Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial.

BACKGROUND: Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y12 inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE). METHODS: In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; pnon-inferiority<0·0001, psuperiority=0·89). INTERPRETATION: In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Glioblastoma Margin as a Diffusion Barrier Revealed by Photoactivation of Plasmonic Nanovesicles.

Glioblastoma (GBM) is the most complex and lethal primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including the angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.

Live Mapping of the Brain Extracellular Matrix and Remodeling in Neurological Disorders.

Live imaging of the brain extracellular matrix (ECM) provides vital insights into changes that occur in neurological disorders. Current techniques such as second or third-harmonic generation offer limited contrast for live imaging of the brain ECM. Here, a new method, pan-ECM via chemical labeling of extracellular proteins, is introduced for live brain ECM imaging. pan-ECM labels all major ECM components in live tissue including the interstitial matrix, basement membrane, and perineuronal nets. pan-ECM enables in vivo observation of the ECM heterogeneity between the glioma core and margin, as well as the assessment of ECM deterioration under stroke condition, without ECM shrinkage from tissue fixation. These findings indicate that the pan-ECM approach is a novel way to image the entire brain ECM in live brain tissue with optical resolution. pan-ECM has the potential to advance the understanding of ECM in brain function and neurological diseases.

Middle aged CAMKII-Cre:Cbsfl/fl mice: a new model for studying perioperative neurocognitive disorders.

Postoperative complications, such as perioperative neurocognitive disorders (PND), have become a major issue affecting surgical outcomes. However, the mechanism of PND remains unclear, and stable animal models of middle-aged PND are lacking. S-adenosylmethionine (SAM), a cystathionine beta-synthase (CBS) allosteric activator, can reduce the level of plasma homocysteine and prevent the occurrence of PND. However, the time and resource-intensive process of constructing models of PND in elderly animals have limited progress in PND research and innovative therapy development. The present study aimed to construct a stable PND model in middle-aged CAMKII-Cre:Cbsfl/fl mice whose Cbs was specifically knocked out in CAMKII positive neurons. Behavioral tests showed that these middle-aged mice displayed cognitive deficits which were aggravated by exploratory laparotomy under isoflurane anesthesia. Compared with typical PND mice which were 18-month-old, these middle-aged mice showed similar cognitive deficits after undergoing exploratory laparotomy under isoflurane anesthesia. Though there was no significant difference in the number of neurons in either the hippocampus or the cortex, a significant increase in numbers of microglia and astrocytes in the hippocampus was observed. These indicate that middle-aged CAMKII-Cre:Cbsfl/fl mice can be used as a new PND model for mechanistic studies and therapy development for PND.

Glioblastoma Margin as a Diffusion Barrier Revealed by Photoactivation of Plasmonic Nanovesicles.

Glioblastoma (GBM) is the most complex and lethal adult primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that the tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.

Regulatory factor X1 induces macrophage M1 polarization by promoting DNA demethylation in autoimmune inflammation.

Abnormal macrophage polarization is generally present in autoimmune diseases. Overwhelming M1 macrophage activation promotes the continuous progression of inflammation, which is one of the reasons for the development of autoimmune diseases. However, the underlying mechanism is still unclear. Here we explore the function of Regulatory factor X1 (RFX1) in macrophage polarization by constructing colitis and lupus-like mouse models. Both in vivo and in vitro experiments confirmed that RFX1 can promote M1 and inhibit M2 macrophage polarization. Furthermore, we found that RFX1 promoted DNA demethylation of macrophage polarization-related genes by increasing APOBEC3A/Apobec3 expression. We identified a potential RFX1 inhibitor, adenosine diphosphate (ADP), providing a potential strategy for treating autoimmune diseases.

Optical blood-brain-tumor barrier modulation expands therapeutic options for glioblastoma treatment.

The treatment of glioblastoma has limited clinical progress over the past decade, partly due to the lack of effective drug delivery strategies across the blood-brain-tumor barrier. Moreover, discrepancies between preclinical and clinical outcomes demand a reliable translational platform that can precisely recapitulate the characteristics of human glioblastoma. Here we analyze the intratumoral blood-brain-tumor barrier heterogeneity in human glioblastoma and characterize two genetically engineered models in female mice that recapitulate two important glioma phenotypes, including the diffusely infiltrative tumor margin and angiogenic core. We show that pulsed laser excitation of vascular-targeted gold nanoparticles non-invasively and reversibly modulates the blood-brain-tumor barrier permeability (optoBBTB) and enhances the delivery of paclitaxel in these two models. The treatment reduces the tumor volume by 6 and 2.4-fold and prolongs the survival by 50% and 33%, respectively. Since paclitaxel does not penetrate the blood-brain-tumor barrier and is abandoned for glioblastoma treatment following its failure in early-phase clinical trials, our results raise the possibility of reevaluating a number of potent anticancer drugs by combining them with strategies to increase blood-brain-tumor barrier permeability. Our study reveals that optoBBTB significantly improves therapeutic delivery and has the potential to facilitate future drug evaluation for cancers in the central nervous system.

CD38-Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells.

The robust and stable expression of CD38 in T-cell acute lymphoblastic leukemia (T-ALL) blasts makes CD38 chimeric antigen receptor (CAR)-T/natural killer (NK) a potential therapy for T-ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR-T/NK cells. Here a "2-in-1" gene editing strategy is developed to generate fratricide-resistant locus-specific CAR-T/NK cells. CD38-specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38KO/KI ) or exogenous EF1α promoter (CD38KO/KI EF1α). CD38 knockout reduces fratricide and allows the expansion of CAR-T cells. Meanwhile, CD38KO/KI EF1α results in higher CAR expression than CD38KO/KI in both CAR-T and CAR-NK cells. In a mouse T-ALL model, CD38KO/KI EF1α CAR-T cells eradicate tumors better than CD38KO/KI CAR-T cells. Surprisingly, CD38KO/KI CAR-NK cells show superior tumor control than CD38KO/KI EF1α CAR-NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR-T and CAR-NK cells differently. Therefore, these results support the efficacy of CD38 CAR-T/NK against T-ALL and demonstrate that the "2-in-1" strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation.

Inserting EF1α-driven CD7-specific CAR at CD7 locus reduces fratricide and enhances tumor rejection.

CAR-T therapies to treat T-cell malignancies face unique hurdles. Normal and malignant T cells usually express the same target for CAR, leading to fratricide. CAR-T cells targeting CD7, which is expressed in various malignant T cells, have limited expansion due to fratricide. Using CRISPR/Cas9 to knockout CD7 can reduce the fratricide. Here we developed a 2-in-1 strategy to insert EF1α-driven CD7-specific CAR at the disrupted CD7 locus and compared it to two other known strategies: one was random integration of CAR by a retrovirus and the other was site-specific integration at T-cell receptor alpha constant (TRAC) locus, both in the context of CD7 disruption. All three types of CD7 CAR-T cells with reduced fratricide could expand well and displayed potent cytotoxicity to both CD7+ tumor cell lines and patient-derived primary tumors. Moreover, EF1α-driven CAR expressed at the CD7 locus enhances tumor rejection in a mouse xenograft model of T-cell acute lymphoblastic leukemia (T-ALL), suggesting great clinical application potential. Additionally, this 2-in-1 strategy was adopted to generate CD7-specific CAR-NK cells as NK also expresses CD7, which would prevent contamination from malignant cells. Thus, our synchronized antigen-knockout CAR-knockin strategy could reduce the fratricide and enhance anti-tumor activity, advancing clinical CAR-T treatment of T-cell malignancies.

pan-ECM: live brain extracellular matrix imaging with protein-reactive dye.

The brain extracellular matrix (ECM), consisting of proteins and glycosaminoglycans, is a critical scaffold in the development, homeostasis, and disorders of the central nervous system (CNS) and undergoes remodeling in response to environmental cues. Live imaging of brain ECM structure represents a native view of the brain ECM but, until now, remains challenging due to the lack of a robust fluorescent labeling approach. Here, we developed a pan-ECM method for labeling the entire (Greek: pan) brain ECM network by screening and delivering a protein-reactive dye into the brain. pan-ECM enables imaging of ECM compartments in live brain tissue, including the interstitial matrix, basement membrane (BM), and perineuronal nets (PNNs), and even the ECM in glioblastoma and stroke mouse brains. This approach provides access to the structure and dynamics of the ECM and enhances our understanding of the complexities of the brain ECM and its contribution to brain health and disease.

Cordycepin protects islet ß-cells against glucotoxicity and lipotoxicity via modulating related proteins of ROS/JNK signaling pathway.

Type 2 diabetes mellitus (T2DM) is a common and multiple endocrine metabolic disease. When pancreatic ß cell in case of dysfunction, the synthesis and secretion of insulin are reduced. This study is to explore the effect of cordycepin (the molecular formula C10H13N5O3), a natural adenosine isolated from Cordyceps militaris, on high glucose/lipid-induced glucotoxicity and lipotoxicity in INS-1 cells. Our results showed that cordycepin improved cell viability, improved cell energy metabolism and promoted insulin synthesis and secretion. The mechanism may be related to that cordycepin reduces intracellular reactive oxygen species (ROS), increases ATP content in cells, causes membrane depolarization and balances the steady state of Ca2+ concentration, cordycepin inhibits cell apoptosis, which may be related to the downregulation of proteins level of c-Jun N-terminal kinases (JNK) phosphorylation, cytochrome c (Cyt-c), Cleaved Capase-3, the mRNA level of JNK, Cyt-c, Capase-3 and upregulation of proteins/mRNA level of pancreatic and duodenal homeobox factor-1 (PDX-1). These results suggest that cordycepin can inhibit cell apoptosis and protect cell number by downregulating ROS/JNK mitochondrial apoptosis pathway under high glucose/lipid environment, thereby improving the function of pancreatic islet cells, providing a theoretical basis for the related research on the prevention and control of cordycepin on T2DM.

Balancing activation and co-stimulation of CAR tunes signaling dynamics and enhances therapeutic potency.

CD19-targeting chimeric antigen receptors (CARs) with CD28 and CD3ζ signaling domains have been approved by the US FDA for treating B cell malignancies. Mutation of immunoreceptor tyrosine-based activation motifs (ITAMs) in CD3ζ generated a single-ITAM containing 1XX CAR, which displayed superior antitumor activity in a leukemia mouse model. Here, we investigated whether the 1XX design could enhance therapeutic potency against solid tumors. We constructed both CD19- and AXL-specific 1XX CARs and compared their in vitro and in vivo functions with their wild-type (WT) counterparts. 1XX CARs showed better antitumor efficacy in both pancreatic and melanoma mouse models. Detailed analysis revealed that 1XX CAR-T cells persisted longer in vivo and had a higher percentage of central memory cells. With fluorescence resonance energy transfer (FRET)-based biosensors, we found that decreased ITAM numbers in 1XX resulted in similar 70-kDa zeta chain-associated protein (ZAP70) activation, while 1XX induced higher Ca2+ elevation and faster extracellular signal-regulated kinase (Erk) activation than WT CAR. Thus, our results confirmed the superiority of 1XX against two targets in different solid tumor models and shed light on the underlying molecular mechanism of CAR signaling, paving the way for the clinical applications of 1XX CARs against solid tumors.

Exploring Gas-Liquid Reactions with Microjets: Lessons We Are Learning.

Liquid water is all around us: at the beach, in a cloud, from a faucet, inside a spray tower, covering our lungs. It is fascinating to imagine what happens to a reactive gas molecule as it approaches the surface of water in these examples. Some incoming molecules may first be deflected away after colliding with an evaporating water molecule. Those that do strike surface H2O or other surface species may bounce directly off or become momentarily trapped through hydrogen bonding or other attractive forces. The adsorbed gas molecule can then desorb immediately or instead dissolve, passing through the interfacial region and into the bulk, perhaps diffusing back to the surface and evaporating before reacting. Alternatively, it may react with solute or water molecules in the interfacial or bulk regions, and a reaction intermediate or the final product may then desorb into the gas phase. Building a "blow by blow" picture of these pathways is challenging for vacuum-based techniques because of the high vapor pressure of water. In particular, collisions within the thick vapor cloud created by evaporating molecules just above the surface scramble the trajectories and internal states of the gaseous target molecules, hindering construction of gas-liquid reaction mechanisms at the atomic scale that we strive to map out.The introduction of the microjet in 1988 by Faubel, Schlemmer, and Toennies opened up entirely new possibilities. Their inspired solution seems so simple: narrow the end of a glass tube to a diameter smaller than the mean free path of the vapor molecules and then push the liquid through the tube at speeds of a car on a highway. The narrow liquid stream creates a sparse vapor cloud, with water molecules spaced far enough apart that they and the reactant gases interact, at most, weakly. Experimentalists, however, confront a host of challenges: nozzle clogging, unstable jetting, searching for vacuum-compatible solutions, measuring low signal levels, and teasing out artifacts because the slender jet is the smallest surface in the vacuum chamber. In this Account, we describe lessons that we are learning as we explore gases (DCl, (HCOOH)2, N2O5) reacting with water molecules and solute ions in the near-interfacial region of these fast-flowing aqueous microjets.

A non-canonical retina-ipRGCs-SCN-PVT visual pathway for mediating contagious itch behavior.

Contagious itch behavior informs conspecifics of adverse environment and is crucial for the survival of social animals. Gastrin-releasing peptide (GRP) and its receptor (GRPR) in the suprachiasmatic nucleus (SCN) of the hypothalamus mediates contagious itch behavior in mice. Here, we show that intrinsically photosensitive retina ganglion cells (ipRGCs) convey visual itch information, independently of melanopsin, from the retina to GRP neurons via PACAP-PAC1R signaling. Moreover, GRPR neurons relay itch information to the paraventricular nucleus of the thalamus (PVT). Surprisingly, neither the visual cortex nor superior colliculus is involved in contagious itch. In vivo calcium imaging and extracellular recordings reveal contagious itch-specific neural dynamics of GRPR neurons. Thus, we propose that the retina-ipRGC-SCN-PVT pathway constitutes a previously unknown visual pathway that probably evolved for motion vision that encodes salient environmental cues and enables animals to imitate behaviors of conspecifics as an anticipatory mechanism to cope with adverse conditions.

Design of 3D polycaprolactone/ε-polylysine-modified chitosan fibrous scaffolds with incorporation of bioactive factors for accelerating wound healing.

Electrospun nanofibrous scaffolds show great application potentials for wound healing owing to their effective simulation of extracellular matrix (ECM). Three-dimensional (3D) nanofibrous dressings exhibit relatively high specific surface areas, better mimicry of native ECM, adjustable hydrophilicity and breathability, good histocompatibility, enhanced wound healing, and reduced inflammation. In the present work, we designed the 3D polycaprolactone/ε-polylysine modified chitosan (PCL/PCS) nanofibrous scaffolds by an electrospinning and gas foaming process. Then, gelatin and heparin (Gel/Hep) were assembled onto the surface of PCL/PCS nanofibers by electrostatic adsorption, and vascular endothelial growth factors (VEGFs) were also synchronously incorporated into Gel/Hep layer to form a multifunctional 3D nanofibrous scaffold (PCL/PCS@Gel/Hep+VEGF) for accelerating wound healing. The as-fabricated 3D PCL/PCS@GEL/Hep+VEGF nanofibrous scaffold showed excellent antibacterial ability, hemocompatibility and biocompatibility in vitro and wound healing ability in vivo. Immunological analysis showed that the as-fabricated nanofibrous scaffold inhibited inflammation at the wound sites while promoting angiogenesis during the wound healing process. STATEMENT OF SIGNIFICANCE: The electrospun 3D fibrous scaffolds using polycaprolactone/ε-polylysine modified chitosan (PCL/PCS) have been fabricated as backbone for mimicking the extracellular matrix (ECM). Gelatin and heparin (Gel/Hep) were wrapped onto the surface of PCL/PCS fibers by electrostatic adsorption and vascular endothelial growth factors (VEGFs) were also synchronously incorporated into surface Gel/Hep layer to form multifunctional 3D fibrous scaffolds. The as-fabricated multifunctional 3D fibrous scaffolds with good antibacterial ability and biocompatibility have been used as dressings for accelerating wound healing by inhibiting inflammation at the wound sites while promoting angiogenesis during the wound healing process.

A New iNKT-Cell Agonist-Adjuvanted SARS-CoV-2 Subunit Vaccine Elicits Robust Neutralizing Antibody Responses.

Adjuvants are essential components of vaccines. Invariant natural killer T (iNKT) cells are a distinct subset of T cells that function to bridge the innate and adaptive immunities and are capable of mediating strong and rapid responses to a range of diseases, including cancer and infectious disease. An increasing amount of evidence suggests that iNKT cells can help fight viral infection. In particular, iNKT-secreting IL-4 is a key mediator of humoral immunity and has a positive correlation with the levels of neutralizing antibodies. As iNKT cell agonists, αGC glycolipid (α-galactosylceramide, or KRN7000) and its analogues as vaccine adjuvants have begun to provide vaccinologists with a new toolset. Herein we found that a new iNKT-cell agonist αGC-CPOEt elicited a strong cytokine response with increased IL-4 production. Remarkably, after three immunizations, SARS-CoV-2 RBD-Fc adjuvanted by αGC-CPOEt evoked robust neutralizing antibody responses that were about 5.5-fold more than those induced by αGC/RBD-Fc and 25-fold greater than those induced by unadjuvanted RBD-Fc. These findings imply that αGC-CPOEt could be investigated further as a new COVID-19 vaccine adjuvant to prevent current and future infectious disease outbreaks.

Bismuth fire assay preconcentration and empirical coefficient LA-ICP-MS for the determination of ultra-trace Pt and Pd in geochemical samples.

In this work, a novel method of solid sample pretreatment technique of bismuth fire assay (Bi-FA) combined with solid sample determination by laser ablation ICP-MS (LA-ICP-MS) was reported for the determination of ultra-trace Pt and Pd in geochemical samples. Bismuth oxide (Bi2O3) was used as fire assay collector to directly enrich Pt and Pd from solid samples, and Ag protection cupellation was employed to generate Ag granules. After cleaning, weighing and annealing, the Ag granules were compressed into thin slices and determined by LA-ICP-MS for 195Pt, 105Pd and 109Ag (109Ag was selected as the internal standard isotope). Bi2O3 provided exceptionally low blanks compared to nickel oxide and lead oxide commonly employed in fire assay procedures, and could be applied directly without purification. Different from traditional empirical coefficient method, the Chinese Certified Reference Materials (CRMs) for Pt and Pd were treated by the same procedure to obtain completely matrix matched Ag slices. And then modified empirical coefficient method and internal standard calibration strategy was used to reduce the instability of LA-ICP-MS, and random multipoint laser ablation was employed to further reduce analytical variation resulting from heterogeneity of Pt and Pd in the Ag slice. Under optimal conditions, excellent calibration curves for Pt and Pd were obtained (0.407-2958 µg g-1 and 0.407-2636 µg g-1, respectively), with correlation coefficients exceeding 0.9996. The method detection limits for Pt and Pd were 0.074 and 0.037 ng g-1, respectively. The established method was applied successfully to analysis of real geochemical samples, with determined values in good agreement with the results of traditional Pb-FA graphite furnace atomic absorption spectrometry (GF-AAS), and spiked recoveries between 87.8 and 125.0%.

Responses of submerged macrophyte Ceratophyllum demersum to the gradient concentrations of microcystin-LR (MC-LR).

The responses of Ceratophyllum demersum to gradient concentrations (0, 0.8, 3.2, and 10 µg/L) of microcystin-LR (MC-LR) were comprehensively investigated by laboratory simulation experiments. The high reduction and accumulation efficiency of MC-LR by C. demersum were verified in this study. Results showed that the reduction ratio of MC-LR in the cultivation medium was up to 99% after 14 days of exposure, and the accumulation of MC-LR in C. demersum was highest at an exposure concentration of 10 µg/L, the value of which was 0.9 ng/g fresh weight (FW). Meanwhile, a series of negative effects on C. demersum was detectable, accompanied by a significant biomass reduction of the plant and changes in microbial community composition. In particular, this study indicated that the amount of Flavobacteria was elevated under the stress of MC-LR, provoking great threats to aquatic ecosystems. Moreover, oxidative damage was evidenced by the changes in total antioxidant capacity, superoxide dismutase, and glutathione. The results also demonstrated significant increases in sugar (0.025 mg/g FW), protein (0.3 mg/g FW), and carotenoids (0.6 mg/g FW) in C. demersum stressed by 10 µg/L of MC-LR, compared with the control without microcystins, which were among the defense strategies for dealing with adverse conditions. These results verified the good potential of submerged macrophytes as an eco-friendly strategy for controlling cyanobacterial blooms. However, the negative effects of MC-LR on the macrophytes themselves were also demonstrated, which would be considered in future practice and management.

Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus.

The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.