Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension

The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease

SARS-CoV-2 in Pediatric Inpatient Care: Management, Clinical Presentation and Utilization of Healthcare Capacity

This study scrutinizes management and clinical presentation of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in pediatric inpatient care and evaluates the utilization of pediatric healthcare capacity during the pandemic. Within this retrospective cohort study, we systematically reviewed data of all 16,785 pediatric patients (<18 years admitted to our clinical center between January 2018 and June 2021). Data on SARS-CoV-2 test numbers, hospital admissions and clinical characteristics of infected patients were collected. Since January 2020, a total of 2513 SARS-CoV-2 tests were performed. In total, 36 patients had a positive test result. In total, 25 out of 36 SARS-CoV-2 positive children showed at least mild clinical symptoms while 11 were asymptomatic. Most common clinical symptoms were fever (60%), cough (60%) and rhinitis (20%). In parallel with the rising slope of SARS-CoV-2 in spring and fall 2020, we observed a slight decrease in the number of patients admitted to the pediatric department while the median duration of hospital treatment and intensive care occupancy remained unchanged. This study underlines that SARS-CoV-2 infected children most frequently exhibit an asymptomatic or mild clinical course. Noteworthy, the number of hospital admissions went down during the pandemic. The health and economic consequences need to be discussed within health care society and politics

Interventions to Ameliorate the Psychosocial Effects of the COVID-19 Pandemic on Children-A Systematic Review

The aim of this study was to identify interventions targeting children and their caregivers to reduce psychosocial problems in the course of the COVID-19 pandemic and comparable outbreaks. The review was performed using systematic literature searches in MEDLINE, Embase, PsycINFO and COVID-19-specific databases, including the CDC COVID-19 Research Database, the World Health Organisation (WHO) Global Database on COVID-19 Research and the Cochrane COVID-19 Study Register, ClinicalTrials.gov, the EU Clinical Trials Register and the German Clinical Trials Register (DRKS) up to 25th September 2020. The search yielded 6657 unique citations. After title/abstract and full text screening, 11 study protocols reporting on trials planned in China, the US, Canada, the UK, and Hungary during the COVID-19 pandemic were included. Four interventions targeted children \geq10 years directly, seven system-based interventions targeted the parents and caregivers of younger children and adolescents. Outcome measures encompassed mainly anxiety and depressive symptoms, different dimensions of stress or psychosocial well-being, and quality of supportive relationships. In conclusion, this systematic review revealed a paucity of studies on psychosocial interventions for children during the COVID-19 pandemic. Further research should be encouraged in light of the expected demand for child mental health management

Escherichia coli Can Adapt Its Protein Translocation Machinery for Enhanced Periplasmic Recombinant Protein Production

Recently, we engineered a tunable rhamnose promoter-based setup for the production of recombinant proteins in E. coli. This setup enabled us to show that being able to precisely set the production rate of a secretory recombinant protein is critical to enhance protein production yields in the periplasm. It is assumed that precisely setting the production rate of a secretory recombinant protein is required to harmonize its production rate with the protein translocation capacity of the cell. Here, using proteome analysis we show that enhancing periplasmic production of human Growth Hormone (hGH) using the tunable rhamnose promoter-based setup is accompanied by increased accumulation levels of at least three key players in protein translocation; the peripheral motor of the Sec-translocon (SecA), leader peptidase (LepB), and the cytoplasmic membrane protein integrase/chaperone (YidC). Thus, enhancing periplasmic hGH production leads to increased Sec-translocon capacity, increased capacity to cleave signal peptides from secretory proteins and an increased capacity of an alternative membrane protein biogenesis pathway, which frees up Sec-translocon capacity for protein secretion. When cells with enhanced periplasmic hGH production yields were harvested and subsequently cultured in the absence of inducer, SecA, LepB, and YidC levels went down again. This indicates that when using the tunable rhamnose-promoter system to enhance the production of a protein in the periplasm, E. coli can adapt its protein translocation machinery for enhanced recombinant protein production in the periplasm

New Insights into the Education of Children with Congenital Heart Disease with and without Trisomy 21

Background and Objectives: Patients with congenital heart disease (CHD), especially as a concomitant syndromal disease of trisomy 21 (T21), are at risk for impaired neurodevelopment. This can also affect these patients’ education. However, there continues to be a research gap in the educational development of CHD patients and T21 CHD patients. Materials and Methods: In total, data from 2873 patients from the German National Register for Congenital Heart Defects were analyzed. The data are based on two online education surveys conducted among patients registered in the National Register for Congenital Heart Defects (2017, 2020). Results: Of 2873 patients included (mean age: 14.1 ± 4.7 years, 50.5% female), 109 (3.8%) were identified with T21 (mean age: 12.9 ± 4.4 years, 49.5% female). T21 CHD participants had a high demand for early specific interventions (overall cohort 49.1%; T21 cohort 100%). T21 CHD children more frequently attended special schools and, compared to non-trisomy 21 (nT21) CHD patients, the probability of attending a grammar school was reduced. In total, 87.1% of nT21 CHD patients but 11% of T21 CHD patients were enrolled in a regular elementary school, and 12.8% of T21 CHD patients could transfer to a secondary school in contrast to 35.5% of nT21 CHD patients. Most of the T21 CHD patients were diagnosed with psychiatric disorders, e.g., learning, emotional, or behavioral disorders (T21 CHD patients: 82.6%; nT21 CHD patients: 31.4%; p < 0.001). Conclusions: CHD patients are at risk for impaired academic development, and the presence of T21 is an aggravating factor. Routine follow-up examinations should be established to identify developmental deficits and to provide targeted interventions

Microcephaly is associated with impaired educational development in children with congenital heart disease

Objectives This study aims to evaluate the school careers of patients with congenital heart disease (CHD) and microcephaly. Methods An exploratory online survey was conducted on patients from a previous study on somatic development in children with CHD in 2018 (n = 2818). A total of 750 patients participated in the online survey (26.6%). This publication focuses on 91 patients (12.1%) diagnosed with CHD and microcephaly who participated in the new online survey. Results Microcephaly was significantly associated with CHD severity (p < 0.001). Microcephalic patients suffered from psychiatric comorbidity two times as often (67.0%) as non-microcephalic patients (29.8%). In particular, the percentage of patients with developmental delay, intellectual debility, social disability, learning disorder, or language disorder was significantly increased in microcephalic CHD patients (p < 0.001). A total of 85.7% of microcephalic patients and 47.6% of non-microcephalic patients received early interventions to foster their development. The school enrollment of both groups was similar at approximately six years of age. However, 89.9% of non-microcephalic but only 51.6% of microcephalic patients were enrolled in a regular elementary school. Regarding secondary school, only half as many microcephalic patients (14.3%) went to grammar school, while the proportion of pupils at special schools was eight times higher. Supportive interventions, e.g., for specific learning disabilities, were used by 52.7% of microcephalic patients and 21.6% of non-microcephalic patients. Conclusion Patients with CHD and microcephaly are at high risk for impaired educational development. Early identification should alert clinicians to provide targeted interventions to optimize the developmental potential

What’s a Biofilm?—How the Choice of the Biofilm Model Impacts the Protein Inventory of Clostridioides difficile

The anaerobic pathogen Clostridioides difficile is perfectly equipped to survive and persist inside the mammalian intestine. When facing unfavorable conditions C. difficile is able to form highly resistant endospores. Likewise, biofilms are currently discussed as form of persistence. Here a comprehensive proteomics approach was applied to investigate the molecular processes of C. difficile strain 630Δerm underlying biofilm formation. The comparison of the proteome from two different forms of biofilm-like growth, namely aggregate biofilms and colonies on agar plates, revealed major differences in the formation of cell surface proteins, as well as enzymes of its energy and stress metabolism. For instance, while the obtained data suggest that aggregate biofilm cells express both flagella, type IV pili and enzymes required for biosynthesis of cell-surface polysaccharides, the S-layer protein SlpA and most cell wall proteins (CWPs) encoded adjacent to SlpA were detected in significantly lower amounts in aggregate biofilm cells than in colony biofilms. Moreover, the obtained data suggested that aggregate biofilm cells are rather actively growing cells while colony biofilm cells most likely severely suffer from a lack of reductive equivalents what requires induction of the Wood-Ljungdahl pathway and C. difficile’s V-type ATPase to maintain cell homeostasis. In agreement with this, aggregate biofilm cells, in contrast to colony biofilm cells, neither induced toxin nor spore production. Finally, the data revealed that the sigma factor SigL/RpoN and its dependent regulators are noticeably induced in aggregate biofilms suggesting an important role of SigL/RpoN in aggregate biofilm formation

Comparative proteome analysis in an Escherichia coli CyDisCo strain identifies stress responses related to protein production, oxidative stress and accumulation of misfolded protein

Background The Twin-arginine translocation (Tat) pathway of Escherichia coli has great potential for the export of biopharmaceuticals to the periplasm due to its ability to transport folded proteins, and its proofreading mechanism that allows correctly folded proteins to translocate. Coupling the Tat-dependent protein secretion with the formation of disulfide bonds in the cytoplasm of E. coli CyDisCo provides a powerful platform for the production of industrially challenging proteins. In this study, we investigated the effects on the E. coli cells of exporting a folded substrate (scFv) to the periplasm using a Tat signal peptide, and the effects of expressing an export-incompetent midsfolded variant. Results Cell growth is decreased when either the correctly folded or misfolded scFv is expressed with a Tat signal peptide. However, only the production of misfolded scFv leads to cell aggregation and formation of inclusion bodies. The comprehensive proteomic analysis revealed that both conditions, recombinant protein overexpression and misfolded protein accumulation, lead to downregulation of membrane transporters responsible for protein folding and insertion into the membrane while upregulating the production of chaperones and proteases involved in removing aggregates. These conditions also differentially affect the production of transcription factors and proteins involved in DNA replication. The most distinct stress response observed was the cell aggregation caused by elevated levels of antigen 43. Finally, Tat-dependent secretion causes an increase in tatA expression only after induction of protein expression, while the subsequent post-induction analysis revealed lower tatA and tatB expression levels, which correlate with lowered TatA and TatB protein abundance. Conclusions The study identified characteristic changes occurring as a result of the production of both a folded and a misfolded protein, but also highlights an exclusive unfolded stress response. Countering and compensating for these changes may result in higher yields of pharmaceutically relevant proteins exported to the periplasm

Differential View on the Bile Acid Stress Response of Clostridioides difficile

Clostridioides difficile is an intestinal human pathogen that uses the opportunity of a depleted microbiota to cause an infection. It is known, that the composition of the intestinal bile acid cocktail has a great impact on the susceptibility toward a C. difficile infection. However, the specific response of growing C. difficile cells to diverse bile acids on the molecular level has not been described yet. In this study, we recorded proteome signatures of shock and long-term (LT) stress with the four main bile acids cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA). A general overlapping response to all tested bile acids could be determined particularly in shock experiments which appears plausible in the light of their common steroid structure. However, during LT stress several proteins showed an altered abundance in the presence of only a single or a few of the bile acids indicating the existence of specific adaptation mechanisms. Our results point at a differential induction of the groEL and dnaKJgrpE chaperone systems, both belonging to the class I heat shock genes. Additionally, central metabolic pathways involving butyrate fermentation and the reductive Stickland fermentation of leucine were effected, although CA caused a proteome signature different from the other three bile acids. Furthermore, quantitative proteomics revealed a loss of flagellar proteins in LT stress with LCA. The absence of flagella could be substantiated by electron microscopy which also indicated less flagellated cells in the presence of DCA and CDCA and no influence on flagella formation by CA. Our data break down the bile acid stress response of C. difficile into a general and a specific adaptation. The latter cannot simply be divided into a response to primary and secondary bile acids, but rather reflects a complex and variable adaptation process enabling C. difficile to survive and to cause an infection in the intestinal tract

Measures implemented in the school setting to contain the COVID-19 pandemic: a scoping review.

BACKGROUND: In response to the spread of SARS-CoV-2 and the impact of COVID-19, national and subnational governments implemented a variety of measures in order to control the spread of the virus and the associated disease. While these measures were imposed with the intention of controlling the pandemic, they were also associated with severe psychosocial, societal, and economic implications on a societal level. One setting affected heavily by these measures is the school setting. By mid-April 2020, 192 countries had closed schools, affecting more than 90% of the world's student population. In consideration of the adverse consequences of school closures, many countries around the world reopened their schools in the months after the initial closures. To safely reopen schools and keep them open, governments implemented a broad range of measures. The evidence with regards to these measures, however, is heterogeneous, with a multitude of study designs, populations, settings, interventions and outcomes being assessed. To make sense of this heterogeneity, we conducted a rapid scoping review (8 October to 5 November 2020). This rapid scoping review is intended to serve as a precursor to a systematic review of effectiveness, which will inform guidelines issued by the World Health Organization (WHO). This review is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist and was registered with the Open Science Framework. OBJECTIVES: To identify and comprehensively map the evidence assessing the impacts of measures implemented in the school setting to reopen schools, or keep schools open, or both, during the SARS-CoV-2/COVID-19 pandemic, with particular focus on the types of measures implemented in different school settings, the outcomes used to measure their impacts and the study types used to assess these. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, the CDC COVID-19 Research Articles Downloadable Database for preprints, and the WHO COVID-19 Global literature on coronavirus disease on 8 October 2020. SELECTION CRITERIA: We included studies that assessed the impact of measures implemented in the school setting. Eligible populations were populations at risk of becoming infected with SARS-CoV-2, or developing COVID-19 disease, or both, and included people both directly and indirectly impacted by interventions, including students, teachers, other school staff, and contacts of these groups, as well as the broader community. We considered all types of empirical studies, which quantitatively assessed impact including epidemiological studies, modelling studies, mixed-methods studies, and diagnostic studies that assessed the impact of relevant interventions beyond diagnostic test accuracy. Broad outcome categories of interest included infectious disease transmission-related outcomes, other harmful or beneficial health-related outcomes, and societal, economic, and ecological implications. DATA COLLECTION AND ANALYSIS: We extracted data from included studies in a standardized manner, and mapped them to categories within our a priori logic model where possible. Where not possible, we inductively developed new categories. In line with standard expectations for scoping reviews, the review provides an overview of the existing evidence regardless of methodological quality or risk of bias, and was not designed to synthesize effectiveness data, assess risk of bias, or characterize strength of evidence (GRADE). MAIN RESULTS: We included 42 studies that assessed measures implemented in the school setting. The majority of studies used mathematical modelling designs (n = 31), while nine studies used observational designs, and two studies used experimental or quasi-experimental designs. Studies conducted in real-world contexts or using real data focused on the WHO European region (EUR; n = 20), the WHO region of the Americas (AMR; n = 13), the West Pacific region (WPR; n = 6), and the WHO Eastern Mediterranean Region (EMR; n = 1). One study conducted a global assessment and one did not report on data from, or that were applicable to, a specific country. Three broad intervention categories emerged from the included studies: organizational measures to reduce transmission of SARS-CoV-2 (n = 36), structural/environmental measures to reduce transmission of SARS-CoV-2 (n = 11), and surveillance and response measures to detect SARS-CoV-2 infections (n = 19). Most studies assessed SARS-CoV-2 transmission-related outcomes (n = 29), while others assessed healthcare utilization (n = 8), other health outcomes (n = 3), and societal, economic, and ecological outcomes (n = 5). Studies assessed both harmful and beneficial outcomes across all outcome categories. AUTHORS' CONCLUSIONS: We identified a heterogeneous and complex evidence base of measures implemented in the school setting. This review is an important first step in understanding the available evidence and will inform the development of rapid reviews on this topic