Highly Conductive Covalent-Organic Framework Films.

Chemically inert organic networks exhibiting electrical conductivity comparable to metals can advance organic electronics, catalysis, and energy storage systems. Covalent-organic frameworks (COFs) have emerged as promising materials for those applications due to their high crystallinity, porosity, and tunable functionality. However, their low conductivity has limited their practical utilization. In this study, copper-coordinated-fluorinated-phthalocyanine and 2,3,6,7-tetrahydroxy-9,10-anthraquinone-based COF (CuPc-AQ-COF) films with ultrahigh conductivity are developed. The COF films exhibit an electrical conductivity of 1.53 × 103 S m-1 and a Hall mobility of 6.02 × 102 cm2 V-1 s-1 at 298 K, reaching the level of metals. The films are constructed by linking phthalocyanines and anthraquinones through vapor-assisted synthesis. The high conductivity properties of the films are attributed to the molecular design of the CuPc-AQ-COFs and the generation of high-quality crystals via the vapor-assisted method. Density functional theory analysis reveals that an efficient donor-acceptor system between the copper-coordinated phthalocyanines and anthraquinones significantly promotes charge transfer. Overall, the CuPc-AQ-COF films set new records of COF conductivity and mobility and represent a significant step forward in the development of COFs for electronic, catalytic, and electrochemical applications.

Polyarylene-Based Anion Exchange Membranes for Fuel Cells.

Anion exchange membrane fuel cell (AEMFC) is an emerging and promising technology that can help realize a carbon-neutral, sustainable economy. Also, compared to the proton exchange membrane counterpart, AEMFC can achieve comparable cell outputs with lower costs due to the applicability of non-platinum group metal electrocatalysts for the reaction on the electrodes' surfaces. However, the wide application of the AEMFCs has been impeded by the unsatisfactory stability and performance of the hydroxide-conductive membranes in the past. Recently researchers have made breakthroughs using polyarylene (PA)-based AEMs. This article summarizes the recent advances of a class of AEMs with aromatic backbone without ether bonds, mainly synthesized by Friedel-Crafts polycondensation. Such PA-based AEMs showed high chemical/mechanical stabilities and ionic conductivity, and even the fuel cell with those AEMs showed impressive peak power density of up to 2.58 W cm-2. In this concept article, we classify major strategies for making PA-based AEMs to show the recent trends, highlight synthesis, characterization, and properties, and provide a brief outlook.

Highly Conductive Imidazolate Covalent Organic Frameworks with Ether Chains as Solid Electrolytes for Lithium Metal Batteries.

Poly(ethylene oxide) (PEO)-based electrolytes are often used for Li+ conduction as they can dissociate the Li salts efficiently. However, high entanglement of the chains and lack of pathways for rapid ion diffusion limit their applications in advanced batteries. Recent developments in ionic covalent organic frameworks (iCOFs) showed that their highly ordered structures provide efficient pathways for Li+ transport, solving the limitations of traditional PEO-based electrolytes. Here, we present imidazolate COFs, PI-TMEFB-COFs, having methoxyethoxy chains, synthesized by Debus-Radziszewski multicomponent reactions and their ionized form, Li+@PI-TMEFB-COFs, showing a high Li+ conductivity of 8.81 mS cm-1 and a transference number of 0.974. The mechanism for such excellent electrochemical properties is that methoxyethoxy chains dissociate LiClO4, making free Li+, then those Li+ are transported through the imidazolate COFs' pores. The synthesized Li+@PI-TMEFB-COFs formed a stable interface with Li metal. Thus, employing Li+@PI-TMEFB-COFs as the solid electrolyte to assemble LiFePO4 batteries showed an initial discharge capacity of 119.2 mAh g-1 at 0.5 C, and 82.0 % capacity and 99.9 % Coulombic efficiency were maintained after 400 cycles. These results show that iCOFs with ether chains synthesized via multicomponent reactions can create a new chapter for making solid electrolytes for advanced rechargeable batteries.

Anthraquinone-Based Silicate Covalent Organic Frameworks as Solid Electrolyte Interphase for High-Performance Lithium-Metal Batteries.

Lithium (Li)-metal batteries (LMBs) possess the highest theoretical energy density among current battery designs and thus have enormous potential for use in energy storage. However, the development of LMBs has been severely hindered by safety concerns arising from dendrite growth and unstable interphases on the Li anode. Covalent organic frameworks (COFs) incorporating either redox-active or anionic moieties on their backbones have high Li-ion (Li+) conductivities and mechanical/chemical stabilities, so are promising for solid electrolyte interphases (SEIs) in LMBs. Here, we synthesized anthraquinone-based silicate COFs (AQ-Si-COFs) that contained both redox-active and anionic sites via condensation of tetrahydroxyanthraquinone with silicon dioxide. The nine Li+-mediated charge/discharge processes enabled the AQ-Si-COF to demonstrate an ionic conductivity of 9.8 mS cm-1 at room temperature and a single-ion-conductive transference number of 0.92. Computational studies also supported the nine Li+ mechanism. We used AQ-Si-COF as the solid electrolyte interphase on the Li anode. The LMB cells with a LiCoO2 cathode attained a maximum reversible capacity of 188 mAh g-1 at 0.25 C during high-voltage operation. Moreover, this LMB cell demonstrated suppressed dendrite growth and stable cyclability, with its capacity decreasing by less than 3% up to 100 cycles. These findings demonstrate the effectiveness of our redox-active and anionic COFs and their practical utility as SEI in LMB.

Single-cell RNA sequencing of a poorly metastatic melanoma cell line and its subclones with high lung and brain metastasis potential reveals gene expression signature of metastasis with prognostic implication.

The molecular mechanisms underlying melanoma metastasis remain poorly understood. In this study, we aimed to delineate the mechanisms underlying gene expression alterations during metastatic potential acquisition and characterize the metastatic subclones within primary cell lines. We performed single-cell RNA sequencing of a poorly metastatic melanoma cell line (WM239A) and its subclones with high metastatic potential to the lung (113/6-4L) and the brain (131/4-5B1 and 131/4-5B2). Unsupervised clustering of 8173 melanoma cells identified three distinct clusters according to cell type ('Primary', 'Lung' and 'Brain' clusters) with differential expression of MITF and AXL pathways and putative cancer and cell cycle drivers, with the lung cluster expressing intermediate but distinct gene profiles between primary and brain clusters. Principal component (PC) analysis revealed that PC2 (the second PC), which was positively associated with MITF expression and negatively with AXL pathways, primarily segregated cell types, in addition to PC1 of the cell cycle pathway. Pseudotime trajectory and RNA velocity analyses suggested the existence of cellular subsets with metastatic potential in the Primary cluster and an association between PC2 signature alteration and metastasis potential acquisition. Analysis of The Cancer Genome Atlas melanoma samples by clustering into PC2-high and -low clusters by quartiles of PC2 signature expression revealed that the PC2-high cluster was an independent significant factor for poor prognosis (p-value = 0.003) with distinct genomic and transcriptomic characteristics, compared to the PC2-low cluster. In conclusion, we identified signatures of melanoma metastasis with prognostic significance and putative pro-metastatic subclones within a primary cell line.

Targeted deep sequencing reveals genomic alterations of actinic keratosis/cutaneous squamous cell carcinoma in situ and cutaneous squamous cell carcinoma.

Actinic keratosis (AK) and cutaneous squamous cell carcinoma in situ (CIS) are two of the most common precursors of cutaneous squamous cell carcinoma (cSCC). However, the genomic landscape of AK/CIS and the drivers of cSCC progression remain to be elucidated. The aim of our study was to investigate the genomic alterations between AK/CIS and cSCC in terms of somatic mutations and copy number alterations (CNAs). We performed targeted deep sequencing of 160 cancer-related genes with a median coverage of 515× for AK (N = 9), CIS (N = 9), cSCC lesions (N = 13), and matched germline controls from 17 patients. cSCC harboured higher abundance of total mutations, driver mutations and CNAs than AK/CIS. Driver mutations were found in TP53 (81%), NOTCH1 (32%), RB1 (26%) and CDKN2A (19%). All AK/CIS and cSCC lesions (93.5%), except two, harboured TP53 or NOTCH1 mutations, some of which were known oncogenic mutations or reported mutations in normal skin. RB1 driver mutations were found in CIS/cSCC (36.4%) but not in AK. CDKN2A driver mutations were found more frequently in cSCC (30.8%) than in AK/CIS (11.1%). Among recurrent (≥3 samples) CNAs (gain in MYC and PIK3CA/SOX2/TP63; loss in CDKN2A and RB1), MYC (8q) gain and CDKN2A (9p) loss were more frequently detected in cSCC (30.8%) than in AK/CIS (11.1%). Ultraviolet was responsible for the majority of somatic mutations in both AK/CIS and cSCC. Our study revealed that AK/CIS lesions harbour prevalent TP53 or NOTCH1 mutations and that additional somatic mutations and CNAs may lead to cSCC progression in AK/CIS lesions.

Poly(Ethylene Piperidinium)s for Anion Exchange Membranes.

The lack of anion exchange membranes (AEMs) that possess both high hydroxide conductivity and stable mechanical and chemical properties poses a major challenge to the development of high-performance fuel cells. Improving one side of the balance between conductivity and stability usually means sacrificing the other. Herein, we used facile, high-yield chemical reactions to design and synthesize a piperidinium polymer with a polyethylene backbone for AEM fuel cell applications. To improve the performance, we introduced ionic crosslinking into high-cationic-ratio AEMs to suppress high water uptake and swelling while further improving the hydroxide conductivity. Remarkably, PEP80-20PS achieved a hydroxide conductivity of 354.3 mS cm-1 at 80 °C while remaining mechanically stable. Compared with the base polymer PEP80, the water uptake of PEP80-20PS decreased by 69 % from 813 % to 350 %, and the swelling decreased substantially by 85 % from 350.0 % to 50.2 % at 80 °C. PEP80-20PS also showed excellent alkaline stability, 84.7 % remained after 35 days of treatment with an aqueous KOH solution. The chemical design in this study represents a significant advancement toward the development of simultaneously highly stable and conductive AEMs for fuel cell applications.

Single-cell RNA sequencing reveals the existence of pro-metastatic subpopulation within a parental B16 murine melanoma cell line.

The mechanism of melanoma metastasis is poorly understood, especially at the single-cell level. To understand the evolution from primary melanoma to metastasis, we investigated single-cell transcriptome profiles of parental B16 melanoma cells (B16F0) and its highly metastatic subclone (B16F10). Genomic alterations between cells were also analyzed by whole-exome sequencing. We identified 274 differentially expressed genes (DEGs) in B16F10, including upregulated genes related to metastasis, Lgals3, Sparc, Met, and Tmsb4x, and downregulated Mitf pathway genes, Ptgds, Cyb5a, and Cd63. The proportion of cycling cells and cells highly expressing Kdm5b was significantly high in B16F10 cells. Among the five subclusters of B16 cells (C1-5), C3/C4 clusters comprised both B16F0 and B16F10 cells and exhibited intermediate DEG patterns, whereas the C5 cluster mostly comprised B16F10 and showed typical metastatic characteristics. In trajectory analysis, the C4 cluster in B16F0, which showed unique characteristics (mainly cycling cells and upregulation of Mitf pathway genes), have transition potential to the C5 cluster (B16F10). Regarding genomic alterations, stepwise evolution with shared mutations, including Braf, Pten, and Trp53, and further specific alterations led to metastatic development. Our results provide deeper understanding of melanoma metastasis at the single-cell level, thus aiding further studies in melanoma metastasis control.

Nanofiber Composite for Improved Water Retention and Dendrites Suppression in Flexible Zinc-Air Batteries.

Water loss of the gel polymer electrolytes (GPEs) and dendrites growth on Zn anode are overriding obstacles to applying flexible zinc-air batteries (ZABs) for wearable electronic devices. Nearly all previous efforts aim at developing novel GPEs with enhanced water retention and therefore elongate their lifespan. Herein, a facile interface engineering strategy is proposed to retard the water loss of GPE from the half-open structured air cathode. In detail, the poly(ethylene vinyl acetate)/carbon powder (PEVA-C) nanofiber composite interface layer with features of hydrophobicity, high conductivity, air permeability, and flexibility are prepared on the carbon cloth and set up between the GPE and electrode. The as-assembled ZAB with simple alkaline PVA GPE exhibits an impressive cycle life of 230 h, which outperforms ZAB without the PEVA-C nanofibers interface layer by 14 times. Additionally, the growth of Zn dendrites can be suppressed due to the tardy water loss of GPE.

Pathogenic NF1 truncating mutation and copy number alterations in a dedifferentiated liposarcoma with multiple lung metastasis: a case report.

BACKGROUND: Dedifferentiated liposarcoma (DDLPS), which accounts for an estimated 15-20% of liposarcomas, is a high-grade and aggressive malignant neoplasm, exhibiting a poor response to available therapeutic agents. However, genetic alteration profiles of DDLPS as well as the role of NF1 mutations have not been studied extensively. CASE PRESENTATION: The current study reports a patient presenting with rapidly growing DDLPS accompanied by multiple lung and pleural metastases, in whom whole-exome sequencing revealed a NF1 truncating mutation of the known pathogenic variant, c.C7486T, p.R2496X, as well as multiple copy number alterations (CNAs), including the well-known 12q13-15 amplification, and multiple chromothripsis events encompassing potential cancer-related genes. CONCLUSIONS: Our results suggest that, in addition to the 12q13-15 amplification, NF1 inactivation mutation and other CNAs may contribute to DDLPS tumorigenesis accompanied by aggressive clinical features.

Ionic Highways from Covalent Assembly in Highly Conducting and Stable Anion Exchange Membrane Fuel Cells.

A major challenge in the development of anion exchange membranes for fuel cells is the design and synthesis of highly stable (chemically and mechanically) conducting membranes. Membranes that can endure highly alkaline environments while rapidly transporting hydroxides are desired. Herein, we present a design using cross-linked polymer membranes containing ionic highways along charge-delocalized pyrazolium cations and homoconjugated triptycenes. These ionic highway membranes show improved performance. Specifically, a conductivity of 111.6 mS cm-1 at 80 °C was obtained with a low 7.9% water uptake and 0.91 mmol g-1 ion exchange capacity. In contrast to existing materials, ionic highways produce higher conductivities at reduced hydration and ionic exchange capacities. The membranes retain more than 75% of their initial conductivity after 30 days of an alkaline stability test. The formation of ionic highways for ion transport is confirmed by density functional theory and Monte Carlo studies. A single cell with platinum metal catalysts at 80 °C showed a high peak density of 0.73 W cm-2 (0.45 W cm-2 from a silver-based cathode) and stable performance throughout 400 h tests.

Stretchable nanoparticle conductors with self-organized conductive pathways.

Research in stretchable conductors is fuelled by diverse technological needs. Flexible electronics, neuroprosthetic and cardiostimulating implants, soft robotics and other curvilinear systems require materials with high conductivity over a tensile strain of 100 per cent (refs 1-3). Furthermore, implantable devices or stretchable displays need materials with conductivities a thousand times higher while retaining a strain of 100 per cent. However, the molecular mechanisms that operate during material deformation and stiffening make stretchability and conductivity fundamentally difficult properties to combine. The macroscale stretching of solids elongates chemical bonds, leading to the reduced overlap and delocalization of electronic orbitals. This conductivity-stretchability dilemma can be exemplified by liquid metals, in which conduction pathways are retained on large deformation but weak interatomic bonds lead to compromised strength. The best-known stretchable conductors use polymer matrices containing percolated networks of high-aspect-ratio nanometre-scale tubes or nanowires to address this dilemma to some extent. Further improvements have been achieved by using fillers (the conductive component) with increased aspect ratio, of all-metallic composition, or with specific alignment (the way the fillers are arranged in the matrix). However, the synthesis and separation of high-aspect-ratio fillers is challenging, stiffness increases with the volume content of metallic filler, and anisotropy increases with alignment. Pre-strained substrates, buckled microwires and three-dimensional microfluidic polymer networks have also been explored. Here we demonstrate stretchable conductors of polyurethane containing spherical nanoparticles deposited by either layer-by-layer assembly or vacuum-assisted flocculation. High conductivity and stretchability were observed in both composites despite the minimal aspect ratio of the nanoparticles. These materials also demonstrate the electronic tunability of mechanical properties, which arise from the dynamic self-organization of the nanoparticles under stress. A modified percolation theory incorporating the self-assembly behaviour of nanoparticles gave an excellent match with the experimental data.

Polyaniline Nanofiber Electrodes for Reversible Capture and Release of Mercury(II) from Water.

π-Conjugated polyaniline nanofiber networks are an attractive material platform for reversible and selective capture and release of toxic heavy metal ions from water. The nanofiber geometry facilitates fastsorption kinetics, sulfur functionalization of the backbone for improved adsorption, and electrochemical control of the oxidation (charge) state for reversible triggered sorption/desorption of metal ions. These active materials also function as sensors in that the sorption of mercury ions can be detected by analysis of cyclic voltammograms. Calculations of binding energies between polyaniline and metal ions using molecular dynamics and density functional theory support the electrochemically controlled reversible sorption/desorption mechanism. These redox-active materials for removing Hg2+ from water create an attractive system that combines efficiency, capacity, selectivity, and reusability.

Reconfigurable chiroptical nanocomposites with chirality transfer from the macro- to the nanoscale.

Nanostructures with chiral geometries exhibit strong polarization rotation. However, achieving reversible modulation of chirality and polarization rotation in device-friendly solid-state films is difficult for rigid materials. Here, we describe nanocomposites, made by conformally coating twisted elastic substrates with films assembled layer-by-layer from plasmonic nanocolloids, whose nanoscale geometry and rotatory optical activity can be reversibly reconfigured and cyclically modulated by macroscale stretching, with up to tenfold concomitant increases in ellipticity. We show that the chiroptical activity at 660 nm of gold nanoparticle composites is associated with circular extinction from linear effects. The polarization rotation at 550 nm originates from the chirality of nanoparticle chains with an S-like shape that exhibit a non-planar buckled geometry, with the handedness of the substrate's macroscale twist determining the handedness of the S-like chains. Chiroptical effects at the nexus of mechanics, excitonics and plasmonics open new operational principles for optical and optoelectronic devices from nanoparticles, carbon nanotubes and other nanoscale components.

Branched Aramid Nanofibers.

Interconnectivity of components in three-dimensional networks (3DNs) is essential for stress transfer in hydrogels, aerogels, and composites. Entanglement of nanoscale components in the network relies on weak short-range intermolecular interactions. The intrinsic stiffness and rod-like geometry of nanoscale components limit the cohesive energy of the physical crosslinks in 3DN materials. Nature realizes networked gels differently using components with extensive branching. Branched aramid nanofibers (BANFs) mimicking polymeric components of biological gels were synthesized to produce 3DNs with high efficiency stress transfer. Individual BANFs are flexible, with the number of branches controlled by base strength in the hydrolysis process. The extensive connectivity of the BANFs allows them to form hydro- and aerogel monoliths with an order of magnitude less solid content than rod-like nanocomponents. Branching of nanofibers also leads to improved mechanics of gels and nanocomposites.

Single-Atom Catalysts on Covalent Organic Frameworks for Energy Applications.

Single-atom catalysts (SACs) have been investigated and applied to energy conversion devices. However, issues of metal agglomeration, low metal loading, and substrate stability have hindered realization of the SACs' full potential. Recently, covalent organic framework (COF)-based SACs have emerged as promising materials to enable highly efficient catalytic reactions. Here, we summarize the representative COF-based SACs and their wide application in clean energy devices and conversion reactions, such as hydrogen evolution reaction, carbon dioxide reduction reaction, nitrogen reduction reaction, oxygen reduction reaction, and oxygen evolution reaction. Based on their catalysis conditions, these reactions are categorized into photocatalyzed and electrocatalyzed reactions. We also summarize their design strategies, including heteroatom inclusion, donor-acceptor pairs, pore engineering, interface engineering, etc. Although COF-based SACs are promising, more efforts, such as linkage engineering, functional groups, ionization, multifunctional sites for cocatalyzed systems, etc., could improve them to be the ideal SAC materials. At the end, we provide our perspectives on where the field will proceed in the next 5 years.

Biomimetic Chiral Nanomaterials with Selective Catalysis Activity.

Chiral nanomaterials with unique chiral configurations and biocompatible ligands have been booming over the past decade for their interesting chiroptical effect, unique catalytical activity, and related bioapplications. The catalytic activity and selectivity of chiral nanomaterials have emerged as important topics, that can be potentially controlled and optimized by the rational biochemical design of nanomaterials. In this review, chiral nanomaterials synthesis, composition, and catalytic performances of different biohybrid chiral nanomaterials are discussed. The construction of chiral nanomaterials with multiscale chiral geometries along with the underlying principles for enhancing chiroptical responses are highlighted. Various biochemical approaches to regulate the selectivity and catalytic activity of chiral nanomaterials for biocatalysis are also summarized. Furthermore, attention is paid to specific chiral ligands, materials compositions, structure characteristics, and so on for introducing selective catalytic activities of representative chiral nanomaterials, with emphasis on substrates including small molecules, biological macromolecule, and in-site catalysis in living systems. Promising progress has also been emphasized in chiral nanomaterials featuring structural versatility and improved chiral responses that gave rise to unprecedented chances to utilize light for biocatalytic applications. In summary, the challenges, future trends, and prospects associated with chiral nanomaterials for catalysis are comprehensively proposed.

Intratumoral IL-12 delivery via mesenchymal stem cells combined with PD-1 blockade leads to long-term antitumor immunity in a mouse glioblastoma model.

BACKGROUND: Although PD-1 blockade is effective for treating several types of cancer, the efficacy of this agent in glioblastoma is largely limited. To overcome non-responders and the immunosuppressive tumor microenvironment, combinational immunotherapeutic strategies with anti-PD-1 need to be considered. Here, we developed IL-12-secreting mesenchymal stem cells (MSC_IL-12) with glioblastoma tropism and evaluated the therapeutic effects of anti-PD-1, MSC_IL-12, and their combination against glioblastoma. METHODS: Therapeutic responses were evaluated using an immunocompetent mouse orthotopic model. Tumor-infiltrating lymphocytes (TILs) were analyzed using immunofluorescent imaging. Single-cell transcriptome was obtained from mouse brains after treatments. RESULTS: Anti-PD-1 and MSC_IL-12 showed complete tumor remission in 25.0% (4/16) and 23.1% (3/13) of glioblastoma-implanted mice, respectively, and their combination yielded synergistic antitumor efficacy indicated by 50.0% (6/12) of complete tumor remission. Analyses of TILs revealed that anti-PD-1 increased CD8+ T cells, while MSC_IL-12 led to infiltration of CD4+ T cells and NK cells. Both therapies reduced frequencies of Tregs. All these aspects observed in each monotherapy group were superimposed in the combination group. Notably, no tumor growth was observed upon rechallenge in cured mice, indicating long-term immunity against glioblastoma provoked by the therapies. Single-cell RNA-seq data confirmed these results and revealed that the combined treatment led to immune-favorable tumor microenvironment-CD4+, CD8+ T cells, effector memory T cells, and activated microglia were increased, whereas exhausted T cells, Tregs, and M2 polarized microglia were reduced. CONCLUSION: Anti-PD-1 and MSC_IL-12 monotherapies show long-term therapeutic responses, and their combination further enhances antitumor efficacy against glioblastoma via inducing immune-favorable tumor microenvironment.

Accelerated Selective Li+ Transports Assisted by Microcrack-Free Anionic Network Polymer Membranes for Long Cyclable Lithium Metal Batteries.

Rechargeable Li metal batteries have the potential to meet the demands of high-energy density batteries for electric vehicles and grid-energy storage system applications. Achieving this goal, however, requires resolving not only safety concerns and a shortened battery cycle life arising from a combination of undesirable lithium dendrite and solid-electrolyte interphase formations. Here, a series of microcrack-free anionic network polymer membranes formed by a facile one-step click reaction are reported, displaying a high cation conductivity of 3.1 × 10-5 S cm-1 at high temperature, a wide electrochemical stability window up to 5 V, a remarkable resistance to dendrite growth, and outstanding non-flammability. These enhanced properties are attributed to the presence of tethered borate anions in microcrack-free membranes, which benefits the acceleration of selective Li+ cations transport as well as suppression of dendrite growth. Ultimately, the microcrack-free anionic network polymer membranes render Li metal batteries a safe and long-cyclable energy storage device at high temperatures with a capacity retention of 92.7% and an average coulombic efficiency of 99.867% at 450 cycles.

Mutational Landscape of Normal Human Skin: Clues to Understanding Early-Stage Carcinogenesis in Keratinocyte Neoplasia.

Normal skin contains numerous clones carrying cancer driver mutations. However, the mutational landscape of normal skin and its clonal relationship with skin cancer requires further elucidation. The aim of our study was to investigate the mutational landscape of normal human skin. We performed whole-exome sequencing using physiologically normal skin tissues and the matched peripheral blood (n = 39) and adjacent-matched skin cancers from a subset of patients (n = 10). Exposed skin harbored a median of 530 mutations (10.4/mb, range = 51-2,947), whereas nonexposed skin majorly exhibited significantly fewer mutations (median = 13, 0.25/mb, range = 1-166). Patient age was significantly correlated with the mutational burden. Mutations in six driver genes (NOTCH1, FAT1, TP53, PPM1D, KMT2D, and ASXL1) were identified. De novo mutational signature analysis identified a single signature with components of UV- and aging-related signatures. Normal skin harbored only three instances of copy-neutral loss of heterozygosity in 9q (n = 2) and 6q (n = 1). The mutational burden of normal skin was not correlated with that of matched skin cancers, and no protein-coding mutations were shared. In conclusion, we revealed the mutational landscape of normal skin, highlighting the role of driver genes in the malignant progression of normal skin.