Topologically protected magnetoelectric switching in a multiferroic.

Electric control of magnetism and magnetic control of ferroelectricity can improve the energy efficiency of magnetic memory and data-processing devices1. However, the necessary magnetoelectric switching is hard to achieve, and requires more than just a coupling between the spin and the charge degrees of freedom2-5. Here we show that an application and subsequent removal of a magnetic field reverses the electric polarization of the multiferroic GdMn2O5, thus requiring two cycles to bring the system back to the original configuration. During this unusual hysteresis loop, four states with different magnetic configurations are visited by the system, with one half of all spins undergoing unidirectional full-circle rotation in increments of about 90 degrees. Therefore, GdMn2O5 acts as a magnetic crankshaft that converts the back-and-forth variations of the magnetic field into a circular spin motion. This peculiar four-state magnetoelectric switching emerges as a topologically protected boundary between different two-state switching regimes. Our findings establish a paradigm of topologically protected switching phenomena in ferroic materials.

No pulsed radio emission during a bursting phase of a Galactic magnetar.

Fast radio bursts (FRBs) are millisecond-duration radio transients of unknown physical origin observed at extragalactic distances1-3. It has long been speculated that magnetars are the engine powering repeating bursts from FRB sources4-13, but no convincing evidence has been collected so far14. Recently, the Galactic magnetar SRG 1935+2154 entered an active phase by emitting intense soft γ-ray bursts15. One FRB-like event with two peaks (FRB 200428) and a luminosity slightly lower than the faintest extragalactic FRBs was detected from the source, in association with a soft γ-ray/hard-X-ray flare18-21. Here we report an eight-hour targeted radio observational campaign comprising four sessions and assisted by multi-wavelength (optical and hard-X-ray) data. During the third session, 29 soft-γ-ray repeater (SGR) bursts were detected in γ-ray energies. Throughout the observing period, we detected no single dispersed pulsed emission coincident with the arrivals of SGR bursts, but unfortunately we were not observing when the FRB was detected. The non-detection places a fluence upper limit that is eight orders of magnitude lower than the fluence of FRB 200428. Our results suggest that FRB-SGR burst associations are rare. FRBs may be highly relativistic and geometrically beamed, or FRB-like events associated with SGR bursts may have narrow spectra and characteristic frequencies outside the observed band. It is also possible that the physical conditions required to achieve coherent radiation in SGR bursts are difficult to satisfy, and that only under extreme conditions could an FRB be associated with an SGR burst.

Five decades of northern land carbon uptake revealed by the interhemispheric CO2 gradient.

The global land and ocean carbon sinks have increased proportionally with increasing carbon dioxide emissions during the past decades1. It is thought that Northern Hemisphere lands make a dominant contribution to the global land carbon sink2-7; however, the long-term trend of the northern land sink remains uncertain. Here, using measurements of the interhemispheric gradient of atmospheric carbon dioxide from 1958 to 2016, we show that the northern land sink remained stable between the 1960s and the late 1980s, then increased by 0.5 ± 0.4 petagrams of carbon per year during the 1990s and by 0.6 ± 0.5 petagrams of carbon per year during the 2000s. The increase of the northern land sink in the 1990s accounts for 65% of the increase in the global land carbon flux during that period. The subsequent increase in the 2000s is larger than the increase in the global land carbon flux, suggesting a coincident decrease of carbon uptake in the Southern Hemisphere. Comparison of our findings with the simulations of an ensemble of terrestrial carbon models5,8 over the same period suggests that the decadal change in the northern land sink between the 1960s and the 1990s can be explained by a combination of increasing concentrations of atmospheric carbon dioxide, climate variability and changes in land cover. However, the increase during the 2000s is underestimated by all models, which suggests the need for improved consideration of changes in drivers such as nitrogen deposition, diffuse light and land-use change. Overall, our findings underscore the importance of Northern Hemispheric land as a carbon sink.

Programmable Ferroelectricity in Hf0.5Zr0.5O2 Enabled by Oxygen Defect Engineering.

Ferroelectricity, especially the Si-compatible type recently observed in hafnia-based materials, is technologically useful for modern memory and logic applications, but it is challenging to differentiate intrinsic ferroelectric polarization from the polar phase and oxygen vacancy. Here, we report electrically controllable ferroelectricity in a Hf0.5Zr0.5O2-based heterostructure with Sr-doped LaMnO3, a mixed ionic-electronic conductor, as an electrode. Electrically reversible extraction and insertion of an oxygen vacancy into Hf0.5Zr0.5O2 are macroscopically characterized and atomically imaged in situ. Utilizing this reversible process, we achieved multilevel polarization states modulated by the electric field. Our study demonstrates the usefulness of the mixed conductor to repair, create, manipulate, and utilize advanced ferroelectric functionality. Furthermore, the programmed ferroelectric heterostructures with Si-compatible doped hafnia are desirable for the development of future ferroelectric electronics.

Breath Biomarkers of Pediatric Malaria: Reproducibility and Response to Antimalarial Therapy.

BACKGROUND: Many insect-borne pathogens appear to manipulate the odors of their hosts in ways that influence vector behaviors. In our prior work, we identified characteristic changes in volatile emissions of cultured Plasmodium falciparum parasites in vitro and during natural human falciparum malaria. In the current study, we prospectively evaluate the reproducibility of these findings in an independent cohort of children in Blantyre, Malawi. METHODS: We enrolled febrile children under evaluation for malaria and collected breath from children with and without malaria, as well as healthy controls. Using gas chromatography/mass spectrometry, we characterized breath volatiles associated with malaria. By repeated sampling of children with malaria before and after antimalarial use, we determined how breath profiles respond to treatment. In addition, we investigated the stage-specificity of biomarkers through correlation with asexual and sexual-stage parasitemia. RESULTS: Our data provide robust evidence that P. falciparum infection leads to specific, reproducible changes in breath compounds. While no individual compound served as an adequate classifier in isolation, selected volatiles together yielded high sensitivity for diagnosis of malaria. Overall, the results of our predictive models suggest the presence of volatile signatures that reproducibly predict malaria infection status and determine response to therapy, even in cases of low parasitemia.

Evaluation for genetic disease in kidney transplant candidates: A practice resource.

The increasing availability of clinically approved genetic tests for kidney disease has spurred the growth in the use of these tests in kidney transplant practice. Neither the testing options nor the patient population where this should be deployed has been defined and its value in kidney transplant evaluation has not been demonstrated. Transplant providers may not always be aware of the limitations of genetic testing and may need guidance on comprehending test results and providing counsel, as many centers do not have easy access to a renal genetic counselor or a clinical geneticist. In this practice resource, a working group of nephrologists, geneticists and a genetic counselor provide a pragmatic, tailored approach to genetic testing, advocating for its use only where the genetic diagnosis or its exclusion can impact the choices available for transplantation or post-transplant management or the work-up of living donor candidates at increased risk for heritable disease.

Tumor mutational burden for the prediction of PD-(L)1 blockade efficacy in cancer: challenges and opportunities.

Tumor mutational burden (TMB) is a biomarker that measures the number of somatic mutations in a tumor's genome. TMB has emerged as a predictor of response to immune checkpoint inhibitors (ICIs) in various cancer types, and several studies have shown that patients with high TMB have better outcomes when treated with programmed death-ligand 1-based therapies. Recently, the Food and Drug Administration has approved TMB as a companion diagnostic for the use of pembrolizumab in solid tumors. However, despite its potential, the use of TMB as a biomarker for immunotherapy efficacy is limited by several factors. Here we review the limitations of TMB in predicting immunotherapy outcomes in patients with cancer and discuss potential strategies to optimize its use in the clinic.

Phase II clinical trial of neoadjuvant anti-PD-1 (toripalimab) combined with axitinib in resectable mucosal melanoma.

BACKGROUND: The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months in a phase Ib trial. It was hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma, so we conducted this trial. PATIENTS AND METHODS: This single-arm phase II trial enrolled patients with resectable mucosal melanoma. Patients received toripalimab 3 mg/kg once every 2 weeks (Q2W) plus axitinib 5 mg two times a day (b.i.d.) for 8 weeks as neoadjuvant therapy, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2 ± 1weeks after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to the International Neoadjuvant Melanoma Consortium recommendations. RESULTS: Between August 2019 and October 2021, 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median follow-up time was 34.2 months (95% confidence interval 20.4-48.0 months). The pathologic response rate was 33.3% (8/24; 4 pathological complete responses and 4 pathological partial responses). The median event-free survival for all patients was 11.1 months (95% confidence interval 5.3-16.9 months). The median overall survival was not reached. Neoadjuvant therapy was tolerable with 8 (27.5%) grade 3-4 treatment-related adverse events and no treatment-related deaths. Tissue samples of 17 patients at baseline and after surgery were collected (5 responders and 12 nonresponders). Multiplex immunohistochemistry demonstrated a significant increase in CD3+ (P = 0.0032) and CD3+CD8+ (P = 0.0038) tumor-infiltrating lymphocytes after neoadjuvant therapy, particularly in pathological responders. CONCLUSIONS: Neoadjuvant toripalimab combined with axitinib in resectable mucosal melanoma demonstrated a promising pathologic response rate with significantly increased infiltrating CD3+ and CD3+CD8+ T cells after therapy.

Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer.

BACKGROUND: Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. PATIENTS AND METHODS: Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. RESULTS: In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ -50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. CONCLUSIONS: Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible.

High-throughput screen to identify and optimize NOT gate receptors for cell therapy.

Logic-gated engineered cells are an emerging therapeutic modality that can take advantage of molecular profiles to focus medical interventions on specific tissues in the body. However, the increased complexity of these engineered systems may pose a challenge for prediction and optimization of their behavior. Here we describe the design and testing of a flow cytometry-based screening system to rapidly select functional inhibitory receptors from a pooled library of candidate constructs. In proof-of-concept experiments, this approach identifies inhibitory receptors that can operate as NOT gates when paired with activating receptors. The method may be used to generate large datasets to train machine learning models to better predict and optimize the function of logic-gated cell therapeutics.

Terahertz manipulation of nonlinear optical response in topological material PtBi2.

The substantial nonlinear optical response observed in numerous topological materials renders them well-suited for optic and photonic applications, underscoring the critical need to devise effective strategies for manipulating their nonlinearity to enhance their versatility across different applications. In this Letter, we focus on the second-harmonic generation (SHG) response of the topological material PtBi2 under intense terahertz (THz) pulses and unveil the transient nonlinearity manipulated by a THz electric field. Our findings demonstrate that upon excitation of an intense THz pulse, there emerges a substantial enhancement in the SHG signal of PtBi2, which is predominantly attributed to the linear term involving the THz field, i.e., χ(2)χ(3)ETHz. We also clearly observe the transient change in the nonlinear coefficients, which could arise from the excitation of the bands with linear dispersion via the intense THz pulse. These findings bear significant implications for achieving ultrafast modulation of nonlinearity in topological materials, thereby opening avenues for advanced applications in this field.

Anisotropic Galvanomagnetic Effects in Single Cubic Crystals: A Theory and Its Verification.

A theory of anisotropic galvanomagnetic effects in single cubic crystals and its experimental verifications are presented for the current in the (001) plane. In contrast to the general belief that galvanomagnetic effects in single crystals are highly sensitive to many internal and external effects and have no universal features, the theory predicts universal angular dependencies of longitudinal and transverse resistivity and various characteristics when magnetization rotates in the (001) plane, the plane perpendicular to the current, and the plane containing the current and [001] direction. The universal angular dependencies are verified by experiments on Fe_{30}Co_{70} single cubic crystal film. The findings provide new avenues for fundamental research and applications of galvanomagnetic effects, because single crystals offer advantages over polycrystalline materials for band structure and crystallographic orientation engineering.

Origin of a Topotactic Reduction Effect for Superconductivity in Infinite-Layer Nickelates.

Topotactic reduction utilizing metal hydrides as reagents has emerged as an effective approach to achieve exceptionally low oxidization states of metal ions and unconventional coordination networks. This method opens avenues to the development of entirely new functional materials, with one notable example being the infinite-layer nickelate superconductors. However, the reduction effect on the atomic reconstruction and electronic structures-crucial for superconductivity-remains largely unresolved. We designed two sets of control Nd_{0.8}Sr_{0.2}NiO_{2} thin films and used secondary ion mass spectroscopy to highlight the absence of reduction-induced hydrogen intercalation. X-ray absorption spectroscopy revealed a significant linear dichroism with dominant Ni 3d_{x2-y2} orbitals on superconducting samples, indicating a Ni single-band nature of infinite-layer nickelates. Consistent with the superconducting T_{c}, the Ni 3d orbitals asymmetry manifests a domelike dependence on the reduction duration. Our results unveil the critical role of reduction in modulating the Ni-3d orbital polarization and its impact on the superconducting properties.

Search for Periodic Time Variations of the Solar

We report a search for time variations of the solar ^{8}B neutrino flux using 5804 live days of Super-Kamiokande data collected between May 31, 1996, and May 30, 2018. Super-Kamiokande measured the precise time of each solar neutrino interaction over 22 calendar years to search for solar neutrino flux modulations with unprecedented precision. Periodic modulations are searched for in a dataset comprising five-day interval solar neutrino flux measurements with a maximum likelihood method. We also applied the Lomb-Scargle method to this dataset to compare it with previous reports. The only significant modulation found is due to the elliptic orbit of the Earth around the Sun. The observed modulation is consistent with astronomical data: we measured an eccentricity of (1.53±0.35)%, and a perihelion shift of (-1.5±13.5) days.

Convergence of dissolving and melting at the nanoscale.

Phase transitions of water and its mixtures are of fundamental importance in physical chemistry, the pharmaceutical industry, materials sciences, and atmospheric sciences. However, current understanding remains elusive to explain relevant observations, especially at the nanoscale. Here, by using molecular dynamics simulations, we investigate the dissolution of sodium chloride (NaCl) nanocrystals with volume-equivalent diameters from 0.51 to 1.75 nm. Our results show that the dissolution of NaCl in aqueous nanodroplets show a strong size dependence, and its solubility can be predicted by the Ostwald-Freundlich equation and Gibbs-Duhem equation after considering a size-dependent solid-liquid surface tension. We find that the structure of dissolved ions in the saturated aqueous nanodropplet resembles the structure of a molten NaCl nanoparticle. With decreasing nanodroplet size, this similarity grows and the average potential energy of NaCl in solution, the molten phase and the crystal phase converges.

Photo-induced structural dynamics of o-nitrophenol by ultrafast electron diffraction.

The photo-induced dynamics of o-nitrophenol, particularly its photolysis, has garnered significant scientific interest as a potential source of nitrous acid in the atmosphere. Although the photolysis products and preceding photo-induced electronic structure dynamics have been investigated extensively, the nuclear dynamics accompanying the non-radiative relaxation of o-nitrophenol on the ultrafast timescale, which include an intramolecular proton transfer step, have not been experimentally resolved. Herein, we present a direct observation of the ultrafast nuclear motions mediating photo-relaxation using ultrafast electron diffraction. This work spatiotemporally resolves the loss of planarity which enables access to a conical intersection between the first excited state and the ground state after the proton transfer step, on the femtosecond timescale and with sub-Angstrom resolution. Our observations, supported by ab initio multiple spawning simulations, provide new insights into the proton transfer mediated relaxation mechanism in o-nitrophenol.

Pretreatment synthetic MRI features for triple-negative breast cancer.

AIM: To evaluate the quantitative parameters derived from synthetic magnetic resonance imaging (SyMRI) for predicting triple-negative breast cancer (TNBC). MATERIALS AND METHODS: This prospective study enrolled participants with invasive ductal breast carcinoma (IDBC) and separated them into a TNBC group and a Non-TNBC group. Preoperative breast MRI included both the SyMRI and conventional MRI sequences. The quantitative parameters derived from the SyMRI included T1 and T2 relaxation times, proton density (PD), and their standard deviations (SD). Clinicopathological characteristics, conventional MRI findings, and quantitative synthetic parameters were assessed for all participants. Multivariable logistic regression analysis was performed to determine the potential independent imaging predictors for TNBC preoperatively. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of these parameters. RESULTS: A total of 231 participants with histopathological proven IDBC were included in this study (n=46 in the TNBC group and n=185 in the Non-TNBC group). The TNBC group had significantly larger tumour size (p=0.011) and more frequent intratumoural cystic or necrotic lesions (p<0.001) as compared to the Non-TNBC group. The univariate analysis showed that the TNBC tumours had significantly higher T1 (p=0.006) and T2 (p<0.001) values than Non-TNBC tumours. Subsequent multivariable analysis indicated that T2 values and the presence of cystic or necrotic lesions were the independent predictors for TNBC. CONCLUSION: The T2 from synthetic imaging and the presence of cystic degeneration or necrosis within the breast cancer may serve as potential imaging biomarkers for preoperative differentiation of TNBC from Non-TNBC.

Myocardial strain combined with clinical risk factors in the prediction of in-hospital heart failure among patients with ST-segment elevation myocardial infarction.

AIMS: To investigate the predictive value of myocardial strain derived from cardiac magnetic resonance (CMR) combined with clinical indicators for in-hospital heart failure (HF) in STEMI patients. MATERIALS AND METHODS: In all, 139 STEMI patients were included, with 28 in the heart failure group and 111 in the non-HF group, and clinical and laboratory data were collected. Left ventricular (LV) global radial strain (GRS), global longitudinal strain (GLS), global circumferential strain (GCS), left ventricular ejection fraction (LVEF), stroke volume (SV), and infarct size (IS) were assessed by CMR. RESULTS: The HF group had worse GRS, GLS, GCS, LVEF, SV, larger IS, longer symptom to balloon time (SBT) and higher levels of high-sensitivity C-reactive protein (hs-CRP) and neutrophil percentage (N%) than the non-HF group (P<0.05). There was a strong correlation between GRS and LVEF (r=0.741, P<0.001). After adjustment for CMR and clinical risk factors, GRS<15.6%, LVEF<37.7%, SBT>350 min, hs-CRP>11.45 mg/L, and N%>74% were independently associated with HF. Clinical model (SBT>350 min + hs-CRP>11.45 mg/L + N%>74%) were associated with a lower diagnostic accuracy for predicting in-hospital HF than GRS + clinical co-model and LVEF + clinical co-model (P<0.05), respectively. There was no significant difference in the area under the curve (AUC) between GRS + clinical co-model and LVEF + clinical co-model (P=0.620): AUC for clinical model = 0.824, AUC for GRS + clinical co-model = 0.895, and AUC for LVEF + clinical co-model = 0.907. CONCLUSIONS: GRS may be effective in predicting in-hospital heart failure after STEMI compared to LVEF, a classical cardiac function parameter, and its combination with clinical risk factors, especially SBT, hs-CRP, and N%, may provide further evidence for early prognostic assessment.

Fluorine-18 prostate-specific membrane antigen-1007-avid indeterminate bone lesions in prostate cancer: clinical and PET/CT features to predict outcomes and prognosis.

AIM: To determine clinical and fluorine-18 prostate-specific membrane antigen-1007 (18F-PSMA-1007) integrated positron-emission tomography (PET)/computed tomography (CT) features that could be used to interpret indeterminate bone lesions (IBLs) and assess the prognosis of prostate cancer (PCa) in patients with IBLs. MATERIALS AND METHODS: Consecutive patients who underwent PSMA PET/CT were analysed retrospectively. IBLs were identified as benign or malignant based on follow-up imaging and clinical management. Lesion- and patient-based assessments were performed to define features predictive of bone lesion results and determine clinical risk. Patients' prognosis was analysed based on clinical characteristics, including prostate-specific antigen (PSA) and alkaline phosphatase (ALP), respectively. RESULTS: A total of 105 patients (mean age ± SD, 72.1 ± 8 years) were evaluated and 158 IBLs were identified. Fifty-three (33.5%), 36 (22.8%), and 69 (43.7%) IBLs were benign, malignant, and equivocal, respectively. Variables including location, maximum standard uptake value (SUVmax), and lymph node metastases (LNM) were related to the benignancy or malignancy of IBLs (p=0.046, p<0.001 and p<0.001, respectively). Regression analysis indicated that LNM, SUVmax, and location of IBLs could be predictors of lesion interpretation (p<0.001, p=0.002 and p=0.035). Patients with benign IBLs experienced the most considerable decreases in PSA and ALP levels. CONCLUSIONS: LNM, SUVmax, and location may contribute to IBL interpretation. A rapid decrease in PSA and ALP levels might suggest a better prognosis for patients with benign IBLs.

Contrast-enhanced CT-based radiomics differentiate anterior mediastinum lymphoma from thymoma without myasthenia gravis and calcification.

AIM: To explore the value of a radiomics model based on enhanced computed tomography (CT) in differentiating anterior mediastinal lymphoma (AML) and thymoma without myasthenia gravis (MG) and calcification. MATERIALS AND METHODS: The present study analysed patients who were diagnosed histologically with AML and thymoma in three independent institutions. All pre-treatment patients underwent enhanced CT. In the training group of patients from institutions 1 (the First Affiliated Hospital of Kunming Medical University) and 3 (the Yunnan Cancer Hospital), two radiologists independently analysed the enhanced CT images and performed manual segmentation of each tumour. Radiomics features were screened using interobserver interclass coefficient (ICC) analysis, feature correlation analysis, and L1 regularisation. The discriminative efficacy of the logistic regression model was evaluated using receiver operating characteristic (ROC) analysis. Validation group of patients from institution 2 (the Second Affiliated Hospital of Zhejiang University School of Medicine) was used to validate the proposed models. RESULTS: A total of 114 patients were enrolled in this study and 1,743 radiomics features were extracted from the enhanced CT images. After feature screening, the remaining 37 robust radiomics features were used to construct the model. In the training group, the AUC of the model was 0.987 (95% confidence interval [CI]: 0.976-0.999), the sensitivity, specificity, and accuracy were 0.912, 0.946, and 0.924, respectively. In the validation group, the AUC of the model was 0.798 (95% CI: 0.683-0.913), the sensitivity, specificity, and accuracy were 0.760, 0.700, and 0.743, respectively. CONCLUSION: The radiomics model created provided effective information to assist in the selection of clinical strategies, thus reducing unnecessary procedures in patients with AML and guiding direct surgery in patients with thymoma to avoid biopsy.