While electrical activity in neurons has been extensively studied, the transport and distribution of adenosine triphosphate (ATP), the primary cellular energy carrier, remain less understood, particularly in relation to metabolic processes in axons. ATP is primarily generated in mitochondria and consumed at synapses, the primary sites of energy demand. Even in healthy axons, approximately half of synaptic boutons lack stationary mitochondria, raising questions about ATP transport between boutons with and without mitochondrial ATP production. This study addresses two key questions: the role of ..read more

Misfolding and aggregation of proteins into amyloidogenic assemblies are key features of several metabolic and neurodegenerative diseases. Human insulin has long been known to form amyloid fibrils under various conditions, which affects its bioavailability and function. Clinically, insulin aggregation at recurrent injection sites poses a challenge for diabetic patients who rely on insulin therapy. Furthermore, decreased responsiveness to insulin in type 2 diabetic (T2D) patients may lead to its overproduction and accumulation as aggregates. Earlier reports have reported that various factors su ..read more

Cell mechanical properties regulate biological processes such as oocyte development. Cortical tension is regulated via actomyosin cortex remodeling to ensure optimal oocyte quality. However, the evolution of other mechanical parameters and their relationship with cortex structure remain poorly understood in mammalian oocytes. In this work, we propose a methodology combining multiple mechanical parameters measured through Atomic Force Microscopy to investigate the relationship between oocyte mechanical properties and cortex organization. By studying mouse oocytes at various stages of developmen ..read more

Focal adhesions are protein complexes that transmit actin cytoskeleton forces to the extracellular matrix and serve as signaling hubs that regulate cell physiology. While their growth is achieved through a local force-dependent process, the requirement of sustaining stress at the cell scale suggests a global regulation of the collective organization of focal adhesions. To investigate evidence of such large-scale regulation, we compared changes in cell shape and the organization of focal adhesion-like structures during the early spreading of fibroblasts either on a two-dimensional substrate or ..read more

A polypeptide folds into its protein tertiary structure in the native state through a folding intermediate in the non-native state. The transition between these states is thermodynamically driven. A folding intermediate of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) autophosphorylates intramolecularly, whereas DYRK1A in the native state no longer catalyzes this reaction. The alteration in substrate specificity suggests a conformational transition of DYRK1A during its folding process. Consistent with this hypothesis, we identified FINDY (1), which inhibits the intramo ..read more

Cytoplasmic dynein is an essential microtubule motor that drives cellular processes ranging from organelle transport to mitotic spindle assembly. Its function relies on forming dynein-dynactin-cargo adaptor (DDA) complexes, typically powered by two dynein motors. We reveal that mechanical tension recruits a third dynein motor, increasing DDA force generation. This load-dependent adaptation is facilitated by Lis1, which relieves dynein's auto-inhibitory state and fully activates the complex. With one dynein, DDA generates 2.5 pN of force, but Lis1 increases it to 4.5 pN. Complexes with two or t ..read more

KIF1A, a neuron-specific Kinesin-3 motor, powers nuclear migration and axonal cargo transport, essential for neuronal function. Here, we reveal how two class-specific structural elements&mdasha six-lysine K-loop and a shorter neck linker&mdash support its superprocessivity. Using MINFLUX tracking to monitor KIF1A's motor domains at high spatio-temporal resolution, we show that, contrary to models proposing a one-head-bound rate-limiting step, KIF1A predominantly adopts a two-heads-bound state, even under limiting ATP. The positively charged K-loop interacts with negatively charged tubu ..read more

We introduce Hydrogen-Exchange Experimental Structure Prediction (HX-ESP), a method that integrates hydrogen exchange (HX) data with molecular dynamics (MD) simulations to accurately predict ligand binding modes, even for targets requiring significant conformational changes. Benchmarking HX-ESP by fitting two ligands to PAK1 and four ligands to MAP4K1 (HPK1), and comparing the results to X-ray crystallography structures, demonstrated that HX-ESP successfully identified binding modes across a range of affinities significantly outperforming flexible docking for ligands necessitating large confor ..read more

We demonstrate that the newly designed amino acid phosphordiamidate-resins (APdA), containing vinyl reactive groups for polymerization, can be utilized to fabricate sub-100 nm features through 3D multiphoton lithography. We have quantitatively analyzed the feature size, Young's modulus, and functionalization of the nanostructures using atomic force and single-molecule fluorescence microscopy. Our results indicate that the polymer backbone, composed of either valine or alanine, imparts hydrophobic properties to the monomer, restricting the swelling of the polymeric nanostructure to 8% in aqueou ..read more

Transcranial temporal interference stimulation (TI, TIS, or tTIS), also known as interferential stimulation (IFS), is able to focally stimulate deep brain regions, provided it is properly optimized. We previously presented an algorithm for optimizing TI using two arrays of electrodes and showed that it can achieve more focal stimulation compared to optimized high-definition transcranial electrical stimulation (HD-TES) and conventional optimized TI using two pairs of electrodes, especially in the deep brain areas such as the hippocampus. However, those modeling studies were only performed on an ..read more