SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation.

Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and >30 spike variants. Together with quantitative cell biology approaches, the screen reveals an essential role for biophysical aspects of the membrane, particularly cholesterol-rich regions, in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings potentially provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.

Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells.

Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate-glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate-glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.

Topological solitons, cholesteric fingers and singular defect lines in Janus liquid crystal shells.

Topological solitons are non-singular but topologically nontrivial structures in fields, which have fundamental significance across various areas of physics, similar to singular defects. Production and observation of singular and solitonic topological structures remain a complex undertaking in most branches of science - but in soft matter physics, they can be realized within the director field of a liquid crystal. Additionally, it has been shown that confining liquid crystals to spherical shells using microfluidics resulted in a versatile experimental platform for the dynamical study of topological transformations between director configurations. In this work, we demonstrate the triggered formation of topological solitons, cholesteric fingers, singular defect lines and related structures in liquid crystal shells. We show that to accommodate these objects, shells must possess a Janus nature, featuring both twisted and untwisted domains. We report the formation of linear and axisymmetric objects, which we identify as cholesteric fingers and skyrmions or elementary torons, respectively. We then take advantage of the sensitivity of shells to numerous external stimuli to induce dynamical transitions between various types of structures, allowing for a richer phenomenology than traditional liquid crystal cells with solid flat walls. Using gradually more refined experimental techniques, we induce the targeted transformation of cholesteric twist walls and fingers into skyrmions and elementary torons. We capture the different stages of these director transformations using numerical simulations. Finally, we uncover an experimental mechanism to nucleate arrays of axisymmetric structures on shells, thereby creating a system of potential interest for tackling crystallography studies on curved spaces.

Dynamics of topological solitons, knotted streamlines, and transport of cargo in liquid crystals.

Active colloids and liquid crystals are capable of locally converting the macroscopically supplied energy into directional motion and promise a host of new applications, ranging from drug delivery to cargo transport at the mesoscale. Here we uncover how topological solitons in liquid crystals can locally transform electric energy to translational motion and allow for the transport of cargo along directions dependent on frequency of the applied electric field. By combining polarized optical video microscopy and numerical modeling that reproduces both the equilibrium structures of solitons and their temporal evolution in applied fields, we uncover the physical underpinnings behind this reconfigurable motion and study how it depends on the structure and topology of solitons. We show that, unexpectedly, the directional motion of solitons with and without the cargo arises mainly from the asymmetry in rotational dynamics of molecular ordering in liquid crystal rather than from the asymmetry of fluid flows, as in conventional active soft matter systems.

Tuning and Switching a Plasmonic Quantum Dot "Sandwich" in a Nematic Line Defect.

We study the quantum-mechanical effects arising in a single semiconductor core/shell quantum dot (QD) controllably sandwiched between two plasmonic nanorods. Control over the position and the "sandwich" confinement structure is achieved by the use of a linear-trap liquid crystal (LC) line defect and laser tweezers that "push" the sandwich together. This arrangement allows for the study of exciton-plasmon interactions in a single structure, unaltered by ensemble effects or the complexity of dielectric interfaces. We demonstrate the effect of plasmonic confinement on the photon antibunching behavior of the QD and its luminescence lifetime. The QD behaves as a single emitter when nanorods are far away from the QD but shows possible multiexciton emission and a significantly decreased lifetime when tightly confined in a plasmonic "sandwich". These findings demonstrate that LC defects, combined with laser tweezers, enable a versatile platform to study plasmonic coupling phenomena in a nanoscale laboratory, where all elements can be arranged almost at will.

Topological transformations of Hopf solitons in chiral ferromagnets and liquid crystals.

Liquid crystals are widely known for their facile responses to external fields, which forms a basis of the modern information display technology. However, switching of molecular alignment field configurations typically involves topologically trivial structures, although singular line and point defects often appear as short-lived transient states. Here, we demonstrate electric and magnetic switching of nonsingular solitonic structures in chiral nematic and ferromagnetic liquid crystals. These topological soliton structures are characterized by Hopf indices, integers corresponding to the numbers of times that closed-loop-like spatial regions (dubbed "preimages") of two different single orientations of rod-like molecules or magnetization are linked with each other. We show that both dielectric and ferromagnetic response of the studied material systems allow for stabilizing a host of topological solitons with different Hopf indices. The field transformations during such switching are continuous when Hopf indices remain unchanged, even when involving transformations of preimages, but discontinuous otherwise.

Older Age Predicts Worse Function 1 Year After an Acute Achilles Tendon Rupture: A Prognostic Multicenter Study on 391 Patients.

BACKGROUND: There is limited evidence regarding the patient-related factors that influence treatment outcomes after an acute Achilles tendon rupture. PURPOSE/HYPOTHESIS: The purpose of this study was to determine the predictors of functional and patient-reported outcomes 1 year after an acute Achilles tendon rupture using a multicenter cohort and to determine patient characteristics for reporting within the top and bottom 10% of the Achilles tendon Total Rupture Score (ATRS) and heel-rise height outcomes. The hypothesis was that older age, greater body mass index (BMI), and female sex would lead to inferior outcomes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Patients were selected by combining 5 randomized controlled trials from 2 different centers in Sweden. Functional outcomes were assessed using validated heel-rise tests (height, number of repetitions, total work, and concentric power) for muscular endurance and strength, and the relationship between injured and uninjured legs was calculated as the limb symmetry index (LSI). Patient-reported outcomes were measured using the ATRS. All outcomes were collected at the 1-year follow-up. Independent predictors included were patient sex, smoking, BMI, age, and surgical versus nonsurgical treatment. RESULTS: Of the 391 included patients, 307 (79%) were treated surgically. The LSI of heel-rise height at the 1-year follow-up decreased by approximately 4% for every 10-year increment in age (beta, -3.94 [95% CI, -6.19 to -1.69]; P = .0006). In addition, every 10-year increment in age resulted in a 1.79-fold increase in the odds of being in the lowest 10% of the LSI of heel-rise height. Moreover, a nonsignificant superior LSI of heel-rise height was found in patients treated surgically compared with nonsurgical treatment (beta, -4.49 [95% CI, -9.14 to 0.16]; P = .058). No significant predictor was related to the ATRS. Smoking, patient sex, and BMI did not significantly affect the 1-year results for the LSI of the heel-rise tests. CONCLUSION: Older age at the time of injury negatively affected heel-rise height 1 year after an Achilles tendon rupture. Irrespective of age, a nonsignificant relationship toward the superior recovery of heel-rise height was seen in patients treated surgically. None of the factors studied affected patient-reported outcomes.

Squirming motion of baby skyrmions in nematic fluids.

Skyrmions are topologically protected continuous field configurations that cannot be smoothly transformed to a uniform state. They behave like particles and give origins to the field of skyrmionics that promises racetrack memory and other technological applications. Unraveling the non-equilibrium behavior of such topological solitons is a challenge. We realize skyrmions in a chiral liquid crystal and, using numerical modeling and polarized video microscopy, demonstrate electrically driven squirming motion. We reveal the intricate details of non-equilibrium topology-preserving textural changes driving this behavior. Direction of the skyrmion's motion is robustly controlled in a plane orthogonal to the applied field and can be reversed by varying frequency. Our findings may spur a paradigm of soliton dynamics in soft matter, with a rich interplay between topology, chirality, and orientational viscoelasticity.A skyrmion is a topological object originally introduced to model elementary particles and a baby skyrmion is its two-dimensional counterpart which can be realized as a defect in liquid crystals. Here the authors show that an electric field can drive uniform motion of baby skyrmions in liquid crystals.

Static three-dimensional topological solitons in fluid chiral ferromagnets and colloids.

Three-dimensional (3D) topological solitons are continuous but topologically nontrivial field configurations localized in 3D space and embedded in a uniform far-field background, that behave like particles and cannot be transformed to a uniform state through smooth deformations. Many topologically nontrivial 3D solitonic fields have been proposed. Yet, according to the Hobart-Derrick theorem, physical systems cannot host them, except for nonlinear theories with higher-order derivatives such as the Skyrme-Faddeev model. Experimental discovery of such solitons is hindered by the need for spatial imaging of the 3D fields, which is difficult in high-energy physics and cosmology. Here we experimentally realize and numerically model stationary topological solitons in a fluid chiral ferromagnet formed by colloidal dispersions of magnetic nanoplates. Such solitons have closed-loop preimages-3D regions with a single orientation of the magnetization field. We discuss localized structures with different linking of preimages quantified by topological Hopf invariants. The chirality is found to help in overcoming the constraints of the Hobart-Derrick theorem, like in two-dimensional ferromagnetic solitons, dubbed 'baby skyrmions'. Our experimental platform may lead to solitonic condensed matter phases and technological applications.

Biaxial ferromagnetic liquid crystal colloids.

The design and practical realization of composite materials that combine fluidity and different forms of ordering at the mesoscopic scale are among the grand fundamental science challenges. These composites also hold a great potential for technological applications, ranging from information displays to metamaterials. Here we introduce a fluid with coexisting polar and biaxial ordering of organic molecular and magnetic colloidal building blocks exhibiting the lowest symmetry orientational order. Guided by interactions at different length scales, rod-like organic molecules of this fluid spontaneously orient along a direction dubbed "director," whereas magnetic colloidal nanoplates order with their dipole moments parallel to each other but pointing at an angle to the director, yielding macroscopic magnetization at no external fields. Facile magnetic switching of such fluids is consistent with predictions of a model based on competing actions of elastic and magnetic torques, enabling previously inaccessible control of light.

Reversal of helicoidal twist handedness near point defects of confined chiral liquid crystals.

Handedness of the director twist in cholesteric liquid crystals is commonly assumed to be the same throughout the medium, determined solely by the chirality of constituent molecules or chiral additives, albeit distortions of the ground-state helicoidal configuration often arise due to the effects of confinement and external fields. We directly probe the twist directionality of liquid crystal director structures through experimental three-dimensional imaging and numerical minimization of the elastic free energy and show that spatially localized regions of handedness opposite to that of the chiral liquid crystal ground state can arise in the proximity of twisted-soliton-bound topological point defects. In chiral nematic liquid crystal confined to a film that has a thickness less than the cholesteric pitch and perpendicular surface boundary conditions, twisted solitonic structures embedded in a uniform unwound far-field background with chirality-matched handedness locally relieve confinement-imposed frustration and tend to be accompanied by point defects and smaller geometry-required, energetically costly regions of opposite twist handedness. We also describe a spatially localized structure, dubbed a "twistion," in which a twisted solitonic three-dimensional director configuration is accompanied by four point defects. We discuss how our findings may impinge on the stability of localized particlelike director field configurations in chiral and nonchiral liquid crystals.

Plasmon-Exciton Interactions Probed Using Spatial Coentrapment of Nanoparticles by Topological Singularities.

We study plasmon-exciton interaction by using topological singularities to spatially confine, selectively deliver, cotrap and optically probe colloidal semiconductor and plasmonic nanoparticles. The interaction is monitored in a single quantum system in the bulk of a liquid crystal medium where nanoparticles are manipulated and nanoconfined far from dielectric interfaces using laser tweezers and topological configurations containing singularities. When quantum dot-in-a-rod particles are spatially colocated with a plasmonic gold nanoburst particle in a topological singularity core, its fluorescence increases because blinking is significantly suppressed and the radiative decay rate increases by nearly an order of magnitude owing to the Purcell effect. We argue that the blinking suppression is the result of the radiative rate change that mitigates Auger recombination and quantum dot ionization, consequently reducing nonradiative recombination. Our work demonstrates that topological singularities are an effective platform for studying and controlling plasmon-exciton interactions.

Ferromagnetic Switching of Knotted Vector Fields in Liquid Crystal Colloids.

We experimentally realize polydomain and monodomain chiral ferromagnetic liquid crystal colloids that exhibit solitonic and knotted vector field configurations. Formed by dispersions of ferromagnetic nanoplatelets in chiral nematic liquid crystals, these colloidal ferromagnets exhibit spontaneous long-range alignment of magnetic dipole moments of individual platelets, giving rise to a continuum of the magnetization field M(r). Competing effects of surface confinement and chirality prompt spontaneous formation and enable the optical generation of localized twisted solitonic structures with double-twist tubes and torus knots of M(r), which exhibit a strong sensitivity to the direction of weak magnetic fields ∼1 mT. Numerical modeling, implemented through free energy minimization to arrive at a field-dependent three-dimensional M(r), shows a good agreement with experiments and provides insights into the torus knot topology of observed field configurations and the corresponding physical underpinnings.

Self-assembly and electrostriction of arrays and chains of hopfion particles in chiral liquid crystals.

Some of the most exotic condensed matter phases, such as twist grain boundary and blue phases in liquid crystals and Abrikosov phases in superconductors, contain arrays of topological defects in their ground state. Comprised of a triangular lattice of double-twist tubes of magnetization, the so-called 'A-phase' in chiral magnets is an example of a thermodynamically stable phase with topologically nontrivial solitonic field configurations referred to as two-dimensional skyrmions, or baby-skyrmions. Here we report that three-dimensional skyrmions in the form of double-twist tori called 'hopfions', or 'torons' when accompanied by additional self-compensating defects, self-assemble into periodic arrays and linear chains that exhibit electrostriction. In confined chiral nematic liquid crystals, this self-assembly is similar to that of liquid crystal colloids and originates from long-range elastic interactions between particle-like skyrmionic torus knots of molecular alignment field, which can be tuned from isotropic repulsive to weakly or highly anisotropic attractive by low-voltage electric fields.

Two-dimensional skyrmions and other solitonic structures in confinement-frustrated chiral nematics.

We explore spatially localized solitonic configurations of a director field, generated using optical realignment and laser-induced heating, in frustrated chiral nematic liquid crystals confined between substrates with perpendicular surface anchoring. We demonstrate that, in addition to recently studied torons and Hopf-fibration solitonic structures (hopfions), one can generate a host of other axially symmetric stable and metastable director field configurations where local twist is matched to the surface boundary conditions through introduction of point defects and loops of singular and nonsingular disclinations. The experimentally demonstrated structures include the so-called "baby-skyrmions" in the form of double twist cylinders oriented perpendicular to the confining substrates where their double twist field configuration is matched to the perpendicular boundary conditions by loops of twist disclinations. We also generate complex textures with arbitrarily large skyrmion numbers. A simple back-of-the-envelope theoretical analysis based on free energy considerations and the nonpolar nature of chiral nematics provides insights into the long-term stability and diversity of these inter-related solitonic field configurations, including different types of torons, cholestric-finger loops, two-dimensional skyrmions, and more complex structures comprised of torons, hopfions, and various disclination loops that are experimentally observed in a confinement-frustrated chiral nematic system.

Transpterygoid stent placement for management of a recurrent infratemporal fossa epidermoid cyst: a technical note.

Epidermoid cysts (ECs) are benign congenital cysts that typically develop from misplaced stratified squamous epithelium during neural tube closure. They are most commonly encountered in the cerebellopontine angle, the fourth ventricle, and the region of the sella turcica. Recurrence of an EC or regrowth of residual components following surgery is known to occur, but the exact incidence is not defined. Repeat surgical removal is generally considered but may be complicated by significant morbidity. We present a novel endoscopic method by which to manage a recurrent EC of the infratemporal fossa using a silastic stent through a transpterygoid approach that permits periodic drainage of recurrent cyst material in the outpatient setting with minimal morbidity.

The efficacy and safety of preoperative lumbar drain placement in anterior skull base surgery.

This study assesses the efficacy of preoperative lumbar drain (LD) placement prior to elective open cranial and endoscopic anterior skull base (ASB) surgery in reducing postoperative cerebrospinal fluid (CSF) leak. A retrospective review of 93 patients who underwent LD placement at our institution between 2006 and 2011 was performed. Of these patients, 43 underwent elective LD placement prior to ASB surgery; 2 patients had evidence of CSF rhinorrhea prior to surgery, and 41 had no evidence of a preoperative CSF leak. Of those 41 patients, 2 developed CSF rhinorrhea (2/41= 4.9%) as a result of surgery-all in our endoscopic patient population (N = 21; 2/21= 9.5%). No postoperative CSF leaks were noted in our open ASB surgery cohort (N = 20). Other complications were rare, but we encountered two instances of delayed malignant cerebral edema in the open ASB cohort that are discussed in detail. Overall, preoperative LD placement was found to be an effective means of preventing postoperative CSF leaks after ASB approaches, but potential and significant intracranial complications may occur in select patients that merit careful consideration prior to LD placement.

Generating the Hopf fibration experimentally in nematic liquid crystals.

The Hopf fibration is an example of a texture: a topologically stable, smooth, global configuration of a field. Here we demonstrate the controlled sculpting of the Hopf fibration in nematic liquid crystals through the control of point defects. We demonstrate how these are related to torons by use of a topological visualization technique derived from the Pontryagin-Thom construction.

Optical generation of crystalline, quasicrystalline, and arbitrary arrays of torons in confined cholesteric liquid crystals for patterning of optical vortices in laser beams.

Condensed matter systems with topological defects in the ground states range from the Abrikosov phases in superconductors, to various blue phases and twist grain boundary phases in liquid crystals, and to phases of skyrmion lattices in chiral ferromagnets and Bose-Einstein condensates. In nematic and chiral nematic liquid crystals, which are true fluids with long-range orientational ordering of constituent molecules, point and line defects spontaneously occur as a result of symmetry-breaking phase transitions or due to flow, but they are unstable, hard to control, and typically annihilate with time. Here we describe the optical generation of two-dimensional crystalline, quasicrystalline, and arbitrary ensembles of particlelike structures manifesting both skyrmionlike and Hopf fibration features--dubbed "torons"--composed of looped double twist cylinders and point defects embedded in a uniform director field. In these two-dimensional lattices, we then introduce various dislocations, defects in positional ordering of the torons. We show that the periodic defect lattices with and without dislocation are light- and voltage-tunable reconfigurable two-dimensional diffraction gratings and can be used to generate various controlled phase singularities in the diffracted laser beams. The results of computer simulations of optical images, diffraction patterns, and phase distributions with optical vortices are in a good agreement with the corresponding experimental findings.