Temporal coordination of the transcription factor response to H2O2 stress.

Oxidative stress from excess H2O2 activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H2O2, it is unclear whether they are activated at the same H2O2 concentration, or time. Dose-dependent activation is likely as oxidative stress is not a singular state and exhibits dose-dependent outcomes including cell-cycle arrest and cell death. Here, we show that transcription factor activation is both dose-dependent and coordinated over time. Low levels of H2O2 activate p53, NRF2 and JUN. Yet under high H2O2, these transcription factors are repressed, and FOXO1, NF-κB, and NFAT1 are activated. Time-lapse imaging revealed that the order in which these two groups of transcription factors are activated depends on whether H2O2 is administered acutely by bolus addition, or continuously through the glucose oxidase enzyme. Finally, we provide evidence that 2-Cys peroxiredoxins control which group of transcription factors are activated.

Soft Tissue Management Around the Dental Implant: A Comprehensive Review.

In the modern world, there is an increasing concern among people regarding dental esthetics. Edentulism can impact one's appearance, affect the regular bite, and can even affect mental well-being. There are various options to replace the missing teeth, such as removable dentures, fixed crown and bridge prostheses, and resin-retained bridges. Various factors are evaluated before giving a suitable prosthesis for missing teeth. Implant installation is highly desired by patients as it has a high success and long-term survival rate when used to replace lost teeth. However, several difficulties relating to errors in treatment planning, surgery, soft tissue, and hard tissue care, and infections may compromise the efficacy of implant therapy. An increasing body of research indicates that long-term clinical stability and esthetics may be significantly impacted by the stability of the soft tissues around osseointegrated dental implants. Consequently, when implant therapy is planned, the dental surgeon has to have the necessary expertise to appropriately handle any possible causes of difficulties in addition to being able to carry out the necessary actions to maintain or develop stable soft tissue. Various augmentation procedures can be done for the correction of any deformity or inadequacy of soft tissues. Osseointegration is a fundamental part of the success of the implant treatment. It is the formation of a biological and functional connection between the bone and the implant increasing the stability of implant prosthesis. After the treatment, the patient should be counseled for regular and proper oral hygiene practices suitable for the implant. A proper follow-up has to be done after implant treatment in regular intervals. Any postoperative soft tissue complications, such as peri-implantitis or peri-implant mucositis, should be addressed immediately, and appropriate treatment has to be given. This article reviews about the procedures before and after the implant placement to prevent or treat soft tissue complications, ultimately leading to the success of the implant.

Temporal Coordination of the Transcription Factor Response to H2O2 stress.

Oxidative stress from excess H2O2 activates transcription factors (TFs) that restore redox balance and repair oxidative damage. Though many TFs are activated by H2O2, it is unknown whether they are activated at the same H2O2 concentration or time after H2O2 stress. We found TF activation is tightly coordinated over time and dose dependent. We first focused on p53 and FOXO1 and found that in response to low H2O2, p53 is activated rapidly while FOXO1 remains inactive. In contrast, cells respond to high H2O2 in two temporal phases. In the first phase FOXO1 rapidly shuttles to the nucleus while p53 remains inactive. In the second phase FOXO1 shuts off and p53 levels rise. Other TFs are activated in the first phase with FOXO1 (NF-κB, NFAT1), or the second phase with p53 (NRF2, JUN), but not both. The two phases result in large differences in gene expression. Finally, we provide evidence that 2-Cys peroxiredoxins control which TF are activated and the timing of TF activation.

Temporal Coordination of the Transcription Factor Response to H2O2 stress.

The p53 and FOXO transcription factors (TFs) share many similarities despite their distinct evolutionary origins. Both TFs are activated by a variety of cellular stresses and upregulate genes in similar pathways including cell-cycle arrest and apoptosis. Oxidative stress from excess H2O2 activates both FOXO1 and p53, yet whether they are activated at the same time is unclear. Here we found that cells respond to high H2O2 levels in two temporal phases. In the first phase FOXO1 rapidly shuttles to the nucleus while p53 levels remain low. In the second phase FOXO1 exits the nucleus and p53 levels rise. We found that other oxidative stress induced TFs are activated in the first phase with FOXO1 (NF-κB, NFAT1), or the second phase with p53 (NRF2, JUN) but not both following H2O2 stress. The two TF phases result in large differences in gene expression patterns. Finally, we provide evidence that 2-Cys peroxiredoxins control the timing of the TF phases in response to H2O2.

FOXO nuclear shuttling dynamics are stimulus-dependent and correspond with cell fate.

FOXO transcription factors are regulators of cellular homeostasis linked to increased lifespan and tumor suppression. FOXOs are activated by diverse cell stresses including serum starvation and oxidative stress. FOXO activity is regulated through posttranslational modifications that control shuttling of FOXO proteins to the nucleus. In the nucleus, FOXOs up-regulate genes in multiple, often conflicting pathways, including cell-cycle arrest and apoptosis. How cells control FOXO activity to ensure the proper response for a given stress is an open question. Using quantitative immunofluorescence and live-cell imaging, we found that the dynamics of FOXO nuclear shuttling is stimulus-dependent and corresponds with cell fate. H2O2 treatment leads to an all-or-none response where some cells show no nuclear FOXO accumulation, while other cells show a strong nuclear FOXO signal. The time that FOXO remains in the nucleus increases with the dose and is linked with cell death. In contrast, serum starvation causes low-amplitude pulses of nuclear FOXO and predominantly results in cell-cycle arrest. The accumulation of FOXO in the nucleus is linked with low AKT activity for both H2O2 and serum starvation. Our findings suggest the dynamics of FOXO nuclear shuttling is one way in which the FOXO pathway dictates different cellular outcomes.

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease.

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Novel mechanisms of Collagenase Santyl Ointment (CSO) in wound macrophage polarization and resolution of wound inflammation.

Collagenases are useful in enzymatic wound debridement. Clostridial collagenase, marketed as Collagenase Santyl Ointment (CSO), is FDA approved for such use. Building on the scientific premise that collagenases as well as collagen degradation products may regulate immune cell function, we sought to investigate the potential role of CSO in wound inflammation. We tested the hypothesis that in addition to enacting debridement, CSO contributes to the resolution of persistent wound inflammation. Wound macrophages were isolated from PVA sponges loaded with CSO or petrolatum and implanted in mice. Significant increase in pro-reparative and decrease in pro-inflammatory polarization was noted in macrophages of acute as well as diabetic wounds. Wound macrophages from CSO-treated group displayed increased production of anti-inflammatory cytokines IL-10 and TGF-ß, and decreased levels of pro-inflammatory cytokines TNF-α and IL-1ß. The active ingredient of CSO, CS-API, induced the expression of mϕheal /M(IL-4) polarization markers ex vivo. CS-API treatment attenuated transactivation of NF-κB and significantly induced STAT6 phosphorylation. A significant role of a novel PGE2-EP4 pathway in CS-API induced STAT6 activation and the mϕheal /M(IL-4) polarization was identified. Taken together, findings of this work reposition CSO as a potential agent that may be effective in resolving wound inflammation, including diabetic wounds.

Significant association of close homologue of L1 gene polymorphism rs2272522 with schizophrenia in Qatar.

INTRODUCTION: Previous reports have found that polymorphisms in the close homologue of L1 (CHL1) gene located on chromosome 3p26 are associated with schizophrenia among different ethnic populations. The aim of this study was to examine the associations of single nucleotides polymorphisms (SNPs) of the CHL1 gene locus, including rs2055314 (C/T), rs2272522 (C/T) and rs331894 (A/G), with schizophrenia in the Qatari population. METHODS: An association case control study was carried out on 86 Qatari schizophrenic patients from the Psychiatry Hospital, Hammed Medical Corporation, Qatar and 88 Qatari unrelated, healthy, control subjects. Schizophrenia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) criteria for schizophrenia by two independent psychiatrists. Genotyping of the SNPs rs2055314 (C/T), rs2272522 (C/T) and rs331894 (A/G) was conducted using the 5' nuclease assay with the TaqMan MGB probe and an ABI 7500. RESULTS: Individuals with the rs2272522 TT genotype had approximately 4.2 times greater risk of schizophrenia compared to individuals with the CC genotype (OR = 4.21; 95% CI: 1.12-15.53; P = 0.047). In addition, individuals carrying a T allele of the rs2272522 SNP had a significantly increased risk of schizophrenia (1.78 times) among the population (P = 0.028). SNPs rs2055314 and rs331894 had no significant association with schizophrenia. Pairwise linkage disequilibrium (LD) between the three polymorphisms was modest in the schizophrenic group. DISCUSSION: The rs2272522 polymorphism was found to exhibit a highly significant association with schizophrenia in the Qatari population. This finding supports the hypothesis that cell adhesion molecules may be involved in the etiology of this disease among Qatari patients.