Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug's mode of inhibition has not been fully investigated. METHODS: We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H2O2) as a surrogate of oxidative stress in non-lethal APAP overdose. RESULTS: Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (Ki) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion. CONCLUSIONS: T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity.

HMGB1-mediated restriction of EPO signaling contributes to anemia of inflammation.

Anemia of inflammation, also known as anemia of chronic disease, is refractory to erythropoietin (EPO) treatment, but the mechanisms underlying the EPO refractory state are unclear. Here, we demonstrate that high mobility group box-1 protein (HMGB1), a damage-associated molecular pattern molecule recently implicated in anemia development during sepsis, leads to reduced expansion and increased death of EPO-sensitive erythroid precursors in human models of erythropoiesis. HMGB1 significantly attenuates EPO-mediated phosphorylation of the Janus kinase 2/STAT5 and mTOR signaling pathways. Genetic ablation of receptor for advanced glycation end products, the only known HMGB1 receptor expressed by erythroid precursors, does not rescue the deleterious effects of HMGB1 on EPO signaling, either in human or murine precursors. Furthermore, surface plasmon resonance studies highlight the ability of HMGB1 to interfere with the binding between EPO and the EPOR. Administration of a monoclonal anti-HMGB1 antibody after sepsis onset in mice partially restores EPO signaling in vivo. Thus, HMGB1-mediated restriction of EPO signaling contributes to the chronic phase of anemia of inflammation.

Phosphorus desorption regulates phosphorus fraction dynamics in soil aggregates of revegetated ecosystems.

To elucidate the mechanisms and effects of phosphorus (P) desorption on P fractions in soil aggregates of revegetated ecosystems is fundamental for regulating the P supply and biogeochemical cycle. We selected four aggregate sizes (1-5, 0.5-1, 0.25-0.5, and <0.25 mm) from a desert revegetation chronosequence (11, 31, 40, 57, and 65 years) as our study targets and used the Freundlich model to reveal the dynamics of P desorption and changes in P fractions. The results showed that the calibrated model [Formula: see text] for different size aggregates in seven deserts (two natural and five revegetated) described the P desorption characteristics well. In soil aggregates of revegetated deserts, smaller aggregates with higher specific surface area did not desorb more P, nor did older aggregates after revegetation. The natural P desorption process in aggregates resulted in significant changes in Ca2-P, Ca8-P, Al-P and Fe-P fractions (p < 0.05), and revegetation years also affected P fraction dynamics significantly (p < 0.05). This study highlights that the calibrated kinetic model in the revegetated soil aggregates elucidated the P desorption characteristics, and that the P desorption process drove P fraction changes.

Effect of a novel interocclusal recording method on occlusal accuracy of implant-supported fixed prostheses: A randomized clinical trial.

OBJECTIVES: To investigate the effect of a novel interocclusal recording method on the occlusal accuracy of implant-supported fixed prostheses for partially dentate patients with distal extension. MATERIALS AND METHODS: Twenty patients with two or more adjacent teeth missing in the distal extension and scheduled to receive implant-supported fixed prostheses were enrolled. Two interocclusal recording methods were used: placing polyvinyl siloxane (PVS) on the interocclusal recording caps (test), and placing PVS on healing abutments (control). The intraoral occlusal contacts in maximal intercuspal position (MIP) were compared with those in the mounted casts to calculate sensitivity and positive predictive value (PPV). Then, patients were randomly allocated into two groups to determine which interocclusal record would be used. The implant prostheses' evaluations mainly included occlusal adjustment height, volume, and time, occlusal contact score based on articulating paper examination. Paired-samples t-test, Mann-Whitney U test, and least squares regression analyzed the statistic differences. RESULTS: The test method had higher sensitivity to detect intraoral occlusal contacts than the control method (p = .002), but similar PPV (p = .10). During the prostheses' evaluations, the occlusal adjustment height in the test group was significantly lower than that in the control group [99.4 (53.2, 134.2) vs. 159.0 (82.3, 247.8) µm, p = .03], while the occlusal contact score before adjustment was higher (p = .006). The groups had similar occlusal adjustment volume and time. CONCLUSIONS: The novel interocclusal recording method for implant-supported fixed prostheses was more accurate and could reduce the occlusal adjustment.

Microplastic transport during desertification in drylands: Abundance and characterization of soil microplastics in the Amu Darya-Aral Sea basin, Central Asia.

Desertification and microplastic pollution are major environmental issues that impact the function of the ecosystem and human well-being of drylands. Land desertification may influence soil microplastics' abundance, transport, and distribution, but their distribution in the dryland deserts of Central Asia's Amu Darya-Aral Sea basin is unknown. Here, we investigated the abundance and distribution of microplastics in dryland desert soils from the Amu Darya River to the Aral Sea basin in Central Asia at a spatial scale of 1000 km and soil depths ranging from 0 to 50 cm. Microplastics were found in soils from all sample locations, with abundances ranging from 182 to 17841 items kg-1 and a median of 3369. Twenty-four polymers were identified, with polyurethane (PU, 37.3%), silicone resin (SR, 17.0%), and chlorinated polyethylene (CPE, 9.8%) accounting for 64.1% of all polymer types. The abundance of microplastics was significantly higher in deep (20-50 cm) soils than in surface (0-5, 5-20 cm) soils. The main morphological characteristics of the observed microplastics were small size (20-50 µm) and irregular particles with no round edges (mean eccentricity 0.65). The abundance was significantly and positively related to soil EC and TP. According to the findings, desertification processes increase the abundance of microplastic particles in soils and promote migration to deeper soil layers. Human activities, mainly grazing, may be the region's primary cause of desertification and microplastic pollution. Our findings provide new information on the diffusion of microplastics in drylands during desertification; these findings are critical for understanding and promoting dryland plastic pollution prevention and control.

Atmospheric dryness thresholds of grassland productivity decline in China.

Atmospheric dryness events are bound to have a broad and profound impact on the functions and structures of grassland ecosystems. Current research has confirmed that atmospheric dryness is a key moisture constraint that inhibits grassland productivity, yet the risk threshold for atmospheric dryness to initiate ecosystem productivity loss has not been explored. Based on this, we used four terrestrial ecosystem models to simulate gross primary productivity (GPP) data, analyzed the role of vapor pressure deficit (VPD) in regulating interannual variability in Chinese grasslands by focusing on the dependence structure of VPD and GPP, and then constructed a bivariate linkage function to calculate the conditional probability of ecosystem GPP loss under atmospheric dryness, and further analyzed the risk threshold of ecosystem GPP loss triggered by atmospheric dryness. The main results are as follows: we found that (1) the observed and modeled VPD of Chinese grasslands increases rapidly in both historical and future periods. VPD has a strongly negative regulation on ecosystem GPP, and atmospheric dryness is an important moisture constraint that causes deficit and even death to ecosystem GPP. (2) The probability of the enhanced atmospheric dryness that induced GPP decline in Chinese grasslands in the future period increases significantly. (3) When the VPD is higher than 40.07 and 27.65 percentile of the past and future time series, respectively, the risk threshold of slight ecosystem GPP loss can be easily initiated by atmospheric dryness. (4) When the VPD is higher than 82.57 and 65.09 percentile, respectively, the threshold of moderate ecosystem GPP loss can be exceeded by the benchmark probability. (5) The risk threshold of severe ecosystem GPP loss is not initiated by atmospheric dryness in the historical period, and the threshold of severe ecosystem GPP loss can be initiated when the future VPD is higher than 91.92 percentile. In total, a slight atmospheric dryness event is required to initiate a slight ecosystem GPP loss threshold, and a stronger atmospheric dryness event is required to initiate a severe ecosystem GPP loss. Our study enhances the understandings of past and future atmospheric dryness on grassland ecosystems, and strongly suggests that more attention be invested in improving next-generation models of vegetation dynamics processes with respect to the response of mechanisms of ecosystem to atmospheric dryness.

Occlusal contact and clearance of posterior implant-supported single crowns designed by two different methods: a self-controlled study.

BACKGROUND: Precise occlusal design of implant-supported fixed prostheses is difficult to achieve by the conventional wax-up method, often requiring chairside adjustments. The computer-aided design (CAD) method is promising. This study aims to compare the occlusal contacts and clearance of posterior implant-supported single crowns designed by the CAD and conventional methods. METHODS: Sample size calculation indicated fourteen samples per group. Two sets of type-IV plaster casts with a single implant analog inserted in the posterior teeth region were mounted as master casts in a mechanical articulator in maximal intercuspal position (MIP). Seven working cast sets were obtained from each master cast by a closed tray technique, and mounted in MIP. Two implant-supported single crowns were designed with an occlusal clearance to achieve light occlusal contact in each working cast set by CAD and conventional method, separately. For the CAD group, the crown was designed in digital models obtained by scanning the working casts. For the conventional group, wax-up of the crown was prepared on the working casts and scanned to generate a STL file. In the working and master casts, mean and minimum occlusal clearances in the designed occlusal contact area of the both finished prostheses were calculated using the occlusal clearance (OC) and occlusal record (OR) method. The prostheses' occlusion was evaluated in master casts. RESULTS: For the evaluation in the working casts, both design methods had similar mean occlusal clearances by the OC method (195.4 ± 43.8 vs. 179.8 ± 41.8 µm; P = 0.300), while CAD group resulted in a significantly larger minimum occlusal clearance in the designed occlusal contact area (139.5 ± 52.3 vs. 99.8 ± 43.8 µm; P = 0.043). Both design methods had similar mean and minimum occlusal clearances by the OR method (P > 0.05). For the evaluation in the master casts, both design techniques had similar mean and minimum occlusal clearances, number and distribution of occlusal contacts, and lateral interference ratios (P > 0.05). CONCLUSION: Occlusal contact and clearance of posterior implant-supported single crowns designed by the CAD method can be at least as good as those designed by the conventional wax-up method.

Extracellular microRNA 130b-3p inhibits eCIRP-induced inflammation.

Although microRNAs regulate mRNA expression intracellularly, they are often released into the circulation in inflammatory diseases. During sepsis, secreted extracellular cold-inducible RNA-binding protein (eCIRP) acts as a damage-associated molecular pattern (DAMP), inducing tissue damage by elevating inflammatory cytokines and chemokines. Here, we report that the circulating microRNA 130b-3p inhibits eCIRP-mediated sterile and cecal ligation and puncture (CLP)-induced non-sterile inflammation. We find that levels of miR-130b-3p are increased in the serum of septic mice and patients and that it strongly interacts with recombinant murine (rm) CIRP in vitro and with eCIRP in the serum of septic mice in vivo. Combining a miR-130b-3p mimic with rmCIRP significantly decreases TNF-α release by macrophages compared to only rmCIRP-treated cells. This combined treatment also dose-dependently decreases the affinity of rmCIRP with its receptor TLR4/MD2. Finally, injection of a miR-130b-3p mimic significantly reduces rmCIRP- or CLP-induced systemic inflammation and acute lung injury in mice. These data show that extracellular miR-130b-3p functions as a novel endogenous inhibitor of eCIRP and point to an innovative therapeutic approach to treat inflammatory diseases.

Determination of catechin and glutathione using copper aspartate nanofibers with multiple enzyme-like activities.

Copper aspartate nanofibers were facilely prepared based on aspartic acid and copper (CuAsp nanofibers). It is found that the prepared CuAsp nanofibers have catalytic activities of five enzymes, including peroxidase, laccase, catalase, ascorbate oxidase, and superoxide dismutase mimetic activities. The kinetic and catalytic properties of CuAsp nanofibers were systematically investigated, showing their high catalytic activity, excellent stability, and reusability. The laccase mimetic activity of nanofibers could be used to detect catechin in the range 20-1200 µM with a detection limit of 5.88 µM. In addition, a sensing platform for glutathione with a detection limit of 0.25 µM and a detection range of 1-50 µM was established based on CuAsp nanofibers which have the peroxidase-mimicking activity. The sensor had good selectivity and could detect glutathione in actual samples of human serum. Therefore, CuAsp nanofibers with multi-enzyme activity have broad application prospects such as biosensing, environmental management, and disease diagnosis.

Dynamics of soil organic carbon and nitrogen and their relations to hydrothermal variability in dryland.

Carbon (C) and nitrogen (N) cycles of terrestrial ecosystems play key roles in global climate change and ecosystem sustainability. In recent decades, climate change has threatened the nutrient balance of dryland ecosystems. However, its impact on soil organic carbon (SOC) and soil total nitrogen (STN) in drylands of China are still unclear. In this study, the structural equation model (SEM) was used to explain the relationship between environmental variables used by the best model and SOC or STN. Then Adaptive Boosting Regressor (AdaBoost), Gradient Boosting Regression (GBRT), Extreme gradient boosting Regression (XGBoost) and Random Forest Regression (RF) were used to establish the prediction model of SOC and STN based on soil samples along with environmental variables. The performance of these models was assessed based on a 10-fold cross-validation method using three statistical indicators. Finally, we predicted the SOC and STN of soil samples from 2000 to 2019 based on the best model. Overall, the RF model performed better at predicting SOC and STN in drylands than the other three prediction models (AdaBoost, GBRT, XGBoost). Climate factors were the main factors affecting SOC and STN in the study area. In the Alashan, a dryland in northern China, the precipitation in the growing season increased from 2000 to 2019, at a rate of 12.9 mm/decade. During the same period, the annual sunshine duration significantly decreased by 66 h/decade. Along with interannual hydrothermal variability, SOC showed a fluctuating upward trend at a rate of 0.04 g/kg/decade, while STN exhibited a fluctuating downward trend at 0.003 g/kg/decade from 2000 to 2019. Due to the effects of climate change, dryland were considered as potential sites for carbon sequestration. However, due to the annual hydrothermal variance causing dynamic annual changes, it was deemed unstable. Moreover, it would cause STN loss, which might reduce soil fertility. More attention should be paid to STN monitoring in dryland in the future.

The Accuracy of Transferring Casts in Maximal Intercuspal Position to a Virtual Articulator.

PURPOSE: To analyze the accuracy of transferring casts in maximal intercuspal position to a virtual articulator by using transfer plates in the laboratory scanner before and after occlusal optimization. MATERIAL AND METHODS: Five sets of standard dental casts were mounted on a mechanical articulator in maximal intercuspal position. The number and position of occlusal contacts were determined with 12-µm articulating foil. After a calibration process according to the manufacturer's instructions, the mountings were transferred to a virtual articulator using the transfer plates in a laboratory scanner. The occlusion of the digital casts was determined before and after the occlusal optimization process. Then, the sensitivity and positive predictive value were determined by comparing the occlusal contact points in the virtual articulator with those in the mechanical articulator. To evaluate trueness, the occlusal surface of the maxillary teeth in the mechanical articulator was recorded by polyvinyl siloxane occlusal record in maximal intercuspal position and retained on the mandibular arch. The trueness was calculated as the deviation between the occlusal surface of the maxillary teeth in the mechanical articulator and the virtual articulator. To evaluate precision, one set of the casts was scanned 10 times. And the deviation of the interarch position of the maxillary arches when superimposing the mandibular arches of every 2 different scans was calculated. RESULTS: The sensitivity before occlusal optimization (0.14 ± 0.15) was significantly lower than that after occlusal optimization (0.82 ± 0.10) (p = 0.003). However, there was no significant difference between the positive predictive value before (0.80 ± 0.45) and after (0.81 ± 0.09) occlusal optimization (p = 0.952). The trueness before (91.0 ± 10.7 µm) and after (75.4 ± 25.2 µm) occlusal optimization had no significant difference (p = 0.249). The precision before occlusal optimization (11.6 ± 3.8 µm) was significantly superior to that after occlusal optimization (75.6 ± 39.2 µm ) (p < 0.001). CONCLUSIONS: The accuracy of transferring casts in maximal intercuspal position to a virtual articulator using transfer plates in the laboratory scanner could be improved after occlusal optimization and can meet the clinical needs for occlusal design and analysis of prostheses.

Carbon fluxes response of an artificial sand-binding vegetation system to rainfall variation during the growing season in the Tengger Desert.

Revegetation is considered as an effective approach for desertification control, and artificial sand-binding vegetation exerts a significant contributor to carbon cycling in arid and semiarid regions; however, this is largely determined by the rainfall regime. We measured carbon fluxes (the net ecosystem CO2 exchange (NEE), the gross ecosystem productivity (GEP) and the ecosystem respiration (Reco)) during the growing season of 2014-2016 using the eddy covariance technique and explored the effects of rainfall variables (amount, timing distribution and pulse size) and environmental factors on carbon fluxes at different time scales. The system had NEE values of -117.5 and -98.9 g C m-2 during the growing seasons of 2015 (dry year) and 2016 (wet year), respectively. When the rainfall amount did not differ significantly between spring and autumn, the cumulative GEP was greater in spring than in autumn, whereas the cumulative Reco and NEE showed the opposite pattern. Small (<5 mm) rain events failed to trigger obvious GEP and NEE pulses, whereas ≥ 5 mm or a series of small rain events led to high assimilation but with hysteresis. The magnitude of Reco increased as the rain pulses increased. The Random Forest (RF) algorithm revealed that soil water contents had a great impact on carbon fluxes at different integration periods. A correlation analysis showed that the soil water contents were positively correlated with GEP and Reco and negatively correlated with NEE over different time scales in most cases. These findings suggest that artificial vegetation not only improves habitat restoration but is a significant carbon sink during both dry and wet growing season, which is likely to supplement our knowledge gap to accurately evaluate the current carbon budget in dry land.

Inhibition of HMGB1/RAGE-mediated endocytosis by HMGB1 antagonist box A, anti-HMGB1 antibodies, and cholinergic agonists suppresses inflammation.

BACKGROUND: Extracellular high mobility group box 1 protein  (HMGB1) serves a central role in inflammation as a transporter protein, which binds other immune-activating molecules that are endocytosed via the receptor for advanced glycation end-products (RAGE). These pro-inflammatory complexes are targeted to the endolysosomal compartment, where HMGB1 permeabilizes the lysosomes. This enables HMGB1-partner molecules to avoid degradation, to leak into the cytosol, and to reach cognate immune-activating sensors. Lipopolysaccharide (LPS) requires this pathway to generate pyroptosis by accessing its key cytosolic receptors, murine caspase 11, or the human caspases 4 and 5. This lytic, pro-inflammatory cell death plays a fundamental pathogenic role in gram-negative sepsis. The aim of the study was to identify molecules inhibiting HMGB1 or HMGB1/LPS cellular internalization. METHODS: Endocytosis was studied in cultured macrophages using Alexa Fluor-labeled HMGB1 or complexes of HMGB1 and Alexa Fluor-labeled LPS in the presence of an anti-HMGB1 monoclonal antibody (mAb), recombinant HMGB1 box A protein, acetylcholine, the nicotinic acetylcholine receptor subtype alpha 7 (α7 nAChR) agonist GTS-21, or a dynamin-specific inhibitor of endocytosis. Images were obtained by fluorescence microscopy and quantified by the ImageJ processing program (NIH). Data were analyzed using student's t test or one-way ANOVA followed by the least significant difference or Tukey's tests. RESULTS: Anti-HMGB1 mAb, recombinant HMGB1 antagonist box A protein, acetylcholine, GTS-21, and the dynamin-specific inhibitor of endocytosis inhibited internalization of HMGB1 or HMGB1-LPS complexes in cultured macrophages. These agents prevented macrophage activation in response to HMGB1 and/or HMGB1-LPS complexes. CONCLUSION: These results demonstrate that therapies based on HMGB1 antagonists and the cholinergic anti-inflammatory pathway share a previously unrecognized molecular mechanism of substantial clinical relevance.

Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo.

We generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-differentiation of melanoma cells to Schwann-like cells. In melanoma cancer cell lines, both lopinavir and lopinavir-NO induced morphological changes, minor apoptosis and reactive oxygen species (ROS) production. However, caspase activation and autophagy were detected only in B16 cells, indicating a cell line-specific treatment response. Lopinavir-NO released NO intracellularly, and NO neutralization restored cell viability. Treatment with lopinavir-NO induced only a transient activation of Akt and inhibition of P70S6 kinase. The results of this study identify lopinavir-NO as a promising candidate for further clinical trials in melanoma and possibly other solid tumours.

Exploring the biological functional mechanism of the HMGB1/TLR4/MD-2 complex by surface plasmon resonance.

BACKGROUND: High Mobility Group Box 1 (HMGB1) was first identified as a nonhistone chromatin-binding protein that functions as a pro-inflammatory cytokine and a Damage-Associated Molecular Pattern molecule when released from necrotic cells or activated leukocytes. HMGB1 consists of two structurally similar HMG boxes that comprise the pro-inflammatory (B-box) and the anti-inflammatory (A-box) domains. Paradoxically, the A-box also contains the epitope for the well-characterized anti-HMGB1 monoclonal antibody "2G7", which also potently inhibits HMGB1-mediated inflammation in a wide variety of in vivo models. The molecular mechanisms through which the A-box domain inhibits the inflammatory activity of HMGB1 and 2G7 exerts anti-inflammatory activity after binding the A-box domain have been a mystery. Recently, we demonstrated that: 1) the TLR4/MD-2 receptor is required for HMGB1-mediated cytokine production and 2) the HMGB1-TLR4/MD-2 interaction is controlled by the redox state of HMGB1 isoforms. METHODS: We investigated the interactions of HMGB1 isoforms (redox state) or HMGB1 fragments (A- and B-box) with TLR4/MD-2 complex using Surface Plasmon Resonance (SPR) studies. RESULTS: Our results demonstrate that: 1) intact HMGB1 binds to TLR4 via the A-box domain with high affinity but an appreciable dissociation rate; 2) intact HMGB1 binds to MD-2 via the B-box domain with low affinity but a very slow dissociation rate; and 3) HMGB1 A-box domain alone binds to TLR4 more stably than the intact protein and thereby antagonizes HMGB1 by blocking HMGB1 from interacting with the TLR4/MD-2 complex. CONCLUSIONS: These findings not only suggest a model whereby HMGB1 interacts with TLR4/MD-2 in a two-stage process but also explain how the A-box domain and 2G7 inhibit HMGB1.

Correction to: Exploring the biological functional mechanism of the HMGB1/TLR4/MD-2 complex by surface plasmon resonance.

After publication of this article (He et al., 2018), the corresponding authors recognised an error in Scheme 1, in particular to section "A. HMGB1/TLR4/MD-2 complex formation". Above "Step 2: B box binding to MD-2", the text incorrectly read: "Low affinity / extremely slow off". In addition, some text was omitted below "TLR4/MD-2". The correct version of Scheme 1 is included in this Correction article. The original article (He et al., 2018) has been corrected.

C1q and HMGB1 reciprocally regulate human macrophage polarization.

A healthy immune system results from a balance of stimulatory and inhibitory pathways that allow effective responses to acute insults, without descending into chronic inflammation. Failed homeostasis is characteristic of autoimmune diseases such as systemic lupus erythematosus. Although HMGB1 induces proinflammatory M1-like macrophage differentiation, we describe a mechanism by which C1q modulates this activity and collaborates with HMGB1 to induce the differentiation of monocytes to anti-inflammatory M2-like macrophages. These anti-inflammatory macrophages are unresponsive to dendritic cell induction factors, effectively removing them from participation in an adaptive immune response. This pathway is mediated through a complex with RAGE and LAIR-1 and depends on relative levels of C1q and HMGB1. Importantly, these data provide insight into a homeostatic mechanism in which C1q and HMGB1 can cooperate to terminate inflammation, and which may be impaired in C1q-deficient patients with autoimmune disease.

Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors.

Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with ß-hemoglobinopathies.

339 J high-energy Ti:sapphire chirped-pulse amplifier for 10 PW laser facility.

We report on the laser pulse output of 339 J centered at 800 nm from a chirped-pulse amplification (CPA) Ti:sapphire laser system at the Shanghai Superintense Ultrafast Laser Facility. The experimental results demonstrated that the parasitic lasing as well as the transverse amplified spontaneous emission of the homemade 235-mm-diameter Ti:sapphire final amplifier were suppressed successfully via the temporal dual-pulse pumped scheme and the index-matching liquid cladding technique. The maximum pump-to-signal conversion efficiency of 32.1% was measured for the final amplifier. With a compressor transmission efficiency of 64% and a compressed pulse duration of 21 fs obtained for the sample light at a lower energy level, this laser system could potentially generate a compressed laser pulse with a peak power of 10.3 PW. The experimental results represent significant progress with respect to the CPA laser.

Neutral alleles at hybrid sterility loci of Oryza glaberrima from AA genome relatives in Genus Oryza.

Hybrid sterility between Oryza sativa and O. glaberrima is a main reproduction barrier when transferring the favorable alleles from O. glaberrima to O. sativa and it happens due to allelic interaction at sterility loci. Neutral alleles at each locus have the potential to overcome the sterility between the two cultivated rice species. In this study, an O. sativa cultivar Dianjingyou 1 (DJY1) and its near-isogenic lines (NILs) harboring the single sterility allele S1-glab, S19-glab, S20-glab, S37-glab, S38-glab and S39-glab as the tested lines were crossed with O. glaberrima, O. rufipogon, O. nivara, O. glumaepatula, O. barthii, O. meridionalis and O. sativa so as to detect the neutral alleles of these loci. Pollen fertility was investigated in the paired F1s based on two seasons' result and genotypic segregation was also analyzed in some F2 populations to confirm the results of pollen fertility investigation. The neutral alleles of S38-n and S39-n were identified based upon the pollen fertility and genotypic segregation analysis for the first time. The neutral alleles of sterility loci detected from present report have the potential to know of the nature of interspecific hybrid sterility, and to overcome the interspecific hybrid sterility between O. sativa and O. glaberrima.