Autoimmune Consequences of Histone Deimination during Neutrophil Activation

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins, thus, are crucial questions for the understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death deserves attention because it occurs as a consequence of neutrophil activation, requires the post-translational modification of histones and results in the extracellular release of chromatin. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4) creating structures that capture or trap bacterial pathogens. Neutrophil extracellular traps (NETs), as these structures are known, generate an extracellular complex of deiminated histones and bacterial cell adjuvants. The complex of bacterial antigens and deiminated chromatin may be internalized by host phagocytes during inflammatory conditions, as arise during bacterial infections or chronic autoinflammatory disorders. The uptake and processing of deiminated chromatin together with bacterial adjuvants by phagocytes may induce the presentation of modified histone epitopes and co-stimulation, thus yielding a powerful stimulus to break tolerance. To test the hypothesis that NETs can lead to autoimmunity, we measured autoantibodies to deiminated histones in human autoimmune disorders. We detected autoantibodies to deiminated histones in Felty\u27s syndrome (FS) patients, whereas autoantibodies from Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) patients did not distinguish deiminated from non-deiminated histones. FS autoantibodies colocalized with deiminated histone H3 in LPS-treated neutrophils suggesting activated neutrophils as the source of autoantigens. In addition, we identified and characterized deimination of linker histone H1 and found rare autoantibodies to deiminated H1 in SLE and Sjogren\u27s syndrome patients. We also studied sera of autoimmune lupus prone mice to determine if they would recognize deiminated histones and found that deimination represses binding of murine lupus autoantibodies to histones. The inability of immunoglobin from sera of lupus mice to recognize deiminated histones suggests the presence of effective tolerance to NET components released during innate neutrophil response to infections. Our finding of antibodies to deiminated histones in Felty\u27s syndrome supports the idea that tolerance to deiminated histones is compromised only in exceptional circumstances. Understanding the tolerance mechanism to deiminated histones and how they are compromised in patients could be useful to design strategies for the prevention and treatment of many autoimmune disorders

Distributed physics informed neural network for data-efficient solution to partial differential equations

The physics informed neural network (PINN) is evolving as a viable method to solve partial differential equations. In the recent past PINNs have been successfully tested and validated to find solutions to both linear and non-linear partial differential equations (PDEs). However, the literature lacks detailed investigation of PINNs in terms of their representation capability. In this work, we first test the original PINN method in terms of its capability to represent a complicated function. Further, to address the shortcomings of the PINN architecture, we propose a novel distributed PINN, named DPINN. We first perform a direct comparison of the proposed DPINN approach against PINN to solve a non-linear PDE (Burgers' equation). We show that DPINN not only yields a more accurate solution to the Burgers' equation, but it is found to be more data-efficient as well. At last, we employ our novel DPINN to two-dimensional steady-state Navier-Stokes equation, which is a system of non-linear PDEs. To the best of the authors' knowledge, this is the first such attempt to directly solve the Navier-Stokes equation using a physics informed neural network.Comment: 16 pages, 8 figure

Bioactive Materials: A Short Review

In every field of dentistry and medicine, bioactive materials have been widely used. These materials are used for regeneration, repair, and reconstruction in the field of conservative dentistry and endodontics. These materials are used in different forms and composition and act directly on vital tissue, helping in its healing and repair. These materials directly function because of induction of various growth factors and different cells. This article summarizes the types and uses of bioactive materials

Role of Family Milieu in Tobacco Addiction: A Study in a Tertiary-care Institution in India

Use of tobacco is singularly responsible for most cases of cancer and coronary artery disease (CAD). Efforts to stop tobacco-use need to be guided by social circumstances. It is believed that family milieu may play a role in tobacco addiction. We studied the prevalence and pattern of tobacco-use in families of 50 consecutive tobacco-user patients who presented to a tobacco-cessation clinic and compared with age- and gendermatched controls (non-users of tobacco). The tobacco-use rates were significantly higher in the family of patients with tobacco-use compared to the control group. We conclude that problems of tobacco-use are not related to individual phenomenon, and efforts for control of tobacco addiction must be focused on entire family

B Cell Tolerance to Deiminated Histones in BALB/c, C57BL/6, and Autoimmune-Prone Mouse Strains

https://doi.org/10.3389/fimmu.2017.00362 Deimination, a posttranslational modification of arginine to citrulline carried out by peptidylarginine deiminases, may compromise tolerance of self-antigens. Patients with connective tissue autoimmunity, particularly rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or Felty’s syndrome, present with autoantibodies to deiminated histones (dH), which thus form a category of antibodies to citrullinated protein antigens (ACPA). In general, ACPA are a sensitive diagnostic for RA and may form in response to the release of nuclear chromatin (DNA plus dH) from granulocytes, usually referred to as neutrophil extracellular traps. The aim of this study was to examine spontaneously autoimmune mice for autoantibodies and T cell responses to dH. We compared IgG binding to deiminated and non-deiminated histones (nH) by ELISA and Western blotting in spontaneously autoimmune strains of (NZB × NZW) F1 and NZM2410 together with their derivative congenic strains, C57BL/6.Sle1 and C57BL/6.Sle1.Sle3, which display profound autoreactivity against nuclear self-antigens. The splenocyte proliferation against the two antigens was determined in the spontaneously autoimmune (NZB × NZW) F1 strain from which other autoimmune strains used in the study were derived. Immunizations with dH and nH were attempted in BALB/c mice to assess their splenocyte response. Splenocytes from BALB/c mice and from autoimmune mice at the time of conversion to autoimmunity proliferated strongly in response to dH, yet serum IgG from autoimmune (NZB × NZW) F1, NZM2410, and C57BL/6.Sle1.Sle3 mice displayed a remarkable bias against binding to dH. At the time of seroconversion, the antibodies already exhibited preference for nH, and only nH were recovered from circulating immune complexes. Analysis of histone deimination showed constitutive deimination in thymic extracts from C57BL/6 and C57BL/6.Sle1.Sle2.Sle3 triply congenic mice and in spleens of autoimmune triply congenic mice. Our study demonstrates that tolerance mechanisms against dH are intact in BALB/c and C57BL/6 mice and continue to be effective in mice with overt autoimmunity to nH. We conclude that, in contrast to human RA and SLE patients, where we frequently observe autoantibodies against dH, autoimmune mice maintain strong tolerance mechanisms to prevent the development of autoantibodies to dH

Trapeziectomy with ligament reconstruction/ suspensionplasty compared to suture tape suspensionplasty for the surgical treatment of advanced thumb carpometacarpal osteoarthritis

PURPOSE: Trapeziectomy with tendon reconstruction/suspensionplasty (TRS) is the most commonly performed surgical procedure in the United States for treatment of thumb carpometacarpal (CMC) osteoarthritis (OA). Trapeziectomy with suture tape suspensionplasty (STS) has been used recently at the study institution as an alternative surgical treatment option with perceived benefits of earlier return to function and reduced operative time. The purpose of this study was to compare patient outcomes following TRS versus STS for treatment of thumb CMC OA. METHODS: All patients who underwent primary, isolated TRS or STS for treatment of thumb CMC OA between 1/1/2014 and 9/1/2020 were analyzed. We assessed demographics and preoperative and postoperative patient-rated outcome scores including Patient-reported outcomes measurement information system scores as well as pain outcomes, satisfaction, and appearance at a mean of 2.6 years after surgery (minimum 6 months). Time to return to work and activities was compared between groups. Bivariate statistics compared outcomes between groups. RESULTS: Ninety-four patients were included in the final study cohort, of which 53 underwent TRS and 41 underwent STS. There were no differences in preoperative, postoperative, or final patient-rated outcome scores between groups. Patients reported high global and appearance satisfaction scores at final follow-up in both groups. Mean tourniquet time was 15 minutes (26%) shorter and return to work was on average 3 weeks faster for the STS group. CONCLUSIONS: There were no differences in postoperative patient-rated outcome scores between the STS and TRS groups. The STS group had a shorter surgical time and faster return-to-work after surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III

CD4<SUP>+</SUP> T Cell-derived novel peptide Thp5 induces interleukin-4 production in CD4<SUP>+</SUP> T cells to direct T helper 2 cell differentiation

The differentiation of naïve CD4+ T cells into T helper 2 (Th2) cells requires production of the cytokine IL-4 in the local microenvironment. It is evident that naïve/quiescently activated CD4+ T cells produce the IL-4 that drives Th2 cell differentiation. Because early production of IL-4 in naïve T cells leads to preferential Th2 cell differentiation, this process needs to be tightly regulated so as to avoid catastrophic and misdirected Th2 cell differentiation. Here, we show that Thp5, a novel peptide with structural similarity to vasoactive intestinal peptide, regulates production of early IL-4 in newly activated CD4+ T cells. Induction of IL-4 in CD4+ T cells by Thp5 is independent of the transcription factor STAT6 but dependent on ERK1/2 signaling. Furthermore, cytokines (IL-12 and TGF-β) that promote the differentiation of Th1 or Th17 cells inhibit Thp5 induction, thus suppressing Th2 cell differentiation. We further showed that Thp5 enhances Th2 responses and exacerbates allergic airway inflammation in mice. Taken together, our findings reveal that early activated CD4+ T cells produce Thp5, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response toward the Th2 cell phenotype

Climate Change and COP26: Are Digital Technologies and Information Management Part of the Problem or the Solution? An Editorial Reflection and Call to Action

The UN COP26 2021 conference on climate change offers the chance for world leaders to take action and make urgent and meaningful commitments to reducing emissions and limit global temperatures to 1.5 °C above pre-industrial levels by 2050. Whilst the political aspects and subsequent ramifications of these fundamental and critical decisions cannot be underestimated, there exists a technical perspective where digital and IS technology has a role to play in the monitoring of potential solutions, but also an integral element of climate change solutions. We explore these aspects in this editorial article, offering a comprehensive opinion based insight to a multitude of diverse viewpoints that look at the many challenges through a technology lens. It is widely recognized that technology in all its forms, is an important and integral element of the solution, but industry and wider society also view technology as being part of the problem. Increasingly, researchers are referencing the importance of responsible digitalization to eliminate the significant levels of e-waste. The reality is that technology is an integral component of the global efforts to get to net zero, however, its adoption requires pragmatic tradeoffs as we transition from current behaviors to a more climate friendly society

Climate change and COP26: Are digital technologies and information management part of the problem or the solution? An editorial reflection and call to action

The UN COP26 2021 conference on climate change offers the chance for world leaders to take action and make urgent and meaningful commitments to reducing emissions and limit global temperatures to 1.5 °C above pre-industrial levels by 2050. Whilst the political aspects and subsequent ramifications of these fundamental and critical decisions cannot be underestimated, there exists a technical perspective where digital and IS technology has a role to play in the monitoring of potential solutions, but also an integral element of climate change solutions. We explore these aspects in this editorial article, offering a comprehensive opinion based insight to a multitude of diverse viewpoints that look at the many challenges through a technology lens. It is widely recognized that technology in all its forms, is an important and integral element of the solution, but industry and wider society also view technology as being part of the problem. Increasingly, researchers are referencing the importance of responsible digitalization to eliminate the significant levels of e-waste. The reality is that technology is an integral component of the global efforts to get to net zero, however, its adoption requires pragmatic tradeoffs as we transition from current behaviors to a more climate friendly society

Climate change and COP26: Are digital technologies and information management part of the problem or the solution? An editorial reflection and call to action

The UN COP26 2021 conference on climate change offers the chance for world leaders to take action and make urgent and meaningful commitments to reducing emissions and limit global temperatures to 1.5 °C above pre-industrial levels by 2050. Whilst the political aspects and subsequent ramifications of these fundamental and critical decisions cannot be underestimated, there exists a technical perspective where digital and IS technology has a role to play in the monitoring of potential solutions, but also an integral element of climate change solutions. We explore these aspects in this editorial article, offering a comprehensive opinion based insight to a multitude of diverse viewpoints that look at the many challenges through a technology lens. It is widely recognized that technology in all its forms, is an important and integral element of the solution, but industry and wider society also view technology as being part of the problem. Increasingly, researchers are referencing the importance of responsible digitalization to eliminate the significant levels of e-waste. The reality is that technology is an integral component of the global efforts to get to net zero, however, its adoption requires pragmatic tradeoffs as we transition from current behaviors to a more climate friendly society.</p