Differential expression of mitogen activating protein kinases in periodontitis

Aim Following toll‐like receptor ( TLR ) engagement, lipopolysaccharide ( LPS ) can stimulate the expression of pro‐inflammatory cytokines thus activating the innate immune response. The production of inflammatory cytokines results, in part, from the activation of kinase‐induced signalling cascades and transcriptional factors. Of the four distinct classes of mitogen‐activated protein kinases ( MAPK ) described in mammals, p38, c‐Jun N‐terminal activated kinases ( JNK 1‐3) and extracellular activated kinases ( ERK 1,2) are the best studied. Previous data have established that p38 MAPK signalling is required for inflammation and bone loss in periodontal disease pre‐clinical animal models. Materials & Methods In this study, we obtained healthy and diseased periodontal tissues along with clinical parameters and microbiological parameters. Excised fixed tissues were immunostained with total and phospho‐specific antibodies against p38, JNK and ERK kinases. Results Intensity scoring from immunostained tissues was correlated with clinical periodontal parameters. Rank correlations with clinical indices were statistically significantly positive ( p ‐value < 0.05) for total p38 (correlations ranging 0.49–0.68), phospho‐p38 (range 0.44–0.56), and total ERK (range 0.52–0.59) levels, and correlations with JNK levels also supported association (range 0.42–0.59). Phospho‐ JNK and phospho‐ ERK showed no significant positive correlation with clinical parameters of disease. Conclusion These data strongly implicate p38 MAPK as a major MAPK involved in human periodontal inflammation and severity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98997/1/jcpe12123.pd

Tristetraprolin Regulates Interleukin-6 Expression Through p38 MAPK-Dependent Affinity Changes with mRNA 3' Untranslated Region

Tristetraprolin (TTP) is a well-characterized, zinc finger-containing, RNA-binding protein. TTP targets tumor necrosis factor alpha for degradation via the 3- untranslated region (3-UTR). Although AU-rich elements (AREs) in the 3-UTR of interleukin-6 (IL-6) mRNA dictate mRNA degradation, the role of TTP in the post-transcriptional regulation of IL-6 gene expression is unclear. Here we used TTP-deficient mice to test the hypothesis that IL-6 expression is influenced by TTP. Genetic and siRNA-mediated knockdown of TTP resulted in increased IL-6 production and overexpression of TTP had the reverse effect. IL-6 and tumor necrosis factor alpha production were elevated after injection of IL-1- in TTP-deficient mice. Further, embryonic fibroblasts from these mice (mouse embryonic fibroblasts) exhibited greater IL-6 mRNA expression and longer half-life than wild-type mouse embryonic fibroblasts. Overexpression of TTP reduced IL-6 3-UTR luciferase reporter activity in an ARE-dependent manner. Proximal and distal regions of the 3-UTR acted synergistically to produce the full repression of TTP. Mutation-based luciferase assays show that ARE2, ARE3, and ARE4 are required for TTP-mediated repression. The constitutively activated p38-MK2 pathway abrogated TTP-mediated repression of IL-6 3-UTR reporter activity. RNA immunoprecipitation assay indicated that the deficiency of p38alpha resulted in the increased affinity of TTP to IL-6 mRNA. Taken together, we propose that TTP downregulates IL-6 gene expression at the post-transcriptional level by targeting ARE elements in the 3-UTR region.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90500/1/jir-2E2010-2E0154.pd

ProPane: Image Warping with Fire

In this paper we introduce the software package ProPane, written for the R data analysis language. ProPane combines the full range of wcslib projections with the C++ image manipulation routines provided by the CImg library. ProPane offers routines for image warping and combining (including stacking), and various related tasks such as image alignment tweaking and pixel masking. It can stack an effectively unlimited number of target frames using multiple parallel cores, and offers threading for many lower level routines. It has been used for a number of current and upcoming large surveys, and we present a range of its capabilities and features. ProPane is already available under a permissive open-source LGPL-3 license at github.com/asgr/ProPane (DOI: 10.5281/zenodo.10057053).Comment: 19 pages, 17 figures, 5 tables, accepted to MNRA

Bisphosphonates Inhibit Expression of p63 by Oral Keratinocytes

Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of amino-bisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated controlindividuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonate-treated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8 ± 1.1% and 31.9 ± 5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone

Association of Race and Ethnicity With COVID‐19 Outcomes in Rheumatic Disease: Data From the COVID‐19 Global Rheumatology Alliance Physician Registry

OBJECTIVE: Racial/ethnic minorities experience more severe outcomes of COVID-19 in the general United States (US) population. The aim of this study was to examine the association between race/ethnicity and COVID-19 hospitalization, ventilation status, and mortality in people with rheumatic disease. METHODS: US patients with rheumatic disease and COVID-19 entered into the COVID-19 Global Rheumatology Alliance physician registry March 24 - August 26, 2020 were included. Race/ethnicity was defined as white, Black, Latinx, Asian and other/mixed race. Outcomes included hospitalization, requirement for ventilatory support, and death. Multivariable regression models were used to estimate odds ratios (OR) and 95% confidence intervals controlling for age, sex, smoking, rheumatic disease diagnosis, comorbidities, medications taken prior to infection, and rheumatic disease activity. RESULTS: A total of 1,324 patients were included, of whom 36% were hospitalized and 6% died; 26% of hospitalized patients required mechanical ventilation. In multivariable models, Black (OR=2.74, 95% CI 1.90, 3.95), Latinx (OR=1.71, 95% CI 1.18, 2.49), and Asian (OR=2.69, 95% CI 1.16, 6.24) patients had higher odds of being hospitalized compared to white patients. Latinx patients also had three-fold increased odds of requiring ventilatory support (OR=3.25, 95% CI 1.75, 6.05). No differences in mortality based on race/ethnicity were found, though power may have been limited to detect associations. CONCLUSION: Similar to findings in the general US population, racial/ethnic minorities with rheumatic disease and COVID-19 had increased odds of hospitalization and ventilatory support. These results illustrate significant health disparities related to COVID-19 in people with rheumatic diseases. The rheumatology community should proactively address the needs of patients currently experiencing inequitable health outcomes during the pandemic

What should be done with antisocial personality disorder in the new edition of the diagnostic and statistical manual of mental disorders (DSM-V)?

Antisocial personality disorder, psychopathy, dissocial personality disorder and sociopathy are constructs that have generally been used to predict recidivism and dangerousness, alongside being used to exclude patients from treatment services. However, 'antisocial personality disorder' has recently begun to emerge as a treatment diagnosis, a development reflected within cognitive behaviour therapy and mentalisation-based psychotherapy. Many of the behaviour characteristics of antisocial personality disorder are, at the same time, being targeted by interventions at criminal justice settings. A significantly higher proportion of published articles focusing on antisocial personality concern treatment when compared to articles on psychopathy. Currently, the proposal for antisocial personality disorder for the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, suggests a major change in the criteria for this disorder. While the present definition focuses mainly on observable behaviours, the proposed revision stresses interpersonal and emotional aspects of the disorder drawing on the concept of psychopathy. The present commentary suggests that developments leading to improvement in the diagnosis of this type of disorder should, rather than focusing exclusively on elements such as dangerousness and risk assessment, point us to ways in which patients can be treated for their problems

Deep Extragalactic Visible Legacy Survey (DEVILS): evolution of the σSFR –M relation and implications for self-regulated star formation

We present the evolution of the star formation dispersion–stellar mass relation ( σSFR –M ) in the DEVILS D10 region using new measurements derived using the PROSPECT spectral energy distribution fitting code. We find that σSFR –M shows the characteristic ‘U-shape’ at intermediate stellar masses from 0.1 < z < 0.7 for a number of metrics, including using the deconvolved intrinsic dispersion. A physical interpretation of this relation is the combination of stochastic star formation and stellar feedback causing large scatter at low stellar masses and AGN feedback causing asymmetric scatter at high stellar masses. As such, the shape of this distribution and its evolution encodes detailed information about the astrophysical processes affecting star formation, feedback and the lifecycle of galaxies. We find that the stellar mass that the minimum σSFR occurs evolves linearly with redshift, moving to higher stellar masses with increasing lookback time and traces the turno v er in the star-forming sequence. This minimum σSFR point is also found to occur at a fixed specific star formation rate (sSFR) at all epochs (sSFR ∼10 −9.6 Gyr −1 ). The physical interpretation of this is that there exists a maximum sSFR at which galaxies can internally self-regulate on the tight sequence of star formation. At higher sSFRs, stochastic stellar processes begin to cause galaxies to be pushed both above and below the star-forming sequence leading to increased SFR dispersion. As the Universe evolves, a higher fraction of galaxies will drop below this sSFR threshold, causing the dispersion of the low stellar mass end of the star-forming sequence to decrease with time

Spectroscopy of the Supernova H0pe Host Galaxy at Redshift 1.78

Supernova (SN) H0pe was discovered as a new transient in James Webb Space Telescope (JWST) NIRCam images of the galaxy cluster PLCK G165.7+67.0 taken as part of the "Prime Extragalactic Areas for Reionization and Lensing Science" (PEARLS) JWST GTO program (# 1176) on 2023 March 30 (AstroNote 2023-96; Frye et al. 2023). The transient is a compact source associated with a background galaxy that is stretched and triply-imaged by the cluster's strong gravitational lensing. This paper reports spectra in the 950-1370 nm observer frame of two of the galaxy's images obtained with Large Binocular Telescope (LBT) Utility Camera in the Infrared (LUCI) in longslit mode two weeks after the \JWST\ observations. The individual average spectra show the [OII] doublet and the Balmer and 4000 Angstrom breaks at redshift z=1.783+/-0.002. The CIGALE best-fit model of the spectral energy distribution indicates that SN H0pe's host galaxy is massive (Mstar~6x10^10 Msun after correcting for a magnification factor ~7) with a predominant intermediate age (~2 Gyr) stellar population, moderate extinction, and a magnification-corrected star formation rate ~13 Msun/yr, consistent with being below the main sequence of star formation. These properties suggest that H0pe might be a type Ia SN. Additional observations of SN H0pe and its host recently carried out with JWST (JWST-DD-4446; PI: B. Frye) will be able to both determine the SN classification and confirm its association with the galaxy analyzed in this work.Comment: 6 pages, 4 figures, Letter accepted for publication in Astronomy & Astrophysic

Stromal‐Derived Factor‐1α (CXCL12) Levels Increase in Periodontal Disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142300/1/jper0845.pd

Association between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death among Patients with Immune-Mediated Inflammatory Disease and COVID-19

Importance: Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective: To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants: This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures: Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures: The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results: A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P =.006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P =.001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P &lt;.001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P =.004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P =.33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. Conclusions and Relevance: In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs