Plant thermosensors help optimize plant development and architecture for ambient temperatures, and morphogenic adaptation to warm temperatures has been extensively studied in recent years. ...Phytochrome B (phyB)-mediated thermosensing and the gene regulatory networks governing thermomorphogenic responses are well understood at the molecular level. However, it is unknown how plants manage their responsiveness to fluctuating temperatures in inducing thermomorphogenic behaviors. Here, we demonstrate that SUPPRESSOR OF MAX2 1 (SMAX1), known as a karrikin signaling repressor, enhances the thermosensitivity of hypocotyl morphogenesis in Arabidopsis thaliana. Hypocotyl thermomorphogenesis was largely disrupted in SMAX1-deficient mutants. SMAX1 interacts with phyB to alleviate its suppressive effects on the transcription factor activity of PHYTOCHROME-INTERACTING FACTOR 4 (PIF4), promoting hypocotyl thermomorphogenesis. Interestingly, the SMAX1 protein is slowly destabilized at warm temperatures, preventing hypocotyl overgrowth. Our findings indicate that the thermodynamic control of SMAX1 abundance serves as a molecular gatekeeper for phyB function in thermosensitizing PIF4-mediated hypocotyl morphogenesis.
Light and temperature cues share many common signaling events towards plant photothermal morphogenesis. Particularly, the red (R)/far-red (FR)-absorbing phytochrome photoreceptors also function as ...temperature sensors, suggesting that light and temperature responses are intimately associated with each other. Here, we present data from physicochemical modeling of temperature sensing and thermomorphogenic patterning of hypocotyl growth, which illustrate that the two seemingly distinct stimulating cues are tightly coupled through physicochemical principles and temperature effects can be described as a function of infra-red (IR) thermal radiation. It is possible that the dark reversion from the FR-absorbing Pfr to the R-absorbing Pr phytochromes is essentially an IR-mediated thermal conversion. We propose that the phytochromes modulate photothermal responses by monitoring R:IR ratios, as they sense R:FR ratios during photomorphogenesis.
Alzheimer's disease is the most common neurodegenerative brain disease causing dementia. It is characterized by slow onset and gradual worsening of memory and other cognitive functions. Recently, ...parabiosis and infusion of plasma from young mice have been proposed to have positive effects in aging and Alzheimer's disease. Therefore, this study examined whether infusion of plasma from exercised mice improved cognitive functions related to the hippocampus in a 3xTg-Alzheimer's disease (AD) model. We collected plasma from young mice that had exercised for 3 months and injected 100 µL of plasma into the tail vein of 12-month-old 3xTg-AD mice 10 times at 3-day intervals. We then analyzed spatial learning and memory, long-term memory, hippocampal GSK3β/tau proteins, synaptic proteins, mitochondrial function, apoptosis, and neurogenesis. In the hippocampus of 3xTg-AD mice, infusion of plasma from exercised mice improved neuroplasticity and mitochondrial function and suppressed apoptosis, ultimately improving cognitive function. However, there was no improvement in tau hyperphosphorylation. This study showed that plasma from exercised mice could have a protective effect on cognitive dysfunction and neural circuits associated with AD via a tau-independent mechanism involving elevated brain-derived neurotrophic factor due to exercise.
During the metastatic phase, cancer cells require the dissolution of cadherin-mediated cell-cell adhesion and a dramatic re-organization of the cytoskeleton through epithelial-mesenchymal transition ...(EMT), thereby acquiring migratory and invasive capabilities. In most tumors, EMT is accompanied by hypoxia. However, the intracellular signaling molecule that mediates hypoxia-induced EMT remained overlooked. By utilizing the microarray database system of the Cancer Genome Atlas, we identified ubiquitin-specific protease 47 (USP47), a deubiquitinating enzyme, as a potential mediator of hypoxia-induced EMT. Immunofluorescence staining of human colorectal tissue microarrays revealed that USP47 is overexpressed in colorectal adenocarcinoma tissues compared with normal adjacent tissues. The expression of USP47 was found to be elevated in three different human colorectal cancer cell lines. The enhancement of USP47 in colorectal cancer cells under hypoxic conditions induced the disassembly of E-cadherin and promoted EMT through deubiquitination of Snail. Silencing of USP47 accelerated the proteasomal degradation of Snail and inhibited EMT. Notably, hypoxia-induced USP47 upregulation was mediated by Sox9. These results demonstrate, for the first time, the role for USP47, as a novel target of Sox9, in the regulation of EMT and metastasis of colorectal cancer cells.
To determine optimal quarantine duration, we evaluated time from exposure to diagnosis for 107 close contacts of severe acute respiratory syndrome coronavirus 2 Omicron variant case-patients. Average ...time from exposure to diagnosis was 3.7 days; 70% of diagnoses were made on day 5 and 99.1% by day 10, suggesting 10-day quarantine.
Abstract
Background
Despite continued efforts using chemical similarity methods in virtual screening, currently developed approaches suffer from time-consuming multistep procedures and low success ...rates. We recently developed a machine learning-based chemical binding similarity model considering common structural features from molecules binding to the same, or evolutionarily related targets. The chemical binding similarity measures the resemblance of chemical compounds in terms of binding site similarity to better describe functional similarities that arise from target binding. In this study, we have shown how the chemical binding similarity could be used in virtual screening together with the conventional structure-based methods.
Results
The chemical binding similarity, receptor-based pharmacophore, chemical structure similarity, and molecular docking methods were evaluated to identify an effective virtual screening procedure for desired target proteins. When we tested the chemical binding similarity method with test sets of 51 kinases, it outperformed the traditional structural similarity-based methods as well as structure-based methods, such as molecular docking and receptor-based pharmacophore modeling, in terms of finding active compounds. We further validated the results by performing virtual screening (using the chemical binding similarity and receptor-based pharmacophore methods) against a completely blind dataset for mitogen-activated protein kinase kinase 1 (MEK1), ephrin type-B receptor 4 (EPHB4) and wee1-like protein kinase (WEE1). The in vitro kinase binding assay confirmed that 6 out of 13 (46.2%) for MEK1 and 2 out of 12 (16.7%) for EPHB4 were newly identified only by the chemical binding similarity model.
Conclusions
We report that the virtual screening results could further be improved by combining the chemical binding similarity model with 3D-QSAR pharmacophore and molecular docking models. Not only the new inhibitors are identified in this study, but also many of the identified molecules have low structural similarity scores against already reported inhibitors and that show the revelation of novel scaffolds.
Acetaminophen (APAP) is widely used as an antifebrile and analgesic drug at recommended doses, whereas an overdose of APAP can cause severe liver damage. The molecular mechanisms underlying ...APAP‐induced liver damage remain incompletely understood. Carbon monoxide (CO), an end‐product of heme oxygenase (HO)‐1 activity, can confer anti‐inflammatory and antiapoptotic properties in cellular models of toxicity via regulation of mitochondrial function. The objective of this study was to evaluate the effects of CO on APAP‐induced hepatotoxicity and CO's relationship to regulation of endoplasmic reticulum (ER) stress and mitochondrial signaling using CO‐releasing molecules or low concentrations of CO applied as pretreatment or post‐treatment. Using genetic deletion or knockdown approaches in alpha mouse liver cells or primary hepatocytes, respectively, we investigated the role of HO‐1 and the mitophagy regulator protein Parkin on APAP‐induced expression of the ER stress‐associated apoptosis regulator cytosine‐cytosine‐adenosine‐adenosine‐thymidine (CCAAT)/enhancer‐binding protein homologous protein (CHOP). We found that CO induced Parkin expression in hepatocytes via the protein kinase RNA‐like ER kinase/eukaryotic translation initiation factor 2‐α/activating transcription factor‐4 signaling pathway. Additionally, CO gas inhalation significantly alleviated APAP‐induced liver damage in vivo and correspondingly reduced serum alanine aminotransferase and aspartate aminotransferase levels as well as proinflammatory cytokines and reduced the expression of CHOP in liver tissues while dramatically increasing hepatic HO‐1 and Parkin expression. We found that the protective effects of CO on APAP‐induced liver damage were mediated by down‐regulation of CHOP at a transcriptional and post‐translational level via induction of HO‐1 and Parkin, respectively, and associated with decreases in reactive oxygen species production and JNK phosphorylation. We conclude that CO may represent a promising therapeutic agent for APAP‐induced liver injury.—Chen, Y., Park, H.‐J., Park, J., Song, H.‐C., Ryter, S. W., Surh, Y.‐J., Kim, U.‐H., Joe, Y., Chung, H. T. Carbon monoxide ameliorates acetaminophen‐induced liver injury by increasing hepatic HO‐1 and Parkin expression. FASEB J. 33, 13905‐13919 (2019). www.fasebj.org
We conducted a nationwide retrospective cohort study to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection among recipients of 4 different vaccines in South ...Korea. Age-adjusted breakthrough infection rate per month was highest for Janssen (42.6/100,000 population), followed by AstraZeneca (21.7/100,000 population), Pfizer-BioNTech (8.5/100,000 population), and Moderna (1.8/100,000 population).
The tumor microenvironment provides a niche in which cancer cells and their surrounding stromal cells reside and in which their interactions occur. The cross talk between cancer and stromal cells in ...the tumor microenvironment promotes many biological processes to support cancer cell growth, invasion, angiogenesis, and metastasis. Recently, not only cancer cells but also multiple types of surrounding stromal cells, including endothelial cells, immune cells, and fibroblasts in the tumor microenvironment, have been recognized to be attractive targets for reducing resistance to anticancer therapy and tumor recurrence. Many natural products present in fruits, vegetables, herbs, spices, and some marine organisms have been reported to inhibit, delay, or reverse multistage carcinogenesis and to inhibit the proliferation of cancerous cells and the self‐renewal capacity of preexisting cancer stem‐like cells. Some of these naturally occurring chemopreventive and anticarcinogenic substances can modulate the signal transduction involved in maintaining the activities/functions of stromal cells and their interactions with cancer cells within the tumor microenvironment.
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