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Supplementary Figure 2: Knockdown efficacy of siRNA treatment

Supplementary Figure 1: Transfection efficacy of siRNA treatment

Supplementary Table 3: List of STK11-associated markers in lung cancer cell lines

Supplementary Table 1: Categorization of 318 cancer cell lines and the occurrence of category-sensitive (and specific) gene expression markers

Growing demands for comprehending complicated nano-scale phenomena in atomic resolution has attracted in-situ transmission electron microscopy (TEM) techniques for understanding their dynamics. However, simple to safe TEM sample preparation for in-situ observation has been limited. Here, we suggested the optical microscopy based micro-manipulating system for transferring TEM samples. By adopting our manipulator system, several types of samples from nano-wires to plate-like thin samples were transferred on micro-electro mechanical systems (MEMS) chip in a single step. Furthermore, the control of electrostatic force between the sample and the probe tip is found to be a key role in transferring process.

Magnetic skyrmions are topologically protected spin textures that have nanoscale dimensions and can be manipulated by an electric current. These properties make the structures potential information carriers in data storage, processing and transmission devices. However, the development of functional all-electrical electronic devices based on skyrmions remains challenging. Here we show that the current-induced creation, motion, detection and deletion of skyrmions at room temperature can be used to mimic the potentiation and depression behaviours of biological synapses. In particular, the accumulation and dissipation of magnetic skyrmions in ferrimagnetic multilayers can be controlled with electrical pulses to represent the variations in the synaptic weights. Using chip-level simulations, we demonstrate that such artificial synapses based on magnetic skyrmions could be used for neuromorphic computing tasks such as pattern recognition. For a handwritten pattern dataset, our system achieves a recognition accuracy of ~89%, which is comparable to the accuracy achieved with software-based ideal training (~93%). The electrical current-induced creation, motion, detection and deletion of skyrmions in ferrimagnetic multilayers can be used to mimic the behaviour of biological synapses, providing devices that could be used for neuromorphic computing tasks such as pattern recognition.

IL-31 is involved in pruritus in atopic dermatitis (AD) and the pathogenesis of AD. However, the mechanism of IL-31 production is not fully understood. We sought to investigate the association between CD45RO+CLA+H4R+ T cells and IL-31 production. Immunofluorescence studies were performed retrospectively on punch-biopsy specimens from five people with AD and three healthy controls. In addition, blood samples were collected prospectively from eight patients with AD and eight healthy controls for sorting CD45RO+CLA+H4R+ T cells. There was no overlap of patients between the biopsy group and the blood sampling group. Sorted cells were stimulated with 4-methylhistamine (4MH), and the level of IL-31 was measured by an enzyme-linked immunosorbent assay. Immunofluorescence showed co-localization of H4R and IL-31 in lesional AD skin but not in normal skin of healthy controls. The proportion of CLA+H4R+ T cells among CD3+CD45RO+ lymphocytes was 18.3 ± 6.2% in patients with AD and 11.2 ± 7.6% in healthy controls. In the AD group, production of IL-31 by CD45RO+CLA+H4R+ T cells increased from 32.4 ± 13.3 pg/mL to 47.5 ± 18.7 pg/mL by 4MH stimulation after 24 h (p &lt, 0.001). However, in the control group, production of IL-31 was 20.1 ± 10.6 pg/mL without and 22.1 ± 9.3 pg/mL with 4MH stimulation (p &gt, 0.05). According to our study, CD45RO+CLA+H4R+ T cells are an important source of IL-31 in AD, and may be a target for treatment of IL-31-induced pruritus.

The origin of 2D electron gas (2DEG) at LaAlO3/SrTiO3 (LAO/STO) interfaces has remained highly controversial since its discovery. Various models are proposed, which include electronic reconstruction via surface‐to‐interface charge transfer and defect‐mediated doping involving cation intermixing or oxygen vacancy (V O) formation. It is shown that the polar field‐assisted V O formation at the LAO/STO surface plays critical roles in the 2DEG formation and concurrent structural transition. Comprehensive scanning transmission electron microscopy analyses, in conjunction with density functional theory calculations, demonstrate that V O forming at the LAO/STO surface above the critical thickness (t c) cancels the polar field by doping the interface with 2DEG. The antiferrodistortive (AFD) octahedral rotations in LAO, which are suppressed below the t c, evolve with the formation of V O above the t c. The present study reveals that local symmetry breaking and shallow donor behavior of V O induce the AFD rotations and relieve the electrical field by electron doping the oxide heterointerface., Comprehensive scanning transmission electron microscopy analyses, in conjunction with density functional theory calculations, demonstrate that oxygen vacancy forming at LaAlO3/SrTiO3 (001) surface above the critical thickness (t c) cancels the polar electric field by doping the interface with two‐dimensional electron gas. The antiferrodistortive octahedral rotations in LaAlO3, which are suppressed below t c, evolve with the formation of oxygen vacancy above t c.

The electric field-induced modifications of magnetic anisotropy in CoFeB/MgO systems are studied using X-ray resonant magnetic scattering and magneto-optical Kerr effect. Voltage dependent changes of the magnetic anisotropy of −12.7 fJ/Vm and −8.32 fJ/Vm are observed for Ta/CoFeB/MgO and Hf/CoFeB/MgO systems, respectively. This implies that the interfacial perpendicular magnetic anisotropy is reduced (enhanced) when electron density is increased (decreased). X-ray resonant magnetic scattering measurements reveal that the small in-plane magnetic component of the remanent state of CoFeB/MgO systems with weak magnetic anisotropy changes depending on the applied voltage leading to modification of the magnetic anisotropy at the CoFeB/MgO interface.

Current-induced magnetic domain wall (DW) motion is an important operating principle of spintronic devices. Injected current generates spin torques (STs) on the DWs in two ways. One is the spin transfer from magnetic domains to the walls by the current flowing in the magnet. Current flow in attached heavy metals also generates another ST because of the spin-Hall effect. Both phenomena explain the wall motions well; therefore, their respective contribution is an important issue. Here, we show the simultaneous measurement of both torques by using magnetic facet domains that form mountain-shaped domains with straight walls. When the STs and the external magnetic field push the walls in opposite directions, the walls should have equilibrium angles to create balanced states. Such angles can be modulated by an additional in-plane magnetic field. Angle measurements distinguish the STs because each torque has a distinct mechanism related to the DW structure.

Cancer precision medicine requires clinically actionable biomarkers for patient stratification and a better prediction of clinical outcome. Although thousands of cancer-enriched mutated genes have been reported by global sequencing projects, to date, only a few oncogenic mutations have been confirmed as effective biomarkers in cancer therapies. The low frequency and varied profile (i.e., allele frequency, mutation position) of mutant genes among cancer types limit the utility of predictive biomarkers. The recent explosion of cancer transcriptome and phenotypic screening data provides another opportunity for finding transcript-level biomarkers and targets, thus overcoming the limitation of cancer mutation analyses. Technological developments enable the rapid and extensive discovery of potential target-biomarker combinations from large-scale transcriptome-level screening combined with physiologically relevant phenotypic assays. Here, we summarized recent progress as well as discussed the outlook of transcriptome-oriented data mining strategies and phenotypic assays for the identification of non-genetic biomarkers and targets in cancer drug discovery.

Diffuse alveolar hemorrhage (DAH) may occur with vasculitis, infection, and coagulation disorders. In patients with hematologic malignancies such as leukemia, lymphoma and multiple myeloma, the risk of death from DAH is 70%. Although their effectiveness remains uncertain, corticosteroids are the mainstay of treatment. It is not easy to determine the use of corticosteroids because of the adverse effects such as worsening of infections, gastrointestinal (GI) bleeding and poor blood glucose control. Retrospective analysis was performed at a single medical center in South Korea from August 2005 to April 2018. DAH was diagnosed by strict clinical criteria and the presence of progressively bloodier return on bronchoalveolar lavage. 49 patients had alveolar hemorrhage (26 with non-infection associated hemorrhage(IAH), 23 with IAH). Patients who received corticosteroids had 60-day survival of 31% (95% CI, 25%–39%), compared with 33% (95% CI, 21%–45%) for those who did not (P=0.78). There are no differences about mortality rate, weaning rate of mechanical ventilator, intensive care unit (ICU) stay, hospital length of stay and complications(ventilator associated pneumonia, GI bleeding and catheter related blood stream infection). Naturally, the insulin requirement was high in the corticosteroid treatment group. Regardless of infection in alveolar hemorrhage with hematologic malignancy, the survival rate did not increase or the ICU stay did not decrease in the steroid treatment group. So, the use of steroids especially high dose steroid in diffuse alveolar hemorrhage should be considered be carefully.

Although a large amount of screening data comprising target genes and/or drugs tested against cancer cell line panels are available, different assay conditions and readouts limit the integrated analysis and batch-to-batch comparison of these data. Here, we systematically produced and analyzed the anticancer effect of the druggable targetome to understand the varied phenotypic outcomes of diverse functional classes of target genes. A library of siRNAs targeting ~4,800 druggable genes was screened against cancer cell lines under 2D and/or 3D assay conditions. The anticancer effect was simultaneously measured by quantifying cell proliferation and/or viability. Hit rates varied significantly depending on assay conditions and/or phenotypic readouts. Functional classes of hit genes were correlated with the microenvironment difference between the 2D monolayer cell proliferation and 3D sphere formation assays. Furthermore, multiplexing of cell proliferation and viability measures enabled us to compare the sensitivity and resistance responses to the gene knockdown. Many target genes that inhibited cell proliferation increased the single-cell-level viability of surviving cells, leading to an increase in self-renewal potential. In this study, combinations of parallel 2D/3D assays and multiplexing of cell proliferation and viability measures provided functional insights into the varied phenotypic outcomes of the cancer targetome.

Since the discovery of ferromagnetic two-dimensional (2D) van der Waals (vdW) crystals, significant interest on such 2D magnets has emerged, inspired by their appealing properties and integration with other 2D family for unique heterostructures. In known 2D magnets, spin-orbit coupling (SOC) stabilizes perpendicular magnetic anisotropy (PMA). Such a strong SOC could also lift the chiral degeneracy, leading to the formation of topological magnetic textures such as skyrmions through the Dzyaloshinskii-Moriya interaction (DMI). Here, we report the experimental observation of N\'eel-type chiral magnetic skyrmions and their lattice (SkX) formation in a vdW ferromagnet Fe3GeTe2 (FGT). We demonstrate the ability to drive individual skyrmion by short current pulses along a vdW heterostructure, FGT/h-BN, as highly required for any skyrmion-based spintronic device. Using first principle calculations supported by experiments, we unveil the origin of DMI being the interfaces with oxides, which then allows us to engineer vdW heterostructures for desired chiral states. Our finding opens the door to topological spin textures in the 2D vdW magnet and their potential device application., Comment: 26 pages, 5 figures

The field of magnetic skyrmions has been actively investigated across a wide range of topics during the last decades. In this topical review, we mainly review and discuss key results and findings in skyrmion research since the first experimental observation of magnetic skyrmions in 2009. We particularly focus on the theoretical, computational and experimental findings and advances that are directly relevant to the spintronic applications based on magnetic skyrmions, i.e. their writing, deleting, reading and processing driven by magnetic field, electric current and thermal energy. We then review several potential applications including information storage, logic computing gates and non-conventional devices such as neuromorphic computing devices. Finally, we discuss possible future research directions on magnetic skyrmions, which also cover rich topics on other topological textures such as antiskyrmions and bimerons in antiferromagnets and frustrated magnets., Comment: 80 pages, 14 figures

How might we measure the Dzyaloshinskii-Moriya interaction (DMI), which can be so important in spintronics? When this magnetic exchange interaction is small, knowing the actual value becomes significant, since operating speed is proportional to it in spintronic devices based on domain-wall movement. The authors develop a method for measuring a weak DMI: When current and a magnetic field are applied to a perpendicularly magnetized thin film, the characteristic morphology of the magnetic domains that form can be observed, and the DMI obtained from the angles present in the unusual domain shapes. This will improve the engineering of spintronic logic and memory applications.

Cancer stem-like cells (CSLCs) contribute to the initiation and recurrence of tumors and to their resistance to conventional therapies. In this study, small interfering RNA (siRNA)-based screening of ∼4800 druggable genes in 3-dimensional CSLC cultures in comparison to 2-dimensional bulk cultures of U87 glioma cells revealed 3 groups of genes essential for the following: survival of the CSLC population only, bulk-cultured population only, or both populations. While diverse biologic processes were associated with siRNAs reducing the bulk-cultured population, CSLC-eliminating siRNAs were enriched in a few functional categories, such as lipid metabolism, protein metabolism, and gene expression. Interestingly, siRNAs that selectively reduced CSLC only were found to target genes for cholesterol and unsaturated fatty acid synthesis. The lipidomic profile of CSLCs revealed increased levels of monounsaturated lipids. Pharmacologic blockage of these target pathways reduced CSLCs, and this effect was eliminated by addition of downstream metabolite products. The present CSLC-sensitive target categories provide a useful resource that can be exploited for the selective elimination of CSLCs.-Song, M., Lee, H., Nam, M.-H., Jeong, E., Kim, S., Hong, Y., Kim, N., Yim, H. Y., Yoo, Y.-J., Kim, J. S., Kim, J.-S., Cho, Y.-Y., Mills, G. B., Kim, W.-Y., Yoon, S. Loss-of-function screens of druggable targetome against cancer stem-like cells.

Spitz nevus commonly appears as a solitary lesion. A 12-year-old male patient presented with a 6-month history of several pigmented lesions on his trunk and lower extremities. He had undergone chemoradiotherapy and unrelated umbilical cord blood transplantation against recurring acute lymphoblastic leukemia for 6 years. After that, several pigmented lesions abruptly developed on his trunk and lower extremities, and the number of those increased significantly. Pathologically, the diagnosis of multiple Spitz nevi was made. In a clinical correlation, we diagnosed multiple Spitz nevi resulting from such an immunocompromised condition. This is the first description of clinical, dermoscopic, and histopathologic features of multiple Spitz nevi in the hematopoietic cell transplantation (HSCT) recipient child.

Magnetic skyrmions are topologically protected spin textures with attractive properties suitable for high-density and low-power spintronic device applications. Much effort has been dedicated to understanding the dynamical behaviours of the magnetic skyrmions. However, experimental observation of the ultrafast dynamics of this chiral magnetic texture in real space, which is the hallmark of its quasiparticle nature, has so far remained elusive. Here, we report nanosecond-dynamics of a 100nm-diameter magnetic skyrmion during a current pulse application, using a time-resolved pump-probe soft X-ray imaging technique. We demonstrate that distinct dynamic excitation states of magnetic skyrmions, triggered by current-induced spin–orbit torques, can be reliably tuned by changing the magnitude of spin–orbit torques. Our findings show that the dynamics of magnetic skyrmions can be controlled by the spin–orbit torque on the nanosecond time scale, which points to exciting opportunities for ultrafast and novel skyrmionic applications in the future., Magnetic skyrmions are potentially suitable for future spintronic devices, but their dynamical behaviour in real space remains elusive. Here, Woo et al. report nanosecond-dynamics of a 100nm-size magnetic skyrmion triggered by current-induced spin-orbit torques.

Spintronic devices based on magnetic skyrmions are a promising candidate for next-generation memory applications due to their nanometre-size, topologically-protected stability and efficient current-driven dynamics. Since the recent discovery of room-temperature magnetic skyrmions, there have been reports of current-driven skyrmion displacement on magnetic tracks and demonstrations of current pulse-driven skyrmion generation. However, the controlled annihilation of a single skyrmion at room temperature has remained elusive. Here we demonstrate the deterministic writing and deleting of single isolated skyrmions at room temperature in ferrimagnetic GdFeCo films with a device-compatible stripline geometry. The process is driven by the application of current pulses, which induce spin-orbit torques, and is directly observed using a time resolved nanoscale X-ray imaging technique. We provide a current-pulse profile for the efficient and deterministic writing and deleting process. Using micromagnetic simulations, we also reveal the microscopic mechanism of the topological fluctuations that occur during this process., Comment: 27 pages, 4 figures

The recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage- and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here, we leverage these resources to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes. Among a total of 1,455 category-specific expression patterns, the expression of cAMP phosphodiesterase-4D (PDE4D) with 11 isoforms, one of the PDE4(A-D) subfamilies, was predicted to be regulated by a mutant form of serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) present in lung cancer. STK11/LKB1 is the primary upstream kinase of adenine monophosphate–activated protein kinase (AMPK). Subsequently, we found that the knockdown of PDE4D gene expression inhibited proliferation of STK11-mutated lung cancer lines. Furthermore, challenge with a panel of PDE4-specific inhibitors was shown to selectively reduce the growth of STK11-mutated lung cancer lines. Thus, we show that multidimensional analysis of a well-characterized large-scale panel of cancer cell lines provides unprecedented opportunities for the identification of unexpected oncogenic mechanisms and mutation-specific drug targets. Mol Cancer Ther; 13(10); 2463–73. ©2014 AACR.

Low-molecular weight saturated aliphatic aldehydes (LSAAs), which include propanal, butanal, pentanal, hexanal, octanal, nonanal and heptanal, are volatile organic compounds (VOCs). They are ubiquitous in the environment of our daily life. Although LSAAs are harmful, with mutagenic and carcinogenic effects, the mechanisms underlying the toxicity of volatile aldehydes are still unclear. Therefore, in this study, we performed genome-wide expression profile analysis of A549 human alveolar epithelial cells exposed to seven LSSAs. We selected genes whose expression was changed more than 1.5-fold in A549 cells exposed to LSAAs by analysis of gene expression profiles using human oligonucleotide chips. Through gene expression profiling, we showed that LSSAs are related to the key biological processes “defense response”, “inflammatory response” and “immune response” in gene ontology (GO) analysis. In addition, we identified two genes that were up-regulated (GREB1, BC009808) and four that were down-regulated (UCP1, TCP11, FNDC3A, LOC645206) by all the tested LSAAs. Our data suggest that LSAAs exert toxic effects on A549 cells by modulating mRNA expression. Moreover, we suggest that genes expressed in response to LSAAs represent a molecular signature that can be widely used, in combination with more traditional techniques, to assess and predict the toxicity caused by exposure to LSAAs.

In spintronic devices consisting of ferromagnetic/nonmagnetic systems, the ferromagnet-induced magnetic moment in the adjacent nonmagnetic material significantly influences the spin transport properties. In this study, such magnetic proximity effect in a Pd/Co/Pd trilayer system is investigated by x-ray magnetic circular dichroism and x-ray resonant magnetic reflectivity, which enables magnetic characterizations with element and depth resolution. We observe that the total Pd magnetic moments induced at the top Co/Pd interface are significantly larger than the Pd moments at the bottom Pd/Co interface, whereas transmission electron microscopy and reflectivity analysis indicate the two interfaces are nearly identical structurally. Such asymmetry in magnetic proximity effects could be important for understanding spin transport characteristics in ferromagnetic/nonmagnetic systems and its potential application to spin devices.

Toxicology studies assessing the risk of environmental toxicants in humans frequently use in vitro systems in combination with transcriptomics to characterize toxic responses. Thus far, changes have mostly been investigated at the mRNA level. Recently, microRNAs (miRNAs) have attracted attention because they are powerful negative regulators of mRNA levels and thus may be responsible for the modulation of important mRNA networks implicated in toxicity. This study aimed to identify possible miRNA-mRNA networks as novel interactions at the gene expression level after exposure to environmental toxicants. Benzo[k]fluoranthene (BF), a polycyclic aromatic hydrocarbon that is ubiquitously distributed throughout the environment, was used. We analyzed mRNA and miRNA profiles in HepG2 cells, a human liver cell line, using a human oligonucleotide chip. Changes in miRNA expression in response to BF, in combination with multiple alterations of mRNA levels, were observed. Many of the altered mRNAs were targets of altered miRNAs. Using gene ontology (GO) and KEGG pathway analysis, we determined the relevance of such miRNA deregulation to carcinogenicity. This revealed five miRNAs that appear to participate in specific BFresponsive pathways relevant to genotoxicity and carcinogenicity, such as DNA damage repair, apoptosis, cancer, VEGF signaling, and Jak-STAT signaling. Our results indicate that miR-146a, miR-365, let-7f, miR-199b-5p, and miR-30c-1* are novel players in the BF response. Therefore, this study demonstrates the added value of an integrated miRNA-mRNA approach for identification of the molecular mechanisms induced by BF in an in vitro human model.

Dibutyl phthalates (DBP) are widely used as plasticizers to soften and increase the flexibility of polyvinyl chloride plastics, although they can leach into the surrounding environment. Many studies have reported that changes in thyroid function are linked to a variety of chemicals in the environment. Although the mechanism is not known, DBP decreases T3 and T4, and downregulates the sodium/iodide symporter promoter in the thyroid. We undertook a genome-wide analysis of transcriptional responses in human thyroid follicular carcinoma FTC-238 cells to non-toxic doses of DBP (100 μM). Whole human genome microarrays detected a total of 4,480 genes that exhibited altered expression after exposure to non-toxic doses of DBP compared with the vehicle control. We found that 2,218 and 2,262 genes showed different expression levels following treatment with non-toxic doses of DBP (1.5-fold (p

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) that is carcinogenic to humans. Although the environmental distribution and metabolism of BaP have been reported and many researchers are performing risk-assessment and toxicological studies of BaP by means of physical and chemical measurements, only a few studies have examined the expression of mRNAs and their functions in BaP-induced toxicity. Toxicogenomic technology, a new paradigm in toxicity screening, is a useful approach for evaluating the toxic properties of environmental pollutants. We analyzed gene expression profiles using human oligonucleotide chips and identified genes in human hepatocellular carcinoma (HepG2) cells whose expression changed > 1.5-fold after exposure to BaP. The expression of 4,048 and 3,926 genes was up-and down-regulated > 1.5-fold (P < 0.01), respectively, after exposure. Gene ontology (GO) analysis of these genes revealed significant enrichment in several key biological processes related to DNA damage, including DNA repair, cell cycle arrest, and apoptosis. We also performed a contrastive study of cellular effects in HepG2 cells exposed to BaP, and identified increased expression of related genes, cell cycle arrest, and apoptotic cells. These results suggest that genetic markers of BaP-induced toxicity may be molecular blueprints that can be more widely implemented in combination with more traditional techniques for assessment and prediction.