Biology subjects

Luo, G.

Publications and source records attributed to Luo, G..

6 recordsLinked to original sources

bioRxiv2018

Differential T cell reactivity to hypocretin and flu antigen epitopes provides clues to the pathophysiology of Type 1 narcolepsy

Type 1 narcolepsy (T1N) is caused by hypocretin (HCRT) neuronal loss. Association with the Human Leukocyte Antigen (HLA)-DQB1*06:02/DQA1*01:02 (98% vs 25%) heterodimer (DQ0602), T cell receptor (TCR) and other immune loci suggest autoimmunity but autoantigen(s) are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1). An extensive unbiased DQ0602 binding peptide screen was performed encompassing peptides derived from Pandemrix(R) X-179-A pH1N1 influenza-A vaccine, a known T1N trigger, other H1N1 strains, and potential human autoantigens HCRT and RFX4, identifying 109 binders. The presence of cognate tetramer-peptide specific CD4+ T cells was studied in 35 narcolepsy cases and 22 DQ0602 controls after expansion of antigen-specific cells in Peripheral Blood Monocytes Cell (PBMC) cultures. Higher reactivity to influenza epitopes pHA273-287 (pH1N1 specific) and PR8 (H1N1 pre 2009)-specific NP17-31 were observed in T1N. Extensive reactivity to C-amidated but not native version of HCRT54-66 and HCRT86-97, which are two highly homologous peptides (HCRTNH2) was observed with higher frequencies of specific T cells in T1N. TCR/{beta} CDR3 sequences found in pHA273-287, NP17-31 and HCRTNH2 tetramer positive CD4+ cells were also retrieved in single INF{gamma}-secreting CD4+ sorted cells stimulated with Pandemrix(R), confirming immunodominance and functional significance in DQ0602-mediated responses and molecular mimicry. TCR/{beta} CDR3 motifs of HCRT54-66 and HCRT86-97 tetramers were extensively shared. Particularly notable was sharing across subjects of an CDR3, CAVETDSWGKLQF (in association with various CDR3{beta} that used TRAJ24, a chain modulated by Single Nucleotide Polymorphism (SNPs) rs1154155 and rs1483979 associated with T1N. Sharing of CDR3{beta} CASSQETQGRNYGYTF (in association with various CDR3 was also observed with HCRTNH2 and pHA273-287-tetramers across subjects. This segment uses TRBV4-2, a segment modulated by narcolepsy-associated SNP rs1008599. Higher HCRTNH2 positive CD4+ T cell numbers in T1N together with sharing of J24 CAVETDSWGKLQF in HCRTNH2 autoimmune responses, indicates causal DQ0602-mediated CD4+ autoreactivity to HCRT in T1N. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.

immunology↗

bioRxiv2018

Narcolepsy risk loci are enriched in immune cells and suggest autoimmune modulation of the T cell receptor repertoire

Type 1 narcolepsy (T1N) is a neurological condition, in which the death of hypocretin-producing neurons in the lateral hypothalamus leads to excessive daytime sleepiness and symptoms of abnormal Rapid Eye Movement (REM) sleep. Known triggers for narcolepsy are influenza-A infection and associated immunization during the 2009 H1N1 influenza pandemic. Here, we genotyped all remaining consented narcolepsy cases worldwide and assembled this with the existing genotyped individuals. We used this multi-ethnic sample in genome wide association study (GWAS) to dissect disease mechanisms and interactions with environmental triggers (5,339 cases and 20,518 controls). Overall, we found significant associations with HLA (2 GWA significant subloci) and 11 other loci. Six of these other loci have been previously reported (TRA, TRB, CTSH, IFNAR1, ZNF365 and P2RY11) and five are new (PRF1, CD207, SIRPG, IL27 and ZFAND2A). Strikingly, in vaccination-related cases GWA significant effects were found in HLA, TRA, and in a novel variant near SIRPB1. Furthermore, IFNAR1 associated polymorphisms regulated dendritic cell response to influenza-A infection in vitro (p-value =1.92*10-25). A partitioned heritability analysis indicated specific enrichment of functional elements active in cytotoxic and helper T cells. Furthermore, functional analysis showed the genetic variants in TRA and TRB loci act as remarkable strong chain usage QTLs for TRAJ*24 (p-value = 0.0017), TRAJ*28 (p-value = 1.36*10-10) and TRBV*4-2 (p-value = 3.71*10-117). This was further validated in TCR sequencing of 60 narcolepsy cases and 60 DQB1*06:02 positive controls, where chain usage effects were further accentuated. Together these findings show that the autoimmune component in narcolepsy is defined by antigen presentation, mediated through specific T cell receptor chains, and modulated by influenza-A as a critical trigger.

genetics↗

bioRxiv2018

Hazard detection with monocular bioptic telescopes in a driving simulator

ABSTRACT\n\nPurpose: Recently we developed a driving simulator paradigm to evaluate detection of road hazards when using a bioptic telescope and conducted an initial study using normally-sighted observers with simulated vision loss. We now extend our investigation to quantifying the extent to which visually impaired bioptic users are able to use their fellow (non-telescope) eye to compensate for the ring scotoma of a monocular bioptic telescope. We tested the hypothesis that detection rates would be higher in binocular viewing (fellow eye could potentially compensate) than monocular viewing (fellow eye patched so it could not compensate) for pedestrian hazards present in the scene only while the telescope was being used.\n\nMethods: Sixteen bioptic telescope users (17-80 y) completed six test drives, including three with binocular viewing interleaved between three with monocular viewing. While driving, they used their own monocular bioptic telescopes to read information on highway road signs (n = 71) and pressed the horn when they saw a pedestrian hazard (n = 50). Twenty-six of the pedestrians were programed to appear, run on the road ahead of the driver for 1s within the ring scotoma and then disappear, within the period when participants were reading signs through the bioptic. The timing of the head movement to look into and out of the bioptic was determined and events were then categorized by whether or not the pedestrian hazard was present in the scene only while using the bioptic.\n\nResults: When pedestrian hazards were in the scene only while subjects were using the bioptic to read a sign, detection rates were significantly higher in binocular than monocular viewing (68% vs. 40%). However, when pedestrians when subjects had a brief view of the pedestrian either beforeor after looking through the bioptic, then detection rates did not differ in binocular and monocular viewing (78% vs. 79%). By comparison, when not using the bioptic detection rates were higher (> 90%) and reaction times were shorter (without 0.95 s vs. with 1.25 s)\n\nConclusions: Our results suggest that under binocular viewing conditions the fellow eye was able to compensate for the ring scotoma to a certain extent when subjects used a monocular telescope to read road signs; however, performance was not as good as without the bioptic.

neuroscience↗

bioRxiv2018

Roles of motion perception and visual acuity for driving hazard perception

PURPOSEThere are many visually impaired people who can drive legally with bioptic telescope. Drawing on the experience of drivers with reduced vision, this study investigated the role of motion perception and visual acuity in driving, under simulated low visual acuity.\n\nMETHODSTwenty normally sighted participants took part in a driving hazard perception (HP) test, in four different conditions: with/without motion interruption and with/without simulated low visual acuity. In interrupted motion conditions a mask frame was inserted between every frame of the driving videos. In simulated low visual acuity conditions, participants wore glasses with diffusing filters that lowered their visual acuity to 20/120 on average. Participants response time, hazard detection rates, and HP scores, which combined response time and detection rate, were compared.\n\nRESULTSRepeated measure ANOVA revealed that the HP scores significantly declined from 20.46 to 16.82 due to the motion mask (F(1,19) = 9.343, p = 0.006). However, simulated low visual acuity did not affect HP scores (F(1,19) = 1.807, p = 0.195). The interaction between vision and mask was not significant (F(1,19) = 1. 295, p = 0.269). The decline in score was mostly due to significant decrease in detection rate, from 0.80 to 0.64, due to the motion mask (F(1,19) = 16.686, p = 0.001).\n\nCONCLUSIONSIn this experimental setting, human observers relied largely on motion information for detecting driving hazards, rather than high visual acuity. This finding might help explain how visually impaired drivers can compensate for their impaired vision during driving.

neuroscience↗

bioRxiv2018

The Roles of Different Spatial Frequency Channels in Real-World Visual Motion Perception

Speed perception is an important task performed by our visual system in various daily life tasks. In various psychophysical tests, relationship between spatial frequency, temporal frequency, and speed has been examined in human subjects. The role of vision impairment in speed perception has also been previously examined. In this work, we examine the inter-relationship between speed, spatial frequency, low vision conditions, and the type of input motion stimuli in motion perception accuracy. For this purpose, we propose a computational model for speed perception and evaluate it in custom generated natural and stochastic sequences by simulating low-vision conditions (low pass filtering at different cutoff frequencies) as well as complementary vision conditions (high pass versions at the same cutoff frequencies). Our results show that low frequency components are critical for accurate speed perception, whereas high frequencies do not play any important role in speed estimation. Since perception of low frequencies may not be impaired in visual acuity loss, speed perception was not found to be impaired in low vision conditions compared to normal vision condition. We also report significant differences between natural and stochastic stimuli, notably an increase in speed estimation error when using stochastic stimuli compared to natural sequences, emphasizing the use of natural stimuli when performing future psychophysical studies for speed perception.

neuroscience↗

bioRxiv2017

Influence of APOA5 locus on the treatment efficacy of three statins: evidence from a randomized pilot study in Chinese subjects

Pharmacogenetics or pharmacogenomics approaches are important for addressing the individual variabilities of drug efficacy especially in the era of precision medicine. One particular interesting gene to investigate is APOA5 which has been repeatedly linked with the inter-individual variations of serum triglycerides. Here, we explored APOA5-statin interactions in 195 Chinese subjects randomized to rosuvastatin (5-10 mg/day), atorvastatin (10-20 mg/day), or simvastatin (40 mg/day) for 12 weeks by performing a targeted genotyping analysis of the APOA5 promoter SNP rs662799 (-1131T>C). There were no significant differences between the treatment arms for any of the statin-induced changes in clinical biomarkers. Reductions in LDL cholesterol were influenced by the APOA5 genotype in all three treatment groups. By contrast, changes in HDL cholesterol and triglycerides were only affected by the APOA5 genotype in the atorvastatin and simvastatin groups and not in the rosuvastatin group. Our results support earlier findings indicating that rosuvastatin is a better treatment option and that future studies should consider stratifying subjects not only by genetic background but also by statin type.\n\nAbbreviations

clinical trials↗