Ancestral genetic components are consistently associated with the complex trait landscape in European biobanks.

The genetic structure in Europe was mostly shaped by admixture between the Western Hunter-Gatherers, Early European Farmers and Steppe Bronze Age ancestral components. Such structure is regarded as a confounder in GWAS and follow-up studies, and gold-standard methods exist to correct for it. However, it is still poorly understood to which extent these ancestral components contribute to complex trait variation in present-day Europe.

SGLT2 inhibitors activate pantothenate kinase in the human heart.

Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart.

Left ventricular unloading via percutaneous assist device during extracorporeal membrane oxygenation in acute myocardial infarction and cardiac arrest.

Introduction: A feared complication of an acute myocardial infarction (AMI) is cardiac arrest (CA). Even if return of spontaneous circulation is achieved, cardiogenic shock (CS) is common. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) supports patients with CS and is often used in conjunction with an Impella device (2.

Cobalt Ferrite Nanorods Synthesized with a Facile "Green" Method in a Magnetic Field.

We report a new facile method for the synthesis of prolate cobalt ferrite nanoparticles without additional stabilizers, which involves a co-precipitation reaction of Fe and Co ions in a static magnetic field. The magnetic field is demonstrated to be a key factor for the 1D growth of cobalt ferrite nanocrystals in the synthesis. Transmission electron microscopy (TEM), X-ray diffraction (XRD), and Raman spectroscopy are applied to characterize the morphology and structure of the obtained nanoparticles.

Effect of mitochondrial circulation on mitochondrial age density distribution.

Recent publications report that although the mitochondria population in an axon can be quickly replaced by a combination of retrograde and anterograde axonal transport (often within less than 24 hours), the axon contains much older mitochondria. This suggests that not all mitochondria that reach the soma are degraded and that some are recirculating back into the axon. To explain this, we developed a model that simulates mitochondria distribution when a portion of mitochondria that return to the soma are redirected back to the axon rather than being destroyed in somatic lysosomes.

Mitochondrial transport in symmetric and asymmetric axons with multiple branching junctions: a computational study.

Mitochondrial aging has been proposed to be involved in a variety of neurodegenerative disorders, such as Parkinson's disease. Here, we explore the impact of multiple branching junctions in axons on the mean age of mitochondria and their age density distributions in demand sites. The study examined mitochondrial concentration, mean age, and age density distribution in relation to the distance from the soma.

Development and Replication of a Genome-Wide Polygenic Risk Score for Chronic Back Pain.

Chronic back pain (CBP) is a complex heritable trait and a major cause of disability worldwide. We developed and validated a genome-wide polygenic risk score (PRS) for CBP using a large-scale GWAS based on UK Biobank participants of European ancestry (N = 265,000). The PRS showed poor overall predictive ability (AUC = 0.

Genotype-by-environment interactions in chronic back pain.

Background Context: Chronic back pain (CBP) is a common debilitating condition with substantial societal impact. While understanding genotype-by-environment (GxE) interactions may be crucial to achieving the goals of personalized medicine, there are few large-scale studies investigating this topic for CBP. None of them systematically explore multiple CBP risk factors.

Why slow axonal transport is bidirectional - can axonal transport of tau protein rely only on motor-driven anterograde transport?

Slow axonal transport (SAT) moves multiple proteins from the soma, where they are synthesized, to the axon terminal. Due to the great lengths of axons, SAT almost exclusively relies on active transport, which is driven by molecular motors. The puzzling feature of slow axonal transport is its bidirectionality.

ATP diffusional gradients are sufficient to maintain bioenergetic homeostasis in synaptic boutons lacking mitochondria.

Previous work on mitochondrial distribution in axons has shown that approximately half of the presynaptic release sites do not contain mitochondria, raising the question of how the boutons that do not contain mitochondria are supplied with ATP. Here, we develop and apply a mathematical model to study this question. Specifically, we investigate whether diffusive transport of ATP is sufficient to support the exocytic functionality in synaptic boutons which lack mitochondria.

Mitochondrial Transport in Symmetric and Asymmetric Axons with Multiple Branching Junctions: A Computational Study.

We explore the impact of multiple branching junctions in axons on the mean age of mitochondria and their age density distributions in demand sites. The study looked at mitochondrial concentration, mean age, and age density distribution in relation to the distance from the soma. We developed models for a symmetric axon containing 14 demand sites and an asymmetric axon containing 10 demand sites.

Dynein Dysfunction Prevents Maintenance of High Concentrations of Slow Axonal Transport Cargos at the Axon Terminal: A Computational Study.

Here, we report computational studies of bidirectional transport in an axon, specifically focusing on predictions when the retrograde motor becomes dysfunctional. We are motivated by reports that mutations in dynein-encoding genes can cause diseases associated with peripheral motor and sensory neurons, such as type 2O Charcot-Marie-Tooth disease. We use two different models to simulate bidirectional transport in an axon: an anterograde-retrograde model, which neglects passive transport by diffusion in the cytosol, and a full slow transport model, which includes passive transport by diffusion in the cytosol.

Computation of the mitochondrial age distribution along the axon length.

We describe a compartmental model of mitochondrial transport in axons, which we apply to compute mitochondrial age at different distances from the soma. The model predicts that at the tip of an axon that has a length of 1 cm, the average mitochondrial age is approximately 22 h. The mitochondria are youngest closest to the soma and their age scales approximately linearly with distance from the soma.

Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: A computational study.

We report a computational study of mitochondria transport in a branched axon with two branches of different sizes. For comparison, we also investigate mitochondria transport in an axon with symmetric branches and in a straight (unbranched) axon. The interest in understanding mitochondria transport in branched axons is motivated by the large size of arbors of dopaminergic neurons, which die in Parkinson's disease.

Computational framework for single-cell spatiotemporal dynamics of optogenetic membrane recruitment.

We describe a modular computational framework for analyzing cell-wide spatiotemporal signaling dynamics in single-cell microscopy experiments that accounts for the experiment-specific geometric and diffractive complexities that arise from heterogeneous cell morphologies and optical instrumentation. Inputs are unique cell geometries and protein concentrations derived from confocal stacks and spatiotemporally varying environmental stimuli. After simulating the system with a model of choice, the output is convolved with the microscope point-spread function for direct comparison with the observable image.

An analytical solution simulating growth of Lewy bodies.

This paper reports a minimal model simulating the growth of a Lewy body (LB). To the best of our knowledge, this is the first model simulating LB growth. The LB is assumed to consist of a central spherical core, which is composed of membrane fragments and various dysfunctional intracellular organelles, and a halo, which is composed of alpha-synuclein (α-syn) fibrils.

Bidirectional, unlike unidirectional transport, allows transporting axonal cargos against their concentration gradient.

Even though most axonal cargos are synthesized in the soma, the concentration of many of these cargos is larger at the presynaptic terminal than in the soma. This requires transport of these cargos from the soma to the presynaptic terminal or other active sites in the axon. Axons utilize both bidirectional (for example, slow axonal transport) and unidirectional (for example, fast anterograde axonal transport) modes of cargo transport.

ANANASTRA: annotation and enrichment analysis of allele-specific transcription factor binding at SNPs.

We present ANANASTRA, https://ananastra.autosome.org, a web server for the identification and annotation of regulatory single-nucleotide polymorphisms (SNPs) with allele-specific binding events.

Designing Single-Component Optogenetic Membrane Recruitment Systems: The Rho-Family GTPase Signaling Toolbox.

We describe the efficient creation of single-component optogenetic tools for membrane recruitment-based signaling perturbation using BcLOV4 technology. The workflow requires two plasmids to create six different domain arrangements of the dynamic membrane binder BcLOV4, a fluorescent reporter, and the fused signaling protein of interest. Screening of this limited set of genetic constructs for expression characteristics and dynamic translocation in response to one pulse of light is sufficient to identify viable signaling control tools.

Temperature-responsive optogenetic probes of cell signaling.

We describe single-component optogenetic probes whose activation dynamics depend on both light and temperature. We used the BcLOV4 photoreceptor to stimulate Ras and phosphatidyl inositol-3-kinase signaling in mammalian cells, allowing activation over a large dynamic range with low basal levels. Surprisingly, we found that BcLOV4 membrane translocation dynamics could be tuned by both light and temperature such that membrane localization spontaneously decayed at elevated temperatures despite constant illumination.

Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?

Finding the causative pathophysiological mechanisms for Parkinson's disease (PD) is important for developing therapeutic interventions. Until recently, it was believed that Lewy bodies (LBs), the hallmark of PD, are mostly composed of alpha-synuclein (α-syn) fibrils. Recent results (Shahmoradian et al.

Simulation of a sudden drop-off in distal dense core vesicle concentration in Drosophila type II motoneuron terminals.

Recent experimental observations have shown evidence of an unexpected sudden drop-off in the dense core vesicles (DCVs) content at the ends of certain types of axon endings. This article seeks to determine whether these observations may be explained without modifying the parameters characterizing the ability of distal en passant boutons to capture and accumulate DCVs. We developed a mathematical model that is based on the conservation of captured and transiting DCVs in boutons.

Single-Component Optogenetic Tools for Inducible RhoA GTPase Signaling.

Optogenetic tools are created to control RhoA GTPase, a central regulator of actin organization and actomyosin contractility. RhoA GTPase, or its upstream activator ARHGEF11, is fused to BcLOV4, a photoreceptor that can be dynamically recruited to the plasma membrane by a light-regulated protein-lipid electrostatic interaction with the inner leaflet. Direct membrane recruitment of these proteins induces potent contractile signaling sufficient to separate adherens junctions with as little as one pulse of blue light.