Higgs Oscillations in a Unitary Fermi Superfluid.

Symmetry-breaking phase transitions are central to our understanding of states of matter. When a continuous symmetry is spontaneously broken, new excitations appear that are tied to fluctuations of the order parameter. In superconductors and fermionic superfluids, the phase and amplitude can fluctuate independently, giving rise to two distinct collective branches. However, amplitude fluctuations are difficult to both generate and measure, as they do not couple directly to the density of fermions and have only been observed indirectly to date. Here, we excite amplitude oscillations in an atomic Fermi gas with resonant interactions by an interaction quench. Exploiting the sensitivity of Bragg spectroscopy to the amplitude of the order parameter, we measure the time-resolved response of the atom cloud, directly revealing amplitude oscillations at twice the frequency of the gap. The magnitude of the oscillatory response shows a strong temperature dependence, and the oscillations appear to decay faster than predicted by time-dependent Bardeen-Cooper-Schrieffer theory applied to our experimental setup.

Publisher Correction: G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3.

The adhesion G-protein-coupled receptor (GPCR) latrophilin 3 (ADGRL3) has been associated with increased risk of attention deficit hyperactivity disorder (ADHD) and substance use in human genetic studies. Knockdown in multiple species leads to hyperlocomotion and altered dopamine signaling. Thus, ADGRL3 is a potential target for treatment of neuropsychiatric disorders that involve dopamine dysfunction, but its basic signaling properties are poorly understood. Identification of adhesion GPCR signaling partners has been limited by a lack of tools to acutely activate these receptors in living cells. Here, we design a novel acute activation strategy to characterize ADGRL3 signaling by engineering a receptor construct in which we could trigger acute activation enzymatically. Using this assay, we found that ADGRL3 signals through G12/G13 and Gq, with G12/13 the most robustly activated. Gα12/13 is a new player in ADGRL3 biology, opening up unexplored roles for ADGRL3 in the brain. Our methodological advancements should be broadly useful in adhesion GPCR research.

Dynamics of a Fermi Gas Quenched to Unitarity.

We present an experimental study of a two component Fermi gas following an interaction quench into the superfluid phase. Starting with a weakly attractive gas in the normal phase, interactions are ramped to unitarity at a range of rates and we measure the subsequent dynamics as the gas approaches equilibrium. Both the formation and condensation of fermion pairs are mapped via measurements of the pair momentum distribution and can take place on very different timescales, depending on the adiabaticity of the quench. The contact parameter is seen to respond very quickly to changes in the interaction strength, indicating that short-range correlations, based on the occupation of high-momentum modes, evolve far more rapidly than the correlations in low-momentum modes necessary for pair condensation.

High-Frequency Sound in a Unitary Fermi Gas.

We present an experimental and theoretical study of the phonon mode in a unitary Fermi gas. Using two-photon Bragg spectroscopy, we measure excitation spectra at a momentum of approximately half the Fermi momentum, both above and below the superfluid critical temperature T_{c}. Below T_{c}, the dominant excitation is the Bogoliubov-Anderson (BA) phonon mode, driven by gradients in the phase of the superfluid order parameter. The temperature dependence of the BA phonon is consistent with a theoretical model based on the quasiparticle random phase approximation in which the dominant damping mechanism is via collisions with thermally excited quasiparticles. As the temperature is increased above T_{c}, the phonon evolves into a strongly damped collisional mode, accompanied by an abrupt increase in spectral width. Our study reveals strong similarities between sound propagation in the unitary Fermi gas and bosonic liquid helium.

Contact and Sum Rules in a Near-Uniform Fermi Gas at Unitarity.

We present an experimental study of the high-energy excitation spectra of unitary Fermi gases. Using focused beam Bragg spectroscopy, we locally probe atoms in the central region of a harmonically trapped cloud where the density is nearly uniform, enabling measurements of the dynamic structure factor for a range of temperatures both below and above the superfluid transition. Applying sum rules to the measured Bragg spectra, we resolve the characteristic behavior of the universal contact parameter, C, across the superfluid transition. We also employ a recent theoretical result for the kinetic (second-moment) sum rule to obtain the internal energy of gases at unitarity.

Quantum Anomaly and 2D-3D Crossover in Strongly Interacting Fermi Gases.

We present an experimental investigation of collective oscillations in harmonically trapped Fermi gases through the crossover from two to three dimensions. Specifically, we measure the frequency of the radial monopole oscillation or breathing mode in highly oblate gases with tunable interactions. The breathing mode frequency is set by the adiabatic compressibility and probes the thermodynamic equation of state. In 2D, a dynamical scaling symmetry for atoms interacting via a δ potential predicts the breathing mode to occur at exactly twice the harmonic confinement frequency. However, a renormalized quantum treatment introduces a new length scale which breaks this classical scale invariance resulting in a so-called quantum anomaly. Our measurements deep in the 2D regime lie above the scale-invariant prediction for a range of interaction strengths providing evidence for the quantum anomaly and signifying the breakdown of an elementary δ-potential model of atomic interactions. By varying the atom number we can tune the chemical potential and see the breathing mode frequency evolve smoothly between the 2D to 3D thermodynamic limits.

Thermodynamics of an Attractive 2D Fermi Gas.

Thermodynamic properties of matter are conveniently expressed as functional relations between variables known as equations of state. Here we experimentally determine the compressibility, density, and pressure equations of state for an attractive 2D Fermi gas in the normal phase as a function of temperature and interaction strength. In 2D, interacting gases exhibit qualitatively different features to those found in 3D. This is evident in the normalized density equation of state, which peaks at intermediate densities corresponding to the crossover from classical to quantum behavior.

Role for myosin-V motor proteins in the selective delivery of Kv channel isoforms to the membrane surface of cardiac myocytes.

RATIONALE: Kv1.5 (KCNA5) mediates the ultra-rapid delayed rectifier current that controls atrial action potential duration. Given its atrial-specific expression and alterations in human atrial fibrillation, Kv1.5 has emerged as a promising target for the treatment of atrial fibrillation. A necessary step in the development of novel agents that selectively modulate trafficking pathways is the identification of the cellular machinery controlling Kv1.5 surface density, of which little is yet known. OBJECTIVE: To investigate the role of the unconventional myosin-V (MYO5A and MYO5B) motors in determining the cell surface density of Kv1.5. METHODS AND RESULTS: Western blot analysis showed MYO5A and MYO5B expression in the heart, whereas disruption of endogenous motors selectively reduced IKur current in adult rat cardiomyocytes. Dominant negative constructs and short hairpin RNA silencing demonstrated a role for MYO5A and MYO5B in the surface trafficking of Kv1.5 and connexin-43 but not potassium voltage-gated channel, subfamily H (eag-related), member 2 (KCNH2). Live-cell imaging of Kv1.5-GFP and retrospective labeling of phalloidin demonstrated motility of Kv1.5 vesicles on actin tracts. MYO5A participated in anterograde trafficking, whereas MYO5B regulated postendocytic recycling. Overexpression of mutant motors revealed a selective role for Rab11 in coupling MYO5B to Kv1.5 recycling. CONCLUSIONS: MYO5A and MYO5B control functionally distinct steps in the surface trafficking of Kv1.5. These isoform-specific trafficking pathways determine Kv1.5-encoded IKur in myocytes to regulate repolarizing current and, consequently, cardiac excitability. Therapeutic strategies that manipulate Kv1.5 selective trafficking pathways may prove useful in the treatment of arrhythmias.

ISG15/GRAIL1/CD3 axis influences survival of patients with esophageal adenocarcinoma.

Immunosuppression is a common feature of esophageal adenocarcinoma (EAC) and has been linked to poor overall survival (OS). We hypothesized that upstream factors might negatively influence CD3 levels and T cell activity, thus promoting immunosuppression and worse survival. We used clinical data and patient samples of those who progressed from Barrett's to dysplasia to EAC, investigated gene (RNA-Seq) and protein (tissue microarray) expression, and performed cell biology studies to delineate a pathway impacting CD3 protein stability that might influence EAC outcome. We showed that the loss of both CD3-ε expression and CD3+ T cell number correlated with worse OS in EAC. The gene related to anergy in lymphocytes isoform 1 (GRAIL1), which is the prominent isoform in EACs, degraded (ε, γ, δ) CD3s and inactivated T cells. In contrast, isoform 2 (GRAIL2), which is reduced in EACs, stabilized CD3s. Further, GRAIL1-mediated CD3 degradation was facilitated by interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein. Consequently, the overexpression of a ligase-dead GRAIL1, ISG15 knockdown, or the overexpression of a conjugation-defective ISG15-leucine-arginine-glycine-glycine mutant could increase CD3 levels. Together, we identified an ISG15/GRAIL1/mutant p53 amplification loop negatively influencing CD3 levels and T cell activity, thus promoting immunosuppression in EAC.

Factors affecting timing of surgery following neoadjuvant chemoradiation for esophageal cancer.

Background: Neoadjuvant chemoradiation with esophagectomy is standard management for locally advanced esophageal cancer. Studies have shown that surgical timing following chemoradiation is important for minimizing postoperative complications, however in practice timing is often variable and delayed. Although postoperative impact of surgical timing has been studied, less is known about factors associated with delays. Materials and methods: A retrospective review was performed for 96 patients with esophageal cancer who underwent chemoradiation then esophagectomy between 2018 and 2020 at a single institution. Univariable and stepwise multivariable analyses were used to assess association between social (demographics, insurance) and clinical variables (pre-operative weight, comorbidities, prior cardiothoracic surgery, smoking history, disease staging) with time to surgery (≤8 weeks "on-time" vs. >8 weeks "delayed"). Results: Fifty-one patients underwent esophagectomy within 8 weeks of chemoradiation; 45 had a delayed operation. Univariate analysis showed the following characteristics were significantly different between on-time and delayed groups: weight loss within 3 months of surgery (3.9 ± 5.1 kg vs. 1.5 ± 3.6 kg; P = 0.009), prior cardiovascular disease (29% vs. 49%; P = 0.05), prior cardiothoracic surgery (4% vs. 22%; P = 0.01), history of ever smoked (69% vs. 87%; P = 0.04), absent nodal metastasis on pathology (57% vs. 82%; P = 0.008). Multivariate analysis demonstrated that prior cardiothoracic surgery (OR 8.924, 95%CI 1.67-47.60; P = 0.01) and absent nodal metastasis (OR 4.186, 95%CI 1.50-11.72; P = 0.006) were associated with delayed surgery. Conclusions: Delayed esophagectomy following chemoradiotherapy is associated with prior cardiothoracic surgery and absent nodal metastasis. Further investigations should focus on understanding how these factors contribute to delays to guide treatment planning and mitigate sources of outcome disparities.

Single molecule imaging reveals differences in microtubule track selection between Kinesin motors.

Cells generate diverse microtubule populations by polymerization of a common alpha/beta-tubulin building block. How microtubule associated proteins translate microtubule heterogeneity into specific cellular functions is not clear. We evaluated the ability of kinesin motors involved in vesicle transport to read microtubule heterogeneity by using single molecule imaging in live cells. We show that individual Kinesin-1 motors move preferentially on a subset of microtubules in COS cells, identified as the stable microtubules marked by post-translational modifications. In contrast, individual Kinesin-2 (KIF17) and Kinesin-3 (KIF1A) motors do not select subsets of microtubules. Surprisingly, KIF17 and KIF1A motors that overtake the plus ends of growing microtubules do not fall off but rather track with the growing tip. Selection of microtubule tracks restricts Kinesin-1 transport of VSVG vesicles to stable microtubules in COS cells whereas KIF17 transport of Kv1.5 vesicles is not restricted to specific microtubules in HL-1 myocytes. These results indicate that kinesin families can be distinguished by their ability to recognize microtubule heterogeneity. Furthermore, this property enables kinesin motors to segregate membrane trafficking events between stable and dynamic microtubule populations.

Temperature dependence of the universal contact parameter in a unitary Fermi gas.

The contact I, introduced by Tan, has emerged as a key parameter characterizing universal properties of strongly interacting Fermi gases. For ultracold Fermi gases near a Feshbach resonance, the contact depends upon two quantities: the interaction parameter 1/(k(F)a), where k(F) is the Fermi wave vector and a is the s-wave scattering length, and the temperature T/T(F), where T(F) is the Fermi temperature. We present the first measurements of the temperature dependence of the contact in a unitary Fermi gas using Bragg spectroscopy. The contact is seen to follow the predicted decay with temperature and shows how pair-correlations at high momentum persist well above the superfluid transition temperature.

Crossover from 2D to 3D in a weakly interacting Fermi gas.

We have studied the transition from two to three dimensions in a low temperature weakly interacting 6Li Fermi gas. Below a critical atom number N(2D) only the lowest transverse vibrational state of a highly anisotropic oblate trapping potential is occupied and the gas is two dimensional. Above N(2D) the Fermi gas enters the quasi-2D regime where shell structure associated with the filling of individual transverse oscillator states is apparent. This dimensional crossover is demonstrated through measurements of the cloud size and aspect ratio versus atom number.

Antiarrhythmic drug-induced internalization of the atrial-specific k+ channel kv1.5.

Conventional antiarrhythmic drugs target the ion permeability of channels, but increasing evidence suggests that functional ion channel density can also be modified pharmacologically. Kv1.5 mediates the ultrarapid potassium current (I(Kur)) that controls atrial action potential duration. Given the atrial-specific expression of Kv1.5 and its alterations in human atrial fibrillation, significant effort has been made to identify novel channel blockers. In this study, treatment of HL-1 atrial myocytes expressing Kv1.5-GFP with the class I antiarrhythmic agent quinidine resulted in a dose- and temperature-dependent internalization of Kv1.5, concomitant with channel block. This quinidine-induced channel internalization was confirmed in acutely dissociated neonatal myocytes. Channel internalization was subunit-dependent, activity-independent, stereospecific, and blocked by pharmacological disruption of the endocytic machinery. Pore block and channel internalization partially overlap in the structural requirements for drug binding. Surprisingly, quinidine-induced endocytosis was calcium-dependent and therefore unrecognized by previous biophysical studies focused on isolating channel-drug interactions. Importantly, whereas acute quinidine-induced internalization was reversible, chronic treatment led to channel degradation. Together, these data reveal a novel mechanism of antiarrhythmic drug action and highlight the possibility for new agents that selectively modulate the stability of channel protein in the membrane as an approach for treating cardiac arrhythmias.

Immune determinants of Barrett's progression to esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) develops from Barrett's esophagus (BE), a chronic inflammatory state that can progress through a series of transformative dysplastic states before tumor development. While molecular and genetic changes of EAC tumors have been studied, immune microenvironment changes during Barrett's progression to EAC remain poorly understood. In this study, we identify potential immunologic changes that can occur during BE-to-EAC progression. RNA sequencing (RNA-Seq) analysis on tissue samples from EAC patients undergoing surgical resection demonstrated that a subset of chemokines and cytokines, most notably IL6 and CXCL8, increased during BE progression to EAC. xCell deconvolution analysis investigating immune cell population changes demonstrated that the largest changes in expression during BE progression occurred in M2 macrophages, pro-B cells, and eosinophils. Multiplex immunohistochemical staining of tissue microarrays showed increased immune cell populations during Barrett's progression to high-grade dysplasia. In contrast, EAC tumor sections were relatively immune poor, with a rise in PD-L1 expression and loss of CD8+ T cells. These data demonstrate that the EAC microenvironment is characterized by poor cytotoxic effector cell infiltration and increased immune inhibitory signaling. These findings suggest an immunosuppressive microenvironment, highlighting the need for further studies to explore immune modulatory therapy in EAC.

Universal behavior of pair correlations in a strongly interacting Fermi gas.

We show that short-range pair correlations in a strongly interacting Fermi gas follow a simple universal law described by Tan's relations. This is achieved through measurements of the static structure factor which displays a universal scaling proportional to the ratio of Tan's contact to the momentum C/q. Bragg spectroscopy of ultracold 6Li atoms from a periodic optical potential is used to measure the structure factor for a wide range of momenta and interaction strengths, providing broad confirmation of this universal law. We calibrate our Bragg spectra using the f-sum rule, which is found to improve the accuracy of the structure factor measurement.

Ciliary targeting of olfactory CNG channels requires the CNGB1b subunit and the kinesin-2 motor protein, KIF17.

Nonmotile cilia on olfactory sensory neurons (OSNs) compartmentalize signaling molecules, including odorant receptors and cyclic nucleotide-gated (CNG) channels, allowing for efficient, spatially confined responses to sensory stimuli . Little is known about the mechanisms of the ciliary targeting of olfactory CNG channels, composed of three subunits: CNGA2, CNGA4, and CNGB1b . Recent reports suggest that subunit composition of the retinal CNG channel influences localization, leading to disease . However, the mechanistic role of subunits in properly targeting native olfactory CNG channels remains unclear. Here, we show that heteromeric assembly with CNGB1b, containing a critical carboxy-terminal motif (RVxP), is required for ciliary trafficking of olfactory CNG channels. Movement of proteins within the cilia is governed by intraflagellar transport (IFT), a process that facilitates bidirectional movement of cargo along microtubules. Work in C. elegans has established that heterotrimeric and homodimeric kinesin-2 family members play a critical role in anterograde transport . In mammalian systems, the heterotrimeric KIF3a/KIF3b/KAP-3 complex plays a clear role in IFT; however, no role has been established for KIF17, the mammalian homolog of OSM-3 . Here, we demonstrate that KIF17 is required for olfactory CNG channel targeting, providing novel insights into mechanisms of mammalian ciliary transport.

Olfactory cilia: linking sensory cilia function and human disease.

The olfactory system gives us an awareness of our immediate environment by allowing us to detect airborne stimuli. The components necessary for detection of these odorants are compartmentalized in the cilia of olfactory sensory neurons. Cilia are microtubule-based organelles, which can be found projecting from the surface of almost any mammalian cell, and are critical for proper olfactory function. Mislocalization of ciliary proteins and/or the loss of cilia cause impaired olfactory function, which is now recognized as a clinical manifestation of a broad class of human diseases, termed ciliopathies. Future work investigating the mechanisms of olfactory cilia function will provide us important new information regarding the pathogenesis of human sensory perception diseases.

Caveolin regulates kv1.5 trafficking to cholesterol-rich membrane microdomains.

The targeting of ion channels to cholesterol-rich membrane microdomains has emerged as a novel mechanism of ion channel localization. Previously, we reported that Kv1.5, a prominent cardiovascular K(+) channel alpha-subunit, localizes to caveolar microdomains. However, the mechanisms regulating Kv1.5 targeting and the functional significance of this localization are largely unknown. In this study, we demonstrate a role for caveolin in the trafficking of Kv1.5 to lipid raft microdomains where cholesterol modulates channel function. In cells lacking endogenous caveolin-1 or -3, the association of Kv1.5 with low-density, detergent-resistant membrane fractions requires coexpression with exogenous caveolin, which can form channel-caveolin complexes. Caveolin is not required for cell surface expression, however, and caveolin-trafficking mutants sequester Kv1.5, but not Kv2.1, in intracellular compartments, resulting in a loss of functional cell surface channel. Coexpression with wild type caveolin-1 does not alter Kv1.5 current density; rather, it induces depolarizing shifts in steady-state activation and inactivation. These shifts are analogous to those produced by elevation of membrane cholesterol. Together, these results show that caveolin modulates channel function by regulating trafficking to cholesterol-rich membrane microdomains.