Anthropogenic fingerprints in daily precipitation revealed by deep learning.

According to twenty-first century climate-model projections, greenhouse warming will intensify rainfall variability and extremes across the globe1-4. However, verifying this prediction using observations has remained a substantial challenge owing to large natural rainfall fluctuations at regional scales3,4. Here we show that deep learning successfully detects the emerging climate-change signals in daily precipitation fields during the observed record. We trained a convolutional neural network (CNN)5 with daily precipitation fields and annual global mean surface air temperature data obtained from an ensemble of present-day and future climate-model simulations6. After applying the algorithm to the observational record, we found that the daily precipitation data represented an excellent predictor for the observed planetary warming, as they showed a clear deviation from natural variability since the mid-2010s. Furthermore, we analysed the deep-learning model with an explainable framework and observed that the precipitation variability of the weather timescale (period less than 10 days) over the tropical eastern Pacific and mid-latitude storm-track regions was most sensitive to anthropogenic warming. Our results highlight that, although the long-term shifts in annual mean precipitation remain indiscernible from the natural background variability, the impact of global warming on daily hydrological fluctuations has already emerged.

Thiophene-based lipids for mRNA delivery to pulmonary and retinal tissues.

Lipid nanoparticles (LNPs) largely rely on ionizable lipids to yield successful nucleic acid delivery via electrostatic disruption of the endosomal membrane. Here, we report the identification and evaluation of ionizable lipids containing a thiophene moiety (Thio-lipids). The Thio-lipids can be readily synthesized via the Gewald reaction, allowing for modular lipid design with functional constituents at various positions of the thiophene ring. Through the rational design of ionizable lipid structure, we prepared 47 Thio-lipids and identified some structural criteria required in Thio-lipids for efficient mRNA (messenger RNA) encapsulation and delivery in vitro and in vivo. Notably, none of the tested lipids have a pH-response profile like traditional ionizable lipids, potentially due to the electron delocalization in the thiophene core. Placement of the tails and localization of the ionizable headgroup in the thiophene core can endow the nanoparticles with the capability to reach various tissues. Using high-throughput formulation and barcoding techniques, we optimized the formulations to select two top lipids-20b and 29d-and investigated their biodistribution in mice. Lipid 20b enabled LNPs to transfect the liver and spleen, and 29d LNP transfected the lung and spleen. Unexpectedly, LNP with lipid 20b was especially potent in mRNA delivery to the retina with no acute toxicity, leading to the successful delivery to the photoreceptors and retinal pigment epithelium in non-human primates.

Deep learning for multi-year ENSO forecasts.

Variations in the El Niño/Southern Oscillation (ENSO) are associated with a wide array of regional climate extremes and ecosystem impacts1. Robust, long-lead forecasts would therefore be valuable for managing policy responses. But despite decades of effort, forecasting ENSO events at lead times of more than one year remains problematic2. Here we show that a statistical forecast model employing a deep-learning approach produces skilful ENSO forecasts for lead times of up to one and a half years. To circumvent the limited amount of observation data, we use transfer learning to train a convolutional neural network (CNN) first on historical simulations3 and subsequently on reanalysis from 1871 to 1973. During the validation period from 1984 to 2017, the all-season correlation skill of the Nino3.4 index of the CNN model is much higher than those of current state-of-the-art dynamical forecast systems. The CNN model is also better at predicting the detailed zonal distribution of sea surface temperatures, overcoming a weakness of dynamical forecast models. A heat map analysis indicates that the CNN model predicts ENSO events using physically reasonable precursors. The CNN model is thus a powerful tool for both the prediction of ENSO events and for the analysis of their associated complex mechanisms.

Chemistry of Lipid Nanoparticles for RNA Delivery.

Lipid nanoparticles (LNPs) are a type of lipid vesicles that possess a homogeneous lipid core. These vesicles are widely used in small-molecule drug and nucleic acid delivery and recently gained much attention because of their remarkable success as a delivery platform for COVID-19 mRNA vaccines. Nonetheless, the utility of transient protein expression induced by mRNA extends far beyond vaccines against infectious diseases─they also hold promise as cancer vaccines, protein replacement therapies, and gene editing components for rare genetic diseases. However, naked mRNA is inherently unstable and prone to rapid degradation by nucleases and self-hydrolysis. Encapsulation of mRNA within LNPs protects mRNA from extracellular ribonucleases and assists with intracellular mRNA delivery.In this Account, we discuss the core features of LNPs for RNA delivery. We focus our attention on LNPs designed to deliver mRNA; however, we also include examples of siRNA-LNP delivery where appropriate to highlight the commonalities and the dissimilarities due to the nucleic acid structure. First, we introduce the concept of LNPs, the advantages and disadvantages of utilizing nucleic acids as therapeutic agents, and the general reasoning behind the molecular makeup of LNPs. We also briefly highlight the most recent clinical successes of LNP-based nucleic acid therapies. Second, we describe the theory and methods of LNP self-assembly. The common idea behind all of the preparation methods is inducing electrostatic interactions between the nucleic acid and charged lipids and promoting nanoparticle growth via hydrophobic interactions. Third, we break down the LNP composition with special attention to the fundamental properties and purposes of each component. This includes the identified molecular design criteria, commercial sourcing, impact on intracellular trafficking, and contribution to the properties of LNPs. One of the key components of LNPs is ionizable lipids, which initiate electrostatic binding with endosomal membranes and facilitate cytosolic release; however, the roles of other lipid components should not be disregarded, as they are associated with stability, clearance, and distribution of LNPs. Fourth, we review the attributes of LNP constructs as a whole that can heavily influence RNA delivery. These attributes are LNP size, charge, internal structure, lipid packing, lipid membrane hydration, stability, and affinity toward biomacromolecules. We also discuss the specific techniques used to examine these attributes and how they can be adjusted. Finally, we offer our perspective on the future of RNA therapies and some questions that remain in the realm of LNP formulation and optimization.

Effects of Gas and Steam Humidity on Particulate Matter Measurements Obtained Using Light-Scattering Sensors.

With the increasing need for particulate matter (PM) monitoring, the demand for light-scattering sensors that allow for real-time measurements of PM is increasing. This light-scattering method involves irradiating light to the aerosols in the atmosphere to analyze the scattered light and measure mass concentrations. Humidity affects the measurement results. The humidity in an outdoor environment may exist as gas or steam, such as fog. While the impact of humidity on the light-scattering measurement remains unclear, an accurate estimation of ambient PM concentration is a practical challenge. Therefore, this study investigated the effects of humidity on light-scattering measurements by analyzing the variation in the PM concentration measured by the sensor when relative humidity was due to gaseous and steam vapor. The gaseous humidity did not cause errors in the PM measurements via the light-scattering method. In contrast, steam humidity, such as that caused by fog, resulted in errors in the PM measurement. The results help determine the factors to be considered before applying a light-scattering sensor in an outdoor environment. Based on these factors, directions for technological development can be presented regarding the correction of measurement errors induced by vapor in outdoor environments.

Stimulus-Responsive Ultrathin Films for Bioapplications: A Concise Review.

The term "nanosheets" has been coined recently to describe supported and free-standing "ultrathin film" materials, with thicknesses ranging from a single atomic layer to a few tens of nanometers. Owing to their physicochemical properties and their large surface area with abundant accessible active sites, nanosheets (NSHs) of inorganic materials such as Au, amorphous carbon, graphene, and boron nitride (BN) are considered ideal building blocks or scaffolds for a wide range of applications encompassing electronic and optical devices, membranes, drug delivery systems, and multimodal contrast agents, among others. A wide variety of synthetic methods are employed for the manufacturing of these NSHs, and they can be categorized into (1) top-down approaches involving exfoliation of layered materials, or (2) bottom-up approaches where crystal growth of nanocomposites takes place in a liquid or gas phase. Of note, polymer template liquid exfoliation (PTLE) methods are the most suitable as they lead to the fabrication of high-performance and stable hybrid NSHs and NSH composites with the appropriate quality, solubility, and properties. Moreover, PTLE methods allow for the production of stimulus-responsive NSHs, whose response is commonly driven by a favorable growth in the appropriate polymer chains onto one side of the NSHs, resulting in the ability of the NSHs to roll up to form nanoscrolls (NSCs), i.e., open tubular structures with tunable interlayer gaps between their walls. On the other hand, this review gives insight into the potential of the stimulus-responsive nanostructures for biosensing and controlled drug release systems, illustrating the last advances in the PTLE methods of synthesis of these nanostructures and their applications.

Nanoparticle-Based Follistatin Messenger RNA Therapy for Reprogramming Metastatic Ovarian Cancer and Ameliorating Cancer-Associated Cachexia.

This study presents the first messenger RNA (mRNA) therapy for metastatic ovarian cancer and cachexia-induced muscle wasting based on lipid nanoparticles that deliver follistatin (FST) mRNA predominantly to cancer clusters following intraperitoneal administration. The secreted FST protein, endogenously synthesized from delivered mRNA, efficiently reduces elevated activin A levels associated with aggressive ovarian cancer and associated cachexia. By altering the cancer cell phenotype, mRNA treatment prevents malignant ascites, delays cancer progression, induces the formation of solid tumors, and preserves muscle mass in cancer-bearing mice by inhibiting negative regulators of muscle mass. Finally, mRNA therapy provides synergistic effects in combination with cisplatin, increasing the survival of mice and counteracting muscle atrophy induced by chemotherapy and cancer-associated cachexia. The treated mice develop few nonadherent tumors that are easily resected from the peritoneum. Clinically, this nanomedicine-based mRNA therapy can facilitate complete cytoreduction, target resistance, improve resilience during aggressive chemotherapy, and improve survival in advanced ovarian cancer.

Matrix stiffness regulates lipid nanoparticle-mRNA delivery in cell-laden hydrogels.

mRNA therapeutics have increased in popularity, largely due to the transient and fast nature of protein expression and the low risk of off-target effects. This has increased drastically with the remarkable success of mRNA-based vaccines for COVID-19. Despite advances in lipid nanoparticle (LNP)-based delivery, the mechanisms that regulate efficient endocytic trafficking and translation of mRNA remain poorly understood. Although it is widely acknowledged that the extracellular matrix (ECM) regulates uptake and expression of exogenous nano-complexed genetic material, its specific effects on mRNA delivery and expression have not yet been examined. Here, we demonstrate a critical role for matrix stiffness in modulating both mRNA transfection and expression and uncover distinct mechano-regulatory mechanisms for endocytosis of mRNA through RhoA mediated mTOR signaling and cytoskeletal dynamics. Our findings have implications for effective delivery of therapeutic mRNA to targeted tissues that may be differentially affected by tissue and matrix stiffness.

FOXO1 Is a Key Mediator of Glucocorticoid-Induced Expression of Tristetraprolin in MDA-MB-231 Breast Cancer Cells.

The mRNA destabilizing factor tristetraprolin (TTP) functions as a tumor suppressor by down-regulating cancer-associated genes. TTP expression is significantly reduced in various cancers, which contributes to cancer processes. Enforced expression of TTP impairs tumorigenesis and abolishes maintenance of the malignant state, emphasizing the need to identify a TTP inducer in cancer cells. To search for novel candidate agents for inducing TTP in cancer cells, we screened a library containing 1019 natural compounds using MCF-7 breast cancer cells transfected with a reporter vector containing the TTP promoter upstream of the luciferase gene. We identified one molecule, of which the enantiomers are betamethasone 21-phosphate (BTM-21-P) and dexamethasone 21-phosphate (BTM-21-P), as a potent inducer of TTP in cancer cells. We confirmed that BTM-21-P, DXM-21-P, and dexamethasone (DXM) induced the expression of TTP in MDA-MB-231 cells in a glucocorticoid receptor (GR)-dependent manner. To identify potential pathways linking BTM-21-P and DXM-21-P to TTP induction, we performed an RNA sequencing-based transcriptome analysis of MDA-MB-231 cells at 3 h after treatment with these compounds. A heat map analysis of FPKM expression showed a similar expression pattern between cells treated with the two compounds. The KEGG pathway analysis results revealed that the upregulated DEGs were strongly associated with several pathways, including the Hippo signaling pathway, PI3K-Akt signaling pathway, FOXO signaling pathway, NF-κB signaling pathway, and p53 signaling pathway. Inhibition of the FOXO pathway using a FOXO1 inhibitor blocked the effects of BTM-21-P and DXM-21-P on the induction of TTP in MDA-MB-231 cells. We found that DXM enhanced the binding of FOXO1 to the TTP promoter in a GR-dependent manner. In conclusion, we identified a natural compound of which the enantiomers are DXM-21-P and BTM-21-P as a potent inducer of TTP in breast cancer cells. We also present new insights into the role of FOXO1 in the DXM-21-P- and BTM-21-P-induced expression of TTP in cancer cells.

MRTF potentiates TEAD-YAP transcriptional activity causing metastasis.

Yes-associated protein (YAP) and myocardin-related transcription factor (MRTF) play similar roles and exhibit significant crosstalk in directing transcriptional responses to chemical and physical extracellular cues. The mechanism underlying this crosstalk, however, remains unclear. Here, we show MRTF family proteins bind YAP via a conserved PPXY motif that interacts with the YAP WW domain. This interaction allows MRTF to recruit NcoA3 to the TEAD-YAP transcriptional complex and potentiate its transcriptional activity. We show this interaction of MRTF and YAP is critical for LPA-induced cancer cell invasion in vitro and breast cancer metastasis to the lung in vivo We also demonstrate the significance of MRTF-YAP binding in regulation of YAP activity upon acute actin cytoskeletal damage. Acute actin disruption induces nucleo-cytoplasmic shuttling of MRTF, and this process underlies the LATS-independent regulation of YAP activity. Our results provide clear evidence of crosstalk between MRTF and YAP independent of the LATS kinases that normally act upstream of YAP signaling. Our results also suggest a mechanism by which extracellular stimuli can coordinate physiological events downstream of YAP.

Characteristics of HONO and its impact on O3 formation in the Seoul Metropolitan Area during the Korea-US Air Quality Study.

Photolysis of nitrous acid (HONO) is recognized as an early-morning source of OH radicals in the urban air. During the Korea-US air quality (KORUS-AQ) campaign, HONO was measured using quantum cascade - tunable infrared laser differential absorption spectrometer (QC-TILDAS) at Olympic Park in Seoul from 17 May, 2016 to 14 June, 2016. The HONO concentration was in the range of 0.07-3.46 ppbv, with an average of 0.93 ppbv. Moreover, it remained high from 00:00-05:00 LST. During this time, the mean concentration was higher during the high-O3 episodes (1.82 ppbv) than the non-episodes (1.20 ppbv). In the morning, the OH radicals that were produced from HONO photolysis were 50% higher (0.95 pptv) during the high-O3 episodes than the non-episodes. Diurnal variations in HOx and O3 concentrations were simulated by the F0AM model, which revealed a difference of ~20 ppbv in the daily maximum O3 concentrations between the high-O3 episodes and non-episodes. Furthermore, the HONO concentration increased with an increase in relative humidity (RH) up to 80%; the highest HONO was associated with the top 10% NO2 in each RH group, confirming that NO2 is one of the main precursors of HONO. At night, the conversion ratio of NO2 to HONO was estimated to be 0.88×10-2 h-1; this ratio was found to increase with an increase in RH. The Aitken mode particles (30-120 nm), which act as catalyst surfaces, exhibited a similar tendency with a conversion ratio that increased along with RH, indicating the coupling of surfaces with HONO conversion. Using an artificial neural network (ANN) model, HONO concentrations were successfully simulated with measured variables (r2 = 0.66 as an average of five models). Among these variables, NOx, aerosol surface area, and RH were found to be the main factors affecting the ambient HONO concentrations. The results reveal that RH facilitates the conversion of NO2 to HONO by constraining the availability of aerosol surfaces. This study demonstrates the coupling of HONO with the HOx-O3 cycle in the Seoul Metropolitan Area (SMA) and provides practical evidence of the heterogeneous formation of HONO by employing the ANN model.

Spermidine Attenuates Oxidative Stress-Induced Apoptosis via Blocking Ca2+ Overload in Retinal Pigment Epithelial Cells Independently of ROS.

Retinal pigment epithelial (RPE) cells occupy the outer layer of the retina and perform various biological functions. Oxidative damage to RPE cells is a major risk factor for retinal degeneration that ultimately leads to vision loss. In this study, we investigated the role of spermidine in a hydrogen peroxide (H2O2)-induced oxidative stress model using human RPE cells. Our findings showed that 300 µM H2O2 increased cytotoxicity, apoptosis, and cell cycle arrest in the G2/M phase, whereas these effects were markedly suppressed by 10 µM spermidine. Furthermore, spermidine significantly reduced H2O2-induced mitochondrial dysfunction including mitochondrial membrane potential and mitochondrial activity. Although spermidine displays antioxidant properties, the generation of intracellular reactive oxygen species (ROS) upon H2O2 insult was not regulated by spermidine. Spermidine did suppress the increase in cytosolic Ca2+ levels resulting from endoplasmic reticulum stress in H2O2-stimulated human RPE cells. Treatment with a cytosolic Ca2+ chelator markedly reversed H2O2-induced cellular dysfunction. Overall, spermidine protected against H2O2-induced cellular damage by blocking the increase of intracellular Ca2+ independently of ROS. These results suggest that spermidine protects RPE cells from oxidative stress, which could be a useful treatment for retinal diseases.

Methylation of the CDX2 promoter in Helicobacter pylori-infected gastric mucosa increases with age and its rapid demethylation in gastric tumors is associated with upregulated gene expression.

Pathological changes in the epigenetic landscape of chromatin are hallmarks of cancer. The caudal-type homeobox gene CDX2 is not expressed in normal gastric epithelia but rather in adult intestinal epithelia, and it is overexpressed in intestinal metaplasia (IM). However, it remains unclear how CDX2 transcription is suppressed in normal gastric epithelial cells and overexpressed in IM. Here, we demonstrate that methylation of the CDX2 promoter increases with age in Helicobacter pylori-positive, noncancerous gastric tissue, whereas the promoter is demethylated in paired gastric tumors in which CDX2 is upregulated. Moreover, we also found that the CDX2 promoter is demethylated in IM as well as gastric tumor. Immunohistochemistry revealed that CDX2 is present in foci of parts of the gastric mucosae but highly expressed in IM as well as in gastric tumors, suggesting that the elevated level of CDX2 in IM and gastric tumors may be attributable to promoter demethylation. Our data suggest that CDX2 repression may be associated with promoter methylation in noncancerous H. pylori-positive mucosa but its upregulation might be attributable to increased promoter activity mediated by chromatin remodeling during gastric carcinogenesis.

A study of skin characteristics with long-term sleep restriction in Korean women in their 40s.

BACKGROUND: Previous studies have demonstrated increased pore size and darkening skin color with total sleep deprivation. There are many studies of skin characteristics with short-term sleep restriction, but there are few studies on skin characteristics when sleep is restricted more than three consecutive days. This study evaluated skin changes with sleep limited to 4 hours per night for six nights. MATERIALS AND METHODS: The study included 32 Korean women in their 40s. Skin hydration, desquamation, barrier recovery, texture, gloss, transparency, elasticity, crow's feet, frown lines, and color were measured. Individual sleep time was monitored by smartwatches. Subjects slept 8 hours per night for six nights in week one and 4 hours per night for six nights in week two. RESULTS: Skin hydration was significantly reduced after 1 day of sleep deprivation, and it continued to decrease. Skin gloss, desquamation, transparency, elasticity, and wrinkles were significantly aggravated after 1 day of sleep deprivation. Skin texture was significantly aggravated on the fourth day of sleep restriction. Elasticity was most affected by reduced sleep, with a standardized coefficient of -.320, indicating a significant decrease over time as compared to other characteristics. CONCLUSION: Skin hydration was gradually decreased with sleep restriction. Skin texture did not change after only 1 day of sleep restriction. It is a new finding that elasticity decreases more than other skin characteristics with prolonged sleep restriction.

Molecular Drug Discovery of Single Ginsenoside Compounds as a Potent Bruton's Tyrosine Kinase Inhibitor.

: Bruton's tyrosine kinase (BTK) is known as a direct regulator of inflammasome, which is an intracellular target to therapeutically modulate innate immunity. Although there is great interest in developing small molecule-based drugs with BTK inhibition, there are only a few drugs available in the market, due to the difficulty of drug discovery and the potential side effects. To select suitable drug compounds to inhibit BTK signaling, molecular drug screening bioassay processes of single ginsenosides integrated with in silico molecular simulation were performed. The experimental results for the ginsenoside compositions (Rb2 and Rb3) exhibited showed that they effectively suppressed the activity of BTK expression in a rational agreement with molecular docking calculations of the compounds against the BTK binding site. They implemented a possible inhibiting effect of BTK signaling through increasing their molecular affinity for targeting BTK, enabling them to be useful in treating BTK-mediated diseases.

Inhibition of melanogenesis by sodium 2-mercaptoethanesulfonate.

Sodium 2-mercaptoethanesulfonate (mesna) is a protective agent that is widely used in medicine because of its antioxidant effects. Recently, reactive oxygen species (ROS) were shown to increase pigmentation. Thus, ROS scavengers and inhibitors of ROS production may suppress melanogenesis. Forkhead box-O3a (FoxO3a) is an antimelanogenic factor that mediates ROS-induced skin pigmentation. In this study, we aimed to investigate the whitening effect of mesna and the signaling mechanism mediating this effect. Human melanoma (MNT-1) cells were used in this study. mRNA and protein expression were measured by real-time quantitative PCR and Western blotting analysis to track changes in FoxO3a-related signals induced by mesna. An immunofluorescence assay was performed to determine the nuclear translocation of FoxO3a. When MNT-1 melanoma cells were treated with mesna, melanin production and secretion decreased. These effects were accompanied by increases in FoxO3a activation and nuclear translocation, resulting in downregulation of four master genes of melanogenesis: MITF, TYR, TRP1, and TRP2. We found that mesna, an antioxidant and radical scavenger, suppresses melanin production and may therefore be a useful agent for the clinical treatment of hyperpigmentation disorders.

Protective effect of diphlorethohydroxycarmalol against oxidative stress-induced DNA damage and apoptosis in retinal pigment epithelial cells.

Purpose: Reactive oxygen species (ROS) contribute to the onset and progression of disease pathogenesis in a variety of organs, including age-related macular degeneration (AMD). Diphlorethohydroxycarmalol (DPHC), a phlorotannin compound, is one of the major components of the brown alga Ishige okamurae Yendo, and has been shown to have strong antioxidant capacity. The purpose of this study was to evaluate the protective effects of DPHC against oxidative stress (hydrogen peroxide, H2O2)-induced DNA damage and apoptosis in cultured ARPE19 retinal pigment epithelial (RPE) cells. Materials and methods: Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay. Intracellular ROS generation was measured by flow cytometer using 2',7'-dichlorofluorescin diacetate. The magnitude of apoptosis was measured by flow cytometry using the annexin V/propidium iodide double staining. DNA damage was evaluated by DNA fragmentation assay, comet assay and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analysis. To observe the mitochondrial membrane potential, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide staining was performed. In order to identify the underling mechanism of DPHC against H2O2-induced cellular alteration, we performed immune blotting. Results: The results of this study showed that the decreased survival rate brought about by H2O2 could be attributed to the induction of DNA damage and apoptosis accompanied by the increased production of ROS, which was remarkably reversed by DPHC. In addition, the loss of H2O2-induced mitochondrial membrane potential was significantly attenuated in the presence of DPHC. The inhibitory effect of DPHC on H2O2-induced apoptosis was associated with a reduced Bax/Bcl-2 ratio, the protection of the activation of caspase-9 and -3 and the inhibition of poly (ADP-ribose) polymerase cleavage, which was associated with the blockage of cytochrome c release to the cytoplasm. Conclusions: Our data proved that DPHC protects ARPE19 cells against H2O2-induced DNA damage and apoptosis by scavenging ROS and thus suppressing the mitochondrial-dependent apoptosis pathway. Therefore, this study suggests that DPHC has the therapeutic potential to prevent AMD by inhibiting oxidative stress-induced injury in RPE cells.

Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer.

Even when targets responsible for chemoresistance are identified, drug development is often hampered due to the poor druggability of these proteins. We systematically analyzed therapy-resistance with a large-scale cancer cell transcriptome and drug-response datasets and predicted the candidate drugs based on the gene expression profile. Our results implicated the epithelial-mesenchymal transition as a common mechanism underlying resistance to chemotherapeutic drugs. Notably, we identified ITGB3, whose expression was abundant in both drug resistance and mesenchymal status, as a promising target to overcome chemoresistance. We also confirmed that depletion of ITGB3 sensitized cancer cells to conventional chemotherapeutic drugs by modulating the NF-κB signaling pathway. Considering the poor druggability of ITGB3 and the lack of feasible drugs to directly inhibit this protein, we took an in silico screening for drugs mimicking the transcriptome-level changes caused by knockdown of ITGB3. This approach successfully identified atorvastatin as a novel candidate for drug repurposing, paving an alternative path to drug screening that is applicable to undruggable targets.

The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity.

Iron-salen, i.e., µ-oxo-N,N'-bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25 mg/kg)-induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.

SERBP1 affects homologous recombination-mediated DNA repair by regulation of CtIP translation during S phase.

DNA double-strand breaks (DSBs) are the most severe type of DNA damage and are primarily repaired by non-homologous end joining (NHEJ) and homologous recombination (HR) in the G1 and S/G2 phase, respectively. Although CtBP-interacting protein (CtIP) is crucial in DNA end resection during HR following DSBs, little is known about how CtIP levels increase in an S phase-specific manner. Here, we show that Serpine mRNA binding protein 1 (SERBP1) regulates CtIP expression at the translational level in S phase. In response to camptothecin-mediated DNA DSBs, CHK1 and RPA2 phosphorylation, which are hallmarks of HR activation, was abrogated in SERBP1-depleted cells. We identified CtIP mRNA as a binding target of SERBP1 using RNA immunoprecipitation-coupled RNA sequencing, and confirmed SERBP1 binding to CtIP mRNA in S phase. SERBP1 depletion resulted in reduction of polysome-associated CtIP mRNA and concomitant loss of CtIP expression in S phase. These effects were reversed by reconstituting cells with wild-type SERBP1, but not by SERBP1 ΔRGG, an RNA binding defective mutant, suggesting regulation of CtIP translation by SERBP1 association with CtIP mRNA. These results indicate that SERBP1 affects HR-mediated DNA repair in response to DNA DSBs by regulation of CtIP translation in S phase.