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"Schneider, Michael"
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P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development
Ensuring the fitness of the pluripotent cells that will contribute to future development is important both for the integrity of the germline and for proper embryogenesis. Consequently, it is becoming increasingly apparent that pluripotent cells can compare their fitness levels and signal the elimination of those cells that are less fit than their neighbours. In mammals the nature of the pathways that communicate fitness remain largely unknown. Here we identify that in the early mouse embryo and upon exit from naive pluripotency, the confrontation of cells with different fitness levels leads to an inhibition of mTOR signalling in the less fit cell type, causing its elimination. We show that during this process, p53 acts upstream of mTOR and is required to repress its activity. Finally, we demonstrate that during normal development around 35% of cells are eliminated by this pathway, highlighting the importance of this mechanism for embryonic development.
During embryo development, cell fitness determines survival but how this is regulated is unclear. Here, the authors show that in early embryonic development and stem cells exiting the naive state, cells sense the fitness of their neighbours and trigger p53 to repress mTOR to eliminate a third of cells.
Journal Article
A survey of the standard location-routing problem
In this paper, we define the standard LRP as a deterministic, static, discrete, single-echelon, single-objective location-routing problem in which each customer (vertex) must be visited exactly once for the delivery of a good from a facility, and in which no inventory decisions are relevant. We review the literature on the standard LRP published since the survey by Nagy and Salhi appeared in 2006. We provide concise paper excerpts that convey the central ideas of each work, discuss recent developments in the field, provide a numerical comparison of the most successful heuristic algorithms, and list promising topics for further research.
Journal Article
The Role of Biomarkers in Hospitalized COVID-19 Patients With Systemic Manifestations
The following article aims to review COVID-19 biomarkers used in hospital practice. It is apparent that COVID-19 is not simply a pulmonary disease but has systemic manifestations. For this reason, biomarkers must be used in the management of diagnosed patients to provide holistic care. Patients with COVID-19 have been shown to have pulmonary, hepatobiliary, cardiovascular, neurologic, and renal injury, along with coagulopathy and a distinct cytokine storm. Biomarkers can effectively inform clinicians of systemic organ injury due to COVID-19. Furthermore, biomarkers can be used in predictive models for severe COVID-19 in admitted patients. The utility of doing so is to allow for risk stratification and utilization of proper treatment protocols. In addition, COVID-19 biomarkers in the pediatric population are discussed, specifically in predicting Multisystem Inflammatory Syndrome. Ultimately, biomarkers can be used as predictive tools to allow clinicians to identify and adequately manage patients at increased risk for worse outcomes from COVID-19. Both literature review and anecdotal evidence has shown that severe COVID-19 is a systemic disease, and understanding associated biomarkers are crucial for hospitalized patients’ proper clinical decision-making. For example, the cytokine storm releases inflammatory markers in different organ systems such as the pulmonary, hepatobiliary, hematological, cardiac, neurological, and renal systems. This review summarizes the latest research of COVID-19 that can help inform healthcare professionals how to better mitigate morbidity and mortality associated with this disease and provides information about certain systemic biomarkers that can be incorporated into hospital practice to provide more comprehensive care for hospitalized COIVD-19 patients.
Journal Article
scAbsolute: measuring single-cell ploidy and replication status
Cancer cells often exhibit DNA copy number aberrations and can vary widely in their ploidy. Correct estimation of the ploidy of single-cell genomes is paramount for downstream analysis. Based only on single-cell DNA sequencing information,
scAbsolute
achieves accurate and unbiased measurement of single-cell ploidy and replication status, including whole-genome duplications. We demonstrate
scAbsolute’s
capabilities using experimental cell multiplets, a FUCCI cell cycle expression system, and a benchmark against state-of-the-art methods.
scAbsolute
provides a robust foundation for single-cell DNA sequencing analysis across different technologies and has the potential to enable improvements in a number of downstream analyses.
Journal Article
Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (
Acvr1
tnR206H
). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type
Acvr1
allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted
Acvr1
R206H/+
FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.
Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.
Journal Article
Peer feedback improves students' academic self-concept in higher education
Peer feedback has been shown to be an effective strategy to improve academic achievement. However, little evidence is available about the effects of peer feedback on academic outcomes other than achievement, such as academic self-concept (ASC). ASC and achievement are reciprocally related and thus mutual reinforce themselves. The present study focuses on the effect of a four week long structured web-based peer feedback intervention on ASC in the domain of academic writing as a part of a seminar assignment in a sample of undergraduate psychology students. The study investigated the effectiveness with 49 students in a randomized-controlled trial with a pre-and post-test. Each student acted as an author and a reviewer. Results indicated significant improvements in ASC for the domain of academic writing over time as compared to a control group. Furthermore, the causal effect of peer feedback compared to no feedback on ASC for academic writing was strong with d = 0.72. The effect was domain specific, as the ASCs for the sub-domains statistics and language remained unchanged by the intervention. Overall, the results revealed that participation in a peer feedback system is an effective method to enhance ASC in the context of higher education. (ZPID).
Journal Article
NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart
NAD(P)H oxidases (Noxs) produce O 2 − and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4 −/− (c-Nox4 −/− ) mice. Nox4 expression was inhibited in c-Nox4 −/− mice in a heart-specific manner, and there was no compensatory up-regulation in other Nox enzymes. These mice exhibited reduced levels of O 2 − in the heart, indicating that Nox4 is a significant source of O 2 − in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4 −/− mice. In response to pressure overload (PO), however, increases in Nox4 expression and O 2 − production in mitochondria were abolished in c-Nox4 −/− mice, and c-Nox4 −/− mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4 −/− mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.
Journal Article