Unifying machine learning and quantum chemistry with a deep neural network for molecular wavefunctions

Machine learning advances chemistry and materials science by enabling large-scale exploration of chemical space based on quantum chemical calculations. While these models supply fast and accurate predictions of atomistic chemical properties, they do not explicitly capture the electronic degrees of freedom of a molecule, which limits their applicability for reactive chemistry and chemical analysis. Here we present a deep learning framework for the prediction of the quantum mechanical wavefunction in a local basis of atomic orbitals from which all other ground-state properties can be derived. This approach retains full access to the electronic structure via the wavefunction at force-field-like efficiency and captures quantum mechanics in an analytically differentiable representation. On several examples, we demonstrate that this opens promising avenues to perform inverse design of molecular structures for target electronic property optimisation and a clear path towards increased synergy of machine learning and quantum chemistry

A Cell-Free System for Regulated Exocytosis in Pc12 Cells

We have developed a cell-free system for regulated exocytosis in the PC12 neuroendocrine cell line. Secretory vesicles were preloaded with acridine orange in intact cells, and the cells were sonicated to produce flat, carrier-supported plasma membrane patches with attached vesicles. Exocytosis resulted in the release of acridine orange which was visible as a disappearance of labeled vesicles and, under optimal conditions, produced light flashes by fluorescence dequenching. Exocytosis in vitro requires cytosol and Ca2+ at concentrations in the micromolar range, and is sensitive to Tetanus toxin. Imaging of membrane patches at diffraction- limited resolution revealed that 42% of docked granules were released in a Ca2+-dependent manner dur- ing 1 min of stimulation. Electron microscopy of membrane patches confirmed the presence of dense-core vesicles. Imaging of membrane patches by atomic force microscopy revealed the presence of numerous particles attached to the membrane patches which decreased in number upon stimula- tion. Thus, exocytotic membrane fusion of single vesicles can be monitored with high temporal and spatial resolution, while providing access to the site of exocytosis for biochemical and molecular tools

BMD-based assessment of local porosity in human femoral cortical bone

Cortical pores are determinants of the elastic properties and of the ultimate strength of bone tissue. An increase of the overall cortical porosity (Ct.Po) as well as the local coalescence of large pores cause an impairment of the mechanical competence of bone Therefore, Ct Po represents a relevant target for identifying patients with high fracture risk. However, given their small size, the in vivo imaging of cortical pores remains challenging. The advent of modern high-resolution peripheral quantitative computed tomography (HR-pQCT) triggered new methods for the clinical assessment of Ct Po at the peripheral skeleton, either by pore segmentation or by exploiting local bone mineral density (BMD) In this work, we compared BMD-based Ct.Po estimates with highresolution reference values measured by scanning acoustic microscopy. A calibration rule to estimate local Ct.Po from BMD as assessed by HR-pQCT was derived experimentally. Within areas of interest smaller than 0.5 mm(2), our model was able to estimate the local Ct.Po with an error of 3.4%. The incorporation of the BMD mhomogeneity and of one parameter from the BMD distribution of the entire scan volume led to a relative reduction of the estimate error of 30%, if compared to an estimate based on the average BMD. When applied to the assessment of Ct.Po within entire cortical bone cross-sections, the proposed BMD-based method had better accuracy than measurements performed with a conventional threshold-based approach.</p

Determination of the Carrier-Envelope Phase of Few-Cycle Laser Pulses with Terahertz-Emission Spectroscopy

The availability of few-cycle optical pulses opens a window to physical phenomena occurring on the attosecond time scale. In order to take full advantage of such pulses, it is crucial to measure and stabilise their carrier-envelope (CE) phase, i.e., the phase difference between the carrier wave and the envelope function. We introduce a novel approach to determine the CE phase by down-conversion of the laser light to the terahertz (THz) frequency range via plasma generation in ambient air, an isotropic medium where optical rectification (down-conversion) in the forward direction is only possible if the inversion symmetry is broken by electrical or optical means. We show that few-cycle pulses directly produce a spatial charge asymmetry in the plasma. The asymmetry, associated with THz emission, depends on the CE phase, which allows for a determination of the phase by measurement of the amplitude and polarity of the THz pulse

STARBOARD: encorafenib + binimetinib + pembrolizumab for first-line metastatic/unresectable BRAF V600-mutant melanoma

Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options: targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma in comparison to pembrolizumab

Rods progressively escape saturation to drive visual responses in daylight conditions

Rod and cone photoreceptors support vision across large light intensity ranges. Rods, active under dim illumination, are thought to saturate at higher (photopic) irradiances. The extent of rod saturation is not well defined; some studies report rod activity well into the photopic range. Using electrophysiological recordings from retina and dorsal lateral geniculate nucleus of cone-deficient and visually intact mice, we describe stimulus and physiological factors that influence photopic rod-driven responses. We find that rod contrast sensitivity is initially strongly reduced at high irradiances, but progressively recovers to allow responses to moderate contrast stimuli. Surprisingly, rods recover faster at higher light levels. A model of rod phototransduction suggests that phototransduction gain adjustments and bleaching adaptation underlie rod recovery. Consistently, exogenous chromophore reduces rod responses at bright background. Thus, bleaching adaptation renders mouse rods responsive to modest contrast at any irradiance. Paradoxically, raising irradiance across the photopic range increases the robustness of rod responses.Peer reviewe