Resolving length-scale-dependent transient disorder through an ultrafast phase transition.

Material functionality can be strongly determined by structure extending only over nanoscale distances. The pair distribution function presents an opportunity for structural studies beyond idealized crystal models and to investigate structure over varying length scales. Applying this method with ultrafast time resolution has the potential to similarly disrupt the study of structural dynamics and phase transitions. Here we demonstrate such a measurement of CuIr2S4 optically pumped from its low-temperature Ir-dimerized phase. Dimers are optically suppressed without spatial correlation, generating a structure whose level of disorder strongly depends on the length scale. The redevelopment of structural ordering over tens of picoseconds is directly tracked over both space and time as a transient state is approached. This measurement demonstrates the crucial role of local structure and disorder in non-equilibrium processes as well as the feasibility of accessing this information with state-of-the-art XFEL facilities.

Cascaded nanooptics to probe microsecond atomic-scale phenomena.

Plasmonic nanostructures can focus light far below the diffraction limit, and the nearly thousandfold field enhancements obtained routinely enable few- and single-molecule detection. However, for processes happening on the molecular scale to be tracked with any relevant time resolution, the emission strengths need to be well beyond what current plasmonic devices provide. Here, we develop hybrid nanostructures incorporating both refractive and plasmonic optics, by creating SiO2 nanospheres fused to plasmonic nanojunctions. Drastic improvements in Raman efficiencies are consistently achieved, with (single-wavelength) emissions reaching 107 counts⋅mW-1⋅s-1 and 5 × 105 counts∙mW-1∙s-1∙molecule-1, for enhancement factors >1011 We demonstrate that such high efficiencies indeed enable tracking of single gold atoms and molecules with 17-µs time resolution, more than a thousandfold improvement over conventional high-performance plasmonic devices. Moreover, the obtained (integrated) megahertz count rates rival (even exceed) those of luminescent sources such as single-dye molecules and quantum dots, without bleaching or blinking.

Non-invasive electrocardiographic mapping on the ward to guide ablation of premature ventricular contractions.

Premature ventricular contracts (PVCs) are commonly encountered in clinical practice, but their ablation can prove difficult. In 15 patients with idiopathic PVCs, non-invasive mapping system View Into Ventricular Onset ™ (VIVO) in combination with 12­lead Holter monitoring on the ward accurately guided catheter ablation via the creation of 'electrical roadmaps' of ventricular activation. This allowed for better discussions of risks and benefits with the patient prior to the procedure, and is likely to have particular advantages for patients with a low PVC burden, multiple morphologies, or difficult to reach origins. CLINICAL PERSPECTIVE: PERSONALISED APPROACH: A novel non-invasive mapping tool in combination with technology, such as 12 lead Holter monitoring, allows for individualised, accurate prediction of PVC origin outside the electrophysiology (EP) lab. NON-INVASIVE MAPPING: An "electrical road map" can be implemented into 3D electroanatomical mapping systems, shortening procedure times and resulting in excellent clinical outcomes. POTENTIAL BENEFITS: VIVO could be used to improve catheter ablation outcomes for patients with infrequent PVCs, multiple morphologies and/or difficult to reach origins.

Multivalent Patchy Colloids for Quantitative 3D Self-Assembly Studies.

We report methods to synthesize sub-micron- and micron-sized patchy silica particles with fluorescently labeled hemispherical titania protrusions, as well as routes to efficiently characterize these particles and self-assemble these particles into non-close-packed structures. The synthesis methods expand upon earlier work in the literature, in which silica particles packed in a colloidal crystal were surface-patterned with a silane coupling agent. Here, hemispherical amorphous titania protrusions were successfully labeled with fluorescent dyes, allowing for imaging by confocal microscopy and super-resolution techniques. Confocal microscopy was exploited to experimentally determine the numbers of protrusions per particle over large numbers of particles for good statistical significance, and these distributions were compared to simulations predicting the number of patches as a function of core particle polydispersity and maximum separation between the particle surfaces. We self-assembled these patchy particles into open percolating gel networks by exploiting solvophobic attractions between the protrusions.

Involuntary arm movements post-pacemaker insertion - real or Reel syndrome?

BACKGROUND: Twiddler syndrome, and the variant Reel syndrome, are rare but important complications of pacemaker implantation. CASE SUMMARY: We describe a rare complication of conventional permanent pacemaker implantation of rhythmic arm twitching secondary to brachial plexus stimulation from a displaced pacing lead caused by Reel syndrome. DISCUSSION: Twiddler syndrome and its variants are rare but important complications of pacemaker insertion. Holistic planning of cardiac procedures in elderly patients should identify those at risk to allow for targeted education and post-procedural care.

Maternal hypertensive traits and adverse outcome in pregnancy: a Mendelian randomization study.

INTRODUCTION: Hypertensive disorders of pregnancy are associated with adverse feto-maternal outcomes. Existing evidence is mostly limited to observational studies, which are liable to confounding and bias. This study investigated the causal relevance of component hypertensive indices on multiple adverse pregnancy outcomes using Mendelian randomization. METHODS: Uncorrelated ( r2  < 0.001) genome-wide significant ( P  < 5 × 10 -8 ) single-nucleotide polymorphisms associated with SBP, DBP and pulse pressure (PP) were selected as instrumental variables. Genetic association estimates for outcomes of preeclampsia or eclampsia, preterm birth, placental abruption and hemorrhage in early pregnancy were extracted from summary statistics of genome-wide association studies in the FinnGen cohort. Two-sample, inverse-variance weighted Mendelian randomization formed the primary analysis method. Odds ratios (OR) are presented per-10 mmHg higher genetically predicted hypertensive index. RESULTS: Higher genetically predicted SBP were associated with higher odds of preeclampsia or eclampsia [OR 1.81, 95% confidence interval (CI) 1.68-1.96, P  = 5.45 × 10 -49 ], preterm birth (OR 1.09, 95% CI 1.03-1.16, P  = 0.005) and placental abruption (OR 1.33, 95% CI 1.05-1.68, P  = 0.016). Higher genetically-predicted DBP was associated with preeclampsia or eclampsia (OR 2.54, 95% CI 2.21-2.92, P  = 5.35 × 10 -40 ). Higher genetically predicted PP was associated with preeclampsia or eclampsia (OR 1.68, 95% CI 1.47-1.92, P  = 1.9 × 10 -14 ) and preterm birth (OR 1.18, 95% CI 1.06-1.30, P  = 0.002). CONCLUSION: This study provides genetic evidence to support causal associations of SBP, DBP and PP on multiple adverse outcomes of pregnancy. SBP and PP were associated with the broadest range of adverse outcomes, suggesting that optimized management of blood pressure, particularly SBP, is a key priority to improve feto-maternal health.

Mapping Atomic-Scale Metal-Molecule Interactions: Salient Feature Extraction through Autoencoding of Vibrational Spectroscopy Data.

Atomic-scale features, such as step edges and adatoms, play key roles in metal-molecule interactions and are critically important in heterogeneous catalysis, molecular electronics, and sensing applications. However, the small size and often transient nature of atomic-scale structures make studying such interactions challenging. Here, by combining single-molecule surface-enhanced Raman spectroscopy with machine learning, spectra are extracted of perturbed molecules, revealing the formation dynamics of adatoms in gold and palladium metal surfaces. This provides unique insight into atomic-scale processes, allowing us to resolve where such metallic protrusions form and how they interact with nearby molecules. Our technique paves the way to tailor metal-molecule interactions on an atomic level and assists in rational heterogeneous catalyst design.

Emergence of liquid following laser melting of gold thin films.

X-ray structural science is undergoing a revolution driven by the emergence of X-ray Free-electron Laser (XFEL) facilities. The structures of crystalline solids can now be studied on the picosecond time scale relevant to phonons, atomic vibrations which travel at acoustic velocities. In the work presented here, X-ray diffuse scattering is employed to characterize the time dependence of the liquid phase emerging from femtosecond laser-induced melting of polycrystalline gold thin films using an XFEL. In a previous analysis of Bragg peak profiles, we showed the supersonic disappearance of the solid phase and presented a model of pumped hot electrons carrying energy from the gold surface to scatter at internal grain boundaries. This generates melt fronts propagating relatively slowly into the crystal grains. By conversion of diffuse scattering to a partial X-ray pair distribution function, we demonstrate that it has the characteristic shape obtained by Fourier transformation of the measured F(Q). The diffuse signal fraction increases with a characteristic rise-time of 13 ps, roughly independent of the incident pump fluence and consequent final liquid fraction. This suggests the role of further melt-front nucleation processes beyond grain boundaries.

Optical suppression of energy barriers in single molecule-metal binding.

Transient bonds between molecules and metal surfaces underpin catalysis, bio/molecular sensing, molecular electronics, and electrochemistry. Techniques aiming to characterize these bonds often yield conflicting conclusions, while single-molecule probes are scarce. A promising prospect confines light inside metal nanogaps to elicit in operando vibrational signatures through surface-enhanced Raman scattering. Here, we show through analysis of more than a million spectra that light irradiation of only a few microwatts on molecules at gold facets is sufficient to overcome the metallic bonds between individual gold atoms and pull them out to form coordination complexes. Depending on the molecule, these light-extracted adatoms persist for minutes under ambient conditions. Tracking their power-dependent formation and decay suggests that tightly trapped light transiently reduces energy barriers at the metal surface. This opens intriguing prospects for photocatalysis and controllable low-energy quantum devices such as single-atom optical switches.

Catheter Ablation for Atrial Fibrillation in Adult Congenital Heart Disease: An International Multicenter Registry Study.

BACKGROUND: Data on atrial fibrillation (AF) ablation and outcomes are limited in patients with congenital heart disease (CHD). We aimed to investigate the characteristics of patients with CHD presenting for AF ablation and their outcomes. METHODS: A multicenter, retrospective analysis was performed of patients with CHD undergoing AF ablation between 2004 and 2020 at 13 participating centers. The severity of CHD was classified using 2014 Pediatric and Congenital Electrophysiology Society/Heart Rhythm Society guidelines. Clinical data were collected. One-year complete procedural success was defined as freedom from atrial tachycardia or AF in the absence of antiarrhythmic drugs or including previously failed antiarrhythmic drugs (partial success). RESULTS: Of 240 patients, 127 (53.4%) had persistent AF, 62.5% were male, and mean age was 55.2±13.3 years. CHD complexity categories included 147 (61.3%) simple, 68 (28.3%) intermediate, and 25 (10.4%) severe. The most common CHD type was atrial septal defect (n=78). More complex CHD conditions included transposition of the great arteries (n=14), anomalous pulmonary veins (n=13), tetralogy of Fallot (n=8), cor triatriatum (n=7), single ventricle physiology (n=2), among others. The majority (71.3%) of patients had trialed at least one antiarrhythmic drug. Forty-six patients (22.1%) had reduced systemic ventricular ejection fraction <50%, and mean left atrial diameter was 44.1±8.2 mm. Pulmonary vein isolation was performed in 227 patients (94.6%); additional ablation included left atrial linear ablations (40%), complex fractionated atrial electrogram (19.2%), and cavotricuspid isthmus ablation (40.8%). One-year complete and partial success rates were 45.0% and 20.5%, respectively, with no significant difference in the rate of complete success between complexity groups. Overall, 38 patients (15.8%) required more than one ablation procedure. There were 3 (1.3%) major and 13 (5.4%) minor procedural complications. CONCLUSIONS: AF ablation in CHD was safe and resulted in AF control in a majority of patients, regardless of complexity. Future work should address the most appropriate ablation targets in this challenging population.

Locating Single-Atom Optical Picocavities Using Wavelength-Multiplexed Raman Scattering.

Transient atomic protrusions in plasmonic nanocavities confine optical fields to sub-1-nm3 picocavities, allowing the optical interrogation of single molecules at room temperature. While picocavity formation is linked to both the local chemical environment and optical irradiation, the role of light in localizing the picocavity formation is unclear. Here, we combine information from thousands of picocavity events and simultaneously compare the transient Raman scattering arising from two incident pump wavelengths. Full analysis of the data set suggests that light suppresses the local effective barrier height for adatom formation and that the initial barrier height is decreased by reduced atomic coordination numbers near facet edges. Modeling the system also resolves the frequency-dependent picocavity field enhancements supported by these atomic scale features.

Tracking interfacial single-molecule pH and binding dynamics via vibrational spectroscopy.

Understanding single-molecule chemical dynamics of surface ligands is of critical importance to reveal their individual pathways and, hence, roles in catalysis, which ensemble measurements cannot see. Here, we use a cascaded nano-optics approach that provides sufficient enhancement to enable direct tracking of chemical trajectories of single surface-bound molecules via vibrational spectroscopy. Atomic protrusions are laser-induced within plasmonic nanojunctions to concentrate light to atomic length scales, optically isolating individual molecules. By stabilizing these atomic sites, we unveil single-molecule deprotonation and binding dynamics under ambient conditions. High-speed field-enhanced spectroscopy allows us to monitor chemical switching of a single carboxylic group between three discrete states. Combining this with theoretical calculation identifies reversible proton transfer dynamics (yielding effective single-molecule pH) and switching between molecule-metal coordination states, where the exact chemical pathway depends on the intitial protonation state. These findings open new domains to explore interfacial single-molecule mechanisms and optical manipulation of their reaction pathways.

Resolving sub-angstrom ambient motion through reconstruction from vibrational spectra.

Metal/organic-molecule interactions underpin many key chemistries but occur on sub-nm scales where nanoscale visualisation techniques tend to average over heterogeneous distributions. Single molecule imaging techniques at the atomic scale have found it challenging to track chemical behaviour under ambient conditions. Surface-enhanced Raman spectroscopy can optically monitor the vibrations of single molecules but understanding is limited by the complexity of spectra and mismatch between theory and experiment. We demonstrate that spectra from an optically generated metallic adatom near a molecule of interest can be inverted into dynamic sub-Å metal-molecule interactions using a comprehensive model, revealing anomalous diffusion of a single atom. Transient metal-organic coordination bonds chemically perturb molecular functional groups > 10 bonds away. With continuous improvements in computational methods for modelling large and complex molecular systems, this technique will become increasingly applicable to accurately tracking more complex chemistries.

Out-of-Plane Nanoscale Reorganization of Lipid Molecules and Nanoparticles Revealed by Plasmonic Spectroscopy.

Lipid bilayers assembled on solid substrates have been extensively studied with single-molecule resolution as the constituent molecules diffuse in 2D; however, the out-of-plane motion is typically ignored. Here we present the subnanometer out-of-plane diffusion of nanoparticles attached to hybrid lipid bilayers (HBLs) assembled on metal surfaces. The nanoscale cavity formed between the Au nanoparticle and Au film provides strongly enhanced optical fields capable of locally probing HBLs assembled in the gaps. This allows us to spectroscopically resolve the nanoparticles assembled on bilayers, near edges, and in membrane defects, showing the strong influence of charged lipid rafts. Nanoparticles sitting on the edges of the HBL are observed to flip onto and off of the bilayer, with flip energies of ∼10 meV showing how thermal energies dynamically modify lipid arrangements around a nanoparticle. We further resolve the movement of individual lipid molecules by doping the HBL with low concentrations of Texas Red (TxR) dye-labeled lipids.

Flickering nanometre-scale disorder in a crystal lattice tracked by plasmonic flare light emission.

The dynamic restructuring of metal nanoparticle surfaces is known to greatly influence their catalytic, electronic transport, and chemical binding functionalities. Here we show for the first time that non-equilibrium atomic-scale lattice defects can be detected in nanoparticles by purely optical means. These fluctuating states determine interface electronic transport for molecular electronics but because such rearrangements are low energy, measuring their rapid dynamics on single nanostructures by X-rays, electron beams, or tunnelling microscopies, is invasive and damaging. We utilise nano-optics at the sub-5nm scale to reveal rapid (on the millisecond timescale) evolution of defect morphologies on facets of gold nanoparticles on a mirror. Besides dynamic structural information, this highlights fundamental questions about defining bulk plasma frequencies for metals probed at the nanoscale.

Room-Temperature Optical Picocavities below 1 nm3 Accessing Single-Atom Geometries.

Reproducible confinement of light on the nanoscale is essential for the ability to observe and control chemical reactions at the single-molecule level. Here we reliably form millions of identical nanocavities and show that the light can be further focused down to the subnanometer scale via the creation of picocavities, single-adatom protrusions with angstrom-level resolution. For the first time, we stabilize and analyze these cavities at room temperatures through high-speed surface-enhanced Raman spectroscopy on specifically selected molecular components, collecting and analyzing more than 2 million spectra. Data obtained on these picocavities allows us to deduce structural information on the nanoscale, showing that thiol binding to gold destabilizes the metal surface to optical irradiation. Nitrile moieties are found to stabilize picocavities by 10-fold against their disappearance, typically surviving for >1 s. Such constructs demonstrate the accessibility of single-molecule chemistry under ambient conditions.

An Aspartate-Specific Solute-Binding Protein Regulates Protein Kinase G Activity To Control Glutamate Metabolism in Mycobacteria.

Signaling by serine/threonine phosphorylation controls diverse processes in bacteria, and identification of the stimuli that activate protein kinases is an outstanding question in the field. Recently, we showed that nutrients stimulate phosphorylation of the protein kinase G substrate GarA in Mycobacterium smegmatis and Mycobacterium tuberculosis and that the action of GarA in regulating central metabolism depends upon whether it is phosphorylated. Here we present an investigation into the mechanism by which nutrients activate PknG. Two unknown genes were identified as co-conserved and co-expressed with PknG: their products were a putative lipoprotein, GlnH, and putative transmembrane protein, GlnX. Using a genetic approach, we showed that the membrane protein GlnX is functionally linked to PknG. Furthermore, we determined that the ligand specificity of GlnH matches the amino acids that stimulate GarA phosphorylation. We determined the structure of GlnH in complex with different amino acid ligands (aspartate, glutamate, and asparagine), revealing the structural basis of ligand specificity. We propose that the amino acid concentration in the periplasm is sensed by GlnH and that protein-protein interaction allows transmission of this information across the membrane via GlnX to activate PknG. This sensory system would allow regulation of nutrient utilization in response to changes in nutrient availability. The sensor, signaling, and effector proteins are conserved throughout the Actinobacteria, including the important human pathogen Mycobacterium tuberculosis, industrial amino acid producer Corynebacterium glutamicum, and antibiotic-producing Streptomyces species.IMPORTANCE Tuberculosis (TB) kills 5,000 people every day, and the prevalence of multidrug-resistant TB is increasing in every country. The processes by which the pathogen Mycobacterium tuberculosis senses and responds to changes in its environment are attractive targets for drug development. Bacterial metabolism differs dramatically between growing and dormant cells, and these changes are known to be important in pathogenesis of TB. Here, we used genetic and biochemical approaches to identify proteins that allow M. tuberculosis to detect amino acids in its surroundings so that it can regulate its metabolism. We have also shown how individual amino acids are recognized. The findings have broader significance for other actinobacterial pathogens, such as nontuberculous mycobacteria, as well as Actinobacteria used to produce billions of dollars of amino acids and antibiotics every year.