Novel ferrofluid based on hydrophobic deep eutectic solvents for separation and analysis of trace estrogens in environmental water and urine samples.

A novel ferrofluid prepared from a hydrophobic deep eutectic solvent (DES) and Fe3O4@graphite composite materials was introduced as a green microextraction medium for the separation and enrichment of trace estrogens in real samples. It was found that the ferrofluid greatly improved the capacity and selectivity of target analytes, benefiting from the enrichment of both DES and Fe3O4@graphite composite materials. Using a combination of high-performance liquid chromatography-fluorescence detection (HPLC-FLD) and vortex-assisted liquid-liquid microextraction (VALLME), a new method was established for simultaneous rapid processing and accurate determination of three estrogens (estradiol [E2], estriol [E3], and ethinyl estradiol [EE2]) in environmental water and urine samples. Key parameters affecting the extraction efficiency were optimized using a single-factor approach and response surface methodology. Under optimal conditions, this method yielded a low limit of detection (1.01 ng L-1, 3.03 ng L-1, and 25.0 ng L-1 for EE2, E2, and E3, respectively), wide linear range (3-200,000 ng L-1), high enrichment factors (9.81-47.2), and satisfactory recovery (73.8-129.0%). Compared with traditional analytical techniques, this method avoids the use of volatile toxic organic extraction solvents and cumbersome phase separation operations.

Agomelatine promotes differentiation of oligodendrocyte precursor cells and preserves white matter integrity after cerebral ischemic stroke.

White matter injury contributes to neurological disorders after acute ischemic stroke (AIS). The repair of white matter injury is dependent on the re-myelination by oligodendrocytes. Both melatonin and serotonin antagonist have been proved to protect against post-stroke white matter injury. Agomelatine (AGM) is a multi-functional treatment which is both a melatonin receptor agonist and selective serotonin receptor antagonist. Whether AGM protects against white matter injury after stroke and the underlying mechanisms remain elusive. Here, using the transient middle cerebral artery occlusion (tMCAO) model, we evaluated the therapeutic effects of AGM in stroke mice. Sensorimotor and cognitive functions, white matter integrity, oligodendroglial regeneration and re-myelination in stroke hemisphere after AGM treatment were analyzed. We found that AGM efficiently preserved white matter integrity, reduced brain tissue loss, attenuated long-term sensorimotor and cognitive deficits in tMCAO models. AGM treatment promoted OPC differentiation and enhanced re-myelination both in vitro, ex vivo and in vivo, although OPC proliferation was unaffected. Mechanistically, AGM activated low density lipoprotein receptor related protein 1 (LRP1), peroxisome proliferator-activated receptor γ (PPARγ) signaling thus promoted OPC differentiation and re-myelination after stroke. Inhibition of PPARγ or knock-down of LRP1 in OPCs reversed the beneficial effects of AGM. Altogether, our data indicate that AGM represents a novel therapy against white matter injury after cerebral ischemia.

Association of co-exposure to metal(loid)s during pregnancy with birth outcomes in the Tibetan plateau.

Maternal metal (loid)s exposure has been related to birth outcomes but the results are still inconclusive. Most previous studies have discussed the single metal (loid)s, neglecting the scene of co-exposure. We examined the associations of both single metal (loid)s and metal mixtures with birth outcomes in a birth cohort from the Tibetan Plateau, including body weight, body length, head circumference, small for gestational age (SGA), and Ponderal index (PI). In our analysis of 1069 women, we measured 29 metal (loid)s in urine samples in the third trimester. The associations of single metal (loid)s with categorical or continuous birth outcomes were evaluated using a generalized linear mixed-effects model or linear mixed-effects model, respectively. The least absolute shrinkage and selection operator, Bayesian kernel machine, and Quantile g-computation regression were used to explore the joint association. We also evaluated the interactive effects of ethnicity and altitude on the effect of metal (loid)s on birth outcomes. Copper (Cu) concentration in maternal urine was positively associated with SGA, birth weight, birth length, and head circumference in the single pollutant models. For instance, Cu was associated with an increased risk of SGA [OR (95% CI) = 1.56 (1.23, 1.97); P < 0.001]. We didn't find significant joint association of metal mixtures with birth outcomes except a positive association between the mixture of Cu, Magnesium (Mg), and Iron (Fe) with the risk of SGA when the exposure level was above its 80th percentile, and Cu dominated the adverse association in a non-linear manner. Living altitude modified the associations of Cu with SGA and the positive association was only found in participants living at high altitude. In conclusion, maternal urinary metal (loid)s, especially Cu, was the dominant harmful metal (loid)s when associated with SGA on the Tibetan Plateau.

Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model.

Accumulation of amyloid beta protein (Aß) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aß and produce disease-modifying mediators. Herein, we report that Aß40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

Overexpression of a novel small auxin-up RNA gene, OsSAUR11, enhances rice deep rootedness.

BACKGROUND: Deep rooting is an important factor affecting rice drought resistance. However, few genes have been identified to control this trait in rice. Previously, we identified several candidate genes by QTL mapping of the ratio of deep rooting and gene expression analysis in rice. RESULTS: In the present work, we cloned one of these candidate genes, OsSAUR11, which encodes a small auxin-up RNA (SAUR) protein. Overexpression of OsSAUR11 significantly enhanced the ratio of deep rooting of transgenic rice, but knockout of this gene did not significantly affect deep rooting. The expression of OsSAUR11 in rice root was induced by auxin and drought, and OsSAUR11-GFP was localized both in the plasma membrane and cell nucleus. Through an electrophoretic mobility shift assay and gene expression analysis in transgenic rice, we found that the transcription factor OsbZIP62 can bind to the promoter of OsSAUR11 and promote its expression. A luciferase complementary test showed that OsSAUR11 interacts with the protein phosphatase OsPP36. Additionally, expression of several auxin synthesis and transport genes (e.g., OsYUC5 and OsPIN2) were down-regulated in OsSAUR11-overexpressing rice plants. CONCLUSIONS: This study revealed a novel gene OsSAUR11 positively regulates deep rooting in rice, which provides an empirical basis for future improvement of rice root architecture and drought resistance.

Bone Marrow Mesenchymal Stem Cell-Derived Dermcidin-Containing Migrasomes enhance LC3-Associated Phagocytosis of Pulmonary Macrophages and Protect against Post-Stroke Pneumonia.

Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.

A green extraction strategy for the detection of antioxidants in food simulants and beverages migrated from plastic packaging materials.

Antioxidants, widely utilized in the food packaging field, have a risk of migrating into foodstuffs and eventually entering the human body. In this work, a novel method was established for green extraction and determination of antioxidants in food simulants migrated from plastic packaging materials. It was found that the antioxidants could be extracted directly from food simulants by in-situ formation of hydrophobic deep eutectic solvents with low toxic medium-chain fatty alcohols. Under the optimal conditions, the limit of detection was 0.15 to 0.25 µg/L, and the limit of quantification was 0.5 to 1.0 µg/L for the antioxidants. The extraction reaches equilibrium in 2 min. Importantly, butylated hydroxytoluene was detected in two types of the surveyed food contact materials. The established method shows high sensitivity, high enrichment factor, and strong anti-interference ability, and can be used for the separation and enrichment of ultra-trace antioxidants in foodstuffs.

Simultaneous degradation and separation of antibiotics in sewage effluent by photocatalytic nanofiltration membrane in a continuous dynamic process.

Bifunctional photocatalytic nanofiltration (PNF) membrane is increasingly concerned in practical micro-polluted water purification, but there are still several bottlenecks that inhibit its practicality. In this context, the feasibility of a novel metal-free and visible light-responsive surface-anchored PNF membrane for simultaneously removing target antibiotics in real sewage effluent in a continuous dynamic process was explored. The results showed that the optimal PNF-4 membrane was expectedly consisted of an inside tight sub-nanopore structured separation layer and an outside thinner, smoother, super hydrophilic mesoporous degradation layer, respectively. Consequently, the activated PNF-4 membrane could synergistically reduce trimethoprim and sulfamethoxazole concentrations to below two orders of magnitude, accompanying with almost constant high water permeability, suggesting that the hydrophilic modification of the mesoporous degradation layer basically offsets its inherent hydraulic resistance. Also, after repeating the fouling-physical rinsing process three times lasted for 78 h, only sporadic adherent contaminants remained onto the top surface, together with the minimal total and irreversible fouling ratios (as low as 7.2% and 1.2%, respectively), strongly demonstrated that PNF-4 membrane displayed good self-cleaning performance. Undoubtedly, this will significantly reduce its potential cleaning frequency and maintenance cost in long-term operation. Meanwhile, the acute and chronic biotoxicities of its permeate to Virbrio qinghaiensis sp. -67 were also reduced sharply to 2.22% and 0.45%, respectively. All of these evidences suggest that the dual functions of PNF-4 membrane are synergetic in an uninterrupted permeating process. It will provide useful insights for continuously enhancing the practicality and effectiveness of PNF membrane in actual micro-polluted water purification scenarios.

FOXP3+ macrophage represses acute ischemic stroke-induced neural inflammation.

Proper termination of cell-death-induced neural inflammation is the premise of tissue repair in acute ischemic stroke (AIS). Macrophages scavenge cell corpses/debris and produce inflammatory mediators that orchestrate immune responses. Here, we report that FOXP3, the key immune-repressive transcription factor of Tregs, is conditionally expressed in macrophages in stroke lesion. FOXP3 ablation in macrophages results in detrimental stroke outcomes, emphasizing the beneficial role of FOXP3+ macrophages. FOXP3+ macrophages are distinct from the M1 or M2 subsets and display superactive efferocytic capacity. With scRNAseq and analysis of FOXP3-bound-DNA isolated with CUT & RUN, we show that FOXP3 facilitates macrophage phagocytosis through enhancing cargo metabolism. FOXP3 expression is controlled by macroautophagic/autophagic protein degradation in resting macrophages, while initiation of LC3-associated phagocytosis (LAP) competitively occupies the autophagic machineries, and thus permits FOXP3 activation. Our data demonstrate a distinct set of FOXP3+ macrophages with enhanced scavenging capability, which could be a target in immunomodulatory therapy against AIS.Abbreviations: ADGRE1/F4/80: adhesion G protein-coupled receptor E1; AIF1/Iba1: allograft inflammatory factor 1; AIS: acute ischemic stroke; ARG1: arginase 1; ATP: adenosine triphosphate; BECN1/Beclin1: Beclin 1, autophagy related; BMDM: bone marrow-derived macrophages; CKO: conditional knockout; CSF1/M-CSF: colony stimulating factor 1 (macrophage); CSF2/GM-CSF: colony stimulating factor 2; CSF3/G-CSF: colony stimulating factor 3; CUT & RUN: cleavage under targets and release using nuclease; CyD: cytochalasin D; DAMP: danger/damage-associated molecular pattern; DIL: dioctadecyl-3,3,3,3-tetramethylin docarbocyanine; ELISA: enzyme linked immunosorbent assay; GO: Gene Ontology; FCGR3/CD16: Fc receptor, IgG, low affinity III; HMGB1: high mobility group box 1; IFNG/IFNγ: interferon gamma; IP: immunoprecipitation; KEGG: Kyoto Encyclopedia of Genes and Genomes; ITGAM/CD11b: integrin subunit alpha M; ITGAX/CD11c: integrin subunit alpha X; LAP: LC3-associated phagocytosis; LC-MS: liquid chromatography-mass spectrometry; LPS: lipopolysaccharide; MRC1/CD206: mannose receptor, C type 1; O4: oligodendrocyte marker O4; PBMC: peripheral blood mononuclear cells; RBC: red blood cells; PTPRC/CD45: protein tyrosine phosphatase, receptor type, C; RBFOX3/NeuN: RNA binding protein, fox 1 homolog (C. elegans) 3; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; scRNAseq: single cell RNA sequencing; SQSTM1/p62 (sequestosome 1); TGFB/TGFß: transforming growth factor, beta; tMCAO: transient middle cerebral artery occlusion; TNF/TNFα: tumor necrosis factor; Treg: regulatory T cell.

Melatonin Offers Dual-Phase Protection to Brain Vessel Endothelial Cells in Prolonged Cerebral Ischemia-Recanalization Through Ameliorating ER Stress and Resolving Refractory Stress Granule.

Ischemic-reperfusion injury limits the time window of recanalization therapy in cerebral acute ischemic stroke (AIS). Brain vessel endothelial cells (BVECs) form the first layer of the blood-brain barrier (BBB) and are thus the first sufferer of ischemic-reperfusion disorder. The current study demonstrates that melatonin can reduce infarct volume, alleviate brain edema, ameliorate neurological deficits, and protect BBB integrity in prolonged-stroke mice. Here, we demonstrate that endoplasmic reticulum (ER)-associated injury contributes to BVEC death in the dural phase of reperfusion after prolonged ischemia. When encountering ischemia, ER stress arises, specifically activating PERK-EIF2α signaling and the subsequent programmed cell death. Prolonged ischemia leads stress granules (SGs) to be refractory, which remain unresolved and accumulate in ER during recanalization. During reperfusion, refractory SGs activate PKR-EIF2α and further exacerbate BVEC injury. We report that melatonin treatment downregulates ER stress in the ischemic period and enhances dissociation of the refractory SGs during reperfusion, thus offering dual-phase protection to BVECs in prolonged cerebral stroke. Mechanistically, melatonin enhances autophagy in BVECs, which preserves ER function and resolves refractory SGs. We, therefore, propose that melatonin is a potential treatment to extend the time window of delayed recanalization therapy in AIS.

Multi-residue analysis of 206 pesticides in grass forage by the one-step quick, easy, cheap, effective, rugged, and safe method combined with ultrahigh-performance liquid chromatography quadrupole orbitrap mass spectrometry.

A novel method for detecting pesticide multi-residue in grass forage (alfalfa and oat) was established based on the one-step automatic extraction and purification technology of quick, easy, cheap, effective, rugged, and safe combined with ultrahigh-performance liquid chromatography quadrupole Orbitrap high-resolution mass spectrometry. The crushed sample was extracted with acetonitrile with 1% acetate, followed by a cleanup step with a primary-secondary amine, octadecylsilane, and graphitized carbon black. The extraction and purification were carried out using the one-step automatic pretreatment equipment. The target pesticides were acquired in positive ion electrospray ionization mode and full scan/data dependent secondary scan mode. The calibration curve shows good linearity over the corresponding concentration range, with the coefficient of determination greater than 0.99. The screening detection limits were 0.5-50 µg/kg, and the limit of quantification for the 206 pesticides was set at 1-50 µg/kg. At the spiking levels of one, two, and 10 times of limit of quantification, more than 95% of pesticides had recovery between 70-120%, with a relative standard deviation ≤20%. The method was proved to be simple, rapid, high-sensitivity, and could be routinely used for the high throughput screening and quantitative analysis of pesticide residues in alfalfa and oat.

A Sustainable Strategy for Solid-Phase Extraction of Antiviral Drug from Environmental Waters by Immobilized Hydrogen Bond Acceptor.

Deep eutectic solvents are a new generation of green solvents composed of hydrogen bond acceptors and donors. However, when used as extractants in liquid-liquid separation, they are difficult to recycle and easy to lose. In order to solve these problems, herein, immobilized hydrogen bond acceptor adsorbent material was prepared for the separation and enrichment of antiviral drug arbidol from seven kinds of environmental water samples by in situ formation of hydrophobic deep eutectic solvents. The structure, morphology and thermal stability of the adsorbents were characterized, the separation and enrichment conditions for the targeted analyte were optimized, and the adsorption thermodynamics and kinetics were investigated. It was found that the adsorbent material could effectively enrich trace arbidol with the recovery more than 95% at the concentration above 7.5 ng/mL, and the enrichment factor was as high as 634.7. Coexisting substances, such as NaCl, KCl, CaCl2 and MgCl2, did not interfere with the adsorption of arbidol, even if their concentration was high, up to 1.0 mol/L, and the relative recovery for real samples was in the range from 92.5% to 100.3%. Furthermore, the immobilized hydrogen bond acceptor could be recycled and reused, and the recovery of arbidol was still above 95% after 12 adsorption-desorption cycles. The mechanism study demonstrates that the synergistic effect of hydrogen bonding and π-π stacking is the primary factor for the high adsorption efficiency.

Disparities of obesity and non-communicable disease burden between the Tibetan Plateau and developed megacities in China.

Background: Non-communicable diseases (NCDs) including risk factors, e.g., obesity, are the major causes of preventable deaths in China, yet NCD disparities in China remain under-studied. Objective: This study aimed to compare the determinants and burden of NCDs within four selected provinces in mainland China: the least developed Qinghai-Tibet Plateau group (PG, Tibetan Autonomous Region [TAR] and Qinghai Province) and most developed megacity group (MCG, Shanghai, and Beijing). Methods: Studies, reports, and other official sources with comparable data for NCD burden and related determinants for the four provinces were searched. Geographic, demographic, socioeconomic, and dietary characteristics and selected health indicators (e.g., life expectancy) were extracted from the China Statistical Yearbook and China Health Statistics Yearbook. Data on NCD burdens were extracted from the National Chronic Disease and Risk Factor Surveillance Study and other nationally representative studies. Results: The overall NCD mortality rates and prevalence of metabolic risk factors including obesity, hypertension, and diabetes in mainland China have increased in the past 20 years, and this trend is expected to continue. The PG had the highest level of standardized mortality rates (SMRs) on NCDs (711.6-896.1/100,000, 6th/6-level); the MCG had the lowest (290.6-389.6/100,000, 1st/6-level) in mainland China. The gaps in SMRs were particularly high with regard to chronic respiratory diseases (PG 6th/6-level, MCG 1st/6-level) and cardiovascular diseases (6th/6 and 4th/6 in TAR and Qinghai; 1st/6-level and 2nd/6-level in Shanghai and Beijing). In contrast, the prevalence rates of obesity, hypertension, and diabetes were generally higher or comparable in MCG compared to PG. Diabetes prevalence was particularly high in MCG (5th/5-level, 13.36-14.35%) and low in PG (1st/5-level, 6.20-10.39%). However, awareness, treatment, and control of hypertension were poor in PG. Additionally, PG had much lower and severely inadequate intakes of vegetables, fruits, and dairy products, with additional indicators of lower socioeconomic status (education, income, etc.,) compared with MCG. Conclusion: Evidence showed large disparities in NCD burden in China's provinces. Socioeconomic disparity and dietary determinants are probably the reasons. Integrated policies and actions are needed.

Adsorption and fouling behaviors of customized nanocomposite membrane to trace pharmaceutically active compounds under multiple influent matrices.

Rare information is available on fouling behavior of customized nanofiltration (NF) membrane evoked by pharmaceutically active compounds (PhACs) under real multiple influent matrices pretreated by ultrafiltration module beforehand. To this end, a novel tight NF membrane with excellent perm-selectivity and antiadhesion was fabricated and used to assess its separation performance/mechanism and fouling behavior to a broad range of small molecular PhACs in the context. The adsorption ratio results revealed that the affinities between five selected PhACs and the customized nanocomposite membrane surface were all much weaker (below 5.5%) than the solute-solute interacting forces (between 23.6 and 83.2%), whether for natural or synthetic complex micropollutants. The predominant membrane fouling could be interpreted by the incomplete blocking model in the permeation of both influent conditions. For neat nanocomposite membrane, the order of critical factors important on separation mechanism was electrostatic effect, adsorption and steric hindrance. The fouling layer seemed to act as a secondary separating layer for those negatively charged or hydrophilic PhACs, but showed the cake enhanced concentration polarization effect for the neutral and hydrophobic ones. This study provides valuable insights for defining PhACs fate and NF membrane fouling behavior to fit increasingly stringent criteria for wastewater treatment.

Mammalian SIRT6 Represses Invasive Cancer Cell Phenotypes through ATP Citrate Lyase (ACLY)-Dependent Histone Acetylation.

The modulation of dynamic histone acetylation states is key for organizing chromatin structure and modulating gene expression and is regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. The mammalian SIRT6 protein, a member of the Class III HDAC Sirtuin family of NAD+-dependent enzymes, plays pivotal roles in aging, metabolism, and cancer biology. Through its site-specific histone deacetylation activity, SIRT6 promotes chromatin silencing and transcriptional regulation of aging-associated, metabolic, and tumor suppressive gene expression programs. ATP citrate lyase (ACLY) is a nucleo-cytoplasmic enzyme that produces acetyl coenzyme A (acetyl-CoA), which is the required acetyl donor for lysine acetylation by HATs. In addition to playing a central role in generating cytosolic acetyl-CoA for de novo lipogenesis, a growing body of work indicates that ACLY also functions in the nucleus where it contributes to the nutrient-sensitive regulation of nuclear acetyl-CoA availability for histone acetylation in cancer cells. In this study, we have identified a novel function of SIRT6 in controlling nuclear levels of ACLY and ACLY-dependent tumor suppressive gene regulation. The inactivation of SIRT6 in cancer cells leads to the accumulation of nuclear ACLY protein and increases nuclear acetyl-CoA pools, which in turn drive locus-specific histone acetylation and the expression of cancer cell adhesion and migration genes that promote tumor invasiveness. Our findings uncover a novel mechanism of SIRT6 in suppressing invasive cancer cell phenotypes and identify acetyl-CoA responsive cell migration and adhesion genes as downstream targets of SIRT6.

Novel recyclable acidic hydrophobic deep eutectic solvents for highly efficient extraction of calcium dobesilate in water and urine samples.

Deep eutectic solvents (DESs) have been considered to be one of the most promising green alternatives of conventional volatile solvents for liquid-liquid separation. However, acidic hydrophobic DESs have been less studied although they are of great importance for the extraction of compounds which are unstable in alkaline conditions. In this study, a novel family of acidic hydrophobic deep eutectic solvents was designed and prepared from methyl trioctyl ammonium chloride and a series of haloacetic acids. For the first time, the obtained DESs were used for extraction and determination of calcium dobesilate, which is an extensively used medicine for treating vascular diseases, but it can be easily oxidized under alkaline and neutral conditions. The factors influencing extraction process including pH, temperature, extract time, inorganic salts and organic coexistence were systematically investigated. It is found that these DESs exhibited outstanding extraction performance towards calcium dobesilate. The extraction equilibrium time was only 3 min in a wide range of pH (1.2-9.2) at room temperature and the extraction capacity was up to 504 mg/g. The detection limit of calcium dobesilate extracting from water samples was 0.05 µg/L and the limit of quantification was 0.5 µg/L. A variety of inorganic salts with the concentration up to 1.0 mol/L and common coexisting organic compounds, such as glucose and starch, with the concentration more than 1000 times higher than the target analyte had no obvious impact on the extraction efficiency. The relative recovery for real samples ranged from 93.2% to 108.6%. Furthermore, the DESs could be recycled and regenerated through back extraction. After fifteen cycles, the extraction efficiency was still up to 99%. Finally, the extraction and back extraction mechanism was discussed in detail.

Glyoxalase I-4 functions downstream of NAC72 to modulate downy mildew resistance in grapevine.

Glyoxalase I (GLYI) is part of the glyoxalase system; its major function is the detoxification of α-ketoaldehydes, including the potent and cytotoxic methylglyoxal (MG). Methylglyoxal disrupts mitochondrial respiration and increases production of reactive oxygen species (ROS), which also increase during pathogen infection of plant tissues; however, there have been few studies relating the glyoxalase system to the plant pathogen response. We used the promoter of VvGLYI-4 to screen the upstream transcription factors and report a NAC (NAM/ATAF/CUC) domain-containing transcription factor VvNAC72 in grapevine, which is localized to the nucleus. Our results show that VvNAC72 expression is induced by downy mildew, Plasmopara viticola, while the transcript level of VvGLYI-4 decreases. Further analysis revealed that VvNAC72 can bind directly to the promoter region of VvGLYI-4 via the CACGTG element, leading to inhibition of VvGLYI-4 transcription. Stable overexpression of VvNAC72 in grapevine and tobacco showed a decreased expression level of VvGLYI-4 and increased content of MG and ROS, as well as stronger resistance to pathogen stress. Taken together, these results demonstrate that grapevine VvNAC72 negatively modulates detoxification of MG through repression of VvGLYI-4, and finally enhances resistance to downy mildew, at least in part, via the modulation of MG-associated ROS homeostasis through a salicylic acid-mediated defense pathway.

Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

Multivalent tumor suppressor adenomatous polyposis coli promotes Axin biomolecular condensate formation and efficient ß-catenin degradation.

The tumor suppressor adenomatous polyposis coli (APC) is frequently mutated in colorectal cancers. APC and Axin are core components of a destruction complex that scaffolds GSK3ß and CK1 to earmark ß-catenin for proteosomal degradation. Disruption of APC results in pathologic stabilization of ß-catenin and oncogenesis. However, the molecular mechanism by which APC promotes ß-catenin degradation is unclear. Here, we find that the intrinsically disordered region (IDR) of APC, which contains multiple ß-catenin and Axin interacting sites, undergoes liquid-liquid phase separation (LLPS) in vitro. Expression of the APC IDR in colorectal cells promotes Axin puncta formation and ß-catenin degradation. Our results support the model that multivalent interactions between APC and Axin drives the ß-catenin destruction complex to form biomolecular condensates in cells, which concentrate key components to achieve high efficient degradation of ß-catenin.

Age-related cerebral small vessel disease and inflammaging.

The continued increase in global life expectancy predicts a rising prevalence of age-related cerebral small vessel diseases (CSVD), which requires a better understanding of the underlying molecular mechanisms. In recent years, the concept of "inflammaging" has attracted increasing attention. It refers to the chronic sterile low-grade inflammation in elderly organisms and is involved in the development of a variety of age-related chronic diseases. Inflammaging is a long-term result of chronic physiological stimulation of the immune system, and various cellular and molecular mechanisms (e.g., cellular senescence, immunosenescence, mitochondrial dysfunction, defective autophagy, metaflammation, gut microbiota dysbiosis) are involved. With the deepening understanding of the etiological basis of age-related CSVD, inflammaging is considered to play an important role in its occurrence and development. One of the most critical pathophysiological mechanisms of CSVD is endothelium dysfunction and subsequent blood-brain barrier (BBB) leakage, which gives a clue in the identification of the disease by detecting circulating biological markers of BBB disruption. The regional analysis showed blood markers of vascular inflammation are often associated with deep perforating arteriopathy (DPA), while blood markers of systemic inflammation appear to be associated with cerebral amyloid angiopathy (CAA). Here, we discuss recent findings in the pathophysiology of inflammaging and their effects on the development of age-related CSVD. Furthermore, we speculate the inflammaging as a potential target for future therapeutic interventions to delay or prevent the progression of the age-related CSVD.