Development of a rapid screener to elicit patient preferences for antiseizure medication discontinuation.

Objective: While guidelines encourage individualized discussions of the risks and benefits of antiseizure medication (ASM) withdrawal after a period of seizure-freedom, no formal methods exist for assessing patient preferences. We report the initial development of a rapid patient preferences screener.

Methods: We conducted a mixed-methods study of adults who were ≥1 year seizure-free and seen for epilepsy across three institutions.

Topological Superconductivity in Heavily Doped Single-Layer Graphene.

The existence of superconductivity (SC) appears to be established in both twisted and nontwisted graphene multilayers. However, whether their building block, single-layer graphene (SLG), can also host SC remains an open question. Earlier theoretical works predicted that SLG could become a chiral -wave superconductor driven by electronic interactions when doped to its van Hove singularity, but questions such as whether the -wave SC survives the strong band renormalizations seen in experiments, its robustness against the source of doping, or if it will occur at any reasonable critical temperature () have remained difficult to answer, in part due to uncertainties in model parameters.

Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets.

Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome.

Thieno[3,2-b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode.

Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2-b]pyridine scaffold. The weak interaction of the thieno[3,2-b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome-wide selectivity, as illustrated by the isomers MU1464 and MU1668.

Decoupling of Light and Dark Reactions in a 2D Niobium Tungstate for Light-Induced Charge Storage and On-Demand Hydrogen Evolution.

The direct coupling of light harvesting and charge storage in a single material opens new avenues to light storing devices. Here we demonstrate the decoupling of light and dark reactions in the two-dimensional layered niobium tungstate (TBA)(NbWO) for on-demand hydrogen evolution and solar battery energy storage. Light illumination drives Li/H photointercalation into the (TBA)(NbWO) photoanode, leading to small polaron formation assisted by structural distortions on the WO sublattice, along with a light-induced decrease in material resistance over 2 orders of magnitude compared to the dark.

Joining forces for pathology diagnostics with AI assistance: The EMPAIA initiative.

Over the past decade, artificial intelligence (AI) methods in pathology have advanced substantially. However, integration into routine clinical practice has been slow due to numerous challenges, including technical and regulatory hurdles in translating research results into clinical diagnostic products and the lack of standardized interfaces. The open and vendor-neutral EMPAIA initiative addresses these challenges.

Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice.

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2).

Direct visualization of stacking-selective self-intercalation in epitaxial NbSe films.

Two-dimensional (2D) van der Waals (vdW) materials offer rich tuning opportunities generated by different stacking configurations or by introducing intercalants into the vdW gaps. Current knowledge of the interplay between stacking polytypes and intercalation often relies on macroscopically averaged probes, which fail to pinpoint the exact atomic position and chemical state of the intercalants in real space. Here, by using atomic-resolution electron energy-loss spectroscopy in a scanning transmission electron microscope, we visualize a stacking-selective self-intercalation phenomenon in thin films of the transition-metal dichalcogenide (TMDC) NbSe.

Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.

Cytosolic aggregation of the nuclear protein TDP-43 is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress.

Observation of a single protein by ultrafast X-ray diffraction.

The idea of using ultrashort X-ray pulses to obtain images of single proteins frozen in time has fascinated and inspired many. It was one of the arguments for building X-ray free-electron lasers. According to theory, the extremely intense pulses provide sufficient signal to dispense with using crystals as an amplifier, and the ultrashort pulse duration permits capturing the diffraction data before the sample inevitably explodes.

Multicenter Collaborative Study to Optimize Mass Spectrometry Workflows of Clinical Specimens.

The foundation for integrating mass spectrometry (MS)-based proteomics into systems medicine is the development of standardized start-to-finish and fit-for-purpose workflows for clinical specimens. An essential step in this pursuit is to highlight the common ground in a diverse landscape of different sample preparation techniques and liquid chromatography-mass spectrometry (LC-MS) setups. With the aim to benchmark and improve the current best practices among the proteomics MS laboratories of the CLINSPECT-M consortium, we performed two consecutive round-robin studies with full freedom to operate in terms of sample preparation and MS measurements.

Generation of Large Vortex-Free Superfluid Helium Nanodroplets.

Superfluid helium nanodroplets are an ideal environment for the formation of metastable, self-organized dopant nanostructures. However, the presence of vortices often hinders their formation. Here, we demonstrate the generation of vortex-free helium nanodroplets and explore the size range in which they can be produced.

Interaction Effects in a 1D Flat Band at a Topological Crystalline Step Edge.

Step edges of topological crystalline insulators can be viewed as predecessors of higher-order topology, as they embody one-dimensional edge channels embedded in an effective three-dimensional electronic vacuum emanating from the topological crystalline insulator. Using scanning tunneling microscopy and spectroscopy, we investigate the behavior of such edge channels in PbSnSe under doping. Once the energy position of the step edge is brought close to the Fermi level, we observe the opening of a correlation gap.

Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor.

The ephrin type-A receptor 2 (EPHA2) kinase belongs to the largest family of receptor tyrosine kinases. There are several indications of an involvement of EPHA2 in the development of infectious diseases and cancer. Despite pharmacological potential, EPHA2 is an under-examined target protein.

A unified classification approach rating clinical utility of protein biomarkers across neurologic diseases.

A major evolution from purely clinical diagnoses to biomarker supported clinical diagnosing has been occurring over the past years in neurology. High-throughput methods, such as next-generation sequencing and mass spectrometry-based proteomics along with improved neuroimaging methods, are accelerating this development. This calls for a consensus framework that is broadly applicable and provides a spot-on overview of the clinical validity of novel biomarkers.

Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity.

Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly selective inhibitors of CK1α, δ and ϵ. Based on their optimal in vitro and in vivo profiles and their exclusive selectivity, MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms.

Biomolecular condensate phase diagrams with a combinatorial microdroplet platform.

The assembly of biomolecules into condensates is a fundamental process underlying the organisation of the intracellular space and the regulation of many cellular functions. Mapping and characterising phase behaviour of biomolecules is essential to understand the mechanisms of condensate assembly, and to develop therapeutic strategies targeting biomolecular condensate systems. A central concept for characterising phase-separating systems is the phase diagram.