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Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

Protein phosphorylation is one of the most widespread post-translational modifications in biology. With the advent of mass spectrometry-based phosphoproteomics, more than 200,000 sites of serine and threonine phosphorylation have been reported, of which several thousand have been associated with human diseases and biological processes. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein Ser/Thr kinases encoded in the human genome is responsible. Here, we utilize synthetic peptide libraries to profile the substrate sequence specificity of nearly every functional human Ser/Thr kinase. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. Our kinome-wide dataset was used to computationally annotate and identify the most likely protein kinases for every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites where the protein kinases involved have been previously identified, our predictions were in excellent agreement. When this approach was applied to examine the signaling response of tissues and cell lines to hormones, growth factors, targeted inhibitors, and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the full extent of substrate specificity of the human Ser/Thr kinome, illuminate cellular signaling responses, and provide a rich resource to link unannotated phosphorylation events to biological pathways.

Significance Micrometer-sized uniform four-layer (ABCA) rhombohedral graphene is realized by introducing a small twist angle between two bilayers of Bernal graphene. By means of scanning tunneling spectroscopy we observe an extremely sharp van Hove singularity of 3–5-meV half-width and a correlated many-body gap of 9.5 meV at neutrality, thus making small twisted double-bilayer graphene a unique platform to realize electronic correlations in the absence of a moiré potential. Furthermore, ABCA graphene domain walls display tunable topological edge states, of great interest in Floquet engineering., Atomically thin van der Waals materials stacked with an interlayer twist have proven to be an excellent platform toward achieving gate-tunable correlated phenomena linked to the formation of flat electronic bands. In this work we demonstrate the formation of emergent correlated phases in multilayer rhombohedral graphene––a simple material that also exhibits a flat electronic band edge but without the need of having a moiré superlattice induced by twisted van der Waals layers. We show that two layers of bilayer graphene that are twisted by an arbitrary tiny angle host large (micrometer-scale) regions of uniform rhombohedral four-layer (ABCA) graphene that can be independently studied. Scanning tunneling spectroscopy reveals that ABCA graphene hosts an unprecedentedly sharp van Hove singularity of 3–5-meV half-width. We demonstrate that when this van Hove singularity straddles the Fermi level, a correlated many-body gap emerges with peak-to-peak value of 9.5 meV at charge neutrality. Mean-field theoretical calculations for model with short-ranged interactions indicate that two primary candidates for the appearance of this broken symmetry state are a charge-transfer excitonic insulator and a ferrimagnet. Finally, we show that ABCA graphene hosts surface topological helical edge states at natural interfaces with ABAB graphene which can be turned on and off with gate voltage, implying that small-angle twisted double-bilayer graphene is an ideal programmable topological quantum material.

2D materials offer a wide range of perspectives for hosting highly localized 0D states, e.g. vacancy defects, that offer great potential for integrated quantum photonic applications. Here, we create individual defects that act as our single-photon emitters by highly local He-ion irradiation in a monolayer MoS2 van der Waals heterostructure. The defects show anti-bunched light emission at a characteristic energy of ~ 1.75 eV. The emission is highly homogeneous and background free due to the hBN encapsulation with a creation yield of > 70%. Spectroscopic investigation of individual single-photon emitters reveals a strongly asymmetric line shape resembling interaction with acoustic phonons in excellent agreement with an independent boson model. Moreover, emitters are spatially integrated and electrically controlled in field-switchable van der Waals devices. Our work firmly establishes 2D materials as a highly scalable material platform for integrated quantum photonics.

While vaccines are vital for preventing COVID-19 infections, it is critical to develop new therapies to treat patients who become infected. Pharmacological targeting of a host factor required for viral replication can suppress viral spread with a low probability of viral mutation leading to resistance. In particular, host kinases are highly druggable targets and a number of conserved coronavirus proteins, notably the nucleoprotein (N), require phosphorylation for full functionality. In order to understand how targeting kinases could be used to compromise viral replication, we used a combination of phosphoproteomics and bioinformatics as well as genetic and pharmacological kinase inhibition to define the enzymes important for SARS-CoV-2 N protein phosphorylation and viral replication. From these data, we propose a model whereby SRPK1/2 initiates phosphorylation of the N protein, which primes for further phosphorylation by GSK-3α/β and CK1 to achieve extensive phosphorylation of the N protein SR-rich domain. Importantly, we were able to leverage our data to identify an FDA-approved kinase inhibitor, Alectinib, that suppresses N phosphorylation by SRPK1/2 and limits SARS-CoV-2 replication. Together, these data suggest that repurposing or developing novel host-kinase directed therapies may be an efficacious strategy to prevent or treat COVID-19 and other coronavirus-mediated diseases.

Graphene, a single atom thick hexagonally bonded sheet of carbon atoms, was first isolated in 2004 opening a whole new field in condensed matter research and material engineering. Graphene has hosted a whole array of novel physics phenomena as its carriers move at near the speed of light governed by the Dirac Hamiltonian, it has few scattering sites, it is easily gate-tunable, and hosts exciting 2D physics amongst many other properties. Graphene was only the tip of the iceberg in 2D research as researchers have since identified a whole family of materials with similar layered atomic structures allowing isolation into several atom thick monolayers. Monolayer material properties range from metals to semiconductors, superconductors, magnets and most other properties found in 3D materials. Naturally, this has led to making fully 2D heterostructures to study exciting physics and explore applications such as 2D transistors. It has recently been found that not only can you stack these materials at will but you can also tune their properties with an inter-layer twist between layers which at precise twist angles yields on-demand electronic correlations that can be easily tuned with experimental knobs leading to novel correlated phases. The pioneering techniques towards understanding each 2D material and heterostructures thereof have usually been with transport and optics. These techniques are inherently bulk macroscopic measurements which do not give insights into the nanoscale properties such as atomic-scale features or the nanoscale heterostructure properties that govern the systems. Atomic-scale structural and electronic insights are crucial towards understanding each system and providing proper guidelines for comprehensive theoretical understandings. In this thesis, we study the atomic-scale structural and electronic properties of various 2D systems using ultra-high vacuum (UHV) scanning tunneling microscopy and spectroscopy (STM/STS), a technique which utilizes electron tunneling with an atomically sharp tip to visualize atomic structure and low-energy spectroscopic properties. We focus on three major types of systems: twisted graphene heterostructures (magic angle twisted bilayer graphene and small angle double bilayer graphene), bulk and monolayer semiconducting transition metal dichalcogenides (TMDs), and 2D heterointerfaces (TMD - metal and graphene p-n junctions). We establish a number of state of the art methods to study these 2D systems in their cleanest, transport-experiment-like forms using surface probes like STM/STS including robust, clean, reliable contact methods and procedures towards studying micronscale exfoliated 2D samples atop hexagonal boron nitride (hBN) as well as photo-assisted STM towards studying semiconducting TMDs and other poorly conducting materials at low temperatures (13.3 Kelvin). We begin with one of the most currently mainstream topics of twisted bilayer graphene (tBG) where, near the magic angle of 1.1◦ the first correlated insulating and superconducting states in graphene were observed. A lack of detailed understanding of the electronic spectrum and the atomic-scale influence of the moir´e pattern had precluded a coherent theoretical understanding of the correlated states up til our work. We establish novel, robust methods to measure these micron-scale samples with a surface scanning probe technique. We directly map the atomic-scale structural and electronic properties of tBG near the magic angle using scanning tunneling microscopy and spectroscopy (STM/STS). Contrary to previous understandings (which predicted two flat bands with a several meV separation in the system), we observe two distinct van Hove singularities (vHs) in the local density of states (LDOS) around the magic angle, with a doping-dependent separation of 40-57 meV. We find that the vHs separation decreases through the magic angle with a lowest measured value of 7-13 meV at 0.79◦ . When doped near half moir´e band filling where the correlated insulating state emerges, a correlation-induced gap splits the conduction vHs with a maximum size of 6.5 meV at 1.15◦ , dropping to 4 meV at 0.79◦ . We find that more crucial to the magic angle than the vHs separation is that the ratio of the Coulomb interaction (U) to the bandwidth (t) of each individual vHs is maximized (as opposed to the proximity of the individual vHs’s), indicating that indeed electronic correlations are very important and suggesting a Cooper-like pairing mechanism based on electron-electron interactions. This establishes that magic angle tBG is to be understood in a single vHs picture where the band-width of the vHs is minimized. Spectroscopy maps show that three-fold (C3) rotational symmetry of the LDOS is broken in magic angle tBG, with an anisotropy that is strongest near the Fermi level, and is highly enhanced when the doping is in the vicinity of the correlated gap, indicating the presence of a strong electronic nematic susceptibility or even nematic order in tBG in regions of the phase diagram where superconductivity is observed. We next turn to twisted double bilayer graphene (tDBG), a system that is similar to tBG in phenomenology but turns out to be quite different. Correlated insulating and superconducting states were also found using transport in tDBG at a magic angle of 1.2-1.3◦ and ABC rhombohedral trilayer graphene aligned to hBN (ABC-tLG/hBN) with some stark differences such as displacement field tunable correlated states. We perform the first atomic-scale structural and electronic studies of small-angle tDBG as well as ABCA four layer rhombohedral stacked graphene and compare the findings to tBG. We first find that the moir´e pattern formed by tDBG is fundamentally different from tBG in that instead of hosting AB/BA Bernal stacking regions, it hosts BABA/ABCA (Bernal/rhombohedral) stacking domains. While we find this for small angle tDBG, these structural arguments will apply at all angles including the magic angle indicating that the flat bands and electron densities in tDBG are likely dominated at the ABCA sites. We use small angle tDBG to study large domains of four-layer ABCA graphene, revealing its displacement field dependent low energy spectroscopic structure and the flat band structure that comes with the four layer rhombohedral stacking which hosts the flattest band measured in any system of a 3-5 meV half-width. Furthermore, we measure the emergence of a 9.5 meV correlated gap in ABCA four-layer graphene at neutrality indicating that even without a hBN moir´e, ABCA graphene will likely host correlated states purely due to a flat band. These correlated states could be insulating or even superconducting in nature and the study thereof could provide crucial insight into whether superconductivity is related to Mott insulator physics as is suggested in the cuprates. When coupled to an hBN moir´e, these correlated states may be even stronger than that of magic angle tBG, magic angle tDBG and (most cer- tainly) ABC-tLG/hBN. Finally, we show that at Bernal - four-layer rhombohedral domain boundaries, there exists a topologically protected helical surface edge state. We next turn to the semiconducting TMDs. We find that semiconducting MoTe2 and MoSe2 have long range magnetic ordering as measured by muon spin resonance and SQUID at critical temperatures of 40 K and 100 K respectively. Using atomic-resolution STM/STS, we find that the semiconducting TMDs have a variety of intrinsic defects, one of which (a molybdenum substitution for a chalcogen, Mosub) we postulate using DFT is the cause of the long-range magnetism in the semiconducting TMDs which are not expected to host magnetism in their pristine structures. This finding establishes these semiconducting TMDs as magnetically ordered and adds them to the family of potential dilute magnetic semiconductor materials (the uniform robust fabrication of which has been sought-after for decades) which could have applications in spintronics. We then perform 13.3 Kelvin measurements (for the first time in these materials to our knowledge) on the same crystals using photoassisted STM, a technique that we establish to enable this low temperature measurement. The photo-assisted STM measurements reveal that not only are these defects magnetic but they host localized structural distortions which cover a large areas of the crystal surfaces. We find that these structural distortions are localized charge density waves due to a very high amount of localized doping that comes from the defects, putting the materials into a locally metallic regime and causing a phonon instability (found by phonon DFT). This finding of localized charge density waves in these high-quality semiconducting 2D materials is highly atypical for a semiconductor system and could have implications towards all techniques. The charge density waves could also be related to the measured magnetism as they have a much larger area of coverage in MoSe2 as opposed to MoTe2 which could be related to the critical temperature difference. We finally turn to two types of heterointerfaces, the first being metal-monolayer MoS2 junctions. We present measurements of the atomic-scale energy band diagram of junctions between various metals and heavily doped monolayer MoS2 using STM/STS. Our measurements reveal that the electronic properties of these junctions, at the fundamental limit of a minimized Schottky barrier, are dominated by 2D metal induced gap states (MIGS). These MIGS are characterized by a spatially growing measured gap in the local density of states (LDOS) of the MoS2 within 2 nm of the metal-semiconductor interface. Their decay lengths extend from a minimum of about 0.55 nm near mid gap to as long as 2 nm near the band edges and are nearly identical for Au, Pd and graphite contacts, indicating that this is a universal property of the monolayer 2D semiconductor. Our findings indicate that even in heavily doped semiconductors, the presence of MIGS sets the ultimate limit for electrical contact. These findings are generally applicable to any 2D semiconductor. We next look at another type of heterointerface, this time purely electronic in nature, graphene p-n junctions. Graphene p-n junctions should host interesting electron-optical properties such as electron collimation and Veselago lensing. While vague signatures of these have been observed, robust, definitive control of these properties are still lacking. We present the first atomic-scale characterization of state-of-the-art graphene p-n junctions using STM/STS revealing their current imperfections including significant electron-hole asymmetry, nonlinearity, roughness and intrinsic doping. We model the implications thereof and show that these imperfections strongly hinder electron-optical applications. Finally we explore the origin of these imperfections and potential avenues towards realizing better graphene p-n junction devices that may host much improved electron-optical properties.

Post-translational modifications (PTMs) (e.g., ubiquitylation, phosphorylation, acetylation) have been studied for their key role in cell signaling and in regulating cell physiology. Advances in mass spectrometry now enable measuring PTMs and studying their role and prevalence in cancer. Although most studies have focused on a single PTM and its impact on downstream signaling in a single cancer type, understanding PTM-driven commonalities, disparities, and their crosstalk across cancer types will be critical in understanding fundamental oncogenic principles governed by PTMs. Thus, we aim to understand the underlying patterns of PTMs in molecular signaling pathways shared across multiple cancer types by studying changes in protein acetylation and phosphorylation within the largest collection of in-depth genomic, transcriptomic, proteomic, and PTM profiles compiled from 11 cancer types generated across the CPTAC projects.We used matrix factorization methods to extract expression signatures jointly from transcriptomic, proteomic, and PTM data across multiple cancer types. Preliminary analysis of 6 tumor types identified 18 pan-cancer, multi-omic expression signatures. Characterization of these signatures using ranked gene-set enrichment analysis (GSEA) and site-specific PTM signature enrichment analysis (PTM-SEA) highlighted pathways including DNA damage response, immune inactivation/deactivation, tumor invasiveness, and metabolic pathways. To investigate the effect of driver alterations on PPIs, we (i) compute rank correlations of pan-cancer mutational signatures to both expression levels and our multi-omic expression signatures, and (ii) map PTMs and mutations to available crystal structures. We additionally investigate mutations that recur across cancer types (e.g., TP53, PIK3CA, CTNNB1) and impact expression profiles of downstream PTMs. We further connect pan-cancer phosphoproteomic data to a library of biochemical specificities of the human kinome using a novel, unbiased computational platform that builds on extensive and experimentally validated kinase-substrate relationships. We identified activated and deactivated kinases/acetylases based on their altered PTM sites within and across the multi-omic subtypes and compared the effects on different targets. We also characterize the crosstalk between acetylation and phosphorylation across cancer, and, systematically identify acetylation events that prime and enhance kinase activity. Finally, we define kinases, acetylases, and PTM outliers as potential druggable targets (using The Drug Gene Interaction Database and DepMap). Overall, this study presents the landscape of PTMs across cancer and will serve as a community resource to promote a deeper understanding of PTM-governed processes leading to cancer progression, with the potential to improve current therapies or help design new treatment approaches against cancer. Citation Format: Yifat Geffen, Shankara Anand, Yo Akiyama, Tommer M. Yaron, Alexander Kerelsky, Jared L. Johnson, Karsten Krug, David Heiman, Shankha Satpathy, Karl Clauser, Michael Gillette, D. R. Mani, Chet Birger, Steven Carr, Lewis C. Cantley, Francois Aguet, Gad Getz, Oncogenic Drivers and Pathways Group, Clinical Proteomic Tumor Analysis Consortium (CPTAC). Patterns and regulation of post translational modifications in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 16.

Graphene p-n junctions offer a potentially powerful approach towards controlling electron trajectories via collimation and focusing in ballistic solid-state devices. The ability of p-n junctions to control electron trajectories depends crucially on the doping profile and roughness of the junction. Here, we use four-probe scanning tunneling microscopy and spectroscopy (STM/STS) to characterize two state-of-the-art graphene p-n junction geometries at the atomic scale, one with CMOS polySi gates and another with naturally cleaved graphite gates. Using spectroscopic imaging, we characterize the local doping profile across and along the p-n junctions. We find that realistic junctions exhibit non-ideality both in their geometry as well as in the doping profile across the junction. We show that the geometry of the junction can be improved by using the cleaved edge of van der Waals metals such as graphite to define the junction. We quantify the geometric roughness and doping profiles of junctions experimentally and use these parameters in Nonequilibrium Green's Function based simulations of focusing and collimation in these realistic junctions. We find that for realizing Veselago focusing, it is crucial to minimize lateral interface roughness which only natural graphite gates achieve, and to reduce junction width, in which both devices under investigation underperform. We also find that carrier collimation is currently limited by the non-linearity of the doping profile across the junction. Our work provides benchmarks of the current graphene p-n junction quality and provides guidance for future improvements.

The topology of Weyl semimetals requires the existence of unique surface states. Surface states have been visualized in spectroscopy measurements, but their connection to the topological character of the material remains largely unexplored. 1T'-MoTe2, presents a unique opportunity to study this connection. This material undergoes a phase transition at 240 K that changes the structure from orthorhombic (putative Weyl semimetal) to monoclinic (trivial metal), while largely maintaining its bulk electronic structure. Here, we show from temperature-dependent quasiparticle interference measurements that this structural transition also acts as a topological switch for surface states in 1T'-MoTe2. At low temperature, we observe strong quasiparticle scattering, consistent with theoretical predictions and photoemission measurements for the surface states in this material. In contrast, measurements performed at room temperature show the complete absence of the scattering wavevectors associated with the trivial surface states. These distinct quasiparticle scattering behaviors show that 1T'-MoTe2 is ideal for separating topological and trivial electronic phenomena via temperature-dependent measurements. A temperature-induced structural phase transition can provide insight into the effect of Fermi arcs on the properties of Weyl semimetals. Weyl semimetals are topological materials at the surface of which Weyl points—the points at which electron and hole pockets touch—are connected in pairs by Fermi arc surface states. Probing the topological nature of the surface states has so far proven difficult, and a connection with the band structure of the material is complex to establish. An international team of researchers led by Abhay Pasupathy at Columbia University demonstrated, by combining experiments and theory, that the Weyl semimetal MoTe2 undergoes a temperature-driven structural phase transition that switches off the Weyl behavior. This makes it possible to systematically compare the electronic properties of the trivial and topological states.

High quality electrical contact to semiconducting transition metal dichalcogenides (TMDCs) such as MoS

Substrate, environment, and lattice imperfections have a strong impact on the local electronic structure and the optical properties of atomically thin transition metal dichalcogenides. We find by a comparative study of MoS2 on SiO2 and hexagonal boron nitride (hBN) using scanning tunneling spectroscopy (STS) measurements that the apparent bandgap of MoS2 on SiO2 is significantly reduced compared to MoS2 on hBN. The bandgap energies as well as the exciton binding energies determined from all-optical measurements are very similar for MoS2 on SiO2 and hBN. This discrepancy is found to be caused by a substantial amount of band tail states near the conduction band edge of MoS2 supported by SiO2. The presence of those states impacts the local density of states in STS measurements and can be linked to a broad red-shifted photoluminescence peak and a higher charge carrier density that are all strongly diminished or even absent using high quality hBN substrates. By taking into account the substrate effects, we obtain a quasiparticle gap that is in excellent agreement with optical absorbance spectra and we deduce an exciton binding energy of about 0.53 eV on SiO2 and 0.44 eV on hBN.

Transition metal dichalcogenides (TMDs) are interesting for understanding fundamental physics of two-dimensional materials (2D) as well as for many emerging technologies, including spin electronics. Here, we report the discovery of long-range magnetic order below TM = 40 K and 100 K in bulk semiconducting TMDs 2H-MoTe2 and 2H-MoSe2, respectively, by means of muon spin-rotation (muSR), scanning tunneling microscopy (STM), as well as density functional theory (DFT) calculations. The muon spin rotation measurements show the presence of a large and homogeneous internal magnetic fields at low temperatures in both compounds indicative of long-range magnetic order. DFT calculations show that this magnetism is promoted by the presence of defects in the crystal. The STM measurements show that the vast majority of defects in these materials are metal vacancies and chalcogen-metal antisites which are randomly distributed in the lattice at the sub-percent level. DFT indicates that the antisite defects are magnetic with a magnetic moment in the range of 0.9-2.8 mu_B. Further, we find that the magnetic order stabilized in 2H-MoTe2 and 2H-MoSe2 is highly sensitive to hydrostatic pressure. These observations establish 2H-MoTe2 and 2H-MoSe2 as a new class of magnetic semiconductors and opens a path to studying the interplay of 2D physics and magnetism in these interesting semiconductors., Comment: 13 pages, 10 Figures

© 2015 AIP Publishing LLC. Heterostructure devices with specific and extraordinary properties can be fabricated by stacking two-dimensional crystals. Cleanliness at the inter-crystal interfaces within a heterostructure is crucial for maximizing device performance. However, because these interfaces are buried, characterizing their impact on device function is challenging. Here, we show that electron-beam induced current (EBIC) mapping can be used to image interfacial contamination and to characterize the quality of buried heterostructure interfaces with nanometer-scale spatial resolution. We applied EBIC and photocurrent imaging to map photo-sensitive graphene-MoS2heterostructures. The EBIC maps, together with concurrently acquired scanning transmission electron microscopy images, reveal how a device's photocurrent collection efficiency is adversely affected by nanoscale debris invisible to optical-resolution photocurrent mapping.

Heterostructure devices with specific and extraordinary properties can be fabricated by stacking two-dimensional crystals. Cleanliness at the inter-crystal interfaces within a heterostructure is crucial for maximizing device performance. However, because these interfaces are buried, characterizing their impact on device function is challenging. Here, we show that electron-beam induced current (EBIC) mapping can be used to image interfacial contamination and to characterize the quality of buried heterostructure interfaces with nanometer-scale spatial resolution. We applied EBIC and photocurrent imaging to map photo-sensitive graphene-MoS2 heterostructures. The EBIC maps, together with concurrently acquired scanning transmission electron microscopy images, reveal how a device's photocurrent collection efficiency is adversely affected by nanoscale debris invisible to optical-resolution photocurrent mapping.

© 2015 American Chemical Society. Conductive bridge random access memory (CBRAM) is a leading candidate to supersede flash memory, but poor understanding of its switching process impedes widespread implementation. The underlying physics and basic, unresolved issues such as the connecting filament's growth direction can be revealed with direct imaging, but the nanoscale target region is completely encased and thus difficult to access with real-time, high-resolution probes. In Pt/Al2O3/Cu CBRAM devices with a realistic topology, we find that the filament grows backward toward the source metal electrode. This observation, consistent over many cycles in different devices, corroborates the standard electrochemical metallization model of CBRAM operation. Time-resolved scanning transmission electron microscopy (STEM) reveals distinct nucleation-limited and potential-limited no-growth periods occurring before and after a connection is made, respectively. The subfemtoampere ionic currents visualized move some thousands of atoms during a switch and lag the nanoampere electronic currents (Figure Presented).

Conductive bridge random access memory (CBRAM) is a leading candidate to supersede flash memory, but poor understanding of its switching process impedes widespread implementation. The underlying physics and basic, unresolved issues such as the connecting filament's growth direction can be revealed with direct imaging, but the nanoscale target region is completely encased and thus difficult to access with real-time, high-resolution probes. In Pt/Al2O3/Cu CBRAM devices with a realistic topology, we find that the filament grows backward toward the source metal electrode. This observation, consistent over many cycles in different devices, corroborates the standard electrochemical metallization model of CBRAM operation. Time-resolved scanning transmission electron microscopy (STEM) reveals distinct nucleation-limited and potential-limited no-growth periods occurring before and after a connection is made, respectively. The subfemtoampere ionic currents visualized move some thousands of atoms during a switch and lag the nanoampere electronic currents.