Daniel Ward

Electromigrated Nanoscale Gaps for Surface-Enhanced Raman Spectroscopy

Single-molecule detection with chemical specificity is a powerful and much desired tool for biology, chemistry, physics, and sensing technologies. Surface-enhanced spectroscopies enable single-molecule studies, yet reliable substrates of adequate sensitivity are in short supply. We present a simple, scaleable substrate for surface-enhanced Raman spectroscopy (SERS) incorporating nanometer-scale electromigrated gaps between extended electrodes. Molecules in the nanogap active regions exhibit hallmarks of very high Raman sensitivity, including blinking and spectral diffusion. Electrodynamic simulations show plasmonic focusing, giving electromagnetic enhancements approaching those needed for single-molecule SERS.

Optical rectification and field enhancement in a plasmonic nanogap

Metal nanostructures act as powerful optical antennas because collective modes of the electron fluid in the metal are excited when light strikes the surface of the nanostructure. These excitations, known as plasmons, can have evanescent electromagnetic fields that are orders of magnitude larger than the incident electromagnetic field. The largest field enhancements often occur in nanogaps between plasmonically active nanostructures, but it is extremely challenging to measure the fields in such gaps directly. These enhanced fields have applications in surface-enhanced spectroscopies, nonlinear optics and nanophotonics. Here we show that nonlinear tunnelling conduction between gold electrodes separated by a subnanometre gap leads to optical rectification, producing a d.c. photocurrent when the gap is illuminated. Comparing this photocurrent with low-frequency conduction measurements, we determine the optical frequency voltage across the tunnelling region of the nanogap, and also the enhancement of the electric field in the tunnelling region, as a function of gap size. The measured field enhancements exceed 1,000, consistent with estimates from surface-enhanced Raman measurements. Our results highlight the need for more realistic theoretical approaches that are able to model the electromagnetic response of metal nanostructures on scales ranging from the free-space wavelength, λ, down to ∼λ/1,000, and for experiments with new materials, different wavelengths and different incident polarizations.

Simultaneous Measurements of Electronic Conduction and Raman Response in Molecular Junctions

Electronic conduction through single molecules is affected by the molecular electronic structure as well as by other information that is extremely difficult to assess, such as bonding geometry and chemical environment. The lack of an independent diagnostic technique has long hampered single-molecule conductance studies. We report simultaneous measurement of the conductance and the Raman spectra of nanoscale junctions used for single-molecule electronic experiments. Blinking and spectral diffusion in the Raman response of both p-mercaptoaniline and a fluorinated oligophenylyne ethynylene correlate in time with changes in the electronic conductance. Finite difference time domain calculations confirm that these correlations do not result from the conductance modifying the Raman enhancement. Therefore, these observations strongly imply that multimodal sensing of individual molecules is possible in these mass-producible nanostructures.

Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms

The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.

Vibrational and electronic heating in nanoscale junctions

Understanding and controlling the flow of heat is a major challenge in nanoelectronics. When a junction is driven out of equilibrium by light or the flow of electric charge, the vibrational and electronic degrees of freedom are, in general, no longer described by a single temperature. Moreover, characterizing the steady-state vibrational and electronic distributions in situ is extremely challenging. Here, we show that surface-enhanced Raman emission may be used to determine the effective temperatures for both the vibrational modes and the electrons in the current in a biased metallic nanoscale junction decorated with molecules. Molecular vibrations show mode-specific pumping by both optical excitation and d.c. current, with effective temperatures exceeding several hundred kelvin. Anti-Stokes electronic Raman emission indicates that the effective electronic temperature at bias voltages of a few hundred millivolts can reach values up to three times the values measured when there is no current. The precise effective temperatures are model-dependent, but the trends as a function of bias conditions are robust, and allow direct comparisons with theories of nanoscale heating.

Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers.

FMR1 premutations are known to be associated with premature ovarian failure (POF), but the underlying mechanism is unknown. We present evidence for a nonlinear association between menopause age and premutation size suggesting that premutations in the mid-size range are at greatest risk for POF, while larger premutations are at lower risk.

Genetic variation at MECOM , TERT , JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.

Two-axis control of a singlet–triplet qubit with an integrated micromagnet

Significance Qubits, the quantum-mechanical analog of classical bits, are the fundamental building blocks of quantum computers, which have the potential to solve some problems that are intractable using classical computation. This paper reports the fabrication and operation of a qubit in a double-quantum dot in a silicon/silicon–germanium (Si/SiGe) heterostructure in which the qubit states are singlet and triplet states of two electrons. The significant advance over previous work is that a proximal micromagnet is used to create a large local magnetic field difference between the two sides of the quantum dot, which increases the manipulability significantly without introducing measurable noise. The qubit is the fundamental building block of a quantum computer. We fabricate a qubit in a silicon double-quantum dot with an integrated micromagnet in which the qubit basis states are the singlet state and the spin-zero triplet state of two electrons. Because of the micromagnet, the magnetic field difference ΔB between the two sides of the double dot is large enough to enable the achievement of coherent rotation of the qubit’s Bloch vector around two different axes of the Bloch sphere. By measuring the decay of the quantum oscillations, the inhomogeneous spin coherence time T2* is determined. By measuring T2* at many different values of the exchange coupling J and at two different values of ΔB, we provide evidence that the micromagnet does not limit decoherence, with the dominant limits on T2* arising from charge noise and from coupling to nuclear spins.

Electronic and optical properties of electromigrated molecular junctions

Electromigrated nanoscale junctions have proven very useful for studying electronic transport at the single-molecule scale. However, confirming that conduction is through precisely the molecule of interest and not some contaminant or metal nanoparticle has remained a persistent challenge, typically requiring a statistical analysis of many devices. We review how transport mechanisms in both electronic and optical measurements can be used to infer information about the nanoscale junction configuration. The electronic response to optical excitation is particularly revealing. We briefly discuss surface-enhanced Raman spectroscopy on such junctions, and present new results showing that currents due to optical rectification can provide a means of estimating the local electric field at the junction due to illumination.

Evaluation of methods to detect CALR mutations in myeloproliferative neoplasms.

The recent discovery of somatically acquired CALR mutations in a substantial proportion of patients with myeloproliferative neoplasms has provided a new marker of clonal disease, advancing both diagnosis and prognosis in these previously difficult to characterise disorders. The mutations, which can be challenging to detect on a routine basis, are heterogeneous insertions/deletions (indels) in exon 9 with mutant allele burden that vary substantially between patients. We evaluated four genetic screening methods for their ability to detect a series of different CALR mutations; Sanger sequencing, fragment analysis PCR, high resolution melt (HRM) and targeted next generation sequencing (NGS). The limit of detection (LoD) of each assay was tested using serial dilution series made with DNA from CALR positive sample DNA and a cell line, MARIMO, found to carry a heterozygous 61 nucleotide CALR deletion. All methods were capable of detecting each mutation; HRM and fragment analysis PCR were better at detecting low mutation levels compared to Sanger sequencing but targeted NGS had the lowest LoD at a 1% mutation burden.