Out-of-equilibrium charge redistribution in a copper-oxide based superconductor by time-resolved X-ray photoelectron spectroscopy

Charge-transfer excitations are of paramount importance for understanding the electronic structure of copper-oxide based high-temperature superconductors. In this study, we investigate the response of a Bi$_2$Sr$_2$CaCu$_2$O$_{\mathrm{8}+ \delta}$ crystal to the charge redistribution induced by an infrared ultrashort pulse. Element-selective time-resolved core-level photoelectron spectroscopy with a high energy resolution allows disentangling the dynamics of oxygen ions with different coordination and bonds thanks to their different chemical shifts. Our experiment shows that the O\,$1s$ component arising from the Cu-O planes is significantly perturbed by the infrared light pulse. Conversely, the apical oxygen, also coordinated with Sr ions in the Sr-O planes, remains unaffected. This result highlights the peculiar behavior of the electronic structure of the Cu-O planes. It also unlocks the way to study the out-of-equilibrium electronic structure of copper-oxide-based high-temperature superconductors by identifying the O\,$1s$ core-level emission originating from the oxygen ions in the Cu-O planes. This ability could be critical to gain information about the strongly-correlated electron ultrafast dynamical mechanisms in the Cu-O plane in the normal and superconducting phases

New insights into the laser-assisted photoelectric effect from solid-state surfaces

Photoemission from a solid surface provides a wealth of information about the electronic structure of the surface and its dynamic evolution. Ultrafast pump-probe experiments are particularly useful to study the dynamic interactions of photons with surfaces as well as the ensuing electron dynamics induced by these interactions. Time-resolved laser-assisted photoemission (tr-LAPE) from surfaces is a novel technique to gain deeper understanding of the fundamentals underlying the photoemission process. Here, we present the results of a femtosecond time-resolved soft X-ray photoelectron spectroscopy experiment on two different metal surfaces conducted at the X-ray Free-Electron Laser FLASH in Hamburg. We study photoemission from the W 4f and Pt 4f core levels using ultrashort soft X-ray pulses in combination with synchronized infrared (IR) laser pulses. When both pulses overlap in time and space, laser-assisted photoemission results in the formation of a series of sidebands that reflect the dynamics of the laser-surface interaction. We demonstrate a qualitatively new level of sideband generation up to the sixth order and a surprising material dependence of the number of sidebands that has so far not been predicted by theory. We provide a semi-quantitative explanation of this phenomenon based on the different dynamic dielectric responses of the two materials. Our results advance the understanding of the LAPE process and reveal new details of the IR field present in the surface region, which is determined by the dynamic interplay between the IR laser field and the dielectric response of the metal surfaces.Comment: 18 pages, 3 figure

Assessment of synaptic loss in mouse models of β-amyloid and tau pathology using [18F]UCB-H PET imaging

Objective: In preclinical research, the use of [F-18]Fluorodesoxyglucose (FDG) as a biomarker for neuro-degeneration may induce bias due to enhanced glucose uptake by immune cells. In this study, we sought to investigate synaptic vesicle glycoprotein 2A (SV2A) PET with [F-18]UCB-H as an alternative preclinical biomarker for neurodegenerative processes in two mouse models representing the pathological hallmarks of Alzheimer's disease (AD). Methods: A total of 29 PS2APP, 20 P301S and 12 wild-type mice aged 4.4 to 19.8 months received a dynamic [F-18]UCB-H SV2A-PET scan (14.7 +/- 1.5 MBq) 0-60 min post injection. Quantification of tracer uptake in cortical, cerebellar and brainstem target regions was implemented by calculating relative volumes of distribution (V-T) from an image-derived-input-function (IDIF). [F-18]UCB-H binding was compared across all target regions between transgenic and wild-type mice. Additional static scans were performed in a subset of mice to compare [F-18]FDG and [F-18]GE180 (18 kDa translocator protein tracer as a surrogate for microglial activation) standardized uptake values (SUV) with [F-18]UCB-H binding at different ages. Following the final scan, a subset of mouse brains was immunohistochemically stained with synaptic markers for gold standard validation of the PET results. Results: [F-18]UCB-H binding in all target regions was significantly reduced in 8-months old P301S transgenic mice when compared to wild-type controls (temporal lobe: p = 0.014;cerebellum: p = 0.0018;brainstem: p = 0.0014). Significantly lower SV2A tracer uptake was also observed in 13-months (temporal lobe: p = 0.0080;cerebellum: p = 0.006) and 19-months old (temporal lobe: p = 0.0042;cerebellum: p = 0.011) PS2APP transgenic versus wild-type mice, whereas the brainstem revealed no significantly altered [F-18]UCB-H binding. Immunohistochemical analyses of post-mortem mouse brain tissue confirmed the SV2A PET findings. Correlational analyses of [F-18]UCB-H and [F-18]FDG using Pearson's correlation coefficient revealed a significant negative association in the PS2APP mouse model (R = -0.26, p = 0.018). Exploratory analyses further stressed microglial activation as a potential reason for this inverse relationship, since [F-18]FDG and [F-18]GE180 quantification were positively correlated in this cohort (R = 0.36, p = 0.0076). Conclusion: [F-18]UCB-H reliably depicts progressive synaptic loss in PS2APP and P301S transgenic mice, potentially qualifying as a more reliable alternative to [F-18]FDG as a biomarker for assessment of neuro-degeneration in preclinical research

Depletion and activation of microglia impact metabolic connectivity of the mouse brain

AimWe aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG-PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated.Materials and methodsWe analyzed metabolic networks measured by interregional correlation coefficients (ICCs) of FDG-PET scans in WT mice and in mice with mutations in progranulin (Grn) or triggering receptor expressed on myeloid cells 2 (Trem2) knockouts ((-/-)) as well as in double mutant Grn(-/-)/Trem2(-/-) mice. We selected those rodent models as they represent opposite microglial signatures with disease associated microglia in Grn(-/-) mice and microglia locked in a homeostatic state in Trem2(-/-) mice;however, both resulting in lower glucose uptake of the brain. The direct influence of microglia on metabolic networks was further determined by microglia depletion using a CSF1R inhibitor in WT mice at two different ages. Within maps of global mean scaled regional FDG uptake, 24 pre-established volumes of interest were applied and assigned to either cortical or subcortical networks. ICCs of all region pairs were calculated and z-transformed prior to group comparisons. FDG uptake of neurons, microglia, and astrocytes was determined in Grn(-/-) and WT mice via assessment of single cell tracer uptake (scRadiotracing).ResultsMicroglia depletion by CSF1R inhibition resulted in a strong decrease of metabolic connectivity defined by decrease of mean cortical ICCs in WT mice at both ages studied (6-7 m;p = 0.0148, 9-10 m;p = 0.0191), when compared to vehicle-treated age-matched WT mice. Grn(-/-), Trem2(-/-) and Grn(-/-)/Trem2(-/-) mice all displayed reduced FDG-PET signals when compared to WT mice. However, when analyzing metabolic networks, a distinct increase of ICCs was observed in Grn(-/-) mice when compared to WT mice in cortical (p < 0.0001) and hippocampal (p < 0.0001) networks. In contrast, Trem2(-/-) mice did not show significant alterations in metabolic connectivity when compared to WT. Furthermore, the increased metabolic connectivity in Grn(-/-) mice was completely suppressed in Grn(-/-)/Trem2(-/-) mice. Grn(-/-) mice exhibited a severe loss of neuronal FDG uptake (- 61%, p < 0.0001) which shifted allocation of cellular brain FDG uptake to microglia (42% in Grn(-/-) vs. 22% in WT).ConclusionsPresence, absence, and activation of microglia have a strong impact on metabolic connectivity of the mouse brain. Enhanced metabolic connectivity is associated with increased microglial FDG allocation

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma;however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands

Observation of time-reversal symmetry breaking in the band structure of altermagnetic RuO 2

Altermagnets are an emerging elementary class of collinear magnets. Unlike ferromagnets, their distinct crystal symmetries inhibit magnetization while, unlike antiferromagnets, they promote strong spin polarization in the band structure. The corresponding unconventional mechanism of time-reversal symmetry breaking without magnetization in the electronic spectra has been regarded as a primary signature of altermagnetism but has not been experimentally visualized to date. We directly observe strong time-reversal symmetry breaking in the band structure of altermagnetic RuO2 by detecting magnetic circular dichroism in angle-resolved photoemission spectra. Our experimental results, supported by ab initio calculations, establish the microscopic electronic structure basis for a family of interesting phenomena and functionalities in fields ranging from topological matter to spintronics, which are based on the unconventional time-reversal symmetry breaking in altermagnets

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Multispectral time-resolved energy-momentum microscopy using high-harmonic extreme ultraviolet radiation

A 790-nm-driven high-harmonic generation source with a repetition rate of 6 kHz is combined with a toroidal-grating monochromator and a high-detection-efficiency photoelectron time-of-flight momentum microscope to enable time- and momentum-resolved photoemission spectroscopy over a spectral range of 23.6–45.5 eV with sub-100 fs time resolution. Three-dimensional (3D) Fermi surface mapping is demonstrated on graphene-covered Ir(111) with energy and momentum resolutions of ≲100 meV and ≲0.1 Å$^{−1}$, respectively. The tabletop experiment sets the stage for measuring the k$_z$-dependent ultrafast dynamics of 3D electronic structure, including band structure, Fermi surface, and carrier dynamics in 3D materials as well as 3D orbital dynamics in molecular layer