Immunomodulatory soluble HLA-G and HLA-E are associated with rapidly deteriorating CLAD and HCMV viremia after lung transplantation.

Plasma-soluble (s)HLA-G and sHLA-E are immunoregulatory proteins that balance the activation of NKG2A+ immune cells. In lung-transplant recipients (LTRs), dysregulated NKG2A+ natural killer cell responses may result in high-level human cytomegalovirus (HCMV) replication as well as chronic lung allograft dysfunction (CLAD), and especially the development of rapidly deteriorating CLAD is associated with high mortality. We thus analyzed the kinetics and function of sHLA-G and sHLA-E in follow-up samples of N = 76 LTRs to evaluate whether these immunoregulatory proteins are associated with the risk for CLAD and high-level HCMV replication. Here, we demonstrate that rapidly deteriorating CLAD LTRs are hallmarked by continually low (<107 ng/ml) sHLA-G levels. In contrast, high sHLA-E levels were associated with the following development of high-level (>1,000 copies/ml) HCMV episodes. Thus, sHLA-G and sHLA-E may serve as novel biomarkers for the development of rapidly deteriorating CLAD and high-level HCMV replication in LTRs.

Melatonin use in infants and toddlers.

Background Melatonin use in the pediatric population is on the rise in the United States, where it is available as an over-the-counter and online supplement. There are no data regarding the safety and efficacy of melatonin in children less than 2 years old. The aim of this study was to examine various aspects of melatonin use by caregivers of infants and toddlers in the US. Methods Caregiver users of the Nanit baby monitoring system with a child aged 0-36 months were invited to complete an online survey regarding melatonin use, sources of information/recommendations about melatonin, formulations used and reasons for administering melatonin to their child. Participants also completed the Brief Infant Sleep Questionnaire-Revised (BISQ-R). Results A total of 3063 caregivers (1.93%) responded to the survey, of whom 1.7% had ever used melatonin for their child. About half of those caregivers had received a recommendation for melatonin from a source other than a healthcare professional. Caregiver perception of 'sleep as a problem' as assessed by the BISQ-R was not significantly different between those who had or had not used melatonin for their child, and reasons for use included non-supported indications such as sleeping later or promoting "more restful and better sleep". Conclusions The results of this study support mounting concerns regarding the widespread use of melatonin in the US pediatric population, especially given the lack of regulatory oversight and the documented inaccuracy of label claims versus actual melatonin content.

Comparison of clinical outcomes in hospitalized patients with COVID-19 or non-COVID-19 community-acquired pneumonia in a prospective observational cohort study.

PURPOSE: Coronavirus disease 2019 (COVID-19) and non-COVID-19 community-acquired pneumonia (NC-CAP) often result in hospitalization with considerable risks of mortality, ICU treatment, and long-term morbidity. A comparative analysis of clinical outcomes in COVID-19 CAP (C-CAP) and NC-CAP may improve clinical management. METHODS: Using prospectively collected CAPNETZ study data (January 2017 to June 2021, 35 study centers), we conducted a comprehensive analysis of clinical outcomes including in-hospital death, ICU treatment, length of hospital stay (LOHS), 180-day survival, and post-discharge re-hospitalization rate. Logistic regression models were used to examine group differences between C-CAP and NC-CAP patients and associations with patient demography, recruitment period, comorbidity, and treatment. RESULTS: Among 1368 patients (C-CAP: n = 344; NC-CAP: n = 1024), C-CAP showed elevated adjusted probabilities for in-hospital death (aOR 4.48 [95% CI 2.38-8.53]) and ICU treatment (aOR 8.08 [95% CI 5.31-12.52]) compared to NC-CAP. C-CAP patients were at increased risk of LOHS over seven days (aOR 1.88 [95% CI 1.47-2.42]). Although ICU patients had similar in-hospital mortality risk, C-CAP was associated with length of ICU stay over seven days (aOR 3.59 [95% CI 1.65-8.38]). Recruitment period influenced outcomes in C-CAP but not in NC-CAP. During follow-up, C-CAP was linked to a reduced risk of re-hospitalization and mortality post-discharge (aOR 0.43 [95% CI 0.27-0.70]). CONCLUSION: Distinct clinical trajectories of C-CAP and NC-CAP underscore the need for adapted management to avoid acute and long-term morbidity and mortality amid the evolving landscape of CAP pathogens.

Children extract a new linguistic rule more quickly than adults.

Children achieve better long-term language outcomes than adults. However, it remains unclear whether children actually learn language more quickly than adults during real-time exposure to input-indicative of true superior language learning abilities-or whether this advantage stems from other factors. To examine this issue, we compared the rate at which children (8-10 years) and adults extracted a novel, hidden linguistic rule, in which novel articles probabilistically predicted the animacy of associated nouns (e.g., "gi lion"). Participants categorized these two-word phrases according to a second, explicitly instructed rule over two sessions, separated by an overnight delay. Both children and adults successfully learned the hidden animacy rule through mere exposure to the phrases, showing slower response times and decreased accuracy to occasional phrases that violated the rule. Critically, sensitivity to the hidden rule emerged much more quickly in children than adults; children showed a processing cost for violation trials from very early on in learning, whereas adults did not show reliable sensitivity to the rule until the second session. Children also showed superior generalization of the hidden animacy rule when asked to classify nonword trials (e.g., "gi badupi") according to the hidden animacy rule. Children and adults showed similar retention of the hidden rule over the delay period. These results provide insight into the nature of the critical period for language, suggesting that children have a true advantage over adults in the rate of implicit language learning. Relative to adults, children more rapidly extract hidden linguistic structures during real-time language exposure. RESEARCH HIGHLIGHTS: Children and adults both succeeded in implicitly learning a novel, uninstructed linguistic rule, based solely on exposure to input. Children learned the novel linguistic rules much more quickly than adults. Children showed better generalization performance than adults when asked to apply the novel rule to nonsense words without semantic content. Results provide insight into the nature of critical period effects in language, indicating that children have an advantage over adults in real-time language learning.

Real-time teaching and learning: Caregivers teaching infants to descend stairs.

Learning to descend stairs requires motor and cognitive capacities on the part of infants and opportunities for practice and assurance of safety offered by caregivers. The American Academy of Pediatrics prescribes the age strategy to teach toddlers to safely descend stairs but without much consideration for individual differences in infants' skills or caregivers' techniques. The purpose of this study was to observe the natural ways in which caregivers teach infants to descend stairs at home and the extent to which infants abide. Of particular interest was to examine the dynamic nature of caregivers' teaching and infants' learning over the session with attention to individual differences. Dyads (N = 59) were videorecorded on Zoom for 10 min interacting on stairs at home in the United States, Brazil, Canada, Italy, and Spain. Infants (n = 30 girls, 29 boys; 13-month-olds ± 1 week) were novice walkers (M = 2.04 months walking experience). Caregivers used a variety of teaching strategies and focused on "backing" and "scooting." Infants were more likely to heed caregivers' guidance when caregivers provided hands-on support and verbal encouragement suggesting infants were engaged and responsive to caregivers' overtures. Infants' walking experience predicted change in descent strategy over the session. Although infants did not show evidence of learning over the session, consistent caregiver instruction suggested caregivers were persistent, if not effective, teachers. Teaching and learning motor skills in a potentially risky task creates a unique opportunity for interaction, allowing infants and caregivers to learn from one another. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Focused attention as a new sitter: How do infants balance it all?

This study investigated the impact of postural control on infants' Focused Attention (FA). Study 1 examined whether and how sitting independently versus with support impacted 6- to 8-month-old infants' ability to focus attention during object exploration. FA measures did not depend on support condition. However, sitting experience was significantly negatively correlated with FA measures in the supported condition, suggesting that infants with more sitting experience performed fewer exploratory movements, possibly due to faster information processing ability compared to infants with less sitting experience. These unexpected findings prompted an exploration of more subtle looking behaviors during FA in Study 2-a case study of three infants who wore a head-mounted eye-tracker during an FA task. The ability to rapidly shift visual attention was key to gathering environmental information useful for problem solving-an interpretation that is supported by prior findings of the relationship between fast looks and faster information processing.

Three decades of infant motor development: Cohort effects in motor skill onsets.

Infant motor development is affected by the sociocultural context in which it takes place. Because societal and cultural practices are dynamic, this exploratory study examined whether the ages at which infants typically learned to crawl, cruise, and walk changed over the past 3 decades. We compiled archival data from 1,306 infants born between January 31, 1992, and December 10, 2021. Parents originally reported milestone onsets in interviews and by using diaries. For each motor milestone, a linear regression model predicted the onset age using birth date. Segmented regression analyses inspected changes in slopes over time. Covariates included rural/urban housing, gestation age, season of birth, and birth weight. Infants' average crawling, cruising, and walking onset ages changed over time. After controlling for the covariates, infants' crawling onset age steadily increased until 2012, after which crawling onset age decreased. Infants' cruising onset age increased from 1991 to 2001, after which cruising onset age remained stable. After controlling for the covariates, infants' walking onset increased until 2015, after which walking onset age decreased. Thus, when infants were born explained a small but significant amount of variability in infant motor skill onset. While the current study showed that motor development changed over the years, motor development is just a model system for development more generally: Cohort effects may be pervasive across developmental domains. Using motor development as a model system for studying change suggests that generational effects due to a changing society may be pervasive across developmental domains. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

Natural killer cell functional genetics and donor-specific antibody-triggered microvascular inflammation.

Antibody-mediated rejection (ABMR) is a leading cause of graft failure. Emerging evidence suggests a significant contribution of natural killer (NK) cells to microvascular inflammation (MVI). We investigated the influence of genetically determined NK cell functionality on ABMR development and activity. The study included 86 kidney transplant recipients subjected to systematic biopsies triggered by donor-specific antibody detection. We performed killer immunoglobulin-like receptor typing to predict missing self and genotyped polymorphisms determining NK cell functionality (FCGR3AV/F158 [rs396991], KLRC2wt/del, KLRK1HNK/LNK [rs1049174], rs9916629-C/T). Fifty patients had ABMR with considerable MVI and elevated NK cell transcripts. Missing self was not related to MVI. Only KLRC2wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] vs 0 [0-1] in KLRC2wt/del recipients; P = .001) and remained significant in a proportional odds multivariable model (odds ratio, 7.84; 95% confidence interval, 2.37-30.47; P = .001). A sum score incorporating all polymorphisms and missing self did not outperform a score including only KLRC2 and FCGR3A variants, which were predictive in univariable analysis. NK cell genetics did not affect graft functional decline and survival. In conclusion, a functional KLRC2 polymorphism emerged as an independent determinant of ABMR activity, without a considerable contribution of missing self and other NK cell gene polymorphisms.

Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the CNS. Epstein-Barr virus (EBV) contributes to the MS pathogenesis because high levels of EBV EBNA386-405-specific antibodies cross react with the CNS-derived GlialCAM370-389. However, it is unclear why only some individuals with such high autoreactive antibody titers develop MS. Here, we show that autoreactive cells are eliminated by distinct immune responses, which are determined by genetic variations of the host, as well as of the infecting EBV and human cytomegalovirus (HCMV). We demonstrate that potent cytotoxic NKG2C+ and NKG2D+ natural killer (NK) cells and distinct EBV-specific T cell responses kill autoreactive GlialCAM370-389-specific cells. Furthermore, immune evasion of these autoreactive cells was induced by EBV-variant-specific upregulation of the immunomodulatory HLA-E. These defined virus and host genetic pre-dispositions are associated with an up to 260-fold increased risk of MS. Our findings thus allow the early identification of patients at risk for MS and suggest additional therapeutic options against MS.

Agreement of Computerized QT and QTc Interval Measurements Between Both Bedside and Expert Nurses Using Electronic Calipers.

BACKGROUND: In hospitalized patients, QT/QTc (heart rate corrected) prolongation on the electrocardiogram (ECG) increases the risk of torsade de pointes. Manual measurements are time-consuming and often inaccurate. Some bedside monitors automatically and continuously measure QT/QTc; however, the agreement between computerized versus nurse-measured values has not been evaluated. OBJECTIVE: The aim of this study was to examine the agreement between computerized QT/QTc and bedside and expert nurses who used electronic calipers. METHODS: This was a prospective observational study in 3 intensive care units. Up to 2 QT/QTc measurements (milliseconds) per patient were collected. Bland-Altman test was used to analyze measurement agreement. RESULTS: A total of 54 QT/QTc measurements from 34 patients admitted to the ICU were included. The mean difference (bias) for QT comparisons was as follows: computerized versus expert nurses, -11.04 ± 4.45 milliseconds (95% confidence interval [CI], -2.3 to -19.8; P = .016), and computerized versus bedside nurses, -13.72 ± 6.70 (95% CI, -0.70 to -26.8; P = .044). The mean bias for QTc comparisons was as follows: computerized versus expert nurses, -12.46 ± 5.80 (95% CI, -1.1 to -23.8; P = .035), and computerized versus bedside nurses, -18.49 ± 7.90 (95% CI, -3.0 to -33.9; P = .022). CONCLUSION: Computerized QT/QTc measurements calculated by bedside monitor software and measurements performed by nurses were in close agreement; statistically significant differences were found, but differences were less than 20 milliseconds (on-half of a small box), indicating no clinical significance. Computerized measurements may be a suitable alternative to nurse-measured QT/QTc. This could reduce inaccuracies and nurse burden while increasing adherence to practice recommendations. Further research comparing computerized QT/QTc from bedside monitoring to standard 12-lead electrocardiogram in a larger sample, including non-ICU patients, is needed.

Ethical and coordinative challenges in setting up a national cohort study during the COVID-19 pandemic in Germany.

With the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), global researchers were confronted with major challenges. The German National Pandemic Cohort Network (NAPKON) was launched in fall 2020 to effectively leverage resources and bundle research activities in the fight against the coronavirus disease 2019 (COVID-19) pandemic. We analyzed the setup phase of NAPKON as an example for multicenter studies in Germany, highlighting challenges and optimization potential in connecting 59 university and nonuniversity study sites. We examined the ethics application process of 121 ethics submissions considering durations, annotations, and outcomes. Study site activation and recruitment processes were investigated and related to the incidence of SARS-CoV-2 infections. For all initial ethics applications, the median time to a positive ethics vote was less than two weeks and 30 of these study sites (65%) joined NAPKON within less than three weeks each. Electronic instead of postal ethics submission (9.5 days (Q1: 5.75, Q3: 17) vs. 14 days (Q1: 11, Q3: 26), p value = 0.01) and adoption of the primary ethics vote significantly accelerated the ethics application process. Each study center enrolled a median of 37 patients during the 14-month observation period, with large differences depending on the health sector. We found a positive correlation between recruitment performance and COVID-19 incidence as well as hospitalization incidence. Our analysis highlighted the challenges and opportunities of the federated system in Germany. Digital ethics application tools, adoption of a primary ethics vote and standardized formal requirements lead to harmonized and thus faster study initiation processes during a pandemic.

Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis.

Efficient access to the morphinan scaffold remains a major challenge in both synthetic chemistry and biotechnology. Here, a biomimetic chemo-enzymatic strategy to synthesize the natural promorphinan intermediate (+)-salutaridine is demonstrated. By combining early-stage organic synthesis with enzymatic asymmetric key step transformations, the prochiral natural intermediate 1,2-dehydroreticuline was prepared and subsequently stereoselectively reduced by the enzyme 1,2-dehydroreticuline reductase obtaining (R)-reticuline in high ee and yield (>99% ee, up to quant. conversion, 92% isol. yield). In the final step, membrane-bound salutaridine synthase was used to perform the selective ortho-para phenol coupling to give (+)-salutaridine. The synthetic route shows the potential of combining early-stage advanced organic chemistry to minimize protecting group techniques with late-stage multi-step biocatalysis to provide an unprecedented access to the medicinally important compound class of promorphinans.

Inhibitory NKG2A+ and absent activating NKG2C+ NK cell responses are associated with the development of EBV+ lymphomas.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, which infects over 90% of the adult human population worldwide. After primary infections, EBV is recurrently reactivating in most adult individuals. It is, however, unclear, why these EBV reactivations progress to EBV+ Hodgkin (EBV+HL) or non-Hodgkin lymphomas (EBV+nHL) only in a minority of EBV-infected individuals. The EBV LMP-1 protein encodes for a highly polymorphic peptide, which upregulates the immunomodulatory HLA-E in EBV-infected cells, thereby stimulating the inhibitory NKG2A-, but also the activating NKG2C-receptor on natural killer (NK) cells. Using a genetic-association approach and functional NK cell analyses, we now investigated, whether these HLA-E-restricted immune responses impact the development of EBV+HL and EBV+nHL. Therefore, we recruited a study cohort of 63 EBV+HL and EBV+nHL patients and 192 controls with confirmed EBV reactivations, but without lymphomas. Here, we demonstrate that in EBV+ lymphoma patients exclusively the high-affine LMP-1 GGDPHLPTL peptide variant-encoding EBV-strains reactivate. In EBV+HL and EBV+nHL patients, the high-expressing HLA-E*0103/0103 genetic variant was significantly overrepresented. Combined, the LMP-1 GGDPHLPTL and HLA-E*0103/0103 variants efficiently inhibited NKG2A+ NK cells, thereby facilitating the in vitro spread of EBV-infected tumor cells. In addition, EBV+HL and EBV+nHL patients, showed impaired pro-inflammatory NKG2C+ NK cell responses, which accelerated the in vitro EBV-infected tumor cells spread. In contrast, the blocking of NKG2A by monoclonal antibodies (Monalizumab) resulted in efficient control of EBV-infected tumor cell growth, especially by NKG2A+NKG2C+ NK cells. Thus, the HLA-E/LMP-1/NKG2A pathway and individual NKG2C+ NK cell responses are associated with the progression toward EBV+ lymphomas.

The impact of extreme summer temperatures in the United Kingdom on infant sleep: Implications for learning and development.

The U.S. Global Change Research Program reports that the frequency and intensity of extreme heat are increasing globally. Studies of the impact of climate change on child health often exclude sleep, despite its importance for healthy growth and development. To address this gap in the literature, we studied the impact of unusually high temperatures in the summer of 2022 on infants' sleep. Sleep was assessed objectively using Nanit camera monitors in infants' homes. Generally, sleep was not impacted when temperatures stayed below 88° but was negatively impacted when temperatures reached over 100°. Compared to non-heatwave nights, infants had less total sleep, less efficient sleep, took longer to fall asleep, had more fragmented sleep, and parents' visits were more frequent during the night. Following peaks in temperature, sleep metrics rebounded to better than average compared to non-peak nights, suggesting that infants compensated for disrupted sleep by sleeping more and with fewer interruptions once the temperature dropped below 85°. Increased instances of disrupted sleep in infancy have important implications for psychological health and development. Climate disruptions such as heat waves that create occasional or ongoing sleep disruptions can leave infants vulnerable and unprepared for learning.

Barriers and enabling factors for workplace integration of internationally qualified nurses: A qualitative study of perceptions of German nurses.

AIM: Examine perceptions of nurses who obtained a recognised nursing qualification in Germany about the integration of internationally qualified nurses (IQN) in the German nursing workforce. DESIGN: Qualitative interview study. METHODS: Semi-structured interviews with 21 state-qualified nurses who had graduated from a German nursing program were conducted either face-to-face or by telephone. Nurses were selected using the purposive sampling method. Additionally, to reach a sufficient sample size, snowball sampling was applied. Each interview was pseudonymized and transcribed. Transcripts were coded according to Qualitative Content Analysis with data structured into themes and sub-themes. The study was reported according to the Consolidated Criteria for Reporting Qualitative Studies (COREQ) checklist for qualitative research. RESULTS: Two main themes including sub-themes were identified: (a) Enabling Factors to Workplace Integration: motivated nursing team, structured orientation program, support by a preceptor, additional practical skills and specific language training and (b) Barriers to Workplace Integration: lack of language proficiency, cultural differences, othering and racism/discrimination. The findings of the study suggest that working in a diverse workplace can be challenging, it is therefore important for successful integration to recognise not only the experiences of IQN but also the perceptions of nurses who work with internationally qualified peers. No patient or public contribution. REGISTRATION NUMBER: The study has been prospectively registered (27 June 2019) at the German Clinical Trial Register (REDACTED).

Rapid, Label-Free Screening of Diverse Biotransformations by Flow-Injection Mass Spectrometry.

Mass spectrometry-based high-throughput screening methods combine the advantages of photometric or fluorometric assays and analytical chromatography, as they are reasonably fast (throughput ≥1 sample/min) and broadly applicable, with no need for labelled substrates or products. However, the established MS-based screening approaches require specialised and expensive hardware, which limits their broad use throughout the research community. We show that a more common instrumental platform, a single-quadrupole HPLC-MS, can be used to rapidly analyse diverse biotransformations by flow-injection mass spectrometry (FIA-MS), that is, by automated infusion of samples to the ESI-MS detector without prior chromatographic separation. Common organic buffers can be employed as internal standard for quantification, and the method provides readily validated activity and selectivity information with an analytical run time of one minute per sample. We report four application examples that cover a broad range of analyte structures and concentrations (0.1-50 mM before dilution) and diverse biocatalyst preparations (crude cell lysates and whole microbial cells). Our results establish FIA-MS as a versatile and reliable alternative to more traditional methods for screening enzymatic reactions.

Steric hindrance, ligand ejection and associated photocytotoxic properties of ruthenium(II) polypyridyl complexes.

Two ruthenium(II) polypyridyl complexes were prepared with the {Ru(phen)2}2+ moiety and a third sterically non-hindering bidentate ligand, namely 2,2'-dipyridylamine (dpa) and N-benzyl-2,2'-dipyridylamine (Bndpa). Hence, complexes [Ru(phen)2(dpa)](PF6)2 (1) and [Ru(phen)2(Bndpa)](PF6)2 (2) were characterized and their photochemical behaviour in solution (acetonitrile and water) was subsequently investigated. Compounds 1 and 2, which do not exhibit notably distorted octahedral coordination environments, contrarily to the homoleptic "parent" compound [Ru(phen)3](PF6)2, experience two-step photoejection of the dpa and Bndpa ligand upon irradiation (1050-430 nm) for several hours. DNA-binding studies revealed that compounds 1 and 2 affect the biomolecule differently upon irradiation; while 2 solely modifies its electrophoretic mobility, complex 1 is also capable of cleaving it. In vitro cytotoxicity studies with two cancer-cell lines, namely A549 (lung adenocarcinoma) and A375 (melanoma), showed that both 1 and 2 are not toxic in the dark, while only 1 is significantly cytotoxic if irradiated, 2 remaining non-toxic under these conditions. Light irradiation of the complex cation [Ru(phen)2(dpa)]2+ leads to the generation of transient Ru species that is present in the solution medium for several hours, and that is significantly cytotoxic, ultimately producing non-toxic free dpa and [Ru(phen)(OH2)2]2+.

MicroRNA-223 Dampens Pulmonary Inflammation during Pneumococcal Pneumonia.

Community-acquired pneumonia remains a major contributor to global communicable disease-mediated mortality. Neutrophils play a leading role in trying to contain bacterial lung infection, but they also drive detrimental pulmonary inflammation, when dysregulated. Here we aimed at understanding the role of microRNA-223 in orchestrating pulmonary inflammation during pneumococcal pneumonia. Serum microRNA-223 was measured in patients with pneumococcal pneumonia and in healthy subjects. Pulmonary inflammation in wild-type and microRNA-223-knockout mice was assessed in terms of disease course, histopathology, cellular recruitment and evaluation of inflammatory protein and gene signatures following pneumococcal infection. Low levels of serum microRNA-223 correlated with increased disease severity in pneumococcal pneumonia patients. Prolonged neutrophilic influx into the lungs and alveolar spaces was detected in pneumococci-infected microRNA-223-knockout mice, possibly accounting for aggravated histopathology and acute lung injury. Expression of microRNA-223 in wild-type mice was induced by pneumococcal infection in a time-dependent manner in whole lungs and lung neutrophils. Single-cell transcriptome analyses of murine lungs revealed a unique profile of antimicrobial and cellular maturation genes that are dysregulated in neutrophils lacking microRNA-223. Taken together, low levels of microRNA-223 in human pneumonia patient serum were associated with increased disease severity, whilst its absence provoked dysregulation of the neutrophil transcriptome in murine pneumococcal pneumonia.