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Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.

A protocol outlining a scoping review focusing on the extent of literature surrounding naturalistic decision-making in nursing practice.

IntroductionAutoinflammatory diseases are characterized by dysregulation of innate immune system leading to spontaneous sterile inflammation. One of the well-established animal models of this group of disorders is the mouse strain Pstpip2cmo. In this strain, the loss of adaptor protein PSTPIP2 leads to the autoinflammatory disease chronic multifocal osteomyelitis. It is manifested by sterile inflammation of the bones and surrounding soft tissues of the hind limbs and tail. The disease development is propelled by elevated production of IL-1β and reactive oxygen species by neutrophil granulocytes. However, the molecular mechanisms linking PSTPIP2 and these pathways have not been established. Candidate proteins potentially involved in these mechanisms include PSTPIP2 binding partners, PEST family phosphatases (PEST-PTPs) and phosphoinositide phosphatase SHIP1.MethodsTo address the role of these proteins in PSTPIP2-mediated control of inflammation, we have generated mouse strains in which PEST-PTP or SHIP1 binding sites in PSTPIP2 have been disrupted. In these mouse strains, we followed disease symptoms and various inflammation markers.ResultsOur data show that mutation of the PEST-PTP binding site causes symptomatic disease, whereas mice lacking the SHIP1 interaction site remain asymptomatic. Importantly, both binding partners of PSTPIP2 contribute equally to the control of IL-1β production, while PEST-PTPs have a dominant role in the regulation of reactive oxygen species. In addition, the interaction of PEST-PTPs with PSTPIP2 regulates the production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues.ConclusionsWe demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β pathway. In addition, PEST-PTPs have unique roles in the control of reactive oxygen species and chemokine production, which in the absence of PEST-PTP binding to PSTPIP2 shift the balance towards symptomatic disease.

Objective: This scoping review aims to systematically identify the types, characteristics, and possible pathophysiologic etiologies of the oral ulcers that emerge in COVID-19 patients. Introduction: The oral cavity is a vulnerable niche for the most diverse microbial ecosystem in the human body; therefore, it presents a wide array of mucocutaneous complications that could indicate various acute and chronic conditions. The COVID-19-related oral conditions, including oral ulcers, had been widely debated as direct manifestations or indirect complications of the SARS-CoV-2 infection. According to a preliminary search of PROSPERO, MEDLINE, the Cochrane Database of Systematic Reviews and the JBI Evidence Synthesis, there is no published nor registered scoping review concerned with the oral ulcers of COVID-19 patients. Inclusion criteria: The review will include studies included COVID-19 patients whose infection had been confirmed by RT-PCR testing regardless of infection severity and clinical course. Only the studies that reported COVID-19 patients with oral ulcers. Methods: A three-phase search strategy will be carried out: an initial limited search, a full electronic search, and hand search using the reference lists of all included records. The main bibliographic databases of published literature will include MEDLINE (PubMed), Cochrane COVID-19 Study Register, EMBASE via Ovid, and Scopus. All identified records will be managed using EndNote 9.2, and the titles and abstracts will be screened against the inclusion criteria before the full text of all potentially relevant studies will be examined. The data will be presented in tabular form, rating maps, and narrative summary.

Subclinical changes in response to different types and generations of toothbrushes represent a challenging knowledge gap in the context of self-administered oral hygiene regimes. The aim of this project is to evaluate the current evidence regarding the microbiological changes and how they correlate with empirical findings namely the clinical parameters.

Subclinical changes in response to different types and generations of toothbrushes represent a challenging knowledge gap in the context of self-administered oral hygiene regimes. The aim of this project is to evaluate the current evidence regarding the microbiological changes and how they correlate with empirical findings namely the clinical parameters.

Background: ACE inhibitors (ACEi) have been reported cardioprotective in a secondary prevention of anthracycline (ANT) cardiotoxicity in high-risk patients. However, it remains to be determined whether they can also prevent the onset of ANT-induced cardiac damage and provide long-lasting cardioprotection in primary settings similarly as approved drug dexrazoxane (DEX). Objectives: The aim of this study was to assess whether ACEis can prevent TOP2B-mediated DNA damage induced by ANTs in the heart as a very upstream event, and thus provide long-lasting cardioprotection against chronic ANT cardiotoxicity. Methods: Chronic cardiotoxicity was induced in rabbits by daunorubicin (DAU, 3 mg/kg weekly for 10 weeks). Perindopril (PER) in two clinically relevant doses (0.05 and 0.1 mg/kg/day) was administered before and throughout the chronic DAU treatment. The cardioprotection was evaluated at the end of treatment period and after 3- and 10-week drug-free post-treatment follow-up (FU). TOP2B-depedent DNA damage signaling in the heart was determined 6 h after single dose of DAU, while TOPB interaction was studied in vitro ; the results were compared to DEX. Results: A week after completion of the chronic DAU administration, PER-co-treatment completely overcame or markedly reduced DAU-induced mortality, blood congestion and systolic dysfunction (LVFS 41.5% vs. 34.3% in the DAU group, pin vitro and did not prevent DAU-induced acute p53-mediated DNA damage signaling in the heart. Conclusions: Unlike approved drug DEX, the ACEi treatment provided only temporary control of ANT cardiotoxicity development which may be associated with the lack of the effects on ANT-induced and TOP2B-mediated DNA damage response in the heart.

Recognition of single-stranded RNA (ssRNA) by RNA recognition motif (RRM) domains is an important class of protein-RNA interactions. Many such complexes were characterized using NMR and/or X-ray crystallography techniques, revealing ensemble-averaged pictures of the bound states. However, it is becoming widely accepted that better understanding of protein-RNA interactions would be obtained from ensemble descriptions. Indeed, earlier molecular dynamics (MD) simulations of bound states indicated visible dynamics at the RNA-RRM interfaces. Here, we report the first atomistic simulation study of spontaneous binding of short RNA sequences to RRM domains of HuR and SRSF1 proteins. Using millisecond-scale aggregate ensemble of unbiased simulations we were able to observe a few dozens of binding events. The HuR RRM3 utilizes a pre-binding state to navigate the RNA sequence to its partially disordered bound state and then to dynamically scan its different binding registers. The SRFS1 RRM2 binding is more straightforward but still multiple-pathway. The present study necessitated development of a goal-specific force-field modification scaling down the intramolecular vdW interactions of the RNA which also improves description of the RNA-RRM bound state. Our study opens a new avenue for large-scale atomistic investigations of binding landscapes of protein-RNA complexes and future perspectives of such research are discussed.

The TP63 gene encodes two major protein variants; TAp63 contains a p53-like transcription domain and consequently has tumor suppressor activities whereas ΔNp63 lacks this domain and acts as an oncogene. The two variants show distinct expression patterns in normal tissues and tumors, with lymphocytes and lymphomas/leukemias expressing TAp63, and basal epithelial cells and some carcinomas expressing high levels of ΔNp63, most notably squamous cell carcinomas (SCC). Whilst the transcriptional functions of TAp63 and ΔNp63 isoforms are known, the mechanisms involved in their regulation are poorly understood. Using squamous epithelial cells that contain high levels of ΔNp63 and low/undetectable TAp63, the DNA demethylating agent decitabine (5-aza-2’-deoxycytidine, 5-dAza) caused a dose-dependent increase in TAp63, with a simultaneous reduction in ΔNp63, indicating DNA methylation-dependent regulation at the isoform-specific promoters. The basal cytokeratin KRT5, a direct ΔNp63 transcriptional target, was also reduced, confirming functional alteration of p63 activity after DNA demethylation. We also showed high level methylation of three CpG sites in the TAP63 promoter in these cells, which was reduced by decitabine. DNMT1 depletion using inducible shRNAs partially replicated these effects, including an increase in the ratio of TAP63:ΔNP63 mRNAs, a reduction in ΔNp63 protein and reduced KRT5 mRNA levels. Finally, high DNA methylation levels were found at the TAP63 promoter in clinical SCC samples and matched normal tissues. We conclude that DNA methylation at the TAP63 promoter normally silences transcription in squamous epithelial cells, indicating DNA methylation as a therapeutic approach to induce this tumor suppressor in cancer. That decitabine simultaneously reduced the oncogenic activity of ΔNp63 provides a “double whammy” for SCC and other p63-positive carcinomas. Whilst a variety of mechanisms may be involved in producing the opposite effects of DNA demethylation on TAp63 and ΔNp63, we propose an “either or” mechanism in which TAP63 transcription physically interferes with the ability to initiate transcription from the downstream ΔNP63 promoter on the same DNA strand. This mechanism can explain the observed inverse expression of p63 isoforms in normal cells and cancer.

The current study is a secondary analysis using collected data from a randomised controlled trial - Supporting Parents and Kids Through Lockdown Experiences (SPARKLE; Kostyrka-Allchorne et al., 2021). This study aims to conduct exploratory non-hypotheses driven analyses to assess whether the effects of a digital parenting intervention (Parent Positive) on child conduct and emotional difficulties are predicted and/or moderated by baseline characteristics.

PERUN/Reanalysis (PERRea) is a product based on the ALADIN system, which shares its model code with the global NWP systems ARPEGE/IFS. It is the first step towards the regional climate simulations within the CMIP6 framework. PERRea is being calculated for the period 1989–2019 on the domain covering Central Europe and its surroundings, with the horizontal mesh size 2.3km and 87 vertical levels. It provides not only the consistent 3D information about regional weather and climate on hourly footing, but its verification against the measurements and the driving ERA5 reanalysis quantifies accuracy of underlying ALADIN configuration, intended for simulations of future climate.In order to guarantee reliable operation at convection permitting scales, PERRea employs ALADIN non-hydrostatic dynamical kernel combined with the so-called ALARO-1 physics. Its main highlights are: 1) self-switching-off convection parameterization with microphysical calculations sandwiched between updraft and downdraft computation, seeing joint output from subgrid and resolved condensation, 2) turbulence scheme incorporating the moist effects and using two prognostic energies, and 3) broadband radiation scheme enabling full cloud-radiation interaction. As for data assimilation component, PERRea analyses the soil properties using the optimal interpolation of SYNOP screen level temperature and humidity measurements. The upper air analysis combines the large scales from driving ERA5 reanalysis with the small scales from the previous high-resolution short range forecast. Their optimal combination is ensured via digital filter blending technique.In this contribution, comparison of the PERRea with different reference datasets is presented for the period 1990–1999 over the full domain. Daily, monthly and seasonal precipitation, 2m temperature, 10m wind speed and surface solar radiation were selected for the comparison. Validation sets include ERA5 (the driving reanalysis of PERRea), station data from ECA&D dataset and E-OBS v23.0 (gridded station data over Europe) in 0.1° resolution.The preliminary results show generally good agreement between PERRea and the two reference datasets, ERA5 and E-OBS. A weak systematic overestimation of precipitation in PERRea in selected regions with respect to ERA5 may indicate a difficulties in simulation of dry spells. The comparison of 2m temperature in PERRea against E-OBS shows insufficient diurnal amplitude especially in summer; whilst maximum daily temperature is underestimated in Central Europe, the minimum temperature is overestimated by more than 3 °C.This research is supported by the Technology Agency of the Czech Republic Czech Technology Agency, under the SS02030040 project.

BackgroundIntravenous paracetamol added to morphine reduces postoperative morphine consumption in (near)term neonates. However, there are only sparse data on intravenous paracetamol as multimodal strategy in extremely low birth weight (ELBW) neonates.ObjectivesThis study aims to assess the effects of rescue intravenous paracetamol on postoperative pain management (≤48 h postoperatively) in relation to both analgesic efficacy (validated pain assessment, drug consumption, adequate rescue medication) and safety (hypotension and bradycardia). This rescue practice was part of a standardized pain management approach in a single neonatal intensive care unit (NICU).MethodsA single-center retrospective observational study included 20 ELBW neonates, who underwent major abdominal surgery. The primary endpoints of the postoperative study period were pain intensity, over-sedation, time to first rescue analgesic dose, and the effect of paracetamol on opiate consumption. Secondary endpoints were safety parameters (hypotension, bradycardia). And as tertiary endpoints, the determinants of long-term outcome were evaluated (i.e., duration of mechanical ventilation, intraventricular hemorrhage - IVH, periventricular leukomalacia - PVL, postnatal growth restriction, stage of chronic lung disease – CLD or neurodevelopmental outcome according to Bayley-II Scales of Infant Development at 18–24 months).ResultsAll neonates received continuous opioids (sufentanil or morphine) and 13/20 also intravenous paracetamol as rescue pain medication during a 48-h postoperative period. Although opioid consumption was equal in the non-paracetamol and the paracetamol group over 48 h, the non-paracetamol group was characterized by oversedation (COMFORTneo < 9), a higher incidence of severe hypotension, and younger postnatal age (p < 0.05). All long-term outcome findings were similar between both groups.ConclusionsOur study focused on postoperative pain management in ELBW neonates, and showed that intravenous paracetamol seems to be safe. Prospective validation of dosage regimens of analgesic drugs is needed to achieve efficacy goals.