Epigenetic attenuation of interferon signaling drives aging-related improvements in systemic lupus
Rithwik NarendraHoang Van PhanSarah PattersonAna Laura Almonte LoyaCristina LanataChristina LoveJoon‐Suk ParkEmily LydonMasayuki ShimodaLisa F. BarcellosHoney MekonenAngela M. DetweilerPadmini DeosthaleNorma NeffLindsey A. CriswellLenka MaliskovaWalter L. EckalbarGabriela K. FragiadakisJinoos YazdanyMaria Dall’EraPatricia KatzChun YeMarina SirotaCharles Langelier
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Abstract In the general human population, aging is associated with a rise in systemic inflammation, primarily involving innate immune pathways related to interferon (IFN), toll-like receptor, and cytokine signaling. In systemic lupus erythematosus (SLE), a prototypical systemic autoimmune disease, aging is distinctly associated with improvements in disease activity, suggesting a unique relationship between aging and inflammation in this disease. Using a multi-omic approach incorporating transcriptional profiling, single cell RNA sequencing, proteomics and methylation analysis, we studied age-related changes in the immune profiles of 287 SLE patients between 20 and 83 years old, and compared the results against 928 healthy controls aged between 21 and 89 years old. In contrast to the increase in inflammatory gene expression that occurs with aging in most healthy adults, SLE patients exhibited the opposite. Most notable was a decrease in type I IFN signaling that was evident across multiple cell types, with CD56-dim natural killer (NK) cells, CD4 + effector memory T cells, and naïve B cells exhibiting the most significant differences. We found that aging in SLE patients was also associated with decreased IFN-α2 and IFN-λ1 levels, and differential methylation of the genome. Notably, of the genes both downregulated and hypermethylated with older age, IFN-related genes were disproportionately represented, suggesting that age-related decreases in IFN signaling were driven in part by epigenetic silencing. Both SLE patients and healthy controls demonstrated age-related declines in naïve T cells and lymphoid progenitor cells, but only SLE patients demonstrated age-related increases in CD56-dim NK cells. Taken together, our work provides new insight into the phenomenon of inflammaging and the unique clinical improvement in disease activity that occurs in SLE patients as they age.Keywords:
Systemic lupus
Systemic lupus erythematosis (SLE) is an inflammatory autoimmune disease with multiple organs, systems damage. To date, the clear pathogenesis of SLE has not been fully clarified. However, genetics, environmental factors and dysregulated immunity were related to onset of this complex disease.
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Human lupus is strongly associated with a gene expression signature characterized by over-expression of type I interferon-regulated genes. A strong interferon signature is not seen in the standard mouse models of lupus, despite considerable evidence for the involvement of toll-like receptor (TLR)-driven interferon production. In contrast, pristane-induced lupus exhibits a prominent TLR7-dependent interferon signature. Importantly, genetic disorders with dysregulated interferon production in both humans and mice cause severe autoinflammatory diseases but not the typical manifestations of lupus suggesting that interferon over-production by itself is insufficient to cause SLE. Murine single-gene models suggest that lupus-like disease may result from abnormalities in B cell activation and the clearance of dead cells. Pristane may mimic human SLE by causing interferon production along with synergistic abnormalities affecting clearance of apoptotic cells and activation of B cell signaling.
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Based on the analysis and calculation of attenuation of the light-blocked attenuator in theory and experiment, it is found that the total attenuation should include light-blocked-only attenuation and mode-mismatched attenuation and their relationship.
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Epigenetic alterations during aging are manifested with altered gene expression linking it to lifespan regulation, genetic instability, and diseases. Diet and epigenetic modifiers exert a profound effect on the lifespan of an organism by modulating the epigenetic marks. However, our understanding of the multifactorial nature of the epigenetic process during aging and the onset of disease conditions as well as its reversal by epidrugs, diet, or environmental factors is still mystifying. This review covers the key findings in epigenetics related to aging and age-related diseases. Furthermore, it holds a discussion about the epigenetic clocks and their implications in various age-related disease conditions, including cancer. Although, epigenetics is a reversible process, how fast the epigenetic alterations can revert to normal is an intriguing question. Therefore, this article touches on the possibility of utilizing nutrition and mesenchymal stem cell secretome to accelerate the epigenetic reversal and emphasizes the identification of new therapeutic epigenetic modifiers to counter epigenetic alteration during aging.
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We analyze a range of VSP datasets for evidence of fracture related attenuation anisotropy, focusing on three attributes: P-wave attenuation anisotropy, differential shear-wave attenuation and frequency dependent shear-wave splitting. We find examples of all three phenomena and are able to reproduce the behaviour with well constrained, unified, theoretical models. Our results suggest a correlation between attenuation anisotropy and fracture properties. It is apparent that in all cases the reservoir displays much higher attenuation than the overburden. Measuring relative attenuation appears to be more robust than measuring absolute attenuation.
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In an update on systemic lupus erythematous, this article provides an overview of the classification and available treatments for variants of cutaneous lupus erythematous. Also discussed are the induction and maintenance therapy for lupus nephritis, as well as other treatments to induce and maintain improvement and prevent further damage for lupus patients.
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A simple artificial neural network is considered for real-time estimation of excess atmospheric attenuation on a satellite communication link with known attenuation at two frequencies. All atmospheric contributors to attenuation are considered except for gases. The network has a two-layer feed-forward structure with 32 neurons in the hidden layer. Its performance is evaluated by computer simulation using 447 hours of measured attenuation data at 20, 40, and 50 GHz. Estimated attenuation tracks well the measured attenuation at 50 GHz. Estimation error standard deviation is 0.36 dB. RMS error is a function of attenuation: it increases slowly with attenuation, but the ratio of error to attenuation decreases with increasing attenuation. This approach accurately estimates excess attenuation without requiring assumptions, but required training data. (4 pages)
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Measurement of disease activity in systemic lupus erythematosus (SLE) is central to evaluating outcomes, differences among SLE patient groups, responses to a new drug proposed, and also for assessing disease longitudinally for observational and clinical trials. Several validated and updated instruments have been available since the early 1980s, but more recent studies gauging reliability and validity for classifying and monitoring groups of patients in the research setting are now available.
Two cardinal features of SLE have challenged investigators refining these tools: first, the complex multisystem nature of this disease with fluctuating levels of disease activity, which may vary between patients and within the same patient over time; second, the absence of a “gold standard” for determining the psychometric properties of each proposed scale limits comparisons to expert opinion using a physician’s visual analog scale or by comparing one scale against other to assess performance across proposed instruments. However, these strategies do not eliminate bias based on personal experience, nor do they differentiate between different opinions on the relative importance of disease manifestations in different systems.
Therefore, an experience-based evaluation may be subject to greater interrater variability than the use of the disease activity instrument itself. Furthermore, psychometric properties should be influenced by the length of the scale (number of items and scoring scale), number of patients included, or disease severity of patients under study.
Two main types of activity measures in SLE have been developed: global score systems (for example, the European Consensus Lupus Activity Measurements, Systemic Lupus Activity Measure [SLAM], and Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), which provide an overall measure of activity, and individual organ/system assessment scales that assess disease activity in single organs (such as the British Isles Lupus Assessment Group Index [BILAG]). The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score is a measure for chronic damage; it has been included due to its prognostic value in clinical and research basis.
The SLEDAI, SLAM, and BILAG have performed in effective and reliable manners in studies; furthermore, they correlate with one another (1-3). The SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)–SLEDAI, SLEDAI 2000 (4-7), and BILAG (8-10) have been successfully used in observational trials and case studies, although baseline disease activity index (DAI) scores were not always predictors of subsequent damage or other outcomes (11,12). These DAIs were validated in the context of long-term observational trials studies and not in randomized clinical trials (RCTs) (1,9,10,13-15). The few RCTs conducted have shown that improvement in DAI scores correlates with response rates, disease remission, and flare prevention; however, a threshold of clinically meaningful change has not been established (1,13,16,17). Current work has focused on developing a responder index developed in collaboration with the Food and Drug Administration–defined response as improvement and/or no deterioration in patient- and physician-reported outcomes. The SLE responder index, which utilizes the SELENA–SLEDAI score to determine global improvement, BILAG domain scores to ensure no significant worsening in heretofore unaffected organ systems, and physician’s global assessment to ensure that improvements in disease activity are not achieved at the expense of the patient’s overall condition, which may have been missed by either DAI, is one example used in a recent clinical trial (18). Ongoing work to refine or develop responder indices will enhance our ability to measure meaningful outcomes in future RCTs.
For purpose of this review, we selected those indices that have shown the strongest evidence of validity when used by investigators from different countries in large studies of patients with SLE. The exact choice of instrument should be governed by the purpose for which it is required in clinicalpractice or research.
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E-19 NUMERICAL STUDY OF SCATTERING ATTENUATION IN FRACTURED MEDIA – FREQUENCY DEPENDENCE AND EFFECTS OF CHARACTERISTIC LENGTH SCALES Introduction 1 Seismic attenuation is in general a combined effect of absorption (intrinsic attenuation) which is affected by lithological parameters and scattering (apparent) attenuation which is related to structural parameters. Which of these two mechanisms dominates in any given situation depends on the relative wavelengths of the seismic wave and the heterogeneities of the fracture system. In this study we deal exclusively with scattering attenuation. Synthetic modeling studies with and without intrinsic attenuation show that the contribution of scattering attenuation is significant.
Anelastic attenuation factor
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