Transport-Associated Vibrational Stress Triggers Drug-Reversible Apoptosis and Cardiac Allograft Failure in Mice.

Increasingly complex and long-range donor organ allocation routes coupled with implementation of unmanned aerial vehicles (UAVs) have prompted investigations of the conditions affecting organs once packaged for shipment. Our group has previously demonstrated that different modes of organ transport exert unique environmental stressors, in particular vibration. Using a mouse heart transplant model, we demonstrated that vibrational forces exert tangible, cellular effects in the form of cardiomyocyte apoptosis and cytoskeletal derangement. Functionally, these changes translated into accelerated allograft loss. Notably, administration of an apoptosis inhibitor, Z-VAD-FMK, helped to ameliorate the detrimental cellular and functional effects of mechanical vibration in a dose-dependent manner. These findings constitute one of the first reports of the negative impact of transit environment on transplant outcomes, a contributing mechanism underpinning this effect, and a potential agent to prophylax against this process. Given current limitations in measuring donor organ transit environments in situ, further study is required to better characterize the impact of transport environment and to potentially improve the care of donor organs during shipment. Clinical and Translational Impact Statement: We show that apoptosis inhibitor, Z-VAD-FMK, ameliorated transport-related vibrational stress in murine heart transplants, which presents a potential therapeutic or preservation solution additive for future use in transporting donor organs.

Quasi-One-Dimensional Metallicity in Compressed CsSnI3.

Low-dimensional metal halides exhibit strong structural and electronic anisotropies, making them candidates for accessing unusual electronic properties. Here, we demonstrate pressure-induced quasi-one-dimensional (quasi-1D) metallicity in δ-CsSnI3. With the application of pressure up to 40 GPa, the initially insulating δ-CsSnI3 transforms to a metallic state. Synchrotron X-ray diffraction and Raman spectroscopy indicate that the starting 1D chain structure of edge-sharing Sn-I octahedra in δ-CsSnI3 is maintained in the high-pressure metallic phase while the SnI6 octahedral chains are distorted. Our experiments combined with first-principles density functional theory calculations reveal that pressure induces Sn-Sn hybridization and enhances Sn-I coupling within the chain, leading to band gap closure and formation of conductive SnI6 distorted octahedral chains. In contrast, the interchain I...I interactions remain minimal, resulting in a highly anisotropic electronic structure and quasi-1D metallicity. Our study offers a high-pressure approach for achieving diverse electronic platforms in the broad family of low-dimensional metal halides.

Cesium-mediated electron redistribution and electron-electron interaction in high-pressure metallic CsPbI3.

Electron-phonon coupling was believed to govern the carrier transport in halide perovskites and related phases. Here we demonstrate that electron-electron interaction enhanced by Cs-involved electron redistribution plays a direct and prominent role in the low-temperature electrical transport of compressed CsPbI3 and renders Fermi liquid (FL)-like behavior. By compressing δ-CsPbI3 to 80 GPa, an insulator-semimetal-metal transition occurs, concomitant with the completion of a slow structural transition from the one-dimensional Pnma (δ) phase to a three-dimensional Pmn21 (ε) phase. Deviation from FL behavior is observed upon CsPbI3 entering the metallic ε phase, which progressively evolves into a FL-like state at 186 GPa. First-principles density functional theory calculations reveal that the enhanced electron-electron coupling results from the sudden increase of the 5d state occupation in Cs and I atoms. Our study presents a promising strategy of cationic manipulation for tuning the electronic structure and carrier scattering of halide perovskites at high pressure.

Circulating Tumor DNA Identifies Diverse Landscape of Acquired Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Metastatic Colorectal Cancer.

PURPOSE: Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance. METHODS: Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment. RESULTS: ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR (P = .0007), KRAS (P = .0017), LRP1B (P = .0046), ZNF217 (P = .0086), MAP2K1 (P = .018), PIK3CG (P = .018), BRAF (P = .048), and NRAS (P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR (P < .0001), SMO (P < .0001), BRAF (P < .0001), MET (P = .0002), FLT3 (P = .0002), NOTCH4 (P = .0006), ERBB2 (P = .004), and FGFR1 (P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without (P = .010). Although tumor mutation burden (TMB) did not differ pretreatment (P = .63), anti-EGFR exposure increased TMB (P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB (P = .014). CONCLUSION: Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.

Field-tuned ferroquadrupolar quantum phase transition in the insulator TmVO4.

We report results of low-temperature heat-capacity, magnetocaloric-effect, and neutron-diffraction measurements of TmVO4, an insulator that undergoes a continuous ferroquadrupolar phase transition associated with local partially filled 4f orbitals of the thulium (Tm[Formula: see text]) ions. The ferroquadrupolar transition, a realization of Ising nematicity, can be tuned to a quantum critical point by using a magnetic field oriented along the c axis of the tetragonal crystal lattice, which acts as an effective transverse field for the Ising-nematic order. In small magnetic fields, the thermal phase transition can be well described by using a semiclassical mean-field treatment of the transverse-field Ising model. However, in higher magnetic fields, closer to the field-tuned quantum phase transition, subtle deviations from this semiclassical behavior are observed, which are consistent with expectations of quantum fluctuations. Although the phase transition is driven by the local 4f degrees of freedom, the crystal lattice still plays a crucial role, both in terms of mediating the interactions between the local quadrupoles and in determining the critical scaling exponents, even though the phase transition itself can be described via mean field. In particular, bilinear coupling of the nematic order parameter to acoustic phonons changes the spatial and temporal fluctuations of the former in a fundamental way, resulting in different critical behavior of the nematic transverse-field Ising model, as compared to the usual case of the magnetic transverse-field Ising model. Our results establish TmVO4 as a model material and electronic nematicity as a paradigmatic example for quantum criticality in insulators.

Evidence of Magnon-Mediated Orbital Magnetism in a Quasi-2D Topological Magnon Insulator.

We explore spin dynamics in Cu(1,3-bdc), a quasi-2D topological magnon insulator. The results show that the thermal evolution of the Landé g factor (g) is anisotropic: gin-plane decreases while gout-of-plane increases with increasing temperature T. Moreover, the anisotropy of the g factor (Δg) and the anisotropy of saturation magnetization (ΔMs) are correlated below 4 K, but they diverge above 4 K. We show that the electronic orbital moment contributes to the g anisotropy at lower T, while the topological orbital moment induced by thermally excited spin chirality dictates the g anisotropy at higher T. Our work suggests an interplay among topology, spin chirality, and orbital magnetism in Cu(1,3-bdc).

Freezing of the Lattice in the Kagome Lattice Heisenberg Antiferromagnet Zn-Barlowite ZnCu_{3}(OD)_{6}FBr.

We use ^{79}Br nuclear quadrupole resonance (NQR) to demonstrate that ultraslow lattice dynamics set in below the temperature scale set by the Cu-Cu superexchange interaction J (≃160 K) in the kagome lattice Heisenberg antiferromagnet Zn-barlowite. The lattice completely freezes below 50 K, and ^{79}Br NQR line shapes become twice broader due to increased lattice distortions. Moreover, the frozen lattice exhibits an oscillatory component in the transverse spin echo decay, a typical signature of pairing of nuclear spins by indirect nuclear spin-spin interaction. This indicates that some Br sites form structural dimers via a pair of kagome Cu sites prior to the gradual emergence of spin singlets below ∼30 K. Our findings underscore the significant roles played by subtle structural distortions in determining the nature of the disordered magnetic ground state of the kagome lattice.

Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses.

Regulatory T cell (Treg) lymphatic migration is required for resolving inflammation and prolonging allograft survival. Focusing on Treg interactions with lymphatic endothelial cells (LECs), we dissect mechanisms and functional consequences of Treg transendothelial migration (TEM). Using three genetic mouse models of pancreatic islet transplantation, we show that Treg lymphotoxin (LT) αß and LEC LTß receptor (LTßR) signaling are required for efficient Treg migration and suppressive function to prolong allograft survival. Inhibition of LT signaling increases Treg conversion to Foxp3loCD25lo exTregs. In a transwell-based model of TEM across polarized LECs, non-migrated Tregs become exTregs. Such conversion is regulated by LTßR nuclear factor κB (NF-κB) signaling in LECs, which increases interleukin-6 (IL-6) production and drives exTreg conversion. Migrating Tregs are ectonucleotidase CD39hi and resist exTreg conversion in an adenosine-receptor-2A-dependent fashion. Human Tregs migrating across human LECs behave similarly. These molecular interactions can be targeted for therapeutic manipulation of immunity and suppression.

Preclinical studies with ONC201/TIC10 and lurbinectedin as a novel combination therapy in small cell lung cancer (SCLC).

The American Cancer Society estimates that ~15% of all lung cancers are categorized as small cell lung cancer (SCLC) with an overall five-year survival rate of less than 7%. Due to disease aggressiveness, more other malignancies, the standard of care is based on clinical efficacy rather than helpful biomarkers. Lurbinectedin is a small molecule RNA polymerase II inhibitor that binds the minor groove of DNA to induce double-strand breaks. Lurbinectedin has efficacy towards SCLC cells at sub-nM concentration and received accelerated FDA approval in 2020 for metastatic SCLC that progressed on platinum-based therapy. ONC201/TIC10 is a TRAIL pathway-inducing compound that with demonstrated clinical efficacy in H3K27M-mutated diffuse midline glioma and neuroendocrine tumors, in early phase clinical trials. We hypothesized that combining ONC201 and lurbinectedin may yield synergistic and targeted killing of SCLC cells. SCLC cell lines H1048, H1105, H1882, and H1417 were treated with ONC201 and lurbinectedin and cell viability was determined using a CellTiter-Glo assay using varying drug concentrations. Synergistic growth inhibition of SCLC cells was noted with combination of ONC201 and lurbinectedin. Induction of the integrated stress response mediator ATF4 and CHOP was observed with ONC201 and lurbinectedin along with induction of PARP cleavage indicative of apoptosis in response to cellular stress. Additionally, SCLC lines treated with the combination therapy displayed increased DNA breakage-related proteins such as phosphorylated Chk-1, Wee1 and γ-H2AX. Combination index revealed the most potent synergy occurred at the concentrations of 0.16 µM ONC201 and 0.05 nM lurbinectedin in the H1048 cell line, demonstrating highly efficient and selective killing of these tumor cells in vitro. While these therapies showed potency against the cell lines derived from SCLC patients, it is noteworthy that the combination showed significantly less toxicity to healthy human lung epithelial cells. Future studies could explore the combination of ONC201 and lurbinectedin in SCLC cell lines, SCLC patient-derived organoids, other tumor types, including in vivo studies and clinical translation.

A Mobile Health Intervention to Support Parenting Self-Efficacy in the Neonatal Intensive Care Unit from Admission to Home.

OBJECTIVE: To test whether parents of premature infants less than 37 weeks of gestation provided with a unique smartphone app designed to support parents had greater parenting self-efficacy, a key element in parenting confidence, compared with controls. STUDY DESIGN: Using a quasiexperimental, time-lagged study design, parents were assigned to either usual care (control) or NICU2HOME app (intervention) groups. Both groups completed the validated Parenting Sense of Competence (PSOC) scale at 4 time points (approximately day of life 7, 1 day before discharge, and at 14 and 30 days after discharge) representing the neonatal intensive care unit, discharge, and home contexts. App use was described and categorized. Univariate group differences were assessed, and linear mixed effect regression models were used to assess treatment group effect on PSOC score across time, adjusted for covariates and controlling for overall family effect. RESULTS: We enrolled 298 parents (123 control, 175 intervention) with 256 completing 1 or more PSOC screenings. The intervention group had sustained higher PSOC scores than those of the control group (estimate, 4.3; P = .0042) from the first measurement onward with no significant change in PSOC score across time for either group. Average app use was 15 taps per average day; average and above-average users had significantly higher PSOC scores (estimate, 5.16; P = .0024; estimate, 5.16; P = .014) compared with controls or below-average users. CONCLUSIONS: Compared with controls, parents assigned to use the NICU2HOME app reported greater parenting self-efficacy while in the neonatal intensive care unit and this continued once discharged to home. Novel technologies such as point-of-care smartphone applications may hold promise for supporting parents in difficult and stressful situations. TRIAL REGISTRATION: ClincalTrials.gov: NCT03505424.

Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo.

The five-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained a dismal 9% for approximately 40 years with an urgent need for novel therapeutic interventions. ONC201 is the founding member of the imipridone class, comprised of orally bioavailable small molecules that have shown efficacy in multiple tumor types both in animal models and in Phase I/II clinical trials. ONC201 is a potent inducer of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. TRAIL is an innate immune mechanism which induces programmed cell death of cancer cells. We observed that PDAC cells upregulated ATF4, CHOP, and DR5 after treatment with ONC201. This occurred in cell lines that are susceptible to ONC201-induced apoptosis and in ones that are not. In response to ONC201, PDAC cells downregulated anti-apoptotic proteins including c-FLIP, BclXL, XIAP, cIAP1, and survivin. We hypothesized that TRAIL receptor agonists might induce selective, synergistic apoptosis in pancreatic cancer cell lines treated with ONC201. We screened 7 pancreatic cancer cell lines and found synergy with ONC201 and rhTRAIL or the novel TRAIL receptor agonist TLY012 in 6 of the 7 cell lines tested. In vivo experiments using BxPC3 and HPAFII xenograft models showed that the combination of ONC201 plus TLY012 significantly delays tumor growth as compared to controls. Immunohistochemical analysis of the tumors after three doses of the combination showed significantly increased cleavage of caspase 3 in vivo as compared to controls. Taken together, the preclinical efficacy of ONC201 and TLY012 represents a novel therapeutic option for further testing in pancreatic cancer patients. This combination showed marked efficacy in tumor cells that are both sensitive and resistant to the pro-apoptotic effects of ONC201, providing rationale to further investigate the combination of ONC201 plus TLY012 in patients with pancreatic cancer.

Maternal and Paternal Depression Symptoms During NICU Stay and Transition Home.

OBJECTIVE: To examine the trajectory and risk factors of depression symptoms among parents from NICU admission to 30 days postdischarge. We hypothesized depression symptom scores would decrease from admission and then increase from discharge to 30 days. METHODS: Prospective longitudinal cohort study of premature infants in NICU. Parents completed the validated Edinburgh Postnatal Depression Scale (EPDS) at 4 time points: NICU admission, discharge, and 14 days and 30 days postdischarge. EPDS score change across time and probability of a positive screen (EPDS ≥10) were by assessed using mixed effect regression models. RESULTS: Of 431 parents enrolled (mothers, n = 230 [53%]), 33% of mothers (n = 57) and 17% of fathers (n = 21) had a positive EPDS screening. Score change was 1.9 points different between mothers and fathers (confidence interval [CI]: 1.3-2.6; P < .0001), with mothers decreasing 2.9 points (CI: 2.1-3.7; P < .0001) and fathers decreasing 1.0 points (CI: 0.1-2.0; P = .04). Over time, mothers decreased 10.96 times (CI: 2.99-38.20; P = .0003); fathers decreased at a nonsignificant rate. Admission or discharge screening improved 30-day depressive symptom prediction (AUC 0.66 baseline demographics only versus 0.84+initial [P < .0001], and versus 0.80+discharge screening [P < .001]). CONCLUSIONS: Mothers and fathers experience different depressive symptom trajectories from NICU to home. Screening parents for postpartum depression during the NICU stay is likely to result in improved identification of parents at risk for postpartum depression after discharge. Focused attention on fathers appears warranted.

Alloying a single and a double perovskite: a Cu+/2+ mixed-valence layered halide perovskite with strong optical absorption.

Introducing heterovalent cations at the octahedral sites of halide perovskites can substantially change their optoelectronic properties. Yet, in most cases, only small amounts of such metals can be incorporated as impurities into the three-dimensional lattice. Here, we exploit the greater structural flexibility of the two-dimensional (2D) perovskite framework to place three distinct stoichiometric cations in the octahedral sites. The new layered perovskites AI 4[CuII(CuIInIII)0.5Cl8] (1, A = organic cation) may be derived from a CuI-InIII double perovskite by replacing half of the octahedral metal sites with Cu2+. Electron paramagnetic resonance and X-ray absorption spectroscopy confirm the presence of Cu2+ in 1. Crystallographic studies demonstrate that 1 represents an averaging of the CuI-InIII double perovskite and CuII single perovskite structures. However, whereas the highly insulating CuI-InIII and CuII perovskites are colorless and yellow, respectively, 1 is black, with substantially higher electronic conductivity than that of either endmember. We trace these emergent properties in 1 to intervalence charge transfer between the mixed-valence Cu centers. We further propose a tiling model to describe how the Cu+, Cu2+, and In3+ coordination spheres can pack most favorably into a 2D perovskite lattice, which explains the unusual 1 : 2 : 1 ratio of these cations found in 1. Magnetic susceptibility data of 1 further corroborate this packing model. The emergence of enhanced visible light absorption and electronic conductivity in 1 demonstrates the importance of devising strategies for increasing the compositional complexity of halide perovskites.

G-CSF promotes alloregulatory function of MDSCs through a c-Kit dependent mechanism.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that expand in inflammatory conditions including transplantation. MDSCs may be capable of controlling rejection. The critical mechanisms underlying MDSC mediated alloregulation remain unexplored. G-CSF potently stimulates MDSC expansion. We hypothesized that G-CSF-induced MDSCs use a novel mechanism to suppress T cell responses. G-CSF promoted expansion of MDSCs and enhanced their suppressive function against T cell proliferation. Gene expression analysis revealed MDSCs expanded with G-CSF upregulated immune-related genes, but downregulated proliferation-related genes when compared to naïve control MDSCs. The KIT oncogene, encoding the c-Kit (CD117) transmembrane tyrosine kinase receptor, was the most significantly increased in MDSCs expanded with G-CSF. c-Kit inhibition with both imatinib and monoclonal blocking antibody reduced expression of ARG-1, iNOS, PD-L1, and SAA3. Further, imatinib also reduced MDSC-mediated T cell suppression in vitro. Modulation of c-Kit activity may represent a therapeutic target for alloregulatory MDSCs.

Materializing rival ground states in the barlowite family of kagome magnets: quantum spin liquid, spin ordered, and valence bond crystal states.

The spin- 1 2 kagome antiferromagnet is considered an ideal host for a quantum spin liquid (QSL) ground state. We find that when the bonds of the kagome lattice are modulated with a periodic pattern, new quantum ground states emerge. Newly synthesized crystalline barlowite (Cu4(OH)6FBr) and Zn-substituted barlowite demonstrate the delicate interplay between singlet states and spin order on the spin- 1 2 kagome lattice. Comprehensive structural measurements demonstrate that our new variant of barlowite maintains hexagonal symmetry at low temperatures with an arrangement of distorted and undistorted kagome triangles, for which numerical simulations predict a pinwheel valence bond crystal (VBC) state instead of a QSL. The presence of interlayer spins eventually leads to an interesting pinwheel q = 0 magnetic order. Partially Zn-substituted barlowite (Cu3.44Zn0.56(OH)6FBr) has an ideal kagome lattice and shows QSL behavior, indicating a surprising robustness of the QSL against interlayer impurities. The magnetic susceptibility is similar to that of herbertsmithite, even though the Cu2+ impurities are above the percolation threshold for the interlayer lattice and they couple more strongly to the nearest kagome moment. This system is a unique playground displaying QSL, VBC, and spin order, furthering our understanding of these highly competitive quantum states.

High resolution time- and angle-resolved photoemission spectroscopy with 11 eV laser pulses.

Performing time- and angle-resolved photoemission (tr-ARPES) spectroscopy at high momenta necessitates extreme ultraviolet laser pulses, which are typically produced via high harmonic generation (HHG). Despite recent advances, HHG-based setups still require large pulse energies (from hundreds of µJ to mJ) and their energy resolution is limited to tens of meV. Here, we present a novel 11 eV tr-ARPES setup that generates a flux of 5 × 1010 photons/s and achieves an unprecedented energy resolution of 16 meV. It can be operated at high repetition rates (up to 250 kHz) while using input pulse energies down to 3 µJ. We demonstrate these unique capabilities by simultaneously capturing the energy and momentum resolved dynamics in two well-separated momentum space regions of a charge density wave material ErTe3. This novel setup offers the opportunity to study the non-equilibrium band structure of solids with exceptional energy and time resolutions at high repetition rates.

Myeloid-derived suppressor cells expand after transplantation and their augmentation increases graft survival.

Myeloid-derived suppressor cells (MDSCs) expand in an inflammatory microenvironment such as cancer and autoimmunity. To study if transplantation induces MDSCs and these cells regulate allograft survival, C57BL/6 donor hearts were transplanted into BALB/c recipients and endogenous MDSCs were characterized. The effects of adoptive transfer of transplant (tx), tumor (tm), and granulocyte-colony stimulating factor (g-csf)-expanded MDSCs or depletion of MDSC were assessed. MDSCs expanded after transplantation (1.7-4.6-fold) in the absence of immunosuppression, homed to allografts, and suppressed proliferation of CD4 T cells in vitro. Tx-MDSCs differed phenotypically from tm-MDSCs and g-csf-MDSCs. Among various surface markers, Rae-1 expression was notably low and TGF-ß receptor II was high in tx-MDSCs when compared to tm-MDSCs and g-csf-MDSCs. Adoptive transfer of these three MDSCs led to differential graft survival: control (6 days), tx-MDSCs (7.5 days), tm-MDSCs (9.5 days), and g-csf-MDSCs (19.5 days). In combination with anti-CD154 mAb, MDSCs synergistically extended graft survival from 40 days (anti-CD154 alone) to 86 days with tm-MDSCs and 132 days with g-csf-MDSCs. Early MDSC depletion (day 0 or 20), however, abrogated graft survival, but late depletion (day 25) did not. In conclusion, MDSCs expanded following transplantation, migrated to cardiac allografts, prolonged graft survival, and were synergistic with anti-CD154 mAb.

Site-Specific Structure at Multiple Length Scales in Kagome Quantum Spin Liquid Candidates.

Realizing a quantum spin liquid (QSL) ground state in a real material is a leading issue in condensed matter physics research. In this pursuit, it is crucial to fully characterize the structure and influence of defects, as these can significantly affect the fragile QSL physics. Here, we perform a variety of cutting-edge synchrotron X-ray scattering and spectroscopy techniques, and we advance new methodologies for site-specific diffraction and L-edge Zn absorption spectroscopy. The experimental results along with our first-principles calculations address outstanding questions about the local and long-range structures of the two leading kagome QSL candidates, Zn-substituted barlowite (Cu3Zn x Cu1-x (OH)6FBr) and herbertsmithite (Cu3Zn(OH)6Cl2). On all length scales probed, there is no evidence that Zn substitutes onto the kagome layers, thereby preserving the QSL physics of the kagome lattice. Our calculations show that antisite disorder is not energetically favorable and is even less favorable in Zn-barlowite compared to herbertsmithite. Site-specific X-ray diffraction measurements of Zn-barlowite reveal that Cu2+ and Zn2+ selectively occupy distinct interlayer sites, in contrast to herbertsmithite. Using the first measured Zn L-edge inelastic X-ray absorption spectra combined with calculations, we discover a systematic correlation between the loss of inversion symmetry from pseudo-octahedral (herbertsmithite) to trigonal prismatic coordination (Zn-barlowite) with the emergence of a new peak. Overall, our measurements suggest that Zn-barlowite has structural advantages over herbertsmithite that make its magnetic properties closer to an ideal QSL candidate: its kagome layers are highly resistant to nonmagnetic defects while the interlayers can accommodate a higher amount of Zn substitution.

Switching from Conventional to Nano-natural Phytochemicals to Prevent and Treat Cancers: Special Emphasis on Resveratrol.

BACKGROUND: Natural phytochemicals and their derivatives have been used in medicine since prehistoric times. Natural phytochemicals have potential uses against various disorders, including cancers. However, due to low bioavailability, their success in clinical trials has not been reproduced. Nanotechnology has played a vital role in providing new directions for diagnosis, prevention, and treatment of different disorders, and of cancer in particular. Nanotechnology has demonstrated the capability to deliver conventional natural products with poor solubility or a short half-life to target specific sites in the body and regulate the release of drugs. Among the natural products, the phytoalexin resveratrol has demonstrated therapeutic effects, including antioxidant, antiinflammatory, and anti-proliferative effects, as well as the potential to inhibit the initiation and promotion of cancer. However, low water solubility and extensive first-pass metabolism lead to poor bioavailability of resveratrol, hindering its potential. Conventional dosage forms of resveratrol, such as tablets, capsules, dry powder, and injections, have met with limited success. Nanoformulations are now being investigated to improve the pharmacokinetic characteristics, as well as to enhance the bioavailability and targetability of resveratrol. OBJECTIVES: This review details the therapeutic effectiveness, mode of action, and pharmacokinetic limitations of resveratrol, as well as discusses the successes and challenges of resveratrol nanoformulations. Modern nanotechnology techniques to enhance the encapsulation of resveratrol within nanoparticles and thereby enhance its therapeutic effects are emphasized. CONCLUSION: To date, no resveratrol-based nanosystems are in clinical use, and this review would provide a new direction for further investigations on innovative nanodevices that could consolidate the anticancer potential of resveratrol.

Fermi surface reconstruction in electron-doped cuprates without antiferromagnetic long-range order.

Fermi surface (FS) topology is a fundamental property of metals and superconductors. In electron-doped cuprate Nd2-x Ce x CuO4 (NCCO), an unexpected FS reconstruction has been observed in optimal- and overdoped regime (x = 0.15-0.17) by quantum oscillation measurements (QOM). This is all the more puzzling because neutron scattering suggests that the antiferromagnetic (AFM) long-range order, which is believed to reconstruct the FS, vanishes before x = 0.14. To reconcile the conflict, a widely discussed external magnetic-field-induced AFM long-range order in QOM explains the FS reconstruction as an extrinsic property. Here, we report angle-resolved photoemission (ARPES) evidence of FS reconstruction in optimal- and overdoped NCCO. The observed FSs are in quantitative agreement with QOM, suggesting an intrinsic FS reconstruction without field. This reconstructed FS, despite its importance as a basis to understand electron-doped cuprates, cannot be explained under the traditional scheme. Furthermore, the energy gap of the reconstruction decreases rapidly near x = 0.17 like an order parameter, echoing the quantum critical doping in transport. The totality of the data points to a mysterious order between x = 0.14 and 0.17, whose appearance favors the FS reconstruction and disappearance defines the quantum critical doping. A recent topological proposal provides an ansatz for its origin.