Biology subjects

Wei, A.

Publications and source records attributed to Wei, A..

27 records · Page 2Linked to original sources

bioRxiv2021

Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer's disease progression.

It is unknown whether specific microglia are selectively induced by amyloid-{beta} (A{beta}), tau pathologies, or both in combination. To address this, we use single-cell RNA-sequencing to profile mice bearing both A{beta} and tau pathologies during Alzheimers disease (AD) progression. We identify novel microglia subtypes induced in a disease stage-specific manner. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed EADAM. During late-stage disease, a second microglia subtype termed LADAM is detected. While EADAM and LADAM-like microglia are observed in other neurodegenerative models, the magnitude and composition of subtype markers are distinct from microglia observed with AD-like pathology. The pattern of EADAM- and LADAM-associated gene expression is observed in microglia from human AD, during the early and late stages of disease, respectively. Furthermore, we observe that several siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of the human orthologue of Siglecg is progressively elevated in AD-stage-dependent manner but not shown in non-AD tauopathy. Our findings imply that both A{beta} and tau pathologies are required for disease stage-specific induction of EADAM and LADAM.

neuroscience↗

bioRxiv2021

DMRscaler: A Scale-Aware Method to Identify Regions of Differential DNA Methylation Spanning Basepair to Multi-Megabase Features

BackgroundPathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity in the scale of the epigenetic changes they affect, from single basepair modifications by DNMT1 to whole genome structural changes by PRM1/2. Patterns of DNA methylation are related to a diverse set of epigenetic features across this full range of epigenetic scale, making DNA methylation valuable for mapping regions of general epigenetic dysregulation. However,existing methods are unable to accurately identify regions of differential methylation across this full range of epigenetic scale directly from DNA methylation data. ResultsTo address this, we developed DMRscaler, a novel method that uses an iterative windowing procedure to capture regions of differential DNA methylation (DMRs) ranging in size from single basepairs to whole chromosomes. We benchmarked DMRscaler against several DMR callers in simulated and natural data comparing XX and XY peripheral blood samples. DMRscaler was the only method that accurately called DMRs ranging in size from 100 bp to 1 Mb (pearsons r = 0.96) and up to 152 Mb on the X-chromosome. We then analyzed methylation data from rare-disease cohorts that harbor chromatin modifier gene mutations in NSD1, EZH2, and KAT6A where DMRscaler identified novel DMRs spanning gene clusters involved in development. ConclusionTaken together, our results show DMRscaler is uniquely able to capture the size of DMR features across the full range of epigenetic scale and identify novel, co-regulated regions that drive epigenetic dysregulation in human disease.

genomics↗

bioRxiv2020

Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute myeloid leukemias for therapeutic benefit

Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit, particularly against hematological malignancies. While these agents can affect tumor cell growth and proliferation, recent studies have demonstrated that pharmacological de-regulation of epigenetic modifiers may additionally mediate anti-tumor immune responses. Here we discovered a novel mechanism of immune regulation through the inhibition of histone deacetylases (HDACs). In a genetically engineered model of t(8;21) AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) signaling pathway. Plasmacytoid dendritic cells (pDCs) were identified as the cells producing type I IFN in response to panobinostat, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated activation of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and recombinant IFN improved therapeutic outcomes. These discoveries offer a new therapeutic approach for t(8;21) AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this cell type as a new target for immunotherapy.

cancer biology↗

bioRxiv2020

Title: Two-Photon Microperimetry: A media opacity-independent retinal function assay

Humans perceive light in the visible portion of electromagnetic radiation. However, visible light is scattered and attenuated by optical media opacities. Because all conventional visual function tests rely on visible light, test results are reduced in patients with optical media opacities like corneal scars, cataracts, and vitreous hemorrhages. Infrared (IR) light has greater penetrance through tissue than visible light. Two-photon IR visual stimulation, a recently pioneered technology, should enable testing of retinal visual function and produce results that are less susceptible to media opacities. The effects of simulated media opacities on visual performance in young healthy volunteers and the change in visual function in healthy phakic patients of two age ranges (20-40 and 60-80-year-old) were studied using conventional testing and 2-photon infrared visual stimulation. All subjects completed visual function testing using cone contrast threshold (CCT) testing, conventional microperimetry, visible light microperimetry from a novel device (2PM-Vis), and infrared 2-photon microperimetry (2PM-IR). Retinal sensitivity measured by 2PM-IR demonstrated lower variability than all other devices relying on visible spectrum stimuli. Retinal sensitivity decreased proportionally with the transmittance of light through each filter. CCT scores and retinal sensitivity decreased with age in all testing modalities. Visible spectrum testing modalities demonstrated larger test result differences between young and old patient cohorts; this difference was inversely proportional to the wavelength of the visual function test. 2PM-IR mitigates media opacities which may mask small differences in retinal sensitivity when tested with conventional visual function testing devices.Competing Interest StatementGrazyna Palczewska has a conflict of interest in this study, as she is an employee of Polgenix, Inc.View Full Text

bioengineering↗

bioRxiv2020

Quantifying Color Vision Changes Associated with Cataracts Using Cone Contrast Thresholds

PurposeThe cone contrast threshold (CCT) test quantified color vision changes in subjects of all ages and those undergoing cataract surgery. MethodsTwenty-four healthy volunteers from two cohort studies performed CCT using best corrected visual acuity, filters, mydriasis, and pinhole correction. Retrospective cross-sectional study of patients seen in eye clinics evaluated the relationship between age and color vision, and age and lens status in 355 eyes. Lastly, 25 subjects performed CCT before and after cataract surgery. ResultsCCT scores were most reliable in the non-mydriatic condition without pinhole correction. Progressively dense brown filters produced small but significant reductions in S-cone sensitivity. Linear regression analysis of phakic subjects showed a decline for all cone classes with age. Rate of decline was greater for S-cones (slope (95% CI) = -1.09 (-1.23, 0.94)) than M-cones (slope (95% CI) = -0.80 (-0.95, -0.66)) and L-cones (slope (95% CI) = -0.66 (-0.81, - 0.52)). CCT scores increased for S-cones but reduced for L- and M-cones in pseudophakic subjects compared to phakic patients. CCT scores after cataract surgery increased for S-cones, M-cones, and L-cones by 33.0 (p<0.001), 24.9 (p=0.001), and 22.0 (p=0.008). ConclusionsCCT assessment allows for clinically practical quantitation of color and contrast vision improvement after cataract surgery and aging patients who note poor vision despite good visual acuity. Translational RelevanceCCT testing, historically used in research, is now a clinically practical tool to evaluate age and cataract related changes in color and contrast vision and routinely quantify vision beyond black and white visual acuity testing.

pathology↗

bioRxiv2020

A novel fibrinogen gamma-chain mutation, p. γAla327Val, causes structural abnormality of D region and ultimately leads to congenital dysfibrinogenemia

Congenital dysfibrinogenemia (CD) is a coagulation disorder caused by mutations in the fibrinogen gene, which result in abnormal fibrinogen function. Many studies have confirmed that over half of dysfibrinogenemia cases are asymptomatic. In this study, we aimed to investigate the pathogenesis of CD caused by {gamma} Ala327Val heterozygous mutation, a new mutation, by studying fibrinogen function. Blood samples of patients were collected and the coagulation function, fibrinogen (Fg) aggregation test, fibrin clot lysis test, and SDS-PAGE were performed. Coagulation was monitored using a thromboelastometer, and the fibrin clot network structure was observed by scanning electron microscopy. The effect of the mutation on fibrinogen structure and function was predicted by molecular modeling. The fibrinogen activity concentration in patients with CD was significantly lower than that in healthy individuals. Thromboelastography showed that the K value of patients with CD was higher than that for healthy individuals. The Angle values were also decreased. The function of fibrinogen in patients with CD was low. Compared to fibrinogen from healthy individuals, fibrin size was different, the fiber network structure was loose, the pore size was increased, and the fiber branch nodes were increased for fibrinogen isolated from the proband. The {gamma} Ala327Val mutation led to changes in the structure of fibrinogen D region, affecting its structural stability. Ala327Val heterozygous missense mutation in exon 8 of FGG gene {gamma}-chain thus leads to abnormal fibrinogen structure and impairs the aggregation function of fibrinogen. This mutation is reported here for the first time.

molecular biology↗

bioRxiv2019

Identification of microRNA-target interactions for antioxidant defense response under drought stress by high-throughput sequencing in Zanthoxylum bungeanum Maxim.

When the plant is in an unfavorable environment such as drought or high temperature, it will accumulate a large amount of active oxygen, which will seriously affect the normal growth and development of the plant. The antioxidant system can remove the reactive oxygen species produced under drought conditions and so mitigate oxidative damage. We examined the trends of antioxidant enzymes, miRNAs and their target genes in Zanthoxylum bungeanum under drought stress. According to the changes of antioxidant enzymes, miRNAs and their target genes expression patterns of Zanthoxylum bungeanum under drought stress, an interaction model was constructed to provide a reference for further understanding of plant antioxidant mechanism. The results indicate that under drought stress, POD, CAT, APX, proline, MDA and related genes all show positive responses to drought, while SOD and its genes showed a negative response. It is speculated that in the antioxidant process of Zanthoxylum bungeanum, POD, CAT, and APX play a major role, and SOD plays a supporting role. In addition, the expression levels of miRANs and their target genes were basically negatively correlated, indicating that miRNAs are involved in the regulation of the antioxidant system of Zanthoxylum bungeanum.

cell biology↗

bioRxiv2019

Drought Affects the Antioxidant System and Stomatal Aperture in Zanthoxylum bungeanum Maxim.

When under drought, plants activate a range of self-protective responses. Among these are activation of the antioxidant system and changes in stomatal aperture. The antioxidant system can remove the reactive oxygen species produced under drought conditions and so mitigate oxidative damage. Water becomes a severely limiting resource for plants suffering drought stress, so they generally close their stomata to reduce water loss. We examined changes in the activities of the antioxidant enzymes and altered gene expression patterns in Zanthoxylum bungeanum plants exposed to drought by irrigation with 20% PEG6000. We also recorded changes in stomatal aperture as the drought persisted. Relationships between the antioxidant system and stomatal aperture were analyzed in relation to gene expression. The results indicate that under drought stress, POD, CAT, APX, proline, MDA and related genes all show positive responses to drought, while SOD and its genes showed a negative response. The relationship between drought duration and stomatal aperture was considered. Stomatal aperture declines exponentially as drought duration increases.

cell biology↗

bioRxiv2019

An Interscholastic Network to Generate LexA Enhancer Trap Lines in Drosophila

Binary expression systems like the LexA-LexAop system provide a powerful experimental tool kit to study gene and tissue function in developmental biology, neurobiology and physiology. However, the number of well-defined LexA enhancer trap insertions remains limited. In this study, we present the molecular characterization and initial tissue expression analysis of nearly 100 novel StanEx LexA enhancer traps, derived from the StonEx1 index line. This includes 76 insertions into novel, distinct gene loci not previously associated with enhancer traps or targeted LexA constructs. Additionally, our studies revealed evidence for selective transposase-dependent replacement of a previously-undetected KP element on chromosome III within the StanEx1 genetic background during hybrid dysgenesis, suggesting a molecular basis for the over-representation of LexA insertions at the NK7.1 locus in our screen. Production and characterization of novel fly lines were performed by students and teachers in experiment-based genetics classes within a geographically diverse network of public and independent high schools. Thus, unique partnerships between secondary schools and university-based programs have produced and characterized novel genetic and molecular resources in Drosophila for open-source distribution, and provide paradigms for development of science education through experience-based pedagogy.

genetics↗