Interplay of hidden orbital order and superconductivity in CeCoIn5.

Visualizing atomic-orbital degrees of freedom is a frontier challenge in scanned microscopy. Some types of orbital order are virtually imperceptible to normal scattering techniques because they do not reduce the overall crystal lattice symmetry. A good example is dxz/dyz (π,π) orbital order in tetragonal lattices. For enhanced detectability, here we consider the quasiparticle scattering interference (QPI) signature of such (π,π) orbital order in both normal and superconducting phases. The theory reveals that sublattice-specific QPI signatures generated by the orbital order should emerge strongly in the superconducting phase. Sublattice-resolved QPI visualization in superconducting CeCoIn5 then reveals two orthogonal QPI patterns at lattice-substitutional impurity atoms. We analyze the energy dependence of these two orthogonal QPI patterns and find the intensity peaked near E = 0, as predicted when such (π,π) orbital order is intertwined with d-wave superconductivity. Sublattice-resolved superconductive QPI techniques thus represent a new approach for study of hidden orbital order.

Droplet-based forward genetic screening of astrocyte-microglia cross-talk.

Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms.

Immunotherapy approaches for adult glioma: knowledge gained from recent clinical trials.

PURPOSE OF REVIEW: Summarize principles behind various immunotherapy approaches for high and low-grade glioma in the context of recently completed clinical trials and the new insights they provide. RECENT FINDINGS: Despite the widespread success of therapies targeting the T-cell checkpoints programmed-death 1 and cytotoxic T lymphocyte antigen 4 in other malignancies, recent phase III trials in glioblastoma confirm the lack of efficacy of anti-programmed-death 1 monotherapy in more than 90% of patients. Vaccination approaches remain under investigation for high-grade glioma and have shown activity in some low-grade glioma patients. Chimeric antigen receptor T cells now feature a new generation of products engineered to potentially withstand glucocorticoid therapy. Oncolytic viral therapies have similarly advanced in sophistication, with drug-sensitive gene expression and tumor-selective modifications. Combinations of therapies hold promise for overcoming the numerous mechanisms of immune suppression in glioma. SUMMARY: Although immunotherapies have yet to show rates of efficacy compared with other malignancies, new knowledge of immunology and combination therapies brings hope for improved efficacy in the future.

Identification of environmental factors that promote intestinal inflammation.

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPß signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.

Superconducting Instabilities in Strongly Correlated Infinite-Layer Nickelates.

The discovery of superconductivity in infinite-layer nickelates has added a new family of materials to the fascinating growing class of unconventional superconductors. By incorporating the strongly correlated multiorbital nature of the low-energy electronic degrees of freedom, we compute the leading superconducting instability from magnetic fluctuations relevant for infinite-layer nickelates. Specifically, by properly including the doping dependence of the Ni d_{x^{2}-y^{2}} and d_{z^{2}} orbitals as well as the self-doping band, we uncover a transition from d-wave pairing symmetry to nodal s_{±} superconductivity, driven by strong fluctuations in the d_{z^{2}}-dominated orbital states. We discuss the properties of the resulting superconducting condensates in light of recent tunneling and penetration depth experiments probing the detailed superconducting gap structure of these materials.

Orbital-Selective High-Temperature Cooper Pairing Developed in the Two-Dimensional Limit.

For multiband superconductors, the orbital multiplicity yields orbital differentiation in normal-state properties and can lead to orbital-selective spin-fluctuation Cooper pairing. The orbital-selective phenomenon has become increasingly pivotal in clarifying the pairing "enigma", particularly for multiband high-temperature superconductors. Meanwhile, in one-unit-cell (1-UC) FeSe/SrTiO3, since the standard electron-hole Fermi pocket nesting scenario is inapplicable, the actual pairing mechanism is subject to intense debate. Here, by measuring high-resolution Bogoliubov quasiparticle interference, we report observations of highly anisotropic magnetic Cooper pairing in 1-UC FeSe. Theoretically, it is important to incorporate orbitally selective effects of electronic correlations within a spin-fluctuation pairing calculation, where the dxy orbital becomes coherence-suppressed. The resulting pairing gap is compatible with the experimental findings, which suggests that high-Tc Cooper pairing with orbital selectivity applies to 2D-limit 1-UC FeSe. Our findings imply the general existence of orbital selectivity in iron-based superconductors and the universal significance of electron correlations in high-Tc superconductors.

Glial and myeloid heterogeneity in the brain tumour microenvironment.

Brain cancers carry bleak prognoses, with therapeutic advances helping only a minority of patients over the past decade. The brain tumour microenvironment (TME) is highly immunosuppressive and differs from that of other malignancies as a result of the glial, neural and immune cell populations that constitute it. Until recently, the study of the brain TME was limited by the lack of methods to de-convolute this complex system at the single-cell level. However, novel technical approaches have begun to reveal the immunosuppressive and tumour-promoting properties of distinct glial and myeloid cell populations in the TME, identifying new therapeutic opportunities. Here, we discuss the immune modulatory functions of microglia, monocyte-derived macrophages and astrocytes in brain metastases and glioma, highlighting their disease-associated heterogeneity and drawing from the insights gained by studying these malignancies and other neurological disorders. Lastly, we consider potential approaches for the therapeutic modulation of the brain TME.

Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma.

PURPOSE: Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors. METHODS: We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women's Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed. RESULTS: Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22-69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2-11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7-38.9). CONCLUSION: Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.

Spatially dispersing Yu-Shiba-Rusinov states in the unconventional superconductor FeTe0.55Se0.45.

By using scanning tunneling microscopy (STM) we find and characterize dispersive, energy-symmetric in-gap states in the iron-based superconductor FeTe0.55Se0.45, a material that exhibits signatures of topological superconductivity, and Majorana bound states at vortex cores or at impurity locations. We use a superconducting STM tip for enhanced energy resolution, which enables us to show that impurity states can be tuned through the Fermi level with varying tip-sample distance. We find that the impurity state is of the Yu-Shiba-Rusinov (YSR) type, and argue that the energy shift is caused by the low superfluid density in FeTe0.55Se0.45, which allows the electric field of the tip to slightly penetrate the sample. We model the newly introduced tip-gating scenario within the single-impurity Anderson model and find good agreement to the experimental data.

Spin-orbit quantum impurity in a topological magnet.

Quantum states induced by single-atomic impurities are at the frontier of physics and material science. While such states have been reported in high-temperature superconductors and dilute magnetic semiconductors, they are unexplored in topological magnets which can feature spin-orbit tunability. Here we use spin-polarized scanning tunneling microscopy/spectroscopy (STM/S) to study the engineered quantum impurity in a topological magnet Co3Sn2S2. We find that each substituted In impurity introduces a striking localized bound state. Our systematic magnetization-polarized probe reveals that this bound state is spin-down polarized, in lock with a negative orbital magnetization. Moreover, the magnetic bound states of neighboring impurities interact to form quantized orbitals, exhibiting an intriguing spin-orbit splitting, analogous to the splitting of the topological fermion line. Our work collectively demonstrates the strong spin-orbit effect of the single-atomic impurity at the quantum level, suggesting that a nonmagnetic impurity can introduce spin-orbit coupled magnetic resonance in topological magnets.

Quantum Phase Transition of Correlated Iron-Based Superconductivity in LiFe_{1-x}Co_{x}As.

The interplay between unconventional Cooper pairing and quantum states associated with atomic scale defects is a frontier of research with many open questions. So far, only a few of the high-temperature superconductors allow this intricate physics to be studied in a widely tunable way. We use scanning tunneling microscopy to image the electronic impact of Co atoms on the ground state of the LiFe_{1-x}Co_{x}As system. We observe that impurities progressively suppress the global superconducting gap and introduce low energy states near the gap edge, with the superconductivity remaining in the strong-coupling limit. Unexpectedly, the fully opened gap evolves into a nodal state before the Cooper pair coherence is fully destroyed. Our systematic theoretical analysis shows that these new observations can be quantitatively understood by the nonmagnetic Born-limit scattering effect in an s±-wave superconductor, unveiling the driving force of the superconductor to metal quantum phase transition.

Anisotropic spin fluctuations in detwinned FeSe.

Superconductivity in FeSe emerges from a nematic phase that breaks four-fold rotational symmetry in the iron plane. This phase may arise from orbital ordering, spin fluctuations or hidden magnetic quadrupolar order. Here we use inelastic neutron scattering on a mosaic of single crystals of FeSe, detwinned by mounting on a BaFe2As2 substrate to demonstrate that spin excitations are most intense at the antiferromagnetic wave vectors QAF = (±1, 0) at low energies E = 6-11 meV in the normal state. This two-fold (C2) anisotropy is reduced at lower energies, 3-5 meV, indicating a gapped four-fold (C4) mode. In the superconducting state, however, the strong nematic anisotropy is again reflected in the spin resonance (E = 3.6 meV) at QAF with incommensurate scattering around 5-6 meV. Our results highlight the extreme electronic anisotropy of the nematic phase of FeSe and are consistent with a highly anisotropic superconducting gap driven by spin fluctuations.

Leptomeningeal metastases in glioma: The Memorial Sloan Kettering Cancer Center experience.

OBJECTIVE: To perform a retrospective analysis examining the incidence and prognosis of glioma patients with leptomeningeal disease (LMD) at Memorial Sloan Kettering Cancer Center over a 15-year period and correlate these findings with clinicopathologic characteristics. METHODS: We conducted a retrospective review of glioma patients with LMD at Memorial Sloan Kettering Cancer Center diagnosed from 2001 to 2016. Patients were identified through a keyword search of their electronic medical record and by ICD-9 codes. RESULTS: One hundred three patients were identified with disseminated LMD and 85 patients with subependymal spread of disease, 4.7% of all patients with glioma. These cohorts were analyzed separately for time to development of disseminated LMD/subependymal LMD, median overall survival, and survival from LMD diagnosis. Patients were pooled for subsequent analyses (n = 188) because of comparable clinical behavior. LMD was present at glioma diagnosis in 10% of patients. In the remaining 90% of patients diagnosed at recurrence, time to LMD diagnosis, survival after LMD diagnosis, and overall survival varied by original histology. Patients with oligodendroglioma had a median survival of 10.8 (range 1.8-67.7) months, astrocytoma 6.5 (0.1-28.5) months, and glioblastoma 3.8 (0.1-32.6) months after LMD diagnosis. In addition, we found that treatment of LMD was associated with superior performance status and increased survival. CONCLUSION: Patients with LMD diagnosed at relapse may not have decreased overall survival as compared to historical controls with parenchymal relapse and may benefit from treatment.

Spin Waves in Detwinned BaFe_{2}As_{2}.

Understanding magnetic interactions in the parent compounds of high-temperature superconductors forms the basis for determining their role for the mechanism of superconductivity. For parent compounds of iron pnictide superconductors such as AFe_{2}As_{2} (A=Ba, Ca, Sr), although spin excitations have been mapped out throughout the entire Brillouin zone, the respective measurements were carried out on twinned samples and did not allow for a conclusive determination of the spin dynamics. Here we use inelastic neutron scattering to completely map out spin excitations of ∼100% detwinned BaFe_{2}As_{2}. By comparing observed spectra with theoretical calculations, we conclude that the spin excitations can be well described by an itinerant model when taking into account moderate electronic correlation effects.

Raising the Critical Temperature by Disorder in Unconventional Superconductors Mediated by Spin Fluctuations.

We propose a mechanism whereby disorder can enhance the transition temperature T_{c} of an unconventional superconductor with pairing driven by exchange of spin fluctuations. The theory is based on a self-consistent real space treatment of pairing in the disordered one-band Hubbard model. It has been demonstrated before that impurities can enhance pairing by softening the spin fluctuations locally; here, we consider the competing effect of pair breaking by the screened Coulomb potential also present. We show that, depending on the impurity potential strength and proximity to magnetic order, this mechanism results in a weakening of the disorder-dependent T_{c}-suppression rate expected from Abrikosov-Gor'kov theory, or even in disorder-generated T_{c} enhancements.

Spin-Orbit Coupling and Magnetic Anisotropy in Iron-Based Superconductors.

We determine theoretically the effect of spin-orbit coupling on the magnetic excitation spectrum of itinerant multiorbital systems, with specific application to iron-based superconductors. Our microscopic model includes a realistic ten-band kinetic Hamiltonian, atomic spin-orbit coupling, and multiorbital Hubbard interactions. Our results highlight the remarkable variability of the resulting magnetic anisotropy despite constant spin-orbit coupling. At the same time, the magnetic anisotropy exhibits robust universal behavior upon changes in the band structure corresponding to different materials of iron-based superconductors. A natural explanation of the observed universality emerges when considering optimal nesting as a resonance phenomenon. Our theory is also of relevance to other itinerant systems with spin-orbit coupling and nesting tendencies in the band structure.

Emergent Magnetic Degeneracy in Iron Pnictides due to the Interplay between Spin-Orbit Coupling and Quantum Fluctuations.

Recent experiments in iron pnictide superconductors reveal that, as the putative magnetic quantum critical point is approached, different types of magnetic order coexist over a narrow region of the phase diagram. Although these magnetic configurations share the same wave vectors, they break distinct symmetries of the lattice. Importantly, the highest superconducting transition temperature takes place close to this proliferation of near-degenerate magnetic states. In this Letter, we employ a renormalization group calculation to show that such a behavior naturally arises due to the effects of spin-orbit coupling on the quantum magnetic fluctuations. Formally, the enhanced magnetic degeneracy near the quantum critical point is manifested as a stable Gaussian fixed point with a large basin of attraction. Implications of our findings to the superconductivity of the iron pnictides are also discussed.

Imaging the real space structure of the spin fluctuations in an iron-based superconductor.

Spin fluctuations are a leading candidate for the pairing mechanism in high temperature superconductors, supported by the common appearance of a distinct resonance in the spin susceptibility across the cuprates, iron-based superconductors and many heavy fermion materials. The information we have about the spin resonance comes almost exclusively from neutron scattering. Here we demonstrate that by using low-temperature scanning tunnelling microscopy and spectroscopy we can characterize the spin resonance in real space. We show that inelastic tunnelling leads to the characteristic dip-hump feature seen in tunnelling spectra in high temperature superconductors and that this feature arises from excitations of the spin fluctuations. Spatial mapping of this feature near defects allows us to probe non-local properties of the spin susceptibility and to image its real space structure.

Scanning tunnelling spectroscopy as a probe of multi-Q magnetic states of itinerant magnets.

The combination of electronic correlations and Fermi surfaces with multiple nesting vectors can lead to the appearance of complex multi-Q magnetic ground states, hosting unusual states such as chiral density waves and quantum Hall insulators. Distinguishing single-Q and multi-Q magnetic phases is however a notoriously difficult experimental problem. Here we propose theoretically that the local density of states (LDOS) near a magnetic impurity, whose orientation may be controlled by an external magnetic field, can be used to map out the detailed magnetic configuration of an itinerant system and distinguish unambiguously between single-Q and multi-Q phases. We demonstrate this concept by computing and contrasting the LDOS near a magnetic impurity embedded in three different magnetic ground states relevant to iron-based superconductors-one single-Q and two double-Q phases. Our results open a promising avenue to investigate the complex magnetic configurations in itinerant systems via standard scanning tunnelling spectroscopy, without requiring spin-resolved capability.