The human immune system displays substantial variation between individuals, leading to differences in susceptibility to autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from ...1,267,758 peripheral blood mononuclear cells from 982 healthy human subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing cell type-specific effects on gene expression. We subsequently show how eQTLs have dynamic allelic effects in B cells that are transitioning from naïve to memory states and demonstrate how commonly segregating alleles lead to interindividual variation in immune function. Finally, using a Mendelian randomization approach, we identify the causal route by which 305 risk loci contribute to autoimmune disease at the cellular level. This work brings together genetic epidemiology with scRNA-seq to uncover drivers of interindividual variation in the immune system.
IL-17A Enhances Retinal Neovascularization Taylor, Brooklyn E; Lee, Chieh A; Zapadka, Thomas E ...
International journal of molecular sciences,
01/2023, Letnik:
24, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Retinal neovascularization occurs in proliferative diabetic retinopathy, neovascular glaucoma, and age-related macular degeneration. This type of retinal pathology normally occurs in the later stages ...of these ocular diseases and is a prevalent cause of vision loss. Previously, we determined that Interleukin (IL)-17A plays a pivotal role in the onset and progression of non-proliferative diabetic retinopathy in diabetic mice. Unfortunately, none of our diabetic murine models progress to proliferative diabetic retinopathy. Hence, the role of IL-17A in vascular angiogenesis, neovascularization, and the onset of proliferative diabetic retinopathy was unclear. In the current study, we determined that diabetes-mediated IL-17A enhances vascular endothelial growth factor (VEGF) production in the retina, Muller glia, and retinal endothelial cells. Further, we determined that IL-17A can initiate retinal endothelial cell proliferation and can enhance VEGF-dependent vascular angiogenesis. Finally, by utilizing the oxygen induced retinopathy model, we determined that IL-17A enhances retinal neovascularization. Collectively, the results of this study provide evidence that IL-17A plays a pivotal role in vascular proliferation in the retina. Hence, IL-17A could be a potentially novel therapeutic target for retinal neovascularization, which can cause blindness in multiple ocular diseases.
Diabetic retinopathy is a diabetes-mediated retinal microvascular disease that is the leading cause of blindness in the working-age population worldwide. Interleukin (IL)-17A is an inflammatory ...cytokine that has been previously shown to play a pivotal role in the promotion and progression of diabetic retinopathy. Retinoic acid-related orphan receptor gammaT (RORγt) is a ligand-dependent transcription factor that mediates IL-17A production. However, the role of RORγt in diabetes-mediated retinal inflammation and capillary degeneration, as well as its potential therapeutic attributes for diabetic retinopathy has not yet been determined. In the current study, we examined retinal inflammation and vascular pathology in streptozotocin-induced diabetic mice. We found RORγt expressing cells in the retinal vasculature of diabetic mice. Further, diabetes-mediated retinal inflammation, oxidative stress, and retinal endothelial cell death were all significantly lower in RORγt
mice. Finally, when a RORγt small molecule inhibitor (SR1001) was subcutaneously injected into diabetic mice, retinal inflammation and capillary degeneration were ameliorated. These findings establish a pathologic role for RORγt in the onset of diabetic retinopathy and identify a potentially novel therapeutic for this blinding disease.
DNA double-strand break (DSB) signaling and repair are critical for cell viability, and rely on highly coordinated pathways whose molecular organization is still incompletely understood. Here, we ...show that heterogeneous nuclear ribonucleoprotein U-like (hnRNPUL) proteins 1 and 2 play key roles in cellular responses to DSBs. We identify human hnRNPUL1 and -2 as binding partners for the DSB sensor complex MRE11-RAD50-NBS1 (MRN) and demonstrate that hnRNPUL1 and -2 are recruited to DNA damage in an interdependent manner that requires MRN. Moreover, we show that hnRNPUL1 and -2 stimulate DNA-end resection and promote ATR-dependent signaling and DSB repair by homologous recombination, thereby contributing to cell survival upon exposure to DSB-inducing agents. Finally, we establish that hnRNPUL1 and -2 function downstream of MRN and CtBP-interacting protein (CtIP) to promote recruitment of the BLM helicase to DNA breaks. Collectively, these results provide insights into how mammalian cells respond to DSBs.
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► hnRNPUL proteins associate with the DSB sensor complex MRN ► hnRNPUL proteins display both exclusion from and MRN-dependent recruitment to DSBs ► hnRNPUL proteins stimulate DSB resection, signaling, and repair ► hnRNPUL proteins promote BLM recruitment to sites of DNA damage
Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC ...detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation‐specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele‐specific real‐time target and signal amplification assays on independent plasma‐extracted DNA from 21 HCC cases and 30 controls with cirrhosis. A phase II plasma study was then performed in 95 HCC cases, 51 controls with cirrhosis, and 98 healthy controls using target enrichment long‐probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross‐validated by randomly splitting the data 2:1 for training and testing. Random forest (rForest) regression models performed on the training set predicted disease status in the testing set; median areas under the receiver operating characteristics curve (AUCs; and 95% confidence interval CI) were reported after 500 iterations. In phase II, a six‐marker MDM panel (homeobox A1 HOXA1, empty spiracles homeobox 1 EMX1, AK055957, endothelin‐converting enzyme 1 ECE1, phosphofructokinase PFKP, and C‐type lectin domain containing 11A CLEC11A) normalized by beta‐1,3‐galactosyltransferase 6 (B3GALT6) level yielded a best‐fit AUC of 0.96 (95% CI, 0.93‐0.99) with HCC sensitivity of 95% (88%‐98%) at specificity of 92% (86%‐96%). The panel detected 3 of 4 (75%) stage 0, 39 of 42 (93%) stage A, 13 of 14 (93%) stage B, 28 of 28 (100%) stage C, and 7 of 7 (100%) stage D HCCs. The AUC value for alpha‐fetoprotein (AFP) was 0.80 (0.74‐0.87) compared to 0.94 (0.9‐0.97) for the cross‐validated MDM panel (P < 0.0001). Conclusion: MDMs identified in this study proved to accurately detect HCC by plasma testing. Further optimization and clinical testing of this promising approach are indicated.
In clinical movement biomechanics, kinematic data are often depicted as waveforms (i.e. signals), characterising the motion of articulating joints. Clinically meaningful interpretations of the ...underlying joint kinematics, however, require an objective understanding of whether two different kinematic signals actually represent two different underlying physical movement patterns of the joint or not. Previously, the accuracy of IMU-based knee joint angles was assessed using a six-degrees-of-freedom joint simulator guided by fluoroscopy-based signals. Despite implementation of sensor-to-segment corrections, observed errors were clearly indicative of cross-talk, and thus inconsistent reference frame orientations. Here, we address these limitations by exploring how minimisation of dedicated cost functions can harmonise differences in frame orientations, ultimately facilitating consistent interpretation of articulating joint kinematic signals. In this study, we present and investigate a frame orientation optimisation method (FOOM) that aligns reference frames and corrects for cross-talk errors, hence yielding a consistent interpretation of the underlying movement patterns. By executing optimised rotational sequences, thus producing angular corrections around each axis, we enable a reproducible frame definition and hence an approach for reliable comparison of kinematic data. Using this approach, root-mean-square errors between the previously collected (1) IMU-based data using functional joint axes, and (2) simulated fluoroscopy-based data relying on geometrical axes were almost entirely eliminated from an initial range of 0.7°-5.1° to a mere 0.1°-0.8°. Our results confirm that different local segment frames can yield different kinematic patterns, despite following the same rotation convention, and that appropriate alignment of reference frame orientation can successfully enable consistent kinematic interpretation.
Age-related macular degeneration (AMD) remains a disease with high morbidity and an incompletely understood pathophysiological mechanism. The ocular blood supply has been implicated in the ...development of the disease process, of which most research has focused on the role of the choroid and choriocapillaris. Recently, interest has developed into the role of the retinal vasculature in AMD, particularly with the advent of optical coherence tomography angiography (OCTA), which enables non-invasive imaging of the eye's blood vessels. This review summarises the up-to-date body of work in this field including the proposed links between observed changes in the retinal vessels and the development of AMD and potential future directions for research in this area. The review highlights that the strongest evidence supports the observation that patients with early to intermediate AMD have reduced vessel density in the superficial vascular complex of the retina, but also emphasises the need for caution when interpreting such studies due to their variable methodologies and nomenclature.
We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One ...thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic variants in one of three genes (
KCNQ4
,
TECTA
,
WFS1
) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in audioprofiles driven by both mutation type (non-truncating vs. truncating) and ethnic background. The former finding confirms data that ascribe a phenotypic consequence to different mutation types in
KCNQ4
; the latter finding suggests that there are ethnic-specific effects (genetic and/or environmental) that impact gene-specific audioprofiles for
TECTA
and
WFS1
. Identifying the drivers of ethnic differences will refine our understanding of phenotype–genotype relationships and the biology of hearing and deafness.
Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined ...how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.
•Repeated acute resolving inflammation leads to excessive tissue damage•IL-6 regulates profibrotic IFN-γ-secreting T cells•IFN-γ increases detrimental STAT1 signaling in stromal tissue•STAT1 activity alters homeostatic control of extracellular matrix to promote fibrosis
Topic identification can facilitate knowledge curation, discover thematic relationships, trends, and predict future direction. We aimed to determine through an unsupervised, machine learning approach ...to topic modeling the most common research themes in emergency medicine over the last 40 years and summarize their trends and characteristics.
We retrieved the complete reference entries including article abstracts from Ovid for all original research articles from 1980 to 2019 within emergency medicine for six widely-cited journals. Abstracts were processed through a natural language pipeline and analyzed by a latent Dirichlet allocation topic modeling algorithm for unsupervised topic discovery. Topics were further examined through trend analysis, word associations, co-occurrence metrics, and two-dimensional embeddings.
We retrieved 47,158 articles during the defined time period that were filtered to 20,528 articles for further analysis. Forty topics covering methodologic and clinical areas were discovered. These topics separated into distinct clusters when embedded in two-dimensional space and exhibited consistent patterns of interaction. We observed the greatest increase in popularity in research themes involving risk factors (0.4% to 5.2%), health utilization (1.2% to 5.0%), and ultrasound (0.7% to 3.3%), and a relative decline in research involving basic science (8.9% to 1.1%), cardiac arrest (6.5% to 2.2%), and vitals (6.3% to 1.3%) over the past 40 years. Our data show only very modest growth in mental health and substance abuse research (1.0% to 1.6%), despite ongoing crises.
Topic modeling via unsupervised machine learning applied to emergency medicine abstracts discovered coherent topics, trends, and patterns of interaction.
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