Microwave synthesis of amino-functionalized MCM-41 from coal gasification fine slag for efficient bidirectional adsorption of anionic and cationic dyes.

Coal based solid waste has been recognized as a sustainable raw material for the preparation of high added value materials for wastewater treatment. In this paper, a preparation route was designed for the rapid, efficient, and low-cost preparation of MCM-41 zeolite using coal gasification fine slag as raw material. Functionalization modification of MCM-41 was carried out by grafting amino groups on its surface to improve its application performance. Moreover, the prepared functionalized material is used for bidirectional adsorption of anionic and cationic dyes. The experimental results indicate that MCM-41 zeolite with highly ordered pore structure was rapidly prepared using the advantages of fast heating and strong permeability of microwave synthesis method, with a specific surface area of up to 862.03 m2/g. Amine functionalized MCM-41 exhibits strong adsorption capacity for both cationic and anionic dyes, with maximum adsorption capacities for methylene blue and Congo red being 292.40 mg/g and 354.61 mg/g, respectively. The study of adsorption kinetics and adsorption mechanism indicate that the adsorption process is mainly controlled through chemical adsorption, including electrostatic attraction, hydrogen bonding, and π-π interactions. The results of this study will provide useful references for the use of coal based solid waste to prepare functional materials for the treatment of organic wastewater.

Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.

OBJECTIVE: Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A+ TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. DESIGN: The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. RESULTS: MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8+ T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. CONCLUSION: Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.

Novel treatment of acute and acute-on-chronic liver failure: Interleukin-22.

Acute liver failure (ALF) is a life-threatening medical condition, characterized by rapidly progressive hepatic dysfunction, coagulopathy and hepatic encephalopathy in patients without chronic liver disease, while acute-on-chronic liver failure (ACLF) occurs in patients with existing chronic liver disease. ALF and ACLF are often associated with multiple organ failure and a high short-term mortality. In this review, we briefly discuss the causes and pathogenesis of ALF and ACLF, the current options available for the treatment of both deadly maladies and interleukin-22 (IL-22), a novel promising drug that may have great therapeutic potential for ALF and ACLF treatment. IL-22 is a cytokine produced by immune cells but mainly targets epithelial cells including hepatocytes. IL-22 has been shown to protect against organ damage and reduce bacterial infection in many preclinical models and several clinical trials including alcohol-associated hepatitis. The potential application of IL-22 for the treatment of ALF and ACLF is also elaborated.

Glutamate-aspartate transporter 1 attenuates oxygen-glucose deprivation-induced injury by promoting glutamate metabolism in primary cortical neurons.

Ischemic stroke is a common cerebral disease. However, the treatment for the disease is limited. Daurian ground squirrel (GS; Spermophilus dauricus), a hibernating mammalian species, is highly tolerant to ischemia. In the present study, GS neurons in a non-hibernating state were found to be more resistant to oxygen-glucose deprivation (OGD), an ischemic model in vitro. We leveraged the differences in the endurance capacity of GS and rats to investigate the mechanisms of resistance to ischemia in GS neurons. We first identified glutamate-aspartate transporter 1 (GLAST) as a cytoprotective factor that contributed to tolerance against OGD injury of GS neurons. The expression of GLAST in GS neurons was much higher than that in rat neurons. Overexpression of GLAST rescued viability in rat neurons, and GS neurons exhibited decreased viability following GLAST knockdown under OGD conditions. Mechanistically, more glutamate was transported into neurons after GLAST overexpression and served as substrates for ATP production. Furthermore, eukaryotic transcription initiation factor 4E binding protein 1 was downregulated by GLAST to rescue neuronal viability. Our findings not only revealed an important molecular mechanism underlying the survival of hibernating mammals but also suggested that neuronal GLAST may be a potential target for ischemic stroke therapy.

Low-cost Y-type zeolite/carbon porous composite from coal gasification fine slag and its application in the phenol removal from wastewater: fabrication, characterization, equilibrium, and kinetic studies.

As an industrial solid waste, coal gasification fine slag (CGFS), which consists of many elements, such as silicon, aluminum, and carbon, could be used as an important resource. Therefore, this solid waste was used as a raw material to prepare high-value-added adsorption material for the treatment of industrial wastewater in this study. A hydrothermal synthesis method was applied to convert CGFS into a Y-type zeolite/carbon porous composite. The effects of time and temperature on the synthesis were studied. XRD, SEM, and other techniques were used to analyze the material and its physicochemical properties. Additionally, the adsorption performance of the material for phenol was studied. The results showed that the composite has better adsorption capacity for phenol than CGFS. The Freundlich model and pseudo-second-order kinetics well fitted the adsorption behavior of the composite, which demonstrated that the adsorption of phenol was dominated by chemical adsorption.

Levels of bioavailable manganese in river sediment may elevate reproductive risk in model organism Caenorhabditis elegans.

Manganese occurs naturally in sediment, yet anthropogenic sources, such as industrial wastewater and mining, increases Mn concentration. However, the environmental risk of bioavailable Mn is often overlooked and infrequently addressed. A probabilistic risk assessment was conducted to determine the effects of bioavailable Mn in river sediments on reproduction in model organism Caenorhabditis elegans using in utero egg counts and germline apoptosis as biomarkers. The lowest-observed-adverse-effect level (LOAEL) of sediment Mn that decreases in utero egg counts or increases germline apoptosis in C. elegans was 50 or 10 mg of Mn(II) per kg of dry weight sediment, respectively. Effect and exposure analyses were conducted using Hill model-simulated concentration-response curves and Mn concentrations of Laojie River sediment. Risk quotients (RQs) and exceedance risk (ER) analyses showed that bioavailable levels of Mn in Laojie River sediments from downstream sites collected during the dry season elevate reproductive risk as measured by germline apoptosis. These findings suggest that bioavailable levels of Mn in sediment exert negative impacts, and germline apoptosis is a sensitive biomarker for reproductive risk assessment. Our results also suggest that the anthropogenic Mn pollution in river sediment and spatial-seasonal bioavailability of Mn should be considered to improve sediment quality control.

In vivo chemical reprogramming of astrocytes into neurons.

In mammals, many organs lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced cell reprogramming offers a temporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for in vivo reprogramming in organs with notoriously poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram astrocytes into neurons. The in situ chemically induced neurons resemble endogenous neurons in terms of neuron-specific marker expression, electrophysiological properties, and synaptic connectivity. Our study demonstrates the feasibility of in vivo chemical reprogramming in the adult mouse brain and provides a potential approach for developing neuronal replacement therapies.

Transcriptional regulation of intermolecular Ca2+ signaling in hibernating ground squirrel cardiomyocytes: The myocardin-junctophilin axis.

The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs), and the nanodistance between them depends on the interaction between junctophilin-2 (JPH2) in the sarcoplasmic reticulum (SR) and caveolin-3 (CAV3) in the transversal tubule (TT). In heart failure, decreased expression of JPH2 compromises LCC-RyR communication leading to deficient blood-pumping power. In the present study, we found that JPH2 and CAV3 transcription was concurrently regulated by serum response factor (SRF) and myocardin. In cardiomyocytes from torpid ground squirrels, compared with those from euthermic counterparts, myocardin expression was up-regulated, which boosted both JPH2 and CAV3 expression. Transmission electron microscopic imaging showed that the physical coupling between TTs and SRs was tightened during hibernation and after myocardin overexpression. Confocal Ca2+ imaging under the whole-cell patch clamp condition revealed that these changes enhanced the efficiency of LCC-RyR intermolecular signaling and fully compensated the adaptive down-regulation of LCCs, maintaining the power of heart contraction while avoiding the risk of calcium overload during hibernation. Our finding not only revealed an essential molecular mechanism underlying the survival of hibernating mammals, but also demonstrated a "reverse model of heart failure" at the molecular level, suggesting a strategy for treating heart diseases.

The bioavailability and potential ecological risk of copper and zinc in river sediment are affected by seasonal variation and spatial distribution.

River sediment is the ultimate sink for heavy metal pollution. Copper (Cu) and zinc (Zn) are consistently found at environmentally significant levels in sediments worldwide. We hypothesized that the bioavailability and potential ecological risk of Cu and Zn in river sediments may be affected by seasonal variations and spatial distribution. In this study, we tested our hypothesis using highly industrialized river sediments (Laojie River) as an example. The concentration of heavy metals, pollution indexes, and risk indexes were evaluated and multivariate statistical analyses were performed. We found that seasonal variations affect heavy metal contamination, pollution indexes, and potential ecological risk in sediments and this effect was more severe in the dry season. In addition, higher levels of metal contamination, pollution indexes, and potential ecological risk were observed midstream and downstream of the Laojie River. We found that Cu and Zn were the primary contaminants in Laojie River sediments and may originate from common anthropogenic sources. Analysis of the chemical fractions further revealed that Cu and Zn exhibited high mobility and potential bioavailability risk. In addition, a high percentage and amount of Cu and Zn were found in exchangeable fractions, suggesting they pose a great risk to aquatic organisms. Our results indicate that seasonal variations and spatial distribution affect the bioavailability and potential ecological risk of Cu and Zn in river sediments. These findings suggest that seasonal variations and spatial distribution are important parameters to consider for environmental monitoring and environmental management in aquatic environments.

Bazedoxifene effects on osteoprotegerin, insulin-like growth factor, tumor necrosis factor and bone mineral density.

To observe the clinical effect of estrogenic drugs (Bazedoxifene) on bone targeting in the treatment of osteoporosis and explore its mechanism. METHODS: 112 patients with postmenopausal osteoporosis who received Bazedoxifene drugs in our hospital from January to December 2018 were collected as a study group, and 56 patients treated with calcium alone were collected as a control group. the risk of adverse events such as bone mineral density, osteoprotegerin (OPG), insulin-like growth factor (IGF), tumor necrosis factor (TNF-α), and fracture after treatment were analyzed before and after treatment. RESULTS: There was no significant difference in the mean lumbar positive position (L2-4) and right femoral neck bone density and OPG, IGF, TNF-α level between the two groups before treatment (P>0.05). The total effective rate of clinical treatment in the study group was 88.39%, the control group was 23.21%, the difference between the two groups was statistically significant (P˂0.05). After treatment, the mean lumbar positive position (L2-4) and the right femoral neck bone density and OPG, IGF in the study group were higher than those in the control group, lower than those in the control group (P<0.05). the occurrence of adverse events such as fracture, spinal deformation and fatigue in the study group after 12 months of treatment was significantly lower than that in the control group (P<0.05), but there was no significant difference in the occurrence of hot flashes and venous thromboembolism between the two groups (P>0.05). CONCLUSION: Bazedoxifene is an effective drug for the treatment of postmenopausal osteoporosis. It can not only prevent the rapid loss of bone mass, effectively relieve the symptoms of menopause, but also improve bone density and reduce the risk of fracture.

Exciton polaritons based on planar dielectric Si asymmetric nanogratings coupled with J-aggregated dyes film.

Optical cavity polaritons, originated from strong coupling between the excitons in materials and photons in the confined cavities field, have recently emerged as their applications in the high-speed lowpower polaritons devices, low-threshold lasing and so on. However, the traditional exciton polaritons based on metal plasmonic structures or Fabry-Perot cavities suffer from the disadvantages of large intrinsic losses or hard to integrate and nanofabricate. This greatly limits the applications of exciton poalritons. Thus, here we implement a compact low-loss dielectric photonic - organic nanostructure by placing a 2-nm-thick PVA doped with TDBC film on top of a planar Si asymmetric nanogratings to reveal the exciton polaritons modes. We find a distinct anti-crossing dispersion behavior appears with a 117.16 meV Rabi splitting when varying the period of Si nanogratings. Polaritons dispersion and mode anti-crossing behaviors are also observed when considering the independence of the height of Si, width of Si nanowire B, and distance between the two Si nanowires in one period. This work offers an opportunity to realize low-loss novel polaritons applications.

Down-regulation of miR-3068-3p enhances kcnip4-regulated A-type potassium current to protect against glutamate-induced excitotoxicity.

The main cause of excitotoxic neuronal death in ischemic stroke is the massive release of glutamate. Recently, microRNAs (miRNAs) have been found to play an essential role in stroke pathology, although the molecular mechanisms remain to be investigated. Here, to identify potential candidate miRNAs involved in excitotoxicity, we treated rat primary cortical neurons with glutamate and found that miR-3068-3p, a novel miRNA, was up-regulated. We hypothesized that restoring miR-3068-3p expression might influence the neuronal injury outcomes. The inhibition of miR-3068-3p, using tough decoy lentiviruses, significantly attenuated the effects of glutamate on neuronal viability and intracellular calcium overload. To unravel the mechanisms, we employed bioinformatics analysis and RNA sequencing to identify downstream target genes. Additional luciferase assays and western blots validated kcnip4, a Kv4-mediated A-type potassium current (IA ) regulator, as a direct target of miR-3068-3p. The inhibition of miR-3068-3p increased kcnip4 expression and vice versa. In addition, the knockdown of kcnip4 by shRNA abolished the protective effect of miR-3068-3p, and over-expressing kcnip4 alone was sufficient to play a neuroprotective role in excitotoxicity. Moreover the inhibition of miR-3068-3p enhanced the IA density, and the pharmacological inhibition of IA abrogated the protective role of miR-3068-3p inhibition and kcnip4 over-expression. Therefore, we conclude that inhibition of miR-3068-3p protects against excitotoxicity via its target gene, kcnip4, and kcnip4-regulated IA . Our data suggest that the miR-3068-3p/kcnip4 axis may serve as a novel target for the treatment of ischemic stroke.

Prolonged Capecitabine Chemotherapy Following Capecitabine and Oxaliplatin (CAPOX) Regimen Chemotherapy Failed to Improve Survival of Stage III Colorectal Cancer After Radical Resection.

BACKGROUND Colorectal cancer (CRC) is considered to be a worldwide health problem because of its increasing incidence and prevalence. Surgery offers an opportunity for cure, but the postoperative recurrence rate is still high despite the advancement of chemotherapy. This study aimed to assess the efficacy and safety of prolonged capecitabine chemotherapy following CAPOX chemotherapy for stage III  CRC after radical surgery. MATERIAL AND METHODS This study included 212 patients with stage III CRC undergoing open radical surgery from July 2010 to June 2015. Among those patients, 104 patients received prolonged capecitabine chemotherapy (prolonged group) following 8 cycles of CAPOX regimen chemotherapy, while the other 108 patients (control group) received no prolonged chemotherapy. The prolonged chemotherapy consisted of capecitabine (1000 mg/m² per day for 2 weeks) and was repeated every 3 weeks for 8 cycles at most. Long-term survival and toxicities were retrospectively compared. RESULTS Patient characteristics did not differ between the 2 groups. For all patients, no significant difference was found in the 3-year disease-free survival (DFS) (P=0.7775) or 3-year overall survival (OS) rates between the 2 groups (P=0.5787). The prolonged group had significantly higher frequency of hand-foot syndrome (P=0.0267) and paresthesia (P=0.0164). In further subgroup analyses, no benefit for 3-year DFS or 3-year OS of prolonged capecitabine chemotherapy was found in colon cancer or rectal cancer. CONCLUSIONS Prolonged capecitabine chemotherapy following CAPOX regimen chemotherapy failed to improve the survival of patients with stage III CRC after radical surgery.

Mild Acidosis Protects Neurons during Oxygen-Glucose Deprivation by Reducing Loss of Mitochondrial Respiration.

Brain ischemia is often accompanied by brain acidosis and this acidosis can affect ischemic neuronal injury. Ischemic neuronal injury is initiated by a decrease in ATP production which mainly relies on mitochondrial oxidative phosphorylation. Ischemia often causes mitochondrial dysfunction, and acidosis has been found to affect mitochondrial function, suggesting that acidosis accompanying ischemia may influence neurons by targeting mitochondrial metabolism. However, the effects of acidosis on mitochondrial energy metabolism during ischemia lacks thorough investigation. Here, we found that mild acidosis significantly reduced neuronal death possibly by slowing the process of ATP deprivation during oxygen-glucose deprivation (OGD), an in vitro ischemic model. The maintaining of neuronal ATP depended on protecting mitochondrial ATP production. Further investigation of mitochondrial function revealed that mild acidosis alleviated OGD-induced collapse of mitochondrial membrane potentials as well as damage to respiratory function, at least in part by reducing impacts on complex I and II activities. Inhibition of complex I activity aggravated neuronal death, which suggests that the contribution of mild acidosis to maintaining complex I activity promoted neuronal survival during OGD. Our findings reveal maintaining mitochondrial respiration as a new possible protective mechanism of mild acidosis during ischemia, on neurons.

Fano-resonance in one-dimensional topological photonic crystal heterostructure.

We theoretically realize the Fano resonance with a high quality factor of 106 using a structure, which is constructed from three one-dimensional photonic crystals and a defect layer. The emerged Fano resonance can be attributed to the weak coupling between a Fabry-Perot cavity mode and a topological edge state mode provided by the topological photonic crystal heterostructure. Moreover, we experimentally reproduce this Fano resonance in the optical communication range with a high quality of 104. This may be useful reference for the study of applications of photonic topological states in integrated photonic devices and information processing chips.

Neurons with Multiple Axons Have Functional Axon Initial Segments.

Neurons grow multiple axons after treatment with glycogen synthase kinase-3 (GSK-3) inhibitors. However, whether they are electrically active is not known. Here, we examined the role of multiple axons as electrophysiological components during neuronal firing. Combining pharmacological, immunofluorescence, and electrophysiological methods, we found that more neurons had multiple axon initial segments (AISs) after inhibition of GSK-3 activity with SB415286. The multiple AISs induced by GSK-3 inhibition were enriched with voltage-gated sodium channels. The depolarization rate of the multiple-AIS neurons was increased, but their action potential threshold and half-width were normal. By calculating derivatives of the action-potential rising phase, an extra d2 V/dt 2 peak from the extra AIS was distinguished; this indicated that the extra AIS fired ahead of the soma and increased the rate of depolarization. Our study demonstrates that the multiple axons induced by GSK-3 inhibition have AIS structures that are electrically active, and provides insight for axon and AIS studies.

Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State.

Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte-like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state.

Brain-derived neurotrophic factor/neurotrophin 3 regulate axon initial segment location and affect neuronal excitability in cultured hippocampal neurons.

Plasticity of the axon initial segment (AIS) has aroused great interest in recent years because it regulates action potential initiation and neuronal excitability. AIS plasticity manifests as modulation of ion channels or variation in AIS structure. However, the mechanisms underlying structural plasticity of the AIS are not well understood. Here, we combined immunofluorescence, patch-clamp recordings, and pharmacological methods in cultured hippocampal neurons to investigate the factors participating in AIS structural plasticity during development. With lowered neuronal density, the distance between the AIS and the soma increased, while neuronal excitability decreased, as shown by the increased action potential threshold and current threshold for firing an action potential. This variation in the location of the AIS was associated with cellular secretory substances, including brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3). Indeed, blocking BDNF and NT3 with TrkB-Fc eliminated the effect of conditioned medium collected from high-density cultures on AIS relocation. Elevating the extracellular concentration of BDNF or NT3 promoted movement of the AIS proximally to the soma and increased neuronal excitability. Furthermore, knockdown of neurotrophin receptors TrkB and TrkC caused distal movement of the AIS. Our results demonstrate that BDNF and NT3 regulate AIS location and neuronal excitability. These regulatory functions of neurotrophic factors provide insight into the molecular mechanisms underlying AIS biology.

Cyclodextrin-gated mesoporous silica nanoparticles as drug carriers for red light-induced drug release.

Long wavelength light-responsive drug delivery systems based on mesoporous silica nanoparticles (MSNs) have attracted much attention in the last few years. In this paper, a red light (660 nm)-responsive drug delivery system based on low-cost cyclodextrin (CD)-gated MSNs containing a photodynamic therapy (PDT) photosensitizer (Chlorin e6, Ce6) was developed for the first time. The drug release experiment in water demonstrated that with the irradiation of red light, Ce6 can be excited to generate singlet oxygen, which can further cleave the singlet oxygen sensitive linker to trigger the departure of CD and the release of cargo. Further in vitro release experiments confirmed that cargo can be released from MSNs with the irradiation of red light and spread into the entire cell. The relative low power density (0.5 W cm-2) of excitation light together with the short irradiation time (one-three min) result in a low light dose (30-90 J cm-2) for the drug delivery, contributing to their potential clinical applications.

Identification of Factors for the Preoperative Prediction of Tumour Subtype and Prognosis in Patients with T1 Lung Adenocarcinoma.

Aims. Identification of factors that can predict the subtypes of lung adenocarcinoma preoperatively is important for selecting the appropriate surgical procedure and for predicting postoperative survival. Methods. We retrospectively evaluated 87 patients with lung adenocarcinomas ≤30 mm. Results. Preoperative radiological findings, serum CEA level, serum microRNA-183 (miR-183) level, and tumour size differed significantly between patients with adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) and those with invasive adenocarcinoma (IAC). Receiver operating characteristic curves and univariate analysis revealed that patients who were older than 57 years or had a pure solid nodule or a tumour with mixed ground-glass opacity (mGGO), a tumour >11 mm, a serum CEA level >2.12 ng/mL, or a serum miR-183 level >1.233 (2-ΔΔCt) were more likely to be diagnosed with IAC than with AIS or MIA. The combination of all five factors had an area under the curve of 0.946, with a sensitivity of 89.13% and a specificity of 95.12%. Moreover, patients with a cut-off value >0.499 for the five-factor combination had poor overall survival. Conclusions. The five-factor combination enables clinicians to distinguish AIS or MIA from IAC, thereby aiding in selecting the appropriate treatment, and to predict the prognosis of lung adenocarcinoma patients.