•COVID-19 infection can lead to the development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome MODS within a few days of disease onset.•A powerful cytokine ...storm accompanies COVID-19 pneumonia.•The capacity to accurately predict and intervene in the cytokine storm during COVID-19 pneumonia, as well as the ability to design effective specific strategies to block excessive inflammation, is critical for patient survival.
Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response.
The ability of coronaviruses to infect humans is invariably associated with their binding strengths to human receptor proteins. Both SARS-CoV-2, initially named 2019-nCoV, and SARS-CoV were reported ...to utilize angiotensin-converting enzyme 2 (ACE2) as an entry receptor in human cells. To better understand the interplay between SARS-CoV-2 and ACE2, we performed computational alanine scanning mutagenesis on the “hotspot” residues at protein–protein interfaces using relative free energy calculations. Our data suggest that the mutations in SARS-CoV-2 lead to a greater binding affinity relative to SARS-CoV. In addition, our free energy calculations provide insight into the infectious ability of viruses on a physical basis and also provide useful information for the design of antiviral drugs.
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•MiR-17-5p expression was significantly upregulated, while RUNX3 level was downregulated in GC cancer tissue compared with adjacent normal tissues.•MiR-17-5p promotes the ...proliferation, migration and invasion of SGC-7901 cells via negatively regulating the expression of RUNX3.•The regulation of RUNX3 by miR-17-5p was not different between humans and mice.
Dysregulated microRNAs (miRNAs/miRs) directly modulate the biological functions of gastric cancer (GC) cells and contribute to the initiation and progression of GC. MiR-17-5p and runt-related transcription factor 3 (RUNX3) have been reported to be related to GC progression; however, the specific interaction between miR-17-5p and RUNX3 in GC require further investigation.
Western blotting, real-time PCR and immunohistochemistry were used to study the expression level of miR-17-5p and RUNX3 in gastric cancer tissues and plasma. The biological function of miR-17-5p was examined by measuring cell proliferation, apoptosis and cell invasion in vitro; the target gene of miR17-5p was identified by luciferase reporter assays, RNA Binding protein immunoprecipitation (RIP) and western blotting. In vivo animal study was conducted to confirm the role of miR-17-5p during tumorigensis of gastric cancer.
This study showed that miR17-5p was upregulated in the plasma and tissues of patients with GC, while RUNX3 was downregulated in GC tissues. Functional experiments indicated that miR-17-5p mimics promoted the proliferation and invasion of GC via suppressing apoptosis in vitro. Furthermore, bioinformatics prediction, luciferase reporter assays, reverse transcription quantitative polymerase chain reaction assays, RIP and western blotting analysis demonstrated that RUNX3 was a direct target gene of miR-17-5p in GC. In addition, overexpression of RUNX3 suppressed the proliferation and invasiveness of GC cells. In vivo data indicated miR-17-5p agomir significantly promoted tumor growth. In contrast, miR-17-5p antagomir notably decreased tumor volume compared with control group.
MiR-17-5p promoted the progression of GC via directly targeting RUNX3, suggesting that miR-17-5p and RUNX3 could be considered as diagnostic and therapeutic targets for patients with GC.
It has been a long standing challenge to efficiently separate oil and water since prehistoric times, and now it has become even more desirable in oily wastewater purification and oil spill cleanup. ...Here we introduce a super oil-water separation filter with superhydrophilicity and underwater superoleophobicity, fabricated using femtosecond laser micro-hole drilling of a titanium foil. Such a simply-made filter, without any modification, can achieve a separation efficiency exceeding 99% in eight typical oil-water mixtures. It remains highly efficient after 40 cycles of recycling and after suffering erosion by corrosive media. Furthermore, the used filter, polluted with oil, could be recovered by ultraviolet illumination. The flux of filtered water is tunable by simply selecting the aperture of the microhole or the spacing between adjacent microholes. Such advanced functionality is due to roughness and the TiO
layers on the ablated surface during fabrication. With superhydrophilic and superoleophobic surfaces, this oil-water filer is also suitable for applications in anti-fouling, anti-smudge, anti-fog, and self-cleaning.
Mitochondrial metabolism is necessary for the maintenance of oxidative TCA cycle function and mitochondrial membrane potential. Previous attempts to decipher whether mitochondria are necessary for ...biological outcomes have been hampered by genetic and pharmacologic methods that simultaneously disrupt multiple functions linked to mitochondrial metabolism. Here, we report that inducible depletion of mitochondrial DNA (ρο cells) diminished respiration, oxidative TCA cycle function, and the mitochondrial membrane potential, resulting in diminished cell proliferation, hypoxic activation of HIF-1, and specific histone acetylation marks. Genetic reconstitution only of the oxidative TCA cycle function specifically in these inducible ρο cells restored metabolites, resulting in re-establishment of histone acetylation. In contrast, genetic reconstitution of the mitochondrial membrane potential restored ROS, which were necessary for hypoxic activation of HIF-1 and cell proliferation. These results indicate that distinct mitochondrial functions associated with respiration are necessary for cell proliferation, epigenetics, and HIF-1 activation.
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•Two essential functions of mitochondria are TCA cycle and membrane potential•Mitochondria control cell proliferation, HIF-1 activation, and histone acetylation•Oxidative TCA cycle is necessary for histone acetylation•Mitochondrial membrane potential is required for proliferation and HIF-1 activation
Martínez-Reyes et al. report that mitochondrial metabolism is necessary for cell proliferation, histone acetylation, and HIF-1 activation. Mitochondrial metabolism linked to the oxidative TCA cycle controls histone acetylation, while the mitochondrial membrane potential dependent ROS generation is essential for cell proliferation and HIF-1 activation.
Abstract
Context
Poor uterine receptivity is one major factor leading to pregnancy loss and infertility. Understanding the molecular events governing successful implantation is hence critical in ...combating infertility.
Objective
To define Progesterone Receptor (PGR)-regulated molecular mechanisms and epithelial roles in receptivity.
Design
RNA-sequencing and PGR-ChIP-seq were conducted in parallel to identify PGR-regulated pathways during the Window of implantation (WOI) in endometrium of fertile women.
Setting
Endometrial biopsies from the proliferative and mid-secretory phases were analyzed.
Patients or Other Participants
Participants were fertile, reproductive aged (18–37 years) women with normal cycle length, and without any history of dysmenorrhea, infertility, or irregular cycles. In total, 42 endometrial biopsies obtained from 42 women were analyzed in this study.
Interventions
There were no interventions during this study.
Main Outcome Measures
Here we measured the alterations in gene expression and PGR occupancy in the genome during the WOI, based on the hypothesis that PGR binds uterine chromatin cycle dependently to regulate genes involved in uterine cell differentiation and function.
Results
653 genes were identified with regulated PGR binding and differential expression during the WOI. These were involved in regulating inflammatory response, xenobiotic metabolism, epithelial mesenchymal transition, cell death, interleukin/Signal Transducer And Activator Of Transcription (STAT) signaling, estrogen response, and Mammalian target of rapamycin complex 1 (MTORC1) response. Transcriptome of the epithelium identified 3052 differentially expressed genes, of which 658 were uniquely regulated. Transcription factors Interferon Regulatory Factor 8 (IRF8) and Myocyte Enhancer Factor 2C (MEF2C) were found to be regulated in the epithelium during the WOI at the protein level, suggesting potentially important functions that are previously unrecognized.
Conclusion
PGR binds the genomic regions of genes regulating critical processes in uterine receptivity and function.
Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation ...patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted.
Successful embryo implantation requires a receptive endometrium. Poor uterine receptivity can account for implantation failure in women who experience recurrent pregnancy loss or multiple rounds of ...unsuccessful in vitro fertilization cycles. Here, we demonstrate that the transcription factor Forkhead Box O1 (FOXO1) is a critical regulator of endometrial receptivity in vivo. Uterine ablation of Foxo1 using the progesterone receptor Cre (PgrCre) mouse model resulted in infertility due to altered epithelial cell polarity and apoptosis, preventing the embryo from penetrating the luminal epithelium. Analysis of the uterine transcriptome after Foxo1 ablation identified alterations in gene expression for transcripts involved in the activation of cell invasion, molecular transport, apoptosis, β-catenin (CTNNB1) signaling pathway, and an increase in PGR signaling. The increase of PGR signaling was due to PGR expression being retained in the uterine epithelium during the window of receptivity. Constitutive expression of epithelial PGR during this receptive period inhibited expression of FOXO1 in the nucleus of the uterine epithelium. The reciprocal expression of PGR and FOXO1 was conserved in human endometrial samples during the proliferative and secretory phase. This demonstrates that expression of FOXO1 and the loss of PGR during the window of receptivity are interrelated and critical for embryo implantation.
Abstract
Currently, a major challenge for metal-halide perovskite light emitting diodes (LEDs) is to achieve stable and efficient white light emission due to halide ion segregation. Herein, we report ...a promising method to fabricate white perovskite LEDs using lanthanide (Ln
3+
) ions doped CsPbCl
3
perovskite nanocrystals (PeNCs). First, K
+
ions are doped into the lattice to tune the perovskite bandgap by partially substituting Cs
+
ions, which are well matched to the transition energy of some Ln
3+
ions from the ground state to the excited state, thereby greatly improving the Förster energy transfer efficiency from excitons to Ln
3+
ions. Then, creatine phosphate (CP), a phospholipid widely found in organisms, serves as a tightly binding surface-capping multi-functional ligand which regulates the film formation and enhances the optical and electrical properties of PeNC film. Consequently, the Eu
3+
doped PeNCs based-white LEDs show a peak luminance of 1678 cd m
-2
and a maximum external quantum efficiency (EQE) of 5.4%, demonstrating excellent performance among existing white PeNC LEDs from a single chip. Furthermore, the method of bandgap modulation and the defect passivation were generalized to other Ln
3+
ions doped perovskite LEDs and successfully obtained improved electroluminescence (EL). This work demonstrates the comprehensive and universal strategies in the realization of highly efficient and stable white LEDs via single-component Ln
3+
ions doped PeNCs, which provides an optimal solution for the development of low-cost and simple white perovskite LEDs.
Mammalian pregnancy depends on the ability of the uterus to support embryo implantation. Previous studies reveal the Sox17 gene as a downstream target of the Pgr-Gata2-dependent transcription network ...that directs genomic actions in the uterine endometrium receptive for embryo implantation. Here, we report that ablating Sox17 in the uterine epithelium impairs leukemia inhibitory factor (LIF) and Indian hedgehog homolog (IHH) signaling, leading to failure of embryo implantation. In vivo deletion of the SOX17-binding region 19 kb upstream of the Ihh locus by CRISPR-Cas technology reduces Ihh expression specifically in the uterus and alters proper endometrial epithelial-stromal interactions, thereby impairing pregnancy. This SOX17-binding interval is also bound by GATA2, FOXA2, and PGR. This cluster of transcription factor binding is common in 737 uterine genes and may represent a key regulatory element essential for uterine epithelial gene expression.
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