Noise-dependent bias in quantitative STEM-EMCD experiments revealed by bootstrapping.

Electron magnetic circular dichroism (EMCD) is a powerful technique for estimating element-specific magnetic moments of materials on nanoscale with the potential to reach atomic resolution in transmission electron microscopes. However, the fundamentally weak EMCD signal strength complicates quantification of magnetic moments, as this requires very high precision, especially in the denominator of the sum rules. Here, we employ a statistical resampling technique known as bootstrapping to an experimental EMCD dataset to produce an empirical estimate of the noise-dependent error distribution resulting from application of EMCD sum rules to bcc iron in a 3-beam orientation. We observe clear experimental evidence that noisy EMCD signals preferentially bias the estimation of magnetic moments, further supporting this with error distributions produced by Monte-Carlo simulations. Finally, we propose guidelines for the recognition and minimization of this bias in the estimation of magnetic moments.

Enantioselective Adsorption on Magnetic Surfaces.

From the beginning of molecular theory, the interplay of chirality and magnetism has intrigued scientists. There is still the question if enantiospecific adsorption of chiral molecules occurs on magnetic surfaces. Enantiomer discrimination was conjectured to arise from chirality-induced spin separation within the molecules and exchange interaction with the substrate's magnetization. Here, it is shown that single helical aromatic hydrocarbons undergo enantioselective adsorption on ferromagnetic cobalt surfaces. Spin and chirality sensitive scanning tunneling microscopy reveals that molecules of opposite handedness prefer adsorption onto cobalt islands with opposite out-of-plane magnetization. As mobility ceases in the final chemisorbed state, it is concluded that enantioselection must occur in a physisorbed transient precursor state. State-of-the-art spin-resolved ab initio simulations support this scenario by refuting enantio-dependent chemisorption energies. These findings demonstrate that van der Waals interaction should also include spin-fluctuations which are crucial for molecular magnetochiral processes.

Spin-Selective Electron Transport Through Single Chiral Molecules.

The interplay between chirality and magnetism is a source of fascination among scientists for over a century. In recent years, chirality-induced spin selectivity (CISS) has attracted renewed interest. It is observed that electron transport through layers of homochiral molecules leads to a significant spin polarization of several tens of percent. Despite the abundant experimental evidence gathered through mesoscopic transport measurements, the exact mechanism behind CISS remains elusive. This study reports spin-selective electron transport through single helical aromatic hydrocarbons that are sublimed in vacuo onto ferromagnetic cobalt surfaces and examined with spin-polarized scanning tunneling microscopy (SP-STM) at a temperature of 5 K. Direct comparison of two enantiomers under otherwise identical conditions revealed magnetochiral conductance asymmetries of up to 50% when either the molecular handedness is exchanged or the magnetization direction of the STM tip or Co substrate is reversed. Importantly, the results rule out electron-phonon coupling and ensemble effects as primary mechanisms responsible for CISS.

Neutron-activated, plasmonically excitable Fe-Pt-Yb2O3 nanoparticles delivering anti-cancer radiation against human glioblastoma cells.

Magnetic nanoparticles can be functionalized in many ways for biomedical applications. Here, we combine four advantageous features in a novel Fe-Pt-Yb2O3 core-shell nanoparticle. (a) The nanoparticles have a size of 10 nm allowing them to diffuse through neuronal tissue. (b) The particles are superparamagnetic after synthesis and ferromagnetic after annealing, enabling directional control by magnetic fields, enhance NMRI contrast, and hyperthermia treatment. (c) After neutron-activation of the shell, they carry low-energetic, short half-life ß-radiation from 175Yb, 177Yb, and 177Lu. (d) Additionally, the particles can be optically visualized by plasmonic excitation and luminescence. To demonstrate the potential of the particles for cancer treatment, we exposed cultured human glioblastoma cells (LN-18) to non-activated and activated particles to confirm that the particles are internalized, and that the ß-radiation of the radioisotopes incorporated in the neutron-activated shell of the nanoparticles kills more than 98% of the LN-18 cancer cells, promising for future anti-cancer applications.

Soft X-ray Fermi surface tomography of palladium and rhodium via momentum microscopy.

Fermi surfaces of transition metals, which describe all thermodynamical and transport quantities of solids, often fail to be modeled by one-electron mean-field theory due to strong correlations among the valence electrons. In addition, relativistic spin-orbit coupling pronounced in heavier elements lifts the degeneracy of the energy bands and further modifies the Fermi surface. Palladium and rhodium, two 4d metals attributed to show significant spin-orbit coupling and electron correlations, are ideal for a systematic and fundamental study of the two fundamental physical phenomena and their interplay in the electronic structure. In this study, we explored the Fermi surface of the 4d noble metals palladium and rhodium obtained via high-resolution constant initial state momentum microscopy. The complete 3D-Fermi surfaces of palladium and rhodium were tomographically mapped using soft X-ray photon energies from 34 eV up to 660 eV. To fully capture the orbital angular momentum of states across the Fermi surface, the Fermi surface tomography was performed using p- and s- polarized light. Applicability and limitations of the nearly-free electron final state model in photoemission are discussed using a complex band structure model supported by experimental evidence. The significance of spin-orbit coupling and electron correlations across the Fermi surfaces will be discussed within the context of the photoemission results. State-of-the-art fully relativistic Korringa-Kohn-Rostoker (KKR) calculations within the one-step model of photoemission are used to support the experimental results.

Long-Term Total Neoadjuvant Therapy Leads to Impressive Response Rates in Rectal Cancer: Results of a German Single-Center Cohort.

Intensified preoperative chemotherapy after (chemo)radiotherapy, (Total Neoadjuvant Therapy-TNT), increases pathological complete response (pCR) rates and local control. In cases of clinically complete response (cCR) and close follow-up, non-operative management (NOM) is feasible. We report early outcomes and toxicities of a long-term TNT regime in a single-center cohort. Fifteen consecutive patients with distal or middle-third locally advanced rectal cancer (UICC stage II-III) were investigated, who received neoadjuvant chemoradiotherapy (total adsorbed dose: 50.4 Gy in 28 fractions and two concomitant courses 5-fluorouracil (250 mg/m2/d)/oxaliplatin (50 mg/m2), followed by consolidating chemotherapy (nine courses of FOLFOX4). NOM was offered if staging revealed cCR 2 months after TNT, with resection performed otherwise. The primary endpoint was complete response (pCR + cCR). Treatment-related side effects were quantified for up two years after TNT. Ten patients achieved cCR, of whom five opted for NOM. Ten patients (five cCR and five non-cCR) underwent surgery, with pCR confirmed in the five patients with cCR. The main toxicities comprised leukocytopenia (13/15), fatigue (12/15) and polyneuropathy (11/15). The most relevant CTC °III + IV events were leukocytopenia (4/15), neutropenia (2/15) and diarrhea (1/15). The long-term TNT regime resulted in promising response rates that are higher than the response rates of short TNT regimes. Overall tolerability and toxicity were comparable with the results of prospective trials.

Surface-Mediated Spin Locking and Thermal Unlocking in a 2D Molecular Array.

Molecule-based functional devices may take advantage of surface-mediated spin state bistability. Whereas different spin states in conventional spin crossover complexes are only accessible at temperatures well below room temperature, and the lifetimes of the high-spin state are relatively short, a different behavior exhibited by prototypical nickel phthalocyanine is shown here. Direct interaction of the organometallic complex with a copper metal electrode mediates the coexistence of a high spin and a low spin state within the 2D molecular array. The spin state bistability is extremely non-volatile, since no external stimuli are required to preserve it. It originates from the surface-induced axial displacement of the functional nickel cores, which generates two stable local minima. Spin state unlocking and the full conversion to the low spin state are only possible by a high temperature stimulus. This spin state transition is accompanied by distinct changes in the molecular electronic structure that might facilitate the state readout at room temperature, as evidenced by valence spectroscopy. The non-volatility of the high spin state up to elevated temperatures and the controllable spin bistability render the system extremely intriguing for applications in molecule-based information storage devices.

Geometry-Induced Spin Filtering in Photoemission Maps from WTe_{2} Surface States.

We demonstrate that an important quantum material WTe_{2} exhibits a new type of geometry-induced spin filtering effect in photoemission, stemming from low symmetry that is responsible for its exotic transport properties. Through the laser-driven spin-polarized angle-resolved photoemission Fermi surface mapping, we showcase highly asymmetric spin textures of electrons photoemitted from the surface states of WTe_{2}. Such asymmetries are not present in the initial state spin textures, which are bound by the time-reversal and crystal lattice mirror plane symmetries. The findings are reproduced qualitatively by theoretical modeling within the one-step model photoemission formalism. The effect could be understood within the free-electron final state model as an interference due to emission from different atomic sites. The observed effect is a manifestation of time-reversal symmetry breaking of the initial state in the photoemission process, and as such it cannot be eliminated, but only its magnitude influenced, by special experimental geometries.

Two C18 hydroxy-cyclohexenone fatty acids from mammalian epidermis: Potential relation to 12R-lipoxygenase and covalent binding of ceramides.

A key requirement in forming the water permeability barrier in the mammalian epidermis is the oxidation of linoleate esterified in a skin-specific acylceramide by the sequential actions of 12R-lipoxygenase, epidermal lipoxygenase-3, and the epoxyalcohol dehydrogenase SDR9C7 (short-chain dehydrogenase-reductase family 7 member 9). By mechanisms that remain unclear, this oxidation pathway promotes the covalent binding of ceramides to protein, forming a critical structure of the epidermal barrier, the corneocyte lipid envelope. Here, we detected, in porcine, mouse, and human epidermis, two novel fatty acid derivatives formed by KOH treatment from precursors covalently bound to protein: a "polar" lipid chromatographing on normal-phase HPLC just before omega-hydroxy ceramide and a "less polar" lipid nearer the solvent front. Approximately 100 µg of the novel lipids were isolated from porcine epidermis, and the structures were established by UV-spectroscopy, LC-MS, GC-MS, and NMR. Each is a C18 fatty acid and hydroxy-cyclohexenone with the ring on carbons C9-C14 in the polar lipid and C8-C13 in the less polar lipid. Overnight culture of [14C]linoleic acid with whole mouse skin ex vivo led to recovery of the 14C-labeled hydroxy-cyclohexenones. We deduce they are formed from covalently bound precursors during the KOH treatment used to release esterified lipids. KOH-induced intramolecular aldol reactions from a common precursor can account for their formation. Discovery of these hydroxy-cyclohexenones presents an opportunity for a reverse pathway analysis, namely to work back from these structures to identify their covalently bound precursors and relationship to the linoleate oxidation pathway.

Diagnostic Image Quality of a Low-Field (0.55T) Knee MRI Protocol Using Deep Learning Image Reconstruction Compared with a Standard (1.5T) Knee MRI Protocol.

OBJECTIVES: Low-field MRI at 0.55 Tesla (T) with deep learning image reconstruction has recently become commercially available. The objective of this study was to evaluate the image quality and diagnostic reliability of knee MRI performed at 0.55T compared with 1.5T. METHODS: A total of 20 volunteers (9 female, 11 male; mean age = 42 years) underwent knee MRI on a 0.55T system (MAGNETOM Free.Max, Siemens Healthcare, Erlangen, Germany; 12-channel Contour M Coil) and a 1.5T scanner (MAGNETOM Sola, Siemens Healthcare, Erlangen, Germany; 18-channel transmit/receive knee coil). Standard two-dimensional (2D) turbo spin echo (TSE), fat-suppressed (fs) proton density-weighted (PDw), T1w TSE, and T2w TSE sequences were acquired in approximately 15 min. In total, 2 radiologists blinded to the field strength subjectively assessed all MRI sequences (overall image quality, image noise, and diagnostic quality) using a 5-point Likert scale (1-5; 5 = best). Additionally, both radiologists evaluated the possible pathologies of menisci, ligaments, and cartilage. Contrast ratios (CRs) of different tissues (bone, cartilage, and menisci) were determined on coronal PDw fs TSE images. The statistical analysis included Cohen's kappa and the Wilcoxon rank sum test. RESULTS: The overall image quality of the 0.55T T2w, T1w, and PDw fs TSE sequences was diagnostic and rated similar for T1w (p > 0.05), but lower for PDw fs TSE and T2w TSE compared with 1.5T (p < 0.05). The diagnostic accordance of meniscal and cartilage pathologies at 0.55T was similar to 1.5T. The CRs of the tissues were not significantly different between 1.5T and 0.55T (p > 0.05). The inter-observer agreement of the subjective image quality was generally fair between both readers and almost perfect for the pathologies. CONCLUSIONS: Deep learning-reconstructed TSE imaging at 0.55T yielded diagnostic image quality for knee MRI compared with standard 1.5T MRI. The diagnostic performance of meniscal and cartilage pathologies was equal for 0.55T and 1.5T without a significant loss of diagnostic information.

The 5-lipoxygenase/cyclooxygenase-2 cross-over metabolite, hemiketal E2, enhances VEGFR2 activation and promotes angiogenesis.

Consecutive oxygenation of arachidonic acid by 5-lipoxygenase and cyclooxygenase-2 yields the hemiketal eicosanoids, HKE2 and HKD2. Hemiketals stimulate angiogenesis by inducing endothelial cell tubulogenesis in culture; however, how this process is regulated has not been determined. Here, we identify vascular endothelial growth factor receptor 2 (VEGFR2) as a mediator of HKE2-induced angiogenesis in vitro and in vivo. We found that HKE2 treatment of human umbilical vein endothelial cells dose-dependently increased the phosphorylation of VEGFR2 and the downstream kinases ERK and Akt that mediated endothelial cell tubulogenesis. In vivo, HKE2 induced the growth of blood vessels into polyacetal sponges implanted in mice. HKE2-mediated effects in vitro and in vivo were blocked by the VEGFR2 inhibitor vatalanib, indicating that the pro-angiogenic effect of HKE2 was mediated by VEGFR2. HKE2 covalently bound and inhibited PTP1B, a protein tyrosine phosphatase that dephosphorylates VEGFR2, thereby providing a possible molecular mechanism for how HKE2 induced pro-angiogenic signaling. In summary, our studies indicate that biosynthetic cross-over of the 5-lipoxygenase and cyclooxygenase-2 pathways gives rise to a potent lipid autacoid that regulates endothelial cell function in vitro and in vivo. These findings suggest that common drugs targeting the arachidonic acid pathway could prove useful in antiangiogenic therapy.

Deposition of Chiral Heptahelicene Molecules on Ferromagnetic Co and Fe Thin-Film Substrates.

The discovery of chirality-induced spin selectivity (CISS), resulting from an interaction between the electron spin and handedness of chiral molecules, has sparked interest in surface-adsorbed chiral molecules due to potential applications in spintronics, enantioseparation, and enantioselective chemical or biological processes. We study the deposition of chiral heptahelicene by sublimation under ultra-high vacuum onto bare Cu(111), Co bilayer nanoislands on Cu(111), and Fe bilayers on W(110) by low-temperature spin-polarized scanning tunneling microscopy/spectroscopy (STM/STS). In all cases, the molecules remain intact and adsorb with the proximal phenanthrene group aligned parallel to the surface. Three degenerate in-plane orientations on Cu(111) and Co(111), reflecting substrate symmetry, and only two on Fe(110), i.e., fewer than symmetry permits, indicate a specific adsorption site for each substrate. Heptahelicene physisorbs on Cu(111) but chemisorbs on Co(111) and Fe(110) bilayers, which nevertheless remain for the sub-monolayer coverage ferromagnetic and magnetized out-of-plane. We are able to determine the handedness of individual molecules chemisorbed on Fe(110) and Co(111), as previously reported for less reactive Cu(111). The demonstrated deposition control and STM/STS imaging capabilities for heptahelicene on Co/Cu(111) and Fe/W(110) substrate systems lay the foundation for studying CISS in ultra-high vacuum and on the microscopic level of single molecules in controlled atomic configurations.

Conservation of Nickel Ion Single-Active Site Character in a Bottom-Up Constructed π-Conjugated Molecular Network.

On-surface chemistry holds the potential for ultimate miniaturization of functional devices. Porphyrins are promising building-blocks in exploring advanced nanoarchitecture concepts. More stable molecular materials of practical interest with improved charge transfer properties can be achieved by covalently interconnecting molecular units. On-surface synthesis allows to construct extended covalent nanostructures at interfaces not conventionally available. Here, we address the synthesis and properties of covalent molecular network composed of interconnected constituents derived from halogenated nickel tetraphenylporphyrin on Au(111). We report that the π-extended two-dimensional material exhibits dispersive electronic features. Concomitantly, the functional Ni cores retain the same single-active site character of their single-molecule counterparts. This opens new pathways when exploiting the high robustness of transition metal cores provided by bottom-up constructed covalent nanomeshes.

Spanning Fermi arcs in a two-dimensional magnet.

The discovery of topological states of matter has led to a revolution in materials research. When external or intrinsic parameters break symmetries, global properties of topological materials change drastically. A paramount example is the emergence of Weyl nodes under broken inversion symmetry. While a rich variety of non-trivial quantum phases could in principle also originate from broken time-reversal symmetry, realizing systems that combine magnetism with complex topological properties is remarkably elusive. Here, we demonstrate that giant open Fermi arcs are created at the surface of ultrathin hybrid magnets where the Fermi-surface topology is substantially modified by hybridization with a heavy-metal substrate. The interplay between magnetism and topology allows us to control the shape and the location of the Fermi arcs by tuning the magnetization direction. The hybridization points in the Fermi surface can be attributed to a non-trivial mixed topology and induce hot-spots in the Berry curvature, dominating spin and charge transport as well as magneto-electric coupling effects.

Ornithine Decarboxylase in Gastric Epithelial Cells Promotes the Immunopathogenesis of Helicobacter pylori Infection.

Colonization by Helicobacter pylori is associated with gastric diseases, ranging from superficial gastritis to more severe pathologies, including intestinal metaplasia and adenocarcinoma. The interplay of the host response and the pathogen affect the outcome of disease. One major component of the mucosal response to H. pylori is the activation of a strong but inefficient immune response that fails to control the infection and frequently causes tissue damage. We have shown that polyamines can regulate H. pylori-induced inflammation. Chemical inhibition of ornithine decarboxylase (ODC), which generates the polyamine putrescine from l-ornithine, reduces gastritis in mice and adenocarcinoma incidence in gerbils infected with H. pylori However, we have also demonstrated that Odc deletion in myeloid cells enhances M1 macrophage activation and gastritis. Here we used a genetic approach to assess the specific role of gastric epithelial ODC during H. pylori infection. Specific deletion of the gene encoding for ODC in gastric epithelial cells reduces gastritis, attenuates epithelial proliferation, alters the metabolome, and downregulates the expression of immune mediators induced by H. pylori Inhibition of ODC activity or ODC knockdown in human gastric epithelial cells dampens H. pylori-induced NF-κB activation, CXCL8 mRNA expression, and IL-8 production. Chronic inflammation is a major risk factor for the progression to more severe pathologies associated with H. pylori infection, and we now show that epithelial ODC plays an important role in mediating this inflammatory response.

Cystathionine γ-lyase exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation.

Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world's population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme cystathionine γ-lyase (CTH) is upregulated in humans and mice with H. pylori infection. Here, we show that induction of CTH in macrophages by H. pylori promoted persistent inflammation. Cth-/- mice had reduced macrophage and T cell activation in H. pylori-infected tissues, an altered metabolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori-induced gastritis. CTH is downstream of the proposed antiinflammatory molecule, S-adenosylmethionine (SAM). Whereas Cth-/- mice exhibited gastric SAM accumulation, WT mice treated with SAM did not display protection against H. pylori-induced inflammation. Instead, we demonstrated that Cth-deficient macrophages exhibited alterations in the proteome, decreased NF-κB activation, diminished expression of macrophage activation markers, and impaired oxidative phosphorylation and glycolysis. Thus, through altering cellular respiration, CTH is a key enhancer of macrophage activation, contributing to a pathogenic inflammatory response that is the universal precursor for the development of H. pylori-induced gastric disease.

Scaling and Confinement in Ultrathin Chalcogenide Films as Exemplified by GeTe.

Chalcogenides such as GeTe, PbTe, Sb2 Te3 , and Bi2 Se3 are characterized by an unconventional combination of properties enabling a plethora of applications ranging from thermo-electrics to phase change materials, topological insulators, and photonic switches. Chalcogenides possess pronounced optical absorption, relatively low effective masses, reasonably high electron mobilities, soft bonds, large bond polarizabilities, and low thermal conductivities. These remarkable characteristics are linked to an unconventional bonding mechanism characterized by a competition between electron delocalization and electron localization. Confinement, that is, the reduction of the sample dimension as realized in thin films should alter this competition and modify chemical bonds and the resulting properties. Here, pronounced changes of optical and vibrational properties are demonstrated for crystalline films of GeTe, while amorphous films of GeTe show no similar thickness dependence. For crystalline films, this thickness dependence persists up to remarkably large thicknesses above 15 nm. X-ray diffraction and accompanying simulations employing density functional theory relate these changes to thickness dependent structural (Peierls) distortions, due to an increased electron localization between adjacent atoms upon reducing the film thickness. A thickness dependence and hence potential to modify film properties for all chalcogenide films with a similar bonding mechanism is expected.

Disproportionation of Nitric Oxide at a Surface-Bound Nickel Porphyrinoid.

Uncommon metal oxidation states in porphyrinoid cofactors are responsible for the activity of many enzymes. The F430 and P450nor co-factors, with their reduced NiI - and FeIII -containing tetrapyrrolic cores, are prototypical examples of biological systems involved in methane formation and in the reduction of nitric oxide, respectively. Herein, using a comprehensive range of experimental and theoretical methods, we raise evidence that nickel tetraphenyl porphyrins deposited in vacuo on a copper surface are reactive towards nitric oxide disproportionation at room temperature. The interpretation of the measurements is far from being straightforward due to the high reactivity of the different nitrogen oxides species (eventually present in the residual gas background) and of the possible reaction intermediates. The picture is detailed in order to disentangle the challenging complexity of the system, where even a small fraction of contamination can change the scenario.

Curcumin activates G protein-coupled receptor 97 (GPR97) in a manner different from glucocorticoid.

Curcumin is a yellow pigment in turmeric (Curcuma longa) with various physiological effects in the body. To elucidate the molecular mechanisms by which bioactive compounds exert their function, identification of their molecular targets is crucial. In this study, we show that curcumin activates G protein-coupled receptor 97 (GPR97). Curcumin dose-dependently activated serum-response element-, but not serum-response factor-response element-, nuclear factor of activated T-cell-response element-, or cAMP-response element-, mediated transcription in cells overexpressed with GPR97. The structure-activity relationship indicated that (i) the double-bonds of the central 7-carbon chain were essential for activation; (ii) a methoxy group on the aromatic ring was required for maximal activity; (iii) the addition of glucuronic acid moiety or a methoxy group to the aromatic ring, but not the methylation of the aromatic p-hydroxy group, eliminated the activity; (iv) the stability of curcumin would be related to receptor activation. Both mutant GPR97(T250A) lacking the cleavage at GPCR proteolysis site and mutant GPR97(ΔN) lacking the N-terminal extracellular region were activated by curcumin and its related compounds similar to wild-type GPR97. In contrast, the synthetic glucocorticoid beclomethasone dipropionate and l-Phe activated wild-type GPR97 and GPR97(T250A), but not GPR97(ΔN). Moreover, curcumin exerted an additive effect on the activation of wild-type GPR97 with beclomethasone dipropionate, but not with l-Phe. Taken together, these results indicate that curcumin activates GPR97 coupled to Gi/Go subunit, and suggest that curcumin and glucocorticoid activate GPR97 in a different manner.