Disentangling Lattice and Electronic Instabilities in the Excitonic Insulator Candidate Ta_{2}NiSe_{5} by Nonequilibrium Spectroscopy.

Ta_{2}NiSe_{5} is an excitonic insulator candidate showing the semiconductor or semimetal-to-insulator (SI) transition below T_{c}=326 K. However, since a structural transition accompanies the SI transition, deciphering the role of electronic and lattice degrees of freedom in driving the SI transition has remained controversial. Here, we investigate the photoexcited nonequilibrium state in Ta_{2}NiSe_{5} using pump-probe Raman and photoluminescence spectroscopies. The combined nonequilibrium spectroscopic measurements of the lattice and electronic states reveal the presence of a photoexcited metastable state where the insulating gap is suppressed, but the low-temperature structural distortion is preserved. We conclude that electron correlations play a vital role in the SI transition of Ta_{2}NiSe_{5}.

Nematic-Fluctuation-Mediated Superconductivity Revealed by Anisotropic Strain in Ba(Fe_{1-x}Co_{x})_{2}As_{2}.

Anisotropic strain is an external field capable of selectively addressing the role of nematic fluctuations in promoting superconductivity. We demonstrate this using polarization-resolved elasto-Raman scattering by probing the evolution of nematic fluctuations under strain in the normal and superconducting state of the paradigmatic iron-based superconductor Ba(Fe_{1-x}Co_{x})_{2}As_{2}. In the parent compound BaFe_{2}As_{2} we observe a strain-induced suppression of the nematic susceptibility which follows the expected behavior of an Ising order parameter under a symmetry breaking field. For the superconducting compound, the suppression of the nematic susceptibility correlates with the decrease of the critical temperature T_{c}, indicating a significant contribution of nematic fluctuations to electron pairing. Our results validate theoretical scenarios of enhanced T_{c} near a nematic quantum critical point.

Healthy Donors Exhibit a CD4 T Cell Repertoire Specific to the Immunogenic Human Hormone H2-Relaxin before Injection.

H2-relaxin (RLN2) is a two-chain peptide hormone structurally related to insulin with a therapeutic potential in multiple indications. However, multiple injections of human RLN2 induced anti-RLN2 Abs in patients, hampering its clinical development. As T cell activation is required to produce Abs, we wondered whether T cells specific for RLN2 might be already present in the human blood before any injection. We therefore quantified the RLN2-specific T cell repertoire using PBMCs collected from healthy donors. CD4 T cells were stimulated in multiple replicates by weekly rounds of stimulation by dendritic cells loaded with RLN2, and their specificity was assessed by IFN-γ ELISPOT. The number of specific T cell lines was used to estimate the frequency of circulating T cells. In vitro T cell response was demonstrated in 18 of the 23 healthy donors, leading to the generation of 70 independent RLN2-specific T cell lines. The mean frequency of RLN2-specific CD4 T cells was similar to that of T cells specific for known immunogenic therapeutic proteins. Using overlapping peptides, we identified multiple T cell epitopes hosted in the N-terminal parts of the α- and ß-chains and common to multiple donors, in agreement with their capacity to bind to multiple HLA-DR molecules. Our results provide important clues to the immunogenicity of RLN2 and highlight the weak central immune tolerance induced against this self-hormone.

Pressure-Induced Collapse of the Charge Density Wave and Higgs Mode Visibility in 2H-TaS_{2}.

The pressure evolution of the Raman active electronic excitations of the transition metal dichalcogenides 2H-TaS_{2} is followed through the pressure phase diagram embedding incommensurate charge-density-wave and superconducting states. At high pressure, the charge-density wave is found to collapse at 8.5 GPa. In the coexisting charge-density-wave and superconducting orders, we unravel a strong in-gap superconducting mode, attributed to a Higgs mode, coexisting with the expected incoherent Cooper-pair breaking signature. The latter remains in the pure superconducting state reached above 8.5 GPa. Our report constitutes a new observation of such Raman active Higgs mode since the long-standing unique case 2H-NbSe_{2}.

Charge-induced nematicity in FeSe.

The spontaneous appearance of nematicity, a state of matter that breaks rotation but not translation symmetry, is one of the most intriguing properties of the iron-based superconductors (Fe SC), and has relevance for the cuprates as well. Establishing the critical electronic modes behind nematicity remains a challenge, however, because their associated susceptibilities are not easily accessible by conventional probes. Here, using FeSe as a model system, and symmetry-resolved electronic Raman scattering as a probe, we unravel the presence of critical charge nematic fluctuations near the structural/nematic transition temperature, [Formula: see text] 90 K. The diverging behavior of the associated nematic susceptibility foretells the presence of a Pomeranchuk instability of the Fermi surface with d-wave symmetry. The excellent scaling between the observed nematic susceptibility and elastic modulus data demonstrates that the structural distortion is driven by this d-wave Pomeranchuk transition. Our results make a strong case for charge-induced nematicity in FeSe.

Collapse of Critical Nematic Fluctuations in FeSe under Pressure.

We report the evolution of the electronic nematic susceptibility in FeSe via Raman scattering as a function of hydrostatic pressure up to 5.8 GPa where the superconducting transition temperature T_{c} reaches its maximum. The critical nematic fluctuations observed at low pressure vanish above 1.6 GPa, indicating they play a marginal role in the fourfold enhancement of T_{c} at higher pressures. The collapse of nematic fluctuations appears to be linked to a suppression of low energy electronic excitations which manifests itself by optical phonon anomalies at around 2 GPa, in agreement with lattice dynamical and electronic structure calculations using local density approximation combined with dynamical mean field theory. Our results reveal two different regimes of nematicity in the phase diagram of FeSe under pressure: a d-wave Pomeranchuk instability of the Fermi surface at low pressure and a magnetic driven orthorhombic distortion at higher pressure.

Higgs Mode in the d-Wave Superconductor Bi_{2}Sr_{2}CaCu_{2}O_{8+x} Driven by an Intense Terahertz Pulse.

We investigate the terahertz (THz)-pulse-driven nonlinear response in the d-wave cuprate superconductor Bi_{2}Sr_{2}CaCu_{2}O_{8+x} (Bi2212) using a THz pump near-infrared probe scheme in the time domain. We observe an oscillatory behavior of the optical reflectivity that follows the THz electric field squared and is markedly enhanced below T_{c}. The corresponding third-order nonlinear effect exhibits both A_{1g} and B_{1g} symmetry components, which are decomposed from polarization-resolved measurements. A comparison with a BCS calculation of the nonlinear susceptibility indicates that the A_{1g} component is associated with the Higgs mode of the d-wave order parameter.

Effect of growth hormone and IgG aggregates on dendritic cells activation and T-cells polarization.

Patients treated with therapeutic biological products (BP) frequently develop anti-drug antibodies (ADA) with potential neutralizing capacities leading to loss of clinical response or serious side effects. BP aggregates have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are key effectors in T-cell and B-cell fates, and the subsequent generation of immunogenicity. The objective of this work was to determine if BP aggregates can participate to DC maturation and T-cell activation. We compared aggregates from three different proteins: human growth hormone (hGH), Rituximab, a chimeric anti-CD20 antibody and a serum-purified human IgG1. All three proteins underwent a stir stress, generating comparable populations of aggregated particles. Maturation of human monocyte-derived DC (moDC) upon exposure to native BPs or aggregates was evaluated in vitro. Results showed that hGH aggregates induced an increased expression of moDC co-stimulation markers, and augmented levels of IL-6, IL-8, IL-12p40, CCL2, CCL3, CCL4 and CXCL10. Both antibodies aggregates were also able to modify DC phenotype, but cytokine and chemokine productions were seen only with IL-6, IL-8, IL-12p40 and CXCL10. Aggregates-treated moDC enhanced allogenic T-cell proliferation and cytokines production, suggesting Th1 polarization with hGH, and mixed T-cell responses with antibodies aggregates. These results showed that BP aggregates provoked DC maturation, thus driving adaptive T-cell responses and polarization.

Nematic Resonance in the Raman Response of Iron-Based Superconductors.

In a fully gapped superconductor the electronic Raman response has a pair-breaking peak at twice the superconducting gap Δ, if the Bogoliubov excitations are uncorrelated. Motivated by the iron based superconductors, we study how this peak is modified if the superconducting phase hosts a nematic-structural quantum critical point. We show that, upon approaching this point by tuning, e.g., doping, the growth of nematic correlations between the quasiparticles transforms the pair-breaking peak into a nematic resonance. The mode energy is below 2Δ, and stays finite at the quantum critical point, where its spectral weight is sharply enhanced. The latter is consistent with recent experiments on electron-doped iron based superconductors and provides direct evidence of nematic correlations in their superconducting phases.

Rapid collapse of spin waves in nonuniform phases of the second Landau level.

The spin degree of freedom in quantum phases of the second Landau level is probed by resonant light scattering. The long wavelength spin wave, which monitors the degree of spin polarization, is at the Zeeman energy in the fully spin-polarized state at ν = 3. At lower filling factors, the intensity of the Zeeman mode collapses, indicating loss of polarization. A novel continuum of low-lying excitations emerges that dominates near ν = 8/3 and ν = 5/2. Resonant Rayleigh scattering reveals that quantum fluids for ν < 3 break up into robust domain structures. While the state at ν = 5/2 is considered to be fully polarized, these results reveal unprecedented roles for spin degrees of freedom.

Higher-energy composite fermion levels in the fractional quantum Hall effect.

Even though composite fermions in the fractional quantum Hall liquid are well established, it is not yet known up to what energies they remain intact. We probe the high-energy spectrum of the 1/3 liquid directly by resonant inelastic light scattering, and report the observation of a large number of new collective modes. Supported by our theoretical calculations, we associate these with transitions across two or more composite fermions levels. The formation of quasiparticle levels up to high energies is direct evidence for the robustness of topological order in the fractional quantum Hall effect.

Possible observation of the signature of the bad metal phase and its crossover to a Fermi liquid in Κ-(BEDT-TTF)2Cu(NCS)2bulk and nanoparticles by Raman scattering.

Κ-(BEDT-TTF)2Cu(NCS)2has been investigated by Raman scattering in both bulk and nanoparticle compounds. Phonon modes from 20 to 1600 cm-1have been assigned. Focusing on the unexplored low frequency phonons, a plateau in frequencies is observed in the bulk phonons between 50 and 100 K and assigned to the signature of the bad metal phase. Nanoparticles of Κ-(BEDT-TTF)2Cu(NCS)2exhibit anomalies at 50 K associated to the crossover from a bad metal to a Fermi liquid whose origins are discussed.

Growth Hormone Aggregates Activation of Human Dendritic Cells Is Controlled by Rac1 and PI3 Kinase Signaling Pathways.

The presence of protein aggregates in biological products is suggested to promote immunogenicity, leading to the production of anti-drug antibodies with neutralizing capacities. This suggests a CD4+ T-cell dependent adaptive immune response, thus a pivotal role for antigen-presenting cells, such as dendritic cells (DCs). We previously showed that human growth hormone aggregates induced DC maturation, with notably an increase in CXCL10 production. DC phenotypic modifications were sufficient to promote allogeneic CD4+ T-cell proliferation with Th1 polarization. In this work, we identified the main intracellular signaling pathways involved in DC activation by human growth hormone aggregates, showing that aggregates induced p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and c-Jun N-terminal kinase phosphorylation, as well as nuclear factor κB subunit p65 nuclear translocation. Next, investigating the implication of Rho GTPases and phosphoinositide 3-kinase (PI3K) in activated DC showed that Rac1 and Cdc42 regulated the phosphorylation of MAP kinases, whereas PI3K was only implicated in c-Jun N-terminal kinase phosphorylation. Furthermore, we showed that Rac1 and PI3K pathways, but not Cdc42, regulated the production of CXCL10 via the MAP kinases and nuclear factor κB. Taken together, our results bring new insight on how protein aggregates could induce DC activation, leading to a better understanding of aggregates role in therapeutic proteins immunogenicity.

Magnon bound states versus anyonic Majorana excitations in the Kitaev honeycomb magnet α-RuCl3.

The pure Kitaev honeycomb model harbors a quantum spin liquid in zero magnetic fields, while applying finite magnetic fields induces a topological spin liquid with non-Abelian anyonic excitations. This latter phase has been much sought after in Kitaev candidate materials, such as α-RuCl3. Currently, two competing scenarios exist for the intermediate field phase of this compound (B = 7 - 10 T), based on experimental as well as theoretical results: (i) conventional multiparticle magnetic excitations of integer quantum number vs. (ii) Majorana fermionic excitations of possibly non-Abelian nature with a fractional quantum number. To discriminate between these scenarios a detailed investigation of excitations over a wide field-temperature phase diagram is essential. Here, we present Raman spectroscopic data revealing low-energy quasiparticles emerging out of a continuum of fractionalized excitations at intermediate fields, which are contrasted by conventional spin-wave excitations. The temperature evolution of these quasiparticles suggests the formation of bound states out of fractionalized excitations.

4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a severe autoimmune vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) mainly targeting proteinase 3 (PR3), a neutrophilic serine proteinase. PR3-ANCA binding to membrane-bound PR3 on neutrophils induce their auto-immune activation responsible for vascular lesions. However, the correlation between PR3-ANCA level and disease activity remains inconsistent, suggesting the existence of non-pathogenic PR3-ANCA. In order to prove their existence, we immortalized B lymphocytes from blood samples of GPA patients in remission having persistent PR3-ANCA to isolate non-activating PR3-ANCA. We obtained for the first time a non-activating human IgG1κ anti-PR3 monoclonal antibody (mAb) named 4C3. This new mAb binds soluble PR3 with a high affinity and membrane-bound PR3 on an epitope close to the PR3 hydrophobic patch and in the vicinity of the active site. 4C3 is able to bind FcγRIIA and FcγRIIIB and has a G2F glycosylation profile on asparagine 297. 4C3 did not induce activation of neutrophils and could inhibit human polyclonal PR3-ANCA-induced activation suggesting that 4C3 is non-pathogenic. This characteristic relies on the recognized epitope on PR3 rather than to the Fc portion properties. The existence of non-pathogenic PR3-ANCA, which do not activate neutrophils, could explain the persistence of high PR3-ANCA levels in some GPA patients in remission and why PR3-ANCA would not predict relapse. Finally, these results offer promising perspectives particularly regarding the understanding of PR3-ANCA pathogenicity and the development of new diagnostic and therapeutic strategies in GPA.

Phase-resolved Higgs response in superconducting cuprates.

In high-energy physics, the Higgs field couples to gauge bosons and fermions and gives mass to their elementary excitations. Experimentally, such couplings can be inferred from the decay product of the Higgs boson, i.e., the scalar (amplitude) excitation of the Higgs field. In superconductors, Cooper pairs bear a close analogy to the Higgs field. Interaction between the Cooper pairs and other degrees of freedom provides dissipation channels for the amplitude mode, which may reveal important information about the microscopic pairing mechanism. To this end, we investigate the Higgs (amplitude) mode of several cuprate thin films using phase-resolved terahertz third harmonic generation (THG). In addition to the heavily damped Higgs mode itself, we observe a universal jump in the phase of the driven Higgs oscillation as well as a non-vanishing THG above Tc. These findings indicate coupling of the Higgs mode to other collective modes and potentially a nonzero pairing amplitude above Tc.

Evaluation of in vitro Assays to Assess the Modulation of Dendritic Cells Functions by Therapeutic Antibodies and Aggregates.

Therapeutic antibodies have the potential to induce immunogenicity leading to the development of anti-drug antibodies (ADA) that consequently may result in reduced serum drug concentrations, a loss of efficacy or potential hypersensitivity reactions. Among other factors, aggregated antibodies have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are the most efficient antigen-presenting cell population and are crucial for the initiation of T cell responses and the subsequent generation of an adaptive immune response. This work focuses on the development of predictive in vitro assays that can monitor DC maturation, in order to determine whether drug products have direct DC stimulatory capabilities. To this end, four independent laboratories aligned a common protocol to differentiate human monocyte-derived DC (moDC) that were treated with either native or aggregated preparations of infliximab, natalizumab, adalimumab, or rituximab. These drug products were subjected to different forms of physical stress, heat and shear, resulting in aggregation and the formation of subvisible particles. Each partner developed and optimized assays to monitor diverse end-points of moDC maturation: measuring the upregulation of DC activation markers via flow cytometry, analyzing cytokine, and chemokine production via mRNA and protein quantification and identifying cell signaling pathways via quantification of protein phosphorylation. These study results indicated that infliximab, with the highest propensity to form aggregates when heat-stressed, induced a marked activation of moDC as measured by an increase in CD83 and CD86 surface expression, IL-1ß, IL-6, IL-8, IL-12, TNFα, CCL3, and CCL4 transcript upregulation and release of respective proteins, and phosphorylation of the intracellular signaling proteins Syk, ERK1/2, and Akt. In contrast, natalizumab, which does not aggregate under these stress conditions, induced no DC activation in any assay system, whereas adalimumab or rituximab aggregates induced only slight parameter variation. Importantly, the data generated in the different assay systems by each partner site correlated and supported the use of these assays to monitor drug-intrinsic propensities to drive maturation of DC. This moDC assay is also a valuable tool as an in vitro model to assess the intracellular mechanisms that drive DC activation by aggregated therapeutic proteins.

Human blood monocytes are able to form extracellular traps.

Neutrophil extracellular traps (NETs) are extracellular DNA filaments formed during neutrophil activation. This process, called netosis, was originally associated with neutrophil antibacterial properties. However, several lines of evidence now suggest a major role for netosis in thrombosis, autoimmune diseases, and cancer. We demonstrate here that highly purified human blood monocytes are also capable of extracellular trap (ET) release in response to several stimuli. Monocyte ETs display a morphology analogous to NETs and are associated with myeloperoxidase (MPO), lactoferrin (LF), citrullinated histones, and elastase. Monocyte ET release depends on oxidative burst but not on MPO activity, in contrast to neutrophils. Moreover, we demonstrate procoagulant activity for monocyte ETs, a feature that could be relevant to monocyte thrombogenic properties. This new cellular mechanism is likely to have implications in the multiple pathologic contexts where monocytes are implicated, such as inflammatory disorders, infection, or thrombosis.

Protein kinase CK2 controls T-cell polarization through dendritic cell activation in response to contact sensitizers.

Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T-cell-mediated inflammatory skin disease caused by chemicals present in the daily or professional environment. NiSO4 and 2,4-dinitrochlorobenzene (DNCB) are 2 chemicals involved in ACD. These contact sensitizers are known to induce an up-regulation of phenotypic markers and cytokine secretion in dendritic cells (DCs; professional APCs), leading to the generation of CD8+ Tc1/Tc17 and CD4+ Th1/Th17 effector T cells. In the present study, using a peptide array approach, we identified protein kinase CK2 as a novel kinase involved in the activation of human monocyte-derived DCs (MoDCs) in response to NiSO4 and DNCB. Inhibition of CK2 activity in MoDCs led to an altered mature phenotype with lower expression of CD54, PDL-1, CD86, and CD40 in response to NiSO4 or DNCB. CK2 activity also regulated proinflammatory cytokine production, such as TNF-α, IL-1ß, and IL-23 in MoDCs. Moreover, in a DC/T cell coculture model in an allogeneic setup, CK2 activity in MoDCs played a major role in Th1 polarization in response to NiSO4 and DNCB. CK2 inhibition in MoDCs led to an enhanced Th2 polarization in the absence of contact sensitizer stimulation.