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Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line– and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models.Significance:The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.See related commentary by Klempner and Hata, p. 20.This article is highlighted in the In This Issue feature, p. 1

Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell driven malignancies. However, approved covalent BTK inhibitors (cBTKi) are associated with treatment limitations due to off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here we describe the preclinical profile of pirtobrutinib, a potent, highly selective, non-covalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate (ATP)-binding region and shows no direct interaction with C481. As a result, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKi, prevented Y551 phosphorylation in the activation loop. These data suggest pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. Collectively, these findings suggest pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical and structural attributes with the potential to treat B-cell driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.

Covalent Bruton tyrosine kinase inhibitors (cBTKi) have transformed the treatment of B cell malignancies. Despite the efficacy of cBTKi, treatment failure often occurs through development of resistance or intolerance. Pirtobrutinib, a highly selective, non-covalent BTKi, potently inhibits both WT and C481 mutant BTK. Pirtobrutinib has favorable oral pharmacology, is well tolerated, and has shown promising efficacy in patients with poor prognosis B cell malignancies following prior therapy, including prior cBTKi. Here we report in vitro BTK binding, conformation, and activation differences between cBTKi and pirtobrutinib. Cellular studies showed pirtobrutinib inhibited BTK phosphorylation at both Y223 and Y551 in REC-1 and Ramos A1 human lymphoma cell lines. In contrast, despite inhibition of Y223 phosphorylation, both cell lines treated with cBTKi, ibrutinib, acalabrutinib or zanubrutinib, retained Y551 phosphorylation. The differential effects on Y551 were also observed in PBMC isolated from treatment naïve human CLL donors treated in vitro with pirtobrutinib or ibrutinib. To investigate the binding effects of cBTKi and pirtobrutinib on BTK stability and conformation, a series of biophysical and structural studies were performed. In a hydrogen/deuterium exchange mass spectrometry study using full length BTK, all compounds significantly inhibited exchange in regions surrounding the ATP binding site in the kinase domain. While cBTKi induced significantly increased exchange for peptides in the SH3 and SH2 domains, pirtobrutinib significantly reduced exchange in a portion of the SH3 domain, nearly the entire SH2 domain, and SH2 linker, suggesting that pirtobrutinib uniquely stabilizes BTK in a closed/inactive conformation. Consistent with this proposed model, crosslinking mass spectrometry results of inhibitor bound BTK showed that pirtobrutinib promoted different interactions between the SH2 domain and kinase domain than cBTKi. To confirm that pirtobrutinib promotes greater stabilization of BTK, a mass spectrometry based cellular thermal shift assay was performed in both Ramos and BTK overexpressing HEK293 cells. In both cell lines, pirtobrutinib showed significantly greater stabilization of BTK compared to cBTKi. In addition, crystallographic studies of BTK in complex with pirtobrutinib revealed domain organization consistent with stabilized SH2-SH3 interactions with the kinase domain. These data suggest pirtobrutinib may differentially impact BTK stability and conformation compared to cBTKi. The cellular and biophysical data are consistent with a model in which cBTKi shift BTK toward an open conformation, whereas pirtobrutinib allosterically stabilizes a closed BTK conformation, preventing activation by upstream kinases. Additional studies are underway to further characterize the differential effects of pirtobrutinib on BTK conformation. Citation Format: Joshua A. Ballard, Kevin Ebata, Hetal S. Randeria, Garrett Tinline, Thomas Lee, Lauren M. Hanson, John A. Latham, E. Peder Cedervall, Jenny Chong, Kyle B. Del Valle, Bernard C. Collins, Tony H. Morales, Thomas C. Benedict, Marc A. Schureck, Ethan T. Bender, Christopher Mendoza, David Molina, Meagan Nakamoto, Hsiao-Chiao Shiah, Hao Xu, Alfonso Espada, Leticia Cano, Charles K. Allerston, Paul Schnier, Barbara J. Brandhuber. Unique pharmacodynamic properties conferred by differential binding to BTK, pirtobrutinib vs covalent inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2780.

A fundamental understanding and advancement of nanopatterning and nanometrology are essential in the future development of nanotechnology, atomic scale manipulation, and quantum technology industries. Scanning probe-based patterning/imaging techniques have been attractive for many research groups to conduct their research in nanoscale device fabrication and nanotechnology mainly due to its cost-effective process; however, the current tip materials in these techniques suffer from poor durability, limited resolution, and relatively high fabrication costs. Here, we report on employing GaN nanowires as a robust semiconductor material in scanning probe lithography (SPL) and microscopy (SPM) with a relatively low-cost fabrication process and the capability to provide sub-10 nm lithography and atomic scale (

In this article, we demonstrate diamagnetically levitated milli-robots performing 3D heterogeneous micro-assembly of silicon micro-machined parts and polymer microspheres. Diamagnetically levitated milli-robots, in conjunction with controlled magnetic fields from printed circuit boards, can enable very precise, low cost, high density, and an easily scalable approach to massively parallel micro-assembly. By using an eddy-current dampening layer to suppress ambient external forces, we measured an open-loop in-plane equilibrium motion repeatability of 28.6 nm rms over cm’s of travel and a total vertical range of 50–70 μm. To perform micro-assembly, light-weight end effectors and force compatible micro-processes (i.e. micro-grasping and liquid handling) were integrated with the diamagnetic levitated milli-robots. Various tele-operated micro-assembly tasks were demonstrated such as joining polymer micro-spheres, interlocking silicon micro-parts, and printing electrical interconnects. Multiple specialized milli-robots, each taking up only 31 mm2, are used to perform each individual micro-task. In the future, by developing more sophisticated milli-robots and operating many more of these milli-robots in parallel, a dense, automated, rapid milli-robot assembly may be possible.

Alterations in the fibroblast growth factor receptors (FGFRs) have been identified as oncogenic drivers in many human cancers. Specifically, activating FGFR3 gene alterations are found in ~15% of metastatic bladder cancers. One pan-FGFR inhibitor has been approved for patients with FGFR3-altered bladder cancer and others are in clinical development. Importantly, all of these agents inhibit FGFR1-3 with approximate equal potency. Consequently, these agents are associated with toxicities driven by off-target inhibition of FGFR1 and FGFR2, potentially limiting efficacy. Additionally, existing drugs lose potency in the setting of FGFR3 gatekeeper mutations and acquired resistance due to gatekeeper mutations has been described. LOX-24350 is a highly potent and isoform-selective FGFR3 inhibitor with activity against wild-type FGFR3, FGFR3 activating mutations such as S249C, and FGFR3 gatekeeper (V555M) mutations. Here, we describe the preclinical profile of LOX-24350. Compound potency and selectivity were measured using enzyme fluorescent activity assays, and cell-based assays using in-cell western and cell-titer Glo methods. Tumor growth inhibition and PK/PD studies were performed in mice. LOX-24350 showed greater than 56-fold selectivity for FGFR3 S249C over wild-type FGFR1 in mechanistic cellular inhibition assays, while maintaining potency for the V555M gatekeeper mutation. In HEK293 cells stably expressing FGFR3 S249C and FGFR3 S249C/V555M, LOX-24350 inhibited FGFR3 phosphorylation with IC50 values of 3.1 and 5.0 nM, respectively, as compared to FGFR1 and FGFR2 IC50 values of 174.5 and 90.7 nM, respectively. Similarly, in NIH3T3 cells engineered to express FGFR3 S249C or FGFR3 S249C/V555M, LOX-24350 inhibited cell growth with IC50 values of 12.2 and 22.9 nM, respectively. LOX-24350’s isoform-selectivity was best exemplified in cancer cell line models, with IC50 values of 15.1 and 12.6 nM in RT112 (FGFR3-TACC3) and UMUC14 (FGFR3 S249C) cell lines, respectively, as compared to 4712.6 nM in DMS114 (FGFR1 amp). LOX-24350 demonstrated high oral bioavailability in preclinical species as well as favorable in vitro ADME properties. In vivo, LOX-24350 demonstrated tumor regressions in FGFR3-driven tumor models on par with pan-FGFR inhibitors, without body weight loss or hyperphosphatemia seen with pan-FGFR inhibitors. This wider therapeutic index is predicted to allow for greater efficacy in patients. These data demonstrate that LOX-24350 potently and selectively inhibits FGFR3, the S249C activating mutation, and its gatekeeper mutation, V555M, while sparing FGFR1, FGFR2, and other problematic off-targets. We hypothesize that this profile will lead to differentiated efficacy and tolerability for patients with FGFR3-driven cancers. An IND submission is planned for 2022. Citation Format: Joshua A. Ballard, Timothy Kercher, David Abraham, Ryan Brecht, Nathan A. Brooks, Thomas Buckles, Desta Bume, David Busha, Ernst Peder Cedervall, Kevin Condroski, Kevin Ebata, Severine Isabelle Gharbi, Robert Hazlitt, Tony Morales, Nisha Patel, Jessica Podoll, Kaveri Urkalan, Sandra Gomez Villalain, Shane Walls, Faith Watson, Peiyi Yang, Barbara J. Brandhuber, Steven W. Andrews. Preclinical characterization of LOX-24350, a highly potent and isoform-selective FGFR3 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P141.

Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRAS

The selectivity of clean Si(100)-(2 × 1) surfaces fully reacted with H2O- and hydrogen-passivated Si(100)-(2 × 1) surfaces is investigated for atomic layer deposition (ALD) of TiO2, Al2O3, and HfO2 using TiCl4, TMA, or TDMA-Hf precursors with H2O, respectively, in an ultra-high-vacuum (UHV) environment. The initial reaction probability is estimated by determining the minimum exposure necessary for complete reaction of the metal precursors on both H2O-reacted and H-passivated Si(100)-(2 × 1) surfaces and examining the first full cycle of the ALD process for each oxide. Under these UHV conditions, the first cycle selectivity is 17:1 for TiO2, 37:1 for Al2O3, and only 4:3 for HfO2. Additionally, TMA is found to react with approximately half of the Si-H sites in addition to all the Si-OH sites, while TiCl4 and TDMA-Hf gases are found to react principally with the surface −OH on H2O-reacted Si(100) surfaces with no reaction with the −H sites.

In this paper, we use density functional theory (DFT) calculations to investigate the initial surface reactions involved in the atomic layer deposition (ALD) of Al2O3 from H2O and Al(CH3)3 (trimethylaluminum, TMA) molecular precursors on the Si(001)-(2×1) reconstructed surface with different chemical terminations. Our results for the kinetic barriers and adsorption energies of both Al and oxygen precursors along different reaction pathways show the dependence of the ALD nucleation rate on the surface defects (Si dangling bonds or dimer trench) and how it can be modified with suitable p-doping. Finally, our ab initio thermodynamics study clearly determines the relation between typical ALD working conditions and the different chemical functionalizations of the Si(001) surface with the growth properties of Al2O3 nanofilms.

In this article, we demonstrate the application of diamagnetically levitated milli-robots for the 2D micro-assembly of 10-μm polymer microspheres and other silicon microfabricated parts. By using an optical microscope for feedback (imaged at 27 Hz), we are able to demonstrate long-term open-loop stability (up to 78 hr) and sub-micron stability of the levitated micro-robots. Furthermore, due to the low hysteresis and high compliance in the magnetic drive of the milli-robots, we are able to directly use the milli-robots in conjunction with machine vision as a force sensor. Soft polymer-based end effectors are used for the micromanipulation of parts and show modest reliability of pick (>70%) and high reliability of place (>99%) that is insensitive to the pick surface material. Finally, we implement autonomous micro-assembly from randomly deposited microspheres into ordered arrays.

H depassivation lithography is a process by which a monolayer of H absorbed on a Si(100) 2x1 surface may be patterned by the removal of H atoms using a scanning tunneling microscope. This process can achieve atomic resolution where individual atoms are targeted and removed. This paper suggests that such a patterning process can be carried out as a digital process, where the pixels of the pattern are the individual H atoms. The goal is digital fabrication rather than digital information processing. The margins for the read and write operators appear to be sufficient for a digital process, and the tolerance for physical addressing of the atoms is technologically feasible. A digital fabrication process would enjoy some of the same advantages of digital computation; namely high reliability, error checking and correction, and the creation of complex systems.

We image frequency-modulated single-molecule optical absorption using a scanning tunneling microscope as the detector (SMA−STM). As a first example of the technique, a semiconducting carbon nanotube adsorbed on a silicon surface is studied. Excitation is achieved using laser amplitude as well as frequency modulation, and these two complementary approaches are compared. Detection is achieved via the resulting change in tunneling current through the excited molecule. We distinguish three mechanisms, direct, relaxed, and bolometric, for detecting single-molecule absorption spectra. Kinetic models for these mechanisms as well as for surface heating are presented. The latter effect can be eliminated by frequency modulation, keeping the laser power density on the surface constant.

Using ultrafast pump–probe spectroscopy, we observe quantum beats between rovibrational states located on the uncoupled bound G 1 Π g + and F 1 Σ g + electronic curves of Li 2 . From a pure launch state ( A 1 Σ u + v A , J A = 11 , 28 ) , a wave packet is prepared using the output from a visible ultrafast optical parametric amplifier and is photoionized by an 800 nm ultrafast pulse. As the OPA wavelength is scanned, a vibrational progression of rotational quantum beats on the G curve is observed. At energies around 35 000 cm −1 , in addition to rotational beats on the G curve, vibrational, rotational, and electronic beating between the G and F curves is observed.

Optical phase manipulation of nonresonant frequencies is investigated as a method of achieving optimal population transfer during resonant impulsive stimulated Raman scattering. Wave packets containing quantum beats between an initially prepared rovibrational level in the A(1Σu+) electronic state of Li2 and states populated via a resonance-enhanced rotational Raman process are created using a shaped ultrafast pulse centered near 800 nm. Study of these wave packets allows a quantitative comparison of population transfer as a function of applied phases in the ultrafast pulse. Two cases are explored to determine the ability to enhance population transfer: one with a wide state spacing [A(νA=11, JA=28)-A(11,30) at 50.1 cm−1] and one with a narrow spacing [A(11,8)-A(11,10) at 16.6 cm−1]. In both cases, several different phase masks are applied to the wave packet preparation pulse to enhance the population transferred to the newly formed state of interest. One phase mask involves the application of a −90° phase...

Using feedback and an evolutionary algorithm (EA), the weak field pump–probe photoionization signal at a single time delay is optimized in Li2. A single launch state is prepared via excitation with a cw laser, from which a pump pulse excites a superposition of two rotational states on an excited electronic potential energy curve: E 1Σg+(vE=9, JE=27 and 29). The EA modifies the phase pattern versus wavelength of the ultrafast pump pulses using a pulse shaper with a 128 pixel liquid crystal spatial light modulator. Limitations of frequency resolution for the pulse shaper create an effective temporal window in which pulses can be shaped. Optimization of the photoionization signal at pump–probe time delays outside of this temporal pulse shaping window involves phase shifts of only the two frequencies resonant with the transition of the wave packet states, effectively introducing a phase shift in the wave packet recurrences. For pump–probe time delays inside the pulse shaping window, optimization of the photoionization shows the influence of not only resonant but also nonresonant wavelengths. In this regime, the phase shift of wave packet recurrences as well as the time-dependent wave packet amplitude coefficients are optimized. First order time dependent perturbation theory is used to explain the mechanism by which the photoionization is maximized. These experiments are the first to use an optimization routine as a tool to identify a variety of simultaneous mechanisms that underlie the maximization of a process.

State-selective phase control of rotational Li2 wave packets, prepared simultaneously in the E(1∑g+) electronic state by one photon absorption and the A(1∑u+) electronic state by resonant impulsive stimulated Raman scattering, is demonstrated. Following the initial population of a rovibrational launch state on the A electronic potential energy curve with a cw laser, a single sub-picosecond wave packet preparation pulse centered near 800 nm simultaneously creates a two-state rotational wave packet in the E state (νE=18, JE=23 and 25) and a three-state rotational wave packet in the A state (νA=15, JA=22, 24, and 26). A temporally delayed 800 nm probe pulse subsequently ionizes both electronic components of the wave packet to allow measurement of the time-dependent coherence in these two electronic states. Via phase manipulation of resonant transition frequencies contained within the preparation pulse, the phases of the E(18,25) and A(15,26) quantum states are either varied concurrently or individually controlled, whereas the phases of the other rovibronic states of the wave packet are in all cases held essentially constant. This phase manipulation is shown to be more complex than a simple additive effect involving the phases applied to the resonant frequencies. These experimental results are compared with the predictions of second order time-dependent perturbation theory. Although systematic discrepancies exist, most likely due to an additional phase introduced during the two-photon probe process, once these differences are accounted for, good agreement is found between experiment and perturbation theory.

Time shifting (up to a global arbitrary phase) the dynamics of molecular wave packets, i.e, |Ψ(t)〉→|Ψ(t−tshift)〉, is demonstrated using a high degree of state selective coherent phase control with shaped femtosecond laser pulses. The benchmark system for the present work is the lithium dimer molecule. The phase-tailored Li2 wave packets are composed of several rovibrational states of the electronic E 1 Σ g + shelf state excited from a single rovibrational level (selected using a cw laser) of the A 1 Σ u + state. The time-shifting operation has implications for the experimental implementation of coherent control, as well as for the use of the control ability to study coherent configurations and dynamics that otherwise would be difficult (sometimes impossible) to access experimentally. This is due, for example, to dephasing and/or depopulation of the wave packet in combination with long recurrence times. One such inaccessible coherent configuration of the present Li2 wave packets corresponds to the global maximum of their ionization yield (as probed in the present experiment).

Fifty years ago, Richard Feynman famously stated that “I am not afraid to consider the final question as to whether, ultimately—in the great future—we can arrange the atoms the way we want” (Feynman, “There’s Plenty of Room at the Bottom”, speech on December 29th 1959 at the annual meeting of the American Physical Society at the California Institute of Technology). Twenty years ago, Don Eigler of IBM, did arrange atoms the way he wanted (Eigler and Schweizer, Nature 344:524, 1990). We contend that in the very near future, that arranging atoms the way we want will become a manufacturing technology. This technology will start small, very small, in making practical and profitable products, and from there scale-up to a wide range of products and applications with very large economic and societal impacts. We will explain some of the details of the path that we are on to achieve Atomically Precise Manufacturing (APM), some of the challenges we must overcome to succeed, and the surprising number of applications that we have identified that are waiting for us to exploit.

The atomic and electronic structures of pyramidal model STM tips of transition metals (W, Rh, Pd, Ir and Pt) were investigated using density functional theory (DFT) method. The calculated density of states show that d electrons of the apex atoms in the M4 (M = W, Rh, Pd, Ir, Pt) model tips behave differently near the Fermi level, with the dz2 state being dominant only for W tip. The electronic structures of pyramid structures of W and Pd single-atom tips with larger sizes are studied and compared. The density of states of Pd apex atom and W apex atom show different occupation of d-bands leading to asymmetric density of states for Pd tip. The asymmetric tunneling currents measured by W and Pt-Ir STM tips are explained by the calculated electronic structures of W and Pd model tips.

We report single molecule laser absorption by carbon nanotubes stamped under ultrahigh vacuum onto Si(100)2x1:H surfaces. Absorption is detected by scanning tunneling microscopy. Images are obtained with and without modulated laser excitation using lock-in amplification and a rear-illumination geometry to reduce thermal effects. Noise appears at topographic edges and is analyzed by a quantitative model in terms of scan speed, mechanical instabilities, and feedback current fluctuations at the edge of the nanotubes. Noise due to mechanical instabilities is shown to persist even in the limit of slow scan speed.

A hydrogen passivated Si(100)-2/spl times/1 surface is studied using ultrafast laser excitation with a novel total internal reflection geometry. The incoherent tip and sample heating dynamics are studied, and it is shown that as long as the STM feedback is faster than the heating and cooling processes, atomic scale imaging can be achieved, even in the presence of significant tip and sample expansion and contraction. This opens the door for studies of surface processes on the ultrafast timescale.

An ultrafast pulse shaping scheme is presented that transiently modifies a two-state superposition on the E {sup 1}{sigma}{sub g}{sup +} curve of the lithium dimer. At short time delays, the wave-function amplitude of one of the states is forced to undergo a sign change, while the sign of the second state is programmed to remain static, analogous to the operation of a quantum-computational Z gate. This is observed as a {pi} phase shift in the time-dependent wave-packet signal for pump-probe delays

State-selective phase control over rotational wave packets in two Li2 electronic states using tailored femtosecond pulses is demonstrated. A shaped preparation pulse simultaneously creates wave packets in the A and E electronic states, which are probed using a second time-delayed pulse. This allows independent phase control of selected rotational wave packet components in both electronic states.bl]References

Ultrafast pulse shapes are used to control simultaneously the optimal population transfer coefficients and rotational wave-packet quantum interferences in the E 1 Σ + g state of Li 2 (v E =9, J E =27 and 29). By dividing the spectral bandwidth of the ultrafast pulses into multiple "control domains" centered on each resonant wavelength, the population transfer coefficients can be manipulated independently of the wave-packet interferences to maximize the Li 2 photoionization yield at arbitrary short pump-probe time delays. To investigate the population transfer coefficients with and without wave-packet interferences, respectively, the pump polarization is set to be either parallel to or at the magic angle (∼55°) relative to the probe polarization. A comparison is made between phases that are symmetric and antisymmetric about the resonances. The effects of resonant and nonresonant frequencies are separately established and quantified. It is estimated that up to 90% of the possible nonresonant Rabi oscillations can be brought into phase simultaneously for each rovibrational state in the wave packet, while at the same time a constant phase offset added to one of the control domains establishes the phase of the wave-packet interference.

Reducing the scale of etched nanostructures below the 10 nm range eventually will require an atomic scale understanding of the masks being used in order to maintain exquisite control over both feature size and feature density. Here, the authors demonstrate a method for tracking atomically resolved and controlled structures from initial template definition through final nanostructure metrology, opening up a pathway for top–down atomic control over nanofabrication. First, hydrogen depassivation lithography is performed on hydrogen terminated Si(100) using a scanning tunneling microscope, which spatially defined chemically reactive regions. Next, atomic layer deposition of titanium dioxide produces an etch-resistant hard mask pattern on these regions. Reactive ion etching then transfers the mask pattern onto Si with pattern height of 17 nm, critical dimension of approximately 6 nm, and full-pitch down to 13 nm. The effects of linewidth, template atomic defect density, and line-edge roughness are examined in the context of controlling fabrication with arbitrary feature control, suggesting a possible critical dimension down to 2 nm on 10 nm tall features. A metrology standard is demonstrated, where the atomically resolved mask template is used to determine the size of a nanofabricated sample showing a route to image correction.

The production of spurious dangling bonds during the hydrogen depassivation lithography process on Si(100)-H is studied. It is shown that the number of spurious dangling bonds produced depends on the size of the primary pattern on the surface, not on the electron dose, indicating that the spurious dangling bonds are formed via an interaction of the liberated hydrogen with the surface. It is also shown that repassivation may occur if hydrogen depassivation lithography is performed near an already patterned area. Finally, it is argued that the product of the interaction is a single dangling bond next to a monohydride silicon on a silicon dimer, with a reaction probability much in excess of that previously observed.

A method to enhance the speed of scanning tunneling microscope based hydrogen depassivation lithography is presented. In order to maximize patterning speed while maintaining the capability to retain atomic precision with respect to line edges and feature positions, a multimode technique is used where the modes are characterized either by large or small spot sizes. For areas where atomically precise lithography is required, a tip sample bias of 4–4.5 V is used. In other areas, such as in the center of a large solid pattern, large (∼7 nm) linewidth field emission lithography with a tip sample bias of 8 V is used. A method to generate an optimized set of writing vectors for each mode is described and applied to a fundamental square pattern on the Si(100) surface with an experimental 78% write time reduction. An analysis of the optimal vectors indicates that patterning times may be reduced by up to 95%.

We aim to develop techniques for the building of atomically precise structures. On the H-terminated Si(001) surface, H atoms can be selectively removed using an STM tip with appropriate lithography conditions, creating arbitrary patterns of reactive dangling bonds with atomic precision. The exposed patterns are used as templates for the growth of Si and Ge by gas-source epitaxy, using disilane and digermane as the precursor gases. The quality of the epitaxy, in terms of island size and defect density of the second and subsequent monolayer (ML), is dependent upon the electron exposure. Good-quality growth of the second and following MLs requires a multiple of the exposure required for good-quality growth of the first ML. This is interpreted in terms of remanent hydrogen in island sites in the first ML.

We present a study addressing the effectiveness of a monolayer of hydrogen as the lithographic resist for controlled three-dimensional (3D) growth of nanostructures on the Si(100) surface. Nanoscale regions on the H-terminated Si(100) were defined by H-desorption lithography via the biased tip of a scanning tunneling microscope (STM) to create well-defined regions of surface “dangling bonds,” and the growth of 3D nanostructures within these regions was achieved using a simultaneous disilane deposition and STM H-desorption technique. We demonstrate that 3D growth is strongly confined within STM depassivated regions while unpatterned H:Si(100) regions are robust against adsorption of the precursor molecules.

Lithographic precision is as or more important than resolution. For decades, the semiconductor industry has been able to work with ±5% precision. However, for other applications such as micronanoelectromechanical systems, optical elements, and biointerface applications, higher precision is desirable. Lyding et al. [Appl. Phys. Lett. 64, 11 (1999)] have demonstrated that a scanning tunneling microscope can be used to remove hydrogen (H) atoms from a silicon (100) 2 × 1 H-passivated surface through an electron stimulated desorption process. This can be considered e-beam lithography with a thin, self-developing resist. Patterned hydrogen layers do not make a robust etch mask, but the depassivated areas are highly reactive since they are unsatisfied covalent bonds and have been used for selective deposition of metals, oxides, semiconductors, and dopants. The depassivation lithography has shown the ability to remove single H atoms, suggesting the possibility of precise atomic patterning. This patterning proces...

Linearly chirped femtosecond laser pulses are used to excite ro-vibrational wave packets in lithium dimers from a single well-prepared launch state. Two-photon resonant Raman transitions excite a manifold of rotational states in a coherent superposition. Excitation with positively chirped laser pulses is shown to enhance a quantum beat involving states with lower rotational quantum numbers, whereas negatively chirped pulses enhance a quantum beat between states with higher rotational quantum numbers, thus steering the rotational coherences to higher or lower rotational states. Time-dependent perturbation theory calculations verify the magnitudes and directions of the enhancement as a function of the applied chirp. The quantitative calculations and experimental results demonstrate that excitation with chirped pulses is an effective method for enhancing specific rotational coherences involving higher or lower rotational states.