Dendritic branch structure compartmentalizes voltage-dependent calcium influx in cortical layer 2/3 pyramidal cells

Back-propagating action potentials (bAPs) regulate synaptic plasticity by evoking voltage-dependent calcium influx throughout dendrites. Attenuation of bAP amplitude in distal dendritic compartments alters plasticity in a location-specific manner by reducing bAP-dependent calcium influx. However, it is not known if neurons exhibit branch-specific variability in bAP-dependent calcium signals, independent of distance-dependent attenuation. Here, we reveal that bAPs fail to evoke calcium influx through voltage-gated calcium channels (VGCCs) in a specific population of dendritic branches in cortical layer 2/3 pyramidal cells, despite evoking substantial VGCC-mediated calcium influx in sister branches. These branches contain VGCCs and successfully propagate bAPs in the absence of synaptic input; nevertheless, they fail to exhibit bAP-evoked calcium influx due to a branch-specific reduction in bAP amplitude. We demonstrate that these branches have more elaborate branch structure compared to sister branches, which causes a local reduction in electrotonic impedance and bAP amplitude. Finally, we show that bAPs still amplify synaptically-mediated calcium influx in these branches because of differences in the voltage-dependence and kinetics of VGCCs and NMDA-type glutamate receptors. Branch-specific compartmentalization of bAP-dependent calcium signals may provide a mechanism for neurons to diversify synaptic tuning across the dendritic tree.

Temperature Profiles During Cryolipolysis

Cryolipolysis is a noninvasive clinical procedure for the local reduction of adipose tissue. Paddles as cold as ~10 °C are placed in good thermal contact the epidermis. The goal is to cool the subcutaneous adipose tissue to ~10 °C, which induces apoptosis and an inflammatory response in the adipocytes. The dermis is, of course, cooler than the adipocytes, but the triglyceride in the adipocytes are thought to crystalize, causing apoptosis. The clinical procedure have been developed empirically. A mathematical model could aid in understanding the mechanisms of response and improving the design of the procedure. Here, the Pennes equation is used to model the temperature of the tissue during cooling. The two parameters identified are the thermal diffusivity of the tissue and a blood perfusion parameter, which also gives the characteristic length. Green's functions are used to solve the Pennes equation, which simplifies to a transient fin equation.

Formation of Cytoplasmic Actin-Cofilin Rods is Triggered by Metabolic Stress and Changes in Cellular pH

Actin dynamics plays a crucial role in regulating essential cell functions and thereby is largely responsible to a considerable extent for cellular energy consumption. Certain pathological conditions in humans, like neurological disorders such as Alzheimer’s disease or amyotrophic lateral sclerosis (ALS) as well as variants of nemaline myopathy are associated with cytoskeletal abnormalities, so-called actin-cofilin rods. Actin-cofilin rods are aggregates consisting mainly of actin and cofilin, which are formed as a result of cellular stress and thereby help to ensure the survival of cells under unfavorable conditions. We have used Dictyostelium discoideum, an established model system for cytoskeletal research to study formation and principles of cytoplasmic actin rod assembly in response to energy depletion. Experimentally, depletion of ATP was provoked by addition of either sodium azide, dinitrophenol, or 2-deoxy-glucose, and the formation of rod assembly was recorded by live-cell imaging. Furthermore, we show that hyperosmotic shock induces actin-cofilin rods, and that a drop in the intracellular pH accompanies this condition. Our data reveal that acidification of the cytoplasm can induce the formation of actin-cofilin rods to varying degrees and suggest that a local reduction in cellular pH may be a cause for the formation of cytoplasmic rods. We hypothesize that local phase separation mechanistically triggers the assembly of actin-cofilin rods and thereby influences the material properties of actin structures.

First-in-class topical therapeutic omilancor ameliorates disease severity and inflammation through activation of LANCL2 pathway in psoriasis

Psoriasis (PsO) is a complex immune-mediated disease that afflicts 100 million people. Omilancor is a locally-acting, small molecule that selectively activates the Lanthionine Synthetase C-like 2 (LANCL2) pathway, resulting in immunoregulatory effects at the intersection of immunity and metabolism. Topical omilancor treatment in an imiquimod-induced mouse model of PsO ameliorates disease severity, epidermal hyperplasia and acanthosis. Further, pharmacological activation of LANCL2 results in significant downregulation of proinflammatory markers including local reduction of IL17, and infiltration of proinflammatory cell subsets. These therapeutic effects were further validated in an IL-23 PsO model. This model reported increased preservation of homeostatic skin structure, accompanied by a decreased infiltration of proinflammatory T cell subsets. In CD4+ T cells and Th17 cells, the LANCL2 pathway regulates proinflammatory cytokine production, proliferation and glucose metabolism. Metabolically, the loss of Lancl2 resulted in increased glycolytic rates, lactate production and upregulated enzymatic activity of hexokinase and lactate dehydrogenase (LDH). Inhibition of LDH activity abrogated the increased proliferation rate in Lancl2−/− CD4+ T cells. Additionally, topical omilancor treatment decreased the metabolic upregulation in keratinocytes, keratinocyte hyperproliferation and expression of inflammatory markers. Omilancor is a promising topical, LANCL2-targeting therapeutic candidate for the treatment of PsO and other dermatology indications.

INFLUENCE OF GNP ON THE TENSILE RESPONSE OF STITCHED COMPOSITES

Through-the-thickness stitching of layered composites provides through-the- thickness reinforcement to enhance the interlaminar tensile and shear strengths while maintaining structural continuity. However, under planar mechanical loads, stitched composites develop strain concentrations in the resin rich areas around the stitch seam causing a local reduction in mechanical properties. In this study, nanographene toughened epoxy is used to reduce strain concentrations around stitch seams and increase the global tensile performance in stitched composites. Stitched carbon fiber preforms ([+45/-45] ), infused with an unmodified epoxy resin were used as baseline laminates and compared to specimens infused with an epoxy resin containing a dispersion of 9 nm nanographene platelets. Specimens with two different periodic stitching patterns (0o and 90o) were fabricated and tested under uniaxial loading. The surface strain fields were obtained using digital image correlation (DIC). Noticeable differences were seen in the strain distributions and tensile properties of these test articles. Specimens with the nanographene-modified matrix showed reductions in the strain concentrations around the stitch seams, thereby increasing the local modulus of elasticity. This study presents the influence of nanographene-modified matrix on the tensile response of stitched composites

Ultrastructural plasma membrane asymmetries in tension and curvature promote yeast cell fusion

Cell–cell fusion is central for sexual reproduction, and generally involves gametes of different shapes and sizes. In walled fission yeast Schizosaccharomyces pombe, the fusion of h+ and h− isogametes requires the fusion focus, an actin structure that concentrates glucanase-containing vesicles for cell wall digestion. Here, we present a quantitative correlative light and electron microscopy (CLEM) tomographic dataset of the fusion site, which reveals the fusion focus ultrastructure. Unexpectedly, gametes show marked asymmetries: a taut, convex plasma membrane of h− cells progressively protrudes into a more slack, wavy plasma membrane of h+ cells. Asymmetries are relaxed upon fusion, with observations of ramified fusion pores. h+ cells have a higher exo-/endocytosis ratio than h− cells, and local reduction in exocytosis strongly diminishes membrane waviness. Reciprocally, turgor pressure reduction specifically in h− cells impedes their protrusions into h+ cells and delays cell fusion. We hypothesize that asymmetric membrane conformations, due to differential turgor pressure and exocytosis/endocytosis ratios between mating types, favor cell–cell fusion.

Topological Defect-Guided Regular Stacking of Focal Conic Domains in Hybrid-Aligned Smectic Liquid Crystal Shells

We study liquid crystal (LC) shells in hybrid configuration (director tangential to the inside but normal to the outside) as they slowly undergo a transition from a nematic (N) to a smectic-A (SmA) phase. Every shell has two antipodal +1 topological defects, at the thinnest and thickest points, respectively. On cooling from N to SmA, the symmetry axis connecting the defects gradually reorients from along gravity to perpendicular to it, reversibly and continuously, if the LC and aqueous phase are density matched at the N-SmA transition. This suggests reduced density near the defects—reflecting a local reduction in order—under the strong confinement with antagonistic boundary conditions. In the SmA phase, a regular array of focal conic domains (FCDs) develops, templated in position and orientation by the +1 defect at the thinnest point. Around this defect, a single complete toroidal FCD always develops, surrounded by incomplete FCDs. In contrast to similar FCD arrangements on flat aqueous interfaces, this is a stable situation, since the two +1 defects are required by the spherical topology. Our results demonstrate how the topological defects of LC shells can be used to template complex self-organized structures. With a suitable adaption of the LC chemistry, shells might serve as a basis for producing solid particles with complex yet highly regular morphologies.

Near‐Complete Local Reduction of Arctic Stratospheric Ozone by Severe Chemical Loss in Spring 2020

<p>In the Antarctic ozone hole, ozone mixing ratios have been decreasing to extremely low values of 0.01–0.1 ppm in nearly all spring seasons since the late 1980s, corresponding to 95–99% local chemical loss. In contrast, Arctic ozone loss has been much more limited and mixing ratios have never before fallen below 0.5 ppm. In Arctic spring 2020, however, ozonesonde measurements in the most depleted parts of the polar vortex show a highly depleted layer, with ozone loss averaged over sondes peaking at 93% at 18 km. Typical minimum mixing ratios of 0.2 ppm were observed, with individual profiles showing values as low as 0.13 ppm (96% loss). The reason for the unprecedented chemical loss was an unusually strong, long-lasting, and cold polar vortex, showing that for individual winters the effect of the slow decline of ozone-depleting substances on ozone depletion may be counteracted by low temperatures.</p>