Thermoelectric Limitations of Graphene Nanodevices at Ultrahigh Current Densities.

Graphene is atomically thin, possesses excellent thermal conductivity, and is able to withstand high current densities, making it attractive for many nanoscale applications such as field-effect transistors, interconnects, and thermal management layers. Enabling integration of graphene into such devices requires nanostructuring, which can have a drastic impact on the self-heating properties, in particular at high current densities. Here, we use a combination of scanning thermal microscopy, finite element thermal analysis, and operando scanning transmission electron microscopy techniques to observe prototype graphene devices in operation and gain a deeper understanding of the role of geometry and interfaces during high current density operation. We find that Peltier effects significantly influence the operational limit due to local electrical and thermal interfacial effects, causing asymmetric temperature distribution in the device. Thus, our results indicate that a proper understanding and design of graphene devices must include consideration of the surrounding materials, interfaces, and geometry. Leveraging these aspects provides opportunities for engineered extreme operation devices.

Quantum interference enhances the performance of single-molecule transistors.

Quantum effects in nanoscale electronic devices promise to lead to new types of functionality not achievable using classical electronic components. However, quantum behaviour also presents an unresolved challenge facing electronics at the few-nanometre scale: resistive channels start leaking owing to quantum tunnelling. This affects the performance of nanoscale transistors, with direct source-drain tunnelling degrading switching ratios and subthreshold swings, and ultimately limiting operating frequency due to increased static power dissipation. The usual strategy to mitigate quantum effects has been to increase device complexity, but theory shows that if quantum effects can be exploited in molecular-scale electronics, this could provide a route to lower energy consumption and boost device performance. Here we demonstrate these effects experimentally, showing how the performance of molecular transistors is improved when the resistive channel contains two destructively interfering waves. We use a zinc-porphyrin coupled to graphene electrodes in a three-terminal transistor to demonstrate a >104 conductance-switching ratio, a subthreshold swing at the thermionic limit, a >7 kHz operating frequency and stability over >105 cycles. We fully map the anti-resonance interference features in conductance, reproduce the behaviour by density functional theory calculations and trace back the high performance to the coupling between molecular orbitals and graphene edge states. These results demonstrate how the quantum nature of electron transmission at the nanoscale can enhance, rather than degrade, device performance, and highlight directions for future development of miniaturized electronics.

Connections to the Electrodes Control the Transport Mechanism in Single-Molecule Transistors.

When designing a molecular electronic device for a specific function, it is necessary to control whether the charge-transport mechanism is phase-coherent transmission or particle-like hopping. Here we report a systematic study of charge transport through single zinc-porphyrin molecules embedded in graphene nanogaps to form transistors, and show that the transport mechanism depends on the chemistry of the molecule-electrode interfaces. We show that van der Waals interactions between molecular anchoring groups and graphene yield transport characteristic of Coulomb blockade with incoherent sequential hopping, whereas covalent molecule-electrode amide bonds give intermediately or strongly coupled single-molecule devices that display coherent transmission. These findings demonstrate the importance of interfacial engineering in molecular electronic circuits.

WIP1 is a novel specific target for growth hormone action.

DNA damage repair (DDR) is mediated by phosphorylating effectors ATM kinase, CHK2, p53, and γH2AX. We showed earlier that GH suppresses DDR by suppressing pATM, resulting in DNA damage accumulation. Here, we show GH acting through GH receptor (GHR) inducing wild-type p53-inducible phosphatase 1 (WIP1), which dephosphorylated ATM and its effectors in normal human colon cells and three-dimensional human intestinal organoids. Mice bearing GH-secreting xenografts exhibited induced colon WIP1 with suppressed pATM and γH2AX. WIP1 was also induced in buffy coats derived from patients with elevated GH from somatotroph adenomas. In contrast, decreased colon WIP1 was observed in GHR-/- mice. WIP1 inhibition restored ATM phosphorylation and reversed GH-induced DNA damage. We elucidated a novel GH signaling pathway activating Src/AMPK to trigger HIPK2 nuclear-cytoplasmic relocation and suppressing WIP1 ubiquitination. Concordantly, blocking either AMPK or Src abolished GH-induced WIP1. We identify WIP1 as a specific target for GH-mediated epithelial DNA damage accumulation.

A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance.

Cancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later disease stages. Depletion of folylpolyglutamate synthetase (FPGS), which normally promotes intracellular accumulation and activity of natural folates and methotrexate, is linked to methotrexate and 5-fluorouracil resistance and its association with relapse illustrates the need for improved intervention strategies. Here, we describe a novel antifolate (C1) that, like methotrexate, potently inhibits dihydrofolate reductase and downstream one-carbon metabolism. Contrary to methotrexate, C1 displays optimal efficacy in FPGS-deficient contexts, due to decreased competition with intracellular folates for interaction with dihydrofolate reductase. We show that FPGS-deficient patient-derived CRC organoids display enhanced sensitivity to C1, whereas FPGS-high CRC organoids are more sensitive to methotrexate. Our results argue that polyglutamylation-independent antifolates can be applied to exert selective pressure on FPGS-deficient cells during chemotherapy, using a vulnerability created by polyglutamylation deficiency.

Phase-Coherent Charge Transport through a Porphyrin Nanoribbon.

Since the early days of quantum mechanics, it has been known that electrons behave simultaneously as particles and waves, and now quantum electronic devices can harness this duality. When devices are shrunk to the molecular scale, it is unclear under what conditions does electron transmission remain phase-coherent, as molecules are usually treated as either scattering or redox centers, without considering the wave-particle duality of the charge carrier. Here, we demonstrate that electron transmission remains phase-coherent in molecular porphyrin nanoribbons connected to graphene electrodes. The devices act as graphene Fabry-Pérot interferometers and allow for direct probing of the transport mechanisms throughout several regimes. Through electrostatic gating, we observe electronic interference fringes in transmission that are strongly correlated to molecular conductance across multiple oxidation states. These results demonstrate a platform for the use of interferometric effects in single-molecule junctions, opening up new avenues for studying quantum coherence in molecular electronic and spintronic devices.

Charge-State Dependent Vibrational Relaxation in a Single-Molecule Junction.

The outcome of an electron-transfer process is determined by the quantum-mechanical interplay between electronic and vibrational degrees of freedom. Nonequilibrium vibrational dynamics are known to direct electron-transfer mechanisms in molecular systems; however, the structural features of a molecule that lead to certain modes being pushed out of equilibrium are not well understood. Herein, we report on electron transport through a porphyrin dimer molecule, weakly coupled to graphene electrodes, that displays sequential tunneling within the Coulomb-blockade regime. The sequential transport is initiated by current-induced phonon absorption and proceeds by rapid sequential transport via a nonequilibrium vibrational distribution of low-energy modes, likely related to torsional molecular motions. We demonstrate that this is an experimental signature of slow vibrational dissipation, and obtain a lower bound for the vibrational relaxation time of 8 ns, a value dependent on the molecular charge state.

Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis.

Growth hormone (GH) and insulin-like growth factor-1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10-30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA-MB-231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule.

Statistical signature of electrobreakdown in graphene nanojunctions.

Controlled electrobreakdown of graphene is important for the fabrication of stable nanometer-size tunnel gaps, large-scale graphene quantum dots, and nanoscale resistive switches, etc. However, owing to the complex thermal, electronic, and electrochemical processes at the nanoscale that dictate the rupture of graphene, it is difficult to generate conclusions from individual devices. We describe here a way to explore the statistical signature of the graphene electrobreakdown process. Such analysis tells us that feedback-controlled electrobreakdown of graphene in the air first shows signs of joule heating-induced cleaning followed by rupturing of the graphene lattice that is manifested by the lowering of its conductance. We show that when the conductance of the graphene becomes smaller than around 0.1 G0, the effective graphene notch width starts to decrease exponentially slower with time. Further, we show how this signature gets modified as we change the environment and or the substrate. Using statistical analysis, we show that the electrobreakdown under a high vacuum could lead to substrate modification and resistive-switching behavior, without the application of any electroforming voltage. This is attributed to the formation of a semiconducting filament that makes a Schottky barrier with the graphene. We also provide here the statistically extracted Schottky barrier threshold voltages for various substrate studies. Such analysis not only gives a better understanding of the electrobreakdown of graphene but also can serve as a tool in the future for single-molecule diagnostics.

Mapping Conductance and Switching Behavior of Graphene Devices In Situ.

Graphene is proposed for use in various nanodevice designs, many of which harness emergent quantum properties for device functionality. However, visualization, measurement, and manipulation become nontrivial at nanometer and atomic scales, representing a significant challenge for device fabrication, characterization, and optimization at length scales where quantum effects emerge. Here, proof of principle results at the crossroads between 2D nanoelectronic devices, e-beam-induced modulation, and imaging with secondary electron e-beam induced currents (SEEBIC) is presented. A device platform compatible with scanning transmission electron microscopy investigations is introduced. Then how the SEEBIC imaging technique can be used to visualize conductance and connectivity in single layer graphene nanodevices, even while supported on a thicker substrate (conditions under which conventional imaging fails) is shown. Finally, it is shown that the SEEBIC imaging technique can detect subtle differences in charge transport through time in nonohmic graphene nanoconstrictions indicating the potential to reveal dynamic electronic processes.

Imaging Secondary Electron Emission from a Single Atomic Layer.

Graphene-based devices hold promise for a wide range of technological applications. Yet characterizing the structure and the electrical properties of a material that is only one atomic layer thick still poses technical challenges. Recent investigations indicate that secondary-electron electron-beam-induced current (SE-EBIC) imaging can reveal subtle details regarding electrical conductivity and electron transport with high spatial resolution. Here, it is shown that the SEEBIC imaging mode can be used to detect suspended single layers of graphene and distinguish between different numbers of layers. Pristine and contaminated areas of graphene are also compared to show that pristine graphene exhibits a substantially lower SE yield than contaminated regions. This SEEBIC imaging mode may provide valuable information for the engineering of surface coatings where SE yield is a priority.

Controlling the Entropy of a Single-Molecule Junction.

Single molecules are nanoscale thermodynamic systems with few degrees of freedom. Thus, the knowledge of their entropy can reveal the presence of microscopic electron transfer dynamics that are difficult to observe otherwise. Here, we apply thermocurrent spectroscopy to directly measure the entropy of a single free radical molecule in a magnetic field. Our results allow us to uncover the presence of a singlet to triplet transition in one of the redox states of the molecule, not detected by conventional charge transport measurements. This highlights the power of thermoelectric measurements which can be used to determine the difference in configurational entropy between the redox states of a nanoscale system involved in conductance without any prior assumptions about its structure or microscopic dynamics.

Exploiting rotational asymmetry for sub-50 nm mechanical nanocalligraphy.

Nanofabrication has experienced extraordinary progress in the area of lithography-led processes over the last decades, although versatile and adaptable techniques addressing a wide spectrum of materials are still nascent. Scanning probe lithography (SPL) offers the capability to readily pattern sub-100 nm structures on many surfaces; however, the technique does not scale to dense and multi-lengthscale structures. Here, we demonstrate a technique, which we term nanocalligraphy scanning probe lithography (nc-SPL), that overcomes these limitations. Nc-SPL employs an asymmetric tip and exploits its rotational asymmetry to generate structures spanning the micron to nanometer lengthscales through real-time linewidth tuning. Using specialized tip geometries and by precisely controlling the patterning direction, we demonstrate sub-50 nm patterns while simultaneously improving on throughput, tip longevity, and reliability compared to conventional SPL. We further show that nc-SPL can be employed in both positive and negative tone patterning modes, in contrast to conventional SPL. This underlines the potential of this technique for processing sensitive surfaces such as 2D materials, which are prone to tip-induced shear or beam-induced damage.

Charge transport through extended molecular wires with strongly correlated electrons.

Electron-electron interactions are at the heart of chemistry and understanding how to control them is crucial for the development of molecular-scale electronic devices. Here, we investigate single-electron tunneling through a redox-active edge-fused porphyrin trimer and demonstrate that its transport behavior is well described by the Hubbard dimer model, providing insights into the role of electron-electron interactions in charge transport. In particular, we empirically determine the molecule's on-site and inter-site electron-electron repulsion energies, which are in good agreement with density functional calculations, and establish the molecular electronic structure within various oxidation states. The gate-dependent rectification behavior confirms the selection rules and state degeneracies deduced from the Hubbard model. We demonstrate that current flow through the molecule is governed by a non-trivial set of vibrationally coupled electronic transitions between various many-body ground and excited states, and experimentally confirm the importance of electron-electron interactions in single-molecule devices.

Understanding Electrical Conduction and Nanopore Formation During Controlled Breakdown.

Controlled breakdown has recently emerged as a highly appealing technique to fabricate solid-state nanopores for a wide range of biosensing applications. This technique relies on applying an electric field of approximately 0.4-1 V nm-1 across the membrane to induce a current, and eventually, breakdown of the dielectric. Although previous studies have performed controlled breakdown under a range of different conditions, the mechanism of conduction and breakdown has not been fully explored. Here, electrical conduction and nanopore formation in SiNx membranes during controlled breakdown is studied. It is demonstrated that for Si-rich SiNx , oxidation reactions that occur at the membrane-electrolyte interface limit conduction across the dielectric. However, for stoichiometric Si3 N4 the effect of oxidation reactions becomes relatively small and conduction is predominately limited by charge transport across the dielectric. Several important implications resulting from understanding this process are provided which will aid in further developing controlled breakdown in the coming years, particularly for extending this technique to integrate nanopores with on-chip nanostructures.

A Thermodynamic Approach to Measuring Entropy in a Few-Electron Nanodevice.

The entropy of a system gives a powerful insight into its microscopic degrees of freedom; however, standard experimental ways of measuring entropy through heat capacity are hard to apply to nanoscale systems, as they require the measurement of increasingly small amounts of heat. Two alternative entropy measurement methods have been recently proposed for nanodevices: through charge balance measurements and transport properties. We describe a self-consistent thermodynamic framework for applying thermodynamic relations to few-electron nanodevices-small systems, where fluctuations in particle number are significant, whilst highlighting several ongoing misconceptions. We derive a relation (a consequence of a Maxwell relation for small systems), which describes both existing entropy measurement methods as special cases, while also allowing the experimentalist to probe the intermediate regime between them. Finally, we independently prove the applicability of our framework in systems with complex microscopic dynamics-those with many excited states of various degeneracies-from microscopic considerations.

Graphene nanogaps for the directed assembly of single-nanoparticle devices.

Significant advances in the synthesis of low-dimensional materials with unique and tuneable electrical, optical and magnetic properties has led to an explosion of possibilities for realising hybrid nanomaterial devices with unconventional and desirable characteristics. However, the lack of ability to precisely integrate individual nanoparticles into devices at scale limits their technological application. Here, we report on a graphene nanogap based platform which employs the large electric fields generated around the point-like, atomically sharp nanogap electrodes to capture single nanoparticles from solution at predefined locations. We demonstrate how gold nanoparticles can be trapped and contacted to form single-electron transistors with a large coupling to a buried electrostatic gate. This platform offers a route to the creation of novel low-dimensional devices, nano- and optoelectronic applications, and the study of fundamental transport phenomena.

In situ solid-state nanopore fabrication.

Nanopores in solid-state membranes are promising for a wide range of applications including DNA sequencing, ultra-dilute analyte detection, protein analysis, and polymer data storage. Techniques to fabricate solid-state nanopores have typically been time consuming or lacked the resolution to create pores with diameters down to a few nanometres, as required for the above applications. In recent years, several methods to fabricate nanopores in electrolyte environments have been demonstrated. These in situ methods include controlled breakdown (CBD), electrochemical reactions (ECR), laser etching and laser-assisted controlled breakdown (la-CBD). These techniques are democratising solid-state nanopores by providing the ability to fabricate pores with diameters down to a few nanometres (i.e. comparable to the size of many analytes) in a matter of minutes using relatively simple equipment. Here we review these in situ solid-state nanopore fabrication techniques and highlight the challenges and advantages of each method. Furthermore we compare these techniques by their desired application and provide insights into future research directions for in situ nanopore fabrication methods.

Roadmap on quantum nanotechnologies.

Quantum phenomena are typically observable at length and time scales smaller than those of our everyday experience, often involving individual particles or excitations. The past few decades have seen a revolution in the ability to structure matter at the nanoscale, and experiments at the single particle level have become commonplace. This has opened wide new avenues for exploring and harnessing quantum mechanical effects in condensed matter. These quantum phenomena, in turn, have the potential to revolutionize the way we communicate, compute and probe the nanoscale world. Here, we review developments in key areas of quantum research in light of the nanotechnologies that enable them, with a view to what the future holds. Materials and devices with nanoscale features are used for quantum metrology and sensing, as building blocks for quantum computing, and as sources and detectors for quantum communication. They enable explorations of quantum behaviour and unconventional states in nano- and opto-mechanical systems, low-dimensional systems, molecular devices, nano-plasmonics, quantum electrodynamics, scanning tunnelling microscopy, and more. This rapidly expanding intersection of nanotechnology and quantum science/technology is mutually beneficial to both fields, laying claim to some of the most exciting scientific leaps of the last decade, with more on the horizon.

Nanobody-targeted photodynamic therapy for the treatment of feline oral carcinoma: a step towards translation to the veterinary clinic.

Nanobody-targeted photodynamic therapy (NB-PDT) has been developed as a potent and tumor-selective treatment, using nanobodies (NBs) to deliver a photosensitizer (PS) specifically to cancer cells. Upon local light application, reactive oxygen species are formed and consequent cell death occurs. NB-PDT has preclinically shown evident success and we next aim to treat cats with oral squamous cell carcinoma (OSCC), which has very limited therapeutic options and is regarded as a natural model of human head and neck SCC. Immunohistochemistry of feline OSCC tissue confirmed that the epidermal growth factor receptor (EGFR) is a relevant target with expression in cancer cells and not in the surrounding stroma. Three feline OSCC cell lines were employed together with a well-characterized human cancer cell line (HeLa), all with similar EGFR expression, and a low EGFR-expressing human cell line (MCF7), mirroring the EGFR expression level in the surrounding mucosal stroma. NBA was identified as a NB binding human and feline EGFR with comparable high affinity. This NB was developed into NiBh, a NB-PS conjugate with high PS payload able to effectively kill feline OSCC and HeLa cell lines, after illumination. Importantly, the specificity of NB-PDT was confirmed in co-cultures where only the feline OSCC cells were killed while surrounding MCF7 cells were unaffected. Altogether, NiBh can be used for NB-PDT to treat feline OSCC and further advance NB-PDT towards the human clinic.