ChiSCAT: Unsupervised Learning of Recurrent Cellular Micromotion Patterns from a Chaotic Speckle Pattern.

There is considerable evidence that action potentials are accompanied by "intrinsic optical signals", such as a nanometer-scale motion of the cell membrane. Here we present ChiSCAT, a technically simple imaging scheme that detects such signals with interferometric sensitivity. ChiSCAT combines illumination by a aotic speckle pattern and interferometric scattering microscopy () to sensitively detect motion in any direction.

Validation of the maximal cardiopulmonary exercise test in adolescents with major depressive disorder and comparison of cardiorespiratory fitness with sex- and age-related control values.

Endurance training has been shown to be effective in treating adolescents with major depressive disorder (MDD). To integrate endurance training into the therapeutic setting and the adolescents' daily lives, the current performance status of the adolescents should be accurately assessed. This study aims to examine adolescents with MDD concerning exhaustion criteria during a cardiopulmonary exercise test (CPET), as well as to compare the values obtained thereon with sex- and age-related control values.

Protecting endangered megafauna through AI analysis of drone images in a low-connectivity setting: a case study from Namibia.

Assessing the numbers and distribution of at-risk megafauna such as the black rhino () is key to effective conservation, yet such data are difficult to obtain. Many current monitoring technologies are invasive to the target animals and expensive. Satellite monitoring is emerging as a potential tool for very large animals (.

Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism.

The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO.

Robust all-optical single-shot readout of nitrogen-vacancy centers in diamond.

High-fidelity projective readout of a qubit's state in a single experimental repetition is a prerequisite for various quantum protocols of sensing and computing. Achieving single-shot readout is challenging for solid-state qubits. For Nitrogen-Vacancy (NV) centers in diamond, it has been realized using nuclear memories or resonant excitation at cryogenic temperature.

Detection of cellular micromotion by advanced signal processing.

Cellular micromotion-a tiny movement of cell membranes on the nm-µm scale-has been proposed as a pathway for inter-cellular signal transduction and as a label-free proxy signal to neural activity. Here we harness several recent approaches of signal processing to detect such micromotion in video recordings of unlabeled cells. Our survey includes spectral filtering of the video signal, matched filtering, as well as 1D and 3D convolutional neural networks acting on pixel-wise time-domain data and a whole recording respectively.

Direct Automated MALDI Mass Spectrometry Analysis of Cellular Transporter Function: Inhibition of OATP2B1 Uptake by 294 Drugs.

OATP2B1, a member of the solute carrier (SLC) transporter family, is an important mechanism of substrate drug uptake in the intestine and liver and therefore a determinant of clinical pharmacokinetics and site of drug-drug interactions. Other SLC transporters have emerged as pharmacology targets. Studies of SLC transporter uptake to-date relied on radioisotope- or fluorescence-labeled reagents or low-throughput quantification of unlabeled compounds in cell lysate.

A high-resolution fMRI approach to characterize functionally distinct neural pathways within dopaminergic midbrain and nucleus accumbens during reward and salience processing.

Processing of reward and salience without reward association are known to critically rely on the dopamine system. A growing body of evidence from animal studies suggests that both functions may be subserved by distinct subregions in midbrain and ventral striatum, specifically nucleus accumbens (NAcc). Yet in vivo investigation of these brain structures in humans has been rare.

Bioengineering of Cytochrome P450 OleT: How Does Substrate Positioning Affect the Product Distributions?

The cytochromes P450 are versatile enzymes found in all forms of life. Most P450s use dioxygen on a heme center to activate substrates, but one class of P450s utilizes hydrogen peroxide instead. Within the class of P450 peroxygenases, the P450 OleT isozyme binds fatty acid substrates and converts them into a range of products through the α-hydroxylation, β-hydroxylation and decarboxylation of the substrate.

Sluggish reactivity by a nonheme iron(iv)-tosylimido complex as compared to its oxo analogue.

High-valent iron-nitrido intermediates have been postulated as reactive intermediates in various enzymes, including the nitrogenases and the cytochromes P450, but so far few have been trapped and characterized. As little is known about their oxidative and spectroscopic properties, we decided to create biomimetic models of iron(iv)-imido complexes and compare their structure and reactivity with analogous iron(iv)-oxo systems. In this work we report the synthesis and spectroscopic characterization of a novel [Fe(NTs)(Bntpen)] complex (Bntpen = N-benzyl-N,N,N-tris(pyridine-2-ylmethyl)ethane-1,2-diamine) and study its reactivity patterns with respect to hydrogen atom abstraction and nitrogen atom transfer reactions.

Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target.

Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound . Selectivity profiling of compound showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound , which showed improved toxicological outcomes at similar exposure levels to compound .

Clinically Relevant OATP2B1 Inhibitors in Marketed Drug Space.

OATP2B1 is an intestinal and hepatic drug uptake transporter. Intestinal OATP2B1 has been elucidated as the mechanism of unexpected clinical drug-drug interactions (DDIs), where drug exposure was unexpectedly decreased with unchanged half-life. Hepatic OATP2B1 may be an understudied clinical DDI mechanism.

Chemical proteomics reveals target selectivity of clinical Jak inhibitors in human primary cells.

Kinobeads are a set of promiscuous kinase inhibitors immobilized on sepharose beads for the comprehensive enrichment of endogenously expressed protein kinases from cell lines and tissues. These beads enable chemoproteomics profiling of kinase inhibitors of interest in dose-dependent competition studies in combination with quantitative mass spectrometry. We present improved bead matrices that capture more than 350 protein kinases and 15 lipid kinases from human cell lysates, respectively.

Equatorial ligand plane perturbations lead to a spin-state change in an iron(iii) porphyrin dimer.

A complete reversal of the spin state of iron(iii) is observed upon a small change to the diporphyrin bridge from ethane to ethene by keeping all other factors intact. Combined analysis using single crystal X-ray structure determination, Mössbauer, variable-temperature magnetic, 1H NMR and EPR studies has confirmed the spin states of iron(iii) complexes both in solid and solution phases.

Whole body vibration added to treatment as usual is effective in adolescents with depression: a partly randomized, three-armed clinical trial in inpatients.

There is growing evidence for the effectiveness of exercise in the treatment of adult major depression. With regard to adolescents, clinical trials are scarce. Due to the inherent symptoms of depression (lack of energy, low motivation to exercise), endurance training forms could be too demanding especially in the first weeks of treatment.

Quantum sensing of weak radio-frequency signals by pulsed Mollow absorption spectroscopy.

Quantum sensors-qubits sensitive to external fields-have become powerful detectors for various small acoustic and electromagnetic fields. A major key to their success have been dynamical decoupling protocols which enhance sensitivity to weak oscillating (AC) signals. Currently, those methods are limited to signal frequencies below a few MHz.

Holography of Wi-fi Radiation.

Wireless data transmission systems such as wi-fi or Bluetooth emit coherent light-electromagnetic waves with a precisely known amplitude and phase. Propagating in space, this radiation forms a hologram-a two-dimensional wave front encoding a three-dimensional view of all objects traversed by the light beam. Here we demonstrate a scheme to record this hologram in a phase-coherent fashion across a meter-sized imaging region.

Efficient Electrical Spin Readout of NV^{-} Centers in Diamond.

Using pulsed photoionization the coherent spin manipulation and echo formation of ensembles of NV^{-} centers in diamond are detected electrically, realizing contrasts of up to 17%. The underlying spin-dependent ionization dynamics are investigated experimentally and compared to Monte Carlo simulations. This allows the identification of the conditions optimizing contrast and sensitivity, which compare favorably with respect to optical detection.

Combining Human Computing and Machine Learning to Make Sense of Big (Aerial) Data for Disaster Response.

Aerial imagery captured via unmanned aerial vehicles (UAVs) is playing an increasingly important role in disaster response. Unlike satellite imagery, aerial imagery can be captured and processed within hours rather than days. In addition, the spatial resolution of aerial imagery is an order of magnitude higher than the imagery produced by the most sophisticated commercial satellites today.

Thermal proteome profiling monitors ligand interactions with cellular membrane proteins.

We extended thermal proteome profiling to detect transmembrane protein-small molecule interactions in cultured human cells. When we assessed the effects of detergents on ATP-binding profiles, we observed shifts in denaturation temperature for ATP-binding transmembrane proteins. We also observed cellular thermal shifts in pervanadate-induced T cell-receptor signaling, delineating the membrane target CD45 and components of the downstream pathway, and with drugs affecting the transmembrane transporters ATP1A1 and MDR1.

Probing molecular dynamics at the nanoscale via an individual paramagnetic centre.

We demonstrate a protocol using individual nitrogen-vacancy centres in diamond to observe the time evolution of proton spins from organic molecules located a few nanometres from the diamond surface. The protocol records temporal correlations among the interacting protons, and thus is sensitive to the local dynamics via its impact on the nuclear spin relaxation and interaction with the nitrogen vacancy. We gather information on the nanoscale rotational and translational diffusion dynamics by analysing the time dependence of the nuclear magnetic resonance signal.

Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry.

The direct detection of drug-protein interactions in living cells is a major challenge in drug discovery research. Recently, we introduced an approach termed thermal proteome profiling (TPP), which enables the monitoring of changes in protein thermal stability across the proteome using quantitative mass spectrometry. We determined the intracellular thermal profiles for up to 7,000 proteins, and by comparing profiles derived from cultured mammalian cells in the presence or absence of a drug we showed that it was possible to identify direct and indirect targets of drugs in living cells in an unbiased manner.

Relaxometry and Dephasing Imaging of Superparamagnetic Magnetite Nanoparticles Using a Single Qubit.

To study the magnetic dynamics of superparamagnetic nanoparticles, we use scanning probe relaxometry and dephasing of the nitrogen vacancy (NV) center in diamond, characterizing the spin noise of a single 10 nm magnetite particle. Additionally, we show the anisotropy of the NV sensitivity's dependence on the applied decoherence measurement method. By comparing the change in relaxation (T1) and dephasing (T2) time in the NV center when scanning a nanoparticle over it, we are able to extract the nanoparticle's diameter and distance from the NV center using an Ornstein-Uhlenbeck model for the nanoparticle's fluctuations.

Screening Pools of Compounds against Multiple Endogenously Expressed Targets in a Chemoproteomics Binding Assay.

Chemoproteomics-based competition-binding assays allow the screening of compounds against endogenous proteins in cell or tissue extracts, but these assays are hampered by low throughput and high cost. Using compound pools rather than single compounds in a screening campaign holds the promise of increased efficiency and substantial cost reduction. Previous attempts to screen compounds in pools often fell short due to complex data tracking, deconvolution issues, compound interferences, and automation problems.