One-dimensional proximity superconductivity in the quantum Hall regime.

Extensive efforts have been undertaken to combine superconductivity and the quantum Hall effect so that Cooper-pair transport between superconducting electrodes in Josephson junctions is mediated by one-dimensional edge states1-6. This interest has been motivated by prospects of finding new physics, including topologically protected quasiparticles7-9, but also extends into metrology and device applications10-13. So far it has proven challenging to achieve detectable supercurrents through quantum Hall conductors2,3,6. Here we show that domain walls in minimally twisted bilayer graphene14-18 support exceptionally robust proximity superconductivity in the quantum Hall regime, allowing Josephson junctions to operate in fields close to the upper critical field of superconducting electrodes. The critical current is found to be non-oscillatory and practically unchanging over the entire range of quantizing fields, with its value being limited by the quantum conductance of ballistic, strictly one-dimensional, electronic channels residing within the domain walls. The system described is unique in its ability to support Andreev bound states at quantizing fields and offers many interesting directions for further exploration.

Updated guidelines for prescribing opioids to treat patients with chronic non-cancer pain in Korea: developed by committee on hospice and palliative care of the Korean Pain Society.

There are growing concerns regarding the safety of long-term treatment with opioids of patients with chronic non-cancer pain. In 2017, the Korean Pain Society (KPS) developed guidelines for opioid prescriptions for chronic non-cancer pain to guide physicians to prescribe opioids effectively and safely. Since then, investigations have provided updated data regarding opioid therapy for chronic non-cancer pain and have focused on initial dosing schedules, reassessment follow-ups, recommended dosage thresholds considering the risk-benefit ratio, dose-reducing schedules for tapering and discontinuation, adverse effects, and inadvertent problems resulting from inappropriate application of the previous guidelines. Herein, we have updated the previous KPS guidelines based on a comprehensive literature review and consensus development following discussions among experts affiliated with the Committee on Hospice and Palliative Care in the KPS. These guidelines may assist physicians in prescribing opioids for chronic non-cancer pain in adult outpatient settings, but should not to be regarded as an inflexible standard. Clinical judgements by the attending physician and patient-centered decisions should always be prioritized.

Ursodeoxycholic acid may protect from severe acute respiratory syndrome coronavirus 2 Omicron variant by reducing angiotensin-converting enzyme 2.

The SARS-CoV-2 caused COVID-19 pandemic has posed a global health hazard. While some vaccines have been developed, protection against viral infection is not perfect because of the urgent approval process and the emergence of mutant SARS-CoV-2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, which is one of the key pathways activated by SARS-CoV-2 Delta variant infection. UDCA is a well-known reagent of liver health supplements and the only clinically approved bile acid. In this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it has previously been verified for protection against Delta variant. When co-housing with an Omicron variant-infected hamster group resulted in spontaneous airborne transmission, the UDCA pre-supplied group was protected from weight loss relative to the non-treated group at 4 days post-infection by more than 5%-10%. Furthermore, UDCA-treated groups had a 3-fold decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in the respiratory tract. Here, the data show that the UDCA serves an alternative option for preventive drug, providing SARS-CoV-2 protection against not only Delta but also Omicron variant. Our results of this study will help to propose drug-repositioning of UDCA from liver health supplement to preventive drug of SARS-CoV-2 infection.

Self-regulating CAR-T cells modulate cytokine release syndrome in adoptive T-cell therapy.

Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.

Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice.

Introduction: Fusion of the fragment crystallizable (Fc) to protein therapeutics is commonly used to extend the circulation time by enhancing neonatal Fc-receptor (FcRn)-mediated endosomal recycling and slowing renal clearance. This study applied kinetic modeling to gain insights into the cellular processing contributing to the observed pharmacokinetic (PK) differences between the novel recombinant ADAMTS13 fragment (MDTCS) and its Fc-fusion protein (MDTCS-Fc). Methods: For MDTCS and MDTCS-Fc, their plasma PK profiles were obtained at two dose levels following intravenous administration of the respective proteins to mice. The plasma PK profiles of MDTCS were fitted to a kinetic model with three unknown protein-dependent parameters representing the fraction recycled (FR) and the rate constants for endocytosis (kup, for the uptake into the endosomes) and for the transfer from the plasma to the interstitial fluid (kpi). For MDTCS-Fc, the model was modified to include an additional parameter for binding to FcRn. Parameter optimization was done using the Cluster Gauss-Newton Method (CGNM), an algorithm that identifies multiple sets of approximate solutions ("accepted" parameter sets) to nonlinear least-squares problems. Results: As expected, the kinetic modeling results yielded the FR of MDTCS-Fc to be 2.8-fold greater than that of MDTCS (0.8497 and 0.3061, respectively). In addition, MDTCS-Fc was predicted to undergo endocytosis (the uptake into the endosomes) at a slower rate than MDTCS. Sensitivity analyses identified the association rate constant (kon) between MDTCS-Fc and FcRn as a potentially important factor influencing the plasma half-life in vivo. Discussion: Our analyses suggested that Fc fusion to MDTCS leads to changes in not only the FR but also the uptake into the endosomes, impacting the systemic plasma PK profiles. These findings may be used to develop recombinant protein therapeutics with extended circulation time.

Efficacy and Safety of Fibroblast Growth Factor-21 Analogs for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Meta-Analysis.

Fibroblast growth factor (FGF)-21 analogs are potential therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). This systematic review and meta-analysis aimed to assess the efficacy and safety of the FGF-21 analogs, efruxifermin, pegbelfermin, and pegozafermin for MASH treatment. A comprehensive systematic review and meta-analysis of randomized controlled trials from five major databases was conducted. Primary efficacy outcomes focused on liver histological improvement, while secondary efficacy outcomes encompassed reductions in liver fat content and improvements in biochemical parameters. Safety outcomes examined included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Eight eligible studies involving 963 patients were included in this review. Compared with the placebo group, the FGF-21 analog-treated group exhibited significantly improved primary efficacy outcomes, specifically ≥1 stage improvement in fibrosis with no worsening of MASH (risk ratio [RR] = 1.83; 95% confidence interval [CI] = 1.27-2.62) and at least two-point improvement in the non-alcoholic fatty liver disease activity score with no worsening of fibrosis (RR = 2.85; 95% CI = 2.06-3.95). Despite an increased risk of TEAEs (RR = 1.17; 95% CI = 1.08-1.27) and treatment-related adverse events (RR = 1.75; 95% CI = 1.40-2.19), FGF-21 analogs exhibited an acceptable safety profile. FGF-21 analogs were significantly better in achieving liver histological improvements and beneficial biochemical outcomes compared with placebo, with a tolerable safety pattern. These findings shed light on the efficacy and safety of FGF-21 analogs and provide valuable evidence for their application as MASH therapeutics.

Recent Developments in Materials for Physical Hydrogen Storage: A Review.

The depletion of reliable energy sources and the environmental and climatic repercussions of polluting energy sources have become global challenges. Hence, many countries have adopted various renewable energy sources including hydrogen. Hydrogen is a future energy carrier in the global energy system and has the potential to produce zero carbon emissions. For the non-fossil energy sources, hydrogen and electricity are considered the dominant energy carriers for providing end-user services, because they can satisfy most of the consumer requirements. Hence, the development of both hydrogen production and storage is necessary to meet the standards of a "hydrogen economy". The physical and chemical absorption of hydrogen in solid storage materials is a promising hydrogen storage method because of the high storage and transportation performance. In this paper, physical hydrogen storage materials such as hollow spheres, carbon-based materials, zeolites, and metal-organic frameworks are reviewed. We summarize and discuss the properties, hydrogen storage densities at different temperatures and pressures, and the fabrication and modification methods of these materials. The challenges associated with these physical hydrogen storage materials are also discussed.

Thrombocytopenia Independently Leads to Changes in Monocyte Immune Function.

BACKGROUND: While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The physiological implications of these constant transient interactions are poorly understood. Activated platelets induce and amplify immune responses, but platelets may also maintain immune homeostasis in healthy conditions, including maintaining vascular integrity and T helper cell differentiation, meaning that platelets are central to both immune responses and immune quiescence. Clinical data have shown an association between low platelet counts (thrombocytopenia) and immune dysfunction in patients with sepsis and extracorporeal membrane oxygenation, further implicating platelets as more holistic immune regulators, but studies of platelet immune functions in nondisease contexts have had limited study. METHODS: We used in vivo models of thrombocytopenia and in vitro models of platelet and monocyte interactions, as well as RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing), to mechanistically determine how resting platelet and monocyte interactions immune program monocytes. RESULTS: Circulating platelets and monocytes interact in a CD47-dependent manner to regulate monocyte metabolism, histone methylation, and gene expression. Resting platelet-monocyte interactions limit TLR (toll-like receptor) signaling responses in healthy conditions in an innate immune training-like manner. In both human patients with sepsis and mouse sepsis models, thrombocytopenia exacerbated monocyte immune dysfunction, including increased cytokine production. CONCLUSIONS: Thrombocytopenia immune programs monocytes in a manner that may lead to immune dysfunction in the context of sepsis. This is the first demonstration that sterile, endogenous cell interactions between resting platelets and monocytes regulate monocyte metabolism and pathogen responses, demonstrating platelets to be immune rheostats in both health and disease.

Erdheim-Chester Disease Occult on Radiographs and CT but Visible on MRI and PET.

BACKGROUND Erdheim-Chester disease (ECD) is a rare neoplasm of histiocytes that is characterized by prominent involvement of the long bones. Approximately 1500 cases have been reported since the disease was first described in 1930. The imaging appearance of ECD can be highly variable given the numerous systems it can affect. In this case report we discuss a patient whose ECD was occult on multiple imaging modalities. CASE REPORT We report the case of a 60-year-old woman who presented with sub-acute left knee and calf pain that led to an MRI. She was found to have innumerable marrow-replacing lesions in the axial and appendicular skeleton visualized on the initial MRI, as well as on an ¹8F-FDG PET/CT scan. The patient did not have extraosseous abnormal uptake on the PET/CT. Subsequently, a lesion from the left iliac bone was histologically confirmed as ECD on the basis of positive staining for CD68 and CD163 and negative staining for CD1a. Osseous lesions in ECD have a distinct imaging appearance and are typically detected by radiography and bone scintigraphy, among other modalities; however, the lesions in this case were unexpectedly absent from those studies. CONCLUSIONS If there is a high degree of suspicion for ECD, 18F-FDG PET/CT and/or MRI may be necessary for adequate visualization of bone lesions, given that those lesions can have an infiltrative nature that may be difficult to image with other anatomic imaging modalities. Use of 18F-FDG PET/CT and/or MRI may also lead to adequate guidance of confirmatory biopsy.

Significant CO2 emission in the shallow inshore waters of the southeastern Yellow Sea in 2020.

This study investigated the carbonate system and air-sea CO2 exchange in the inshore waters along South Korea's western coastline in 2020. Overlooking these waters might introduce significant errors in estimating air-sea CO2 fluxes of the southeastern Yellow Sea, given their interaction with land, offshore regions, and sediments. During periods other than summer, seasonal variations in seawater CO2 partial pressure (pCO2) could be generally explained by thermal effects. Tidal mixing and shallow depths resulted in weaker stratification-induced carbon export compared to offshore regions. However, during summer, inshore waters exhibited high spatial variability in pCO2, ranging from approximately 185 to 1000 µatm. In contrast to offshore waters that modestly absorbed CO2, inshore waters shallower than 20 m emitted ∼100 Gg C yr-1 to the atmosphere. However, considering the high heterogeneity of the study area, additional observations with high spatial and temporal resolution are required to refine estimates of air-sea CO2 exchange.

A Retrospective View of the Triple-Negative Breast Cancer Microenvironment: Novel Markers, Interactions, and Mechanisms of Tumor-Associated Components Using Public Single-Cell RNA-Seq Datasets.

Triple-negative breast cancer (TNBC) is a significant clinical challenge due to its aggressive nature and limited treatment options. In search of new treatment targets, not only single genes but also gene pairs involved in protein interactions, we explored the tumor microenvironment (TME) of TNBC from a retrospective point of view, using public single-cell RNA sequencing datasets. A High-resolution Cell type Annotation Tool, HiCAT, was used first to identify the cell type in 3-level taxonomies. Tumor cells were then identified based on the estimates of copy number variation. With the annotation results, differentially expressed genes were analyzed to find subtype-specific markers for each cell type, including tumor cells, fibroblast, and macrophage. Cell-cell interactions were also inferred for each cell type pair. Through integrative analysis, we could find unique TNBC markers not only for tumor cells but also for various TME components, including fibroblasts and macrophages. Specifically, twelve marker genes, including DSC2 and CDKN2A, were identified for TNBC tumor cells. Another key finding of our study was the interaction between the DSC2 and DSG2 genes among TNBC tumor cells, suggesting that they are more tightly aggregated with each other than those of other subtypes, including normal epithelial cells. The overexpression of DSC2 in TNBC and its prognostic power were verified by using METABRIC, a large bulk RNA-seq dataset with clinical information. These findings not only corroborate previous hypotheses but also lay the foundation for a new structural understanding of TNBC, as revealed through our single-cell analysis workflow.

Effective vaccination strategies for human papillomavirus (HPV) infection and cervical cancer based on the mathematical model with a stochastic process.

Human papillomavirus (HPV) infection poses a significant risk to women's health by causing cervical cancer. In addition to HPV, cervical cancer incidence rates can be influenced by various factors, including human immunodeficiency virus and herpes, as well as screening policy. In this study, a mathematical model with stochastic processes was developed to analyze HPV transmission between genders and its subsequent impact on cervical cancer incidence. The model simulations suggest that both-gender vaccination is far more effective than female-only vaccination in preventing an increase in cervical cancer incidence. With increasing stochasticity, the difference between the number of patients in the vaccinated group and the number in the nonvaccinated group diminishes. To distinguish the patient population distribution of the vaccinated from the nonvaccinated, we calculated effect size (Cohen's distance) in addition to Student's t-test. The model analysis suggests a threshold vaccination rate for both genders for a clear reduction of cancer incidence when significant stochastic factors are present.

Immunoengineering can overcome the glycocalyx armour of cancer cells.

Cancer cell glycocalyx is a major line of defence against immune surveillance. However, how specific physical properties of the glycocalyx are regulated on a molecular level, contribute to immune evasion and may be overcome through immunoengineering must be resolved. Here we report how cancer-associated mucins and their glycosylation contribute to the nanoscale material thickness of the glycocalyx and consequently modulate the functional interactions with cytotoxic immune cells. Natural-killer-cell-mediated cytotoxicity is inversely correlated with the glycocalyx thickness of the target cells. Changes in glycocalyx thickness of approximately 10 nm can alter the susceptibility to immune cell attack. Enhanced stimulation of natural killer and T cells through equipment with chimeric antigen receptors can improve the cytotoxicity against mucin-bearing target cells. Alternatively, cytotoxicity can be enhanced through engineering effector cells to display glycocalyx-editing enzymes, including mucinases and sialidases. Together, our results motivate the development of immunoengineering strategies that overcome the glycocalyx armour of cancer cells.

Visualizing the Low-Energy Electronic Structure of Prototypical Hybrid Halide Perovskite through Clear Band Measurements.

Organic-inorganic hybrid perovskites (OIHPs) are a promising class of materials that rival conventional semiconductors in various optoelectronic applications. However, unraveling the precise nature of their low-energy electronic structures continues to pose a significant challenge, primarily due to the absence of clear band measurements. Here, we investigate the low-energy electronic structure of CH3NH3PbI3 (MAPI3) using angle-resolved photoelectron spectroscopy combined with ab initio density functional theory. We successfully visualize the electronic structure of MAPI3 near the bulk valence band maximum by using a laboratory photon source (He Iα, 21.2 eV) at low temperature and explore its fundamental properties. The observed valence band exhibits a highly isotropic and parabolic band characterized by small effective masses of 0.20-0.21 me, without notable spectral signatures associated with a large polaron or the Rashba effect, subjects that are intensely debated in the literature. Concurrently, our spin-resolved measurements directly disprove the giant Rashba scenario previously suggested in a similar perovskite compound by establishing an upper limit for the Rashba parameter (αR) of 0.28 eV Å. Our results unveil the unusually complex nature of the low-energy electronic structure of OIHPs, thereby advancing our fundamental understanding of this important class of materials.

Circadian rhythms of macrophages are altered by the acidic pH of the tumor microenvironment.

Macrophages are prime therapeutic targets due to their pro-tumorigenic and immunosuppressive functions in tumors, but varying efficacy of therapeutic approaches targeting macrophages highlights our incomplete understanding of how the tumor microenvironment (TME) can influence regulation of macrophages. The circadian clock is a key internal regulator of macrophage function, but how circadian rhythms of macrophages may be influenced by the tumor microenvironment remains unknown. We found that conditions associated with the TME such as polarizing stimuli, acidic pH, and elevated lactate concentrations can each alter circadian rhythms in macrophages. Circadian rhythms were enhanced in pro-resolution macrophages but suppressed in pro-inflammatory macrophages, while acidic pH had divergent effects on circadian rhythms depending on macrophage phenotype. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate that pH-driven changes in circadian rhythms are not mediated solely by the cAMP signaling pathway. Remarkably, clock correlation distance analysis of tumor-associated macrophages (TAMs) revealed evidence of circadian disorder in TAMs. This is the first report providing evidence that circadian rhythms of macrophages are altered within the TME. Our data suggest that heterogeneity in circadian rhythms at the population level may underlie this circadian disorder. Finally, we sought to determine how circadian regulation of macrophages impacts tumorigenesis, and found that tumor growth was suppressed when macrophages had a functional circadian clock. Our work demonstrates a novel mechanism by which the tumor microenvironment can influence macrophage biology through altering circadian rhythms, and the contribution of circadian rhythms in macrophages to suppressing tumor growth.

Conducting atomic force microscopy studies on domain wall currents of Bi5 Ti3 FeO15 nanodots fabricated by anodic aluminum oxide nanotemplate and sol-gel process.

We investigated the local current characteristics of Bi5 Ti3 FeO15 (BTFO) nanodots on Nb-doped SrTiO3 substrates affected by their ferroelectric domain structures and domain walls. The BTFO nanodots with a diameter of about 50 nm were fabricated by anodic aluminum oxide nanotemplates and a BTFO sol-gel process. Based on a piezoresponse force microscope, it was confirmed that domain walls were formed in the ferroelectric domain structures of the epitaxial BTFO nanodots. Current changes due to ferroelectric tunneling junctions according to ferroelectric polarizations in epitaxial BTFO nanodots were confirmed by conduction atomic force microscopy. In particular, the domain walls formed in the epitaxial BTFO nanodots formed high currents compared to the currents in ferroelectric tunneling junctions due to polarizations. RESEARCH HIGHLIGHTS: Ferroelectric Bi5 Ti3 FeO15 nanodots with a diameter of 50 nm. Ferroelectric domain structures observed with piezoresponse force microscopy. High domain wall currents observed at domain boundaries observed with conducting atomic force microscopy.

Harnessing the Power of Voice: A Deep Neural Network Model for Alzheimer's Disease Detection.

Background and Purpose: Voice, reflecting cerebral functions, holds potential for analyzing and understanding brain function, especially in the context of cognitive impairment (CI) and Alzheimer's disease (AD). This study used voice data to distinguish between normal cognition and CI or Alzheimer's disease dementia (ADD). Methods: This study enrolled 3 groups of subjects: 1) 52 subjects with subjective cognitive decline; 2) 110 subjects with mild CI; and 3) 59 subjects with ADD. Voice features were extracted using Mel-frequency cepstral coefficients and Chroma. Results: A deep neural network (DNN) model showed promising performance, with an accuracy of roughly 81% in 10 trials in predicting ADD, which increased to an average value of about 82.0%±1.6% when evaluated against unseen test dataset. Conclusions: Although results did not demonstrate the level of accuracy necessary for a definitive clinical tool, they provided a compelling proof-of-concept for the potential use of voice data in cognitive status assessment. DNN algorithms using voice offer a promising approach to early detection of AD. They could improve the accuracy and accessibility of diagnosis, ultimately leading to better outcomes for patients.

Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.

The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.