on leukocyte recruitment and neointimal growth, ApoE (-/-) mice received an intraperitoneal injection of a VLA-4 neutralizing monoclonal antibody (PS/2) at the time of injury alone or over a prolonged administration course. Additional mice received an isotype control antibody. RESULTS: IHC demonstrated a marked increase in VLA-4 expression 7 days following injury. Prolonged administration of PS/2 resulted in a 72% reduction (p < 0.02) in neointimal growth 28 days following injury. IHC revealed a marked 95% reduction in neutrophil recruitment at 7 days and a 48% reduction in macrophage recruitment 28 days following injury with prolonged PS/2 administration. CONCLUSIONS: Prolonged VLA-4 blockade reduces leukocyte recruitment and neointimal growth following air desiccation injury in ApoE (-/-) mice. These findings demonstrate an important role for VLA-4 in the response to arterial injury.


Subject(s)
Apolipoproteins E/deficiency , Carotid Artery Injuries/metabolism , Carotid Artery Injuries/pathology , Integrin alpha4beta1/antagonists & inhibitors , Leukocytes/pathology , Tunica Intima/pathology , Animals , Antibodies, Monoclonal/pharmacology , Carotid Artery Injuries/blood , Carotid Artery Injuries/etiology , Desiccation , Female , Flow Cytometry , In Vitro Techniques , Integrin alpha4beta1/immunology , Integrin alpha4beta1/metabolism , Leukocyte Count , Lipids/blood , Macrophages/drug effects , Macrophages/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration/drug effects , Time Factors , Vascular Cell Adhesion Molecule-1/metabolism
13.
Bioinformatics ; 19(15): 1945-51, 2003 Oct 12.
Article in English | MEDLINE | ID: mdl-14555628

ABSTRACT

MOTIVATION: In microarray studies gene discovery based on fold-change values is often misleading because error variability for each gene is heterogeneous under different biological conditions and intensity ranges. Several statistical testing methods for differential gene expression have been suggested, but some of these approaches are underpowered and result in high false positive rates because within-gene variance estimates are based on a small number of replicated arrays. RESULTS: We propose to use local-pooled-error (LPE) estimates and robust statistical tests for evaluating significance of each gene's differential expression. Our LPE estimation is based on pooling errors within genes and between replicate arrays for genes in which expression values are similar. We have applied our LPE method to compare gene expression in naïve and activated CD8+ T-cells. Our results show that the LPE method effectively identifies significant differential-expression patterns with a small number of replicated arrays. AVAILABILITY: The methodology is implemented with S-PLUS and R functions available at http://hesweb1.med.virginia.edu/bioinformatics


Subject(s)
Algorithms , Data Interpretation, Statistical , Gene Expression Profiling/methods , Gene Expression Regulation/physiology , Models, Genetic , Models, Statistical , Oligonucleotide Array Sequence Analysis/methods , Animals , Genetic Variation , Humans , Mice , Sample Size , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
14.
Blood ; 101(12): 4916-22, 2003 Jun 15.
Article in English | MEDLINE | ID: mdl-12623847

ABSTRACT

The adhesion molecules involved in the migration and retention of activated effector CD8 T cells in the lung microcirculation and their recruitment into lung tissue are largely unknown. Here, we have analyzed the role of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) on adhesion of influenza hemagglutinin (HA)-specific CD8 T-cell clone D4 under shear conditions in an in vitro binding assay and in an in vivo homing assay to the lungs of naive or transgenic Balb/c mice expressing HA (HA-Tg) by a lung-specific promoter. Blocking LFA-1 or intercellular adhesion molecule 1 (ICAM-1) significantly inhibited adhesion of D4 cells to lung vascular endothelium and parenchyma of lung sections. However, blocking VLA-4 or vascular cell adhesion molecule 1 (VCAM-1) had no effect on cell adhesion. Blocking LFA-1 in vivo significantly delayed lethal injury following adoptive transfer of D4 cells into HA-Tg mice as assessed by weight loss and histology. Residence time of adoptively transferred Indium 111 (111In)-labeled D4 cells in lungs of normal and HA-Tg mice as analyzed by dual modality imaging revealed a significantly shorter transit time of 4 hours for the D4 cells upon in vivo blockade of LFA-1. These results demonstrate a crucial role for LFA-1 in retention of activated CD8 T cells in normal mouse lungs and in the progression of lethal injury in HA-Tg mice.


Subject(s)
CD8-Positive T-Lymphocytes/physiology , Lung/cytology , Lymphocyte Function-Associated Antigen-1/physiology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/chemistry , CD8-Positive T-Lymphocytes/immunology , Cell Adhesion , Gene Expression , Hemagglutinins, Viral/genetics , Hemagglutinins, Viral/immunology , Integrin alpha4beta1/analysis , Integrin alpha4beta1/antagonists & inhibitors , Integrin alpha4beta1/physiology , Intercellular Adhesion Molecule-1/analysis , Intercellular Adhesion Molecule-1/physiology , Lymphocyte Function-Associated Antigen-1/analysis , Mice , Mice, Inbred BALB C , Mice, Transgenic , Orthomyxoviridae , Vascular Cell Adhesion Molecule-1/analysis , Vascular Cell Adhesion Molecule-1/physiology
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