Learning heterogeneous reaction kinetics from X-ray videos pixel by pixel.

Reaction rates at spatially heterogeneous, unstable interfaces are notoriously difficult to quantify, yet are essential in engineering many chemical systems, such as batteries1 and electrocatalysts2. Experimental characterizations of such materials by operando microscopy produce rich image datasets3-6, but data-driven methods to learn physics from these images are still lacking because of the complex coupling of reaction kinetics, surface chemistry and phase separation7. Here we show that heterogeneous reaction kinetics can be learned from in situ scanning transmission X-ray microscopy (STXM) images of carbon-coated lithium iron phosphate (LFP) nanoparticles. Combining a large dataset of STXM images with a thermodynamically consistent electrochemical phase-field model, partial differential equation (PDE)-constrained optimization and uncertainty quantification, we extract the free-energy landscape and reaction kinetics and verify their consistency with theoretical models. We also simultaneously learn the spatial heterogeneity of the reaction rate, which closely matches the carbon-coating thickness profiles obtained through Auger electron microscopy (AEM). Across 180,000 image pixels, the mean discrepancy with the learned model is remarkably small (<7%) and comparable with experimental noise. Our results open the possibility of learning nonequilibrium material properties beyond the reach of traditional experimental methods and offer a new non-destructive technique for characterizing and optimizing heterogeneous reactive surfaces.

Single-Cell Study Unveils Lead Lifespan in Blood Cell Populations Follows a Universal Lognormal Distribution with Individual Skewness.

Lead is a widespread environmental hazard that can adversely affect multiple biological functions. Blood cells are the initial targets that face lead exposure. However, a systematic assessment of lead dynamics in blood cells at single-cell resolution is still absent. Herein, C57BL/6 mice were fed with lead-contaminated food. Peripheral blood was harvested at different days. Extracted red blood cells and leukocytes were stained with 19 metal-conjugated antibodies and analyzed by mass cytometry. We quantified the time-lapse lead levels in 12 major blood cell subpopulations and established the distribution of lead heterogeneity. Our results show that the lead levels in all major blood cell subtypes follow lognormal distributions but with distinctively individual skewness. The lognormal distribution suggests a multiplicative accumulation of lead with stochastic turnover of cells, which allows us to estimate the lead lifespan of different blood cell populations by calculating the distribution skewness. These findings suggest that lead accumulation by single blood cells follows a stochastic multiplicative process.

Glutaminase potentiates the glycolysis in esophageal squamous cell carcinoma by interacting with PDK1.

Increasing evidence has demonstrated that glutaminase (GLS) as a key mitochondrial enzyme plays a pivotal role in glutaminolysis, which widely participates in glutamine metabolism serving as main energy sources and building blocks for tumor growth. However, the roles and molecular mechanisms of GLS in esophageal squamous cell carcinoma (ESCC) remains unknown. Here, we found that GLS was highly expressed in ESCC tissues and cells. GLS inhibitor CB-839 significantly suppressed cell proliferation, colony formation, migration and invasion of ESCC cells, whereas GLS overexpression displayed the opposite effects. In addition, CB-839 markedly suppressed glucose consumption and lactate production, coupled with the downregulation of glycolysis-related proteins HK2, PFKM, PKM2 and LDHA, whereas GLS overexpression exhibited the adverse results. In vivo animal experiment revealed that CB-839 dramatically suppressed tumor growth, whereas GLS overexpression promoted tumor growth in ESCC cells xenografted nude mice. Mechanistically, GLS was localized in mitochondria of ESCC cells, which interacted with PDK1 protein. CB-839 attenuated the interaction of GLS and PDK1 in ESCC cells by suppressing PDK1 expression, which further evoked the downregulation of p-PDHA1 (s293), however, GLS overexpression markedly enhanced the level of p-PDHA1 (s293). These findings suggest that interaction of GLS with PDK1 accelerates the glycolysis of ESCC cells by inactivating PDH enzyme, and thus targeting GLS may be a novel therapeutic approach for ESCC patients.

Melatonin promotes the restoration of bone defects via enhancement of miR-335-5p combined with inhibition of TNFα/NF-κB signaling.

Accelerating the repair of a bone defect is crucial clinically due to the increased prevalence of trauma, tumor, and infections in bone. Studies have found that excess acute and chronic inflammation attenuate osteogenic differentiation of BMSCs (bone marrow mesenchymal stem cells). Moreover, TNF-α and NF-κB could inhibit osteoblasts differentiation of BMSCs and promote osteoclastogenesis via multiple mechanisms, such as increasing osteoclast precursor cells and acting synergistically with cell cytokines. However, melatonin could inhibit the expression of TNFα/NF-κB and promote bone formation by activating the Wnt/ß-catenin signaling pathway. However, there has been no evidence regarding the effect of melatonin on TNFα/NF-κB-inhibited osteoblastogenesis and bone formation. This study aimed to investigate the role of melatonin on TNFα/NF-κB-inhibited osteoblastogenesis and bone formation. Micro-CT, high-throughput screening, overexpression, and other methods were used, and we found that the number of osteoblasts was elevated with melatonin treatment. Additionally, TNFα/NF-κB signaling was inhibited, while miR-335-5p expression increased markedly following treatment with melatonin. Furthermore, miR-335-5p negatively regulated TNFα/NF-κB signaling, while miR-335-5p inhibitor ameliorated the effects of melatonin on TNFα/NF-κB. In conclusion, melatonin facilitates osteogenesis in bone defect healing by enhancing miR-335-5p expression and inhibiting the TNFα/NF-κB pathway.

Recent advances in pyruvate dehydrogenase kinase inhibitors: Structures, inhibitory mechanisms and biological activities.

Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.

Comparison of rehabilitation outcomes between robot-assisted and freehand screw placement in treatment of femoral neck fractures: a systematic review and meta-analysis.

PURPOSE: To compare the postoperative rehabilitation of femoral neck fractures treated with robot-assisted nailing and freehand nailing. METHODS: We systematically searched the PubMed, EMBASE, Cochrane, China National Knowledge Infrastructure(CNKI), WanFang database, China Science and Technology Journal Database (VIP) and Web of Science databases to identify potentially eligible articles. Indispensable data such as the year of publication, country, study type, robot type, age, number of patients, sex distribution, study design, and outcome indicators were extracted. The outcome indicators of interest included healing rate, length of healing time, Harris score, operation time, frequency of X-ray fluoroscopy, frequency of guide pin insertion, and intraoperative blood loss. RevMan 5.4.1 was used for the meta-analysis. RESULTS: Fourteen studies with 908 participants were included in this meta-analysis. The results showed that in terms of healing rate (SMD = 2.75, 95% CI, 1.03 to 7.32, P = 0.04) and Harris score (SMD = 2.27, 95% CI, 0.79 to 3.75, P = 0.003), robot-assisted screw placement technique scores were higher than the traditional freehand technique. Additionally, operative time (SMD = -12.72, 95% CI, -19.74 to -5.70, P = 0.0004), healing time (SMD = -13.63, 95% CI, -20.18 to -7.08, P < 0.0001), frequency of X-ray fluoroscopy (SMD = - 13.64, 95% CI, - 18.32 to - 8.95, P < 0.00001), frequency of guide pin insertion (SMD = - 7.95, 95% CI, - 10.13 to - 5.76, P < 0.00001), and intraoperative blood loss (SMD = - 17.33, 95% CI, - 23.66 to - 11.00, P < 0.00001) were lower for patients who underwent robotic-assisted screw placement than those for patients who underwent the conventional freehand technique. CONCLUSION: Compared to the freehand nailing technique, robot-assisted nailing helps improve postoperative healing rates in patients with femoral neck fractures; shortens healing times; better restores hip function; reduces the number of intraoperative fluoroscopies, guides pin placements; reduces intraoperative bleeding; and increases perioperative safety.

Platinum-Chimeric Carrier Cells for Ultratrace Cell Analysis in Mass Cytometry.

Mass cytometry by time-of-flight (CyTOF), a high-dimensional single-cell analysis platform, detects up to 50 biomarkers at single-cell resolution. However, CyTOF analysis of biological samples with a minimal number of available cells or rare cell subsets remains a major technical challenge due to the extensive loss of cells during cell recovery, staining, and acquisition. Here, we introduce a platinum-chimeric carrier cell strategy for mass cytometry profiling of ultratrace cell samples. Cisplatin can rapidly enter broken plasma membranes of dead cells and form a chimeric interaction with cellular proteins, peptides, and amino acids. Thus, 198Pt-cisplatin is adopted to tag carrier cells in the pretreatment stage. We investigated 8 cell lines that are commonly accessible in laboratories for their potential as carrier cells to preserve rare target cells for CyTOF analysis. We designed a panel of 35 protein biomarkers to evaluate the comprehensive single-cell subtype classification capability with or without the carrier cell strategy. We further demonstrated the detection and analysis of as few as 1 × 104 immune cells using our method. The proposed method thus allows CyTOF analysis on precious clinical samples with less abundant cells.

Dual Interface Compatibility Enabled via Composite Solid Electrolyte with High Transference Number for Long-Life All-Solid-State Lithium Metal Batteries.

The development of solid-state electrolytes (SSEs) effectively solves the safety problem derived from dendrite growth and volume change of lithium during cycling. In the meantime, the SSEs possess non-flammability compared to conventional organic liquid electrolytes. Replacing liquid electrolytes with SSEs to assemble all-solid-state lithium metal batteries (ASSLMBs) has garnered significant attention as a promising energy storage/conversion technology for the future. Herein, a composite solid electrolyte containing two inorganic components (Li6.25 Al0.25 La3 Zr2 O12 , Al2 O3 ) and an organic polyvinylidene difluoride matrix is designed rationally. X-ray photoelectron spectroscopy and density functional theory calculation results demonstrate the synergistic effect among the components, which results in enhanced ionic conductivity, high lithium-ion transference number, extended electrochemical window, and outstanding dual interface compatibility. As a result, Li||Li symmetric battery maintains a stable cycle for over 2500 h. Moreover, all-solid-state lithium metal battery assembled with LiNi0.6 Co0.2 Mn0.2 O2 cathode delivers a high discharge capacity of 168 mAh g-1 after 360 cycles at 0.1 C at 25 °C, and all-solid-state lithium-sulfur battery also exhibits a high initial discharge capacity of 912 mAh g-1 at 0.1 C. This work demonstrates a long-life flexible composite solid electrolyte with excellent interface compatibility, providing an innovative way for the rational construction of next-generation high-energy-density ASSLMBs.

Coordinated Immobilization and Rapid Conversion of Polysulfide Enabled by a Hollow Metal Oxide/Sulfide/Nitrogen-Doped Carbon Heterostructure for Long-Cycle-Life Lithium-Sulfur Batteries.

Lithium-sulfur batteries (LSBs) are recognized as the prospective candidate in next-generation energy storage devices due to their gratifying theoretical energy density. Nonetheless, they still face the challenges of the practical application including low utilization of sulfur and poor cycling life derived from shuttle effect of lithium polysulfides (LiPSs). Herein, a hollow polyhedron with heterogeneous CoO/Co9 S8 /nitrogen-doped carbon (CoO/Co9 S8 /NC) is obtained through employing zeolitic imidazolate framework as precursor. The heterogeneous CoO/Co9 S8 /NC balances the redox kinetics of Co9 S8 with chemical adsorption of CoO toward LiPSs, effectively inhibiting the shuttle of LiPSs. The mechanisms are verified by both experiment and density functional theory calculation. Meanwhile, the hollow structure acts as a sulfur storage chamber, which mitigates the volumetric expansion of sulfur and maximizes the utilization of sulfur. Benefiting from the above advantages, lithium-sulfur battery with S-CoO/Co9 S8 /NC achieves a high initial discharge capacity (1470 mAh g-1 ) at 0.1 C and long cycle life (ultralow capacity attenuation of 0.033% per cycle after 1000 cycles at 1 C). Even under high sulfur loading of 3.0 mg cm-2 , lithium-sulfur battery still shows the satisfactory electrochemical performance. This work may provide an idea to elevate the electrochemical performance of LSBs by constructing a hollow metal oxide/sulfide/nitrogen-doped carbon heterogeneous structure.

Potential Biomarker of Acute Anthracycline-induced Cardiotoxicity Among Children With Acute Lymphoblastic Leukemia: Cardiac Adriamycin-responsive Protein.

ABSTRACT: This study aimed to investigate whether serum cardiac adriamycin-responsive protein (CARP) can serve as a sensitive and specific biomarker of anthracyclines (ANT)-induced cardiotoxicity. Fifty-five children with acute lymphoblastic leukemia were recruited. Before and after the administration of ANT, serum levels of CARP, high-sensitivity troponin T, creatine kinase-MB, and electrocardiogram were measured. Postchemotherapeutic clinical manifestations of cardiotoxicity were also investigated. Adverse cardiac events (ACEs) were graded according to the Common Terminology Criteria for Adverse Events 4.0. Then, the CARP expression was statistically analyzed among different groups. The receiver operating characteristic curve was used to evaluate the efficacy of CARP in predicting acute ANT-induced cardiotoxicity. After ANT chemotherapy, the serum CARP concentration increased in the non-ACEs group but decreased in the ACEs group ( P < 0.05). In addition, not only the serum CARP levels (△CARP) was negatively correlated with the grade of ACEs (R=-0.754, P < 0.0001) but also the extent of QT interval corrected (QTc) prolongation (△QTc; R=-0.5592, P < 0.01). The area under the receiver operating characteristic curve of CARP was 90.94% ( P < 0.0001), and the sensitivity and specificity were 88.64% and 91.67%, respectively, all of which are superior to △high-sensitivity troponin T, △creatine kinase-MB, and △QTc. In conclusion, serum CARP could serve as a novel sensitive and specific biomarker of acute ANT-induced cardiotoxicity, which is negatively associated with ACE grade.

FTO: a critical role in obesity and obesity-related diseases.

In recent years, obesity is a growing pandemic in the world and has likely contributed to increasing the incidence of obesity-related diseases. Fat mass and obesity-associated gene (FTO) is the first gene discovered which has a close connection with fat. Recent studies suggested that FTO gene has played an important role in the molecular mechanisms of many diseases. Obesity is considered to be a hereditary disease and can evoke many kinds of diseases, including polycystic ovary syndrome (PCOS), type 2 diabetes mellitus (T2DM), cancer, etc., whose exact possible molecular mechanisms responsible for the effect of FTO on obesity and obesity-related diseases remain largely unknown. In this review, we comprehensively discuss the correlation between FTO gene and obesity, cancer, PCOS, T2DM, as well as the molecular mechanism involved in these diseases.

Comparative study of extracellular vesicles derived from mesenchymal stem cells and brain endothelial cells attenuating blood-brain barrier permeability via regulating Caveolin-1-dependent ZO-1 and Claudin-5 endocytosis in acute ischemic stroke.

BACKGROUND: Blood-brain barrier (BBB) disruption is a major adverse event after ischemic stroke (IS). Caveolin-1 (Cav-1), a scaffolding protein, played multiple roles in BBB permeability after IS, while the pros and cons of Cav-1 on BBB permeability remain controversial. Numerous studies revealed that extracellular vesicles (EVs), especially stem cells derived EVs, exerted therapeutic efficacy on IS; however, the mechanisms of BBB permeability needed to be clearly illustrated. Herein, we compared the protective efficacy on BBB integrity between bone marrow mesenchymal stem cells derived extracellular vesicles (BMSC-EVs) and EVs from brain endothelial cells (BEC-EVs) after acute IS and investigated whether the mechanism was associated with EVs antagonizing Cav-1-dependent tight junction proteins endocytosis. METHODS: BMSC-EVs and BEC-EVs were isolated and characterized by nanoparticle tracking analysis, western blotting, and transmission electron microscope. Oxygen and glucose deprivation (OGD) treated b. End3 cells were utilized to evaluate brain endothelial cell leakage. CCK-8 and TRITC-dextran leakage assays were used to measure cell viability and transwell monolayer permeability. Permanent middle cerebral artery occlusion (pMCAo) model was established, and EVs were intravenously administered in rats. Animal neurological function tests were applied, and microvessels were isolated from the ischemic cortex. BBB leakage and tight junction proteins were analyzed by Evans Blue (EB) staining and western blotting, respectively. Co-IP assay and Cav-1 siRNA/pcDNA 3.1 vector transfection were employed to verify the endocytosis efficacy of Cav-1 on tight junction proteins. RESULTS: Both kinds of EVs exerted similar efficacies in reducing the cerebral infarction volume and BBB leakage and enhancing the expressions of ZO-1 and Claudin-5 after 24 h pMCAo in rats. At the same time, BMSC-EVs were outstanding in ameliorating neurological function. Simultaneously, both EVs treatments suppressed the highly expressed Cav-1 in OGD-exposed b. End3 cells and ischemic cerebral microvessels, and this efficacy was more prominent after BMSC-EVs administration. Cav-1 knockdown reduced OGD-treated b. End3 cells monolayer permeability and recovered ZO-1 and Claudin-5 expressions, whereas Cav-1 overexpression aggravated permeability and enhanced the colocalization of Cav-1 with ZO-1 and Claudin-5. Furthermore, Cav-1 overexpression partly reversed the lower cell leakage by BMSC-EVs and BEC-EVs administrations in OGD-treated b. End3 cells. CONCLUSIONS: Our results demonstrated that Cav-1 aggravated BBB permeability in acute ischemic stroke, and BMSC-EVs exerted similar antagonistic efficacy to BEC-EVs on Cav-1-dependent ZO-1 and Claudin-5 endocytosis. BMSC-EVs treatment was superior in Cav-1 suppression and neurological function amelioration.

20(S)- Protopanaxadiol saponins isolated from Panax notoginseng target the binding of HMGB1 to TLR4 against inflammation in experimental ulcerative colitis.

Ulcerative colitis (UC) has emerged as a global healthcare issue due to high prevalence and unsatisfying therapeutic measures. 20(S)- Protopanaxadiol saponins (PDS) from Panax notoginseng with anti-inflammatory properties is a potential anti-colitis agent. Herein, we explored the effects and mechanisms of PDS administration on experimental murine UC. Dextran sulfate sodium-induced murine UC model was employed to investigate anti-colitis effects of PDS, and associated mechanisms were further verified in HMGB1-exposed THP-1 macrophages. Results indicated that PDS administration exerted ameliorative effects against experimental UC. Moreover, PDS administration remarkably downregulated mRNA expressions and productions of related pro-inflammatory mediators, and reversed elevated expressions of proteins related to NLRP3 inflammasome after colitis induction. Furthermore, administration with PDS also suppressed the expression and translocation of HMGB1, interrupting the downstream TLR4/NF-κB pathway. In vitro, ginsenoside CK and 20(S)-protopanaxadiol, the metabolites of PDS, exhibited greater potential in anti-inflammation, and intervened with the TLR4-binding domain of HMGB1 predictably. Expectedly, ginsenoside CK and 20(S)-protopanaxadiol administrations inhibited the activation of TLR4/NF-κB/NLRP3 inflammasome pathway in HMGB1-exposed THP-1 macrophages. Summarily, PDS administration attenuated inflammatory injury in experimental colitis by blocking the binding of HMGB1 to TLR4, majorly attributed to the antagonistic efficacies of ginsenoside CK and 20(S)-protopanaxadiol.

Compositing Benzothieno[3,2-b]Benzofuran Derivatives with Single-Walled Carbon Nanotubes for Enhanced Thermoelectric Performance.

Although numerous thermoelectric (TE) composites of organic materials and single-walled carbon nanotubes (SWCNTs) have been developed in the past decade, most of the research has been related to polymers without much on organic small molecules (OSMs). In this work, benzothieno[3,2-b]benzofuran (BTBF) and its derivatives (BTBF-Br and BTBF-2Br) were synthesized and their TE composites with SWCNTs were prepared. It is found that the highest molecular orbital level and band gap (Eg) of BTBF, BTBF-Br, and BTBF-2Br gradually decrease upon the introduction of electron-withdrawing Br group on BTBF. These changes significantly improve the Seebeck coefficient and power factor (PF) of OSM/SWCNT composites. An appropriate energy barrier between BTBF-2Br and SWCNTs promotes the energy filtering effect, which further contributes to the enhancement of composites' thermoelectric properties. The composites of SWCNTs and BTBF-2Br with the smallest Eg (4.192 eV) afford the best thermoelectric performance with the room temperature power factor of 169.70 ± 3.46 µW m-1 K-2 in addition to good mechanical flexibility and thermal stability. This study provides a feasible strategy for the preparation of OSM/SWCNT composites with improved thermoelectric properties.

Value for combination of T1WI star-VIBE with TWIST-VIBE dynamic contrast-enhanced MRI in distinguishing lung nodules. / T1WI star-VIBE增强结合TWIST-VIBE动态增强MRI对肺结节诊断的应用价值（英文）.

OBJECTIVES: With the increasing detection rate of lung nodules, the qualitative problem of lung nodules has become one of the key clinical issues. This study aims to evaluate the value of combining dynamic contrast-enhanced (DCE) MRI based on time-resolved imaging with interleaved stochastic trajectories-volume interpolated breath hold examination (TWIST-VIBE) with T1 weighted free-breathing star-volumetric interpolated breath hold examination (T1WI star-VIBE) in identifying benign and malignant lung nodules. METHODS: We retrospectively analyzed 79 adults with undetermined lung nodules before the operation. All nodules of patients included were classified into malignant nodules (n=58) and benign nodules (n=26) based on final diagnosis. The unenhanced T1WI-VIBE, the contrast-enhanced T1WI star-VIBE, and the DCE curve based on TWIST-VIBE were performed. The corresponding qualitative [wash-in time, wash-out time, time to peak (TTP), arrival time (AT), positive enhancement integral (PEI)] and quantitative parameters [volume transfer constant (Ktrans), interstitium-to-plasma rate constant (Kep), and fractional extracellular space volume (Ve)] were evaluated. Besides, the diagnostic efficacy (sensitivity and specificity) of enhanced CT and MRI were compared. RESULTS: There were significant differences in unenhanced T1WI-VIBE hypo-intensity, and type of A, B, C DCE curve type between benign and malignant lung nodules (all P<0.001). Pulmonary malignant nodules had a shorter wash-out time than benign nodules (P=0.001), and the differences of the remaining parameters were not statistically significant (all P>0.05). After T1WI star-VIBE contrast-enhanced MRI, the image quality was further improved. Compared with enhanced CT scan, the sensitivity (82.76% vs 80.50%) and the specificity (69.23% vs 57.10%) based on MRI were higher than that of CT (both P<0.001). CONCLUSIONS: T1WI star-VIBE and dynamic contrast-enhanced MRI based on TWIST-VIBE were helpful to improve the image resolution and provide more information for clinical differentiation between benign and malignant lung nodules.

Melatonin increases bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats via the promotion of osteogenesis.

BACKGROUND: Osteoporosis is a disease threatening the health of millions of individuals. Melatonin is found to be a potential anti-osteoporosis drug. However, whether melatonin plays a role against osteoporosis at different stages of the menopause and the underlying mechanisms are unknown. METHODS: Ovariectomy was utilized as a model of perimenopausal and postmenopausal osteoporosis. A total of 100 mg/kg melatonin, or solvent alone, was added to the drinking water of the rats over 8 weeks. Perimenopausal rats immediately received intervention following ovariectomy while postmenopausal rats received intervention 8 weeks after ovariectomy. All rats underwent overdose anesthesia following intervention after which blood samples and femurs were collected for further analysis. Rat femurs were scanned using micro-CT and examined histologically. The serum levels of melatonin and osteogenic biochemical markers were measured and the expression of osteogenesis-associated genes (Runx2, Sp7) were quantified by real-time quantitative PCR. Alkaline phosphatase (ALP) activity and the gene expression (Col1a1, Runx2, Alpl, and Bglap) were measured after bone marrow mesenchymal stem cells (BMSCs) were osteogenically induced, both with and without melatonin in vitro. ALP staining and Alizarin Red S staining were used to identify osteogenesis. RESULTS: Analysis by micro-CT and histological staining demonstrated that bone mass decreased and bone microarchitecture deteriorated over time after ovariectomy. Intervention with melatonin increased bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats. Serum levels of ALP continuously increased after ovariectomy while osteocalcin levels initially rose, then decreased. Melatonin increased the serum levels of ALP and osteocalcin and mRNA expression levels of Runx2 and Sp7 in normal and postmenopausal rats, the opposite of the markers in perimenopausal rats. In vitro study demonstrated that 100 µmol/L melatonin increased the mRNA expression of Col1a1, Runx2, and Alpl three and/or seven days after intervention, and Alpl and Bglap 14 d after intervention. Melatonin increased ALP activity and the extent of ALP and matrix mineralization in the late stage of osteogenesis. CONCLUSIONS: Bone mass continuously decreased after ovariectomy, while melatonin increased bone mass and ameliorated bone metabolism in normal, perimenopausal, and postmenopausal osteoporotic rats due to the induction of osteogenic differentiation in BMSCs.

In situ imaging for tumor microbiome interactions via imaging mass cytometry on single-cell level.

Co-detection of multiplex cancer subtypes and bacteria subtypes in situ is crucial for understanding tumor microbiome interactions in tumor microenvironment. Current standard techniques such as immunohistochemical staining and immunofluorescence staining are limited for their multiplicity. Simultaneously visualizing detailed cell subtypes and bacteria distribution across the same pathological section remains a major technical challenge. Herein, we developed a rapid semi-quantitative method for in situ imaging of bacteria and multiplex cell phenotypes on the same solid tumor tissue sections. We designed a panel of antibody probes labeled with mass tags, namely prokaryotic and eukaryotic cell hybrid probes for in situ imaging (PEHPSI). For application demonstration, PEHPSI stained two bacteria subtypes (lipopolysaccharides (LPS) for Gram-negative bacteria and lipoteichoic acid (LTA) for Gram-positive bacteria) simultaneously with four types of immune cells (leukocytes, CD8 + T-cells, B-cells and macrophages) and four breast cancer subtypes (classified by a panel of 12 human proteins) on the same tissue section. We unveiled that breast cancer cells are commonly enriched with Gram-negative bacteria and almost absent of Gram-positive bacteria, regardless of the cancer subtypes (triple-negative breast cancer [TNBC], HER2+, Luminal A and Luminal B). Further analysis revealed that on the single-cell level, Gram-negative bacteria have a significant correlation with CD8 + T-cells only in HER2+ breast cancer, while PKCD, ER, PR and Ki67 are correlated with Gram-negative bacteria in the other three subtypes of breast cancers. On the cell population level, in TNBC, CD19 expression intensity is up-regulated by approximately 25% in bacteria-enriched cells, while for HER2+, Luminal A and Luminal B breast cancers, the intensity of biomarkers associated with the malignancy, metastasis and proliferation of cancer cells (PKCD, ISG15 and IFI6) is down-regulated by 29%-38%. The flexible and expandable PEHPSI system permits intuitive multiplex co-visualization of bacteria and mammalian cells, which facilitates future research on tumor microbiome and tumor pathogenesis.

Unusual Catalytic Properties of High-Energetic-Facet Polar Metal Oxides.

ConspectusHeterogeneous catalysis is an area of great importance not only in chemical industries but also in energy conversion and environmental technologies. It is well-established that the specific surface morphology and structure of solid catalysts exert remarkable effects on catalytic performances, since most physical and chemical processes take place on the surface during catalytic reactions. Different from the widely studied faceted metallic nanoparticles, metal oxides give more complicated structures and surface features. Great progress has been achieved in controlling the shape and exposed facets of transition metal oxides during nanocrystal growth, usually by using surface-directing agents (SDAs). However, the effects of exposed facets remain controversial among researchers. It should be noted that high-energetic facets, especially polar facets, tend to lower their surface energy via different relaxation processes, such as surface reconstruction, redox change, adsorption of countercharged species, etc. These processes can subsequently lead to surface defect formation and break the surface stoichiometry, and the resulting changes in electronic configurations and charge migration properties all play important roles in heterogeneous catalysis. Because different materials prefer different relaxation methods, various surface features are created, and different techniques are required to investigate the different features from facet to facet. Conventional characterization techniques such as X-ray diffraction, X-ray photoelectron spectroscopy, transmission electron microscopy, etc. appear to be insufficient to elucidate the underlying principles of the facet effects. Consequently, an increasing number of novel techniques have been developed to differentiate the surface features, enabling greater understanding of the effects of facets on heterogeneous catalysis.In this Account, on the basis of previous studies by our own group, we will focus on the effects of tailored facets on heterogeneous catalysis introduced by engineered simple binary metal oxide nanomaterials primarily with exposed polar facets, in combination with detailed surface studies using a range of new characterization techniques. As a result, fundamental principles of the effects of facets are elucidated, and the structure-activity correlations are demonstrated. The surface features introduced by different relaxation processes are also investigated using a range of characterization techniques. For example, electron paramagnetic resonance spectroscopy is used to detect the oxygen vacancies, while probe-assisted solid-state NMR spectroscopy is shown to be facet-sensitive and able to evaluate the surface acidity. It is also shown that such different features influence the heterogeneous catalytic performances in different ways. With the help of first-principles density functional theory calculations, unique properties of the faceted metal oxides are discussed and unraveled. Besides, other materials such as transition metal chalcogenides and layered double hydroxides are also briefly discussed with regard to their application in facet-dependent catalysis studies.

Isolated steroid-resistant nephrotic syndrome in a Chinese child carrying a de novo mutation in WT1 gene:a case report and literature review.

BACKGROUND: Isolated steroid-resistant nephrotic syndrome (ISRNS) is caused by mutations in the Wilms' tumor-1 (WT1) gene, which encodes glomerular podocytes and podocyte slit diaphragm.We report a novel 8-year-old female patient with ISRNS carrying a de novo missense mutation in WT1 gene and presenting a new type of pathology, have never been reported.We also systematically review previous reports of ISRNS in Chinese children. CASE PRESENTATION: A 8-year-old Chinese patient who had steroid-resistant nephrotic syndrome,responded poorly to immunosuppressant, and had no extrarenal manifestations. The patient had a female phenotype and karyotype of 46, XX. A new type of renal pathology, proliferative sclerosing glomerulonephritis (PSG),and a de novo missense mutation in WT1 gene, c.748C > T (p.R250W),which have not yet been reported, were identified. She was diagnosed with ISRNS.The patient progressed to end-stage renal disease at the age of 10 years,underwent dialysis and kidney transplant. Renal function and urine protein were normal during 4-year follow-up. CONCLUSIONS: WT1 gene testing should be performed to guide treatment for patients with steroid-resistant nephrotic syndrome, especially for isolated cases and female patients.

Ferroptosis Related Immunomodulatory Effect of a Novel Extracellular Polysaccharides from Marine Fungus Aureobasidium melanogenum.

Marine fungi represent an important and sustainable resource, from which the search for novel biological substances for application in the pharmacy or food industry offers great potential. In our research, novel polysaccharide (AUM-1) was obtained from marine Aureobasidium melanogenum SCAU-266 were obtained and the molecular weight of AUM-1 was determined to be 8000 Da with 97.30% of glucose, 1.9% of mannose, and 0.08% galactose, owing to a potential backbone of α-D-Glcp-(1→2)-α-D-Manp-(1→4)-α-D-Glcp-(1→6)-(SO3-)-4-α-D-Glcp-(1→6)-1-ß-D-Glcp-1→2)-α-D-Glcp-(1→6)-ß-D-Glcp-1→6)-α-D-Glcp-1→4)-α-D-Glcp-6→1)-[α-D-Glcp-4]26→1)-α-D-Glcp and two side chains that consisted of α-D-Glcp-1 and α-D-Glcp-(1→6)-α-D-Glcp residues. The immunomodulatory effect of AUM-1 was identified. Then, the potential molecular mechanism by which AUM-1 may be connected to ferroptosis was indicated by metabonomics, and the expression of COX2, SLC7A11, GPX4, ACSL4, FTH1, and ROS were further verified. Thus, we first speculated that AUM-1 has a potential effect on the ferroptosis-related immunomodulatory property in RAW 264.7 cells by adjusting the expression of GPX4, regulated glutathione (oxidative), directly causing lipid peroxidation owing to the higher ROS level through the glutamate metabolism and TCA cycle. Thus, the ferroptosis related immunomodulatory effect of AUM-1 was obtained.